TWI816704B - 苯并咪唑衍生物及其用途 - Google Patents
苯并咪唑衍生物及其用途 Download PDFInfo
- Publication number
- TWI816704B TWI816704B TW107137075A TW107137075A TWI816704B TW I816704 B TWI816704 B TW I816704B TW 107137075 A TW107137075 A TW 107137075A TW 107137075 A TW107137075 A TW 107137075A TW I816704 B TWI816704 B TW I816704B
- Authority
- TW
- Taiwan
- Prior art keywords
- methyl
- benzo
- imidazol
- amino
- alkyl
- Prior art date
Links
- 125000003785 benzimidazolyl group Chemical class N1=C(NC2=C1C=CC=C2)* 0.000 title description 11
- 229940058303 antinematodal benzimidazole derivative Drugs 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 283
- 150000003839 salts Chemical class 0.000 claims abstract description 84
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 34
- 238000004519 manufacturing process Methods 0.000 claims abstract description 11
- -1 C 1 -C 6 alkyl Chemical class 0.000 claims description 346
- 229960002715 nicotine Drugs 0.000 claims description 268
- SNICXCGAKADSCV-UHFFFAOYSA-N nicotine Natural products CN1CCCC1C1=CC=CN=C1 SNICXCGAKADSCV-UHFFFAOYSA-N 0.000 claims description 268
- 229910052739 hydrogen Inorganic materials 0.000 claims description 250
- 239000001257 hydrogen Substances 0.000 claims description 239
- 229910052736 halogen Inorganic materials 0.000 claims description 183
- 150000002367 halogens Chemical class 0.000 claims description 182
- 125000005843 halogen group Chemical group 0.000 claims description 163
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 132
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 claims description 122
- 125000002962 imidazol-1-yl group Chemical group [*]N1C([H])=NC([H])=C1[H] 0.000 claims description 120
- 229910052717 sulfur Inorganic materials 0.000 claims description 117
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 112
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 108
- 229910052760 oxygen Inorganic materials 0.000 claims description 103
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 102
- 125000005842 heteroatom Chemical group 0.000 claims description 99
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 98
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 89
- 150000002825 nitriles Chemical group 0.000 claims description 85
- SNICXCGAKADSCV-JTQLQIEISA-N (-)-Nicotine Chemical compound CN1CCC[C@H]1C1=CC=CN=C1 SNICXCGAKADSCV-JTQLQIEISA-N 0.000 claims description 79
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 75
- 229910052757 nitrogen Inorganic materials 0.000 claims description 74
- 239000002585 base Substances 0.000 claims description 73
- 125000000623 heterocyclic group Chemical group 0.000 claims description 64
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 63
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 59
- 201000010099 disease Diseases 0.000 claims description 58
- 125000001424 substituent group Chemical group 0.000 claims description 49
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 47
- 125000001072 heteroaryl group Chemical group 0.000 claims description 46
- 239000003814 drug Substances 0.000 claims description 43
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 41
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 claims description 40
- 238000011282 treatment Methods 0.000 claims description 40
- 230000000694 effects Effects 0.000 claims description 39
- 206010029164 Nephrotic syndrome Diseases 0.000 claims description 38
- 125000000217 alkyl group Chemical group 0.000 claims description 37
- 201000008350 membranous glomerulonephritis Diseases 0.000 claims description 36
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 36
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 35
- 208000009304 Acute Kidney Injury Diseases 0.000 claims description 34
- 208000033626 Renal failure acute Diseases 0.000 claims description 34
- 201000011040 acute kidney failure Diseases 0.000 claims description 34
- 208000012998 acute renal failure Diseases 0.000 claims description 34
- 206010018372 Glomerulonephritis membranous Diseases 0.000 claims description 33
- 231100000855 membranous nephropathy Toxicity 0.000 claims description 33
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 32
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 31
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 28
- 208000007342 Diabetic Nephropathies Diseases 0.000 claims description 26
- 208000033679 diabetic kidney disease Diseases 0.000 claims description 26
- 230000001154 acute effect Effects 0.000 claims description 24
- 208000002815 pulmonary hypertension Diseases 0.000 claims description 24
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 claims description 23
- 206010019280 Heart failures Diseases 0.000 claims description 23
- 206010040047 Sepsis Diseases 0.000 claims description 23
- 208000006011 Stroke Diseases 0.000 claims description 23
- 201000011510 cancer Diseases 0.000 claims description 23
- 208000020832 chronic kidney disease Diseases 0.000 claims description 23
- 208000022831 chronic renal failure syndrome Diseases 0.000 claims description 23
- 201000006938 muscular dystrophy Diseases 0.000 claims description 23
- 206010001052 Acute respiratory distress syndrome Diseases 0.000 claims description 22
- 208000019693 Lung disease Diseases 0.000 claims description 22
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 22
- 239000011593 sulfur Substances 0.000 claims description 22
- 206010028980 Neoplasm Diseases 0.000 claims description 21
- 125000003277 amino group Chemical group 0.000 claims description 21
- 229910052799 carbon Inorganic materials 0.000 claims description 21
- 230000036210 malignancy Effects 0.000 claims description 21
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 20
- 208000004883 Lipoid Nephrosis Diseases 0.000 claims description 20
- 125000003118 aryl group Chemical group 0.000 claims description 20
- 201000005206 focal segmental glomerulosclerosis Diseases 0.000 claims description 20
- 231100000854 focal segmental glomerulosclerosis Toxicity 0.000 claims description 20
- 125000003037 imidazol-2-yl group Chemical group [H]N1C([*])=NC([H])=C1[H] 0.000 claims description 20
- 230000001404 mediated effect Effects 0.000 claims description 20
- 206010018374 Glomerulonephritis minimal lesion Diseases 0.000 claims description 19
- 208000010159 IgA glomerulonephritis Diseases 0.000 claims description 19
- 125000002619 bicyclic group Chemical group 0.000 claims description 19
- PEUGKEHLRUVPAN-UHFFFAOYSA-N piperidin-3-amine Chemical compound NC1CCCNC1 PEUGKEHLRUVPAN-UHFFFAOYSA-N 0.000 claims description 19
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 18
- 208000022461 Glomerular disease Diseases 0.000 claims description 18
- 206010021263 IgA nephropathy Diseases 0.000 claims description 18
- 229920006395 saturated elastomer Polymers 0.000 claims description 17
- 238000006467 substitution reaction Methods 0.000 claims description 17
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 16
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 16
- 206010018370 Glomerulonephritis membranoproliferative Diseases 0.000 claims description 16
- 208000004451 Membranoproliferative Glomerulonephritis Diseases 0.000 claims description 16
- 229910052731 fluorine Inorganic materials 0.000 claims description 16
- 239000011737 fluorine Substances 0.000 claims description 16
- LFKDJXLFVYVEFG-UHFFFAOYSA-N tert-butyl carbamate Chemical compound CC(C)(C)OC(N)=O LFKDJXLFVYVEFG-UHFFFAOYSA-N 0.000 claims description 15
- 239000002253 acid Substances 0.000 claims description 14
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 12
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 12
- 125000002950 monocyclic group Chemical group 0.000 claims description 12
- 238000002360 preparation method Methods 0.000 claims description 12
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 claims description 10
- 150000001412 amines Chemical class 0.000 claims description 10
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 10
- 125000006163 5-membered heteroaryl group Chemical group 0.000 claims description 9
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 9
- 239000003937 drug carrier Substances 0.000 claims description 9
- 241000124008 Mammalia Species 0.000 claims description 8
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 8
- KTFYGXRLCATBAY-HZPDHXFCSA-N (3R,4R)-4-fluoro-1-[1-[(5-methoxypyridin-2-yl)methyl]benzimidazol-2-yl]piperidin-3-amine Chemical compound F[C@H]1[C@@H](CN(CC1)C1=NC2=C(N1CC1=NC=C(C=C1)OC)C=CC=C2)N KTFYGXRLCATBAY-HZPDHXFCSA-N 0.000 claims description 7
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 7
- MNCLTZIBZORLQC-ZIAGYGMSSA-N 2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-3-[(5-chloropyrimidin-2-yl)methyl]benzimidazole-5-carbonitrile Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC1=NC=C(C=N1)Cl)C=C(C=C2)C#N MNCLTZIBZORLQC-ZIAGYGMSSA-N 0.000 claims description 7
- 125000004070 6 membered heterocyclic group Chemical group 0.000 claims description 7
- 239000002671 adjuvant Substances 0.000 claims description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Substances C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 7
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 7
- ZFKGKJRKAKRVRL-ZIAGYGMSSA-N 2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-1-[(5-chloropyrimidin-2-yl)methyl]-6-fluorobenzimidazole-4-carbonitrile Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC1=NC=C(C=N1)Cl)C=C(C=C2C#N)F ZFKGKJRKAKRVRL-ZIAGYGMSSA-N 0.000 claims description 6
- FLAKCDFADVZOJU-HZPDHXFCSA-N 6-[[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-4-methoxybenzimidazol-1-yl]methyl]pyridine-3-carbonitrile Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC1=CC=C(C=N1)C#N)C=CC=C2OC FLAKCDFADVZOJU-HZPDHXFCSA-N 0.000 claims description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 6
- 125000004429 atom Chemical group 0.000 claims description 6
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 claims description 6
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 6
- PLAOJFUMVHWEHA-CHWSQXEVSA-N (3R,4R)-4-fluoro-1-[1-[(5-fluoropyrimidin-2-yl)methyl]benzimidazol-2-yl]piperidin-3-amine Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=CC=CC=C2N1CC1=NC=C(F)C=N1 PLAOJFUMVHWEHA-CHWSQXEVSA-N 0.000 claims description 5
- MFMUDTSISMFXMX-BXUZGUMPSA-N 1-[2-[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-5,6-difluorobenzimidazol-1-yl]acetyl]azetidine-3-carbonitrile Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=CC(F)=C(F)C=C2N1CC(=O)N1CC(C1)C#N MFMUDTSISMFXMX-BXUZGUMPSA-N 0.000 claims description 5
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 5
- 125000002837 carbocyclic group Chemical group 0.000 claims description 5
- WEONLTYVZHXGQG-UKRRQHHQSA-N (3R,4R)-1-[4,6-difluoro-1-[(5-fluoropyridin-2-yl)methyl]benzimidazol-2-yl]-4-fluoropiperidin-3-amine Chemical compound FC1=CC(=CC=2N(C(=NC=21)N1C[C@H]([C@@H](CC1)F)N)CC1=NC=C(C=C1)F)F WEONLTYVZHXGQG-UKRRQHHQSA-N 0.000 claims description 4
- WXJIWGYTLONPMB-IUODEOHRSA-N (3R,4R)-3-amino-1-[1-[(5-chloropyrimidin-2-yl)methyl]-6-fluorobenzimidazol-2-yl]piperidin-4-ol Chemical compound N[C@@H]1CN(CC[C@H]1O)C1=NC2=C(N1CC1=NC=C(C=N1)Cl)C=C(C=C2)F WXJIWGYTLONPMB-IUODEOHRSA-N 0.000 claims description 4
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 4
- GZPHSAQLYPIAIN-UHFFFAOYSA-N 3-pyridinecarbonitrile Chemical compound N#CC1=CC=CN=C1 GZPHSAQLYPIAIN-UHFFFAOYSA-N 0.000 claims description 4
- 235000002637 Nicotiana tabacum Nutrition 0.000 claims description 4
- 241000009298 Trigla lyra Species 0.000 claims description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
- 150000003951 lactams Chemical class 0.000 claims description 4
- KXGFUPWCGIEVCI-QGZVFWFLSA-N (3R)-1-[1-[(1-methylindazol-7-yl)methyl]benzimidazol-2-yl]piperidin-3-amine Chemical compound CN1N=CC2=C1C(CN1C3=CC=CC=C3N=C1N1CCC[C@@H](N)C1)=CC=C2 KXGFUPWCGIEVCI-QGZVFWFLSA-N 0.000 claims description 3
- BWOXTYYUPVPXOI-DGCLKSJQSA-N (3R,4R)-1-[1-[(5-chloropyrimidin-2-yl)methyl]-4,6-difluorobenzimidazol-2-yl]-4-fluoropiperidin-3-amine Chemical compound ClC=1C=NC(=NC=1)CN1C(=NC2=C1C=C(C=C2F)F)N1C[C@H]([C@@H](CC1)F)N BWOXTYYUPVPXOI-DGCLKSJQSA-N 0.000 claims description 3
- PQZGWQDYFRHMCX-DGCLKSJQSA-N (3R,4R)-1-[4,6-difluoro-1-[(5-fluoropyrimidin-2-yl)methyl]benzimidazol-2-yl]-4-fluoropiperidin-3-amine Chemical compound FC1=CC(=CC=2N(C(=NC=21)N1C[C@H]([C@@H](CC1)F)N)CC1=NC=C(C=N1)F)F PQZGWQDYFRHMCX-DGCLKSJQSA-N 0.000 claims description 3
- AILFSOCMHRHYTB-ZWNOBZJWSA-N (3R,4R)-1-[5,6-difluoro-1-[(5-fluoropyrimidin-2-yl)methyl]benzimidazol-2-yl]-4-fluoropiperidin-3-amine Chemical compound FC1=CC2=C(N(C(=N2)N2C[C@H]([C@@H](CC2)F)N)CC2=NC=C(C=N2)F)C=C1F AILFSOCMHRHYTB-ZWNOBZJWSA-N 0.000 claims description 3
- FQDQYRWCWGYLEJ-IUODEOHRSA-N (3R,4R)-3-amino-1-[1-[(5-chloropyrimidin-2-yl)methyl]-5-fluorobenzimidazol-2-yl]piperidin-4-ol Chemical compound N[C@@H]1CN(CC[C@H]1O)C1=NC2=C(N1CC1=NC=C(C=N1)Cl)C=CC(=C2)F FQDQYRWCWGYLEJ-IUODEOHRSA-N 0.000 claims description 3
- CZSRBTBSPLWAAW-UHFFFAOYSA-N 1-[7-fluoro-6-methoxy-1-[[2-(trifluoromethyl)phenyl]methyl]benzimidazol-2-yl]piperidin-3-amine Chemical compound C=1C=CC=C(C(F)(F)F)C=1CN1C2=C(F)C(OC)=CC=C2N=C1N1CCCC(N)C1 CZSRBTBSPLWAAW-UHFFFAOYSA-N 0.000 claims description 3
- DXPPORQKBNJMQH-ZIAGYGMSSA-N 2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-3-[(5-fluoropyrimidin-2-yl)methyl]benzimidazole-5-carbonitrile Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC1=NC=C(C=N1)F)C=C(C=C2)C#N DXPPORQKBNJMQH-ZIAGYGMSSA-N 0.000 claims description 3
- RDNJKWMVQSLSJS-IUODEOHRSA-N 2-[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-5,6-difluorobenzimidazol-1-yl]-1-piperidin-1-ylethanone Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=CC(F)=C(F)C=C2N1CC(=O)N1CCCCC1 RDNJKWMVQSLSJS-IUODEOHRSA-N 0.000 claims description 3
- MVTVYEYKURTDCD-QGZVFWFLSA-N 4-[[2-[(3R)-3-aminopiperidin-1-yl]-6-methoxybenzimidazol-1-yl]methyl]benzonitrile Chemical compound N[C@H]1CN(CCC1)C1=NC2=C(N1CC1=CC=C(C#N)C=C1)C=C(C=C2)OC MVTVYEYKURTDCD-QGZVFWFLSA-N 0.000 claims description 3
- JHVHQFXADQXCBA-GBNZRNLASA-N 4-[[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-6-chlorobenzimidazol-1-yl]methyl]benzonitrile hydrochloride Chemical compound Cl.N[C@@H]1CN(CC[C@H]1F)c1nc2ccc(Cl)cc2n1Cc1ccc(cc1)C#N JHVHQFXADQXCBA-GBNZRNLASA-N 0.000 claims description 3
- ZHIYSTZDOIQQCQ-IAGOWNOFSA-N 4-[[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]benzimidazol-1-yl]methyl]benzonitrile Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC1=CC=C(C#N)C=C1)C=CC=C2 ZHIYSTZDOIQQCQ-IAGOWNOFSA-N 0.000 claims description 3
- ZHIYSTZDOIQQCQ-IRXDYDNUSA-N 4-[[2-[(3S,4S)-3-amino-4-fluoropiperidin-1-yl]benzimidazol-1-yl]methyl]benzonitrile Chemical compound N[C@H]1CN(CC[C@@H]1F)C1=NC2=C(N1CC1=CC=C(C#N)C=C1)C=CC=C2 ZHIYSTZDOIQQCQ-IRXDYDNUSA-N 0.000 claims description 3
- VNBYAILWIWZQJA-HZPDHXFCSA-N 6-[[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-5-(difluoromethoxy)benzimidazol-1-yl]methyl]pyridine-3-carbonitrile Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC1=CC=C(C=N1)C#N)C=CC(=C2)OC(F)F VNBYAILWIWZQJA-HZPDHXFCSA-N 0.000 claims description 3
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 claims description 3
- 239000003513 alkali Substances 0.000 claims description 3
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 3
- 125000004307 pyrazin-2-yl group Chemical group [H]C1=C([H])N=C(*)C([H])=N1 0.000 claims description 3
- 229960005206 pyrazinamide Drugs 0.000 claims description 3
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 claims description 3
- PQPUHXCQNQBITJ-YPXVDWTCSA-N (1R)-1-[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]benzimidazol-1-yl]-2,3-dihydro-1H-indene-5-carbonitrile hydrochloride Chemical compound C1CC2=C([C@@H]1N3C4=CC=CC=C4N=C3N5CC[C@H]([C@@H](C5)N)F)C=CC(=C2)C#N.Cl PQPUHXCQNQBITJ-YPXVDWTCSA-N 0.000 claims description 2
- PEEQUKZBJZQVTB-FXAWDEMLSA-N (1R)-1-[2-[(3S)-3-aminopiperidin-1-yl]benzimidazol-1-yl]-2,3-dihydro-1H-indene-5-carbonitrile Chemical compound N[C@@H]1CN(CCC1)C1=NC2=C(N1[C@@H]1CCC3=CC(=CC=C13)C#N)C=CC=C2 PEEQUKZBJZQVTB-FXAWDEMLSA-N 0.000 claims description 2
- PQPUHXCQNQBITJ-CCAFVWFJSA-N (1S)-1-[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]benzimidazol-1-yl]-2,3-dihydro-1H-indene-5-carbonitrile hydrochloride Chemical compound C1CC2=C([C@H]1N3C4=CC=CC=C4N=C3N5CC[C@H]([C@@H](C5)N)F)C=CC(=C2)C#N.Cl PQPUHXCQNQBITJ-CCAFVWFJSA-N 0.000 claims description 2
- AOCCFASSBWWBHK-LJQANCHMSA-N (3R)-1-[1-(isoquinolin-7-ylmethyl)benzimidazol-2-yl]piperidin-3-amine Chemical compound C1=NC=CC2=CC=C(C=C12)CN1C(=NC2=C1C=CC=C2)N1C[C@@H](CCC1)N AOCCFASSBWWBHK-LJQANCHMSA-N 0.000 claims description 2
- XKCRVBFPUDQVDL-OAHLLOKOSA-N (3R)-1-[1-[(2,4-dichlorophenyl)methyl]benzimidazol-2-yl]piperidin-3-amine Chemical compound ClC1=C(CN2C(=NC3=C2C=CC=C3)N2C[C@@H](CCC2)N)C=CC(=C1)Cl XKCRVBFPUDQVDL-OAHLLOKOSA-N 0.000 claims description 2
- IFQXJABVVUFSPG-OAHLLOKOSA-N (3R)-1-[1-[(2,4-difluorophenyl)methyl]benzimidazol-2-yl]piperidin-3-amine Chemical compound FC1=C(CN2C(=NC3=C2C=CC=C3)N2C[C@@H](CCC2)N)C=CC(=C1)F IFQXJABVVUFSPG-OAHLLOKOSA-N 0.000 claims description 2
- NQVDGYCTHYCAQE-CYBMUJFWSA-N (3R)-1-[1-[(2,6-dichlorophenyl)methyl]benzimidazol-2-yl]piperidin-3-amine Chemical compound ClC1=C(CN2C(=NC3=C2C=CC=C3)N2C[C@@H](CCC2)N)C(=CC=C1)Cl NQVDGYCTHYCAQE-CYBMUJFWSA-N 0.000 claims description 2
- QQQVXLSHPHJFSE-OAHLLOKOSA-N (3R)-1-[1-[(2-chlorophenyl)methyl]benzimidazol-2-yl]piperidin-3-amine Chemical compound ClC1=C(CN2C(=NC3=C2C=CC=C3)N2C[C@@H](CCC2)N)C=CC=C1 QQQVXLSHPHJFSE-OAHLLOKOSA-N 0.000 claims description 2
- LAGPNJIFFJOZOZ-CQSZACIVSA-N (3R)-1-[1-[(3,4-difluorophenyl)methyl]benzimidazol-2-yl]piperidin-3-amine Chemical compound FC=1C=C(CN2C(=NC3=C2C=CC=C3)N2C[C@@H](CCC2)N)C=CC=1F LAGPNJIFFJOZOZ-CQSZACIVSA-N 0.000 claims description 2
- PCSFISJORYNUBL-CQSZACIVSA-N (3R)-1-[1-[(4-chloro-3-fluorophenyl)methyl]benzimidazol-2-yl]piperidin-3-amine Chemical compound ClC1=C(C=C(CN2C(=NC3=C2C=CC=C3)N2C[C@@H](CCC2)N)C=C1)F PCSFISJORYNUBL-CQSZACIVSA-N 0.000 claims description 2
- JUYJTEAYUQTYBS-MRXNPFEDSA-N (3R)-1-[1-[(4-chlorophenyl)methyl]benzimidazol-2-yl]piperidin-3-amine Chemical compound N[C@@H]1CCCN(C1)c1nc2ccccc2n1Cc1ccc(Cl)cc1 JUYJTEAYUQTYBS-MRXNPFEDSA-N 0.000 claims description 2
- IKAJZIXRVZFOKC-MRXNPFEDSA-N (3R)-1-[1-[(4-fluorophenyl)methyl]benzimidazol-2-yl]piperidin-3-amine Chemical compound FC1=CC=C(CN2C(=NC3=C2C=CC=C3)N2C[C@@H](CCC2)N)C=C1 IKAJZIXRVZFOKC-MRXNPFEDSA-N 0.000 claims description 2
- YXBOYJHBEAVPHU-QGZVFWFLSA-N (3R)-1-[1-[(4-methylphenyl)methyl]benzimidazol-2-yl]piperidin-3-amine Chemical compound CC1=CC=C(CN2C(=NC3=C2C=CC=C3)N2C[C@@H](CCC2)N)C=C1 YXBOYJHBEAVPHU-QGZVFWFLSA-N 0.000 claims description 2
- WGOXHBAWIPSRGK-XFULWGLBSA-N (3R)-1-[1-[(5-chloropyridin-2-yl)methyl]-5,7-difluorobenzimidazol-2-yl]-4,4-difluoropiperidin-3-amine hydrochloride Chemical compound C1CN(C[C@H](C1(F)F)N)C2=NC3=C(N2CC4=NC=C(C=C4)Cl)C(=CC(=C3)F)F.Cl WGOXHBAWIPSRGK-XFULWGLBSA-N 0.000 claims description 2
- RLHYDNXREZGTQW-PKLMIRHRSA-N (3R)-1-[1-[(5-chloropyridin-2-yl)methyl]benzimidazol-2-yl]-4,4-difluoropiperidin-3-amine hydrochloride Chemical compound Cl.ClC=1C=CC(=NC1)CN1C(=NC2=C1C=CC=C2)N2C[C@H](C(CC2)(F)F)N RLHYDNXREZGTQW-PKLMIRHRSA-N 0.000 claims description 2
- PBELOQNWBBJRJY-QGZVFWFLSA-N (3R)-1-[1-[[4-(1,1-difluoroethyl)phenyl]methyl]benzimidazol-2-yl]piperidin-3-amine Chemical compound FC(C)(F)C1=CC=C(CN2C(=NC3=C2C=CC=C3)N2C[C@@H](CCC2)N)C=C1 PBELOQNWBBJRJY-QGZVFWFLSA-N 0.000 claims description 2
- CLMHCIOBXVUBHG-MRXNPFEDSA-N (3R)-1-[1-[[4-(difluoromethyl)phenyl]methyl]benzimidazol-2-yl]piperidin-3-amine Chemical compound FC(C1=CC=C(CN2C(=NC3=C2C=CC=C3)N2C[C@@H](CCC2)N)C=C1)F CLMHCIOBXVUBHG-MRXNPFEDSA-N 0.000 claims description 2
- HHFVWSXSNPAJEV-MRXNPFEDSA-N (3R)-1-[1-[[4-(trifluoromethyl)phenyl]methyl]benzimidazol-2-yl]piperidin-3-amine Chemical compound FC(C1=CC=C(CN2C(=NC3=C2C=CC=C3)N2C[C@@H](CCC2)N)C=C1)(F)F HHFVWSXSNPAJEV-MRXNPFEDSA-N 0.000 claims description 2
- CSOQWAIREOONRI-MRXNPFEDSA-N (3R)-1-[5,6-difluoro-1-[(5-fluoropyridin-2-yl)methyl]benzimidazol-2-yl]-4,4-difluoropiperidin-3-amine Chemical compound FC1=CC2=C(N(C(=N2)N2C[C@H](C(CC2)(F)F)N)CC2=NC=C(C=C2)F)C=C1F CSOQWAIREOONRI-MRXNPFEDSA-N 0.000 claims description 2
- NLDVCWAJHXKUOT-LSBZLQRGSA-N (3R)-3-[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-5,6-difluorobenzimidazol-1-yl]-1-(4-chlorophenyl)pyrrolidin-2-one Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1[C@H]1C(N(CC1)C1=CC=C(C=C1)Cl)=O)C=C(C(=C2)F)F NLDVCWAJHXKUOT-LSBZLQRGSA-N 0.000 claims description 2
- NYJJFNOGDKDKJT-HXUWFJFHSA-N (3R)-3-amino-1-[1-[(5-cyanopyridin-2-yl)methyl]benzimidazol-2-yl]piperidine-3-carboxamide Chemical compound N[C@]1(CN(CCC1)C1=NC2=C(N1CC1=NC=C(C=C1)C#N)C=CC=C2)C(=O)N NYJJFNOGDKDKJT-HXUWFJFHSA-N 0.000 claims description 2
- RWKAPXAIYLBZKD-OMXAPOSASA-N (3R,4R)-1-[1-[(1R)-1-(2,4-difluorophenyl)ethyl]-5,6-difluorobenzimidazol-2-yl]-4-fluoropiperidin-3-amine Chemical compound FC1=C(C=CC(=C1)F)[C@@H](C)N1C(=NC2=C1C=C(C(=C2)F)F)N1C[C@H]([C@@H](CC1)F)N RWKAPXAIYLBZKD-OMXAPOSASA-N 0.000 claims description 2
- FTUXLOGTVGDSQF-LGFNAOKASA-N (3R,4R)-1-[1-[(1R)-1-(2,5-dichlorophenyl)ethyl]-5,6-difluorobenzimidazol-2-yl]-4-fluoropiperidin-3-amine Chemical compound ClC1=C(C=C(C=C1)Cl)[C@@H](C)N1C(=NC2=C1C=C(C(=C2)F)F)N1C[C@H]([C@@H](CC1)F)N FTUXLOGTVGDSQF-LGFNAOKASA-N 0.000 claims description 2
- KAKQUGUHRWHQOC-JDSLSITLSA-N (3R,4R)-1-[1-[(1R)-1-(2-chlorophenyl)ethyl]-5,6-difluorobenzimidazol-2-yl]-4-fluoropiperidin-3-amine Chemical compound ClC1=C(C=CC=C1)[C@@H](C)N1C(=NC2=C1C=C(C(=C2)F)F)N1C[C@H]([C@@H](CC1)F)N KAKQUGUHRWHQOC-JDSLSITLSA-N 0.000 claims description 2
- SJPFCKKZFNNRRD-LGFNAOKASA-N (3R,4R)-1-[1-[(1R)-1-(3,4-dichlorophenyl)ethyl]-5,6-difluorobenzimidazol-2-yl]-4-fluoropiperidin-3-amine Chemical compound ClC=1C=C(C=CC=1Cl)[C@@H](C)N1C(=NC2=C1C=C(C(=C2)F)F)N1C[C@H]([C@@H](CC1)F)N SJPFCKKZFNNRRD-LGFNAOKASA-N 0.000 claims description 2
- GLJUIMZYHWOBAB-JDSLSITLSA-N (3R,4R)-1-[1-[(1R)-1-(3-chlorophenyl)ethyl]-5,6-difluorobenzimidazol-2-yl]-4-fluoropiperidin-3-amine Chemical compound ClC=1C=C(C=CC=1)[C@@H](C)N1C(=NC2=C1C=C(C(=C2)F)F)N1C[C@H]([C@@H](CC1)F)N GLJUIMZYHWOBAB-JDSLSITLSA-N 0.000 claims description 2
- LGKLNVYNZDRILE-RVXAEUMZSA-N (3R,4R)-1-[1-[(1R)-1-(5-chloropyridin-2-yl)ethyl]benzimidazol-2-yl]-4-fluoropiperidin-3-amine hydrochloride Chemical compound C[C@H](C1=NC=C(C=C1)Cl)N2C3=CC=CC=C3N=C2N4CC[C@H]([C@@H](C4)N)F.Cl LGKLNVYNZDRILE-RVXAEUMZSA-N 0.000 claims description 2
- SVPGYBYBAFOQTQ-NCAQKEMTSA-N (3R,4R)-1-[1-[(1S)-1-(2,4-dichlorophenyl)ethyl]-5,6-difluorobenzimidazol-2-yl]-4-fluoropiperidin-3-amine Chemical compound ClC1=C(C=CC(=C1)Cl)[C@H](C)N1C(=NC2=C1C=C(C(=C2)F)F)N1C[C@H]([C@@H](CC1)F)N SVPGYBYBAFOQTQ-NCAQKEMTSA-N 0.000 claims description 2
- RYYAUYIUYGVUGA-NCAQKEMTSA-N (3R,4R)-1-[1-[(1S)-1-(2,5-difluorophenyl)ethyl]-5,6-difluorobenzimidazol-2-yl]-4-fluoropiperidin-3-amine Chemical compound FC1=C(C=C(C=C1)F)[C@H](C)N1C(=NC2=C1C=C(C(=C2)F)F)N1C[C@H]([C@@H](CC1)F)N RYYAUYIUYGVUGA-NCAQKEMTSA-N 0.000 claims description 2
- SJPFCKKZFNNRRD-NCAQKEMTSA-N (3R,4R)-1-[1-[(1S)-1-(3,4-dichlorophenyl)ethyl]-5,6-difluorobenzimidazol-2-yl]-4-fluoropiperidin-3-amine Chemical compound ClC=1C=C(C=CC=1Cl)[C@H](C)N1C(=NC2=C1C=C(C(=C2)F)F)N1C[C@H]([C@@H](CC1)F)N SJPFCKKZFNNRRD-NCAQKEMTSA-N 0.000 claims description 2
- GLJUIMZYHWOBAB-FABXCBLPSA-N (3R,4R)-1-[1-[(1S)-1-(3-chlorophenyl)ethyl]-5,6-difluorobenzimidazol-2-yl]-4-fluoropiperidin-3-amine Chemical compound ClC=1C=C(C=CC=1)[C@H](C)N1C(=NC2=C1C=C(C(=C2)F)F)N1C[C@H]([C@@H](CC1)F)N GLJUIMZYHWOBAB-FABXCBLPSA-N 0.000 claims description 2
- OUCOLANUQMACPZ-UFLILYHASA-N (3R,4R)-1-[1-[(1S)-1-(5-chloropyridin-2-yl)ethyl]-5,6-difluorobenzimidazol-2-yl]-4-fluoropiperidin-3-amine hydrochloride Chemical compound C[C@@H](C1=NC=C(C=C1)Cl)N2C3=CC(=C(C=C3N=C2N4CC[C@H]([C@@H](C4)N)F)F)F.Cl OUCOLANUQMACPZ-UFLILYHASA-N 0.000 claims description 2
- QHNICDYPOMWQEF-MLGOLLRUSA-N (3R,4R)-1-[1-[(2,4-difluorophenyl)methyl]-5,6-difluorobenzimidazol-2-yl]-4-fluoropiperidin-3-amine Chemical compound FC1=C(CN2C(=NC3=C2C=C(C(=C3)F)F)N2C[C@H]([C@@H](CC2)F)N)C=CC(=C1)F QHNICDYPOMWQEF-MLGOLLRUSA-N 0.000 claims description 2
- LFIWXEFECOLYTR-CZUORRHYSA-N (3R,4R)-1-[1-[(3,4-dichlorophenyl)methyl]-5,6-difluorobenzimidazol-2-yl]-4-fluoropiperidin-3-amine Chemical compound ClC=1C=C(CN2C(=NC3=C2C=C(C(=C3)F)F)N2C[C@H]([C@@H](CC2)F)N)C=CC=1Cl LFIWXEFECOLYTR-CZUORRHYSA-N 0.000 claims description 2
- JBIOFLXQBZHXMS-MLGOLLRUSA-N (3R,4R)-1-[1-[(3,4-difluorophenyl)methyl]-5,6-difluorobenzimidazol-2-yl]-4-fluoropiperidin-3-amine Chemical compound FC=1C=C(CN2C(=NC3=C2C=C(C(=C3)F)F)N2C[C@H]([C@@H](CC2)F)N)C=CC=1F JBIOFLXQBZHXMS-MLGOLLRUSA-N 0.000 claims description 2
- CVLHVBCZCBKSGQ-CZUORRHYSA-N (3R,4R)-1-[1-[(3-chloro-4-fluorophenyl)methyl]-5,6-difluorobenzimidazol-2-yl]-4-fluoropiperidin-3-amine Chemical compound ClC=1C=C(CN2C(=NC3=C2C=C(C(=C3)F)F)N2C[C@H]([C@@H](CC2)F)N)C=CC=1F CVLHVBCZCBKSGQ-CZUORRHYSA-N 0.000 claims description 2
- ZNUSGXDWXHOTCW-MLGOLLRUSA-N (3R,4R)-1-[1-[(4-chloro-2-fluorophenyl)methyl]-5,6-difluorobenzimidazol-2-yl]-4-fluoropiperidin-3-amine Chemical compound ClC1=CC(=C(CN2C(=NC3=C2C=C(C(=C3)F)F)N2C[C@H]([C@@H](CC2)F)N)C=C1)F ZNUSGXDWXHOTCW-MLGOLLRUSA-N 0.000 claims description 2
- MHANPTLVUOPCKR-CZUORRHYSA-N (3R,4R)-1-[1-[(4-chloro-2-methoxyphenyl)methyl]-5,6-difluorobenzimidazol-2-yl]-4-fluoropiperidin-3-amine Chemical compound ClC1=CC(=C(CN2C(=NC3=C2C=C(C(=C3)F)F)N2C[C@H]([C@@H](CC2)F)N)C=C1)OC MHANPTLVUOPCKR-CZUORRHYSA-N 0.000 claims description 2
- SYYHSBSJXQSIMF-MLGOLLRUSA-N (3R,4R)-1-[1-[(4-chloro-3-fluorophenyl)methyl]-5,6-difluorobenzimidazol-2-yl]-4-fluoropiperidin-3-amine Chemical compound ClC1=C(C=C(CN2C(=NC3=C2C=C(C(=C3)F)F)N2C[C@H]([C@@H](CC2)F)N)C=C1)F SYYHSBSJXQSIMF-MLGOLLRUSA-N 0.000 claims description 2
- NHWPHHIBPPYJNJ-CHWSQXEVSA-N (3R,4R)-1-[1-[(5-bromopyrimidin-2-yl)methyl]benzimidazol-2-yl]-4-fluoropiperidin-3-amine Chemical compound BrC=1C=NC(=NC=1)CN1C(=NC2=C1C=CC=C2)N1C[C@H]([C@@H](CC1)F)N NHWPHHIBPPYJNJ-CHWSQXEVSA-N 0.000 claims description 2
- HVQFXHWZZSBKJM-HZPDHXFCSA-N (3R,4R)-1-[1-[(5-chloropyridin-2-yl)methyl]-6-methylsulfonylbenzimidazol-2-yl]-4-fluoropiperidin-3-amine Chemical compound ClC=1C=CC(=NC=1)CN1C(=NC2=C1C=C(C=C2)S(=O)(=O)C)N1C[C@H]([C@@H](CC1)F)N HVQFXHWZZSBKJM-HZPDHXFCSA-N 0.000 claims description 2
- GGWVGOISHSDXCM-IUODEOHRSA-N (3R,4R)-1-[1-[[2-(difluoromethoxy)phenyl]methyl]-5,6-difluorobenzimidazol-2-yl]-4-fluoropiperidin-3-amine Chemical compound FC(OC1=C(CN2C(=NC3=C2C=C(C(=C3)F)F)N2C[C@H]([C@@H](CC2)F)N)C=CC=C1)F GGWVGOISHSDXCM-IUODEOHRSA-N 0.000 claims description 2
- JTZJLRXMZYTYRW-CZUORRHYSA-N (3R,4R)-1-[1-[[4-(difluoromethyl)phenyl]methyl]-5,6-difluorobenzimidazol-2-yl]-4-fluoropiperidin-3-amine Chemical compound FC(C1=CC=C(CN2C(=NC3=C2C=C(C(=C3)F)F)N2C[C@H]([C@@H](CC2)F)N)C=C1)F JTZJLRXMZYTYRW-CZUORRHYSA-N 0.000 claims description 2
- UOSNQMIUKQEVCU-IUODEOHRSA-N (3R,4R)-1-[1-[[5-chloro-2-(trifluoromethoxy)phenyl]methyl]-5,6-difluorobenzimidazol-2-yl]-4-fluoropiperidin-3-amine Chemical compound ClC=1C=CC(=C(CN2C(=NC3=C2C=C(C(=C3)F)F)N2C[C@H]([C@@H](CC2)F)N)C=1)OC(F)(F)F UOSNQMIUKQEVCU-IUODEOHRSA-N 0.000 claims description 2
- ZTJDCMWNPPRDKN-CRAIPNDOSA-N (3R,4R)-1-[5,6-difluoro-1-(quinolin-5-ylmethyl)benzimidazol-2-yl]-4-fluoropiperidin-3-amine Chemical compound FC1=CC2=C(N(C(=N2)N2C[C@H]([C@@H](CC2)F)N)CC2=C3C=CC=NC3=CC=C2)C=C1F ZTJDCMWNPPRDKN-CRAIPNDOSA-N 0.000 claims description 2
- SJSXYCLHXJBVEM-RHSMWYFYSA-N (3R,4R)-1-[5,6-difluoro-1-[(1-methylindazol-7-yl)methyl]benzimidazol-2-yl]-4-fluoropiperidin-3-amine Chemical compound FC1=CC2=C(N(C(=N2)N2C[C@H]([C@@H](CC2)F)N)CC=2C=CC=C3C=NN(C=23)C)C=C1F SJSXYCLHXJBVEM-RHSMWYFYSA-N 0.000 claims description 2
- GZABZRINCJJJGP-JDSLSITLSA-N (3R,4R)-1-[5,6-difluoro-1-[(1R)-1-[4-(trifluoromethoxy)phenyl]ethyl]benzimidazol-2-yl]-4-fluoropiperidin-3-amine Chemical compound FC1=CC2=C(N(C(=N2)N2C[C@H]([C@@H](CC2)F)N)[C@H](C)C2=CC=C(C=C2)OC(F)(F)F)C=C1F GZABZRINCJJJGP-JDSLSITLSA-N 0.000 claims description 2
- HUSOUMVFQRRHLJ-VVFCZOMOSA-N (3R,4R)-1-[5,6-difluoro-1-[(1R)-1-quinolin-8-ylethyl]benzimidazol-2-yl]-4-fluoropiperidin-3-amine Chemical compound FC1=CC2=C(N(C(=N2)N2C[C@H]([C@@H](CC2)F)N)[C@H](C)C=2C=CC=C3C=CC=NC=23)C=C1F HUSOUMVFQRRHLJ-VVFCZOMOSA-N 0.000 claims description 2
- ZUFGZLBKZLRKTE-CZUORRHYSA-N (3R,4R)-1-[5,6-difluoro-1-[[3-(trifluoromethyl)phenyl]methyl]benzimidazol-2-yl]-4-fluoropiperidin-3-amine Chemical compound FC1=CC2=C(N(C(=N2)N2C[C@H]([C@@H](CC2)F)N)CC2=CC(=CC=C2)C(F)(F)F)C=C1F ZUFGZLBKZLRKTE-CZUORRHYSA-N 0.000 claims description 2
- QNZACQDZPBZWPP-CRAIPNDOSA-N (3R,4R)-1-[5,6-difluoro-1-[[4-(1,2,4-triazol-1-yl)phenyl]methyl]benzimidazol-2-yl]-4-fluoropiperidin-3-amine Chemical compound FC1=CC2=C(N(C(=N2)N2C[C@H]([C@@H](CC2)F)N)CC2=CC=C(C=C2)N2N=CN=C2)C=C1F QNZACQDZPBZWPP-CRAIPNDOSA-N 0.000 claims description 2
- INPORHBIFFWBIP-CZUORRHYSA-N (3R,4R)-1-[5,6-difluoro-1-[[4-fluoro-2-(trifluoromethyl)phenyl]methyl]benzimidazol-2-yl]-4-fluoropiperidin-3-amine Chemical compound FC1=CC2=C(N(C(=N2)N2C[C@H]([C@@H](CC2)F)N)CC2=C(C=C(C=C2)F)C(F)(F)F)C=C1F INPORHBIFFWBIP-CZUORRHYSA-N 0.000 claims description 2
- RZNDXDJSYDDKHX-DGCLKSJQSA-N (3R,4R)-1-[5,7-difluoro-1-[(5-fluoropyrimidin-2-yl)methyl]benzimidazol-2-yl]-4-fluoropiperidin-3-amine Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=CC(F)=CC(F)=C2N1CC1=NC=C(F)C=N1 RZNDXDJSYDDKHX-DGCLKSJQSA-N 0.000 claims description 2
- NJMWXSXGIIOJEU-VOUVTUPYSA-N (3R,4R)-1-[5-chloro-1-[(1R)-1-(5-chloropyridin-2-yl)ethyl]benzimidazol-2-yl]-4-fluoropiperidin-3-amine hydrochloride Chemical compound C[C@H](C1=NC=C(C=C1)Cl)N2C3=C(C=C(C=C3)Cl)N=C2N4CC[C@H]([C@@H](C4)N)F.Cl NJMWXSXGIIOJEU-VOUVTUPYSA-N 0.000 claims description 2
- YVHULNFWNXDXHV-VOUVTUPYSA-N (3R,4R)-1-[6-chloro-1-[(1R)-1-(5-chloropyridin-2-yl)ethyl]benzimidazol-2-yl]-4-fluoropiperidin-3-amine hydrochloride Chemical compound C[C@H](C1=NC=C(C=C1)Cl)N2C3=C(C=CC(=C3)Cl)N=C2N4CC[C@H]([C@@H](C4)N)F.Cl YVHULNFWNXDXHV-VOUVTUPYSA-N 0.000 claims description 2
- YVHULNFWNXDXHV-ZOOLKIEGSA-N (3R,4R)-1-[6-chloro-1-[(1S)-1-(5-chloropyridin-2-yl)ethyl]benzimidazol-2-yl]-4-fluoropiperidin-3-amine hydrochloride Chemical compound C[C@@H](C1=NC=C(C=C1)Cl)N2C3=C(C=CC(=C3)Cl)N=C2N4CC[C@H]([C@@H](C4)N)F.Cl YVHULNFWNXDXHV-ZOOLKIEGSA-N 0.000 claims description 2
- ZLTGUZIEDBBFES-ZIAGYGMSSA-N (3R,4R)-4-fluoro-1-[1-[(5-methoxypyrimidin-2-yl)methyl]benzimidazol-2-yl]piperidin-3-amine Chemical compound F[C@H]1[C@@H](CN(CC1)C1=NC2=C(N1CC1=NC=C(C=N1)OC)C=CC=C2)N ZLTGUZIEDBBFES-ZIAGYGMSSA-N 0.000 claims description 2
- KTEFPSNCGKMUKH-LDXVYITESA-N (3R,4S)-1-[1-[(5-chloropyridin-2-yl)methyl]benzimidazol-2-yl]-4-fluoropiperidin-3-amine hydrochloride Chemical compound C1CN(C[C@H]([C@H]1F)N)C2=NC3=CC=CC=C3N2CC4=NC=C(C=C4)Cl.Cl KTEFPSNCGKMUKH-LDXVYITESA-N 0.000 claims description 2
- JVCMMIKUAGJLNI-NTISSMGPSA-N (3S)-1-[1-[(4-chlorophenyl)methyl]benzimidazol-2-yl]piperidin-3-amine hydrochloride Chemical compound Cl.N[C@H]1CCCN(C1)c1nc2ccccc2n1Cc1ccc(Cl)cc1 JVCMMIKUAGJLNI-NTISSMGPSA-N 0.000 claims description 2
- IKAJZIXRVZFOKC-INIZCTEOSA-N (3S)-1-[1-[(4-fluorophenyl)methyl]benzimidazol-2-yl]piperidin-3-amine Chemical compound FC1=CC=C(CN2C(=NC3=C2C=CC=C3)N2C[C@H](CCC2)N)C=C1 IKAJZIXRVZFOKC-INIZCTEOSA-N 0.000 claims description 2
- YRRCXSBCFOLKAL-AWEZNQCLSA-N (3S)-1-[1-[(5-chloropyridin-2-yl)methyl]benzimidazol-2-yl]piperidin-3-amine Chemical compound ClC=1C=CC(=NC=1)CN1C(=NC2=C1C=CC=C2)N1C[C@H](CCC1)N YRRCXSBCFOLKAL-AWEZNQCLSA-N 0.000 claims description 2
- IOPROEAZDNHCDP-HNNXBMFYSA-N (3S)-1-[1-[(5-fluoropyridin-2-yl)methyl]benzimidazol-2-yl]-N-methylpiperidin-3-amine Chemical compound FC=1C=CC(=NC=1)CN1C(=NC2=C1C=CC=C2)N1C[C@H](CCC1)NC IOPROEAZDNHCDP-HNNXBMFYSA-N 0.000 claims description 2
- MDBYDMYIPJCJRH-GDBMZVCRSA-N 1-[(5-chloropyrimidin-2-yl)methyl]-2-[(3R,4R)-4-fluoro-3-(methylamino)piperidin-1-yl]benzimidazole-5-carbonitrile Chemical compound ClC=1C=NC(=NC=1)CN1C(=NC2=C1C=CC(=C2)C#N)N1C[C@H]([C@@H](CC1)F)NC MDBYDMYIPJCJRH-GDBMZVCRSA-N 0.000 claims description 2
- XLHLZNDAUPKPBZ-LJQANCHMSA-N 2-[(3R)-3-amino-4,4-difluoropiperidin-1-yl]-1-[(4-cyanophenyl)methyl]benzimidazole-5-carbonitrile Chemical compound N[C@@H]1CN(CCC1(F)F)C1=NC2=C(N1CC1=CC=C(C=C1)C#N)C=CC(=C2)C#N XLHLZNDAUPKPBZ-LJQANCHMSA-N 0.000 claims description 2
- IFYFLOAMMIRQHR-OAHLLOKOSA-N 2-[(3R)-3-amino-4,4-difluoropiperidin-1-yl]-1-[(5-chloropyrimidin-2-yl)methyl]benzimidazole-5-carbonitrile Chemical compound N[C@@H]1CN(CCC1(F)F)C1=NC2=C(N1CC1=NC=C(C=N1)Cl)C=CC(=C2)C#N IFYFLOAMMIRQHR-OAHLLOKOSA-N 0.000 claims description 2
- PDMBQFCXHGNEJY-GOSISDBHSA-N 2-[(3R)-3-amino-4,4-difluoropiperidin-1-yl]-1-[(5-cyanopyridin-2-yl)methyl]benzimidazole-5-carbonitrile Chemical compound N[C@@H]1CN(CCC1(F)F)C1=NC2=C(N1CC1=NC=C(C=C1)C#N)C=CC(=C2)C#N PDMBQFCXHGNEJY-GOSISDBHSA-N 0.000 claims description 2
- CQXNJOYTPNWQNI-LJQANCHMSA-N 2-[(3R)-3-amino-4,4-difluoropiperidin-1-yl]-3-[(4-cyanophenyl)methyl]benzimidazole-5-carbonitrile Chemical compound N[C@@H]1CN(CCC1(F)F)C1=NC2=C(N1CC1=CC=C(C=C1)C#N)C=C(C=C2)C#N CQXNJOYTPNWQNI-LJQANCHMSA-N 0.000 claims description 2
- DMPDLJWACCUFIJ-CQSZACIVSA-N 2-[(3R)-3-amino-4,4-difluoropiperidin-1-yl]-3-[(5-chloropyrimidin-2-yl)methyl]-6-fluorobenzimidazole-4-carbonitrile Chemical compound N[C@@H]1CN(CCC1(F)F)C1=NC2=C(N1CC1=NC=C(C=N1)Cl)C(=CC(=C2)F)C#N DMPDLJWACCUFIJ-CQSZACIVSA-N 0.000 claims description 2
- GTUXFSJPSCHKCO-GOSISDBHSA-N 2-[(3R)-3-amino-4,4-difluoropiperidin-1-yl]-3-[(5-cyanopyridin-2-yl)methyl]benzimidazole-5-carbonitrile Chemical compound N[C@@H]1CN(CCC1(F)F)C1=NC2=C(N1CC1=NC=C(C=C1)C#N)C=C(C=C2)C#N GTUXFSJPSCHKCO-GOSISDBHSA-N 0.000 claims description 2
- RSFONQGNUCFAEW-BMDXIMQFSA-N 2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-1-[(1S)-1-(5-cyanopyridin-2-yl)ethyl]benzimidazole-5-carbonitrile hydrochloride Chemical compound C[C@@H](C1=NC=C(C=C1)C#N)N2C3=C(C=C(C=C3)C#N)N=C2N4CC[C@H]([C@@H](C4)N)F.Cl RSFONQGNUCFAEW-BMDXIMQFSA-N 0.000 claims description 2
- VTTJARZQPHCYBF-ZIAGYGMSSA-N 2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-1-[(5-bromopyrimidin-2-yl)methyl]benzimidazole-5-carbonitrile Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC1=NC=C(C=N1)Br)C=CC(=C2)C#N VTTJARZQPHCYBF-ZIAGYGMSSA-N 0.000 claims description 2
- DANVLIWNXGBVAD-QNBGGDODSA-N 2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-1-[(5-chloropyridin-2-yl)methyl]benzimidazole-5-carbonitrile hydrochloride Chemical compound C1CN(C[C@H]([C@@H]1F)N)C2=NC3=C(N2CC4=NC=C(C=C4)Cl)C=CC(=C3)C#N.Cl DANVLIWNXGBVAD-QNBGGDODSA-N 0.000 claims description 2
- CVJGDLMOQFEQNL-IAGOWNOFSA-N 2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-1-[(5-cyanopyridin-2-yl)methyl]-6-fluorobenzimidazole-4-carbonitrile Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC1=NC=C(C=C1)C#N)C=C(C=C2C#N)F CVJGDLMOQFEQNL-IAGOWNOFSA-N 0.000 claims description 2
- HNPHYCRZOCUPKD-IAGOWNOFSA-N 2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-1-[(5-cyanopyridin-2-yl)methyl]benzimidazole-5-carbonitrile Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC1=NC=C(C=C1)C#N)C=CC(=C2)C#N HNPHYCRZOCUPKD-IAGOWNOFSA-N 0.000 claims description 2
- CWLKCAJKNUIBIC-HZPDHXFCSA-N 2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-1-[(5-fluoropyridin-2-yl)methyl]benzimidazole-5-carbonitrile Chemical compound N[C@@H]1CN(CC[C@H]1F)c1nc2cc(ccc2n1Cc1ccc(F)cn1)C#N CWLKCAJKNUIBIC-HZPDHXFCSA-N 0.000 claims description 2
- KALDIWHCOUIPJS-ZIAGYGMSSA-N 2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-1-[(5-fluoropyrimidin-2-yl)methyl]benzimidazole-5-carbonitrile Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC1=NC=C(C=N1)F)C=CC(=C2)C#N KALDIWHCOUIPJS-ZIAGYGMSSA-N 0.000 claims description 2
- MFMBLJAMZXHMMF-CTHHTMFSSA-N 2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-1-[(5-methoxypyrimidin-2-yl)methyl]benzimidazole-5-carbonitrile hydrochloride Chemical compound COC1=CN=C(N=C1)CN2C3=C(C=C(C=C3)C#N)N=C2N4CC[C@H]([C@@H](C4)N)F.Cl MFMBLJAMZXHMMF-CTHHTMFSSA-N 0.000 claims description 2
- SSKXOPMYIUKIDU-CTHHTMFSSA-N 2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-1-[[6-(trifluoromethyl)pyridin-3-yl]methyl]benzimidazole-5-carbonitrile hydrochloride Chemical compound Cl.N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC=1C=NC(=CC1)C(F)(F)F)C=CC(=C2)C#N SSKXOPMYIUKIDU-CTHHTMFSSA-N 0.000 claims description 2
- HRWPGHXCCBBTTM-WGUYJYMSSA-N 2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-3-[(1R)-1-(5-cyanopyridin-2-yl)ethyl]benzimidazole-5-carbonitrile hydrochloride Chemical compound C[C@H](C1=NC=C(C=C1)C#N)N2C3=C(C=CC(=C3)C#N)N=C2N4CC[C@H]([C@@H](C4)N)F.Cl HRWPGHXCCBBTTM-WGUYJYMSSA-N 0.000 claims description 2
- HRWPGHXCCBBTTM-BMDXIMQFSA-N 2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-3-[(1S)-1-(5-cyanopyridin-2-yl)ethyl]benzimidazole-5-carbonitrile hydrochloride Chemical compound C[C@@H](C1=NC=C(C=C1)C#N)N2C3=C(C=CC(=C3)C#N)N=C2N4CC[C@H]([C@@H](C4)N)F.Cl HRWPGHXCCBBTTM-BMDXIMQFSA-N 0.000 claims description 2
- UVMCRJMSXMHNRA-QZTJIDSGSA-N 2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-3-[(4-cyanophenyl)methyl]benzimidazole-5-carbonitrile Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC1=CC=C(C=C1)C#N)C=C(C=C2)C#N UVMCRJMSXMHNRA-QZTJIDSGSA-N 0.000 claims description 2
- JCKZLWZMTAZZBA-ZIAGYGMSSA-N 2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-3-[(5-bromopyrimidin-2-yl)methyl]benzimidazole-5-carbonitrile Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC1=NC=C(C=N1)Br)C=C(C=C2)C#N JCKZLWZMTAZZBA-ZIAGYGMSSA-N 0.000 claims description 2
- XXMSBBGPILTGLY-HZPDHXFCSA-N 2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-3-[(5-cyanopyrazin-2-yl)methyl]benzimidazole-5-carbonitrile Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC1=NC=C(N=C1)C#N)C=C(C=C2)C#N XXMSBBGPILTGLY-HZPDHXFCSA-N 0.000 claims description 2
- GRMJFMDZGKUPDN-IAGOWNOFSA-N 2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-3-[(5-cyanopyridin-2-yl)methyl]benzimidazole-5-carbonitrile Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC1=NC=C(C=C1)C#N)C=C(C=C2)C#N GRMJFMDZGKUPDN-IAGOWNOFSA-N 0.000 claims description 2
- MMCNEKGCKFRUKF-HZPDHXFCSA-N 2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-3-[(5-fluoropyridin-2-yl)methyl]benzimidazole-5-carbonitrile Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC1=NC=C(C=C1)F)C=C(C=C2)C#N MMCNEKGCKFRUKF-HZPDHXFCSA-N 0.000 claims description 2
- MYAWBSOGCJHXES-ZIAGYGMSSA-N 2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-6-fluoro-1-[(5-fluoropyrimidin-2-yl)methyl]benzimidazole-4-carbonitrile Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC1=NC=C(C=N1)F)C=C(C=C2C#N)F MYAWBSOGCJHXES-ZIAGYGMSSA-N 0.000 claims description 2
- HNPHYCRZOCUPKD-DLBZAZTESA-N 2-[(3R,4S)-3-amino-4-fluoropiperidin-1-yl]-1-[(5-cyanopyridin-2-yl)methyl]benzimidazole-5-carbonitrile Chemical compound N[C@@H]1CN(CC[C@@H]1F)C1=NC2=CC(=CC=C2N1CC1=NC=C(C=C1)C#N)C#N HNPHYCRZOCUPKD-DLBZAZTESA-N 0.000 claims description 2
- HIHNVQJZOCUNBC-BXKDBHETSA-N 2-[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-5,6-difluorobenzimidazol-1-yl]-1-(3,3-difluoroazetidin-1-yl)ethanone Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC(=O)N1CC(C1)(F)F)C=C(C(=C2)F)F HIHNVQJZOCUNBC-BXKDBHETSA-N 0.000 claims description 2
- UTUNZZGMXTXSMH-CZUORRHYSA-N 2-[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-5,6-difluorobenzimidazol-1-yl]-1-(7-oxa-2-azaspiro[3.5]nonan-2-yl)ethanone Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC(=O)N1CC3(C1)CCOCC3)C=C(C(=C2)F)F UTUNZZGMXTXSMH-CZUORRHYSA-N 0.000 claims description 2
- DTIHHVNZMDSBEZ-BXUZGUMPSA-N 2-[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-5,6-difluorobenzimidazol-1-yl]-1-pyrrolidin-1-ylethanone Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC(=O)N1CCCC1)C=C(C(=C2)F)F DTIHHVNZMDSBEZ-BXUZGUMPSA-N 0.000 claims description 2
- IOSXZXABBZSPHU-LLQOJDTPSA-N 2-[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-5,6-difluorobenzimidazol-1-yl]-N-(2-cyanopropyl)-N-ethylacetamide Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC(=O)N(CC)CC(C)C#N)C=C(C(=C2)F)F IOSXZXABBZSPHU-LLQOJDTPSA-N 0.000 claims description 2
- YYKNUYNOZSWKKC-ZWNOBZJWSA-N 2-[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-5,6-difluorobenzimidazol-1-yl]-N-propan-2-ylacetamide Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC(=O)NC(C)C)C=C(C(=C2)F)F YYKNUYNOZSWKKC-ZWNOBZJWSA-N 0.000 claims description 2
- HHCPTHLDJOGALV-CHWSQXEVSA-N 2-[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-6-chlorobenzimidazol-1-yl]-1-(azetidin-1-yl)ethanone Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC(=O)N1CCC1)C=C(C=C2)Cl HHCPTHLDJOGALV-CHWSQXEVSA-N 0.000 claims description 2
- REXUOBKSCJATDB-QWHCGFSZSA-N 2-[2-[(3R,4S)-3-amino-4-fluoropiperidin-1-yl]-6-(trifluoromethyl)benzimidazol-1-yl]-1-(azetidin-1-yl)ethanone Chemical compound N[C@@H]1CN(CC[C@@H]1F)C1=NC2=C(N1CC(=O)N1CCC1)C=C(C=C2)C(F)(F)F REXUOBKSCJATDB-QWHCGFSZSA-N 0.000 claims description 2
- VYHWZEANBFCQEW-LJQANCHMSA-N 2-[4-[[2-[(3R)-3-aminopiperidin-1-yl]benzimidazol-1-yl]methyl]phenyl]-2-methylpropanenitrile Chemical compound N[C@H]1CN(CCC1)C1=NC2=C(N1CC1=CC=C(C=C1)C(C#N)(C)C)C=CC=C2 VYHWZEANBFCQEW-LJQANCHMSA-N 0.000 claims description 2
- ZIRSJSIUGFHFCS-QGZVFWFLSA-N 2-[[2-[(3R)-3-aminopiperidin-1-yl]benzimidazol-1-yl]methyl]-5-chlorobenzonitrile Chemical compound N[C@H]1CN(CCC1)C1=NC2=C(N1CC1=C(C#N)C=C(C=C1)Cl)C=CC=C2 ZIRSJSIUGFHFCS-QGZVFWFLSA-N 0.000 claims description 2
- FVRMXEATDFPHMD-QGZVFWFLSA-N 2-[[2-[(3R)-3-aminopiperidin-1-yl]benzimidazol-1-yl]methyl]benzonitrile Chemical compound N[C@H]1CN(CCC1)C1=NC2=C(N1CC1=C(C#N)C=CC=C1)C=CC=C2 FVRMXEATDFPHMD-QGZVFWFLSA-N 0.000 claims description 2
- QIYRJRRKPNIYCE-RHSMWYFYSA-N 2-[[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-5,6-difluorobenzimidazol-1-yl]methyl]benzonitrile Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC1=C(C#N)C=CC=C1)C=C(C(=C2)F)F QIYRJRRKPNIYCE-RHSMWYFYSA-N 0.000 claims description 2
- CKAUMVXMBCKAIP-GDBMZVCRSA-N 3-[(5-chloropyrimidin-2-yl)methyl]-2-[(3R,4R)-4-fluoro-3-(methylamino)piperidin-1-yl]benzimidazole-5-carbonitrile Chemical compound ClC=1C=NC(=NC=1)CN1C(=NC2=C1C=C(C=C2)C#N)N1C[C@H]([C@@H](CC1)F)NC CKAUMVXMBCKAIP-GDBMZVCRSA-N 0.000 claims description 2
- NLDVCWAJHXKUOT-PQHWSOKGSA-N 3-[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-5,6-difluorobenzimidazol-1-yl]-1-(4-chlorophenyl)pyrrolidin-2-one Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1C1C(N(CC1)C1=CC=C(C=C1)Cl)=O)C=C(C(=C2)F)F NLDVCWAJHXKUOT-PQHWSOKGSA-N 0.000 claims description 2
- YFNWXARPXLSQNL-CFILVAQYSA-N 4-[(1R)-1-[2-[(3S)-3-aminopiperidin-1-yl]benzimidazol-1-yl]ethyl]benzonitrile hydrochloride Chemical compound C[C@H](C1=CC=C(C=C1)C#N)N2C3=CC=CC=C3N=C2N4CCC[C@@H](C4)N.Cl YFNWXARPXLSQNL-CFILVAQYSA-N 0.000 claims description 2
- BSBQRHKMLPLRFL-QHADQLFXSA-N 4-[(1S)-1-[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]benzimidazol-1-yl]ethyl]benzonitrile hydrochloride Chemical compound C[C@@H](C1=CC=C(C=C1)C#N)N2C3=CC=CC=C3N=C2N4CC[C@H]([C@@H](C4)N)F.Cl BSBQRHKMLPLRFL-QHADQLFXSA-N 0.000 claims description 2
- SNDOWMLIJWGJSW-PKHIMPSTSA-N 4-[1-[2-[(3S)-3-aminopiperidin-1-yl]benzimidazol-1-yl]ethyl]benzonitrile Chemical compound N[C@@H]1CN(CCC1)C1=NC2=C(N1C(C)C1=CC=C(C#N)C=C1)C=CC=C2 SNDOWMLIJWGJSW-PKHIMPSTSA-N 0.000 claims description 2
- SBURDYYAXNRJEE-UHFFFAOYSA-N 4-[[2-(4-amino-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl)benzimidazol-1-yl]methyl]benzonitrile Chemical compound NC1CCC2CN(CC21)C1=NC2=C(N1CC1=CC=C(C#N)C=C1)C=CC=C2 SBURDYYAXNRJEE-UHFFFAOYSA-N 0.000 claims description 2
- MDHKJOMROOCRAR-UHFFFAOYSA-N 4-[[2-(9-amino-2-azaspiro[4.4]nonan-2-yl)benzimidazol-1-yl]methyl]benzonitrile Chemical compound NC1C2(CCN(C2)C2=NC3=C(N2CC2=CC=C(C#N)C=C2)C=CC=C3)CCC1 MDHKJOMROOCRAR-UHFFFAOYSA-N 0.000 claims description 2
- PZKPEKMWSIDLGI-DYESRHJHSA-N 4-[[2-[(1R,5S)-1-(aminomethyl)-3-azabicyclo[3.1.0]hexan-3-yl]benzimidazol-1-yl]methyl]benzonitrile Chemical compound NC[C@@]12CN(C[C@H]2C1)C1=NC2=C(N1CC1=CC=C(C#N)C=C1)C=CC=C2 PZKPEKMWSIDLGI-DYESRHJHSA-N 0.000 claims description 2
- HMAWAARBIKGMEX-GOSISDBHSA-N 4-[[2-[(3R)-3-amino-4,4-difluoropiperidin-1-yl]-4-methoxybenzimidazol-1-yl]methyl]benzonitrile Chemical compound N[C@@H]1CN(CCC1(F)F)C1=NC2=C(N1CC1=CC=C(C#N)C=C1)C=CC=C2OC HMAWAARBIKGMEX-GOSISDBHSA-N 0.000 claims description 2
- IBNIGSCRHIFDRW-GOSISDBHSA-N 4-[[2-[(3R)-3-amino-4,4-difluoropiperidin-1-yl]-6-chlorobenzimidazol-1-yl]methyl]benzonitrile Chemical compound N[C@@H]1CN(CCC1(F)F)C1=NC2=C(N1CC1=CC=C(C#N)C=C1)C=C(C=C2)Cl IBNIGSCRHIFDRW-GOSISDBHSA-N 0.000 claims description 2
- QYEQTVZYNACASL-QGZVFWFLSA-N 4-[[2-[(3R)-3-aminopiperidin-1-yl]-5-methoxybenzimidazol-1-yl]methyl]benzonitrile Chemical compound N[C@H]1CN(CCC1)C1=NC2=C(N1CC1=CC=C(C#N)C=C1)C=CC(=C2)OC QYEQTVZYNACASL-QGZVFWFLSA-N 0.000 claims description 2
- YPULRWSQYHMHGX-QGZVFWFLSA-N 4-[[2-[(3R)-3-aminopiperidin-1-yl]benzimidazol-1-yl]methyl]-3-methoxybenzonitrile Chemical compound N[C@H]1CN(CCC1)C1=NC2=C(N1CC1=C(C=C(C#N)C=C1)OC)C=CC=C2 YPULRWSQYHMHGX-QGZVFWFLSA-N 0.000 claims description 2
- GKRVHOKRVRQXHT-QGZVFWFLSA-N 4-[[2-[(3R)-3-aminopiperidin-1-yl]benzimidazol-1-yl]methyl]-N-methylbenzamide Chemical compound N[C@H]1CN(CCC1)C1=NC2=C(N1CC1=CC=C(C(=O)NC)C=C1)C=CC=C2 GKRVHOKRVRQXHT-QGZVFWFLSA-N 0.000 claims description 2
- QTAIYBJDKQJHSG-QGZVFWFLSA-N 4-[[2-[(3R)-3-aminopiperidin-1-yl]benzimidazol-1-yl]methyl]benzonitrile Chemical compound N[C@H]1CN(CCC1)C1=NC2=C(N1CC1=CC=C(C#N)C=C1)C=CC=C2 QTAIYBJDKQJHSG-QGZVFWFLSA-N 0.000 claims description 2
- CIAZIILQTJQZTH-IAGOWNOFSA-N 4-[[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-4-chlorobenzimidazol-1-yl]methyl]benzonitrile Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC1=CC=C(C#N)C=C1)C=CC=C2Cl CIAZIILQTJQZTH-IAGOWNOFSA-N 0.000 claims description 2
- YWGVRLKHAJIEGF-IAGOWNOFSA-N 4-[[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-4-methoxybenzimidazol-1-yl]methyl]benzonitrile Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC1=CC=C(C#N)C=C1)C=CC=C2OC YWGVRLKHAJIEGF-IAGOWNOFSA-N 0.000 claims description 2
- GKDLZQRHHJQSJJ-CRAIPNDOSA-N 4-[[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-5,6-difluorobenzimidazol-1-yl]methyl]-2-methylbenzonitrile Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC1=CC(=C(C#N)C=C1)C)C=C(C(=C2)F)F GKDLZQRHHJQSJJ-CRAIPNDOSA-N 0.000 claims description 2
- AXANWTNONTXDCE-CZUORRHYSA-N 4-[[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-5,6-difluorobenzimidazol-1-yl]methyl]-3-(difluoromethoxy)benzonitrile Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC1=C(C=C(C#N)C=C1)OC(F)F)C=C(C(=C2)F)F AXANWTNONTXDCE-CZUORRHYSA-N 0.000 claims description 2
- IJADCZAGLXCIHZ-RTBURBONSA-N 4-[[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-6-ethoxybenzimidazol-1-yl]methyl]benzonitrile Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC1=CC=C(C#N)C=C1)C=C(C=C2)OCC IJADCZAGLXCIHZ-RTBURBONSA-N 0.000 claims description 2
- HBZXSMXBOACHLU-HZPDHXFCSA-N 4-[[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]imidazo[4,5-b]pyridin-1-yl]methyl]benzonitrile Chemical compound N[C@@H]1CN(CC[C@H]1F)C=1N(C=2C(=NC=CC=2)N=1)CC1=CC=C(C#N)C=C1 HBZXSMXBOACHLU-HZPDHXFCSA-N 0.000 claims description 2
- KQHMSMMXAYQXTE-QAPCUYQASA-N 4-[[2-[(3R,4R)-3-amino-4-methylpiperidin-1-yl]benzimidazol-1-yl]methyl]benzonitrile Chemical compound N[C@H]1CN(CC[C@H]1C)C1=NC2=C(N1CC1=CC=C(C#N)C=C1)C=CC=C2 KQHMSMMXAYQXTE-QAPCUYQASA-N 0.000 claims description 2
- ZHIYSTZDOIQQCQ-DLBZAZTESA-N 4-[[2-[(3R,4S)-3-amino-4-fluoropiperidin-1-yl]benzimidazol-1-yl]methyl]benzonitrile Chemical compound N[C@@H]1CN(CC[C@@H]1F)C1=NC2=C(N1CC1=CC=C(C#N)C=C1)C=CC=C2 ZHIYSTZDOIQQCQ-DLBZAZTESA-N 0.000 claims description 2
- WVXWLNNTXZOPKX-YADHBBJMSA-N 4-[[2-[(3R,4S)-3-amino-4-phenylpyrrolidin-1-yl]benzimidazol-1-yl]methyl]benzonitrile Chemical compound N[C@H]1CN(C[C@@H]1C1=CC=CC=C1)C1=NC2=CC=CC=C2N1CC1=CC=C(C=C1)C#N WVXWLNNTXZOPKX-YADHBBJMSA-N 0.000 claims description 2
- LQRYEZAPHBKFCQ-KRWDZBQOSA-N 4-[[2-[(3S)-3-aminopiperidin-1-yl]-6-chlorobenzimidazol-1-yl]methyl]benzonitrile Chemical compound N[C@@H]1CN(CCC1)C1=NC2=C(N1CC1=CC=C(C#N)C=C1)C=C(C=C2)Cl LQRYEZAPHBKFCQ-KRWDZBQOSA-N 0.000 claims description 2
- FUTYPEANHPUEBU-NTISSMGPSA-N 4-[[2-[(3S)-3-aminopiperidin-1-yl]benzimidazol-1-yl]methyl]-3-fluorobenzonitrile hydrochloride Chemical compound C1C[C@@H](CN(C1)C2=NC3=CC=CC=C3N2CC4=C(C=C(C=C4)C#N)F)N.Cl FUTYPEANHPUEBU-NTISSMGPSA-N 0.000 claims description 2
- LAHMQBGJUVMWMJ-NTISSMGPSA-N 4-[[2-[(3S)-3-aminopiperidin-1-yl]imidazo[4,5-b]pyridin-3-yl]methyl]benzonitrile hydrochloride Chemical compound Cl.N[C@@H]1CN(CCC1)C1=NC=2C(=NC=CC2)N1CC1=CC=C(C#N)C=C1 LAHMQBGJUVMWMJ-NTISSMGPSA-N 0.000 claims description 2
- GWFBHPMTPDNRKB-INIZCTEOSA-N 4-[[2-[(3S)-3-aminopyrrolidin-1-yl]benzimidazol-1-yl]methyl]benzonitrile Chemical compound N[C@@H]1CN(CC1)C1=NC2=C(N1CC1=CC=C(C#N)C=C1)C=CC=C2 GWFBHPMTPDNRKB-INIZCTEOSA-N 0.000 claims description 2
- ZHIYSTZDOIQQCQ-SJORKVTESA-N 4-[[2-[(3S,4R)-3-amino-4-fluoropiperidin-1-yl]benzimidazol-1-yl]methyl]benzonitrile Chemical compound N[C@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC1=CC=C(C#N)C=C1)C=CC=C2 ZHIYSTZDOIQQCQ-SJORKVTESA-N 0.000 claims description 2
- WVXWLNNTXZOPKX-FCHUYYIVSA-N 4-[[2-[(3S,4R)-3-amino-4-phenylpyrrolidin-1-yl]benzimidazol-1-yl]methyl]benzonitrile Chemical compound N[C@@H]1CN(C[C@H]1C1=CC=CC=C1)C1=NC2=C(N1CC1=CC=C(C#N)C=C1)C=CC=C2 WVXWLNNTXZOPKX-FCHUYYIVSA-N 0.000 claims description 2
- LPOFZFSNVDYLPO-LPHOPBHVSA-N 4-[[2-[(3S,4S)-3-amino-4-hydroxypiperidin-1-yl]benzimidazol-1-yl]methyl]benzonitrile Chemical compound N[C@H]1CN(CC[C@@H]1O)C1=NC2=C(N1CC1=CC=C(C#N)C=C1)C=CC=C2 LPOFZFSNVDYLPO-LPHOPBHVSA-N 0.000 claims description 2
- KGZHTDDYHBBCEN-MRXNPFEDSA-N 5-[[2-[(3R)-3-amino-4,4-difluoropiperidin-1-yl]-5-chlorobenzimidazol-1-yl]methyl]pyrazine-2-carbonitrile Chemical compound N[C@@H]1CN(CCC1(F)F)C1=NC2=C(N1CC=1N=CC(=NC=1)C#N)C=CC(=C2)Cl KGZHTDDYHBBCEN-MRXNPFEDSA-N 0.000 claims description 2
- UDWJTNNQNYMZPM-UKRRQHHQSA-N 5-[[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-5,7-difluorobenzimidazol-1-yl]methyl]pyrazine-2-carbonitrile Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC=1N=CC(=NC=1)C#N)C(=CC(=C2)F)F UDWJTNNQNYMZPM-UKRRQHHQSA-N 0.000 claims description 2
- NMQSUYIYLNTNLX-HUUCEWRRSA-N 5-[[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]benzimidazol-1-yl]methyl]pyrazine-2-carbonitrile Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC=1N=CC(=NC=1)C#N)C=CC=C2 NMQSUYIYLNTNLX-HUUCEWRRSA-N 0.000 claims description 2
- YKHWYFPQWSMKJR-QWHCGFSZSA-N 5-[[2-[(3R,4S)-3-amino-4-fluoropiperidin-1-yl]-5-(trifluoromethyl)benzimidazol-1-yl]methyl]pyrazine-2-carboxamide Chemical compound N[C@@H]1CN(CC[C@@H]1F)C1=NC2=C(N1CC=1N=CC(=NC=1)C(=O)N)C=CC(=C2)C(F)(F)F YKHWYFPQWSMKJR-QWHCGFSZSA-N 0.000 claims description 2
- CJVGRDMSCJSNSN-QWHCGFSZSA-N 5-[[2-[(3R,4S)-3-amino-4-fluoropiperidin-1-yl]-6-(trifluoromethyl)benzimidazol-1-yl]methyl]pyrazine-2-carboxamide Chemical compound N[C@@H]1CN(CC[C@@H]1F)C1=NC2=C(N1CC=1N=CC(=NC=1)C(=O)N)C=C(C=C2)C(F)(F)F CJVGRDMSCJSNSN-QWHCGFSZSA-N 0.000 claims description 2
- CPURZWYGQJCJCL-HNNXBMFYSA-N 5-[[2-[(3S)-3-aminopiperidin-1-yl]benzimidazol-1-yl]methyl]pyridine-2-carbonitrile Chemical compound N[C@@H]1CN(CCC1)C1=NC2=C(N1CC=1C=CC(=NC=1)C#N)C=CC=C2 CPURZWYGQJCJCL-HNNXBMFYSA-N 0.000 claims description 2
- BSITXNANZKRLKG-WBVHZDCISA-N 6-[(1R)-1-[2-[(3S)-3-(methylamino)piperidin-1-yl]benzimidazol-1-yl]ethyl]pyridine-3-carbonitrile Chemical compound CN[C@@H]1CN(CCC1)C1=NC2=C(N1[C@H](C)C1=CC=C(C=N1)C#N)C=CC=C2 BSITXNANZKRLKG-WBVHZDCISA-N 0.000 claims description 2
- OONLKOWOFDEGGS-CFSSXQINSA-N 6-[(1R)-1-[2-[(4aR,8aR)-2,3,4,4a,5,7,8,8a-octahydropyrido[4,3-b][1,4]oxazin-6-yl]-4,6-difluorobenzimidazol-1-yl]ethyl]pyridine-3-carbonitrile Chemical compound FC1=CC(=CC=2N(C(=NC=21)N1C[C@@H]2[C@H](OCCN2)CC1)[C@H](C)C1=CC=C(C=N1)C#N)F OONLKOWOFDEGGS-CFSSXQINSA-N 0.000 claims description 2
- FEBJCPCERQRRNW-SMHULIPUSA-N 6-[(1R)-1-[2-[(4aR,8aR)-2,3,4,4a,5,7,8,8a-octahydropyrido[4,3-b][1,4]oxazin-6-yl]-5,7-difluorobenzimidazol-1-yl]ethyl]pyridine-3-carbonitrile Chemical compound FC1=CC2=C(N(C(=N2)N2C[C@@H]3[C@H](OCCN3)CC2)[C@H](C)C2=CC=C(C=N2)C#N)C(=C1)F FEBJCPCERQRRNW-SMHULIPUSA-N 0.000 claims description 2
- FEBJCPCERQRRNW-CWVNLOTRSA-N 6-[(1R)-1-[2-[(4aS,8aS)-2,3,4,4a,5,7,8,8a-octahydropyrido[4,3-b][1,4]oxazin-6-yl]-5,7-difluorobenzimidazol-1-yl]ethyl]pyridine-3-carbonitrile Chemical compound FC1=CC2=C(N(C(=N2)N2C[C@H]3[C@@H](OCCN3)CC2)[C@H](C)C2=CC=C(C=N2)C#N)C(=C1)F FEBJCPCERQRRNW-CWVNLOTRSA-N 0.000 claims description 2
- BSITXNANZKRLKG-RDJZCZTQSA-N 6-[(1S)-1-[2-[(3S)-3-(methylamino)piperidin-1-yl]benzimidazol-1-yl]ethyl]pyridine-3-carbonitrile Chemical compound CN[C@@H]1CN(CCC1)C1=NC2=C(N1[C@@H](C)C1=CC=C(C=N1)C#N)C=CC=C2 BSITXNANZKRLKG-RDJZCZTQSA-N 0.000 claims description 2
- FEBJCPCERQRRNW-CJMONDIMSA-N 6-[(1S)-1-[2-[(4aR,8aR)-2,3,4,4a,5,7,8,8a-octahydropyrido[4,3-b][1,4]oxazin-6-yl]-5,7-difluorobenzimidazol-1-yl]ethyl]pyridine-3-carbonitrile Chemical compound FC1=CC2=C(N(C(=N2)N2C[C@@H]3[C@H](OCCN3)CC2)[C@@H](C)C2=CC=C(C=N2)C#N)C(=C1)F FEBJCPCERQRRNW-CJMONDIMSA-N 0.000 claims description 2
- OONLKOWOFDEGGS-GMVOTWDCSA-N 6-[(1S)-1-[2-[(4aS,8aS)-2,3,4,4a,5,7,8,8a-octahydropyrido[4,3-b][1,4]oxazin-6-yl]-4,6-difluorobenzimidazol-1-yl]ethyl]pyridine-3-carbonitrile Chemical compound FC1=CC(=CC=2N(C(=NC=21)N1C[C@H]2[C@@H](OCCN2)CC1)[C@@H](C)C1=CC=C(C=N1)C#N)F OONLKOWOFDEGGS-GMVOTWDCSA-N 0.000 claims description 2
- FEBJCPCERQRRNW-MRFFXTKBSA-N 6-[(1S)-1-[2-[(4aS,8aS)-2,3,4,4a,5,7,8,8a-octahydropyrido[4,3-b][1,4]oxazin-6-yl]-5,7-difluorobenzimidazol-1-yl]ethyl]pyridine-3-carbonitrile Chemical compound FC1=CC2=C(N(C(=N2)N2C[C@H]3[C@@H](OCCN3)CC2)[C@@H](C)C2=CC=C(C=N2)C#N)C(=C1)F FEBJCPCERQRRNW-MRFFXTKBSA-N 0.000 claims description 2
- KXHCSSCRMBAFMK-QGZVFWFLSA-N 6-[[2-[(3R)-3-amino-4,4-difluoropiperidin-1-yl]-5-(trifluoromethyl)benzimidazol-1-yl]methyl]pyridine-3-carbonitrile Chemical compound N[C@@H]1CN(CCC1(F)F)C1=NC2=C(N1CC1=CC=C(C=N1)C#N)C=CC(=C2)C(F)(F)F KXHCSSCRMBAFMK-QGZVFWFLSA-N 0.000 claims description 2
- SSRHJVKYDWGFOT-QGZVFWFLSA-N 6-[[2-[(3R)-3-amino-4,4-difluoropiperidin-1-yl]-6-(trifluoromethyl)benzimidazol-1-yl]methyl]pyridine-3-carbonitrile Chemical compound N[C@@H]1CN(CCC1(F)F)C1=NC2=C(N1CC1=CC=C(C=N1)C#N)C=C(C=C2)C(F)(F)F SSRHJVKYDWGFOT-QGZVFWFLSA-N 0.000 claims description 2
- SKFPVAWAOVLNRS-IAGOWNOFSA-N 6-[[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-4-methylbenzimidazol-1-yl]methyl]pyridine-3-carbonitrile Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC1=CC=C(C=N1)C#N)C=CC=C2C SKFPVAWAOVLNRS-IAGOWNOFSA-N 0.000 claims description 2
- WJWQRCGWGVAJBL-HUUCEWRRSA-N 6-[[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-5-chloro-6-(trifluoromethoxy)benzimidazol-1-yl]methyl]pyridine-3-carbonitrile Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC1=CC=C(C=N1)C#N)C=C(C(=C2)Cl)OC(F)(F)F WJWQRCGWGVAJBL-HUUCEWRRSA-N 0.000 claims description 2
- IHUYVOOLFKXDDH-HZPDHXFCSA-N 6-[[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-5-chloro-6-(trifluoromethyl)benzimidazol-1-yl]methyl]pyridine-3-carbonitrile Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC1=CC=C(C=N1)C#N)C=C(C(=C2)Cl)C(F)(F)F IHUYVOOLFKXDDH-HZPDHXFCSA-N 0.000 claims description 2
- IFTHEPNKBMVCTQ-IAGOWNOFSA-N 6-[[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-5-chloro-6-methylbenzimidazol-1-yl]methyl]pyridine-3-carbonitrile Chemical compound CC1=C(Cl)C=C2N=C(N(CC3=CC=C(C=N3)C#N)C2=C1)N1CC[C@@H](F)[C@H](N)C1 IFTHEPNKBMVCTQ-IAGOWNOFSA-N 0.000 claims description 2
- IIEJXGXDCOULKI-HUUCEWRRSA-N 6-[[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-6-chloro-5-(trifluoromethoxy)benzimidazol-1-yl]methyl]pyridine-3-carbonitrile Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC1=CC=C(C=N1)C#N)C=C(C(=C2)OC(F)(F)F)Cl IIEJXGXDCOULKI-HUUCEWRRSA-N 0.000 claims description 2
- KLTGFQDFSVXOKX-HZPDHXFCSA-N 6-[[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-6-chloro-5-(trifluoromethyl)benzimidazol-1-yl]methyl]pyridine-3-carbonitrile Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC1=CC=C(C=N1)C#N)C=C(C(=C2)C(F)(F)F)Cl KLTGFQDFSVXOKX-HZPDHXFCSA-N 0.000 claims description 2
- IVZOPLCIRYOPPV-NVXWUHKLSA-N 6-[[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-6-fluoro-5-methylbenzimidazol-1-yl]methyl]pyridine-3-carbonitrile Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC1=CC=C(C=N1)C#N)C=C(C(=C2)C)F IVZOPLCIRYOPPV-NVXWUHKLSA-N 0.000 claims description 2
- UXFGKAPVCRNRRK-JKSUJKDBSA-N 6-[[2-[(3R,4S)-3-amino-4-fluoropiperidin-1-yl]-5-(trifluoromethyl)benzimidazol-1-yl]methyl]pyridine-3-carbonitrile Chemical compound N[C@@H]1CN(CC[C@@H]1F)C1=NC2=C(N1CC1=CC=C(C=N1)C#N)C=CC(=C2)C(F)(F)F UXFGKAPVCRNRRK-JKSUJKDBSA-N 0.000 claims description 2
- KJHUADHQNAJJKE-JKSUJKDBSA-N 6-[[2-[(3R,4S)-3-amino-4-fluoropiperidin-1-yl]-6-(trifluoromethyl)benzimidazol-1-yl]methyl]pyridine-3-carbonitrile Chemical compound N[C@@H]1CN(CC[C@@H]1F)C1=NC2=C(N1CC1=CC=C(C=N1)C#N)C=C(C=C2)C(F)(F)F KJHUADHQNAJJKE-JKSUJKDBSA-N 0.000 claims description 2
- XGIQQVILUWKWSA-INIZCTEOSA-N 6-[[2-[(3S)-3-(methylamino)piperidin-1-yl]-5-(trifluoromethyl)benzimidazol-1-yl]methyl]pyridine-3-carbonitrile Chemical compound CN[C@@H]1CN(CCC1)C1=NC2=C(N1CC1=CC=C(C=N1)C#N)C=CC(=C2)C(F)(F)F XGIQQVILUWKWSA-INIZCTEOSA-N 0.000 claims description 2
- SXCYBIQZDVMGFI-INIZCTEOSA-N 6-[[2-[(3S)-3-(methylamino)piperidin-1-yl]-6-(trifluoromethyl)benzimidazol-1-yl]methyl]pyridine-3-carbonitrile Chemical compound CN[C@@H]1CN(CCC1)C1=NC2=C(N1CC1=CC=C(C=N1)C#N)C=C(C=C2)C(F)(F)F SXCYBIQZDVMGFI-INIZCTEOSA-N 0.000 claims description 2
- BBFCAEHJBJURSJ-INIZCTEOSA-N 6-[[2-[(3S)-3-(methylamino)piperidin-1-yl]benzimidazol-1-yl]methyl]pyridine-3-carbonitrile Chemical compound CN[C@H]1CCCN(C1)C1=NC2=CC=CC=C2N1CC1=CC=C(C=N1)C#N BBFCAEHJBJURSJ-INIZCTEOSA-N 0.000 claims description 2
- ZVGQQBXETIAIGZ-UYAOXDASSA-N 6-[[2-[(4aR,8aR)-2,3,4,4a,5,7,8,8a-octahydropyrido[4,3-b][1,4]oxazin-6-yl]benzimidazol-1-yl]methyl]pyridine-3-carbonitrile Chemical compound O1[C@H]2[C@H](NCC1)CN(CC2)C1=NC2=C(N1CC1=CC=C(C=N1)C#N)C=CC=C2 ZVGQQBXETIAIGZ-UYAOXDASSA-N 0.000 claims description 2
- ZVGQQBXETIAIGZ-ICSRJNTNSA-N 6-[[2-[(4aS,8aS)-2,3,4,4a,5,7,8,8a-octahydropyrido[4,3-b][1,4]oxazin-6-yl]benzimidazol-1-yl]methyl]pyridine-3-carbonitrile Chemical compound O1[C@@H]2[C@@H](NCC1)CN(CC2)C1=NC2=C(N1CC1=CC=C(C=N1)C#N)C=CC=C2 ZVGQQBXETIAIGZ-ICSRJNTNSA-N 0.000 claims description 2
- MCAASJPKMFNZIQ-QFIPXVFZSA-N 6-[[2-[(5S)-1,9-diazaspiro[4.5]decan-9-yl]benzimidazol-1-yl]methyl]pyridine-3-carbonitrile Chemical compound N1CCC[C@]11CN(CCC1)C1=NC2=C(N1CC1=CC=C(C=N1)C#N)C=CC=C2 MCAASJPKMFNZIQ-QFIPXVFZSA-N 0.000 claims description 2
- 125000001960 7 membered carbocyclic group Chemical group 0.000 claims description 2
- QOTVBKFASYCSCO-VEIFNGETSA-N C1CN(C[C@@]1(CN)F)C2=NC3=CC=CC=C3N2CC4=CC=C(C=C4)C#N.C(=O)(C(F)(F)F)O Chemical compound C1CN(C[C@@]1(CN)F)C2=NC3=CC=CC=C3N2CC4=CC=C(C=C4)C#N.C(=O)(C(F)(F)F)O QOTVBKFASYCSCO-VEIFNGETSA-N 0.000 claims description 2
- BADKZHGHZYZZLW-VEIFNGETSA-N C1CN(C[C@@]1(CN)O)C2=NC3=CC=CC=C3N2CC4=CC=C(C=C4)C#N.C(=O)(C(F)(F)F)O Chemical compound C1CN(C[C@@]1(CN)O)C2=NC3=CC=CC=C3N2CC4=CC=C(C=C4)C#N.C(=O)(C(F)(F)F)O BADKZHGHZYZZLW-VEIFNGETSA-N 0.000 claims description 2
- QOTVBKFASYCSCO-BDQAORGHSA-N C1CN(C[C@]1(CN)F)C2=NC3=CC=CC=C3N2CC4=CC=C(C=C4)C#N.C(=O)(C(F)(F)F)O Chemical compound C1CN(C[C@]1(CN)F)C2=NC3=CC=CC=C3N2CC4=CC=C(C=C4)C#N.C(=O)(C(F)(F)F)O QOTVBKFASYCSCO-BDQAORGHSA-N 0.000 claims description 2
- VFLALZLWZAYJPC-NTISSMGPSA-N C1C[C@@H](CN(C1)C2=NC3=C(N2CC4=CC=C(C=C4)C#N)C=CC=C3Cl)N.C(=O)(C(F)(F)F)O Chemical compound C1C[C@@H](CN(C1)C2=NC3=C(N2CC4=CC=C(C=C4)C#N)C=CC=C3Cl)N.C(=O)(C(F)(F)F)O VFLALZLWZAYJPC-NTISSMGPSA-N 0.000 claims description 2
- AVDYFABXEVEUMG-XFULWGLBSA-N C1C[C@H](CN(C1)C2=NC3=CC=CC=C3N2CC4=CN=C(C=C4)C#N)N.C(=O)(C(F)(F)F)O Chemical compound C1C[C@H](CN(C1)C2=NC3=CC=CC=C3N2CC4=CN=C(C=C4)C#N)N.C(=O)(C(F)(F)F)O AVDYFABXEVEUMG-XFULWGLBSA-N 0.000 claims description 2
- QQLYWBUFRODCIC-KQKCUOLZSA-N C[C@@H]1CCN(C[C@H]1N)C2=NC3=CC=CC=C3N2CC4=CC=C(C=C4)C#N.C(=O)(C(F)(F)F)O Chemical compound C[C@@H]1CCN(C[C@H]1N)C2=NC3=CC=CC=C3N2CC4=CC=C(C=C4)C#N.C(=O)(C(F)(F)F)O QQLYWBUFRODCIC-KQKCUOLZSA-N 0.000 claims description 2
- 125000002527 bicyclic carbocyclic group Chemical group 0.000 claims description 2
- 230000003647 oxidation Effects 0.000 claims description 2
- 238000007254 oxidation reaction Methods 0.000 claims description 2
- 125000006413 ring segment Chemical group 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims 54
- 102000003623 TRPC6 Human genes 0.000 claims 3
- 108050001421 Transient receptor potential channel, canonical 6 Proteins 0.000 claims 3
- 241000208125 Nicotiana Species 0.000 claims 2
- PEEQUKZBJZQVTB-PXNSSMCTSA-N (1S)-1-[2-[(3S)-3-aminopiperidin-1-yl]benzimidazol-1-yl]-2,3-dihydro-1H-indene-5-carbonitrile Chemical compound N[C@@H]1CN(CCC1)C1=NC2=C(N1[C@H]1CCC3=CC(=CC=C13)C#N)C=CC=C2 PEEQUKZBJZQVTB-PXNSSMCTSA-N 0.000 claims 1
- LQFIGJWKDLTNCN-OAHLLOKOSA-N (3R)-1-[1-[(3-chloro-4-methoxyphenyl)methyl]benzimidazol-2-yl]piperidin-3-amine Chemical compound ClC=1C=C(CN2C(=NC3=C2C=CC=C3)N2C[C@@H](CCC2)N)C=CC=1OC LQFIGJWKDLTNCN-OAHLLOKOSA-N 0.000 claims 1
- AIMABMVMQXYFCW-MRXNPFEDSA-N (3R)-1-[1-[(4-methylsulfonylphenyl)methyl]benzimidazol-2-yl]piperidin-3-amine Chemical compound CS(=O)(=O)C1=CC=C(CN2C(=NC3=C2C=CC=C3)N2C[C@@H](CCC2)N)C=C1 AIMABMVMQXYFCW-MRXNPFEDSA-N 0.000 claims 1
- VNNRHQCTTCIZTL-QGZVFWFLSA-N (3R)-1-[1-[[3-(3-chlorophenyl)-1,2-oxazol-5-yl]methyl]benzimidazol-2-yl]piperidin-3-amine Chemical compound N[C@@H]1CCCN(C1)C1=NC2=CC=CC=C2N1CC1=CC(=NO1)C1=CC(Cl)=CC=C1 VNNRHQCTTCIZTL-QGZVFWFLSA-N 0.000 claims 1
- GPOWRLVRUQVPHM-OAHLLOKOSA-N (3R)-1-[1-[[4-(trifluoromethoxy)phenyl]methyl]benzimidazol-2-yl]piperidin-3-amine Chemical compound FC(OC1=CC=C(CN2C(=NC3=C2C=CC=C3)N2C[C@@H](CCC2)N)C=C1)(F)F GPOWRLVRUQVPHM-OAHLLOKOSA-N 0.000 claims 1
- RYYAUYIUYGVUGA-LGFNAOKASA-N (3R,4R)-1-[1-[(1R)-1-(2,5-difluorophenyl)ethyl]-5,6-difluorobenzimidazol-2-yl]-4-fluoropiperidin-3-amine Chemical compound FC1=C(C=C(C=C1)F)[C@@H](C)N1C(=NC2=C1C=C(C(=C2)F)F)N1C[C@H]([C@@H](CC1)F)N RYYAUYIUYGVUGA-LGFNAOKASA-N 0.000 claims 1
- OUCOLANUQMACPZ-AYJWUPBJSA-N (3R,4R)-1-[1-[(1R)-1-(5-chloropyridin-2-yl)ethyl]-5,6-difluorobenzimidazol-2-yl]-4-fluoropiperidin-3-amine hydrochloride Chemical compound C[C@H](C1=NC=C(C=C1)Cl)N2C3=CC(=C(C=C3N=C2N4CC[C@H]([C@@H](C4)N)F)F)F.Cl OUCOLANUQMACPZ-AYJWUPBJSA-N 0.000 claims 1
- FTUXLOGTVGDSQF-NCAQKEMTSA-N (3R,4R)-1-[1-[(1S)-1-(2,5-dichlorophenyl)ethyl]-5,6-difluorobenzimidazol-2-yl]-4-fluoropiperidin-3-amine Chemical compound ClC1=C(C=C(C=C1)Cl)[C@H](C)N1C(=NC2=C1C=C(C(=C2)F)F)N1C[C@H]([C@@H](CC1)F)N FTUXLOGTVGDSQF-NCAQKEMTSA-N 0.000 claims 1
- NZHFVZCZWGZIFL-CZUORRHYSA-N (3R,4R)-1-[1-[(2,4-dichlorophenyl)methyl]-5,6-difluorobenzimidazol-2-yl]-4-fluoropiperidin-3-amine Chemical compound N[C@@H]1CN(CC[C@H]1F)c1nc2cc(F)c(F)cc2n1Cc1ccc(Cl)cc1Cl NZHFVZCZWGZIFL-CZUORRHYSA-N 0.000 claims 1
- NYTGUEKHBOIBJL-CZUORRHYSA-N (3R,4R)-1-[1-[(2,6-dichlorophenyl)methyl]-5,6-difluorobenzimidazol-2-yl]-4-fluoropiperidin-3-amine Chemical compound ClC1=C(CN2C(=NC3=C2C=C(C(=C3)F)F)N2C[C@H]([C@@H](CC2)F)N)C(=CC=C1)Cl NYTGUEKHBOIBJL-CZUORRHYSA-N 0.000 claims 1
- HYTSBIBLUACIIT-CZUORRHYSA-N (3R,4R)-1-[1-[(2-chloro-4-fluorophenyl)methyl]-5,6-difluorobenzimidazol-2-yl]-4-fluoropiperidin-3-amine Chemical compound ClC1=C(CN2C(=NC3=C2C=C(C(=C3)F)F)N2C[C@H]([C@@H](CC2)F)N)C=CC(=C1)F HYTSBIBLUACIIT-CZUORRHYSA-N 0.000 claims 1
- UOWYDWPNZVCXPO-CZUORRHYSA-N (3R,4R)-1-[1-[(2-chlorophenyl)methyl]-5,6-difluorobenzimidazol-2-yl]-4-fluoropiperidin-3-amine Chemical compound ClC1=C(CN2C(=NC3=C2C=C(C(=C3)F)F)N2C[C@H]([C@@H](CC2)F)N)C=CC=C1 UOWYDWPNZVCXPO-CZUORRHYSA-N 0.000 claims 1
- FFFNXQYENBWXNX-CZUORRHYSA-N (3R,4R)-1-[1-[(3-chlorophenyl)methyl]-5,6-difluorobenzimidazol-2-yl]-4-fluoropiperidin-3-amine Chemical compound ClC=1C=C(CN2C(=NC3=C2C=C(C(=C3)F)F)N2C[C@H]([C@@H](CC2)F)N)C=CC=1 FFFNXQYENBWXNX-CZUORRHYSA-N 0.000 claims 1
- VBHWHDWOWAZTCP-RHSMWYFYSA-N (3R,4R)-1-[5,6-difluoro-1-[(1-methylindazol-4-yl)methyl]benzimidazol-2-yl]-4-fluoropiperidin-3-amine Chemical compound FC1=CC2=C(N(C(=N2)N2C[C@H]([C@@H](CC2)F)N)CC2=C3C=NN(C3=CC=C2)C)C=C1F VBHWHDWOWAZTCP-RHSMWYFYSA-N 0.000 claims 1
- XUUOWQHEDPVWSG-JDSLSITLSA-N (3R,4R)-1-[5,6-difluoro-1-[(1R)-1-[4-(trifluoromethyl)phenyl]ethyl]benzimidazol-2-yl]-4-fluoropiperidin-3-amine Chemical compound FC1=CC2=C(N(C(=N2)N2C[C@H]([C@@H](CC2)F)N)[C@H](C)C2=CC=C(C=C2)C(F)(F)F)C=C1F XUUOWQHEDPVWSG-JDSLSITLSA-N 0.000 claims 1
- HUSOUMVFQRRHLJ-URKNILKWSA-N (3R,4R)-1-[5,6-difluoro-1-[(1S)-1-quinolin-8-ylethyl]benzimidazol-2-yl]-4-fluoropiperidin-3-amine Chemical compound FC1=CC2=C(N(C(=N2)N2C[C@H]([C@@H](CC2)F)N)[C@@H](C)C=2C=CC=C3C=CC=NC=23)C=C1F HUSOUMVFQRRHLJ-URKNILKWSA-N 0.000 claims 1
- SGHTULWYPMVBND-CZUORRHYSA-N (3R,4R)-1-[5,6-difluoro-1-[[2-(trifluoromethyl)phenyl]methyl]benzimidazol-2-yl]-4-fluoropiperidin-3-amine Chemical compound FC1=CC2=C(N(C(=N2)N2C[C@H]([C@@H](CC2)F)N)CC2=C(C=CC=C2)C(F)(F)F)C=C1F SGHTULWYPMVBND-CZUORRHYSA-N 0.000 claims 1
- ZITLUHNZIAYIMU-CZUORRHYSA-N (3R,4R)-1-[5,6-difluoro-1-[[4-(trifluoromethoxy)phenyl]methyl]benzimidazol-2-yl]-4-fluoropiperidin-3-amine Chemical compound FC1=CC2=C(N(C(=N2)N2C[C@H]([C@@H](CC2)F)N)CC2=CC=C(C=C2)OC(F)(F)F)C=C1F ZITLUHNZIAYIMU-CZUORRHYSA-N 0.000 claims 1
- PFRGAZYRLLVXNS-CZUORRHYSA-N (3R,4R)-1-[5,6-difluoro-1-[[4-(trifluoromethyl)phenyl]methyl]benzimidazol-2-yl]-4-fluoropiperidin-3-amine Chemical compound FC1=CC2=C(N(C(=N2)N2C[C@H]([C@@H](CC2)F)N)CC2=CC=C(C=C2)C(F)(F)F)C=C1F PFRGAZYRLLVXNS-CZUORRHYSA-N 0.000 claims 1
- IXTSCGOTBGOTQM-QWHCGFSZSA-N (3R,4S)-1-[1-[(5-chloropyrimidin-2-yl)methyl]-5-fluorobenzimidazol-2-yl]-4-fluoropiperidin-3-amine Chemical compound ClC=1C=NC(=NC=1)CN1C(=NC2=C1C=CC(=C2)F)N1C[C@H]([C@H](CC1)F)N IXTSCGOTBGOTQM-QWHCGFSZSA-N 0.000 claims 1
- FQRCFXLURRRBKB-QWHCGFSZSA-N (3R,4S)-4-fluoro-1-[1-[(5-fluoropyrimidin-2-yl)methyl]-5-(trifluoromethyl)benzimidazol-2-yl]piperidin-3-amine Chemical compound F[C@@H]1[C@@H](CN(CC1)C1=NC2=C(N1CC1=NC=C(C=N1)F)C=CC(=C2)C(F)(F)F)N FQRCFXLURRRBKB-QWHCGFSZSA-N 0.000 claims 1
- CTQHWLVSBDKHTQ-IUPBHXKESA-N (3S)-3-[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-5,6-difluorobenzimidazol-1-yl]-1-methylpyrrolidin-2-one Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1[C@@H]1C(N(CC1)C)=O)C=C(C(=C2)F)F CTQHWLVSBDKHTQ-IUPBHXKESA-N 0.000 claims 1
- BPKWIBBWMYRAGH-AWEZNQCLSA-N 1-(azetidin-1-yl)-2-[2-[(3S)-3-(methylamino)piperidin-1-yl]benzimidazol-1-yl]ethanone Chemical compound N1(CCC1)C(CN1C(=NC2=C1C=CC=C2)N1C[C@H](CCC1)NC)=O BPKWIBBWMYRAGH-AWEZNQCLSA-N 0.000 claims 1
- LJYFETXSAWJLNA-UHFFFAOYSA-N 1h-benzimidazole-4-carbonitrile Chemical compound N#CC1=CC=CC2=C1NC=N2 LJYFETXSAWJLNA-UHFFFAOYSA-N 0.000 claims 1
- XVMHIISTHCFXRM-QZTJIDSGSA-N 2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-1-[(4-cyanophenyl)methyl]benzimidazole-5-carbonitrile Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC1=CC=C(C=C1)C#N)C=CC(=C2)C#N XVMHIISTHCFXRM-QZTJIDSGSA-N 0.000 claims 1
- DKCFSOPQFCKUAP-HUUCEWRRSA-N 2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-1-[(5-cyanopyrimidin-2-yl)methyl]benzimidazole-5-carbonitrile Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC1=NC=C(C=N1)C#N)C=CC(=C2)C#N DKCFSOPQFCKUAP-HUUCEWRRSA-N 0.000 claims 1
- KEERGNBPZFMHRE-QNBGGDODSA-N 2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-3-[(5-chloropyridin-2-yl)methyl]benzimidazole-5-carbonitrile hydrochloride Chemical compound C1CN(C[C@H]([C@@H]1F)N)C2=NC3=C(N2CC4=NC=C(C=C4)Cl)C=C(C=C3)C#N.Cl KEERGNBPZFMHRE-QNBGGDODSA-N 0.000 claims 1
- PVLNOKRRZMUEBV-UONOGXRCSA-N 2-[(3R,4S)-3-amino-4-fluoropiperidin-1-yl]-1-[(5-chloropyrimidin-2-yl)methyl]benzimidazole-5-carbonitrile Chemical compound N[C@@H]1CN(CC[C@@H]1F)C1=NC2=C(N1CC1=NC=C(C=N1)Cl)C=CC(=C2)C#N PVLNOKRRZMUEBV-UONOGXRCSA-N 0.000 claims 1
- GRMJFMDZGKUPDN-DLBZAZTESA-N 2-[(3R,4S)-3-amino-4-fluoropiperidin-1-yl]-3-[(5-cyanopyridin-2-yl)methyl]benzimidazole-5-carbonitrile Chemical compound N[C@@H]1CN(CC[C@@H]1F)C1=NC2=C(N1CC1=NC=C(C=C1)C#N)C=C(C=C2)C#N GRMJFMDZGKUPDN-DLBZAZTESA-N 0.000 claims 1
- MYAWBSOGCJHXES-UONOGXRCSA-N 2-[(3R,4S)-3-amino-4-fluoropiperidin-1-yl]-6-fluoro-1-[(5-fluoropyrimidin-2-yl)methyl]benzimidazole-4-carbonitrile Chemical compound N[C@@H]1CN(CC[C@@H]1F)C1=NC2=C(N1CC1=NC=C(C=N1)F)C=C(C=C2C#N)F MYAWBSOGCJHXES-UONOGXRCSA-N 0.000 claims 1
- ZSZKGVXAQJWUTR-INIZCTEOSA-N 2-[(3S)-3-aminopiperidin-1-yl]-3-[(5-cyanopyridin-2-yl)methyl]benzimidazole-5-carbonitrile Chemical compound N[C@@H]1CN(CCC1)C1=NC2=C(N1CC1=NC=C(C=C1)C#N)C=C(C=C2)C#N ZSZKGVXAQJWUTR-INIZCTEOSA-N 0.000 claims 1
- AYIXCVHEHRGTHA-IUODEOHRSA-N 2-[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-5,6-difluorobenzimidazol-1-yl]-1-(2,2-dimethylpyrrolidin-1-yl)ethanone Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC(=O)N1C(CCC1)(C)C)C=C(C(=C2)F)F AYIXCVHEHRGTHA-IUODEOHRSA-N 0.000 claims 1
- LLWNUTVGLLPTNC-ZWNOBZJWSA-N 2-[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-5,6-difluorobenzimidazol-1-yl]-1-(azetidin-1-yl)ethanone Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC(=O)N1CCC1)C=C(C(=C2)F)F LLWNUTVGLLPTNC-ZWNOBZJWSA-N 0.000 claims 1
- JQJUYVCPXKLFDA-CZUORRHYSA-N 2-[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-5,6-difluorobenzimidazol-1-yl]-1-[3-[(2-methylpropan-2-yl)oxy]azetidin-1-yl]ethanone Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC(=O)N1CC(C1)OC(C)(C)C)C=C(C(=C2)F)F JQJUYVCPXKLFDA-CZUORRHYSA-N 0.000 claims 1
- LSVVCWRGCUJVCT-BXKDBHETSA-N 2-[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-5,6-difluorobenzimidazol-1-yl]-N,N-dimethylacetamide Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC(=O)N(C)C)C=C(C(=C2)F)F LSVVCWRGCUJVCT-BXKDBHETSA-N 0.000 claims 1
- HPOWEKFNWKWOCM-QGZVFWFLSA-N 2-[4-[[2-[(3R)-3-aminopiperidin-1-yl]benzimidazol-1-yl]methyl]phenoxy]acetonitrile Chemical compound N[C@H]1CN(CCC1)C1=NC2=C(N1CC1=CC=C(OCC#N)C=C1)C=CC=C2 HPOWEKFNWKWOCM-QGZVFWFLSA-N 0.000 claims 1
- HJIIPEPTMKOMMK-RHSMWYFYSA-N 2-[[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-5,6-difluorobenzimidazol-1-yl]methyl]-5-chlorobenzonitrile Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC1=C(C#N)C=C(C=C1)Cl)C=C(C(=C2)F)F HJIIPEPTMKOMMK-RHSMWYFYSA-N 0.000 claims 1
- LXXOYDBSBMWOFV-MRHJZYCDSA-N 3-[1-[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-5,6-difluorobenzimidazol-1-yl]ethyl]benzonitrile Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1C(C)C=1C=C(C#N)C=CC=1)C=C(C(=C2)F)F LXXOYDBSBMWOFV-MRHJZYCDSA-N 0.000 claims 1
- FKRSLDSTHMAMIR-RHSMWYFYSA-N 3-[[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-5,6-difluorobenzimidazol-1-yl]methyl]benzonitrile Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC=1C=C(C#N)C=CC=1)C=C(C(=C2)F)F FKRSLDSTHMAMIR-RHSMWYFYSA-N 0.000 claims 1
- BSBQRHKMLPLRFL-ZYCNAHKISA-N 4-[(1R)-1-[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]benzimidazol-1-yl]ethyl]benzonitrile hydrochloride Chemical compound C[C@H](C1=CC=C(C=C1)C#N)N2C3=CC=CC=C3N=C2N4CC[C@H]([C@@H](C4)N)F.Cl BSBQRHKMLPLRFL-ZYCNAHKISA-N 0.000 claims 1
- BSBQRHKMLPLRFL-QSCFYETBSA-N 4-[(1S)-1-[2-[(3R,4S)-3-amino-4-fluoropiperidin-1-yl]benzimidazol-1-yl]ethyl]benzonitrile hydrochloride Chemical compound Cl.C[C@@H](c1ccc(cc1)C#N)n1c(nc2ccccc12)N1CC[C@H](F)[C@H](N)C1 BSBQRHKMLPLRFL-QSCFYETBSA-N 0.000 claims 1
- PZKPEKMWSIDLGI-UWJYYQICSA-N 4-[[2-[(1S,5R)-1-(aminomethyl)-3-azabicyclo[3.1.0]hexan-3-yl]benzimidazol-1-yl]methyl]benzonitrile Chemical compound NC[C@]12CN(C[C@@H]2C1)C1=NC2=C(N1CC1=CC=C(C#N)C=C1)C=CC=C2 PZKPEKMWSIDLGI-UWJYYQICSA-N 0.000 claims 1
- XQMMNNGIYWADKI-QGZVFWFLSA-N 4-[[2-[(3R)-3-(aminomethyl)pyrrolidin-1-yl]benzimidazol-1-yl]methyl]benzonitrile Chemical compound NC[C@@H]1CN(CC1)C1=NC2=C(N1CC1=CC=C(C#N)C=C1)C=CC=C2 XQMMNNGIYWADKI-QGZVFWFLSA-N 0.000 claims 1
- OXLUBKWJHHOAGB-QGZVFWFLSA-N 4-[[2-[(3R)-3-amino-4,4-difluoropiperidin-1-yl]-4-chlorobenzimidazol-1-yl]methyl]benzonitrile Chemical compound N[C@@H]1CN(CCC1(F)F)C1=NC2=C(N1CC1=CC=C(C#N)C=C1)C=CC=C2Cl OXLUBKWJHHOAGB-QGZVFWFLSA-N 0.000 claims 1
- DGQNGUVLFJFGDP-GOSISDBHSA-N 4-[[2-[(3R)-3-amino-4,4-difluoropiperidin-1-yl]benzimidazol-1-yl]methyl]benzonitrile Chemical compound N[C@@H]1CN(CCC1(F)F)C1=NC2=C(N1CC1=CC=C(C#N)C=C1)C=CC=C2 DGQNGUVLFJFGDP-GOSISDBHSA-N 0.000 claims 1
- JNWKXKAKSNTNAB-MRXNPFEDSA-N 4-[[2-[(3R)-3-aminopiperidin-1-yl]benzimidazol-1-yl]methyl]-3-fluorobenzonitrile Chemical compound N[C@H]1CN(CCC1)C1=NC2=C(N1CC1=C(C=C(C#N)C=C1)F)C=CC=C2 JNWKXKAKSNTNAB-MRXNPFEDSA-N 0.000 claims 1
- WNJDGDDEXKLUMP-QGZVFWFLSA-N 4-[[2-[(3R)-3-aminopiperidin-1-yl]benzimidazol-1-yl]methyl]-N,N-dimethylbenzenesulfonamide Chemical compound N[C@H]1CN(CCC1)C1=NC2=C(N1CC1=CC=C(C=C1)S(=O)(=O)N(C)C)C=CC=C2 WNJDGDDEXKLUMP-QGZVFWFLSA-N 0.000 claims 1
- LOTFFLBUEDVDQE-NVXWUHKLSA-N 4-[[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-5,7-difluorobenzimidazol-1-yl]methyl]benzonitrile Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC1=CC=C(C#N)C=C1)C(=CC(=C2)F)F LOTFFLBUEDVDQE-NVXWUHKLSA-N 0.000 claims 1
- CIAZIILQTJQZTH-DLBZAZTESA-N 4-[[2-[(3R,4S)-3-amino-4-fluoropiperidin-1-yl]-4-chlorobenzimidazol-1-yl]methyl]benzonitrile Chemical compound N[C@@H]1CN(CC[C@@H]1F)C1=NC2=C(N1CC1=CC=C(C#N)C=C1)C=CC=C2Cl CIAZIILQTJQZTH-DLBZAZTESA-N 0.000 claims 1
- HBZXSMXBOACHLU-JKSUJKDBSA-N 4-[[2-[(3R,4S)-3-amino-4-fluoropiperidin-1-yl]imidazo[4,5-b]pyridin-1-yl]methyl]benzonitrile Chemical compound N[C@@H]1CN(CC[C@@H]1F)C=1N(C=2C(=NC=CC=2)N=1)CC1=CC=C(C#N)C=C1 HBZXSMXBOACHLU-JKSUJKDBSA-N 0.000 claims 1
- INPQFTHWTOJFGK-KRWDZBQOSA-N 4-[[2-[(3S)-3-aminopiperidin-1-yl]-5-chlorobenzimidazol-1-yl]methyl]benzonitrile Chemical compound N[C@@H]1CN(CCC1)C1=NC2=C(N1CC1=CC=C(C#N)C=C1)C=CC(=C2)Cl INPQFTHWTOJFGK-KRWDZBQOSA-N 0.000 claims 1
- POVMNMBXSJVBLI-UKRRQHHQSA-N 5-[[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-4,6-difluorobenzimidazol-1-yl]methyl]pyrazine-2-carbonitrile Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC=1N=CC(=NC=1)C#N)C=C(C=C2F)F POVMNMBXSJVBLI-UKRRQHHQSA-N 0.000 claims 1
- OONLKOWOFDEGGS-MJWYBRSISA-N 6-[(1R)-1-[2-[(4aS,8aS)-2,3,4,4a,5,7,8,8a-octahydropyrido[4,3-b][1,4]oxazin-6-yl]-4,6-difluorobenzimidazol-1-yl]ethyl]pyridine-3-carbonitrile Chemical compound FC1=CC(=CC=2N(C(=NC=21)N1C[C@H]2[C@@H](OCCN2)CC1)[C@H](C)C1=CC=C(C=N1)C#N)F OONLKOWOFDEGGS-MJWYBRSISA-N 0.000 claims 1
- DTPKAIMYIDJZBQ-NVXWUHKLSA-N 6-[[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-5-fluoro-6-methylbenzimidazol-1-yl]methyl]pyridine-3-carbonitrile Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC1=CC=C(C=N1)C#N)C=C(C(=C2)F)C DTPKAIMYIDJZBQ-NVXWUHKLSA-N 0.000 claims 1
- WFMUIVKBPUPSQO-HZPDHXFCSA-N 6-[[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-6-(difluoromethoxy)benzimidazol-1-yl]methyl]pyridine-3-carbonitrile Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC1=CC=C(C=N1)C#N)C=C(C=C2)OC(F)F WFMUIVKBPUPSQO-HZPDHXFCSA-N 0.000 claims 1
- ZCWPGSRPRKDOQO-IAGOWNOFSA-N 6-[[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-6-methylbenzimidazol-1-yl]methyl]pyridine-3-carbonitrile Chemical compound CC1=CC=C2N=C(N(CC3=CC=C(C=N3)C#N)C2=C1)N1CC[C@@H](F)[C@H](N)C1 ZCWPGSRPRKDOQO-IAGOWNOFSA-N 0.000 claims 1
- RUUBEEYPZRAVPD-HUUCEWRRSA-N 6-[[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]benzimidazol-1-yl]methyl]pyridine-3-carboxamide Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC1=NC=C(C(=O)N)C=C1)C=CC=C2 RUUBEEYPZRAVPD-HUUCEWRRSA-N 0.000 claims 1
- JRPLFWZIMLTJCS-FQEVSTJZSA-N 6-[[2-[(3S)-3-amino-3-methylpiperidin-1-yl]benzimidazol-1-yl]methyl]pyridine-3-carbonitrile Chemical compound N[C@@]1(CN(CCC1)C1=NC2=C(N1CC1=CC=C(C=N1)C#N)C=CC=C2)C JRPLFWZIMLTJCS-FQEVSTJZSA-N 0.000 claims 1
- CPTBYZAYRBSQRO-HNNXBMFYSA-N 6-[[2-[(3S)-3-aminopiperidin-1-yl]-6-methoxybenzimidazol-1-yl]methyl]pyridine-3-carbonitrile Chemical compound COC1=CC2=C(C=C1)N=C(N2CC3=NC=C(C=C3)C#N)N4CCC[C@@H](C4)N CPTBYZAYRBSQRO-HNNXBMFYSA-N 0.000 claims 1
- WHXJBDBOJJJKAR-AWEZNQCLSA-N 6-[[2-[(3S)-3-aminopiperidin-1-yl]benzimidazol-1-yl]methyl]pyridine-3-carboxamide Chemical compound N[C@H]1CCCN(C1)C1=NC2=CC=CC=C2N1CC1=CC=C(C=N1)C(N)=O WHXJBDBOJJJKAR-AWEZNQCLSA-N 0.000 claims 1
- PMIKFECGIMIJOI-AWEZNQCLSA-N 6-[[2-[(3S)-3-aminopiperidin-1-yl]benzimidazol-1-yl]methyl]pyridine-3-carboxylic acid Chemical compound N[C@@H]1CN(CCC1)C1=NC2=C(N1CC1=NC=C(C(=O)O)C=C1)C=CC=C2 PMIKFECGIMIJOI-AWEZNQCLSA-N 0.000 claims 1
- 125000003341 7 membered heterocyclic group Chemical group 0.000 claims 1
- BADKZHGHZYZZLW-BDQAORGHSA-N C1CN(C[C@]1(CN)O)C2=NC3=CC=CC=C3N2CC4=CC=C(C=C4)C#N.C(=O)(C(F)(F)F)O Chemical compound C1CN(C[C@]1(CN)O)C2=NC3=CC=CC=C3N2CC4=CC=C(C=C4)C#N.C(=O)(C(F)(F)F)O BADKZHGHZYZZLW-BDQAORGHSA-N 0.000 claims 1
- QQLYWBUFRODCIC-QVNYQEOOSA-N C[C@H]1CCN(C[C@H]1N)C2=NC3=CC=CC=C3N2CC4=CC=C(C=C4)C#N.C(=O)(C(F)(F)F)O Chemical compound C[C@H]1CCN(C[C@H]1N)C2=NC3=CC=CC=C3N2CC4=CC=C(C=C4)C#N.C(=O)(C(F)(F)F)O QQLYWBUFRODCIC-QVNYQEOOSA-N 0.000 claims 1
- 208000034189 Sclerosis Diseases 0.000 claims 1
- ZUSWDTWYONAOPH-UHFFFAOYSA-N [2-(trifluoromethyl)phenyl]hydrazine;hydrochloride Chemical group [Cl-].[NH3+]NC1=CC=CC=C1C(F)(F)F ZUSWDTWYONAOPH-UHFFFAOYSA-N 0.000 claims 1
- 150000004985 diamines Chemical class 0.000 claims 1
- 150000002390 heteroarenes Chemical class 0.000 claims 1
- BAVYZALUXZFZLV-UHFFFAOYSA-N mono-methylamine Natural products NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 claims 1
- 229950004889 piperamide Drugs 0.000 claims 1
- PMSVVUSIPKHUMT-KTXUZGJCSA-N pyrazine-2-carbonitrile Chemical compound N#[11C]C1=CN=CC=N1 PMSVVUSIPKHUMT-KTXUZGJCSA-N 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 87
- 230000001225 therapeutic effect Effects 0.000 abstract description 5
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 69
- 239000000203 mixture Substances 0.000 description 61
- 239000000543 intermediate Substances 0.000 description 38
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 36
- 150000001768 cations Chemical class 0.000 description 30
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 29
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 27
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 27
- 102000011753 Transient Receptor Potential Channels Human genes 0.000 description 26
- 108010037150 Transient Receptor Potential Channels Proteins 0.000 description 26
- 235000019439 ethyl acetate Nutrition 0.000 description 26
- 238000006243 chemical reaction Methods 0.000 description 25
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 24
- 239000007787 solid Substances 0.000 description 23
- 239000011541 reaction mixture Substances 0.000 description 21
- 229940124597 therapeutic agent Drugs 0.000 description 21
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 20
- 125000004432 carbon atom Chemical group C* 0.000 description 19
- 230000004952 protein activity Effects 0.000 description 19
- 208000035475 disorder Diseases 0.000 description 17
- 230000015572 biosynthetic process Effects 0.000 description 16
- 239000002904 solvent Substances 0.000 description 16
- 239000003795 chemical substances by application Substances 0.000 description 15
- 239000000243 solution Substances 0.000 description 15
- 230000008569 process Effects 0.000 description 14
- PFKFTWBEEFSNDU-UHFFFAOYSA-N 1,1'-Carbonyldiimidazole Substances C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 13
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 13
- 239000000460 chlorine Substances 0.000 description 12
- 238000010511 deprotection reaction Methods 0.000 description 12
- 229910052805 deuterium Inorganic materials 0.000 description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- 102000004169 proteins and genes Human genes 0.000 description 12
- 108090000623 proteins and genes Proteins 0.000 description 12
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical group C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 11
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 11
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 11
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 11
- 239000004480 active ingredient Substances 0.000 description 11
- 239000000047 product Substances 0.000 description 11
- 238000003786 synthesis reaction Methods 0.000 description 11
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 10
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- 229910052801 chlorine Inorganic materials 0.000 description 10
- 230000002829 reductive effect Effects 0.000 description 10
- 229910052938 sodium sulfate Inorganic materials 0.000 description 10
- 235000011152 sodium sulphate Nutrition 0.000 description 10
- 239000003153 chemical reaction reagent Substances 0.000 description 9
- 208000017169 kidney disease Diseases 0.000 description 9
- 239000000725 suspension Substances 0.000 description 9
- 239000003826 tablet Substances 0.000 description 9
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 9
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 8
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 8
- 230000029936 alkylation Effects 0.000 description 8
- 238000005804 alkylation reaction Methods 0.000 description 8
- 239000012044 organic layer Substances 0.000 description 8
- 125000006239 protecting group Chemical group 0.000 description 8
- 238000000926 separation method Methods 0.000 description 8
- 239000000377 silicon dioxide Substances 0.000 description 8
- 238000002560 therapeutic procedure Methods 0.000 description 8
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 7
- 230000002378 acidificating effect Effects 0.000 description 7
- 125000003545 alkoxy group Chemical group 0.000 description 7
- 229940079593 drug Drugs 0.000 description 7
- 238000009472 formulation Methods 0.000 description 7
- 150000002430 hydrocarbons Chemical group 0.000 description 7
- 230000002401 inhibitory effect Effects 0.000 description 7
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 7
- 239000000126 substance Substances 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N DMSO Substances CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 6
- 238000012512 characterization method Methods 0.000 description 6
- 238000004587 chromatography analysis Methods 0.000 description 6
- 125000004122 cyclic group Chemical group 0.000 description 6
- 239000003085 diluting agent Substances 0.000 description 6
- 239000012467 final product Substances 0.000 description 6
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 6
- OKKJLVBELUTLKV-VMNATFBRSA-N methanol-d1 Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 6
- 238000007339 nucleophilic aromatic substitution reaction Methods 0.000 description 6
- 230000003287 optical effect Effects 0.000 description 6
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 239000003755 preservative agent Substances 0.000 description 6
- 230000002265 prevention Effects 0.000 description 6
- 239000007858 starting material Substances 0.000 description 6
- 208000024891 symptom Diseases 0.000 description 6
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 description 5
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 5
- 150000007513 acids Chemical class 0.000 description 5
- 239000000872 buffer Substances 0.000 description 5
- 239000013058 crude material Substances 0.000 description 5
- 239000002552 dosage form Substances 0.000 description 5
- 239000012039 electrophile Substances 0.000 description 5
- 238000000338 in vitro Methods 0.000 description 5
- 238000001727 in vivo Methods 0.000 description 5
- 239000003112 inhibitor Substances 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- 239000003381 stabilizer Substances 0.000 description 5
- 238000004808 supercritical fluid chromatography Methods 0.000 description 5
- GSSPHLVFPXZVDL-CHWSQXEVSA-N (3R,4R)-1-[1-[(5-chloropyrimidin-2-yl)methyl]-6-fluorobenzimidazol-2-yl]-4-fluoropiperidin-3-amine Chemical compound ClC=1C=NC(=NC=1)CN1C(=NC2=C1C=C(C=C2)F)N1C[C@H]([C@@H](CC1)F)N GSSPHLVFPXZVDL-CHWSQXEVSA-N 0.000 description 4
- AYPSHJCKSDNETA-UHFFFAOYSA-N 2-chloro-1h-benzimidazole Chemical compound C1=CC=C2NC(Cl)=NC2=C1 AYPSHJCKSDNETA-UHFFFAOYSA-N 0.000 description 4
- JUYQSMXGDBGGSX-UHFFFAOYSA-N 2-piperidin-1-yl-1h-benzimidazole Chemical class C1CCCCN1C1=NC2=CC=CC=C2N1 JUYQSMXGDBGGSX-UHFFFAOYSA-N 0.000 description 4
- LEMFPQBSCTVLPK-UHFFFAOYSA-N 4-[(2,6-dichlorobenzimidazol-1-yl)methyl]benzonitrile Chemical compound ClC1=NC2=C(N1CC1=CC=C(C#N)C=C1)C=C(C=C2)Cl LEMFPQBSCTVLPK-UHFFFAOYSA-N 0.000 description 4
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 4
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 4
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 4
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 4
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 description 4
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 4
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical group C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 4
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 4
- 150000001408 amides Chemical class 0.000 description 4
- 235000019270 ammonium chloride Nutrition 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 4
- 229910052794 bromium Inorganic materials 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 4
- 238000002648 combination therapy Methods 0.000 description 4
- 229910052802 copper Inorganic materials 0.000 description 4
- 239000010949 copper Substances 0.000 description 4
- 206010061989 glomerulosclerosis Diseases 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- 239000000314 lubricant Substances 0.000 description 4
- KXKVLQRXCPHEJC-UHFFFAOYSA-N methyl acetate Chemical compound COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 4
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 4
- 239000001301 oxygen Substances 0.000 description 4
- FDPIMTJIUBPUKL-UHFFFAOYSA-N pentan-3-one Chemical compound CCC(=O)CC FDPIMTJIUBPUKL-UHFFFAOYSA-N 0.000 description 4
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 description 4
- 238000012545 processing Methods 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 4
- 238000004007 reversed phase HPLC Methods 0.000 description 4
- 239000012453 solvate Substances 0.000 description 4
- 239000011975 tartaric acid Substances 0.000 description 4
- 235000002906 tartaric acid Nutrition 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 4
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 description 3
- ZFKGKJRKAKRVRL-UONOGXRCSA-N 2-[(3R,4S)-3-amino-4-fluoropiperidin-1-yl]-1-[(5-chloropyrimidin-2-yl)methyl]-6-fluorobenzimidazole-4-carbonitrile Chemical compound N[C@@H]1CN(CC[C@@H]1F)C1=NC2=C(C=C(F)C=C2N1CC1=NC=C(Cl)C=N1)C#N ZFKGKJRKAKRVRL-UONOGXRCSA-N 0.000 description 3
- WDWQXEUJKGYNPZ-UHFFFAOYSA-N 2-chloro-3h-benzimidazole-5-carbonitrile Chemical compound N#CC1=CC=C2NC(Cl)=NC2=C1 WDWQXEUJKGYNPZ-UHFFFAOYSA-N 0.000 description 3
- IJIPANRQAMAEJR-UHFFFAOYSA-N 2-chloro-4,6-difluoro-1H-benzimidazole Chemical compound Fc1cc(F)c2nc(Cl)[nH]c2c1 IJIPANRQAMAEJR-UHFFFAOYSA-N 0.000 description 3
- WYUDQMPZFGJEFY-UHFFFAOYSA-N 4,6-difluoro-1,3-dihydrobenzimidazol-2-one Chemical compound FC1=CC(F)=C2NC(O)=NC2=C1 WYUDQMPZFGJEFY-UHFFFAOYSA-N 0.000 description 3
- SKVXWYQDTGKVHB-UHFFFAOYSA-N 4-[(5-chloro-2-nitroanilino)methyl]benzonitrile Chemical compound [O-][N+](=O)C1=CC=C(Cl)C=C1NCC1=CC=C(C#N)C=C1 SKVXWYQDTGKVHB-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 3
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 3
- 108091006146 Channels Proteins 0.000 description 3
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 3
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 description 3
- DMBHHRLKUKUOEG-UHFFFAOYSA-N N-phenyl aniline Natural products C=1C=CC=CC=1NC1=CC=CC=C1 DMBHHRLKUKUOEG-UHFFFAOYSA-N 0.000 description 3
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- AJYVOJRSNUSBPH-RFZPGFLSSA-N [(3R,4R)-4-fluoropiperidin-3-yl]carbamic acid Chemical compound OC(=O)N[C@@H]1CNCC[C@H]1F AJYVOJRSNUSBPH-RFZPGFLSSA-N 0.000 description 3
- 239000000443 aerosol Substances 0.000 description 3
- 125000002947 alkylene group Chemical group 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- CBHOOMGKXCMKIR-UHFFFAOYSA-N azane;methanol Chemical compound N.OC CBHOOMGKXCMKIR-UHFFFAOYSA-N 0.000 description 3
- 229940092714 benzenesulfonic acid Drugs 0.000 description 3
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 3
- 239000011230 binding agent Substances 0.000 description 3
- 239000012267 brine Substances 0.000 description 3
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 3
- 229910000024 caesium carbonate Inorganic materials 0.000 description 3
- 239000001506 calcium phosphate Substances 0.000 description 3
- 229910000389 calcium phosphate Inorganic materials 0.000 description 3
- 235000011010 calcium phosphates Nutrition 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 238000006555 catalytic reaction Methods 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 230000008878 coupling Effects 0.000 description 3
- 238000010168 coupling process Methods 0.000 description 3
- 238000005859 coupling reaction Methods 0.000 description 3
- 125000000000 cycloalkoxy group Chemical group 0.000 description 3
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 description 3
- 238000010828 elution Methods 0.000 description 3
- 239000000839 emulsion Substances 0.000 description 3
- 238000003821 enantio-separation Methods 0.000 description 3
- 235000003599 food sweetener Nutrition 0.000 description 3
- 238000001640 fractional crystallisation Methods 0.000 description 3
- 239000012458 free base Substances 0.000 description 3
- 239000000499 gel Substances 0.000 description 3
- 239000007903 gelatin capsule Substances 0.000 description 3
- 125000001188 haloalkyl group Chemical group 0.000 description 3
- 238000011065 in-situ storage Methods 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 230000000670 limiting effect Effects 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- XBXCNNQPRYLIDE-UHFFFAOYSA-M n-tert-butylcarbamate Chemical compound CC(C)(C)NC([O-])=O XBXCNNQPRYLIDE-UHFFFAOYSA-M 0.000 description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 3
- 239000012038 nucleophile Substances 0.000 description 3
- 125000004483 piperidin-3-yl group Chemical group N1CC(CCC1)* 0.000 description 3
- 125000006684 polyhaloalkyl group Polymers 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- 150000003141 primary amines Chemical class 0.000 description 3
- 108090000765 processed proteins & peptides Proteins 0.000 description 3
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 150000003335 secondary amines Chemical class 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- 239000008107 starch Substances 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 239000003765 sweetening agent Substances 0.000 description 3
- 208000011580 syndromic disease Diseases 0.000 description 3
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 3
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 2
- YASVVIWQWMXEKN-XFULWGLBSA-N (3R)-1-[1-[(5-chloropyridin-2-yl)methyl]-4,6-difluorobenzimidazol-2-yl]-4,4-difluoropiperidin-3-amine hydrochloride Chemical compound C1CN(C[C@H](C1(F)F)N)C2=NC3=C(N2CC4=NC=C(C=C4)Cl)C=C(C=C3F)F.Cl YASVVIWQWMXEKN-XFULWGLBSA-N 0.000 description 2
- IXTSCGOTBGOTQM-CHWSQXEVSA-N (3R,4R)-1-[1-[(5-chloropyrimidin-2-yl)methyl]-5-fluorobenzimidazol-2-yl]-4-fluoropiperidin-3-amine Chemical compound ClC=1C=NC(=NC=1)CN1C(=NC2=C1C=CC(=C2)F)N1C[C@H]([C@@H](CC1)F)N IXTSCGOTBGOTQM-CHWSQXEVSA-N 0.000 description 2
- VPBWULUCLOETQL-CZUORRHYSA-N (3R,4R)-1-[1-[(5-chloropyrimidin-2-yl)methyl]-6-fluorobenzimidazol-2-yl]-4-methoxypiperidin-3-amine Chemical compound ClC=1C=NC(=NC=1)CN1C(=NC2=C1C=C(C=C2)F)N1C[C@H]([C@@H](CC1)OC)N VPBWULUCLOETQL-CZUORRHYSA-N 0.000 description 2
- ZIYJYOBFMRHEAJ-QWHCGFSZSA-N (3R,4S)-4-fluoro-1-[1-[(5-fluoropyrimidin-2-yl)methyl]-6-(trifluoromethyl)benzimidazol-2-yl]piperidin-3-amine Chemical compound F[C@@H]1[C@@H](CN(CC1)C1=NC2=C(N1CC1=NC=C(C=N1)F)C=C(C=C2)C(F)(F)F)N ZIYJYOBFMRHEAJ-QWHCGFSZSA-N 0.000 description 2
- REQICLYJHYBXRP-UHFFFAOYSA-N (5-cyanopyridin-2-yl)methyl methanesulfonate Chemical compound CS(=O)(=O)OCC1=NC=C(C=C1)C#N REQICLYJHYBXRP-UHFFFAOYSA-N 0.000 description 2
- WQADWIOXOXRPLN-UHFFFAOYSA-N 1,3-dithiane Chemical group C1CSCSC1 WQADWIOXOXRPLN-UHFFFAOYSA-N 0.000 description 2
- LOZWAPSEEHRYPG-UHFFFAOYSA-N 1,4-dithiane Chemical group C1CSCCS1 LOZWAPSEEHRYPG-UHFFFAOYSA-N 0.000 description 2
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- 125000003562 2,2-dimethylpentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 125000003660 2,3-dimethylpentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(C([H])([H])[H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- CIBPZVRHWWWFND-CQSZACIVSA-N 2-[(3R)-3-amino-4,4-difluoropiperidin-1-yl]-1-[(5-chloropyrimidin-2-yl)methyl]-6-fluorobenzimidazole-4-carbonitrile Chemical compound N[C@@H]1CN(CCC1(F)F)C1=NC2=C(N1CC1=NC=C(C=N1)Cl)C=C(C=C2C#N)F CIBPZVRHWWWFND-CQSZACIVSA-N 0.000 description 2
- VCFFPIVYDBYASV-IAGOWNOFSA-N 2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-1-[(5-cyanopyridin-2-yl)methyl]benzimidazole-4-carbonitrile Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC1=NC=C(C=C1)C#N)C=CC=C2C#N VCFFPIVYDBYASV-IAGOWNOFSA-N 0.000 description 2
- KRWVJLAPDPURAF-VXGBXAGGSA-N 2-[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-5-fluoro-7-methoxybenzimidazol-1-yl]-N-methyl-N-(2,2,2-trifluoroethyl)acetamide Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC(=O)N(CC(F)(F)F)C)C(=CC(=C2)F)OC KRWVJLAPDPURAF-VXGBXAGGSA-N 0.000 description 2
- ALGMPRHTQBDSHB-VXGBXAGGSA-N 2-[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-6-fluorobenzimidazol-1-yl]-N-methyl-N-(2,2,2-trifluoroethyl)acetamide Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC(=O)N(CC(F)(F)F)C)C=C(C=C2)F ALGMPRHTQBDSHB-VXGBXAGGSA-N 0.000 description 2
- ALGMPRHTQBDSHB-NWDGAFQWSA-N 2-[2-[(3R,4S)-3-amino-4-fluoropiperidin-1-yl]-6-fluorobenzimidazol-1-yl]-N-methyl-N-(2,2,2-trifluoroethyl)acetamide Chemical compound N[C@@H]1CN(CC[C@@H]1F)C1=NC2=C(N1CC(=O)N(CC(F)(F)F)C)C=C(C=C2)F ALGMPRHTQBDSHB-NWDGAFQWSA-N 0.000 description 2
- ZUIFTMGBOXAFKK-GDBMZVCRSA-N 2-[2-[(4aR,8aR)-2,3,4,4a,5,7,8,8a-octahydropyrido[4,3-b][1,4]oxazin-6-yl]-6-fluorobenzimidazol-1-yl]-N-methyl-N-(2,2,2-trifluoroethyl)acetamide Chemical compound FC=1C=CC2=C(N(C(=N2)N2C[C@@H]3[C@H](OCCN3)CC2)CC(=O)N(CC(F)(F)F)C)C=1 ZUIFTMGBOXAFKK-GDBMZVCRSA-N 0.000 description 2
- AEHZZCZERRIRID-QMTHXVAHSA-N 2-[5,6-difluoro-2-[(3R,4R)-4-fluoro-3-[(2-methylpropan-2-yl)oxycarbonylamino]piperidin-1-yl]benzimidazol-1-yl]acetic acid Chemical compound C(C)(C)(C)OC(=O)N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC(=O)O)C=C(C(=C2)F)F AEHZZCZERRIRID-QMTHXVAHSA-N 0.000 description 2
- IZHVBANLECCAGF-UHFFFAOYSA-N 2-hydroxy-3-(octadecanoyloxy)propyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)COC(=O)CCCCCCCCCCCCCCCCC IZHVBANLECCAGF-UHFFFAOYSA-N 0.000 description 2
- BTOVVHWKPVSLBI-UHFFFAOYSA-N 2-methylprop-1-enylbenzene Chemical compound CC(C)=CC1=CC=CC=C1 BTOVVHWKPVSLBI-UHFFFAOYSA-N 0.000 description 2
- MQKNLRFUHOJEGN-UHFFFAOYSA-N 3-[14-hydroxy-3-[4-hydroxy-5-[5-[3-hydroxy-5-(5-hydroxy-4-methoxy-6-methyloxan-2-yl)oxy-4-methoxy-6-methyloxan-2-yl]oxy-4-methoxy-6-methyloxan-2-yl]oxy-6-methyloxan-2-yl]oxy-10,13-dimethyl-1,2,3,4,5,6,7,8,9,11,12,15,16,17-tetradecahydrocyclopenta[a]phenan Chemical compound O1C(C)C(O)C(OC)CC1OC1C(OC)C(O)C(OC2C(CC(OC2C)OC2C(OC(OC3CC4C(C5C(C6(CCC(C6(C)CC5)C=5COC(=O)C=5)O)CC4)(C)CC3)CC2O)C)OC)OC1C MQKNLRFUHOJEGN-UHFFFAOYSA-N 0.000 description 2
- 125000003469 3-methylhexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 2
- UULSTYULZLVBES-UHFFFAOYSA-N 4-[(2-amino-5-chloroanilino)methyl]benzonitrile Chemical compound Nc1ccc(Cl)cc1NCc1ccc(cc1)C#N UULSTYULZLVBES-UHFFFAOYSA-N 0.000 description 2
- WBBMIDLXNGSMSU-NVXWUHKLSA-N 4-[[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-4,6-difluorobenzimidazol-1-yl]methyl]benzonitrile Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC1=CC=C(C#N)C=C1)C=C(C=C2F)F WBBMIDLXNGSMSU-NVXWUHKLSA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- 239000005995 Aluminium silicate Substances 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- 241000282472 Canis lupus familiaris Species 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical group C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 2
- 239000007832 Na2SO4 Substances 0.000 description 2
- 244000061176 Nicotiana tabacum Species 0.000 description 2
- 229910019213 POCl3 Inorganic materials 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- 241000288906 Primates Species 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 235000021355 Stearic acid Nutrition 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 2
- 235000010443 alginic acid Nutrition 0.000 description 2
- 239000000783 alginic acid Substances 0.000 description 2
- 229920000615 alginic acid Polymers 0.000 description 2
- 229960001126 alginic acid Drugs 0.000 description 2
- 150000004781 alginic acids Chemical class 0.000 description 2
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 2
- 125000003282 alkyl amino group Chemical group 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 235000012211 aluminium silicate Nutrition 0.000 description 2
- 238000005576 amination reaction Methods 0.000 description 2
- 229940024606 amino acid Drugs 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 235000006708 antioxidants Nutrition 0.000 description 2
- 235000010323 ascorbic acid Nutrition 0.000 description 2
- 239000011668 ascorbic acid Substances 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical class [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 2
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 2
- 150000008641 benzimidazolones Chemical class 0.000 description 2
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 2
- 230000031018 biological processes and functions Effects 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 description 2
- 235000010216 calcium carbonate Nutrition 0.000 description 2
- KXDHJXZQYSOELW-UHFFFAOYSA-N carbonic acid monoamide Natural products NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 description 2
- 238000005660 chlorination reaction Methods 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 239000003086 colorant Substances 0.000 description 2
- IDLFZVILOHSSID-OVLDLUHVSA-N corticotropin Chemical class C([C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)NC(=O)[C@@H](N)CO)C1=CC=C(O)C=C1 IDLFZVILOHSSID-OVLDLUHVSA-N 0.000 description 2
- 239000007822 coupling agent Substances 0.000 description 2
- 239000006071 cream Substances 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 125000004663 dialkyl amino group Chemical group 0.000 description 2
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 2
- 125000004982 dihaloalkyl group Chemical group 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 238000009826 distribution Methods 0.000 description 2
- 239000003995 emulsifying agent Substances 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 239000011888 foil Substances 0.000 description 2
- 235000013355 food flavoring agent Nutrition 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 230000001434 glomerular Effects 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 229940093915 gynecological organic acid Drugs 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 150000003840 hydrochlorides Chemical class 0.000 description 2
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 2
- 239000003701 inert diluent Substances 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- 238000003402 intramolecular cyclocondensation reaction Methods 0.000 description 2
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical group II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 2
- 239000011630 iodine Chemical group 0.000 description 2
- 229910052740 iodine Chemical group 0.000 description 2
- 238000004255 ion exchange chromatography Methods 0.000 description 2
- 229910052742 iron Inorganic materials 0.000 description 2
- QWTDNUCVQCZILF-UHFFFAOYSA-N isopentane Chemical compound CCC(C)C QWTDNUCVQCZILF-UHFFFAOYSA-N 0.000 description 2
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 2
- 230000000155 isotopic effect Effects 0.000 description 2
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 2
- 239000007937 lozenge Substances 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 2
- 229960002510 mandelic acid Drugs 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 230000002503 metabolic effect Effects 0.000 description 2
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 2
- UAEPNZWRGJTJPN-UHFFFAOYSA-N methylcyclohexane Chemical compound CC1CCCCC1 UAEPNZWRGJTJPN-UHFFFAOYSA-N 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 2
- 125000006682 monohaloalkyl group Chemical group 0.000 description 2
- 150000002772 monosaccharides Chemical class 0.000 description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 2
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 125000001624 naphthyl group Chemical group 0.000 description 2
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 235000005152 nicotinamide Nutrition 0.000 description 2
- 239000011570 nicotinamide Substances 0.000 description 2
- 229960003966 nicotinamide Drugs 0.000 description 2
- 235000001968 nicotinic acid Nutrition 0.000 description 2
- 239000011664 nicotinic acid Substances 0.000 description 2
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 235000019198 oils Nutrition 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 235000005985 organic acids Nutrition 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 238000004806 packaging method and process Methods 0.000 description 2
- 230000001575 pathological effect Effects 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- 238000002600 positron emission tomography Methods 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 102000004196 processed proteins & peptides Human genes 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 229960004641 rituximab Drugs 0.000 description 2
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 238000002603 single-photon emission computed tomography Methods 0.000 description 2
- 238000000638 solvent extraction Methods 0.000 description 2
- 239000011877 solvent mixture Substances 0.000 description 2
- 239000007921 spray Substances 0.000 description 2
- 230000000087 stabilizing effect Effects 0.000 description 2
- 239000008117 stearic acid Substances 0.000 description 2
- 229940124530 sulfonamide Drugs 0.000 description 2
- 150000003456 sulfonamides Chemical class 0.000 description 2
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 2
- 150000003573 thiols Chemical class 0.000 description 2
- KJAMZCVTJDTESW-UHFFFAOYSA-N tiracizine Chemical compound C1CC2=CC=CC=C2N(C(=O)CN(C)C)C2=CC(NC(=O)OCC)=CC=C21 KJAMZCVTJDTESW-UHFFFAOYSA-N 0.000 description 2
- 238000011200 topical administration Methods 0.000 description 2
- 230000000699 topical effect Effects 0.000 description 2
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 2
- 239000000080 wetting agent Substances 0.000 description 2
- 239000011701 zinc Substances 0.000 description 2
- 229910052725 zinc Inorganic materials 0.000 description 2
- DTGKSKDOIYIVQL-WEDXCCLWSA-N (+)-borneol Chemical group C1C[C@@]2(C)[C@@H](O)C[C@@H]1C2(C)C DTGKSKDOIYIVQL-WEDXCCLWSA-N 0.000 description 1
- XGLWNSWZQQPVJN-MRXNPFEDSA-N (3R)-1-[1-[(3-chlorophenyl)methyl]benzimidazol-2-yl]piperidin-3-amine Chemical compound ClC=1C=C(CN2C(=NC3=C2C=CC=C3)N2C[C@@H](CCC2)N)C=CC=1 XGLWNSWZQQPVJN-MRXNPFEDSA-N 0.000 description 1
- CTQHWLVSBDKHTQ-GAJTVXKRSA-N (3R)-3-[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-5,6-difluorobenzimidazol-1-yl]-1-methylpyrrolidin-2-one Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1[C@H]1C(N(CC1)C)=O)C=C(C(=C2)F)F CTQHWLVSBDKHTQ-GAJTVXKRSA-N 0.000 description 1
- IXCOHLZPGJJTLU-CYBMUJFWSA-N (3R)-4,4-difluoro-1-[5-fluoro-1-[(5-methyl-1,3,4-thiadiazol-2-yl)methyl]benzimidazol-2-yl]piperidin-3-amine Chemical compound FC1([C@@H](CN(CC1)C1=NC2=C(N1CC=1SC(=NN=1)C)C=CC(=C2)F)N)F IXCOHLZPGJJTLU-CYBMUJFWSA-N 0.000 description 1
- VSZKRDDRUBPJIV-CYBMUJFWSA-N (3R)-4,4-difluoro-1-[6-fluoro-1-[(5-methyl-1,3,4-thiadiazol-2-yl)methyl]benzimidazol-2-yl]piperidin-3-amine Chemical compound FC1([C@@H](CN(CC1)C1=NC2=C(N1CC=1SC(=NN=1)C)C=C(C=C2)F)N)F VSZKRDDRUBPJIV-CYBMUJFWSA-N 0.000 description 1
- SVPGYBYBAFOQTQ-LGFNAOKASA-N (3R,4R)-1-[1-[(1R)-1-(2,4-dichlorophenyl)ethyl]-5,6-difluorobenzimidazol-2-yl]-4-fluoropiperidin-3-amine Chemical compound ClC1=C(C=CC(=C1)Cl)[C@@H](C)N1C(=NC2=C1C=C(C(=C2)F)F)N1C[C@H]([C@@H](CC1)F)N SVPGYBYBAFOQTQ-LGFNAOKASA-N 0.000 description 1
- LVOYZMRVXVUNAX-GLXFQSAKSA-N (3R,4R)-1-[1-[(1R)-1-(5-chloropyrimidin-2-yl)ethyl]-5,6-difluorobenzimidazol-2-yl]-4-fluoropiperidin-3-amine Chemical compound ClC=1C=NC(=NC=1)[C@@H](C)N1C(=NC2=C1C=C(C(=C2)F)F)N1C[C@H]([C@@H](CC1)F)N LVOYZMRVXVUNAX-GLXFQSAKSA-N 0.000 description 1
- RWKAPXAIYLBZKD-MNRXQERYSA-N (3R,4R)-1-[1-[(1S)-1-(2,4-difluorophenyl)ethyl]-5,6-difluorobenzimidazol-2-yl]-4-fluoropiperidin-3-amine Chemical compound FC1=C(C=CC(=C1)F)[C@H](C)N1C(=NC2=C1C=C(C(=C2)F)F)N1C[C@H]([C@@H](CC1)F)N RWKAPXAIYLBZKD-MNRXQERYSA-N 0.000 description 1
- LGKLNVYNZDRILE-SQFLUBDYSA-N (3R,4R)-1-[1-[(1S)-1-(5-chloropyridin-2-yl)ethyl]benzimidazol-2-yl]-4-fluoropiperidin-3-amine hydrochloride Chemical compound C[C@@H](C1=NC=C(C=C1)Cl)N2C3=CC=CC=C3N=C2N4CC[C@H]([C@@H](C4)N)F.Cl LGKLNVYNZDRILE-SQFLUBDYSA-N 0.000 description 1
- JVSIDIAYJZKVGF-ZIAGYGMSSA-N (3R,4R)-1-[1-[(2,4-dimethyl-1,3-thiazol-5-yl)methyl]-6-fluorobenzimidazol-2-yl]-4-fluoropiperidin-3-amine Chemical compound CC=1SC(=C(N=1)C)CN1C(=NC2=C1C=C(C=C2)F)N1C[C@H]([C@@H](CC1)F)N JVSIDIAYJZKVGF-ZIAGYGMSSA-N 0.000 description 1
- ACLBLBYUGUPJDD-CZUORRHYSA-N (3R,4R)-1-[1-[(2,5-dichlorophenyl)methyl]-5,6-difluorobenzimidazol-2-yl]-4-fluoropiperidin-3-amine Chemical compound N[C@@H]1CN(CC[C@H]1F)c1nc2cc(F)c(F)cc2n1Cc1cc(Cl)ccc1Cl ACLBLBYUGUPJDD-CZUORRHYSA-N 0.000 description 1
- MLKZJGHAUXIXDZ-BXUZGUMPSA-N (3R,4R)-1-[1-[(4,5-dimethyl-1,3-oxazol-2-yl)methyl]-5,6-difluorobenzimidazol-2-yl]-4-fluoropiperidin-3-amine Chemical compound CC=1N=C(OC=1C)CN1C(=NC2=C1C=C(C(=C2)F)F)N1C[C@H]([C@@H](CC1)F)N MLKZJGHAUXIXDZ-BXUZGUMPSA-N 0.000 description 1
- FOEFEANXNAINHN-XRZFDKQNSA-N (3R,4R)-1-[1-[(5-chloropyridin-2-yl)methyl]-5,6-difluorobenzimidazol-2-yl]-4-fluoropiperidin-3-amine hydrochloride Chemical compound C1CN(C[C@H]([C@@H]1F)N)C2=NC3=CC(=C(C=C3N2CC4=NC=C(C=C4)Cl)F)F.Cl FOEFEANXNAINHN-XRZFDKQNSA-N 0.000 description 1
- DZOYGNLXTSJDEX-HZPDHXFCSA-N (3R,4R)-1-[1-[(5-chloropyridin-2-yl)methyl]-5-methylsulfonylbenzimidazol-2-yl]-4-fluoropiperidin-3-amine Chemical compound ClC=1C=CC(=NC=1)CN1C(=NC2=C1C=CC(=C2)S(=O)(=O)C)N1C[C@H]([C@@H](CC1)F)N DZOYGNLXTSJDEX-HZPDHXFCSA-N 0.000 description 1
- KTEFPSNCGKMUKH-CTHHTMFSSA-N (3R,4R)-1-[1-[(5-chloropyridin-2-yl)methyl]benzimidazol-2-yl]-4-fluoropiperidin-3-amine hydrochloride Chemical compound C1CN(C[C@H]([C@@H]1F)N)C2=NC3=CC=CC=C3N2CC4=NC=C(C=C4)Cl.Cl KTEFPSNCGKMUKH-CTHHTMFSSA-N 0.000 description 1
- VGKDOPHHDJDJHL-DGCLKSJQSA-N (3R,4R)-1-[1-[(5-chloropyrimidin-2-yl)methyl]-5,7-difluorobenzimidazol-2-yl]-4-fluoropiperidin-3-amine Chemical compound ClC=1C=NC(=NC=1)CN1C(=NC2=C1C(=CC(=C2)F)F)N1C[C@H]([C@@H](CC1)F)N VGKDOPHHDJDJHL-DGCLKSJQSA-N 0.000 description 1
- XVXAEWVJCULBGD-VXGBXAGGSA-N (3R,4R)-1-[1-[(5-chloropyrimidin-2-yl)methyl]-6-fluoroimidazo[4,5-b]pyridin-2-yl]-4-fluoropiperidin-3-amine Chemical compound ClC=1C=NC(=NC=1)CN1C(=NC2=NC=C(C=C21)F)N1C[C@H]([C@@H](CC1)F)N XVXAEWVJCULBGD-VXGBXAGGSA-N 0.000 description 1
- BMQOZVQDBIZLBA-CHWSQXEVSA-N (3R,4R)-1-[1-[(5-chloropyrimidin-2-yl)methyl]benzimidazol-2-yl]-4-fluoropiperidin-3-amine Chemical compound ClC=1C=NC(=NC=1)CN1C(=NC2=C1C=CC=C2)N1C[C@H]([C@@H](CC1)F)N BMQOZVQDBIZLBA-CHWSQXEVSA-N 0.000 description 1
- UMBVAXZRVXFNFN-ZWNOBZJWSA-N (3R,4R)-1-[1-[(5-cyclopropyl-1,2,4-oxadiazol-3-yl)methyl]-5,6-difluorobenzimidazol-2-yl]-4-fluoropiperidin-3-amine Chemical compound N[C@@H]1CN(CC[C@H]1F)c1nc2cc(F)c(F)cc2n1Cc1noc(n1)C1CC1 UMBVAXZRVXFNFN-ZWNOBZJWSA-N 0.000 description 1
- MPFNLJVHIYCLHL-ZWNOBZJWSA-N (3R,4R)-1-[1-[(5-cyclopropyl-1,3,4-oxadiazol-2-yl)methyl]-5,6-difluorobenzimidazol-2-yl]-4-fluoropiperidin-3-amine Chemical compound C1(CC1)C1=NN=C(O1)CN1C(=NC2=C1C=C(C(=C2)F)F)N1C[C@H]([C@@H](CC1)F)N MPFNLJVHIYCLHL-ZWNOBZJWSA-N 0.000 description 1
- CGNCMFOMEBFWLZ-BXKDBHETSA-N (3R,4R)-1-[1-[(5-ethyl-1,2,4-oxadiazol-3-yl)methyl]-5,6-difluorobenzimidazol-2-yl]-4-fluoropiperidin-3-amine Chemical compound C(C)C1=NC(=NO1)CN1C(=NC2=C1C=C(C(=C2)F)F)N1C[C@H]([C@@H](CC1)F)N CGNCMFOMEBFWLZ-BXKDBHETSA-N 0.000 description 1
- OLUCKDOQLMADBV-CRAIPNDOSA-N (3R,4R)-1-[1-[[3-(3-chlorophenyl)-1,2-oxazol-5-yl]methyl]-5,6-difluorobenzimidazol-2-yl]-4-fluoropiperidin-3-amine Chemical compound ClC=1C=C(C=CC=1)C1=NOC(=C1)CN1C(=NC2=C1C=C(C(=C2)F)F)N1C[C@H]([C@@H](CC1)F)N OLUCKDOQLMADBV-CRAIPNDOSA-N 0.000 description 1
- CJCWHBSQRBQSLO-RHSMWYFYSA-N (3R,4R)-1-[1-[[4-(1,1-difluoroethyl)phenyl]methyl]-5,6-difluorobenzimidazol-2-yl]-4-fluoropiperidin-3-amine Chemical compound FC(C)(F)C1=CC=C(CN2C(=NC3=C2C=C(C(=C3)F)F)N2C[C@H]([C@@H](CC2)F)N)C=C1 CJCWHBSQRBQSLO-RHSMWYFYSA-N 0.000 description 1
- OUEQZKLJNUPKST-PSASIEDQSA-N (3R,4R)-1-[1-[[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]methyl]-5,7-difluorobenzimidazol-2-yl]-4-fluoropiperidin-3-amine Chemical compound FC(C1=NN=C(S1)CN1C(=NC2=C1C(=CC(=C2)F)F)N1C[C@H]([C@@H](CC1)F)N)F OUEQZKLJNUPKST-PSASIEDQSA-N 0.000 description 1
- ILSOJJZIQGJAAD-NXEZZACHSA-N (3R,4R)-1-[1-[[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]methyl]-5-fluorobenzimidazol-2-yl]-4-fluoropiperidin-3-amine Chemical compound FC(C1=NN=C(S1)CN1C(=NC2=C1C=CC(=C2)F)N1C[C@H]([C@@H](CC1)F)N)F ILSOJJZIQGJAAD-NXEZZACHSA-N 0.000 description 1
- ZJFGKKZUPMEVQT-NXEZZACHSA-N (3R,4R)-1-[1-[[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]methyl]-6-fluorobenzimidazol-2-yl]-4-fluoropiperidin-3-amine Chemical compound FC(C1=NN=C(S1)CN1C(=NC2=C1C=C(C=C2)F)N1C[C@H]([C@@H](CC1)F)N)F ZJFGKKZUPMEVQT-NXEZZACHSA-N 0.000 description 1
- WEQGZXYMZDKWLY-ZYHUDNBSSA-N (3R,4R)-1-[4,6-difluoro-1-[(5-methyl-1,3,4-thiadiazol-2-yl)methyl]benzimidazol-2-yl]-4-fluoropiperidin-3-amine Chemical compound FC1=CC(=CC=2N(C(=NC=21)N1C[C@H]([C@@H](CC1)F)N)CC=1SC(=NN=1)C)F WEQGZXYMZDKWLY-ZYHUDNBSSA-N 0.000 description 1
- GERZAVNQRGLBCB-BXUZGUMPSA-N (3R,4R)-1-[5,6-difluoro-1-[(3-methyl-1,2-oxazol-5-yl)methyl]benzimidazol-2-yl]-4-fluoropiperidin-3-amine Chemical compound FC1=CC2=C(N(C(=N2)N2C[C@H]([C@@H](CC2)F)N)CC2=CC(=NO2)C)C=C1F GERZAVNQRGLBCB-BXUZGUMPSA-N 0.000 description 1
- BCANYFFZTNHECD-ZWNOBZJWSA-N (3R,4R)-1-[5,6-difluoro-1-[(4-methyl-1,3-thiazol-2-yl)methyl]benzimidazol-2-yl]-4-fluoropiperidin-3-amine Chemical compound FC1=CC2=C(N(C(=N2)N2C[C@H]([C@@H](CC2)F)N)CC=2SC=C(N=2)C)C=C1F BCANYFFZTNHECD-ZWNOBZJWSA-N 0.000 description 1
- VGAKVJACHDIFAV-XRZFDKQNSA-N (3R,4R)-1-[5,6-difluoro-1-[(5-fluoropyridin-2-yl)methyl]benzimidazol-2-yl]-4-fluoropiperidin-3-amine hydrochloride Chemical compound C1CN(C[C@H]([C@@H]1F)N)C2=NC3=CC(=C(C=C3N2CC4=NC=C(C=C4)F)F)F.Cl VGAKVJACHDIFAV-XRZFDKQNSA-N 0.000 description 1
- WSFALFIJVGGHLH-BXKDBHETSA-N (3R,4R)-1-[5,6-difluoro-1-[(5-methyl-1,2,4-oxadiazol-3-yl)methyl]benzimidazol-2-yl]-4-fluoropiperidin-3-amine Chemical compound FC1=CC2=C(N(C(=N2)N2C[C@H]([C@@H](CC2)F)N)CC2=NOC(=N2)C)C=C1F WSFALFIJVGGHLH-BXKDBHETSA-N 0.000 description 1
- WBDDDCHFCZAHSS-BXKDBHETSA-N (3R,4R)-1-[5,6-difluoro-1-[(5-methyl-1,3,4-oxadiazol-2-yl)methyl]benzimidazol-2-yl]-4-fluoropiperidin-3-amine Chemical compound FC1=CC2=C(N(C(=N2)N2C[C@H]([C@@H](CC2)F)N)CC=2OC(=NN=2)C)C=C1F WBDDDCHFCZAHSS-BXKDBHETSA-N 0.000 description 1
- JZCHIBHPBIRGGT-BXKDBHETSA-N (3R,4R)-1-[5,6-difluoro-1-[(5-methyl-1,3,4-thiadiazol-2-yl)methyl]benzimidazol-2-yl]-4-fluoropiperidin-3-amine Chemical compound FC1=CC2=C(N(C(=N2)N2C[C@H]([C@@H](CC2)F)N)CC=2SC(=NN=2)C)C=C1F JZCHIBHPBIRGGT-BXKDBHETSA-N 0.000 description 1
- ZTXVUQLXTRVTJL-ZWNOBZJWSA-N (3R,4R)-1-[5,6-difluoro-1-[(5-methyl-1,3-oxazol-2-yl)methyl]benzimidazol-2-yl]-4-fluoropiperidin-3-amine Chemical compound FC1=CC2=C(N(C(=N2)N2C[C@H]([C@@H](CC2)F)N)CC=2OC(=CN=2)C)C=C1F ZTXVUQLXTRVTJL-ZWNOBZJWSA-N 0.000 description 1
- XCBYATHPDATRSO-CZUORRHYSA-N (3R,4R)-1-[5,6-difluoro-1-[(5-methylsulfonylpyridin-2-yl)methyl]benzimidazol-2-yl]-4-fluoropiperidin-3-amine Chemical compound FC1=CC2=C(N(C(=N2)N2C[C@H]([C@@H](CC2)F)N)CC2=NC=C(C=C2)S(=O)(=O)C)C=C1F XCBYATHPDATRSO-CZUORRHYSA-N 0.000 description 1
- OMUAWFUGPJFUAS-CZUORRHYSA-N (3R,4R)-1-[5,6-difluoro-1-[[3-(trifluoromethoxy)phenyl]methyl]benzimidazol-2-yl]-4-fluoropiperidin-3-amine Chemical compound FC1=CC2=C(N(C(=N2)N2C[C@H]([C@@H](CC2)F)N)CC2=CC(=CC=C2)OC(F)(F)F)C=C1F OMUAWFUGPJFUAS-CZUORRHYSA-N 0.000 description 1
- ADZXRLMYRDMGEY-UKRRQHHQSA-N (3R,4R)-1-[5,7-difluoro-1-[(5-fluoropyridin-2-yl)methyl]benzimidazol-2-yl]-4-fluoropiperidin-3-amine Chemical compound FC1=CC2=C(N(C(=N2)N2C[C@H]([C@@H](CC2)F)N)CC2=NC=C(C=C2)F)C(=C1)F ADZXRLMYRDMGEY-UKRRQHHQSA-N 0.000 description 1
- UOGZKTSFWMZDNS-ZYHUDNBSSA-N (3R,4R)-1-[5,7-difluoro-1-[(5-methyl-1,3,4-thiadiazol-2-yl)methyl]benzimidazol-2-yl]-4-fluoropiperidin-3-amine Chemical compound FC1=CC2=C(N(C(=N2)N2C[C@H]([C@@H](CC2)F)N)CC=2SC(=NN=2)C)C(=C1)F UOGZKTSFWMZDNS-ZYHUDNBSSA-N 0.000 description 1
- CLRSNPHDFPIIDT-GDBMZVCRSA-N (3R,4R)-1-[5,7-difluoro-1-[(5-methylsulfonylpyridin-2-yl)methyl]benzimidazol-2-yl]-4-fluoropiperidin-3-amine Chemical compound FC1=CC2=C(N(C(=N2)N2C[C@H]([C@@H](CC2)F)N)CC2=NC=C(C=C2)S(=O)(=O)C)C(=C1)F CLRSNPHDFPIIDT-GDBMZVCRSA-N 0.000 description 1
- NJMWXSXGIIOJEU-ZOOLKIEGSA-N (3R,4R)-1-[5-chloro-1-[(1S)-1-(5-chloropyridin-2-yl)ethyl]benzimidazol-2-yl]-4-fluoropiperidin-3-amine hydrochloride Chemical compound C[C@@H](C1=NC=C(C=C1)Cl)N2C3=C(C=C(C=C3)Cl)N=C2N4CC[C@H]([C@@H](C4)N)F.Cl NJMWXSXGIIOJEU-ZOOLKIEGSA-N 0.000 description 1
- BGQFCJGVBPWTFU-HUUCEWRRSA-N (3R,4R)-4-fluoro-1-[1-[(5-fluoropyridin-2-yl)methyl]benzimidazol-2-yl]piperidin-3-amine Chemical compound F[C@H]1[C@@H](CN(CC1)C1=NC2=C(N1CC1=NC=C(C=C1)F)C=CC=C2)N BGQFCJGVBPWTFU-HUUCEWRRSA-N 0.000 description 1
- YBUAKQXGXYDIEB-CHWSQXEVSA-N (3R,4R)-4-fluoro-1-[1-[[5-(trifluoromethyl)pyrimidin-2-yl]methyl]benzimidazol-2-yl]piperidin-3-amine Chemical compound F[C@H]1[C@@H](CN(CC1)C1=NC2=C(N1CC1=NC=C(C=N1)C(F)(F)F)C=CC=C2)N YBUAKQXGXYDIEB-CHWSQXEVSA-N 0.000 description 1
- MFVAOVJXNRYIBP-QZTJIDSGSA-N (3R,4R)-4-fluoro-1-[5-fluoro-1-[(4-methyl-2-phenyl-1,3-thiazol-5-yl)methyl]benzimidazol-2-yl]piperidin-3-amine Chemical compound F[C@H]1[C@@H](CN(CC1)C1=NC2=C(N1CC1=C(N=C(S1)C1=CC=CC=C1)C)C=CC(=C2)F)N MFVAOVJXNRYIBP-QZTJIDSGSA-N 0.000 description 1
- TTWADCVTUYGDIL-ZIAGYGMSSA-N (3R,4R)-4-fluoro-1-[5-fluoro-1-[(5-methoxypyrimidin-2-yl)methyl]benzimidazol-2-yl]piperidin-3-amine Chemical compound F[C@H]1[C@@H](CN(CC1)C1=NC2=C(N1CC1=NC=C(C=N1)OC)C=CC(=C2)F)N TTWADCVTUYGDIL-ZIAGYGMSSA-N 0.000 description 1
- KTQGDYJYHDGDAM-HZPDHXFCSA-N (3R,4R)-4-fluoro-1-[6-fluoro-1-[(4-methoxypyridin-2-yl)methyl]benzimidazol-2-yl]piperidin-3-amine Chemical compound F[C@H]1[C@@H](CN(CC1)C1=NC2=C(N1CC1=NC=CC(=C1)OC)C=C(C=C2)F)N KTQGDYJYHDGDAM-HZPDHXFCSA-N 0.000 description 1
- NXURQEWSCREBKG-QZTJIDSGSA-N (3R,4R)-4-fluoro-1-[6-fluoro-1-[(4-methyl-2-phenyl-1,3-thiazol-5-yl)methyl]benzimidazol-2-yl]piperidin-3-amine Chemical compound F[C@H]1[C@@H](CN(CC1)C1=NC2=C(N1CC1=C(N=C(S1)C1=CC=CC=C1)C)C=C(C=C2)F)N NXURQEWSCREBKG-QZTJIDSGSA-N 0.000 description 1
- WKEZCWVIMRHMBU-ZIAGYGMSSA-N (3R,4R)-4-fluoro-1-[6-fluoro-1-[(5-methoxypyrimidin-2-yl)methyl]benzimidazol-2-yl]piperidin-3-amine Chemical compound F[C@H]1[C@@H](CN(CC1)C1=NC2=C(N1CC1=NC=C(C=N1)OC)C=C(C=C2)F)N WKEZCWVIMRHMBU-ZIAGYGMSSA-N 0.000 description 1
- ALBROXJYOUXWCV-VXGBXAGGSA-N (3R,4R)-4-fluoro-1-[6-fluoro-1-[(5-methyl-1,3,4-thiadiazol-2-yl)methyl]benzimidazol-2-yl]piperidin-3-amine Chemical compound F[C@H]1[C@@H](CN(CC1)C1=NC2=C(N1CC=1SC(=NN=1)C)C=C(C=C2)F)N ALBROXJYOUXWCV-VXGBXAGGSA-N 0.000 description 1
- INJOIUUYEKJNMH-GHMZBOCLSA-N (3R,4R)-4-fluoro-1-[6-fluoro-1-[(5-methyl-1,3,4-thiadiazol-2-yl)methyl]imidazo[4,5-b]pyridin-2-yl]piperidin-3-amine Chemical compound F[C@H]1[C@@H](CN(CC1)C=1N(C=2C(=NC=C(C=2)F)N=1)CC=1SC(=NN=1)C)N INJOIUUYEKJNMH-GHMZBOCLSA-N 0.000 description 1
- FXMTZSBMYUVMSL-NXEZZACHSA-N (3R,4R)-4-fluoro-1-[6-fluoro-1-[[3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl]methyl]benzimidazol-2-yl]piperidin-3-amine Chemical compound F[C@H]1[C@@H](CN(CC1)C1=NC2=C(N1CC1=NC(=NO1)C(F)(F)F)C=C(C=C2)F)N FXMTZSBMYUVMSL-NXEZZACHSA-N 0.000 description 1
- VGPCJMZWFJOQSI-GHMZBOCLSA-N (3R,4R)-4-fluoro-1-[6-fluoro-3-[(5-methyl-1,3,4-thiadiazol-2-yl)methyl]imidazo[4,5-b]pyridin-2-yl]piperidin-3-amine Chemical compound F[C@H]1[C@@H](CN(CC1)C1=NC=2C(=NC=C(C=2)F)N1CC=1SC(=NN=1)C)N VGPCJMZWFJOQSI-GHMZBOCLSA-N 0.000 description 1
- VPBWULUCLOETQL-CJNGLKHVSA-N (3R,4S)-1-[1-[(5-chloropyrimidin-2-yl)methyl]-6-fluorobenzimidazol-2-yl]-4-methoxypiperidin-3-amine Chemical compound ClC=1C=NC(=NC=1)CN1C(=NC2=C1C=C(C=C2)F)N1C[C@H]([C@H](CC1)OC)N VPBWULUCLOETQL-CJNGLKHVSA-N 0.000 description 1
- SXXXRZINHAVGRW-SWLSCSKDSA-N (3R,4S)-1-[5,6-difluoro-1-[(5-fluoropyridin-2-yl)methyl]benzimidazol-2-yl]-4-fluoropiperidin-3-amine Chemical compound FC1=CC2=C(N(C(=N2)N2C[C@H]([C@H](CC2)F)N)CC2=NC=C(C=C2)F)C=C1F SXXXRZINHAVGRW-SWLSCSKDSA-N 0.000 description 1
- SBDGPNAVBJAFJO-JTQLQIEISA-N (3S)-1-(1-methylsulfonylbenzimidazol-2-yl)piperidin-3-amine Chemical compound CS(=O)(=O)N1C(=NC2=C1C=CC=C2)N1C[C@H](CCC1)N SBDGPNAVBJAFJO-JTQLQIEISA-N 0.000 description 1
- OLPZRSTXTYPTCY-HNNXBMFYSA-N (3S)-1-[1-[(5-chloropyridin-2-yl)methyl]benzimidazol-2-yl]-N-methylpiperidin-3-amine Chemical compound ClC=1C=CC(=NC=1)CN1C(=NC2=C1C=CC=C2)N1C[C@H](CCC1)NC OLPZRSTXTYPTCY-HNNXBMFYSA-N 0.000 description 1
- SAHDMSUCXCHYCM-KRWDZBQOSA-N (3S)-1-[1-[[4-(1,2,4-oxadiazol-3-yl)phenyl]methyl]benzimidazol-2-yl]piperidin-3-amine Chemical compound O1N=C(N=C1)C1=CC=C(CN2C(=NC3=C2C=CC=C3)N2C[C@H](CCC2)N)C=C1 SAHDMSUCXCHYCM-KRWDZBQOSA-N 0.000 description 1
- NLDVCWAJHXKUOT-BJZITVGISA-N (3S)-3-[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-5,6-difluorobenzimidazol-1-yl]-1-(4-chlorophenyl)pyrrolidin-2-one Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1[C@@H]1C(N(CC1)C1=CC=C(C=C1)Cl)=O)C=C(C(=C2)F)F NLDVCWAJHXKUOT-BJZITVGISA-N 0.000 description 1
- CUHRMMKCZRVDOO-XFJVYGCCSA-N (3S)-3-[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-5,6-difluorobenzimidazol-1-yl]-1-cyclopropylpyrrolidin-2-one Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1[C@@H]1C(N(CC1)C1CC1)=O)C=C(C(=C2)F)F CUHRMMKCZRVDOO-XFJVYGCCSA-N 0.000 description 1
- RUCZFWMEACWFER-UHFFFAOYSA-N (5-bromopyridin-2-yl)methanol Chemical compound OCC1=CC=C(Br)C=N1 RUCZFWMEACWFER-UHFFFAOYSA-N 0.000 description 1
- PZMVIAVOHVZPIU-UHFFFAOYSA-N (5-chloropyrimidin-2-yl)methyl methanesulfonate Chemical compound CS(=O)(=O)OCC1=NC=C(C=N1)Cl PZMVIAVOHVZPIU-UHFFFAOYSA-N 0.000 description 1
- 125000006661 (C4-C6) heterocyclic group Chemical group 0.000 description 1
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- VDFVNEFVBPFDSB-UHFFFAOYSA-N 1,3-dioxane Chemical group C1COCOC1 VDFVNEFVBPFDSB-UHFFFAOYSA-N 0.000 description 1
- WNXJIVFYUVYPPR-UHFFFAOYSA-N 1,3-dioxolane Chemical group C1COCO1 WNXJIVFYUVYPPR-UHFFFAOYSA-N 0.000 description 1
- IMLSAISZLJGWPP-UHFFFAOYSA-N 1,3-dithiolane Chemical group C1CSCS1 IMLSAISZLJGWPP-UHFFFAOYSA-N 0.000 description 1
- RRUFITRYBOABOX-YBSITQRDSA-N 1-(3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl)-2-[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-5,6-difluorobenzimidazol-1-yl]ethanone Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC(=O)N1CC3CCCCC3CC1)C=C(C(=C2)F)F RRUFITRYBOABOX-YBSITQRDSA-N 0.000 description 1
- FMJIIGQSNJKXOY-CZUORRHYSA-N 1-(4-acetylpiperazin-1-yl)-2-[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-5,6-difluorobenzimidazol-1-yl]ethanone Chemical compound C(C)(=O)N1CCN(CC1)C(CN1C(=NC2=C1C=C(C(=C2)F)F)N1C[C@H]([C@@H](CC1)F)N)=O FMJIIGQSNJKXOY-CZUORRHYSA-N 0.000 description 1
- KTGFLVDKXVWJDH-UHFFFAOYSA-N 1-(azetidin-1-yl)ethanone Chemical compound CC(=O)N1CCC1 KTGFLVDKXVWJDH-UHFFFAOYSA-N 0.000 description 1
- UFFSPDYGLCWTKF-MLLVZBGDSA-N 1-[2-[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-5,6-difluorobenzimidazol-1-yl]acetyl]-3-fluoropyrrolidine-3-carbonitrile Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC(=O)N1CC(CC1)(C#N)F)C=C(C(=C2)F)F UFFSPDYGLCWTKF-MLLVZBGDSA-N 0.000 description 1
- TZOHSAMNHRYIEA-RHSMWYFYSA-N 1-[2-[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-5,6-difluorobenzimidazol-1-yl]acetyl]-4-(methoxymethyl)piperidine-4-carbonitrile Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC(=O)N1CCC(CC1)(C#N)COC)C=C(C(=C2)F)F TZOHSAMNHRYIEA-RHSMWYFYSA-N 0.000 description 1
- FRCRSJXQMHPMRE-CZUORRHYSA-N 1-[2-[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-5,6-difluorobenzimidazol-1-yl]acetyl]-4-methylpiperidine-4-carbonitrile Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC(=O)N1CCC(CC1)(C#N)C)C=C(C(=C2)F)F FRCRSJXQMHPMRE-CZUORRHYSA-N 0.000 description 1
- QOGZACMHQLNSCQ-DTLKIFBZSA-N 1-[2-[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-5,6-difluorobenzimidazol-1-yl]acetyl]-N,N-dimethylpiperidine-3-carboxamide Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC(=O)N1CC(CCC1)C(=O)N(C)C)C=C(C(=C2)F)F QOGZACMHQLNSCQ-DTLKIFBZSA-N 0.000 description 1
- XJLQGHMJZWCCBT-CZUORRHYSA-N 1-[2-[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-5,6-difluorobenzimidazol-1-yl]acetyl]-N-methylpiperidine-4-carboxamide Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC(=O)N1CCC(CC1)C(=O)NC)C=C(C(=C2)F)F XJLQGHMJZWCCBT-CZUORRHYSA-N 0.000 description 1
- RTNSXHITYVRDDD-AADWAWOOSA-N 1-[2-[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-5,6-difluorobenzimidazol-1-yl]acetyl]piperidine-3-carboxamide Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC(=O)N1CC(CCC1)C(=O)N)C=C(C(=C2)F)F RTNSXHITYVRDDD-AADWAWOOSA-N 0.000 description 1
- PWKNBLFSJAVFAB-UHFFFAOYSA-N 1-fluoro-2-nitrobenzene Chemical class [O-][N+](=O)C1=CC=CC=C1F PWKNBLFSJAVFAB-UHFFFAOYSA-N 0.000 description 1
- XWJWSNVCZKWXST-UHFFFAOYSA-N 1-hydroxy-2,3-dihydro-1h-indene-5-carbonitrile Chemical compound N#CC1=CC=C2C(O)CCC2=C1 XWJWSNVCZKWXST-UHFFFAOYSA-N 0.000 description 1
- LNETULKMXZVUST-UHFFFAOYSA-N 1-naphthoic acid Chemical compound C1=CC=C2C(C(=O)O)=CC=CC2=C1 LNETULKMXZVUST-UHFFFAOYSA-N 0.000 description 1
- NWVGXXPWOYZODV-UHFFFAOYSA-N 1h-imidazole-5-carbonitrile Chemical compound N#CC1=CN=CN1 NWVGXXPWOYZODV-UHFFFAOYSA-N 0.000 description 1
- DCYGAPKNVCQNOE-UHFFFAOYSA-N 2,2,2-triphenylacetic acid Chemical class C=1C=CC=CC=1C(C=1C=CC=CC=1)(C(=O)O)C1=CC=CC=C1 DCYGAPKNVCQNOE-UHFFFAOYSA-N 0.000 description 1
- RKMGAJGJIURJSJ-UHFFFAOYSA-N 2,2,6,6-Tetramethylpiperidine Substances CC1(C)CCCC(C)(C)N1 RKMGAJGJIURJSJ-UHFFFAOYSA-N 0.000 description 1
- DYTUAOUIQFNOIH-UHFFFAOYSA-N 2,3-diethyl-2,3-dihydroxybutanedioic acid Chemical compound CCC(O)(C(O)=O)C(O)(CC)C(O)=O DYTUAOUIQFNOIH-UHFFFAOYSA-N 0.000 description 1
- JKTCBAGSMQIFNL-UHFFFAOYSA-N 2,3-dihydrofuran Chemical group C1CC=CO1 JKTCBAGSMQIFNL-UHFFFAOYSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 1
- XZPMCSLHQCZSRZ-OAHLLOKOSA-N 2-[(3R)-3-amino-4,4-difluoropiperidin-1-yl]-3-[(5-chloropyrimidin-2-yl)methyl]benzimidazole-5-carbonitrile Chemical compound N[C@@H]1CN(CCC1(F)F)C1=NC2=C(N1CC1=NC=C(C=N1)Cl)C=C(C=C2)C#N XZPMCSLHQCZSRZ-OAHLLOKOSA-N 0.000 description 1
- RSFONQGNUCFAEW-WGUYJYMSSA-N 2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-1-[(1R)-1-(5-cyanopyridin-2-yl)ethyl]benzimidazole-5-carbonitrile hydrochloride Chemical compound C[C@H](C1=NC=C(C=C1)C#N)N2C3=C(C=C(C=C3)C#N)N=C2N4CC[C@H]([C@@H](C4)N)F.Cl RSFONQGNUCFAEW-WGUYJYMSSA-N 0.000 description 1
- PVLNOKRRZMUEBV-ZIAGYGMSSA-N 2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-1-[(5-chloropyrimidin-2-yl)methyl]benzimidazole-5-carbonitrile Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC1=NC=C(C=N1)Cl)C=CC(=C2)C#N PVLNOKRRZMUEBV-ZIAGYGMSSA-N 0.000 description 1
- IPTPDTAAVLZNOW-CTHHTMFSSA-N 2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-3-[(5-methoxypyrimidin-2-yl)methyl]benzimidazole-5-carbonitrile hydrochloride Chemical compound Cl.N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC1=NC=C(C=N1)OC)C=C(C=C2)C#N IPTPDTAAVLZNOW-CTHHTMFSSA-N 0.000 description 1
- IHURUEADFDGHFN-CTHHTMFSSA-N 2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-3-[[6-(trifluoromethyl)pyridin-3-yl]methyl]benzimidazole-5-carbonitrile hydrochloride Chemical compound C1CN(C[C@H]([C@@H]1F)N)C2=NC3=C(N2CC4=CN=C(C=C4)C(F)(F)F)C=C(C=C3)C#N.Cl IHURUEADFDGHFN-CTHHTMFSSA-N 0.000 description 1
- MNCLTZIBZORLQC-UONOGXRCSA-N 2-[(3R,4S)-3-amino-4-fluoropiperidin-1-yl]-3-[(5-chloropyrimidin-2-yl)methyl]benzimidazole-5-carbonitrile Chemical compound N[C@@H]1CN(CC[C@@H]1F)C1=NC2=C(N1CC1=NC=C(C=N1)Cl)C=C(C=C2)C#N MNCLTZIBZORLQC-UONOGXRCSA-N 0.000 description 1
- XHXNWIHJJJRGAH-UHFFFAOYSA-N 2-[2-(3-amino-4-methylpyrrolidin-1-yl)-6-fluorobenzimidazol-1-yl]-N-methyl-N-(2,2,2-trifluoroethyl)acetamide Chemical compound NC1CN(CC1C)C1=NC2=C(N1CC(=O)N(CC(F)(F)F)C)C=C(C=C2)F XHXNWIHJJJRGAH-UHFFFAOYSA-N 0.000 description 1
- KHYNJAPFNLSXJZ-CYBMUJFWSA-N 2-[2-[(3R)-3-amino-4,4-difluoropiperidin-1-yl]-5-fluorobenzimidazol-1-yl]-N-methyl-N-(2,2,2-trifluoroethyl)acetamide Chemical compound N[C@@H]1CN(CCC1(F)F)C1=NC2=C(N1CC(=O)N(CC(F)(F)F)C)C=CC(=C2)F KHYNJAPFNLSXJZ-CYBMUJFWSA-N 0.000 description 1
- BBORIDDIXCVLCA-CYBMUJFWSA-N 2-[2-[(3R)-3-amino-4,4-difluoropiperidin-1-yl]-6-fluorobenzimidazol-1-yl]-N-methyl-N-(2,2,2-trifluoroethyl)acetamide Chemical compound N[C@@H]1CN(CCC1(F)F)C1=NC2=C(N1CC(=O)N(CC(F)(F)F)C)C=C(C=C2)F BBORIDDIXCVLCA-CYBMUJFWSA-N 0.000 description 1
- UBPFFPNJEICINL-YNODCEANSA-N 2-[2-[(3R)-3-amino-4-hydroxypiperidin-1-yl]-5-fluorobenzimidazol-1-yl]-N-methyl-N-(2,2,2-trifluoroethyl)acetamide Chemical compound N[C@@H]1CN(CCC1O)C1=NC2=C(N1CC(=O)N(CC(F)(F)F)C)C=CC(=C2)F UBPFFPNJEICINL-YNODCEANSA-N 0.000 description 1
- LOPGIQKRTUHJET-LLVKDONJSA-N 2-[2-[(3R)-3-aminopyrrolidin-1-yl]-6-fluorobenzimidazol-1-yl]-N-methyl-N-(2,2,2-trifluoroethyl)acetamide Chemical compound N[C@H]1CN(CC1)C1=NC2=C(N1CC(=O)N(CC(F)(F)F)C)C=C(C=C2)F LOPGIQKRTUHJET-LLVKDONJSA-N 0.000 description 1
- QITDZJNNJINOIM-ZYHUDNBSSA-N 2-[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-4,6-difluorobenzimidazol-1-yl]-N,N-dimethylacetamide Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC(=O)N(C)C)C=C(C=C2F)F QITDZJNNJINOIM-ZYHUDNBSSA-N 0.000 description 1
- GECFJDQNAAJWOT-CHWSQXEVSA-N 2-[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-4-cyano-6-fluorobenzimidazol-1-yl]-N-methyl-N-(2,2,2-trifluoroethyl)acetamide Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC(=O)N(CC(F)(F)F)C)C=C(C=C2C#N)F GECFJDQNAAJWOT-CHWSQXEVSA-N 0.000 description 1
- XONBGGHCWFWARQ-LLQOJDTPSA-N 2-[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-5,6-difluorobenzimidazol-1-yl]-1-(2-ethylmorpholin-4-yl)ethanone Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC(=O)N1CC(OCC1)CC)C=C(C(=C2)F)F XONBGGHCWFWARQ-LLQOJDTPSA-N 0.000 description 1
- ODZJQQQKFKEAHO-AADWAWOOSA-N 2-[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-5,6-difluorobenzimidazol-1-yl]-1-(2-methylmorpholin-4-yl)ethanone Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC(=O)N1CC(OCC1)C)C=C(C(=C2)F)F ODZJQQQKFKEAHO-AADWAWOOSA-N 0.000 description 1
- LBZJMLHYAVALRI-WKQXJPDBSA-N 2-[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-5,6-difluorobenzimidazol-1-yl]-1-(2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)ethanone Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC(=O)N1C3COC(C1)C3)C=C(C(=C2)F)F LBZJMLHYAVALRI-WKQXJPDBSA-N 0.000 description 1
- CJZMGGRWZONQSN-FIOAXKIRSA-N 2-[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-5,6-difluorobenzimidazol-1-yl]-1-(2-propan-2-ylazetidin-1-yl)ethanone Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC(=O)N1C(CC1)C(C)C)C=C(C(=C2)F)F CJZMGGRWZONQSN-FIOAXKIRSA-N 0.000 description 1
- WYWRCWSGYGXNFH-RHSMWYFYSA-N 2-[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-5,6-difluorobenzimidazol-1-yl]-1-(3,4-dihydro-2H-1,8-naphthyridin-1-yl)ethanone Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC(=O)N1CCCC3=CC=CN=C13)C=C(C(=C2)F)F WYWRCWSGYGXNFH-RHSMWYFYSA-N 0.000 description 1
- LXTOLZPWKZZPLJ-MLLVZBGDSA-N 2-[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-5,6-difluorobenzimidazol-1-yl]-1-(3-hydroxy-3-methylpyrrolidin-1-yl)ethanone Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC(=O)N1CC(CC1)(C)O)C=C(C(=C2)F)F LXTOLZPWKZZPLJ-MLLVZBGDSA-N 0.000 description 1
- NRMNMKPIVQCINJ-AADWAWOOSA-N 2-[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-5,6-difluorobenzimidazol-1-yl]-1-(3-hydroxypiperidin-1-yl)ethanone Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC(=O)N1CC(CCC1)O)C=C(C(=C2)F)F NRMNMKPIVQCINJ-AADWAWOOSA-N 0.000 description 1
- XOWPSKMFDNRRSY-IUODEOHRSA-N 2-[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-5,6-difluorobenzimidazol-1-yl]-1-(4-hydroxypiperidin-1-yl)ethanone Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC(=O)N1CCC(CC1)O)C=C(C(=C2)F)F XOWPSKMFDNRRSY-IUODEOHRSA-N 0.000 description 1
- CNUKEEGPMFDXEL-IUODEOHRSA-N 2-[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-5,6-difluorobenzimidazol-1-yl]-1-(4-methylsulfonylpiperazin-1-yl)ethanone Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC(=O)N1CCN(CC1)S(=O)(=O)C)C=C(C(=C2)F)F CNUKEEGPMFDXEL-IUODEOHRSA-N 0.000 description 1
- VRHPCSUBXLEBKV-NWJSVONSSA-N 2-[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-5,6-difluorobenzimidazol-1-yl]-1-[(1R,5S)-3-azabicyclo[3.1.0]hexan-3-yl]ethanone Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC(=O)N1C[C@@H]3C[C@@H]3C1)C=C(C(=C2)F)F VRHPCSUBXLEBKV-NWJSVONSSA-N 0.000 description 1
- MBYZAGYBZAIXIN-FBKDDSFISA-N 2-[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-5,6-difluorobenzimidazol-1-yl]-1-[(1R,5S)-6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl]ethanone Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC(=O)N1C[C@@H]3C([C@@H]3C1)(F)F)C=C(C(=C2)F)F MBYZAGYBZAIXIN-FBKDDSFISA-N 0.000 description 1
- CVGFWRGOVUOYDX-LLQOJDTPSA-N 2-[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-5,6-difluorobenzimidazol-1-yl]-1-[2-(methoxymethyl)morpholin-4-yl]ethanone Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC(=O)N1CC(OCC1)COC)C=C(C(=C2)F)F CVGFWRGOVUOYDX-LLQOJDTPSA-N 0.000 description 1
- UVHBXOSBVIEOHO-MDLDFJCZSA-N 2-[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-5,6-difluorobenzimidazol-1-yl]-1-[3-(difluoromethoxy)pyrrolidin-1-yl]ethanone Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC(=O)N1CC(CC1)OC(F)F)C=C(C(=C2)F)F UVHBXOSBVIEOHO-MDLDFJCZSA-N 0.000 description 1
- MHYWDXVYYXIROC-AADWAWOOSA-N 2-[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-5,6-difluorobenzimidazol-1-yl]-1-[3-(trifluoromethyl)piperidin-1-yl]ethanone Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC(=O)N1CC(CCC1)C(F)(F)F)C=C(C(=C2)F)F MHYWDXVYYXIROC-AADWAWOOSA-N 0.000 description 1
- WQLYWWQQZRSBPH-QHNQYTFYSA-N 2-[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-5,6-difluorobenzimidazol-1-yl]-1-[4-(3-methylpiperidine-1-carbonyl)piperidin-1-yl]ethanone Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC(=O)N1CCC(CC1)C(=O)N1CC(CCC1)C)C=C(C(=C2)F)F WQLYWWQQZRSBPH-QHNQYTFYSA-N 0.000 description 1
- LOSXJDMMTLFLKE-RHSMWYFYSA-N 2-[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-5,6-difluorobenzimidazol-1-yl]-1-[4-(cyclopropanecarbonyl)piperazin-1-yl]ethanone Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC(=O)N1CCN(CC1)C(=O)C1CC1)C=C(C(=C2)F)F LOSXJDMMTLFLKE-RHSMWYFYSA-N 0.000 description 1
- RMAFZIBXGQXAMG-VQIMIIECSA-N 2-[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-5,6-difluorobenzimidazol-1-yl]-1-[4-(pyrrolidine-1-carbonyl)piperidin-1-yl]ethanone Chemical compound N[C@@H]1CN(CC[C@H]1F)c1nc2cc(F)c(F)cc2n1CC(=O)N1CCC(CC1)C(=O)N1CCCC1 RMAFZIBXGQXAMG-VQIMIIECSA-N 0.000 description 1
- PKASEOURSZDIKP-AADWAWOOSA-N 2-[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-5,6-difluorobenzimidazol-1-yl]-N-(1-cyanopropan-2-yl)-N-methylacetamide Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC(=O)N(C)C(CC#N)C)C=C(C(=C2)F)F PKASEOURSZDIKP-AADWAWOOSA-N 0.000 description 1
- BQBFXNQGZQTKOR-BXKDBHETSA-N 2-[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-5,6-difluorobenzimidazol-1-yl]-N-(2,2-difluoroethyl)-N-methylacetamide Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC(=O)N(C)CC(F)F)C=C(C(=C2)F)F BQBFXNQGZQTKOR-BXKDBHETSA-N 0.000 description 1
- BKAKFYVORAPAIN-QTLYGJNZSA-N 2-[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-5,6-difluorobenzimidazol-1-yl]-N-(2-cyanoethyl)-N-(oxolan-3-ylmethyl)acetamide Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC(=O)N(CC1COCC1)CCC#N)C=C(C(=C2)F)F BKAKFYVORAPAIN-QTLYGJNZSA-N 0.000 description 1
- DIGMBJVSDGVEKJ-BXUZGUMPSA-N 2-[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-5,6-difluorobenzimidazol-1-yl]-N-(2-cyanopropan-2-yl)-N-methylacetamide Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC(=O)N(C)C(C)(C)C#N)C=C(C(=C2)F)F DIGMBJVSDGVEKJ-BXUZGUMPSA-N 0.000 description 1
- HAEUTUBSTRLBJB-AADWAWOOSA-N 2-[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-5,6-difluorobenzimidazol-1-yl]-N-(2-cyanopropyl)-N-methylacetamide Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC(=O)N(C)CC(C)C#N)C=C(C(=C2)F)F HAEUTUBSTRLBJB-AADWAWOOSA-N 0.000 description 1
- OLGLVICNEOJMQQ-CRAIPNDOSA-N 2-[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-5,6-difluorobenzimidazol-1-yl]-N-(2-hydroxyethyl)-N-(pyridin-3-ylmethyl)acetamide Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC(=O)N(CC=1C=NC=CC=1)CCO)C=C(C(=C2)F)F OLGLVICNEOJMQQ-CRAIPNDOSA-N 0.000 description 1
- MAVGZEWCHUOHAY-ZWNOBZJWSA-N 2-[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-5,6-difluorobenzimidazol-1-yl]-N-(cyanomethyl)-N-methylacetamide Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC(=O)N(C)CC#N)C=C(C(=C2)F)F MAVGZEWCHUOHAY-ZWNOBZJWSA-N 0.000 description 1
- PMHWXJXBVKNYQE-JTNHKYCSSA-N 2-[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-5,6-difluorobenzimidazol-1-yl]-N-[(1R)-1-cyanoethyl]-N-methylacetamide Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC(=O)N(C)[C@H](C)C#N)C=C(C(=C2)F)F PMHWXJXBVKNYQE-JTNHKYCSSA-N 0.000 description 1
- PMHWXJXBVKNYQE-MISXGVKJSA-N 2-[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-5,6-difluorobenzimidazol-1-yl]-N-[(1S)-1-cyanoethyl]-N-methylacetamide Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC(=O)N(C)[C@@H](C)C#N)C=C(C(=C2)F)F PMHWXJXBVKNYQE-MISXGVKJSA-N 0.000 description 1
- BDCNLXHILCFBGO-BXUZGUMPSA-N 2-[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-5,6-difluorobenzimidazol-1-yl]-N-cyclopropyl-N-(2,2-difluoroethyl)acetamide Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC(=O)N(CC(F)F)C1CC1)C=C(C(=C2)F)F BDCNLXHILCFBGO-BXUZGUMPSA-N 0.000 description 1
- VNWSIRACNKIONS-BXKDBHETSA-N 2-[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-5,6-difluorobenzimidazol-1-yl]-N-ethylacetamide Chemical compound CCNC(=O)CN1C2=CC(F)=C(F)C=C2N=C1N1CC[C@@H](F)[C@H](N)C1 VNWSIRACNKIONS-BXKDBHETSA-N 0.000 description 1
- WHPJRPRQEJFSCN-SVLLLCHKSA-N 2-[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-5,6-difluorobenzimidazol-1-yl]-N-methyl-N-(1,1,1-trifluoropropan-2-yl)acetamide Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC(=O)N(C(C(F)(F)F)C)C)C=C(C(=C2)F)F WHPJRPRQEJFSCN-SVLLLCHKSA-N 0.000 description 1
- JLIOZMAPECJBQD-ZWNOBZJWSA-N 2-[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-5,6-difluorobenzimidazol-1-yl]-N-methyl-N-(1,3-thiazol-2-yl)acetamide Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC(=O)N(C=1SC=CN=1)C)C=C(C(=C2)F)F JLIOZMAPECJBQD-ZWNOBZJWSA-N 0.000 description 1
- TYCOTIKQDMKFGZ-BXKDBHETSA-N 2-[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-5,6-difluorobenzimidazol-1-yl]-N-methyl-N-(2,2,2-trifluoroethyl)acetamide Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC(=O)N(CC(F)(F)F)C)C=C(C(=C2)F)F TYCOTIKQDMKFGZ-BXKDBHETSA-N 0.000 description 1
- XSIDJKRHJMBLQX-CKEIUWERSA-N 2-[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-5,6-difluorobenzimidazol-1-yl]-N-methyl-N-[(1R)-1-pyridin-2-ylethyl]acetamide Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC(=O)N([C@H](C)C1=NC=CC=C1)C)C=C(C(=C2)F)F XSIDJKRHJMBLQX-CKEIUWERSA-N 0.000 description 1
- XSIDJKRHJMBLQX-JJRVBVJISA-N 2-[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-5,6-difluorobenzimidazol-1-yl]-N-methyl-N-[(1S)-1-pyridin-2-ylethyl]acetamide Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC(=O)N([C@@H](C)C1=NC=CC=C1)C)C=C(C(=C2)F)F XSIDJKRHJMBLQX-JJRVBVJISA-N 0.000 description 1
- QAWSEXKNRQUIKE-BXUZGUMPSA-N 2-[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-5,6-difluorobenzimidazol-1-yl]-N-methyl-N-propylacetamide Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC(=O)N(CCC)C)C=C(C(=C2)F)F QAWSEXKNRQUIKE-BXUZGUMPSA-N 0.000 description 1
- PYBDEPQBRVRGCX-LDYMZIIASA-N 2-[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-5,6-difluorobenzimidazol-1-yl]-N-methylacetamide Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC(=O)NC)C=C(C(=C2)F)F PYBDEPQBRVRGCX-LDYMZIIASA-N 0.000 description 1
- YNUULPFWLJLMFD-GMSGAONNSA-N 2-[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-5,6-difluorobenzimidazol-1-yl]acetic acid Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC(=O)O)C=C(C(=C2)F)F YNUULPFWLJLMFD-GMSGAONNSA-N 0.000 description 1
- WPKLGLWQVAXALF-ZYHUDNBSSA-N 2-[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-5,7-difluorobenzimidazol-1-yl]-N,N-dimethylacetamide Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC(=O)N(C)C)C(=CC(=C2)F)F WPKLGLWQVAXALF-ZYHUDNBSSA-N 0.000 description 1
- KSRNQMGMQOICLY-ZYHUDNBSSA-N 2-[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-5,7-difluorobenzimidazol-1-yl]-N-methyl-N-(2,2,2-trifluoroethyl)acetamide Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC(=O)N(CC(F)(F)F)C)C(=CC(=C2)F)F KSRNQMGMQOICLY-ZYHUDNBSSA-N 0.000 description 1
- QKULQKWKOHDDII-VXGBXAGGSA-N 2-[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-5-(trifluoromethyl)benzimidazol-1-yl]-N,N-dimethylacetamide Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC(=O)N(C)C)C=CC(=C2)C(F)(F)F QKULQKWKOHDDII-VXGBXAGGSA-N 0.000 description 1
- JLQKOSBQZBOZSB-CHWSQXEVSA-N 2-[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-5-chlorobenzimidazol-1-yl]-1-(azetidin-1-yl)ethanone Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC(=O)N1CCC1)C=CC(=C2)Cl JLQKOSBQZBOZSB-CHWSQXEVSA-N 0.000 description 1
- UCVBLBDIZFEEOU-ZIAGYGMSSA-N 2-[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-5-chlorobenzimidazol-1-yl]-1-morpholin-4-ylethanone Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=CC(Cl)=CC=C2N1CC(=O)N1CCOCC1 UCVBLBDIZFEEOU-ZIAGYGMSSA-N 0.000 description 1
- SNCLNCQXEBKIPL-VXGBXAGGSA-N 2-[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-5-chlorobenzimidazol-1-yl]-N,N-dimethylacetamide Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC(=O)N(C)C)C=CC(=C2)Cl SNCLNCQXEBKIPL-VXGBXAGGSA-N 0.000 description 1
- LNOUNHSSBXEPRN-VXGBXAGGSA-N 2-[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-5-chlorobenzimidazol-1-yl]-N-methyl-N-(2,2,2-trifluoroethyl)acetamide Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC(=O)N(CC(F)(F)F)C)C=CC(=C2)Cl LNOUNHSSBXEPRN-VXGBXAGGSA-N 0.000 description 1
- GTSNAWKTRDBDSC-VXGBXAGGSA-N 2-[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-5-fluorobenzimidazol-1-yl]-N,N-dimethylacetamide Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC(=O)N(C)C)C=CC(=C2)F GTSNAWKTRDBDSC-VXGBXAGGSA-N 0.000 description 1
- FCYKOYRGCYEPJX-VXGBXAGGSA-N 2-[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-5-fluorobenzimidazol-1-yl]-N-methyl-N-(2,2,2-trifluoroethyl)acetamide Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC(=O)N(CC(F)(F)F)C)C=CC(=C2)F FCYKOYRGCYEPJX-VXGBXAGGSA-N 0.000 description 1
- SFMXUIDDPVVIPX-CHWSQXEVSA-N 2-[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-5-methoxybenzimidazol-1-yl]-N,N-dimethylacetamide Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC(=O)N(C)C)C=CC(=C2)OC SFMXUIDDPVVIPX-CHWSQXEVSA-N 0.000 description 1
- LLUPBWACNJHJCP-CHWSQXEVSA-N 2-[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-5-methoxybenzimidazol-1-yl]-N-methyl-N-(2,2,2-trifluoroethyl)acetamide Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC(=O)N(CC(F)(F)F)C)C=CC(=C2)OC LLUPBWACNJHJCP-CHWSQXEVSA-N 0.000 description 1
- WMYZCVVHVNYYBM-VXGBXAGGSA-N 2-[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-6-(trifluoromethoxy)benzimidazol-1-yl]-N,N-dimethylacetamide Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC(=O)N(C)C)C=C(C=C2)OC(F)(F)F WMYZCVVHVNYYBM-VXGBXAGGSA-N 0.000 description 1
- UCJIHSPLCHLDEV-VXGBXAGGSA-N 2-[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-6-(trifluoromethyl)benzimidazol-1-yl]-N,N-dimethylacetamide Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC(=O)N(C)C)C=C(C=C2)C(F)(F)F UCJIHSPLCHLDEV-VXGBXAGGSA-N 0.000 description 1
- MHTWMVZKFLRRST-VXGBXAGGSA-N 2-[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-6-(trifluoromethyl)benzimidazol-1-yl]-N-methyl-N-(2,2,2-trifluoroethyl)acetamide Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC(=O)N(CC(F)(F)F)C)C=C(C=C2)C(F)(F)F MHTWMVZKFLRRST-VXGBXAGGSA-N 0.000 description 1
- RVBALRWHAZPQQI-CHWSQXEVSA-N 2-[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-6-bromobenzimidazol-1-yl]-1-(azetidin-1-yl)ethanone Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC(=O)N1CCC1)C=C(C=C2)Br RVBALRWHAZPQQI-CHWSQXEVSA-N 0.000 description 1
- UPDDXXZCFMZBBX-VXGBXAGGSA-N 2-[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-6-chlorobenzimidazol-1-yl]-N-methyl-N-(2,2,2-trifluoroethyl)acetamide Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC(=O)N(CC(F)(F)F)C)C=C(C=C2)Cl UPDDXXZCFMZBBX-VXGBXAGGSA-N 0.000 description 1
- BYQSQQZUGDXQCG-HIDCPEKUSA-N 2-[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-6-fluorobenzimidazol-1-yl]-1-(2-methylazetidin-1-yl)ethanone Chemical compound CC1CCN1C(=O)Cn1c(nc2ccc(F)cc12)N1CC[C@@H](F)[C@H](N)C1 BYQSQQZUGDXQCG-HIDCPEKUSA-N 0.000 description 1
- WTIASVPZGQKWTC-BCAXMMLOSA-N 2-[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-6-fluorobenzimidazol-1-yl]-1-(3,5-dimethylmorpholin-4-yl)ethanone Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC(=O)N1C(COCC1C)C)C=C(C=C2)F WTIASVPZGQKWTC-BCAXMMLOSA-N 0.000 description 1
- VDQCNEQODDBWEJ-ANGDWKNPSA-N 2-[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-6-fluorobenzimidazol-1-yl]-1-(3-ethylmorpholin-4-yl)ethanone Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC(=O)N1C(COCC1)CC)C=C(C=C2)F VDQCNEQODDBWEJ-ANGDWKNPSA-N 0.000 description 1
- UHJROBXOBLWBDR-BPLDGKMQSA-N 2-[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-6-fluorobenzimidazol-1-yl]-1-[(2R)-2-methylpyrrolidin-1-yl]ethanone Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC(=O)N1[C@@H](CCC1)C)C=C(C=C2)F UHJROBXOBLWBDR-BPLDGKMQSA-N 0.000 description 1
- UHJROBXOBLWBDR-NWANDNLSSA-N 2-[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-6-fluorobenzimidazol-1-yl]-1-[(2S)-2-methylpyrrolidin-1-yl]ethanone Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC(=O)N1[C@H](CCC1)C)C=C(C=C2)F UHJROBXOBLWBDR-NWANDNLSSA-N 0.000 description 1
- PJEBBHYLJABLKZ-GPMSIDNRSA-N 2-[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-6-fluorobenzimidazol-1-yl]-1-[(3S)-3-cyclopropylmorpholin-4-yl]ethanone Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC(=O)N1[C@H](COCC1)C1CC1)C=C(C=C2)F PJEBBHYLJABLKZ-GPMSIDNRSA-N 0.000 description 1
- ACXKDSRQOIHDDX-NWANDNLSSA-N 2-[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-6-fluorobenzimidazol-1-yl]-1-[(3S)-3-methylmorpholin-4-yl]ethanone Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC(=O)N1[C@H](COCC1)C)C=C(C=C2)F ACXKDSRQOIHDDX-NWANDNLSSA-N 0.000 description 1
- HXWWEDDDTBHXSS-VXGBXAGGSA-N 2-[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-6-fluorobenzimidazol-1-yl]-N-(1,3-thiazol-2-yl)acetamide Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC(=O)NC=1SC=CN=1)C=C(C=C2)F HXWWEDDDTBHXSS-VXGBXAGGSA-N 0.000 description 1
- FVDULQAWDPWXEG-GHMZBOCLSA-N 2-[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-6-fluorobenzimidazol-1-yl]-N-(2,2,2-trifluoroethyl)acetamide Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC(=O)NCC(F)(F)F)C=C(C=C2)F FVDULQAWDPWXEG-GHMZBOCLSA-N 0.000 description 1
- DENQCCXMOHDUFT-ZIAGYGMSSA-N 2-[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-6-fluorobenzimidazol-1-yl]-N-(2-methoxyethyl)-N-methylacetamide Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC(=O)N(C)CCOC)C=C(C=C2)F DENQCCXMOHDUFT-ZIAGYGMSSA-N 0.000 description 1
- IHSBFMPJFZRKET-VXGBXAGGSA-N 2-[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-6-fluorobenzimidazol-1-yl]-N-(3,3,3-trifluoropropyl)acetamide Chemical compound N[C@@H]1CN(CC[C@H]1F)c1nc2ccc(F)cc2n1CC(=O)NCCC(F)(F)F IHSBFMPJFZRKET-VXGBXAGGSA-N 0.000 description 1
- ZGYLECPZKLYCEV-RRFJBIMHSA-N 2-[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-6-fluorobenzimidazol-1-yl]-N-[(3S)-oxolan-3-yl]-N-(2,2,2-trifluoroethyl)acetamide Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC(=O)N(CC(F)(F)F)[C@@H]1COCC1)C=C(C=C2)F ZGYLECPZKLYCEV-RRFJBIMHSA-N 0.000 description 1
- BOXIZUIOYQGSJE-BFHYXJOUSA-N 2-[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-6-fluorobenzimidazol-1-yl]-N-[(3S)-oxolan-3-yl]acetamide Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC(=O)N[C@@H]1COCC1)C=C(C=C2)F BOXIZUIOYQGSJE-BFHYXJOUSA-N 0.000 description 1
- HWBKMVQBBZEGAL-ZIAGYGMSSA-N 2-[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-6-fluorobenzimidazol-1-yl]-N-cyclobutylacetamide Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC(=O)NC1CCC1)C=C(C=C2)F HWBKMVQBBZEGAL-ZIAGYGMSSA-N 0.000 description 1
- KOBRUDSEDRCAOZ-ZIAGYGMSSA-N 2-[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-6-fluorobenzimidazol-1-yl]-N-cyclopropyl-N-(2,2,2-trifluoroethyl)acetamide Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC(=O)N(CC(F)(F)F)C1CC1)C=C(C=C2)F KOBRUDSEDRCAOZ-ZIAGYGMSSA-N 0.000 description 1
- BEAHNZKTYFNLAR-HUUCEWRRSA-N 2-[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-6-fluorobenzimidazol-1-yl]-N-ethyl-N-(2-methoxyethyl)acetamide Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC(=O)N(CCOC)CC)C=C(C=C2)F BEAHNZKTYFNLAR-HUUCEWRRSA-N 0.000 description 1
- RDYZYFZLLWPAQB-CHWSQXEVSA-N 2-[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-6-methoxybenzimidazol-1-yl]-N,N-dimethylacetamide Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC(=O)N(C)C)C=C(C=C2)OC RDYZYFZLLWPAQB-CHWSQXEVSA-N 0.000 description 1
- YQCFJQZBHCXNTB-CHWSQXEVSA-N 2-[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]benzimidazol-1-yl]-1-(azetidin-1-yl)ethanone Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC(=O)N1CCC1)C=CC=C2 YQCFJQZBHCXNTB-CHWSQXEVSA-N 0.000 description 1
- NPSOTWPSCWPMBH-BXUZGUMPSA-N 2-[2-[(3R,4R)-3-amino-4-hydroxypiperidin-1-yl]-6-fluorobenzimidazol-1-yl]-N-methyl-N-(2,2,2-trifluoroethyl)acetamide Chemical compound N[C@@H]1CN(CC[C@H]1O)C1=NC2=C(N1CC(=O)N(CC(F)(F)F)C)C=C(C=C2)F NPSOTWPSCWPMBH-BXUZGUMPSA-N 0.000 description 1
- DWBHJHKNSVTJTO-IUODEOHRSA-N 2-[2-[(3R,4R)-3-amino-4-methoxypiperidin-1-yl]-6-fluorobenzimidazol-1-yl]-N-methyl-N-(2,2,2-trifluoroethyl)acetamide Chemical compound N[C@@H]1CN(CC[C@H]1OC)C1=NC2=C(N1CC(=O)N(CC(F)(F)F)C)C=C(C=C2)F DWBHJHKNSVTJTO-IUODEOHRSA-N 0.000 description 1
- AYVSNTAQEQVCDR-QWHCGFSZSA-N 2-[2-[(3R,4S)-3-amino-4-fluoropiperidin-1-yl]-5-(trifluoromethyl)benzimidazol-1-yl]-1-(azetidin-1-yl)ethanone Chemical compound N[C@@H]1CN(CC[C@@H]1F)C1=NC2=C(N1CC(=O)N1CCC1)C=CC(=C2)C(F)(F)F AYVSNTAQEQVCDR-QWHCGFSZSA-N 0.000 description 1
- OJIOZKKSLRXJDM-UONOGXRCSA-N 2-[2-[(3R,4S)-3-amino-4-fluoropiperidin-1-yl]-5-(trifluoromethyl)benzimidazol-1-yl]-1-morpholin-4-ylethanone Chemical compound N[C@@H]1CN(CC[C@@H]1F)C1=NC2=C(N1CC(=O)N1CCOCC1)C=CC(=C2)C(F)(F)F OJIOZKKSLRXJDM-UONOGXRCSA-N 0.000 description 1
- OFNGTMIESZUFNS-NWDGAFQWSA-N 2-[2-[(3R,4S)-3-amino-4-fluoropiperidin-1-yl]-6-chlorobenzimidazol-1-yl]-N,N-dimethylacetamide Chemical compound N[C@@H]1CN(CC[C@@H]1F)C1=NC2=C(N1CC(=O)N(C)C)C=C(C=C2)Cl OFNGTMIESZUFNS-NWDGAFQWSA-N 0.000 description 1
- ZZEHOKMIOLYXHC-NSHDSACASA-N 2-[2-[(3S)-3-(aminomethyl)pyrrolidin-1-yl]-6-fluorobenzimidazol-1-yl]-N-methyl-N-(2,2,2-trifluoroethyl)acetamide Chemical compound NC[C@H]1CN(CC1)C1=NC2=C(N1CC(=O)N(CC(F)(F)F)C)C=C(C=C2)F ZZEHOKMIOLYXHC-NSHDSACASA-N 0.000 description 1
- POVCNRMXKNRVGW-HOCLYGCPSA-N 2-[2-[(4aS,8aS)-2,3,4,4a,5,7,8,8a-octahydropyrido[4,3-b][1,4]oxazin-6-yl]-5-fluorobenzimidazol-1-yl]-N-methyl-N-(2,2,2-trifluoroethyl)acetamide Chemical compound FC1=CC2=C(N(C(=N2)N2C[C@H]3[C@@H](OCCN3)CC2)CC(=O)N(CC(F)(F)F)C)C=C1 POVCNRMXKNRVGW-HOCLYGCPSA-N 0.000 description 1
- WCMUYZPFKMNMTF-UHFFFAOYSA-N 2-[2-[3-(aminomethyl)-3-fluoropyrrolidin-1-yl]-6-fluorobenzimidazol-1-yl]-N-methyl-N-(2,2,2-trifluoroethyl)acetamide Chemical compound NCC1(CN(CC1)C1=NC2=C(N1CC(=O)N(CC(F)(F)F)C)C=C(C=C2)F)F WCMUYZPFKMNMTF-UHFFFAOYSA-N 0.000 description 1
- YSKNMNVGRWOHER-TZMCWYRMSA-N 2-[5-fluoro-2-[(3R,4R)-4-fluoro-3-(methylamino)piperidin-1-yl]benzimidazol-1-yl]-N-methyl-N-(2,2,2-trifluoroethyl)acetamide Chemical compound CN[C@@H]1CN(CC[C@H]1F)C1=NC2=CC(F)=CC=C2N1CC(=O)N(C)CC(F)(F)F YSKNMNVGRWOHER-TZMCWYRMSA-N 0.000 description 1
- RGKPDFBFAPICDS-RHSMWYFYSA-N 2-[[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-5,6-difluorobenzimidazol-1-yl]methyl]-4-chlorobenzonitrile Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC1=C(C#N)C=CC(=C1)Cl)C=C(C(=C2)F)F RGKPDFBFAPICDS-RHSMWYFYSA-N 0.000 description 1
- MYVDDJBCCQNTBI-ZIAGYGMSSA-N 2-[[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-6-fluorobenzimidazol-1-yl]methyl]pyrimidine-5-carbonitrile Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC1=NC=C(C=N1)C#N)C=C(C=C2)F MYVDDJBCCQNTBI-ZIAGYGMSSA-N 0.000 description 1
- KMGUEILFFWDGFV-UHFFFAOYSA-N 2-benzoyl-2-benzoyloxy-3-hydroxybutanedioic acid Chemical compound C=1C=CC=CC=1C(=O)C(C(C(O)=O)O)(C(O)=O)OC(=O)C1=CC=CC=C1 KMGUEILFFWDGFV-UHFFFAOYSA-N 0.000 description 1
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-M 2-methylbenzenesulfonate Chemical compound CC1=CC=CC=C1S([O-])(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-M 0.000 description 1
- RSEBUVRVKCANEP-UHFFFAOYSA-N 2-pyrroline Chemical group C1CC=CN1 RSEBUVRVKCANEP-UHFFFAOYSA-N 0.000 description 1
- 125000000389 2-pyrrolyl group Chemical group [H]N1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- VWLLPPSBBHDXHK-UHFFFAOYSA-N 3,4-diaminobenzonitrile Chemical compound NC1=CC=C(C#N)C=C1N VWLLPPSBBHDXHK-UHFFFAOYSA-N 0.000 description 1
- QGNXDMSEEPNKCF-UHFFFAOYSA-N 3,5-difluorobenzene-1,2-diamine Chemical compound NC1=CC(F)=CC(F)=C1N QGNXDMSEEPNKCF-UHFFFAOYSA-N 0.000 description 1
- CTQHWLVSBDKHTQ-CWCJDUIQSA-N 3-[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-5,6-difluorobenzimidazol-1-yl]-1-methylpyrrolidin-2-one Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1C1C(N(CC1)C)=O)C=C(C(=C2)F)F CTQHWLVSBDKHTQ-CWCJDUIQSA-N 0.000 description 1
- KZGGVFHFEHGKHB-ILPDQNMUSA-N 3-[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-5,6-difluorobenzimidazol-1-yl]-1-phenylpiperidin-2-one Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1C1C(N(CCC1)C1=CC=CC=C1)=O)C=C(C(=C2)F)F KZGGVFHFEHGKHB-ILPDQNMUSA-N 0.000 description 1
- LAWFLPWPSCRADC-QGZVFWFLSA-N 3-[[2-[(3R)-3-aminopiperidin-1-yl]benzimidazol-1-yl]methyl]benzonitrile Chemical compound N[C@H]1CN(CCC1)C1=NC2=C(N1CC=1C=C(C#N)C=CC=1)C=CC=C2 LAWFLPWPSCRADC-QGZVFWFLSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- ALKYHXVLJMQRLQ-UHFFFAOYSA-M 3-carboxynaphthalen-2-olate Chemical compound C1=CC=C2C=C(C([O-])=O)C(O)=CC2=C1 ALKYHXVLJMQRLQ-UHFFFAOYSA-M 0.000 description 1
- 125000003682 3-furyl group Chemical group O1C([H])=C([*])C([H])=C1[H] 0.000 description 1
- 125000001397 3-pyrrolyl group Chemical group [H]N1C([H])=C([*])C([H])=C1[H] 0.000 description 1
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 description 1
- 125000001845 4 membered carbocyclic group Chemical group 0.000 description 1
- QREZLLYPLRPULF-UHFFFAOYSA-N 4-(aminomethyl)benzonitrile;hydron;chloride Chemical compound Cl.NCC1=CC=C(C#N)C=C1 QREZLLYPLRPULF-UHFFFAOYSA-N 0.000 description 1
- SNDOWMLIJWGJSW-CRAIPNDOSA-N 4-[(1R)-1-[2-[(3R)-3-aminopiperidin-1-yl]benzimidazol-1-yl]ethyl]benzonitrile Chemical compound N[C@H]1CN(CCC1)C1=NC2=C(N1[C@H](C)C1=CC=C(C#N)C=C1)C=CC=C2 SNDOWMLIJWGJSW-CRAIPNDOSA-N 0.000 description 1
- BSBQRHKMLPLRFL-DOEGHLOTSA-N 4-[(1R)-1-[2-[(3R,4S)-3-amino-4-fluoropiperidin-1-yl]benzimidazol-1-yl]ethyl]benzonitrile hydrochloride Chemical compound C[C@H](C1=CC=C(C=C1)C#N)N2C3=CC=CC=C3N=C2N4CC[C@@H]([C@@H](C4)N)F.Cl BSBQRHKMLPLRFL-DOEGHLOTSA-N 0.000 description 1
- VKWBRBDCSGSVOD-NBNXLVQJSA-N 4-[2-[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-5,6-difluorobenzimidazol-1-yl]acetyl]-N-methylmorpholine-2-carboxamide Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC(=O)N1CC(OCC1)C(=O)NC)C=C(C(=C2)F)F VKWBRBDCSGSVOD-NBNXLVQJSA-N 0.000 description 1
- PSULYDTWLXGUPN-AADWAWOOSA-N 4-[2-[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-5,6-difluorobenzimidazol-1-yl]acetyl]morpholine-2-carbonitrile Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC(=O)N1CC(OCC1)C#N)C=C(C(=C2)F)F PSULYDTWLXGUPN-AADWAWOOSA-N 0.000 description 1
- MLZBBFXUQRZZPH-ZWNOBZJWSA-N 4-[2-[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-5,6-difluorobenzimidazol-1-yl]acetyl]piperazin-2-one Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC(=O)N1CC(NCC1)=O)C=C(C(=C2)F)F MLZBBFXUQRZZPH-ZWNOBZJWSA-N 0.000 description 1
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
- DDUHBZVMPDZOBC-GOSISDBHSA-N 4-[[2-[(3R)-3-amino-4,4-difluoropiperidin-1-yl]-6-fluorobenzimidazol-1-yl]methyl]benzonitrile Chemical compound N[C@@H]1CN(CCC1(F)F)C1=NC2=C(N1CC1=CC=C(C#N)C=C1)C=C(C=C2)F DDUHBZVMPDZOBC-GOSISDBHSA-N 0.000 description 1
- AVZFIDQNMABBQV-MRXNPFEDSA-N 4-[[2-[(3R)-3-aminopiperidin-1-yl]benzimidazol-1-yl]methyl]-3-chlorobenzonitrile Chemical compound N[C@H]1CN(CCC1)C1=NC2=C(N1CC1=C(C=C(C#N)C=C1)Cl)C=CC=C2 AVZFIDQNMABBQV-MRXNPFEDSA-N 0.000 description 1
- YGVOYPRHFMUCQQ-RHSMWYFYSA-N 4-[[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-5,6-difluorobenzimidazol-1-yl]methyl]-2-chlorobenzonitrile Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC1=CC(=C(C#N)C=C1)Cl)C=C(C(=C2)F)F YGVOYPRHFMUCQQ-RHSMWYFYSA-N 0.000 description 1
- SNIVDOMOIFDTPJ-HZPDHXFCSA-N 4-[[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]imidazo[4,5-c]pyridin-1-yl]methyl]benzonitrile Chemical compound N[C@@H]1CN(CC[C@H]1F)C=1N(C2=C(C=NC=C2)N=1)CC1=CC=C(C#N)C=C1 SNIVDOMOIFDTPJ-HZPDHXFCSA-N 0.000 description 1
- YXECDOXTXTYQGB-HZPDHXFCSA-N 4-[[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]imidazo[4,5-c]pyridin-3-yl]methyl]benzonitrile Chemical compound N[C@@H]1CN(CC[C@H]1F)C=1N(C=2C(=CC=NC=2)N=1)CC1=CC=C(C#N)C=C1 YXECDOXTXTYQGB-HZPDHXFCSA-N 0.000 description 1
- JHVHQFXADQXCBA-MCJVGQIASA-N 4-[[2-[(3R,4S)-3-amino-4-fluoropiperidin-1-yl]-6-chlorobenzimidazol-1-yl]methyl]benzonitrile hydrochloride Chemical compound Cl.N[C@@H]1CN(CC[C@@H]1F)c1nc2ccc(Cl)cc2n1Cc1ccc(cc1)C#N JHVHQFXADQXCBA-MCJVGQIASA-N 0.000 description 1
- HLDLGIUXGAGMJA-LMOVPXPDSA-N 4-[[2-[(3S)-3-aminopiperidin-1-yl]-6-methoxybenzimidazol-1-yl]methyl]benzonitrile hydrochloride Chemical compound COC1=CC2=C(C=C1)N=C(N2CC3=CC=C(C=C3)C#N)N4CCC[C@@H](C4)N.Cl HLDLGIUXGAGMJA-LMOVPXPDSA-N 0.000 description 1
- QTAIYBJDKQJHSG-KRWDZBQOSA-N 4-[[2-[(3S)-3-aminopiperidin-1-yl]benzimidazol-1-yl]methyl]benzonitrile Chemical compound N[C@@H]1CN(CCC1)C1=NC2=C(N1CC1=CC=C(C#N)C=C1)C=CC=C2 QTAIYBJDKQJHSG-KRWDZBQOSA-N 0.000 description 1
- UOIUYHUYVXUOMW-UHFFFAOYSA-N 4-[[2-[3-(aminomethyl)-3-methylpyrrolidin-1-yl]benzimidazol-1-yl]methyl]benzonitrile Chemical compound NCC1(CN(CC1)C1=NC2=C(N1CC1=CC=C(C#N)C=C1)C=CC=C2)C UOIUYHUYVXUOMW-UHFFFAOYSA-N 0.000 description 1
- PTCPUGKKWNMITF-UHFFFAOYSA-N 4-chloro-2-fluoro-1-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=C(Cl)C=C1F PTCPUGKKWNMITF-UHFFFAOYSA-N 0.000 description 1
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 1
- KDDQRKBRJSGMQE-UHFFFAOYSA-N 4-thiazolyl Chemical compound [C]1=CSC=N1 KDDQRKBRJSGMQE-UHFFFAOYSA-N 0.000 description 1
- 125000001054 5 membered carbocyclic group Chemical group 0.000 description 1
- KHRQUXLNRANNAG-MRXNPFEDSA-N 5-[[2-[(3R)-3-amino-4,4-difluoropiperidin-1-yl]-6-chlorobenzimidazol-1-yl]methyl]pyrazine-2-carbonitrile Chemical compound N[C@@H]1CN(CCC1(F)F)C1=NC2=C(N1CC=1N=CC(=NC=1)C#N)C=C(C=C2)Cl KHRQUXLNRANNAG-MRXNPFEDSA-N 0.000 description 1
- CJVGRDMSCJSNSN-CHWSQXEVSA-N 5-[[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-6-(trifluoromethyl)benzimidazol-1-yl]methyl]pyrazine-2-carboxamide Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC=1N=CC(=NC=1)C(=O)N)C=C(C=C2)C(F)(F)F CJVGRDMSCJSNSN-CHWSQXEVSA-N 0.000 description 1
- ZLNPDTOTEVIMMY-UHFFFAOYSA-N 5-chloropyrimidine Chemical compound ClC1=CN=CN=C1 ZLNPDTOTEVIMMY-UHFFFAOYSA-N 0.000 description 1
- CWDWFSXUQODZGW-UHFFFAOYSA-N 5-thiazolyl Chemical group [C]1=CN=CS1 CWDWFSXUQODZGW-UHFFFAOYSA-N 0.000 description 1
- HXFLZWAZSSPLCO-UHFFFAOYSA-N 6,6-dimethylbicyclo[3.1.1]heptyl Chemical group C1[C-]2C([CH2+])([CH2-])[C+]1CCC2 HXFLZWAZSSPLCO-UHFFFAOYSA-N 0.000 description 1
- OONLKOWOFDEGGS-CYFNAFFESA-N 6-[(1S)-1-[2-[(4aR,8aR)-2,3,4,4a,5,7,8,8a-octahydropyrido[4,3-b][1,4]oxazin-6-yl]-4,6-difluorobenzimidazol-1-yl]ethyl]pyridine-3-carbonitrile Chemical compound FC1=CC(=CC=2N(C(=NC=21)N1C[C@@H]2[C@H](OCCN2)CC1)[C@@H](C)C1=CC=C(C=N1)C#N)F OONLKOWOFDEGGS-CYFNAFFESA-N 0.000 description 1
- BBFCAEHJBJURSJ-MRXNPFEDSA-N 6-[[2-[(3R)-3-(methylamino)piperidin-1-yl]benzimidazol-1-yl]methyl]pyridine-3-carbonitrile Chemical compound CN[C@H]1CN(CCC1)C1=NC2=C(N1CC1=CC=C(C=N1)C#N)C=CC=C2 BBFCAEHJBJURSJ-MRXNPFEDSA-N 0.000 description 1
- BKTSUUYLORUNNJ-GOSISDBHSA-N 6-[[2-[(3R)-3-amino-4,4-difluoropiperidin-1-yl]-5-methoxybenzimidazol-1-yl]methyl]pyridine-3-carbonitrile Chemical compound N[C@@H]1CN(CCC1(F)F)C1=NC2=C(N1CC1=CC=C(C=N1)C#N)C=CC(=C2)OC BKTSUUYLORUNNJ-GOSISDBHSA-N 0.000 description 1
- VPVIALAFIWLOQO-GOSISDBHSA-N 6-[[2-[(3R)-3-amino-4,4-difluoropiperidin-1-yl]-6-methoxybenzimidazol-1-yl]methyl]pyridine-3-carbonitrile Chemical compound N[C@@H]1CN(CCC1(F)F)C1=NC2=C(N1CC1=CC=C(C=N1)C#N)C=C(C=C2)OC VPVIALAFIWLOQO-GOSISDBHSA-N 0.000 description 1
- BRUCFXWXLSFIFU-IAGOWNOFSA-N 6-[[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-5-methylbenzimidazol-1-yl]methyl]pyridine-3-carbonitrile Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC1=CC=C(C=N1)C#N)C=CC(=C2)C BRUCFXWXLSFIFU-IAGOWNOFSA-N 0.000 description 1
- KNRSVFWWNDSTHR-IAGOWNOFSA-N 6-[[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-6-chloro-5-methylbenzimidazol-1-yl]methyl]pyridine-3-carbonitrile Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC1=CC=C(C=N1)C#N)C=C(C(=C2)C)Cl KNRSVFWWNDSTHR-IAGOWNOFSA-N 0.000 description 1
- CDWJKRBFOXHFKI-HUUCEWRRSA-N 6-[[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-6-chloroimidazo[4,5-b]pyridin-1-yl]methyl]pyridine-3-carbonitrile Chemical compound N[C@@H]1CN(CC[C@H]1F)C=1N(C=2C(=NC=C(C=2)Cl)N=1)CC1=NC=C(C#N)C=C1 CDWJKRBFOXHFKI-HUUCEWRRSA-N 0.000 description 1
- MCAASJPKMFNZIQ-JOCHJYFZSA-N 6-[[2-[(5R)-1,9-diazaspiro[4.5]decan-9-yl]benzimidazol-1-yl]methyl]pyridine-3-carbonitrile Chemical compound N1CCC[C@@]11CN(CCC1)C1=NC2=C(N1CC1=CC=C(C=N1)C#N)C=CC=C2 MCAASJPKMFNZIQ-JOCHJYFZSA-N 0.000 description 1
- JCAXQONCLXQDBC-HSZRJFAPSA-N 6-[[2-[(6R)-1,8-diazaspiro[5.5]undecan-8-yl]benzimidazol-1-yl]methyl]pyridine-3-carbonitrile Chemical compound N1CCCC[C@@]11CN(CCC1)C1=NC2=C(N1CC1=CC=C(C=N1)C#N)C=CC=C2 JCAXQONCLXQDBC-HSZRJFAPSA-N 0.000 description 1
- JCAXQONCLXQDBC-QHCPKHFHSA-N 6-[[2-[(6S)-1,8-diazaspiro[5.5]undecan-8-yl]benzimidazol-1-yl]methyl]pyridine-3-carbonitrile Chemical compound N#Cc1ccc(Cn2c(nc3ccccc23)N2CCC[C@@]3(CCCCN3)C2)nc1 JCAXQONCLXQDBC-QHCPKHFHSA-N 0.000 description 1
- OKPAUCNGSFQZJX-AADWAWOOSA-N 7-[2-[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-5,6-difluorobenzimidazol-1-yl]acetyl]-1,2,5,6,8,8a-hexahydroimidazo[1,5-a]pyrazin-3-one Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC(=O)N1CC3N(CC1)C(NC3)=O)C=C(C(=C2)F)F OKPAUCNGSFQZJX-AADWAWOOSA-N 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 241000251468 Actinopterygii Species 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- 241001553178 Arachis glabrata Species 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 241000271566 Aves Species 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- 239000002083 C09CA01 - Losartan Substances 0.000 description 1
- IMJFIPRFRXRCKA-UHFFFAOYSA-N C1CCNCC1.F.F Chemical compound C1CCNCC1.F.F IMJFIPRFRXRCKA-UHFFFAOYSA-N 0.000 description 1
- VECWZINPEHBKLO-VQIMIIECSA-N C1CN[C@H]2[C@H]1CCN(C2)C3=NC4=CC=CC=C4N3CC5=NC=C(C=C5)C#N Chemical compound C1CN[C@H]2[C@H]1CCN(C2)C3=NC4=CC=CC=C4N3CC5=NC=C(C=C5)C#N VECWZINPEHBKLO-VQIMIIECSA-N 0.000 description 1
- QQLYWBUFRODCIC-NKGQWRHHSA-N C[C@H]1CCN(C[C@@H]1N)C2=NC3=CC=CC=C3N2CC4=CC=C(C=C4)C#N.C(=O)(C(F)(F)F)O Chemical compound C[C@H]1CCN(C[C@@H]1N)C2=NC3=CC=CC=C3N2CC4=CC=C(C=C4)C#N.C(=O)(C(F)(F)F)O QQLYWBUFRODCIC-NKGQWRHHSA-N 0.000 description 1
- 229940127291 Calcium channel antagonist Drugs 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- 208000020446 Cardiac disease Diseases 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- 102000034573 Channels Human genes 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- JZUFKLXOESDKRF-UHFFFAOYSA-N Chlorothiazide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC2=C1NCNS2(=O)=O JZUFKLXOESDKRF-UHFFFAOYSA-N 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 102400000739 Corticotropin Human genes 0.000 description 1
- 101800000414 Corticotropin Proteins 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 description 1
- 229930105110 Cyclosporin A Natural products 0.000 description 1
- 108010036949 Cyclosporine Proteins 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 description 1
- AEMOLEFTQBMNLQ-AQKNRBDQSA-N D-glucopyranuronic acid Chemical compound OC1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O AEMOLEFTQBMNLQ-AQKNRBDQSA-N 0.000 description 1
- JVHXJTBJCFBINQ-ADAARDCZSA-N Dapagliflozin Chemical compound C1=CC(OCC)=CC=C1CC1=CC([C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)=CC=C1Cl JVHXJTBJCFBINQ-ADAARDCZSA-N 0.000 description 1
- 108010019673 Darbepoetin alfa Proteins 0.000 description 1
- BUDQDWGNQVEFAC-UHFFFAOYSA-N Dihydropyran Chemical group C1COC=CC1 BUDQDWGNQVEFAC-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- 208000004248 Familial Primary Pulmonary Hypertension Diseases 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- 208000003098 Ganglion Cysts Diseases 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- AEMRFAOFKBGASW-UHFFFAOYSA-M Glycolate Chemical compound OCC([O-])=O AEMRFAOFKBGASW-UHFFFAOYSA-M 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 206010020880 Hypertrophy Diseases 0.000 description 1
- 201000001431 Hyperuricemia Diseases 0.000 description 1
- 206010021143 Hypoxia Diseases 0.000 description 1
- WRYCSMQKUKOKBP-UHFFFAOYSA-N Imidazolidine Chemical group C1CNCN1 WRYCSMQKUKOKBP-UHFFFAOYSA-N 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- 108010007859 Lisinopril Proteins 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 238000003820 Medium-pressure liquid chromatography Methods 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- WPVDCILPTYPXBW-DTLKIFBZSA-N N-[1-[2-[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-5,6-difluorobenzimidazol-1-yl]acetyl]piperidin-3-yl]acetamide Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC(=O)N1CC(CCC1)NC(C)=O)C=C(C(=C2)F)F WPVDCILPTYPXBW-DTLKIFBZSA-N 0.000 description 1
- QIAFMBKCNZACKA-UHFFFAOYSA-N N-benzoylglycine Chemical compound OC(=O)CNC(=O)C1=CC=CC=C1 QIAFMBKCNZACKA-UHFFFAOYSA-N 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- 101100513046 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) eth-1 gene Proteins 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 206010054107 Nodule Diseases 0.000 description 1
- 235000019502 Orange oil Nutrition 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-L Phosphate ion(2-) Chemical compound OP([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-L 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 208000013616 Respiratory Distress Syndrome Diseases 0.000 description 1
- 229910004298 SiO 2 Inorganic materials 0.000 description 1
- BQCADISMDOOEFD-UHFFFAOYSA-N Silver Chemical compound [Ag] BQCADISMDOOEFD-UHFFFAOYSA-N 0.000 description 1
- 208000000453 Skin Neoplasms Diseases 0.000 description 1
- 229940123518 Sodium/glucose cotransporter 2 inhibitor Drugs 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 208000005400 Synovial Cyst Diseases 0.000 description 1
- QJJXYPPXXYFBGM-LFZNUXCKSA-N Tacrolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1\C=C(/C)[C@@H]1[C@H](C)[C@@H](O)CC(=O)[C@H](CC=C)/C=C(C)/C[C@H](C)C[C@H](OC)[C@H]([C@H](C[C@H]2C)OC)O[C@@]2(O)C(=O)C(=O)N2CCCC[C@H]2C(=O)O1 QJJXYPPXXYFBGM-LFZNUXCKSA-N 0.000 description 1
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical group C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 102000014384 Type C Phospholipases Human genes 0.000 description 1
- 108010079194 Type C Phospholipases Proteins 0.000 description 1
- HORIPNNFUYVVIR-UHFFFAOYSA-N [O].S1CCCCC1 Chemical group [O].S1CCCCC1 HORIPNNFUYVVIR-UHFFFAOYSA-N 0.000 description 1
- 239000002250 absorbent Substances 0.000 description 1
- 230000002745 absorbent Effects 0.000 description 1
- 239000003070 absorption delaying agent Substances 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- CSCPPACGZOOCGX-WFGJKAKNSA-N acetone d6 Chemical compound [2H]C([2H])([2H])C(=O)C([2H])([2H])[2H] CSCPPACGZOOCGX-WFGJKAKNSA-N 0.000 description 1
- 150000008043 acidic salts Chemical class 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 206010069351 acute lung injury Diseases 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- WNLRTRBMVRJNCN-UHFFFAOYSA-L adipate(2-) Chemical compound [O-]C(=O)CCCCC([O-])=O WNLRTRBMVRJNCN-UHFFFAOYSA-L 0.000 description 1
- 239000003463 adsorbent Substances 0.000 description 1
- 201000000028 adult respiratory distress syndrome Diseases 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 235000010419 agar Nutrition 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001447 alkali salts Chemical class 0.000 description 1
- 125000004414 alkyl thio group Chemical group 0.000 description 1
- 230000002152 alkylating effect Effects 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 230000000172 allergic effect Effects 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- SNAAJJQQZSMGQD-UHFFFAOYSA-N aluminum magnesium Chemical compound [Mg].[Al] SNAAJJQQZSMGQD-UHFFFAOYSA-N 0.000 description 1
- 238000010976 amide bond formation reaction Methods 0.000 description 1
- 229960000528 amlodipine Drugs 0.000 description 1
- ZPBWCRDSRKPIDG-UHFFFAOYSA-N amlodipine benzenesulfonate Chemical compound OS(=O)(=O)C1=CC=CC=C1.CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1Cl ZPBWCRDSRKPIDG-UHFFFAOYSA-N 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 208000007502 anemia Diseases 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000001315 anti-hyperlipaemic effect Effects 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 229940127219 anticoagulant drug Drugs 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 229940127218 antiplatelet drug Drugs 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 125000002029 aromatic hydrocarbon group Chemical group 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- 229940072107 ascorbate Drugs 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 229940009098 aspartate Drugs 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- PBIUUJCEMUAWJJ-UHFFFAOYSA-N azetidine-3-carbonitrile Chemical compound N#CC1CNC1 PBIUUJCEMUAWJJ-UHFFFAOYSA-N 0.000 description 1
- MJZQSPDYIKSJCN-UHFFFAOYSA-N azetidine-3-carbonitrile;hydrochloride Chemical compound Cl.N#CC1CNC1 MJZQSPDYIKSJCN-UHFFFAOYSA-N 0.000 description 1
- 150000001539 azetidines Chemical group 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 150000007514 bases Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- 150000008107 benzenesulfonic acids Chemical class 0.000 description 1
- 229940050390 benzoate Drugs 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- FFBHFFJDDLITSX-UHFFFAOYSA-N benzyl N-[2-hydroxy-4-(3-oxomorpholin-4-yl)phenyl]carbamate Chemical compound OC1=C(NC(=O)OCC2=CC=CC=C2)C=CC(=C1)N1CCOCC1=O FFBHFFJDDLITSX-UHFFFAOYSA-N 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 238000005574 benzylation reaction Methods 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000012620 biological material Substances 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 239000000480 calcium channel blocker Substances 0.000 description 1
- FATUQANACHZLRT-KMRXSBRUSA-L calcium glucoheptonate Chemical compound [Ca+2].OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)C([O-])=O.OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)C([O-])=O FATUQANACHZLRT-KMRXSBRUSA-L 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- FYHXNYLLNIKZMR-UHFFFAOYSA-N calcium;carbonic acid Chemical compound [Ca].OC(O)=O FYHXNYLLNIKZMR-UHFFFAOYSA-N 0.000 description 1
- MIOPJNTWMNEORI-UHFFFAOYSA-N camphorsulfonic acid Chemical compound C1CC2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-UHFFFAOYSA-N 0.000 description 1
- FAKRSMQSSFJEIM-RQJHMYQMSA-N captopril Chemical compound SC[C@@H](C)C(=O)N1CCC[C@H]1C(O)=O FAKRSMQSSFJEIM-RQJHMYQMSA-N 0.000 description 1
- 229960000830 captopril Drugs 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 150000001244 carboxylic acid anhydrides Chemical class 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000012069 chiral reagent Substances 0.000 description 1
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 1
- 239000002812 cholic acid derivative Substances 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 229910052681 coesite Inorganic materials 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 239000013066 combination product Substances 0.000 description 1
- 229940127555 combination product Drugs 0.000 description 1
- 238000002591 computed tomography Methods 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 239000012050 conventional carrier Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 229960000258 corticotropin Drugs 0.000 description 1
- 239000002537 cosmetic Substances 0.000 description 1
- 229910052906 cristobalite Inorganic materials 0.000 description 1
- 238000006880 cross-coupling reaction Methods 0.000 description 1
- 239000010779 crude oil Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- ATDGTVJJHBUTRL-UHFFFAOYSA-N cyanogen bromide Chemical compound BrC#N ATDGTVJJHBUTRL-UHFFFAOYSA-N 0.000 description 1
- 150000004292 cyclic ethers Chemical class 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 229960003834 dapagliflozin Drugs 0.000 description 1
- 229960005029 darbepoetin alfa Drugs 0.000 description 1
- DEZRYPDIMOWBDS-UHFFFAOYSA-N dcm dichloromethane Chemical compound ClCCl.ClCCl DEZRYPDIMOWBDS-UHFFFAOYSA-N 0.000 description 1
- 125000004855 decalinyl group Chemical group C1(CCCC2CCCCC12)* 0.000 description 1
- GHVNFZFCNZKVNT-UHFFFAOYSA-M decanoate Chemical compound CCCCCCCCCC([O-])=O GHVNFZFCNZKVNT-UHFFFAOYSA-M 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 150000001975 deuterium Chemical group 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 125000006003 dichloroethyl group Chemical group 0.000 description 1
- 125000004774 dichlorofluoromethyl group Chemical group FC(Cl)(Cl)* 0.000 description 1
- 125000004772 dichloromethyl group Chemical group [H]C(Cl)(Cl)* 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 125000006001 difluoroethyl group Chemical group 0.000 description 1
- 125000004786 difluoromethoxy group Chemical group [H]C(F)(F)O* 0.000 description 1
- GPLRAVKSCUXZTP-UHFFFAOYSA-N diglycerol Chemical compound OCC(O)COCC(O)CO GPLRAVKSCUXZTP-UHFFFAOYSA-N 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- AFABGHUZZDYHJO-UHFFFAOYSA-N dimethyl butane Natural products CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 description 1
- 229940113088 dimethylacetamide Drugs 0.000 description 1
- UXGNZZKBCMGWAZ-UHFFFAOYSA-N dimethylformamide dmf Chemical compound CN(C)C=O.CN(C)C=O UXGNZZKBCMGWAZ-UHFFFAOYSA-N 0.000 description 1
- 229940090124 dipeptidyl peptidase 4 (dpp-4) inhibitors for blood glucose lowering Drugs 0.000 description 1
- IZEKFCXSFNUWAM-UHFFFAOYSA-N dipyridamole Chemical compound C=12N=C(N(CCO)CCO)N=C(N3CCCCC3)C2=NC(N(CCO)CCO)=NC=1N1CCCCC1 IZEKFCXSFNUWAM-UHFFFAOYSA-N 0.000 description 1
- 229960002768 dipyridamole Drugs 0.000 description 1
- 230000006806 disease prevention Effects 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000002612 dispersion medium Substances 0.000 description 1
- 230000009429 distress Effects 0.000 description 1
- 239000002934 diuretic Substances 0.000 description 1
- 229940030606 diuretics Drugs 0.000 description 1
- CETRZFQIITUQQL-UHFFFAOYSA-N dmso dimethylsulfoxide Chemical compound CS(C)=O.CS(C)=O CETRZFQIITUQQL-UHFFFAOYSA-N 0.000 description 1
- MOTZDAYCYVMXPC-UHFFFAOYSA-N dodecyl hydrogen sulfate Chemical compound CCCCCCCCCCCCOS(O)(=O)=O MOTZDAYCYVMXPC-UHFFFAOYSA-N 0.000 description 1
- 229940043264 dodecyl sulfate Drugs 0.000 description 1
- 229940112141 dry powder inhaler Drugs 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 238000000132 electrospray ionisation Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 210000002889 endothelial cell Anatomy 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- OLAMWIPURJGSKE-UHFFFAOYSA-N et2o diethylether Chemical compound CCOCC.CCOCC OLAMWIPURJGSKE-UHFFFAOYSA-N 0.000 description 1
- AFAXGSQYZLGZPG-UHFFFAOYSA-N ethanedisulfonic acid Chemical compound OS(=O)(=O)CCS(O)(=O)=O AFAXGSQYZLGZPG-UHFFFAOYSA-N 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- OJCSPXHYDFONPU-UHFFFAOYSA-N etoac etoac Chemical compound CCOC(C)=O.CCOC(C)=O OJCSPXHYDFONPU-UHFFFAOYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- RWTNPBWLLIMQHL-UHFFFAOYSA-N fexofenadine Chemical group C1=CC(C(C)(C(O)=O)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 RWTNPBWLLIMQHL-UHFFFAOYSA-N 0.000 description 1
- 230000004761 fibrosis Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 125000004785 fluoromethoxy group Chemical group [H]C([H])(F)O* 0.000 description 1
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 229940050410 gluconate Drugs 0.000 description 1
- 229940097042 glucuronate Drugs 0.000 description 1
- 229930195712 glutamate Natural products 0.000 description 1
- 229940049906 glutamate Drugs 0.000 description 1
- JFCQEDHGNNZCLN-UHFFFAOYSA-N glutaric acid Chemical compound OC(=O)CCCC(O)=O JFCQEDHGNNZCLN-UHFFFAOYSA-N 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 229940074045 glyceryl distearate Drugs 0.000 description 1
- 229940075507 glyceryl monostearate Drugs 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 150000002357 guanidines Chemical class 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 239000007902 hard capsule Substances 0.000 description 1
- 210000002216 heart Anatomy 0.000 description 1
- 208000019622 heart disease Diseases 0.000 description 1
- 229960002897 heparin Drugs 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 125000006343 heptafluoro propyl group Chemical group 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-M hexadecanoate Chemical compound CCCCCCCCCCCCCCCC([O-])=O IPCSVZSSVZVIGE-UHFFFAOYSA-M 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 229960002003 hydrochlorothiazide Drugs 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 1
- 125000005350 hydroxycycloalkyl group Chemical group 0.000 description 1
- 208000013403 hyperactivity Diseases 0.000 description 1
- 230000007954 hypoxia Effects 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- MTNDZQHUAFNZQY-UHFFFAOYSA-N imidazoline Chemical group C1CN=CN1 MTNDZQHUAFNZQY-UHFFFAOYSA-N 0.000 description 1
- 239000002955 immunomodulating agent Substances 0.000 description 1
- 229940121354 immunomodulator Drugs 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 230000008595 infiltration Effects 0.000 description 1
- 238000001764 infiltration Methods 0.000 description 1
- 239000007972 injectable composition Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
- 150000002540 isothiocyanates Chemical class 0.000 description 1
- 239000000644 isotonic solution Substances 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 230000003907 kidney function Effects 0.000 description 1
- 229940001447 lactate Drugs 0.000 description 1
- 229940099584 lactobionate Drugs 0.000 description 1
- JYTUSYBCFIZPBE-AMTLMPIISA-N lactobionic acid Chemical compound OC(=O)[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O JYTUSYBCFIZPBE-AMTLMPIISA-N 0.000 description 1
- 125000005647 linker group Chemical group 0.000 description 1
- 229940057995 liquid paraffin Drugs 0.000 description 1
- 229960002394 lisinopril Drugs 0.000 description 1
- CZRQXSDBMCMPNJ-ZUIPZQNBSA-N lisinopril dihydrate Chemical compound O.O.C([C@H](N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(O)=O)C(O)=O)CC1=CC=CC=C1 CZRQXSDBMCMPNJ-ZUIPZQNBSA-N 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- KJJZZJSZUJXYEA-UHFFFAOYSA-N losartan Chemical compound CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C=2[N]N=NN=2)C=C1 KJJZZJSZUJXYEA-UHFFFAOYSA-N 0.000 description 1
- 229960004773 losartan Drugs 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- DKXULEFCEORBJK-UHFFFAOYSA-N magnesium;octadecanoic acid Chemical compound [Mg].CCCCCCCCCCCCCCCCCC(O)=O DKXULEFCEORBJK-UHFFFAOYSA-N 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-M mandelate Chemical compound [O-]C(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-M 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- BCVXHSPFUWZLGQ-UHFFFAOYSA-N mecn acetonitrile Chemical compound CC#N.CC#N BCVXHSPFUWZLGQ-UHFFFAOYSA-N 0.000 description 1
- 229960003194 meglumine Drugs 0.000 description 1
- COTNUBDHGSIOTA-UHFFFAOYSA-N meoh methanol Chemical compound OC.OC COTNUBDHGSIOTA-UHFFFAOYSA-N 0.000 description 1
- 108020004999 messenger RNA Proteins 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- GRWIABMEEKERFV-UHFFFAOYSA-N methanol;oxolane Chemical compound OC.C1CCOC1 GRWIABMEEKERFV-UHFFFAOYSA-N 0.000 description 1
- AVAKTJAZXZLGHK-CZUORRHYSA-N methyl 1-[2-[2-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-5,6-difluorobenzimidazol-1-yl]acetyl]piperidine-4-carboxylate Chemical compound N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC(=O)N1CCC(CC1)C(=O)OC)C=C(C(=C2)F)F AVAKTJAZXZLGHK-CZUORRHYSA-N 0.000 description 1
- DAXYXCYGRCEHQB-IAQYHMDHSA-N methyl 2-[5,6-difluoro-2-[(3R,4R)-4-fluoro-3-[(2-methylpropan-2-yl)oxycarbonylamino]piperidin-1-yl]benzimidazol-1-yl]acetate Chemical compound C(C)(C)(C)OC(=O)N[C@@H]1CN(CC[C@H]1F)C1=NC2=C(N1CC(=O)OC)C=C(C(=C2)F)F DAXYXCYGRCEHQB-IAQYHMDHSA-N 0.000 description 1
- YDCHPLOFQATIDS-UHFFFAOYSA-N methyl 2-bromoacetate Chemical compound COC(=O)CBr YDCHPLOFQATIDS-UHFFFAOYSA-N 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- JZMJDSHXVKJFKW-UHFFFAOYSA-M methyl sulfate(1-) Chemical compound COS([O-])(=O)=O JZMJDSHXVKJFKW-UHFFFAOYSA-M 0.000 description 1
- GYNNXHKOJHMOHS-UHFFFAOYSA-N methyl-cycloheptane Natural products CC1CCCCCC1 GYNNXHKOJHMOHS-UHFFFAOYSA-N 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 238000004452 microanalysis Methods 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 150000002780 morpholines Chemical group 0.000 description 1
- RTGDFNSFWBGLEC-SYZQJQIISA-N mycophenolate mofetil Chemical compound COC1=C(C)C=2COC(=O)C=2C(O)=C1C\C=C(/C)CCC(=O)OCCN1CCOCC1 RTGDFNSFWBGLEC-SYZQJQIISA-N 0.000 description 1
- 229960004866 mycophenolate mofetil Drugs 0.000 description 1
- 230000003680 myocardial damage Effects 0.000 description 1
- WIDKTXGNSOORHA-CJHXQPGBSA-N n,n'-dibenzylethane-1,2-diamine;(2s,5r,6r)-3,3-dimethyl-7-oxo-6-[(2-phenylacetyl)amino]-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid;tetrahydrate Chemical compound O.O.O.O.C=1C=CC=CC=1CNCCNCC1=CC=CC=C1.N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1.N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 WIDKTXGNSOORHA-CJHXQPGBSA-N 0.000 description 1
- LVCDXCQFSONNDO-UHFFFAOYSA-N n-benzylhydroxylamine Chemical compound ONCC1=CC=CC=C1 LVCDXCQFSONNDO-UHFFFAOYSA-N 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- PSZYNBSKGUBXEH-UHFFFAOYSA-M naphthalene-1-sulfonate Chemical compound C1=CC=C2C(S(=O)(=O)[O-])=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-M 0.000 description 1
- 201000008383 nephritis Diseases 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 210000000440 neutrophil Anatomy 0.000 description 1
- 229960003512 nicotinic acid Drugs 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 238000010641 nitrile hydrolysis reaction Methods 0.000 description 1
- 125000006574 non-aromatic ring group Chemical group 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 229940049964 oleate Drugs 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 239000010502 orange oil Substances 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- OOFGXDQWDNJDIS-UHFFFAOYSA-N oxathiolane Chemical group C1COSC1 OOFGXDQWDNJDIS-UHFFFAOYSA-N 0.000 description 1
- 239000006174 pH buffer Substances 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- UQPUONNXJVWHRM-UHFFFAOYSA-N palladium;triphenylphosphane Chemical group [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 UQPUONNXJVWHRM-UHFFFAOYSA-N 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000006201 parenteral dosage form Substances 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 230000008529 pathological progression Effects 0.000 description 1
- 230000001991 pathophysiological effect Effects 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 235000019371 penicillin G benzathine Nutrition 0.000 description 1
- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 description 1
- 238000005897 peptide coupling reaction Methods 0.000 description 1
- 230000000737 periodic effect Effects 0.000 description 1
- 229940021222 peritoneal dialysis isotonic solution Drugs 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- NVPICXQHSYQKGM-UHFFFAOYSA-N piperidine-1-carbonitrile Chemical compound N#CN1CCCCC1 NVPICXQHSYQKGM-UHFFFAOYSA-N 0.000 description 1
- ILUDPPGBUXWYAU-UHFFFAOYSA-N piperidine-3-carboxamide Chemical compound NC(=O)C1CCCNC1.NC(=O)C1CCCNC1 ILUDPPGBUXWYAU-UHFFFAOYSA-N 0.000 description 1
- 150000003053 piperidines Chemical class 0.000 description 1
- 210000002826 placenta Anatomy 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 239000000106 platelet aggregation inhibitor Substances 0.000 description 1
- 210000000557 podocyte Anatomy 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 102000054765 polymorphisms of proteins Human genes 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- XOFYZVNMUHMLCC-ZPOLXVRWSA-N prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 description 1
- 229960004618 prednisone Drugs 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 238000007639 printing Methods 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 201000008171 proliferative glomerulonephritis Diseases 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 230000008695 pulmonary vasoconstriction Effects 0.000 description 1
- 125000002206 pyridazin-3-yl group Chemical group [H]C1=C([H])C([H])=C(*)N=N1 0.000 description 1
- 125000004940 pyridazin-4-yl group Chemical group N1=NC=C(C=C1)* 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 description 1
- 125000004528 pyrimidin-5-yl group Chemical group N1=CN=CC(=C1)* 0.000 description 1
- ALSCEGDXFJIYES-UHFFFAOYSA-N pyrrolidine-2-carbonitrile Chemical compound N#CC1CCCN1 ALSCEGDXFJIYES-UHFFFAOYSA-N 0.000 description 1
- ZVJHJDDKYZXRJI-UHFFFAOYSA-N pyrroline Chemical group C1CC=NC1 ZVJHJDDKYZXRJI-UHFFFAOYSA-N 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 208000023504 respiratory system disease Diseases 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- BPRHUIZQVSMCRT-VEUZHWNKSA-N rosuvastatin Chemical compound CC(C)C1=NC(N(C)S(C)(=O)=O)=NC(C=2C=CC(F)=CC=2)=C1\C=C\[C@@H](O)C[C@@H](O)CC(O)=O BPRHUIZQVSMCRT-VEUZHWNKSA-N 0.000 description 1
- 229960000672 rosuvastatin Drugs 0.000 description 1
- 238000007127 saponification reaction Methods 0.000 description 1
- 229940116351 sebacate Drugs 0.000 description 1
- CXMXRPHRNRROMY-UHFFFAOYSA-L sebacate(2-) Chemical compound [O-]C(=O)CCCCCCCCC([O-])=O CXMXRPHRNRROMY-UHFFFAOYSA-L 0.000 description 1
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical group CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 1
- 238000010517 secondary reaction Methods 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 229910052709 silver Inorganic materials 0.000 description 1
- 239000004332 silver Substances 0.000 description 1
- MFFMDFFZMYYVKS-SECBINFHSA-N sitagliptin Chemical compound C([C@H](CC(=O)N1CC=2N(C(=NN=2)C(F)(F)F)CC1)N)C1=CC(F)=C(F)C=C1F MFFMDFFZMYYVKS-SECBINFHSA-N 0.000 description 1
- 229960004034 sitagliptin Drugs 0.000 description 1
- 201000000849 skin cancer Diseases 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 125000003003 spiro group Chemical group 0.000 description 1
- 210000000952 spleen Anatomy 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 208000019411 steroid-resistant nephrotic syndrome Diseases 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 229910052682 stishovite Inorganic materials 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 125000000565 sulfonamide group Chemical group 0.000 description 1
- 230000000475 sunscreen effect Effects 0.000 description 1
- 239000000516 sunscreening agent Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 229960001967 tacrolimus Drugs 0.000 description 1
- QJJXYPPXXYFBGM-SHYZHZOCSA-N tacrolimus Natural products CO[C@H]1C[C@H](CC[C@@H]1O)C=C(C)[C@H]2OC(=O)[C@H]3CCCCN3C(=O)C(=O)[C@@]4(O)O[C@@H]([C@H](C[C@H]4C)OC)[C@@H](C[C@H](C)CC(=C[C@@H](CC=C)C(=O)C[C@H](O)[C@H]2C)C)OC QJJXYPPXXYFBGM-SHYZHZOCSA-N 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- BAGDEUDLBCQEQN-IBGZPJMESA-N tert-butyl N-[(3S)-1-[1-[(5-cyanopyridin-2-yl)methyl]-5-fluorobenzimidazol-2-yl]piperidin-3-yl]carbamate Chemical compound C(#N)C=1C=CC(=NC=1)CN1C(=NC2=C1C=CC(=C2)F)N1C[C@H](CCC1)NC(OC(C)(C)C)=O BAGDEUDLBCQEQN-IBGZPJMESA-N 0.000 description 1
- WUOQXNWMYLFAHT-QMMMGPOBSA-N tert-butyl n-[(3s)-piperidin-3-yl]carbamate Chemical compound CC(C)(C)OC(=O)N[C@H]1CCCNC1 WUOQXNWMYLFAHT-QMMMGPOBSA-N 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- 231100001274 therapeutic index Toxicity 0.000 description 1
- 150000003548 thiazolidines Chemical group 0.000 description 1
- 150000004886 thiomorpholines Chemical group 0.000 description 1
- 239000012443 tonicity enhancing agent Substances 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 230000037317 transdermal delivery Effects 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
- 229910052905 tridymite Inorganic materials 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
- 238000003828 vacuum filtration Methods 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- GTLDTDOJJJZVBW-UHFFFAOYSA-N zinc cyanide Chemical compound [Zn+2].N#[C-].N#[C-] GTLDTDOJJJZVBW-UHFFFAOYSA-N 0.000 description 1
- ZWDZFMQAIVHFHF-UHFFFAOYSA-N zinc;2,2,6,6-tetramethylpiperidin-1-ide Chemical compound [Zn+2].CC1(C)CCCC(C)(C)[N-]1.CC1(C)CCCC(C)(C)[N-]1 ZWDZFMQAIVHFHF-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/10—Spiro-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/08—Bridged systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/10—Spiro-condensed systems
- C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Urology & Nephrology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Abstract
本發明提供式(I)化合物或其醫藥學上可接受之鹽、包含本發明化合物之醫藥組合物、製造本發明化合物之方法及其治療用途。
Description
本發明大體上係關於經典瞬時受體電位(TRPC)通道蛋白,且更具體而言係關於瞬時受體電位通道6(TRPC6)蛋白活性抑制劑、包含該等抑制劑之醫藥組合物及使用該等抑制劑之方法。
TRPC6通道(即瞬時受體電位(TRP)家族之成員,其係非選擇性陽離子可滲透通道)係由二醯甘油及由磷脂酶C之活化產生之類似物活化且發揮生理學及病理生理學效應。TRPC6具有效應,諸如心臟病理性肥大及纖維化、肌肉營養不良症中心肌損害之進展、急性肺血管收縮、慢性缺氧誘導之肺高血壓之病理進展、過敏性氣道反應、諸如嗜中性球等細胞之遷移、關於發炎之內皮細胞之增加滲透性、足細胞之病理性扁平及腎小球損傷之進展以及惡性腫瘤之增殖或浸潤,且不同地分佈於腦、心臟、肺、腎、胎盤、卵巢、脾及諸如此類中(例如,參見J.Clin.Invest.116:3114-3126,2006;Dev.Cell.23:705-715,2012;Circ.Res.114:823-832,2014;Proc.Natl.Acd.Sci.USA 103:19093-19098,2006;J.Cardiovasc.Pharmacol.57:140-147,2011;Hypertension 63:173-80,2014;Clin.Exp.Allergy 38:1548-1558,2008;Acta.Physiol.195:3-11,2009;J.Exp.Med.209:1953-
1968,2011;Arterioscler.Thromb.Vasc.Biol.33:2121-2129,2013;PLoS ONE 5:e12859,2010;Expert.Opin.Ther.Targets.14:513-27,2010;及BMC Cancer 13:116,2013)。在家族性局灶性節段性腎小球硬化症(FSGS)中,已鑑別TRPC6之功能獲得性突變體,且在類固醇抗性腎病症候群或特發性肺動脈高血壓患者中,已鑑別啟動子區中增加TRPC6之mRNA表現的單核苷酸多型性(例如,參見:Pediatr Res.2013年11月;74(5):511-6及Circulation.2009年5月5日;119(17):2313-2322)。因此,認為TRPC6之機能亢進及增加之表現促使腎病症候群、肺高血壓及諸如此類之病理進展(例如,參見Science 308:1801-1804,2005;Nat.Genet.37:739-744,2005;PLoS One 4:e7771,2009;Clin.J.Am.Soc.Nephrol.6:1139-1148,2011;Mol.Biol.Cell.22:1824-1835,2011;BMC Nephrol.14:104,2013;Pediatr.Res.74:511-516,2013;及Nephrol.Dial.Transplant.28:1830-1838,2013)。此外,已在微小變化腎病症候群、膜性腎病變及糖尿病腎病變中報導TRPC6之增加表現(例如,參見Circulation 119:2313-2322,2009;J.Am.Soc.Nephrol.18:29-36,2007;及Nephrol.Dial.Transplant.27:921-929,2012)。
需要新方法來調節TRPC6活性且更具體而言抑制TRPC6活性用於預防及/或治療腎病症候群、微小變化病、局灶性節段性腎小球硬化症、塌陷性腎小球病、膜性腎病變、膜增殖性腎小球性腎炎、IGA腎病變、急性腎衰竭、慢性腎衰竭、糖尿病腎病變、敗血症、肺高血壓、急性肺病症、急性呼吸窘迫症候群(ARDS)、心臟衰竭、中風、惡性腫瘤及肌肉營養不良症。仍需要利用不同作用機制
且可在症狀緩解、安全性及患者死亡率(短期及長期)方面具有更佳結果的藥劑。
本發明提供抑制TRPC蛋白且更特定而言抑制TRPC6蛋白之化合物。在一個態樣中,本發明提供抑制TRPC6活性之苯并咪唑化合物。TRPC6活性之抑制可在各種疾病之治療或預防中尤其合意,該等疾病包括腎病症候群、局灶性節段性腎小球硬化症、膜性腎病變、糖尿病腎病變、心臟衰竭、中風、急性肺損傷、急性呼吸窘迫症候群(ARDS)及急性腎衰竭。
在一個態樣中,本發明提供調節TRPC6之活性之經取代苯并咪唑化合物。較佳地,本發明之經取代苯并咪唑化合物係TRPC6抑制劑。
亦提供包含醫藥學上可接受之賦形劑、載劑或佐劑及至少一種式(I)或其子式之化合物的醫藥組合物。由本發明提供之醫藥組合物適用於治療由TRPC6活性調節之疾病。在某些態樣中,本發明之醫藥組合物適用於治療,例如治療腎病症候群、微小變化病、局灶性節段性腎小球硬化症、塌陷性腎小球病、膜性腎病變、膜增殖性腎小球性腎
炎、IGA腎病變、急性腎衰竭、慢性腎衰竭、糖尿病腎病變、敗血症、肺高血壓、急性肺病症、心臟衰竭、中風、惡性腫瘤或肌肉營養不良症。
亦提供包裝醫藥組合物,其包含含有醫藥學上可接受之賦形劑、載劑或佐劑及至少一種式(I)或其子式之化合物的醫藥組合物及使用該組合物以治療患有由TRPC6活性介導之疾病之患者或更具體而言治療患有腎病症候群、微小變化病、局灶性節段性腎小球硬化症、塌陷性腎小球病、膜性腎病變、膜增殖性腎小球性腎炎、IGA腎病變、急性腎衰竭、慢性腎衰竭、糖尿病腎病變、敗血症、肺高血壓、急性肺病症、急性呼吸窘迫症候群(ARDS)、心臟衰竭、中風、惡性腫瘤或肌肉營養不良症之患者的說明書。在某些情況下,患者患有腎病症候群、膜性腎病變及急性腎衰竭。
亦提供治療或預防哺乳動物之疾病之方法,該方法包括向有需要之哺乳動物投與治療有效量之至少一種式(I)或其子式之化合物或包含醫藥學上可接受之賦形劑、載劑或佐劑及至少一種式(I)或其子式之化合物的醫藥組合物。
亦提供調節哺乳動物之TRPC6活性之方法,該方法包括向有需要之哺乳動物投與治療有效量之至少一種式(I)或其子式之化合物或包含醫藥學上可接受之賦形劑、載劑或佐劑及至少一種式(I)或其子式之化合物的醫藥組合物。本發明之另一態樣係關於治療TRPC6介導之疾病或病症之方法,該方法包括向需要療法之患者投與本發明之TRPC6抑制劑。在某些實施例中,TRPC6介導之疾病或病症係選自腎病症候群、微小變化病、局灶性節段性腎小球硬化症、塌陷性腎小
球病、膜性腎病變、膜增殖性腎小球性腎炎、IGA腎病變、急性腎衰竭、慢性腎衰竭、糖尿病腎病變、敗血症、肺高血壓、急性肺病症、急性呼吸窘迫症候群(ARDS)、心臟衰竭、中風、惡性腫瘤或肌肉營養不良症。在某些情況下,患者患有腎病症候群、膜性腎病變及急性腎衰竭。
亦提供至少一種式I或其子式之化合物的用途,其用於製造用於治療或預防由TRPC6活性介導之疾病的藥劑。
熟習此項技術者自以下詳細說明將明瞭其他態樣及實施例。
本發明大體上係關於式I化合物及其鹽及互變異構物,其抑制TRPC蛋白活性且更具體而言抑制TRPC6蛋白活性。具體而言,本發明係關於選擇性抑制TRPC6蛋白活性之化合物。
其中p係0或1;當p係0時,則R1係氫、C1-C6烷基、鹵素或羥基;R2係胺基或胺基C1-C4烷基;R3係氫;且R4係氫、C1-C6烷基或苯基;或
當p係0時,則R1及R3組合起來形成稠合C3-C6環烷基環或具有1或2個獨立地選自N、O或S之環雜原子之稠合4至6員雜環,該環烷基或雜環視情況經胺基取代;R2係氫、C1-C6烷基或胺基C1-C4烷基;且R4係氫;或當p係1時,則R1係NHR1a;R1a係氫、C1-C4烷基、C3-C7環烷基、羥基C1-C4烷基或具有一個選自N、O或S之環雜原子之4至6員雜環烷基;R2係氫、C1-C4烷基、羥基C1-C4烷基或C(O)NH2;R3係氫、鹵素、C1-C4烷基、C1-C4烷氧基或羥基;且R4係氫、C1-C4烷基或鹵素;或當p係0或1時,則CR1R2組合起來形成螺環4至6員雜環烷基;R3係氫、鹵素、C1-C4烷基、C1-C4烷氧基或羥基;且R4係氫或鹵素;或當p係1時,則R1及R3組合起來形成稠合4至6員雜環或稠合3至7員碳環,該雜環包含環氮原子及視情況0或1個選自N、O及S之額外環雜原子,且該碳環經胺基取代;且R2係氫;且R4係氫、鹵素或羥基;R5表示1或2個獨立地選自氫、鹵素、羥基、胺基、C1-C6烷基或C1-C6烷氧基之取代基;R6係-(CR7R8)-A;或R6係視情況經一個或兩個獨立地選自由以下組成之群之取代基取代的4至7員內醯胺:羥基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C6環烷基、鹵基C1-C6烷基、C1-C6烷氧基、鹵基C1-C6烷氧基、羥基C1-C6烷基、C1-C6烷氧基C1-C6烷基、苯基、具有1個選自N、O或S之環原子及0或1個額外環N原子之4至7員雜環或具有一個選自N、O或S之環雜原子及0或1個額外環氮原子之5或6員雜芳基,其中該雜芳基、
雜環或苯基視情況經0、1或2個C1-C6烷基或鹵素取代;或R6係部分不飽和9或10員雙環碳環,其視情況經1或2個獨立地選自以下之取代基取代:鹵素、氰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、鹵基C1-C6烷基、C1-C6烷氧基、鹵基C1-C6烷氧基、C(O)NH2及C(O)NHC1-C6烷基;A係5或6員雜芳基,該雜芳基包含一個選自N、O或S之環雜原子及0、1或2個額外環氮原子,該雜芳基視情況經0、1、2、3或4個獨立地選自以下之基團取代:鹵素、氰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C6環烷基、鹵基C1-C6烷基、C1-C6烷氧基、鹵基C1-C6烷氧基、C(O)N(RA)2、S(O)2C1-C6烷基、苯基或具有一個選自N、O或S之環雜原子及0、1或2個額外環氮原子之5或6員雜芳基,其中該視情況存在之雜芳基或苯基取代基進一步經0、1或2個C1-C6烷基取代;或A係經1、2或3個獨立地選自以下之取代基取代之苯基:鹵素、C1-C6烷基、C2-C6烯基、C2-C6炔基、鹵基C1-C6烷基、氰基C1-C6烷基、C1-C6烷氧基、鹵基C1-C6烷氧基、氰基C1-C6烷氧基、S(O)qC1-C6烷基、S(O)2NH2、S(O)2NHC1-C6烷基、S(O)2N(C1-C6烷基)2、C(O)NH2、C(O)NHC1-C6烷基、C(O)N(C1-C6烷基)2、羥基、氰基或具有一個選自N、O或S之環雜原子及0、1或2個額外環氮原子之5或6員雜芳基,該雜芳基進一步經0、1或2個C1-C6烷基取代;或A係C(O)OR9或C(O)NR9R10;或A係具有0、1或2個環氮原子及0或1個選自N、O或S之額外環雜原子的視情況經取代之9或10員芳族或部分不飽和雙環,該雙環經0、1或2個獨立地選自由以下組成之群之取代基取代:鹵素、氰基、C1-
C6烷基、C2-C6烯基、C2-C6炔基、鹵基C1-C6烷基、C1-C6烷氧基、鹵基C1-C6烷氧基、C(O)NH2、C(O)OH或C(O)NHC1-C6烷基;RA在每次出現時獨立地選自氫或C1-C4烷基;或N(RA)2組合起來形成視情況經0、1或2個C1-C4烷基取代之4至7員氮雜環;R7係氫、C1-C4烷基或胺基;R8係氫或C1-C4烷基;或CR7R8組合起來形成3至6員環烷二基;R9係氫、C1-C6烷基、C3-C6環烷基、羥基C1-C6烷基、C1-C4烷氧基C1-C6烷基、鹵基C1-C6烷基、氰基C1-C6烷基或-(CH2)rR9A,其中r係0或1且R9A係苯基、具有一個選自N、O或S之環雜原子(該環硫可視情況經氧化)及0或1個額外環N原子之4至7員雜環或具有一個選自N、O或S之環雜原子及0、1或2個額外環N原子之5或6員雜芳基,該苯基、雜環或雜芳基視情況經0、1或2個鹵素、C1-C4烷基或C(O)C1-C4烷基取代;R10係氫、C1-C6烷基、C2-C6烯基、C2-C6炔基、鹵基C1-C6烷基、C3-C7環烷基或具有1或2個獨立地選自N、O及S之環雜原子之飽和、部分不飽和或芳族5或6員雜環,該硫視情況經氧化,且該雜環視情況經1或2個獨立地選自C1-C6烷基及鹵素之取代基取代,該雜環具有1或2個選自N、O或S之環雜原子,該硫可視情況經氧化,且其中每一烷基或環烷基視情況經以下取代:氰基、鹵素、羥基、C1-C6烷氧基、S(O)qC1-C6烷基、具有1或2個選自N、O或S之環雜原子之4至6員雜環或具有1個選自N、O或S之環雜原子及0、1或2個額外環氮原子之5或6
員雜芳基,且其中每一雜環或雜芳基視情況經0、1或2個C1-C4烷基取代;或NR9R10組合起來形成具有一個或兩個環氮原子及0或1個選自N、O或S之額外環雜原子的單環或雙環4至10員飽和或部分不飽和雜環,該環硫可視情況經氧化,該雜環視情況經0、1或2個選自以下之取代基取代:鹵素、側氧基、羥基、氰基、C1-C6烷基、C3-C6環烷基、鹵基C1-C6烷基、羥基C1-C6烷基、氰基C1-C6烷基、C1-C6烷氧基、鹵基C1-C6烷氧基、C1-C6烷氧基C1-C4烷基、S(O)qC1-C6烷基、C1-C6烷基S(O)qC1-C6烷基CO2H、C(O)C1-C6烷基、C(O)OC1-C6烷基、C(O)C3-C6環烷基、N(R15)C(O)C1-C6烷基或C(O)N(R15)2、苯基、具有1或2個選自N、O或S之環雜原子之4至6員雜環或具有1個選自N、O或S之環雜原子及0、1或2個額外環氮原子之5或6員雜芳基,且其中每一雜環或雜芳基視情況經0、1或2個C1-C4烷基取代;q係0、1或2;Z1係N或CR11;Z2係N或CR12;Z3係N或CR13;Z4係N或CR14,Z5及Z6各自獨立地係N或C;其中Z1、Z2、Z3、Z4、Z5及Z6中之0、1或2者係N;R11、R12、R13及R14中之每一者獨立地選自由以下組成之群:氫、鹵素、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6烷氧基、鹵基C1-C6烷基、鹵基C1-C6烷氧基、C3-C7環烷基、氰基、SO2C1-C6烷基、
苯基及具有1或2個獨立地選自N、O及S之環雜原子之飽和、部分不飽和或芳族5或6員雜環,該雜環視情況經1或2個獨立地選自C1-C6烷基及鹵素之取代基取代;且R15在每次出現時係選自氫或C1-C4烷基,或N(R15)2組合起來形成視情況經0、1或2個C1-C4烷基取代之4至7員氮雜環;前提條件係式I化合物不包括1-[7-氟-6-甲氧基-1-[[2-(三氟甲基)苯基]甲基]-1H-苯并咪唑-2-基]-3-哌啶胺。
其中p係0或1;當p係0時,則R1係氫、C1-C6烷基、鹵素或羥基;R2係胺基或胺基C1-C4烷基;R3係氫;且R4係氫、C1-C6烷基或苯基;或當p係0時,則R1及R3組合起來形成稠合C3-C6環烷基環或具有1或2個獨立地選自N、O或S之環雜原子之稠合4至6員雜環,該環烷基或雜環視情況經胺基取代;R2係氫、C1-C6烷基或胺基C1-C4烷基;且R4係氫;或當p係1時,則R1係NHR1a;R1a係氫、C1-C4烷基、C3-C7環烷基、羥基C1-C4烷基或具有一個選自N、O或S之環雜原子之4至6員雜環烷
基;R2係氫、C1-C4烷基、羥基C1-C4烷基或C(O)NH2;R3係氫、鹵素、C1-C4烷基、C1-C4烷氧基或羥基;且R4係氫、C1-C4烷基或鹵素;或當p係0或1時,則C(NHR1a)R2組合起來形成螺環4至6員雜環烷基;R3係氫、鹵素、C1-C4烷基、C1-C4烷氧基或羥基;且R4係氫或鹵素;或當p係1時,則R1及R3組合起來形成稠合4至6員雜環或稠合3至7員碳環,該雜環包含環氮原子及視情況0或1個選自N、O及S之額外環雜原子,且該碳環經胺基取代;且R2係氫;且R4係氫、鹵素或羥基;R5表示1或2個獨立地選自氫、鹵素、羥基、胺基、C1-C6烷基或C1-C6烷氧基之取代基;R6係-(CR7R8)-A;或R6係4至7員內醯胺,其視情況經一個或兩個獨立地選自由以下組成之群之取代基取代:羥基、C1-C6烷基、C2-C6烯基、C2-C6炔基、鹵基C1-C6烷基、C1-C6烷氧基、鹵基C1-C6烷氧基、羥基C1-C6烷基、C1-C6烷氧基C1-C6烷基、苯基或具有一個選自N、O或S之環雜原子及0或1個額外環氮原子之5或6員雜芳基,其中該雜芳基或苯基係視情況經0、1或2個C1-C6烷基或鹵素取代;或R6係部分不飽和9或10員雙環碳環,其視情況經1或2個獨立地選自以下之取代基取代:鹵素、氰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、鹵基C1-C6烷基、C1-C6烷氧基、鹵基C1-C6烷氧基、C(O)NH2及C(O)NHC1-C6烷基;A係5或6員雜芳基,該雜芳基包含一個選自N、O或S之環雜原子
及0、1或2個額外環氮原子,該雜芳基視情況經0、1、2、3或4個獨立地選自以下之基團取代:鹵素、氰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、鹵基C1-C6烷基、C1-C6烷氧基、鹵基C1-C6烷氧基、C(O)NH2、C(O)NHC1-C6烷基、苯基或具有一個選自N、O或S之環雜原子及0、1或2個額外環氮原子之5或6員雜芳基,其中該視情況存在之雜芳基或苯基取代基進一步經0、1或2個C1-C6烷基取代;或A係經1、2或3個獨立地選自以下之取代基取代之苯基:鹵素、C1-C6烷基、C2-C6烯基、C2-C6炔基、鹵基C1-C6烷基、氰基C1-C6烷基、C1-C6烷氧基、鹵基C1-C6烷氧基、氰基C1-C6烷氧基、S(O)qC1-C6烷基、S(O)2NH2、S(O)2NHC1-C6烷基、S(O)2N(C1-C6烷基)2、C(O)NH2、C(O)NHC1-C6烷基、C(O)N(C1-C6烷基)2、羥基、氰基或具有一個選自N、O或S之環雜原子及0、1或2個額外環氮原子之5或6員雜芳基,該雜芳基進一步經0、1或2個C1-C6烷基取代;或A係C(O)OR9或C(O)NR9R10;或A係具有0、1或2個環氮原子及0或1個選自N、O或S之額外環雜原子的視情況經取代之9或10員芳族或部分不飽和雙環,該雙環經0、1或2個獨立地選自由以下組成之群之取代基取代:鹵素、氰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、鹵基C1-C6烷基、C1-C6烷氧基、鹵基C1-C6烷氧基、C(O)NH2、C(O)OH或C(O)NHC1-C6烷基;R7係氫、C1-C4烷基或胺基;R8係氫或C1-C4烷基;或CR7R8組合起來形成3至6員環烷二基;R9係氫、C1-C6烷基、羥基C1-C6烷基、鹵基C1-C6烷基或氰基C1-
C6烷基;R10係氫、C1-C6烷基、C2-C6烯基、C2-C6炔基、鹵基C1-C6烷基、C3-C7環烷基或4至7員雜環,該雜環具有1或2個選自N、O或S之環雜原子,該硫可視情況經氧化,且其中每一烷基或環烷基視情況經以下取代:氰基、鹵素、羥基、C1-C6烷氧基、S(O)qC1-C6烷基、具有1或2個選自N、O或S之環雜原子之4至6員雜環或具有1個選自N、O或S之環雜原子及0、1或2個額外環氮原子之5或6員雜芳基;或NR9R10組合起來形成具有一個環氮原子及0或1個選自N、O或S之額外環雜原子之單環或雙環4至9員雜環,該環硫可視情況經氧化,該雜環視情況經0、1或2個選自以下之取代基取代:鹵素、側氧基、羥基、氰基、C1-C6烷基、鹵基C1-C6烷基、羥基C1-C6烷基、C1-C6烷氧基、S(O)qC1-C6烷基、CO2H、C(O)C1-C6烷基或C(O)NH2;q係0、1或2;Z1係N或CR11;Z2係N或CR12;Z3係N或CR13;Z4係N或CR14,Z5及Z6各自獨立地係N或C;其中Z1、Z2、Z3、Z4、Z5及Z6中之0、1或2者係N;R11、R12、R13及R14中之每一者獨立地選自由以下組成之群:氫、鹵素、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6烷氧基、鹵基C1-C6烷基、鹵基C1-C6烷氧基、C3-C7環烷基、氰基、SO2C1-C6烷基、苯基及具有1或2個獨立地選自N、O及S之環雜原子之飽和、部分不飽
和或芳族5或6員雜環,該雜環視情況經1或2個獨立地選自C1-C6烷基及鹵素之取代基取代;且前提條件係式I化合物不包括1-[7-氟-6-甲氧基-1-[[2-(三氟甲基)苯基]甲基]-1H-苯并咪唑-2-基]-3-哌啶胺。
前提條件提供於第一實施例中以明確排除且放棄索引為CAS號1014407-24-9之鑑別化合物。
其中變數p、R1、R2、R3、R4、R5、R6、Z1、Z2、Z3、Z4、Z5及Z6係如第一或第二實施例中所定義。
在第三實施例中,本發明提供第一或第二實施例之化合物,其中p係0;R1係氫、C1-C6烷基、鹵素或羥基;R2係胺基C1-C4烷基;且R3及R4係氫。
在第四實施例中,本發明提供第一或第二實施例之化合物,其中p係0;R1及R3組合起來形成稠合C3-C6環烷基環或稠合4至6員氮雜環,該環烷基或氮雜環視情況經胺基取代;且R2及R4係氫。
在第五實施例中,本發明提供第四實施例之化合物,其中R1及R3組合起來形成稠合吡咯啶;且R2及R4係氫。
在第六實施例中,本發明提供第一或第二實施例之化合物,其中p係1,R1係NHR1a;R1a係氫、C1-C4烷基、C3-C7環烷基或
具有一個選自N、O或S之環雜原子之4至6員雜環烷基;R2係氫或C1-C4烷基;R3係氫、鹵素、C1-C4烷基、C1-C4烷氧基或羥基;且R4係氫、鹵素或C1-C4烷基。
在第七實施例中,本發明提供第六實施例之化合物,其中R1係NHR1a;R1a係氫、甲基、乙基、丙基、異丙基或環丙基;R2係氫或甲基;R3係氫、鹵素、甲基、乙基、甲氧基、乙氧基或羥基;且R4係氫、鹵素、甲基或乙基。在第七實施例之某些態樣中,提供化合物,其中R1a係氫或甲基;R2係氫,R3係氫、氟、甲基或羥基;且R4係氫、鹵素、甲基或乙基。
在第八實施例中,本發明提供第六或第七實施例之化合物,其中R1係NH2;R2係氫;R3係氫、氟、甲基或羥基;且R4係氫、氟或甲基。
在第九實施例中,本發明提供第一或第二實施例之化合物,其中p係1;CR1R2組合起來形成螺環4至6員雜環烷基;R3係氫、鹵素或C1-C4烷基、C1-C4烷氧基、羥基;且R4係氫或鹵素。
在第十實施例中,本發明提供第一或第二實施例之化合物,其中p係1;R1及R3組合起來形成經胺基取代之稠合4或5員碳環;且R2及R4係氫。
在第十一實施例中,本發明提供第一至第十實施例中任一實施例之化合物,其中R5表示1或2個獨立地選自氫、鹵素、羥基、C1-C4烷基之取代基。
在第十二實施例中,本發明提供第十一實施例之化合物,其中R5表示氫。
在第十三實施例中,本發明提供第一至第十二實施例中任一實施例之化合物,其中R6係-(CR7R8)-A。
在第十四實施例中,本發明提供第十三實施例之化合物,其中R7係氫、甲基或乙基;R8係氫;或CR7R8組合起來形成環丙二基。
在第十五實施例中,本發明提供第十三或第十四實施例之化合物,其中R7係氫或甲基;且R8係氫。
在第十六實施例中,本發明提供第十三至第十五實施例中任一實施例之化合物,其中A係5或6員雜芳基,該雜芳基包含一個選自N、O或S之環雜原子及0、1或2個額外環氮原子,該雜芳基視情況經0、1或2個獨立地選自以下之基團取代:鹵素、氰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、鹵基C1-C6烷基、C1-C6烷氧基、鹵基C1-C6烷氧基、C(O)NH2、C(O)NHC1-C6烷基、苯基或具有一個選自N、O或S之環雜原子及0、1或2個額外環氮原子之5或6員雜芳基,其中該視情況存在之雜芳基或苯基取代基進一步經0、1或2個C1-C6烷基取代。
在第十七實施例中,本發明提供第十六實施例之化合物,其中A係吡啶-2-基、吡啶-3-基、嘧啶-2-基或吡嗪-2-基,其各自經1至3個獨立地選自由以下組成之群之基團取代:鹵素、氰基、C1-C4烷基、鹵基C1-C4烷基、C1-C4烷氧基、鹵基C1-C4烷氧基、C(O)NH2、C(O)NHC1-C4烷基、苯基或具有一個選自N、O或S之環雜原子及0、1或2個額外環氮原子之5員雜芳基,其中該視情況存在之雜芳基或苯基取代基進一步經0、1或2個C1-C6烷基取代。
在第十八實施例中,本發明提供第十三至第十五實施
例中任一實施例之化合物,其中A係經1、2或3個獨立地選自以下之取代基取代之苯基:鹵素、C1-C6烷基、鹵基C1-C6烷基、C1-C6烷氧基、鹵基C1-C6烷氧基、羥基、氰基或具有一個選自N、O或S之環雜原子及0、1或2個額外環氮原子之5或6員雜芳基,該雜芳基進一步經0、1或2個C1-C6烷基取代。
在第十九實施例中,本發明提供第十八實施例之化合物,其中A係經一個選自由以下組成之群之取代基取代的苯基:鹵素、C1-C4烷基、鹵基C1-C4烷基、C1-C4烷氧基、鹵基C1-C4烷氧基、羥基、氰基或具有一個選自N、O或S之環雜原子及0、1或2個額外環氮原子之5員雜芳基,且其中該苯基視情況進一步經鹵素、C1-C4烷基、C1-C4烷氧基、鹵基C1-C4烷基或鹵基C1-C4烷氧基取代。
在第二十實施例中,本發明提供第十八或第十九實施例之化合物,其中A係經1或2個獨立地選自以下之取代基取代之苯基:鹵素、C1-C3烷基、鹵基C1-C4烷基、C1-C4烷氧基、鹵基C1-C4烷氧基、羥基或氰基。
在第二十一實施例中,本發明提供第十三至第十五實施例中任一實施例之化合物,其中A係C(O)NR9R10;R9係氫或C1-C4烷基;R10係C1-C4烷基、鹵基C1-C4烷基、C3-C7環烷基或4至7員雜環,該雜環具有1或2個選自N、O或S之環雜原子,該硫可視情況經氧化,且其中每一烷基或環烷基視情況經氰基、鹵素、羥基、C1-C6烷氧基、S(O)qC1-C6烷基取代;或NR9R10組合起來形成具有一個環氮原子及0或1個選自N、O或S之
額外環雜原子之單環或雙環4至9員氮雜環,該環硫可視情況經氧化,該氮雜環視情況經0、1或2個選自以下之取代基取代:鹵素、側氧基、羥基、氰基、C1-C6烷基、鹵基C1-C6烷基、羥基C1-C6烷基、C1-C6烷氧基、S(O)2C1-C6烷基、CO2H、C(O)C1-C6烷基或C(O)NH2。
在第二十二實施例中,本發明提供第二十一實施例之化合物,其中R9係氫、甲基或乙基;且R10係C1-C4烷基或鹵基C1-C4烷基,其中每一烷基視情況經氰基、鹵素、羥基、C1-C6烷氧基或S(O)qC1-C6烷基取代。
在第二十三實施例中,本發明提供第二十一實施例之化合物,其中NR9R10組合起來形成4至6員單環氮雜環或7至9員雙環氮雜環,其各自具有一個環氮原子及0或1個選自N、O或S之額外環雜原子,該環硫可視情況經氧化,其中每一氮雜環視情況經0、1或2個選自以下之取代基取代:鹵素、側氧基、羥基、氰基、C1-C6烷基、鹵基C1-C6烷基、羥基C1-C6烷基、C1-C6烷氧基、S(O)2C1-C6烷基、CO2H、C(O)C1-C6烷基或C(O)NH2。
在第二十六實施例中,本發明提供第一至第十二實施例中任一實施例之化合物,其中R6係2-側氧基-吡咯啶-3-基或2-側氧基-哌啶-3-基,其各自在氮經以下取代:C1-C6烷基、C2-C6烯基、C2-C6炔基、鹵基C1-C6烷基、C1-C6烷氧基、鹵基C1-C6烷氧基、羥基C1-C6烷基、C1-C6烷氧基C1-C6烷基、苯基或具有一個選自N、O或S之環雜原子及0或1個額外環氮原子之5或6員雜芳基,其中該雜芳基或苯基視情況經0、1或2個C1-C6烷基或鹵素取代。
其中t係1或2;且R19係經0、1或2個鹵素取代之C1-C6烷基、苯基。
在第二十八實施例中,本發明提供第一至第二十七實施例中任一實施例之化合物,其中Z1係CR11;Z2係CR12;Z3係CR13;Z4係N或CR14,Z5及Z6各自係C;R11係氫、鹵素、氰基或C1-C4烷基;R12及R13各自獨立地選自由以下組成之群:氫、鹵素、氰基、
C1-C4烷基、鹵基C1-C4烷基、C1-C4烷氧基、鹵基C1-C4烷氧基、C3-C6環烷基或具有1或2個獨立地選自N、O及S之環雜原子之5員飽和、部分不飽和或芳族5或6員雜環;且R14係氫、鹵素、氰基或C1-C4烷基。
在第二十八實施例之某些態樣中,提供化合物,其中R11係氫。
在第二十八實施例之某些其他態樣中,提供化合物,其中R14係氫、氟、氯、甲基或氰基。在第二十八實施例之某些態樣中,提供化合物,其中R12及R13各自獨立地選自由以下組成之群:氫、氟、氯、氰基、C1-C4烷基、鹵基C1-C4烷基、C1-C4烷氧基及鹵基C1-C4烷氧基。
在第二十八實施例之其他態樣中,提供化合物,其中R11係氫;R14係氫、氟、氯、甲基或氰基;且R12及R13各自獨立地選自由以下組成之群:氫、氟、氯、氰基、甲基、乙基、甲氧基、乙氧基、氟甲基、二氟甲基、三氟甲基、氟甲氧基、二氟甲氧基及三氟甲氧基。
其中R1係NHR1a;
R1a係氫、C1-C4烷基、C3-C7環烷基或具有一個選自N、O或S之環雜原子之4至6員雜環烷基;R2係氫或C1-C4烷基;R3係氫、鹵素、C1-C4烷基、C1-C4烷氧基或羥基;R4係氫或鹵素;R7係氫、甲基或乙基;A係C(O)NR9R10;或A係5或6員雜芳基,該雜芳基包含一個選自N、O或S之環雜原子及0、1或2個額外環氮原子,該雜芳基視情況經0、1或2個獨立地選自以下之基團取代:鹵素、氰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、鹵基C1-C6烷基、C1-C6烷氧基、鹵基C1-C6烷氧基、C(O)NH2、C(O)NHC1-C6烷基、苯基或具有一個選自N、O或S之環雜原子及0、1或2個額外環氮原子之5或6員雜芳基,其中該視情況存在之雜芳基或苯基取代基進一步經0、1或2個C1-C6烷基取代;或A係經一個選自由以下組成之群之取代基取代的苯基:鹵素、C1-C4烷基、鹵基C1-C4烷基、C1-C4烷氧基、鹵基C1-C4烷氧基、羥基、氰基或具有一個選自N、O或S之環雜原子及0、1或2個額外環氮原子之5員雜芳基,且其中該苯基視情況進一步經鹵素、C1-C4烷基、C1-C4烷氧基、鹵基C1-C4烷基或鹵基C1-C4烷氧基取代。
R9係氫或C1-C4烷基;R10係C1-C4烷基、鹵基C1-C4烷基、C3-C7環烷基或4至7員雜環,該雜環具有1或2個選自N、O或S之環雜原子,該硫可視情況經氧化,且其中每一烷基或環烷基視情況經氰基、鹵素、羥基、C1-C6烷氧
基、S(O)qC1-C6烷基取代;或NR9R10組合起來形成具有一個環氮原子及0或1個選自N、O或S之額外環雜原子之單環或雙環4至9員氮雜環,該環硫可視情況經氧化,該氮雜環視情況經0、1或2個選自以下之取代基取代:鹵素、側氧基、羥基、氰基、C1-C6烷基、鹵基C1-C6烷基、羥基C1-C6烷基、C1-C6烷氧基、S(O)2C1-C6烷基、CO2H、C(O)C1-C6烷基或C(O)NH2;Z4係CR14或N;R11係氫、鹵素、氰基或C1-C4烷基;R12及R13各自獨立地選自由以下組成之群:氫、鹵素、氰基、C1-C4烷基、鹵基C1-C4烷基、C1-C4烷氧基、鹵基C1-C4烷氧基、C3-C6環烷基或具有1或2個獨立地選自N、O及S之環雜原子之5員飽和、部分不飽和或芳族5或6員雜環;且R14係氫、鹵素、氰基或C1-C4烷基。
其中X1係CR16或N;X2係CR17或N;X3係CR18或N;Z4係N或CR14;R1係NHR1a;R1a係氫或C1-C4烷基;R2係氫或C1-C4烷基;R3係氫或鹵素;R4係氫或鹵素;R7係氫、甲基或乙基;R11係氫、鹵素、氰基或C1-C4烷基;R12及R13各自獨立地選自由以下組成之群:氫、鹵素、氰基、C1-C4烷基、鹵基C1-C4烷基、C1-C4烷氧基或鹵基C1-C4烷氧基;R14係氫、鹵素、氰基或C1-C4烷基;R15係氫、鹵素、氰基、C1-C4烷基、C1-C4烷氧基、鹵基C1-C4烷基、鹵基C1-C4烷氧基、C(O)NH2、C(O)NH(C1-C4烷基)或具有一個選自N、O或S之環雜原子及0、1或2個額外環氮原子之5員雜芳基;
R16係氫、鹵素、氰基、C1-C4烷基、C1-C4烷氧基、鹵基C1-C4烷基或鹵基C1-C4烷氧基;R17係氫或鹵素;且R18係氫、鹵素、氰基、C1-C4烷基、C1-C4烷氧基、鹵基C1-C4烷基或鹵基C1-C4烷氧基,其中R15、R16、R17或R18中之至少一者不為氫。
在第三十一實施例中,本發明提供第二十九或第三十實施例之化合物,其中R2係氫、R7係氫或甲基;且Z4係CR14。
其中:R1a係氫或C1-C4烷基;R3係氫或鹵素;R4係氫或鹵素;R7係氫、甲基或乙基;R11係氫、鹵素、氰基或C1-C4烷基;R12及R13各自獨立地選自由以下組成之群:氫、鹵素、氰基、C1-C4烷基、鹵基C1-C4烷基、C1-C4烷氧基或鹵基C1-C4烷氧基;
R14係氫、鹵素、氰基或C1-C4烷基;且R15係氫、鹵素、氰基、C1-C4烷基、C1-C4烷氧基、鹵基C1-C4烷基、鹵基C1-C4烷氧基、C(O)NH2或C(O)NH(C1-C4烷基)。
其中:R1a係氫或C1-C4烷基;R3係氫或鹵素;R4係氫或鹵素;R7係氫、甲基或乙基;
R11係氫、鹵素、氰基或C1-C4烷基;R12及R13各自獨立地選自由以下組成之群:氫、鹵素、氰基、C1-C4烷基、鹵基C1-C4烷基、C1-C4烷氧基或鹵基C1-C4烷氧基;R14係氫、鹵素、氰基或C1-C4烷基;且R15係氫、鹵素、氰基、C1-C4烷基、C1-C4烷氧基、鹵基C1-C4烷基、鹵基C1-C4烷氧基、C(O)NH2或C(O)NH(C1-C4烷基)。
其中R1a係氫或C1-C4烷基;
R3係氫或鹵素;R4係氫或鹵素;R7係氫、甲基或乙基;R11係氫、鹵素、氰基或C1-C4烷基;R12及R13各自獨立地選自由以下組成之群:氫、鹵素、氰基、C1-C4烷基、鹵基C1-C4烷基、C1-C4烷氧基或鹵基C1-C4烷氧基;R14係氫、鹵素、氰基或C1-C4烷基;R15係氫、鹵素、氰基、C1-C4烷基、C1-C4烷氧基、鹵基C1-C4烷基、鹵基C1-C4烷氧基、C(O)NH2、C(O)NH(C1-C4烷基)或具有一個選自N、O或S之環雜原子及0、1或2個額外環氮原子之5員雜芳基;R16係氫、鹵素、氰基、C1-C4烷基、C1-C4烷氧基、鹵基C1-C4烷基或鹵基C1-C4烷氧基;R17係氫或鹵素;且R18係氫、鹵素、氰基、C1-C4烷基、C1-C4烷氧基、鹵基C1-C4烷基或鹵基C1-C4烷氧基,其中R15、R16、R17或R18中之至少一者不為氫。
其中R1a係氫或C1-C4烷基;R3係氫或鹵素;R4係氫或鹵素;R7係氫、甲基或乙基;R9係氫、甲基或乙基;R10係C1-C4烷基或鹵基C1-C4烷基,其中每一烷基視情況經氰基、鹵素、羥基、C1-C6烷氧基或S(O)qC1-C6烷基取代;或NR9R10組合起來形成4至6員單環氮雜環或7至9員雙環氮雜環,其各自具有一個環氮原子及0或1個選自N、O或S之額外環雜原子,該
環硫可視情況經氧化,其中每一氮雜環視情況經0、1或2個選自以下之取代基取代:鹵素、側氧基、羥基、氰基、C1-C6烷基、鹵基C1-C6烷基、羥基C1-C6烷基、C1-C6烷氧基、S(O)2C1-C6烷基、CO2H、C(O)C1-C6烷基或C(O)NH2;R11係氫、鹵素、氰基或C1-C4烷基;R12及R13各自獨立地選自由以下組成之群:氫、鹵素、氰基、C1-C4烷基、鹵基C1-C4烷基、C1-C4烷氧基或鹵基C1-C4烷氧基;且R14係氫、鹵素、氰基或C1-C4烷基。
在第三十六實施例中,本發明提供第二十九至第三十五實施例中任一實施例之化合物,其中R11係氫。
在第三十七實施例中,本發明提供第三十一至第三十五實施例中任一實施例之化合物,其中R1a係氫或甲基;R3係氫或氟;且R4係氫或氟。
在第三十八實施例中,本發明提供第一或第二實施例之化合物,其中該化合物列舉於下表A中。
表A
(S)-6-((2-(3-胺基哌啶-1-基)-6-氯-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;(S)-6-((2-(3-胺基哌啶-1-基)-5-氯-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;(S)-6-((2-(3-胺基哌啶-1-基)-4-氯-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;6-((2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-4-氯-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;6-((2-((3R,4S)-3-胺基-4-氟哌啶-1-基)-4-氯-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;6-((2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-6-氯-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;6-((2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5-氯-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;6-((2-((3R,4S)-3-胺基-4-氟哌啶-1-基)-6-氯-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;6-((2-((3R,4S)-3-胺基-4-氟哌啶-1-基)-5-氯-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;(R)-6-((2-(3-胺基-4,4-二氟哌啶-1-基)-4-氯-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-1-((5-氰基吡啶-2-基)甲基)-1H-苯并[d]咪唑-4-甲腈;(R)-6-((2-(3-胺基-4,4-二氟哌啶-1-基)-6-氯-1H-苯并[d]咪唑-1-基)
甲基)菸鹼腈;(R)-6-((2-(3-胺基-4,4-二氟哌啶-1-基)-5-氯-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;6-((2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-6-(三氟甲基)-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;6-((2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5-(三氟甲基)-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;6-((2-((3S,4S)-3-胺基-4-氟哌啶-1-基)-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;(S)-6-((2-(5-胺基-3,3-二氟哌啶-1-基)-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-1-((5-氰基吡啶-2-基)甲基)-6-氟-1H-苯并[d]咪唑-4-甲腈;6-((2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-6-(三氟甲氧基)-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;6-((2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5-(三氟甲氧基)-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;6-((2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-6-氟-5-(三氟甲基)-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;6-((2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5-氟-6-(三氟甲基)-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;6-((2-((3aR,7aR)-六氫-1H-吡咯并[2,3-c]吡啶-6(2H)-基)-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;
6-((2-((3aR,7aS)-六氫-1H-吡咯并[2,3-c]吡啶-6(2H)-基)-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;6-((2-((3aS,7aS)-六氫-1H-吡咯并[2,3-c]吡啶-6(2H)-基)-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;6-((2-((3aS,7aR)-六氫-1H-吡咯并[2,3-c]吡啶-6(2H)-基)-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;(R)-6-((2-(1,6-二氮雜螺[3.5]壬-6-基)-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;(S)-6-((2-(1,6-二氮雜螺[3.5]壬-6-基)-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;(3R,4R)-1-(1-((5-氯吡啶-2-基)甲基)-6-(甲基磺醯基)-1H-苯并[d]咪唑-2-基)-4-氟哌啶-3-胺;(3R,4R)-1-(1-((5-氯吡啶-2-基)甲基)-5-(甲基磺醯基)-1H-苯并[d]咪唑-2-基)-4-氟哌啶-3-胺;2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-1-((5-氯嘧啶-2-基)甲基)-6-氟-1H-苯并[d]咪唑-4-甲腈;(3R,4R)-1-(5,7-二氟-1-((5-氟吡啶-2-基)甲基)-1H-苯并[d]咪唑-2-基)-4-氟哌啶-3-胺;(3R,4R)-1-(4,6-二氟-1-((5-氟吡啶-2-基)甲基)-1H-苯并[d]咪唑-2-基)-4-氟哌啶-3-胺;(3R,4R)-1-(5,7-二氟-1-((5-氟嘧啶-2-基)甲基)-1H-苯并[d]咪唑-2-基)-4-氟哌啶-3-胺;(3R,4R)-1-(4,6-二氟-1-((5-氟嘧啶-2-基)甲基)-1H-苯并[d]咪唑-2-
基)-4-氟哌啶-3-胺;2-((3R,4S)-3-胺基-4-氟哌啶-1-基)-6-氟-1-((5-氟嘧啶-2-基)甲基)-1H-苯并[d]咪唑-4-甲腈;2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-6-氟-1-((5-氟嘧啶-2-基)甲基)-1H-苯并[d]咪唑-4-甲腈;6-((2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;(3R,4S)-1-(1-((5-氯嘧啶-2-基)甲基)-6-氟-1H-苯并[d]咪唑-2-基)-4-氟哌啶-3-胺;(3R,4S)-1-(1-((5-氯嘧啶-2-基)甲基)-5-氟-1H-苯并[d]咪唑-2-基)-4-氟哌啶-3-胺;(R)-2-(3-胺基-4,4-二氟哌啶-1-基)-1-((5-氯嘧啶-2-基)甲基)-1H-苯并[d]咪唑-6-甲腈;(R)-2-(3-胺基-4,4-二氟哌啶-1-基)-1-((5-氯嘧啶-2-基)甲基)-1H-苯并[d]咪唑-5-甲腈;6-((2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氯-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;((3R,4R)-1-(1-((5-氰基吡啶-2-基)甲基)-5,6-二甲基-1H-苯并[d]咪唑-2-基)-4-氟哌啶-3-基)胺基甲酸第三丁基酯;(S)-6-((2-(3-胺基哌啶-1-基)-6-氟-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈鹽酸鹽;(S)-6-((2-(3-胺基哌啶-1-基)-5-氟-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈鹽酸鹽;
6-((2-((3R,4S)-3-胺基-4-氟哌啶-1-基)-6-氟-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈鹽酸鹽;6-((2-((3R,4S)-3-胺基-4-氟哌啶-1-基)-5-氟-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈鹽酸鹽;6-((2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5-氟-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈鹽酸鹽;6-((2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-6-氟-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈鹽酸鹽;(S)-2-(3-胺基哌啶-1-基)-1-((5-氰基吡啶-2-基)甲基)-1H-苯并[d]咪唑-6-甲腈;(S)-2-(3-胺基哌啶-1-基)-1-((5-氰基吡啶-2-基)甲基)-1H-苯并[d]咪唑-5-甲腈;2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-1-((5-氰基吡啶-2-基)甲基)-1H-苯并[d]咪唑-6-甲腈;2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-1-((5-氰基吡啶-2-基)甲基)-1H-苯并[d]咪唑-5-甲腈;(R)-2-(3-胺基-4,4-二氟哌啶-1-基)-1-((5-氰基吡啶-2-基)甲基)-1H-苯并[d]咪唑-6-甲腈;(R)-2-(3-胺基-4,4-二氟哌啶-1-基)-1-((5-氰基吡啶-2-基)甲基)-1H-苯并[d]咪唑-5-甲腈;(S)-6-((2-(3-胺基哌啶-1-基)-4,6-二氯-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;6-((2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-4,6-二氯-1H-苯并[d]咪唑-
1-基)甲基)菸鹼腈;6-((2-((3R,4S)-3-胺基-4-氟哌啶-1-基)-4,6-二氯-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;(R)-6-((2-(3-胺基-4,4-二氟哌啶-1-基)-4,6-二氯-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;(S)-6-((2-(3-胺基哌啶-1-基)-4,6-二氟-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;(S)-6-((2-(3-胺基哌啶-1-基)-5,7-二氟-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;6-((2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-4,6-二氟-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;6-((2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,7-二氟-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;6-((2-((3R,4S)-3-胺基-4-氟哌啶-1-基)-4,6-二氟-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;6-((2-((3R,4S)-3-胺基-4-氟哌啶-1-基)-5,7-二氟-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;(R)-6-((2-(3-胺基-4,4-二氟哌啶-1-基)-5,7-二氟-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;2-((3R,4S)-3-胺基-4-氟哌啶-1-基)-1-((5-氰基吡啶-2-基)甲基)-1H-苯并[d]咪唑-6-甲腈;2-((3R,4S)-3-胺基-4-氟哌啶-1-基)-1-((5-氰基吡啶-2-基)甲基)-1H-苯并[d]咪唑-5-甲腈;
(S)-6-((2-(3-胺基哌啶-1-基)-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;(R)-6-((2-(3-胺基-4,4-二氟哌啶-1-基)-5-氟-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈鹽酸鹽;6-((2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;6-((2-((3R,4S)-3-胺基-4-氟哌啶-1-基)-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;6-((2-((1R,5S)-1-(胺基甲基)-3-氮雜二環[3.1.0]己-3-基)-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈鹽酸鹽;6-((2-((1S,5R)-1-(胺基甲基)-3-氮雜二環[3.1.0]己-3-基)-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈鹽酸鹽;6-((2-((3aR,4R,6aS)-4-胺基六氫環戊[c]吡咯-2(1H)-基)-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈鹽酸鹽;6-((2-((3aS,4S,6aR)-4-胺基六氫環戊[c]吡咯-2(1H)-基)-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈鹽酸鹽;6-((2-((3aR,4S,6aS)-4-胺基六氫環戊[c]吡咯-2(1H)-基)-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈鹽酸鹽;6-((2-((3aS,4R,6aR)-4-胺基六氫環戊[c]吡咯-2(1H)-基)-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈鹽酸鹽;(R)-6-((2-(3-(胺基甲基)吡咯啶-1-基)-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈鹽酸鹽;(S)-6-((2-(3-(胺基甲基)吡咯啶-1-基)-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈鹽酸鹽;
6-((2-((3R,4S)-3-胺基-4-氟哌啶-1-基)-5,6-二氯-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈鹽酸鹽;6-((2-((3R,4S)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈鹽酸鹽;(R)-6-((2-(3-胺基-4,4-二氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈鹽酸鹽;(R)-1-(1-((5-氯吡啶-2-基)甲基)-1H-苯并[d]咪唑-2-基)-4,4-二氟哌啶-3-胺鹽酸鹽;(3R,4S)-1-(1-((5-氯吡啶-2-基)甲基)-1H-苯并[d]咪唑-2-基)-4-氟哌啶-3-胺鹽酸鹽;(R)-6-((2-(3-胺基-4,4-二氟哌啶-1-基)-4,6-二氟-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈鹽酸鹽;(R)-6-((2-(3-胺基-4,4-二氟哌啶-1-基)-6-氟-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;(R)-6-((2-(3-胺基-4,4-二氟哌啶-1-基)-4-(三氟甲基)-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;6-((2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-4-(三氟甲基)-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;6-((2-((3R,4S)-3-胺基-4-氟哌啶-1-基)-4-(三氟甲基)-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;6-((2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-6-氯-3H-咪唑并[4,5-b]吡啶-3-基)甲基)菸鹼腈;6-((2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-6-氯-1H-咪唑并[4,5-b]吡啶
-1-基)甲基)菸鹼腈;6-((2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-6-氯-1H-咪唑并[4,5-b]吡啶-1-基)甲基)-N-(第三丁基)菸鹼醯胺;6-((2-((3R,4R)-3-胺基-4-羥基哌啶-1-基)-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;6-((2-((3S,4S)-3-胺基-4-羥基哌啶-1-基)-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;6-((2-(2,6-二氮雜螺[3.4]辛-6-基)-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;6-((2-((4aR,7aS)-六氫吡咯并[3,4-b][1,4]噁嗪-6(2H)-基)-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈鹽酸鹽;6-((2-((4aS,7aR)-六氫吡咯并[3,4-b][1,4]噁嗪-6(2H)-基)-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈鹽酸鹽;6-((2-((4aR,7aR)-六氫吡咯并[3,4-b][1,4]噁嗪-6(2H)-基)-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;6-((2-((4aS,7aS)-六氫吡咯并[3,4-b][1,4]噁嗪-6(2H)-基)-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;(S)-3-胺基-1-(1-((5-氰基吡啶-2-基)甲基)-1H-苯并[d]咪唑-2-基)哌啶-3-甲醯胺;(R)-3-胺基-1-(1-((5-氰基吡啶-2-基)甲基)-1H-苯并[d]咪唑-2-基)哌啶-3-甲醯胺;(S)-6-((2-(3-胺基-3-(羥基甲基)哌啶-1-基)-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;
(R)-6-((2-(3-胺基-3-(羥基甲基)哌啶-1-基)-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;6-((2-((3R,4S)-3-胺基-4-氟-1-哌啶基)-6-(三氟甲基)-1H-苯并咪唑-1-基)甲基)-3-吡啶甲腈;6-((2-((3R,4S)-3-胺基-4-氟-1-哌啶基)-5-(三氟甲基)-1H-苯并咪唑-1-基)甲基)-3-吡啶甲腈;6-((2-((3R)-3-胺基-4,4-二氟-1-哌啶基)-6-(三氟甲基)-1H-苯并咪唑-1-基)甲基)-3-吡啶甲腈;6-((2-((3R)-3-胺基-4,4-二氟-1-哌啶基)-5-(三氟甲基)-1H-苯并咪唑-1-基)甲基)-3-吡啶甲腈;6-((2-((3R,4R)-3-胺基-4-氟-1-哌啶基)-5-甲基-1H-苯并咪唑-1-基)甲基)-3-吡啶甲腈;6-((2-((3R,4R)-3-胺基-4-氟-1-哌啶基)-6-甲基-1H-苯并咪唑-1-基)甲基)-3-吡啶甲腈;6-((2-((3R,4R)-3-胺基-4-氟-1-哌啶基)-6-氯-5-甲基-1H-苯并咪唑-1-基)甲基)-3-吡啶甲腈;6-((2-((3R,4R)-3-胺基-4-氟-1-哌啶基)-5-氯-6-甲基-1H-苯并咪唑-1-基)甲基)-3-吡啶甲腈;6-((2-((3R,4R)-3-胺基-4-氟-1-哌啶基)-6-氟-5-甲基-1H-苯并咪唑-1-基)甲基)-3-吡啶甲腈;6-((2-((3R,4R)-3-胺基-4-氟-1-哌啶基)-5-氟-6-甲基-1H-苯并咪唑-1-基)甲基)-3-吡啶甲腈;6-((2-((3S)-3-(甲基胺基)-1-哌啶基)-1H-苯并咪唑-1-基)甲基)-3-
吡啶甲腈;6-((2-((3R)-3-(甲基胺基)-1-哌啶基)-1H-苯并咪唑-1-基)甲基)-3-吡啶甲腈;6-((2-((3R,4R)-3-胺基-4-氟-1-哌啶基)-6-(二氟甲氧基)-1H-苯并咪唑-1-基)甲基)-3-吡啶甲腈;6-((2-((3R,4R)-3-胺基-4-氟-1-哌啶基)-5-(二氟甲氧基)-1H-苯并咪唑-1-基)甲基)-3-吡啶甲腈;6-((2-((3R,4R)-3-胺基-4-氟-1-哌啶基)-4-甲氧基-1H-苯并咪唑-1-基)甲基)-3-吡啶甲腈;6-((2-((3R,4R)-3-胺基-4-氟-1-哌啶基)-4-甲基-1H-苯并咪唑-1-基)甲基)-3-吡啶甲腈;5-((2-((3R,4S)-3-胺基-4-氟-1-哌啶基)-6-(三氟甲基)-1H-苯并咪唑-1-基)甲基)-2-吡嗪甲醯胺;5-((2-((3R,4S)-3-胺基-4-氟-1-哌啶基)-5-(三氟甲基)-1H-苯并咪唑-1-基)甲基)-2-吡嗪甲醯胺;6-((2-((3R,4R)-3-胺基-4-氟-1-哌啶基)-6-氯-5-(三氟甲氧基)-1H-苯并咪唑-1-基)甲基)-3-吡啶甲腈;6-((2-((3R,4R)-3-胺基-4-氟-1-哌啶基)-5-氯-6-(三氟甲氧基)-1H-苯并咪唑-1-基)甲基)-3-吡啶甲腈;6-((2-((3R,4R)-3-胺基-4-氟-1-哌啶基)-6-氯-5-(三氟甲基)-1H-苯并咪唑-1-基)甲基)-3-吡啶甲腈;6-((2-((3R,4R)-3-胺基-4-氟-1-哌啶基)-5-氯-6-(三氟甲基)-1H-苯并咪唑-1-基)甲基)-3-吡啶甲腈;
6-((2-((5R)-1,7-二氮雜螺[4.5]癸-7-基)-1H-苯并咪唑-1-基)甲基)-3-吡啶甲腈,6-((2-((5S)-1,7-二氮雜螺[4.5]癸-7-基)-1H-苯并咪唑-1-基)甲基)-3-吡啶甲腈;6-((2-((6R)-1,8-二氮雜螺[5.5]十一-8-基)-1H-苯并咪唑-1-基)甲基)-3-吡啶甲腈;6-((2-((6S)-1,8-二氮雜螺[5.5]十一-8-基)-1H-苯并咪唑-1-基)甲基)-3-吡啶甲腈;6-((2-((4aR,8aR)-六氫-2H-吡啶并[4,3-b][1,4]噁嗪-6(5H)-基)-1H-苯并咪唑-1-基)甲基)-3-吡啶甲腈;6-((2-((4aS,8aS)-六氫-2H-吡啶并[4,3-b][1,4]噁嗪-6(5H)-基)-1H-苯并咪唑-1-基)甲基)-3-吡啶甲腈;5-((2-((3R,4R)-3-胺基-4-氟-1-哌啶基)-5,6-二氟-1H-苯并咪唑-1-基)甲基)-2-吡嗪甲醯胺;5-((2-((3R,4R)-3-胺基-4-氟-1-哌啶基)-6-(三氟甲基)-1H-苯并咪唑-1-基)甲基)-2-吡嗪甲醯胺;6-((2-((5R)-1,7-二氮雜螺[4.5]癸-7-基)-1H-苯并咪唑-1-基)甲基)-3-吡啶甲腈;6-((2-((5S)-1,7-二氮雜螺[4.5]癸-7-基)-1H-苯并咪唑-1-基)甲基)-3-吡啶甲腈;6-((2-((3R)-3-胺基-4,4-二氟-1-哌啶基)-5-甲氧基-1H-苯并咪唑-1-基)甲基)-3-吡啶甲腈;6-((2-((3R)-3-胺基-4,4-二氟-1-哌啶基)-6-甲氧基-1H-苯并咪唑-1-基)甲基)-3-吡啶甲腈;
6-((2-((3S)-3-(甲基胺基)-1-哌啶基)-6-(三氟甲基)-1H-苯并咪唑-1-基)甲基)-3-吡啶甲腈;6-((2-((3S)-3-(甲基胺基)-1-哌啶基)-5-(三氟甲基)-1H-苯并咪唑-1-基)甲基)-3-吡啶甲腈;6-((2-((3S)-3-胺基-3-甲基-1-哌啶基)-1H-苯并咪唑-1-基)甲基)-3-吡啶甲腈;(S)-6-((2-(3-胺基哌啶-1-基)-6-甲氧基-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈2,2,2-三氟乙酸鹽;(S)-6-((2-(3-胺基哌啶-1-基)-5-甲氧基-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈2,2,2-三氟乙酸鹽;6-((2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-4-氯-6-氟-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈2,2,2-三氟乙酸鹽;6-((2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5-甲氧基-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈鹽酸鹽;6-((2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-6-甲氧基-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈鹽酸鹽;6-((2-((3R,4S)-3-胺基-4-氟哌啶-1-基)-6-甲氧基-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈鹽酸鹽;6-((2-((3R,4S)-3-胺基-4-氟哌啶-1-基)-5-甲氧基-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈鹽酸鹽;2-((3R,4S)-3-胺基-4-氟哌啶-1-基)-1-((5-氯嘧啶-2-基)甲基)-6-氟-1H-苯并[d]咪唑-4-甲腈;(R)-2-(3-胺基-4,4-二氟哌啶-1-基)-1-((5-氯嘧啶-2-基)甲基)-5-氟-
1H-苯并[d]咪唑-7-甲腈;(R)-2-(3-胺基-4,4-二氟哌啶-1-基)-1-((5-氯嘧啶-2-基)甲基)-6-氟-1H-苯并[d]咪唑-4-甲腈;6-((2-((3R,4R)-3-胺基-4-羥基哌啶-1-基)-6-氯-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;6-((2-((3R,4S)-3-胺基-4-羥基哌啶-1-基)-6-氯-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;(R)-4-((2-(3-胺基-4,4-二氟哌啶-1-基)-1H-苯并[d]咪唑-1-基)甲基)苯甲腈;4-((2-((3R,4R)-3-胺基-4-羥基哌啶-1-基)-1H-苯并[d]咪唑-1-基)甲基)苯甲腈化合物與4-((2-((3S,4S)-3-胺基-4-羥基哌啶-1-基)-1H-苯并[d]咪唑-1-基)甲基)苯甲腈(1:1)二鹽酸鹽;4-((2-((3R,4R)-3-胺基-4-氟-1-哌啶基)-5,7-二氟-1H-苯并咪唑-1-基)甲基)苯甲腈;4-((2-((3R,4R)-3-胺基-4-氟-1-哌啶基)-4,6-二氟-1H-苯并咪唑-1-基)甲基)苯甲腈;2-((3R,4R)-3-胺基-4-氟-1-哌啶基)-1-(4-氰基苄基)-1H-苯并咪唑-6-甲腈;2-((3R,4R)-3-胺基-4-氟-1-哌啶基)-1-(4-氰基苄基)-1H-苯并咪唑-5-甲腈;2-((3R)-3-胺基-4,4-二氟-1-哌啶基)-1-(4-氰基苄基)-1H-苯并咪唑-6-甲腈;2-((3R)-3-胺基-4,4-二氟-1-哌啶基)-1-(4-氰基苄基)-1H-苯并咪唑-
5-甲腈;(R)-4-((2-(3-胺基哌啶-1-基)-1H-苯并[d]咪唑-1-基)甲基)苯甲腈;4-((2-((3R,4R)-3-胺基-4-甲基哌啶-1-基)-1H-苯并[d]咪唑-1-基)甲基)苯甲腈;4-((2-(3-(胺基甲基)-3-甲基吡咯啶-1-基)-1H-苯并[d]咪唑-1-基)甲基)苯甲腈;4-((2-((3S,4R)-3-胺基-4-苯基吡咯啶-1-基)-1H-苯并[d]咪唑-1-基)甲基)苯甲腈及4-((2-((3R,4S)-3-胺基-4-苯基吡咯啶-1-基)-1H-苯并[d]咪唑-1-基)甲基)苯甲腈;(S)-4-((2-(3-胺基吡咯啶-1-基)-1H-苯并[d]咪唑-1-基)甲基)苯甲腈;(S)-4-((2-(3-胺基哌啶-1-基)-1H-苯并[d]咪唑-1-基)甲基)苯甲腈;4-((2-(6-胺基-2-氮雜螺[4.4]壬-2-基)-1H-苯并[d]咪唑-1-基)甲基)苯甲腈;4-((2-(4-胺基六氫環戊[c]吡咯-2(1H)-基)-1H-苯并[d]咪唑-1-基)甲基)苯甲腈;4-((2-((3S,4S)-3-胺基-4-氟哌啶-1-基)-1H-苯并[d]咪唑-1-基)甲基)苯甲腈;4-((2-((3S,4R)-3-胺基-4-氟哌啶-1-基)-1H-苯并[d]咪唑-1-基)甲基)苯甲腈;4-((2-((3R,4S)-3-胺基-4-氟哌啶-1-基)-1H-苯并[d]咪唑-1-基)甲基)苯甲腈;4-((2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-1H-苯并[d]咪唑-1-基)甲
基)苯甲腈;(R)-4-((2-(3-(胺基甲基)-3-氟吡咯啶-1-基)-1H-苯并[d]咪唑-1-基)甲基)苯甲腈2,2,2-三氟乙酸鹽;(S)-4-((2-(3-(胺基甲基)-3-氟吡咯啶-1-基)-1H-苯并[d]咪唑-1-基)甲基)苯甲腈2,2,2-三氟乙酸鹽;(R)-4-((2-(3-(胺基甲基)-3-羥基吡咯啶-1-基)-1H-苯并[d]咪唑-1-基)甲基)苯甲腈2,2,2-三氟乙酸鹽;(S)-4-((2-(3-(胺基甲基)-3-羥基吡咯啶-1-基)-1H-苯并[d]咪唑-1-基)甲基)苯甲腈2,2,2-三氟乙酸鹽;(S)-4-((2-(3-(胺基甲基)吡咯啶-1-基)-1H-苯并[d]咪唑-1-基)甲基)苯甲腈;(R)-4-((2-(3-(胺基甲基)吡咯啶-1-基)-1H-苯并[d]咪唑-1-基)甲基)苯甲腈;4-((2-((3S,4S)-3-胺基-4-甲基哌啶-1-基)-1H-苯并[d]咪唑-1-基)甲基)苯甲腈2,2,2-三氟乙酸鹽;4-((2-((3S,4R)-3-胺基-4-甲基哌啶-1-基)-1H-苯并[d]咪唑-1-基)甲基)苯甲腈2,2,2-三氟乙酸鹽;4-((2-((3R,4S)-3-胺基-4-甲基哌啶-1-基)-1H-苯并[d]咪唑-1-基)甲基)苯甲腈2,2,2-三氟乙酸鹽;4-((2-((1S,5R)-1-(胺基甲基)-3-氮雜二環[3.1.0]己-3-基)-1H-苯并[d]咪唑-1-基)甲基)苯甲腈;
4-((2-((1R,5S)-1-(胺基甲基)-3-氮雜二環[3.1.0]己-3-基)-1H-苯并[d]咪唑-1-基)甲基)苯甲腈;(R)-4-((2-(3-胺基哌啶-1-基)-6-甲氧基-1H-苯并[d]咪唑-1-基)甲基)苯甲腈;(R)-4-((2-(3-胺基哌啶-1-基)-5-甲氧基-1H-苯并[d]咪唑-1-基)甲基)苯甲腈;2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-1-((5-氯嘧啶-2-基)甲基)-1H-苯并[d]咪唑-6-甲腈;(3R,4R)-4-氟-1-(1-((5-氟嘧啶-2-基)甲基)-1H-苯并[d]咪唑-2-基)哌啶-3-胺;(3R,4R)-4-氟-1-(1-((5-氟吡啶-2-基)甲基)-1H-苯并[d]咪唑-2-基)哌啶-3-胺;2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-1-((5-氟吡啶-2-基)甲基)-1H-苯并[d]咪唑-6-甲腈;2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-1-((5-氟吡啶-2-基)甲基)-1H-苯并[d]咪唑-5-甲腈;(3R,4R)-1-(1-((5-溴嘧啶-2-基)甲基)-1H-苯并[d]咪唑-2-基)-4-氟哌啶-3-胺;(3R,4R)-4-氟-1-(1-((5-(三氟甲基)嘧啶-2-基)甲基)-1H-苯并[d]咪唑-2-基)哌啶-3-胺;(3R,4R)-4-氟-1-(1-((5-甲氧基嘧啶-2-基)甲基)-1H-苯并[d]咪唑-2-基)哌啶-3-胺;(3R,4R)-1-(1-((5-氯嘧啶-2-基)甲基)-1H-苯并[d]咪唑-2-基)-4-氟
哌啶-3-胺;2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-1-((5-氟嘧啶-2-基)甲基)-1H-苯并[d]咪唑-6-甲腈;2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-1-((5-氟嘧啶-2-基)甲基)-1H-苯并[d]咪唑-5-甲腈;2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-1-((5-氰基嘧啶-2-基)甲基)-1H-苯并[d]咪唑-5-甲腈;2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-1-((5-氯嘧啶-2-基)甲基)-1H-苯并[d]咪唑-5-甲腈;2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-1-((5-溴嘧啶-2-基)甲基)-1H-苯并[d]咪唑-6-甲腈;2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-1-((5-溴嘧啶-2-基)甲基)-1H-苯并[d]咪唑-5-甲腈;5-((2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-1H-苯并[d]咪唑-1-基)甲基)吡嗪-2-甲腈;2-((3R,4S)-3-胺基-4-氟哌啶-1-基)-1-((5-氯嘧啶-2-基)甲基)-1H-苯并[d]咪唑-6-甲腈;2-((3R,4S)-3-胺基-4-氟哌啶-1-基)-1-((5-氯嘧啶-2-基)甲基)-1H-苯并[d]咪唑-5-甲腈;(3R,4R)-3-胺基-1-(1-((5-氯嘧啶-2-基)甲基)-6-氟-1H-苯并[d]咪唑-2-基)哌啶-4-醇;(3R,4R)-3-胺基-1-(1-((5-氯嘧啶-2-基)甲基)-5-氟-1H-苯并[d]咪唑-2-基)哌啶-4-醇;
6-((2-((3R,4R)-3-胺基-4-羥基哌啶-1-基)-6-氟-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;6-((2-((3R,4R)-3-胺基-4-羥基哌啶-1-基)-5-氟-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;(S)-1-(1-((5-氯吡啶-2-基)甲基)-1H-苯并[d]咪唑-2-基)哌啶-3-胺;(S)-5-((2-(3-胺基哌啶-1-基)-1H-苯并[d]咪唑-1-基)甲基)吡啶甲腈;(3R,4R)-1-(1-((5-氯吡啶-2-基)甲基)-1H-苯并[d]咪唑-2-基)-4-氟哌啶-3-胺鹽酸鹽;(R)-6-((2-(3-胺基-4,4-二氟哌啶-1-基)-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈鹽酸鹽;2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-1-((5-氯吡啶-2-基)甲基)-1H-苯并[d]咪唑-6-甲腈鹽酸鹽;2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-1-((5-氯吡啶-2-基)甲基)-1H-苯并[d]咪唑-5-甲腈鹽酸鹽;(3R,4R)-1-(1-((R)-1-(5-氯吡啶-2-基)乙基)-1H-苯并[d]咪唑-2-基)-4-氟哌啶-3-胺鹽酸鹽;(3R,4R)-1-(1-((S)-1-(5-氯吡啶-2-基)乙基)-1H-苯并[d]咪唑-2-基)-4-氟哌啶-3-胺鹽酸鹽;(3R,4R)-1-(1-((R)-1-(5-氯吡啶-2-基)乙基)-5,6-二氟-1H-苯并[d]咪唑-2-基)-4-氟哌啶-3-胺鹽酸鹽;(3R,4R)-1-(1-((S)-1-(5-氯吡啶-2-基)乙基)-5,6-二氟-1H-苯并[d]咪
唑-2-基)-4-氟哌啶-3-胺鹽酸鹽;(3R,4R)-1-(5-氯-1-((R)-1-(5-氯吡啶-2-基)乙基)-1H-苯并[d]咪唑-2-基)-4-氟哌啶-3-胺鹽酸鹽;(3R,4R)-1-(5-氯-1-((S)-1-(5-氯吡啶-2-基)乙基)-1H-苯并[d]咪唑-2-基)-4-氟哌啶-3-胺鹽酸鹽;(3R,4R)-1-(6-氯-1-((R)-1-(5-氯吡啶-2-基)乙基)-1H-苯并[d]咪唑-2-基)-4-氟哌啶-3-胺鹽酸鹽;(3R,4R)-1-(6-氯-1-((S)-1-(5-氯吡啶-2-基)乙基)-1H-苯并[d]咪唑-2-基)-4-氟哌啶-3-胺鹽酸鹽;2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-1-((R)-1-(5-氰基吡啶-2-基)乙基)-1H-苯并[d]咪唑-6-甲腈鹽酸鹽;2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-1-((R)-1-(5-氰基吡啶-2-基)乙基)-1H-苯并[d]咪唑-5-甲腈鹽酸鹽;2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-1-((S)-1-(5-氰基吡啶-2-基)乙基)-1H-苯并[d]咪唑-6-甲腈鹽酸鹽;2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-1-((S)-1-(5-氰基吡啶-2-基)乙基)-1H-苯并[d]咪唑-5-甲腈鹽酸鹽;(3R,4R)-1-(1-((5-氯吡啶-2-基)甲基)-5,6-二氟-1H-苯并[d]咪唑-2-基)-4-氟哌啶-3-胺鹽酸鹽;(3R,4R)-1-(5,6-二氟-1-((5-氟吡啶-2-基)甲基)-1H-苯并[d]咪唑-2-基)-4-氟哌啶-3-胺鹽酸鹽;(R)-1-(1-((5-氯吡啶-2-基)甲基)-5,7-二氟-1H-苯并[d]咪唑-2-基)-4,4-二氟哌啶-3-胺鹽酸鹽;
(R)-1-(1-((5-氯吡啶-2-基)甲基)-4,6-二氟-1H-苯并[d]咪唑-2-基)-4,4-二氟哌啶-3-胺鹽酸鹽;(R)-1-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-1H-苯并[d]咪唑-1-基)-2,3-二氫-1H-茚-5-甲腈鹽酸鹽;(S)-1-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-1H-苯并[d]咪唑-1-基)-2,3-二氫-1H-茚-5-甲腈鹽酸鹽;(R)-5-((2-(3-胺基-4,4-二氟哌啶-1-基)-6-氯-1H-苯并[d]咪唑-1-基)甲基)吡嗪-2-甲腈;(R)-5-((2-(3-胺基-4,4-二氟哌啶-1-基)-5-氯-1H-苯并[d]咪唑-1-基)甲基)吡嗪-2-甲腈;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)-N-異丙基乙醯胺;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)-1-(氮雜環丁-1-基)乙酮;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)-N-(2-氰基丙基)-N-乙基乙醯胺;3-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)-1-甲基吡咯啶-2-酮;3-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)-1-苯基哌啶-2-酮;3-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)-1-(4-氯苯基)吡咯啶-2-酮;2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-1-((5-甲氧基嘧啶-2-基)甲基)-
1H-苯并[d]咪唑-5-甲腈鹽酸鹽;2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-1-((5-甲氧基嘧啶-2-基)甲基)-1H-苯并[d]咪唑-6-甲腈鹽酸鹽;2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-1-((6-(三氟甲基)吡啶-3-基)甲基)-1H-苯并[d]咪唑-6-甲腈鹽酸鹽;2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-1-((6-(三氟甲基)吡啶-3-基)甲基)-1H-苯并[d]咪唑-5-甲腈鹽酸鹽;(S)-3-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)-1-甲基吡咯啶-2-酮;(R)-3-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)-1-甲基吡咯啶-2-酮;(S)-3-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)-1-(4-氯苯基)吡咯啶-2-酮;(R)-3-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)-1-(4-氯苯基)吡咯啶-2-酮;2-((3R,4R)-3-胺基-4-氟-1-哌啶基)-1-((5-氰基-2-吡嗪基)甲基)-1H-苯并咪唑-6-甲腈;2-((3R,4R)-3-胺基-4-氟-1-哌啶基)-1-((5-氰基-2-吡嗪基)甲基)-1H-苯并咪唑-5-甲腈;5-((2-((3R,4R)-3-胺基-4-氟-1-哌啶基)-4,6-二氟-1H-苯并咪唑-1-基)甲基)-2-吡嗪甲腈;5-((2-((3R,4R)-3-胺基-4-氟-1-哌啶基)-5,7-二氟-1H-苯并咪唑-1-基)甲基)-2-吡嗪甲腈;
(3S)-1-(1-((5-氟-2-吡啶基)甲基)-1H-苯并咪唑-2-基)-N-甲基-3-哌啶胺;(3S)-1-(1-((5-氯-2-吡啶基)甲基)-1H-苯并咪唑-2-基)-N-甲基-3-哌啶胺;6-((1R)-1-(2-((3S)-3-(甲基胺基)-1-哌啶基)-1H-苯并咪唑-1-基)乙基)-3-吡啶甲腈;6-((1S)-1-(2-((3S)-3-(甲基胺基)-1-哌啶基)-1H-苯并咪唑-1-基)乙基)-3-吡啶甲腈;(3R,4R)-1-(1-((5-氯-2-嘧啶基)甲基)-5,7-二氟-1H-苯并咪唑-2-基)-4-氟-3-哌啶胺;(3R,4R)-1-(1-((5-氯-2-嘧啶基)甲基)-4,6-二氟-1H-苯并咪唑-2-基)-4-氟-3-哌啶胺;(3R,4R)-1-(5,6-二氟-1-((1-甲基-1H-吲唑-4-基)甲基)-1H-苯并咪唑-2-基)-4-氟-3-哌啶胺;(3R,4R)-1-(5,6-二氟-1-(5-喹啉基甲基)-1H-苯并咪唑-2-基)-4-氟-3-哌啶胺;(3R,4R)-1-(5,6-二氟-1-((1R)-1-(8-喹啉基)乙基)-1H-苯并咪唑-2-基)-4-氟-3-哌啶胺;(3R,4R)-1-(5,6-二氟-1-((1S)-1-(8-喹啉基)乙基)-1H-苯并咪唑-2-基)-4-氟-3-哌啶胺;(3R,4R)-1-(1-((3-(3-氯苯基)-1,2-噁唑-5-基)甲基)-5,6-二氟-1H-苯并咪唑-2-基)-4-氟-3-哌啶胺;(3R,4R)-1-(5,6-二氟-1-((1-甲基-1H-吲唑-7-基)甲基)-1H-苯并咪唑
-2-基)-4-氟-3-哌啶胺;(3R,4R)-1-(1-(2,6-二氯苄基)-5,6-二氟-1H-苯并咪唑-2-基)-4-氟-3-哌啶胺;1-(1-氮雜環丁基)-2-(2-((3S)-3-(甲基胺基)-1-哌啶基)-1H-苯并咪唑-1-基)乙酮;6-((1R)-1-(4,6-二氟-2-((4aR,8aR)-六氫-2H-吡啶并[4,3-b][1,4]噁嗪-6(5H)-基)-1H-苯并咪唑-1-基)乙基)-3-吡啶甲腈;6-((1R)-1-(4,6-二氟-2-((4aS,8aS)-六氫-2H-吡啶并[4,3-b][1,4]噁嗪-6(5H)-基)-1H-苯并咪唑-1-基)乙基)-3-吡啶甲腈;6-((1S)-1-(4,6-二氟-2-((4aS,8aS)-六氫-2H-吡啶并[4,3-b][1,4]噁嗪-6(5H)-基)-1H-苯并咪唑-1-基)乙基)-3-吡啶甲腈;6-((1S)-1-(4,6-二氟-2-((4aR,8aR)-六氫-2H-吡啶并[4,3-b][1,4]噁嗪-6(5H)-基)-1H-苯并咪唑-1-基)乙基)-3-吡啶甲腈;6-((1R)-1-(5,7-二氟-2-((4aR,8aR)-六氫-2H-吡啶并[4,3-b][1,4]噁嗪-6(5H)-基)-1H-苯并咪唑-1-基)乙基)-3-吡啶甲腈;6-((1R)-1-(5,7-二氟-2-((4aS,8aS)-六氫-2H-吡啶并[4,3-b][1,4]噁嗪-6(5H)-基)-1H-苯并咪唑-1-基)乙基)-3-吡啶甲腈;6-((1S)-1-(5,7-二氟-2-((4aS,8aS)-六氫-2H-吡啶并[4,3-b][1,4]噁嗪-6(5H)-基)-1H-苯并咪唑-1-基)乙基)-3-吡啶甲腈;6-((1S)-1-(5,7-二氟-2-((4aR,8aR)-六氫-2H-吡啶并[4,3-b][1,4]噁嗪-6(5H)-基)-1H-苯并咪唑-1-基)乙基)-3-吡啶甲腈;2-(2-((3R,4R)-3-胺基-4-氟-1-哌啶基)-5,6-二氟-1H-苯并咪唑-1-基)-N-甲基乙醯胺;
2-(2-((3R,4R)-3-胺基-4-氟-1-哌啶基)-5,6-二氟-1H-苯并咪唑-1-基)-1-(4-嗎啉基)乙酮;2-(2-((3R,4R)-3-胺基-4-氟-1-哌啶基)-5,6-二氟-1H-苯并咪唑-1-基)-1-(1-吡咯啶基)乙酮;2-(2-((3R,4R)-3-胺基-4-氟-1-哌啶基)-5,6-二氟-1H-苯并咪唑-1-基)-N,N-二甲基乙醯胺;(2R)-2-(2-((3R,4R)-3-胺基-4-氟-1-哌啶基)-5,6-二氟-1H-苯并咪唑-1-基)-N,N-二甲基丙醯胺;(2S)-2-(2-((3R,4R)-3-胺基-4-氟-1-哌啶基)-5,6-二氟-1H-苯并咪唑-1-基)-N,N-二甲基丙醯胺;2-(2-((3R,4R)-3-胺基-4-氟-1-哌啶基)-5,6-二氟-1H-苯并咪唑-1-基)-1-(1-哌啶基)乙酮;2-(2-((3R,4R)-3-胺基-4-氟-1-哌啶基)-5,6-二氟-1H-苯并咪唑-1-基)-N-乙基乙醯胺;1-((5-氯-2-嘧啶基)甲基)-2-((3R,4R)-4-氟-3-(甲基胺基)-1-哌啶基)-1H-苯并咪唑-6-甲腈;1-((5-氯-2-嘧啶基)甲基)-2-((3R,4R)-4-氟-3-(甲基胺基)-1-哌啶基)-1H-苯并咪唑-5-甲腈;2-(2-((3R,4R)-3-胺基-4-氟-1-哌啶基)-6-氯-1H-苯并咪唑-1-基)-1-(1-氮雜環丁基)乙酮;2-(2-((3R,4R)-3-胺基-4-氟-1-哌啶基)-5-氯-1H-苯并咪唑-1-基)-1-(1-氮雜環丁基)乙酮;2-((3R,4S)-3-胺基-4-氟-1-哌啶基)-1-(2-(1-氮雜環丁基)-2-側氧基
乙基)-1H-苯并咪唑-6-甲腈;2-((3R,4S)-3-胺基-4-氟-1-哌啶基)-1-(2-(1-氮雜環丁基)-2-側氧基乙基)-1H-苯并咪唑-5-甲腈;(3R,4R)-1-(1-((5-氯嘧啶-2-基)甲基)-6-氟-1H-苯并[d]咪唑-2-基)-4-氟哌啶-3-胺;(3R,4R)-1-(1-((5-氯嘧啶-2-基)甲基)-5-氟-1H-苯并[d]咪唑-2-基)-4-氟哌啶-3-胺;(R)-6-((2-(3-胺基哌啶-1-基)-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;(R)-5-((2-(3-胺基哌啶-1-基)-1H-苯并[d]咪唑-1-基)甲基)吡啶甲腈2,2,2-三氟乙酸鹽;(R)-1-(1-(異喹啉-7-基甲基)-1H-苯并[d]咪唑-2-基)哌啶-3-胺;(R)-1-(1-((1-甲基-1H-吲唑-7-基)甲基)-1H-苯并[d]咪唑-2-基)哌啶-3-胺;6-((R)-1-(2-((S)-3-胺基哌啶-1-基)-1H-苯并[d]咪唑-1-基)乙基)菸鹼腈鹽酸鹽;6-((S)-1-(2-((S)-3-胺基哌啶-1-基)-1H-苯并[d]咪唑-1-基)乙基)菸鹼腈鹽酸鹽;6-((R)-1-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-1H-苯并[d]咪唑-1-基)乙基)菸鹼腈鹽酸鹽;6-((S)-1-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-1H-苯并[d]咪唑-1-基)乙基)菸鹼腈鹽酸鹽;6-((R)-1-(2-((S)-3-胺基哌啶-1-基)-1H-苯并[d]咪唑-1-基)丙基)菸鹼腈鹽酸鹽;
6-((S)-1-(2-((S)-3-胺基哌啶-1-基)-1H-苯并[d]咪唑-1-基)丙基)菸鹼腈鹽酸鹽;(3R,4R)-1-(5,6-二氟-1-((5-氟嘧啶-2-基)甲基)-1H-苯并[d]咪唑-2-基)-4-氟哌啶-3-胺;3-(1-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)乙基)苯甲腈;(3R,4R)-1-(5,6-二氟-1-((5-氟嘧啶-2-基)甲基)-1H-苯并[d]咪唑-2-基)-4-氟哌啶-3-胺;(3R,4S)-1-(5,6-二氟-1-((5-氟吡啶-2-基)甲基)-1H-苯并[d]咪唑-2-基)-4-氟哌啶-3-胺;(3R,4S)-4-氟-1-(1-((5-氟嘧啶-2-基)甲基)-6-(三氟甲基)-1H-苯并[d]咪唑-2-基)哌啶-3-胺;(3R,4S)-4-氟-1-(1-((5-氟嘧啶-2-基)甲基)-5-(三氟甲基)-1H-苯并[d]咪唑-2-基)哌啶-3-胺;(R)-1-(5,6-二氟-1-((5-氟吡啶-2-基)甲基)-1H-苯并[d]咪唑-2-基)-4,4-二氟哌啶-3-胺;2-(2-((3R,4S)-3-胺基-4-氟哌啶-1-基)-6-(三氟甲基)-1H-苯并[d]咪唑-1-基)-1-(氮雜環丁-1-基)乙-1-酮;2-(2-((3R,4S)-3-胺基-4-氟哌啶-1-基)-5-(三氟甲基)-1H-苯并[d]咪唑-1-基)-1-(氮雜環丁-1-基)乙-1-酮;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)-1-(2,2-二甲基吡咯啶-1-基)乙-1-酮;6-((2-((3R,4S)-3-胺基-4-羥基哌啶-1-基)-6-氟-1H-苯并[d]咪唑-1-
基)甲基)菸鹼腈;6-((2-((3R,4S)-3-胺基-4-羥基哌啶-1-基)-5-氟-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;4-((R)-1-(2-((S)-3-胺基哌啶-1-基)-1H-苯并[d]咪唑-1-基)乙基)苯甲腈鹽酸鹽;4-((S)-1-(2-((S)-3-胺基哌啶-1-基)-1H-苯并[d]咪唑-1-基)乙基)苯甲腈鹽酸鹽;(S)-4-((2-(3-胺基哌啶-1-基)-1H-苯并[d]咪唑-1-基)甲基)-3-氟苯甲腈鹽酸鹽;(S)-1-(1-(4-氯苄基)-1H-苯并[d]咪唑-2-基)哌啶-3-胺鹽酸鹽;4-((R)-1-(2-((3R,4S)-3-胺基-4-氟哌啶-1-基)-1H-苯并[d]咪唑-1-基)乙基)苯甲腈鹽酸鹽;4-((S)-1-(2-((3R,4S)-3-胺基-4-氟哌啶-1-基)-1H-苯并[d]咪唑-1-基)乙基)苯甲腈鹽酸鹽;4-((R)-1-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-1H-苯并[d]咪唑-1-基)乙基)苯甲腈鹽酸鹽;4-((S)-1-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-1H-苯并[d]咪唑-1-基)乙基)苯甲腈鹽酸鹽;(S)-4-((2-(3-胺基哌啶-1-基)-1H-苯并[d]咪唑-1-基)甲基)-3-氯苯甲腈鹽酸鹽;(3R,4R)-1-(1-((1R)-1-(2,4-二氯苯基)乙基)-5,6-二氟-1H-苯并咪唑-2-基)-4-氟-3-哌啶胺;(3R,4R)-1-(1-((1S)-1-(2,4-二氯苯基)乙基)-5,6-二氟-1H-苯并咪唑-
2-基)-4-氟-3-哌啶胺;(3R,4R)-1-(1-((1R)-1-(2-氯苯基)乙基)-5,6-二氟-1H-苯并咪唑-2-基)-4-氟-3-哌啶胺;(3R,4R)-1-(1-((1S)-1-(2-氯苯基)乙基)-5,6-二氟-1H-苯并咪唑-2-基)-4-氟-3-哌啶胺;(3R,4R)-1-(1-((1R)-1-(3-氯苯基)乙基)-5,6-二氟-1H-苯并咪唑-2-基)-4-氟-3-哌啶胺;(3R,4R)-1-(1-((1S)-1-(3-氯苯基)乙基)-5,6-二氟-1H-苯并咪唑-2-基)-4-氟-3-哌啶胺;(3R,4R)-1-(1-((1R)-1-(2,5-二氯苯基)乙基)-5,6-二氟-1H-苯并咪唑-2-基)-4-氟-3-哌啶胺;(3R,4R)-1-(1-((1S)-1-(2,5-二氯苯基)乙基)-5,6-二氟-1H-苯并咪唑-2-基)-4-氟-3-哌啶胺;(3R,4R)-1-(1-((1R)-1-(2,4-二氟苯基)乙基)-5,6-二氟-1H-苯并咪唑-2-基)-4-氟-3-哌啶胺;(3R,4R)-1-(1-((1S)-1-(2,4-二氟苯基)乙基)-5,6-二氟-1H-苯并咪唑-2-基)-4-氟-3-哌啶胺;(3R,4R)-1-(1-((1R)-1-(3,4-二氯苯基)乙基)-5,6-二氟-1H-苯并咪唑-2-基)-4-氟-3-哌啶胺;(3R,4R)-1-(1-((1S)-1-(3,4-二氯苯基)乙基)-5,6-二氟-1H-苯并咪唑-2-基)-4-氟-3-哌啶胺;(3R,4R)-1-(1-((1R)-1-(2,5-二氟苯基)乙基)-5,6-二氟-1H-苯并咪唑-2-基)-4-氟-3-哌啶胺;
(3R,4R)-1-(1-((1S)-1-(2,5-二氟苯基)乙基)-5,6-二氟-1H-苯并咪唑-2-基)-4-氟-3-哌啶胺;(3R,4R)-1-(5,6-二氟-1-((1R)-1-(4-(三氟甲基)苯基)乙基)-1H-苯并咪唑-2-基)-4-氟-3-哌啶胺;(3R,4R)-1-(5,6-二氟-1-((1R)-1-(4-(三氟甲氧基)苯基)乙基)-1H-苯并咪唑-2-基)-4-氟-3-哌啶胺;(3R,4R)-1-(1-(5-氯-2-(三氟甲氧基)苄基)-5,6-二氟-1H-苯并咪唑-2-基)-4-氟-3-哌啶胺;(3R,4R)-1-(5,6-二氟-1-(4-(1H-1,2,4-三唑-1-基)苄基)-1H-苯并咪唑-2-基)-4-氟-3-哌啶胺;2-((2-((3R,4R)-3-胺基-4-氟-1-哌啶基)-5,6-二氟-1H-苯并咪唑-1-基)甲基)-5-氯苯甲腈;(3R,4R)-1-(1-(2,4-二氯苄基)-5,6-二氟-1H-苯并咪唑-2-基)-4-氟-3-哌啶胺;4-((2-((3R,4R)-3-胺基-4-氟-1-哌啶基)-5,6-二氟-1H-苯并咪唑-1-基)甲基)-3-(二氟甲氧基)苯甲腈;(3R,4R)-1-(1-(2,5-二氯苄基)-5,6-二氟-1H-苯并咪唑-2-基)-4-氟-3-哌啶胺;(3R,4R)-1-(1-(4-(1,1-二氟乙基)苄基)-5,6-二氟-1H-苯并咪唑-2-基)-4-氟-3-哌啶胺;4-((2-((3R,4R)-3-胺基-4-氟-1-哌啶基)-5,6-二氟-1H-苯并咪唑-1-基)甲基)-2-甲基苯甲腈;4-((2-((3R,4R)-3-胺基-4-氟-1-哌啶基)-5,6-二氟-1H-苯并咪唑-1-
基)甲基)-2-氯苯甲腈;2-((2-((3R,4R)-3-胺基-4-氟-1-哌啶基)-5,6-二氟-1H-苯并咪唑-1-基)甲基)-4-氯苯甲腈;(3R,4R)-1-(1-(2-(二氟甲氧基)苄基)-5,6-二氟-1H-苯并咪唑-2-基)-4-氟-3-哌啶胺;(3R,4R)-1-(1-(3-氯-4-氟苄基)-5,6-二氟-1H-苯并咪唑-2-基)-4-氟-3-哌啶胺;(3R,4R)-1-(1-(4-氯-2-甲氧基苄基)-5,6-二氟-1H-苯并咪唑-2-基)-4-氟-3-哌啶胺;(3R,4R)-1-(1-(2,4-二氟苄基)-5,6-二氟-1H-苯并咪唑-2-基)-4-氟-3-哌啶胺;(3R,4R)-1-(5,6-二氟-1-(2-(三氟甲基)苄基)-1H-苯并咪唑-2-基)-4-氟-3-哌啶胺;2-((2-((3R,4R)-3-胺基-4-氟-1-哌啶基)-5,6-二氟-1H-苯并咪唑-1-基)甲基)苯甲腈;(3R,4R)-1-(1-(2-氯苄基)-5,6-二氟-1H-苯并咪唑-2-基)-4-氟-3-哌啶胺;(3R,4R)-1-(1-(2-氯-4-氟苄基)-5,6-二氟-1H-苯并咪唑-2-基)-4-氟-3-哌啶胺;(3R,4R)-1-(5,6-二氟-1-(4-氟-2-(三氟甲基)苄基)-1H-苯并咪唑-2-基)-4-氟-3-哌啶胺;(3R,4R)-1-(1-(3,4-二氟苄基)-5,6-二氟-1H-苯并咪唑-2-基)-4-氟-3-哌啶胺;
(3R,4R)-1-(1-(4-氯-2-氟苄基)-5,6-二氟-1H-苯并咪唑-2-基)-4-氟-3-哌啶胺;(3R,4R)-1-(1-(3,4-二氯苄基)-5,6-二氟-1H-苯并咪唑-2-基)-4-氟-3-哌啶胺;(3R,4R)-1-(1-(4-氯-3-氟苄基)-5,6-二氟-1H-苯并咪唑-2-基)-4-氟-3-哌啶胺;(3R,4R)-1-(5,6-二氟-1-(4-(三氟甲基)苄基)-1H-苯并咪唑-2-基)-4-氟-3-哌啶胺;(3R,4R)-1-(5,6-二氟-1-(4-(三氟甲氧基)苄基)-1H-苯并咪唑-2-基)-4-氟-3-哌啶胺;(3R,4R)-1-(1-(4-(二氟甲基)苄基)-5,6-二氟-1H-苯并咪唑-2-基)-4-氟-3-哌啶胺;(3R,4R)-1-(5,6-二氟-1-(3-(三氟甲氧基)苄基)-1H-苯并咪唑-2-基)-4-氟-3-哌啶胺;(3R,4R)-1-(5,6-二氟-1-(3-(三氟甲基)苄基)-1H-苯并咪唑-2-基)-4-氟-3-哌啶胺;3-((2-((3R,4R)-3-胺基-4-氟-1-哌啶基)-5,6-二氟-1H-苯并咪唑-1-基)甲基)苯甲腈;(3R,4R)-1-(1-(3-氯苄基)-5,6-二氟-1H-苯并咪唑-2-基)-4-氟-3-哌啶胺;(S)-1-(1-(4-氟苄基)-1H-苯并[d]咪唑-2-基)哌啶-3-胺;(S)-1-(1-(4-(1,2,4-噁二唑-3-基)苄基)-1H-苯并[d]咪唑-2-基)哌啶-3-胺;
(R)-1-(1-(4-(甲基磺醯基)苄基)-1H-苯并[d]咪唑-2-基)哌啶-3-胺;(R)-1-(1-(4-(1H-1,2,4-三唑-1-基)苄基)-1H-苯并[d]咪唑-2-基)哌啶-3-胺;(R)-2-((2-(3-胺基哌啶-1-基)-1H-苯并[d]咪唑-1-基)甲基)苯甲腈;(R)-1-(1-(2,6-二氯苄基)-1H-苯并[d]咪唑-2-基)哌啶-3-胺;(R)-1-(1-(2-氯苄基)-1H-苯并[d]咪唑-2-基)哌啶-3-胺;(R)-1-(1-(4-(三氟甲基)苄基)-1H-苯并[d]咪唑-2-基)哌啶-3-胺;(R)-1-(1-(4-(三氟甲氧基)苄基)-1H-苯并[d]咪唑-2-基)哌啶-3-胺;(R)-1-(1-(4-氯苄基)-1H-苯并[d]咪唑-2-基)哌啶-3-胺;(R)-1-(1-(3-氯苄基)-1H-苯并[d]咪唑-2-基)哌啶-3-胺;(R)-1-(1-(4-(1,1-二氟乙基)苄基)-1H-苯并[d]咪唑-2-基)哌啶-3-胺;(R)-2-(4-((2-(3-胺基哌啶-1-基)-1H-苯并[d]咪唑-1-基)甲基)苯基)-2-甲基丙腈;(R)-1-(1-(4-(二氟甲基)苄基)-1H-苯并[d]咪唑-2-基)哌啶-3-胺;(R)-4-((2-(3-胺基哌啶-1-基)-1H-苯并[d]咪唑-1-基)甲基)-N-甲基苯甲醯胺;(R)-4-((2-(3-胺基哌啶-1-基)-1H-苯并[d]咪唑-1-基)甲基)-3-氟苯甲腈;(R)-2-(4-((2-(3-胺基哌啶-1-基)-1H-苯并[d]咪唑-1-基)甲基)苯氧基)乙腈;(R)-4-((2-(3-胺基哌啶-1-基)-1H-苯并[d]咪唑-1-基)甲基)-N,N-二甲基苯磺醯胺;
(R)-1-(1-(4-甲基苄基)-1H-苯并[d]咪唑-2-基)哌啶-3-胺;(R)-1-(1-(4-氟苄基)-1H-苯并[d]咪唑-2-基)哌啶-3-胺;(R)-1-(1-((1-甲基-1H-吲唑-7-基)甲基)-1H-苯并[d]咪唑-2-基)哌啶-3-胺;(R)-1-(1-(2,4-二氟苄基)-1H-苯并[d]咪唑-2-基)哌啶-3-胺;(R)-1-(1-(3,4-二氟苄基)-1H-苯并[d]咪唑-2-基)哌啶-3-胺;(R)-1-(1-(4-氯-3-氟苄基)-1H-苯并[d]咪唑-2-基)哌啶-3-胺;(R)-1-(1-((3-(3-氯苯基)異噁唑-5-基)甲基)-1H-苯并[d]咪唑-2-基)哌啶-3-胺;(R)-1-(1-(3-氯-4-甲氧基苄基)-1H-苯并[d]咪唑-2-基)哌啶-3-胺;(R)-4-((2-(3-胺基哌啶-1-基)-1H-苯并[d]咪唑-1-基)甲基)-3-氯苯甲腈;(R)-1-(1-(2,4-二氯苄基)-1H-苯并[d]咪唑-2-基)哌啶-3-胺;(R)-4-((2-(3-胺基哌啶-1-基)-1H-苯并[d]咪唑-1-基)甲基)-3-甲氧基苯甲腈;(R)-2-((2-(3-胺基哌啶-1-基)-1H-苯并[d]咪唑-1-基)甲基)-5-氯苯甲腈;4-((R)-1-(2-((R)-3-胺基哌啶-1-基)-1H-苯并[d]咪唑-1-基)乙基)苯甲腈;4-(1-(2-((S)-3-胺基哌啶-1-基)-1H-苯并[d]咪唑-1-基)乙基)苯甲腈;(R)-3-((2-(3-胺基哌啶-1-基)-1H-苯并[d]咪唑-1-基)甲基)苯甲腈;4-((2-((3R,4S)-3-胺基-4-氟哌啶-1-基)-6-氯-1H-苯并[d]咪唑-1-基)
甲基)苯甲腈鹽酸鹽;(S)-4-((2-(3-胺基哌啶-1-基)-6-甲氧基-1H-苯并[d]咪唑-1-基)甲基)苯甲腈鹽酸鹽;4-((2-((3R,4S)-3-胺基-4-氟哌啶-1-基)-6-甲氧基-1H-苯并[d]咪唑-1-基)甲基)苯甲腈;(S)-4-((2-(3-胺基哌啶-1-基)-5-甲氧基-3H-咪唑并[4,5-b]吡啶-3-基)甲基)苯甲腈鹽酸鹽;(R)-4-((2-(3-胺基-4,4-二氟哌啶-1-基)-6-氯-1H-苯并[d]咪唑-1-基)甲基)苯甲腈;(R)-4-((2-(3-胺基-4,4-二氟哌啶-1-基)-6-甲氧基-1H-苯并[d]咪唑-1-基)甲基)苯甲腈;(R)-4-((2-(3-胺基-4,4-二氟哌啶-1-基)-4-氯-1H-苯并[d]咪唑-1-基)甲基)苯甲腈;4-((2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-4-氯-1H-苯并[d]咪唑-1-基)甲基)苯甲腈;4-((2-((3R,4S)-3-胺基-4-氟哌啶-1-基)-4-氯-1H-苯并[d]咪唑-1-基)甲基)苯甲腈;(R)-4-((2-(3-胺基-4,4-二氟哌啶-1-基)-4-甲氧基-1H-苯并[d]咪唑-1-基)甲基)苯甲腈;4-((2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-4-甲氧基-1H-苯并[d]咪唑-1-基)甲基)苯甲腈;4-((2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-1H-咪唑并[4,5-c]吡啶-1-基)甲基)苯甲腈;
4-((2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-3H-咪唑并[4,5-c]吡啶-3-基)甲基)苯甲腈;4-((2-((3R,4R)-3-胺基-4-氟-1-哌啶基)-6-乙氧基-1H-苯并咪唑-1-基)甲基)苯甲腈;4-((2-((3R,4S)-3-胺基-4-氟哌啶-1-基)-1H-咪唑并[4,5-b]吡啶-1-基)甲基)苯甲腈;4-((2-((3R)-3-胺基-4,4-二氟-1-哌啶基)-6-氟-1H-苯并咪唑-1-基)甲基)苯甲腈;4-((2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-1H-咪唑并[4,5-b]吡啶-1-基)甲基)苯甲腈;(S)-4-((2-(3-胺基哌啶-1-基)-4-氯-1H-苯并[d]咪唑-1-基)甲基)苯甲腈2,2,2-三氟乙酸鹽;(S)-4-((2-(3-胺基哌啶-1-基)-3H-咪唑并[4,5-b]吡啶-3-基)甲基)苯甲腈鹽酸鹽;4-((2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-6-氯-1H-苯并[d]咪唑-1-基)甲基)苯甲腈鹽酸鹽;(S)-4-((2-(3-胺基哌啶-1-基)-6-氯-1H-苯并[d]咪唑-1-基)甲基)苯甲腈;(S)-4-((2-(3-胺基哌啶-1-基)-5-氯-1H-苯并[d]咪唑-1-基)甲基)苯甲腈;(R)-1-(2-((S)-3-胺基哌啶-1-基)-1H-苯并[d]咪唑-1-基)-2,3-二氫-1H-茚-5-甲腈;(S)-1-(2-((S)-3-胺基哌啶-1-基)-1H-苯并[d]咪唑-1-基)-2,3-二氫-
1H-茚-5-甲腈;(3R,4R)-4-氟-1-(1-((5-甲氧基吡啶-2-基)甲基)-1H-苯并[d]咪唑-2-基)哌啶-3-胺;1-(2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)乙醯基)氮雜環丁烷-3-甲腈;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)-1-(3-(第三丁氧基)氮雜環丁-1-基)乙-1-酮;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)-1-(3,3-二氟氮雜環丁-1-基)乙酮;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)-1-(3-異丙基氮雜環丁-1-基)乙酮;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)-1-(6,6-二氟-2-氮雜螺[3.3]庚-2-基)乙酮;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)-1-(7-氧雜-2-氮雜螺[3.5]壬-2-基)乙酮;(R)-6-((2-(4,4-二氟-3-(甲基胺基)哌啶-1-基)-6-氟-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;(R)-6-((2-(4,4-二氟-3-((2-羥基乙基)胺基)哌啶-1-基)-6-氟-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;(S)-6-((2-(3-胺基哌啶-1-基)-1H-苯并[d]咪唑-1-基)甲基)菸鹼酸;(S)-6-((2-(3-胺基哌啶-1-基)-1H-苯并[d]咪唑-1-基)甲基)菸鹼醯胺;6-((2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-1H-苯并[d]咪唑-1-基)甲
基)菸鹼醯胺;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)乙酸;6-((R)-1-(4,6-二氟-2-((3R,4R)-4-氟-3-(甲基胺基)哌啶-1-基)-1H-苯并[d]咪唑-1-基)乙基)菸鹼腈;6-((S)-1-(4,6-二氟-2-((3R,4R)-4-氟-3-(甲基胺基)哌啶-1-基)-1H-苯并[d]咪唑-1-基)乙基)菸鹼腈;6-((R)-1-(5,7-二氟-2-((3R,4R)-4-氟-3-(甲基胺基)哌啶-1-基)-1H-苯并[d]咪唑-1-基)乙基)菸鹼腈;及6-((S)-1-(5,7-二氟-2-((3R,4R)-4-氟-3-(甲基胺基)哌啶-1-基)-1H-苯并[d]咪唑-1-基)乙基)菸鹼腈。
在第三十八實施例之另一態樣中,本發明提供第一實施例之化合物,其中該化合物列舉於下表A-1中:表A-1 2-((2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-6-氟-1H-苯并[d]咪唑-1-基)甲基)嘧啶-5-甲腈;2-((2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5-氟-1H-苯并[d]咪唑-1-基)甲基)嘧啶-5-甲腈;(3R,4R)-4-氟-1-(6-氟-1-((5-甲氧基嘧啶-2-基)甲基)-1H-苯并[d]咪唑-2-基)哌啶-3-胺;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-6-氟-1H-苯并[d]咪唑-1-基)-N-甲基-N-(2,2,2-三氟乙基)乙醯胺;(3R,4R)-4-氟-1-(5-氟-1-((5-甲氧基嘧啶-2-基)甲基)-1H-苯并[d]咪
唑-2-基)哌啶-3-胺;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-4-氰基-6-氟-1H-苯并[d]咪唑-1-基)-N-甲基-N-(2,2,2-三氟乙基)乙醯胺;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-6-甲氧基-1H-苯并[d]咪唑-1-基)-N,N-二甲基乙醯胺;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5-甲氧基-1H-苯并[d]咪唑-1-基)-N-甲基-N-(2,2,2-三氟乙基)乙醯胺;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5-甲氧基-1H-苯并[d]咪唑-1-基)-N,N-二甲基乙醯胺;6-((2-((3R,4R)-3-胺基-4-甲氧基哌啶-1-基)-6-氟-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;6-((2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-6-氟-4-甲氧基-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;6-((2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5-(三氟甲基)-3H-咪唑并[4,5-b]吡啶-3-基)甲基)菸鹼腈;(3R,4R)-1-(1-((5-氯嘧啶-2-基)甲基)-6-氟-1H-苯并[d]咪唑-2-基)-4-甲氧基哌啶-3-胺;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-6-溴-1H-苯并[d]咪唑-1-基)-1-(氮雜環丁-1-基)乙-1-酮;(3R,4R)-1-(1-((5-氯嘧啶-2-基)甲基)-6-氟-1H-苯并[d]咪唑-2-基)-4-甲氧基哌啶-3-胺;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-6-氟-1H-苯并[d]咪唑-1-基)-N-甲基-N-(2,2,2-三氟乙基)乙醯胺;
6-((2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5-(三氟甲基)-1H-咪唑并[4,5-b]吡啶-1-基)甲基)菸鹼腈;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-6-(三氟甲基)-1H-苯并[d]咪唑-1-基)-1-嗎啉基乙-1-酮;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5-氟-1H-苯并[d]咪唑-1-基)-N-甲基-N-(2,2,2-三氟乙基)乙醯胺;2-(2-((3R,4S)-3-胺基-4-氟哌啶-1-基)-6-氯-1H-苯并[d]咪唑-1-基)-N,N-二甲基乙醯胺;2-(2-((3R,4S)-3-胺基-4-氟哌啶-1-基)-6-氟-1H-苯并[d]咪唑-1-基)-N-甲基-N-(2,2,2-三氟乙基)乙醯胺;6-((2-((3R,4S)-3-胺基-4-甲氧基哌啶-1-基)-6-氟-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;2-(2-((3R,4S)-3-胺基-4-氟哌啶-1-基)-6-(三氟甲基)-1H-苯并[d]咪唑-1-基)-1-嗎啉基乙-1-酮;(R)-2-(2-(3-胺基-4,4-二氟哌啶-1-基)-6-氟-1H-苯并[d]咪唑-1-基)-N-甲基-N-(2,2,2-三氟乙基)乙醯胺;2-(2-((3R,4S)-3-胺基-4-氟哌啶-1-基)-6-氟-1H-苯并[d]咪唑-1-基)-N-甲基-N-(2,2,2-三氟乙基)乙醯胺;(3R,4S)-1-(1-((5-氯嘧啶-2-基)甲基)-6-氟-1H-苯并[d]咪唑-2-基)-4-甲氧基哌啶-3-胺;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-6-(三氟甲氧基)-1H-苯并[d]咪唑-1-基)-N,N-二甲基乙醯胺;2-(6-氟-2-((3R,4R)-4-氟-3-(甲基胺基)哌啶-1-基)-1H-苯并[d]咪唑
-1-基)-N-甲基-N-(2,2,2-三氟乙基)乙醯胺;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5-溴-1H-苯并[d]咪唑-1-基)-1-(氮雜環丁-1-基)乙-1-酮;2-(2-((3R,4S)-3-胺基-4-氟哌啶-1-基)-5-氯-1H-苯并[d]咪唑-1-基)-N,N-二甲基乙醯胺;2-(6-氟-2-(1,7-二氮雜螺[4.5]癸-7-基)-1H-苯并[d]咪唑-1-基)-N-甲基-N-(2,2,2-三氟乙基)乙醯胺;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5-(三氟甲基)-1H-苯并[d]咪唑-1-基)-1-嗎啉基乙-1-酮;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5-(三氟甲氧基)-1H-苯并[d]咪唑-1-基)-N,N-二甲基乙醯胺;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5-(三氟甲氧基)-1H-苯并[d]咪唑-1-基)-1-嗎啉基乙-1-酮;6-((2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5-氟-7-甲氧基-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;(3R,4S)-1-(1-((5-氯嘧啶-2-基)甲基)-5-氟-1H-苯并[d]咪唑-2-基)-4-甲氧基哌啶-3-胺;2-(2-((3R,4S)-3-胺基-4-氟哌啶-1-基)-5-(三氟甲基)-1H-苯并[d]咪唑-1-基)-1-嗎啉基乙-1-酮;2-(5-氟-2-((3R,4R)-4-氟-3-(甲基胺基)哌啶-1-基)-1H-苯并[d]咪唑-1-基)-N-甲基-N-(2,2,2-三氟乙基)乙醯胺;2-(2-(3-胺基-4-甲基吡咯啶-1-基)-6-氟-1H-苯并[d]咪唑-1-基)-N-甲基-N-(2,2,2-三氟乙基)乙醯胺;
2-(2-((3R,4R)-3-胺基-4-羥基哌啶-1-基)-6-氟-1H-苯并[d]咪唑-1-基)-N-甲基-N-(2,2,2-三氟乙基)乙醯胺;(R)-2-(2-(3-胺基-4,4-二氟哌啶-1-基)-5-氟-1H-苯并[d]咪唑-1-基)-N-甲基-N-(2,2,2-三氟乙基)乙醯胺;2-(2-((3R,4R)-3-胺基-4-甲氧基哌啶-1-基)-5-氟-1H-苯并[d]咪唑-1-基)-N-甲基-N-(2,2,2-三氟乙基)乙醯胺;2-(2-((3R)-3-胺基-4-羥基哌啶-1-基)-5-氟-1H-苯并[d]咪唑-1-基)-N-甲基-N-(2,2,2-三氟乙基)乙醯胺;2-(2-((3R,4R)-3-胺基-4-甲氧基哌啶-1-基)-6-氟-1H-苯并[d]咪唑-1-基)-N-甲基-N-(2,2,2-三氟乙基)乙醯胺;2-(2-(3-(胺基甲基)-3-氟吡咯啶-1-基)-6-氟-1H-苯并[d]咪唑-1-基)-N-甲基-N-(2,2,2-三氟乙基)乙醯胺;2-(2-(3-(胺基甲基)-3-氟吡咯啶-1-基)-5-氟-1H-苯并[d]咪唑-1-基)-N-甲基-N-(2,2,2-三氟乙基)乙醯胺;2-(6-氟-2-((4aR,8aR)-六氫-2H-吡啶并[4,3-b][1,4]噁嗪-6(5H)-基)-1H-苯并[d]咪唑-1-基)-N-甲基-N-(2,2,2-三氟乙基)乙醯胺;(S)-2-(2-(3-胺基吡咯啶-1-基)-6-氟-1H-苯并[d]咪唑-1-基)-N-甲基-N-(2,2,2-三氟乙基)乙醯胺;(R)-2-(2-(3-胺基吡咯啶-1-基)-6-氟-1H-苯并[d]咪唑-1-基)-N-甲基-N-(2,2,2-三氟乙基)乙醯胺;(S)-2-(2-(3-(胺基甲基)吡咯啶-1-基)-6-氟-1H-苯并[d]咪唑-1-基)-N-甲基-N-(2,2,2-三氟乙基)乙醯胺;2-(6-氟-2-((4aR,8aR)-六氫-2H-吡啶并[4,3-b][1,4]噁嗪-6(5H)-基)-
1H-苯并[d]咪唑-1-基)-N-甲基-N-(2,2,2-三氟乙基)乙醯胺;2-(5-氟-2-((4aS,8aS)-六氫-2H-吡啶并[4,3-b][1,4]噁嗪-6(5H)-基)-1H-苯并[d]咪唑-1-基)-N-甲基-N-(2,2,2-三氟乙基)乙醯胺;(3R,4R)-3-胺基-1-(1-((5-氯嘧啶-2-基)甲基)-5-氟-1H-苯并[d]咪唑-2-基)哌啶-4-醇;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-6-氯-1H-苯并[d]咪唑-1-基)-1-嗎啉基乙酮;(3R,4R)-3-胺基-1-(1-((5-氯嘧啶-2-基)甲基)-6-氟-1H-苯并[d]咪唑-2-基)哌啶-4-醇;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5-氯-1H-苯并[d]咪唑-1-基)-1-嗎啉基乙酮;(3R,4R)-1-(1-((R)-1-(5-氯嘧啶-2-基)乙基)-5,6-二氟-1H-苯并[d]咪唑-2-基)-4-氟哌啶-3-胺;6-((2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-6-(三氟甲基)-1H-咪唑并[4,5-b]吡啶-1-基)甲基)菸鹼腈;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)-N-甲基-N-(2,2,2-三氟乙基)乙醯胺;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)-N-甲基-N-(噻唑-2-基)乙醯胺;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-6-氯-1H-苯并[d]咪唑-1-基)-N,N-二甲基乙醯胺;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-6-氟-1H-苯并[d]咪唑-1-基)-1-(氮雜環丁-1-基)乙-1-酮;
2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)-1-(3-(三氟甲基)哌啶-1-基)乙-1-酮;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)-1-(6,7-二氫噻吩并[3,2-c]吡啶-5(4H)-基)乙-1-酮;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5-氯-1H-苯并[d]咪唑-1-基)-N,N-二甲基乙醯胺;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)-1-(2-甲基嗎啉基)乙-1-酮;(3R,4R)-1-(1-((R)-1-(5-氯嘧啶-2-基)乙基)-5,6-二氟-1H-苯并[d]咪唑-2-基)-4-氟哌啶-3-胺;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5-氟-7-甲氧基-1H-苯并[d]咪唑-1-基)-N-甲基-N-(2,2,2-三氟乙基)乙醯胺;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)-1-(氮雜環辛烷-1-基)乙-1-酮;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)-1-(4-(吡嗪-2-基)哌嗪-1-基)乙-1-酮;1-(2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)乙醯基)哌啶-4-甲酸甲基酯;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)-1-(2-乙基嗎啉基)乙-1-酮;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5-氟-1H-苯并[d]咪唑-1-基)-1-(氮雜環丁-1-基)乙-1-酮;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-
基)-N-(1,1-二氧離子基-2,3-二氫噻吩-3-基)-N-苯基乙醯胺;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)-1-(4-甲基哌啶-1-基)乙-1-酮;(3R,4R)-4-氟-1-(6-氟-1-((4-甲氧基吡啶-2-基)甲基)-1H-苯并[d]咪唑-2-基)哌啶-3-胺;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)-1-(2-乙基嗎啉基)乙-1-酮;6-((2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-6-(三氟甲基)-3H-咪唑并[4,5-b]吡啶-3-基)甲基)菸鹼腈;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-1H-苯并[d]咪唑-1-基)-1-(氮雜環丁-1-基)乙-1-酮;1-(2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)乙醯基)哌啶-2-甲醯胺;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)-N-(1,1-二氧離子基四氫噻吩-3-基)-N-(噻吩-2-基甲基)乙醯胺;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)-1-(八氫異喹啉-2(1H)-基)乙-1-酮;(3R,4R)-4-氟-1-(5-氟-1-((4-甲氧基吡啶-2-基)甲基)-1H-苯并[d]咪唑-2-基)哌啶-3-胺;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)-N-(1,1-二氧離子基四氫噻吩-3-基)-N-甲基乙醯胺;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)-N-環丙基-N-(1,1-二氧離子基四氫噻吩-3-基)乙醯胺;
2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)-N-(1,1-二氧離子基四氫噻吩-3-基)-N-乙基乙醯胺;4-(2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)乙醯基)哌嗪-2-酮;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)-1-(4-(吡咯啶-1-羰基)哌啶-1-基)乙-1-酮;1-(2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)乙醯基)哌啶-3-甲醯胺;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)-1-(4-(環丙烷羰基)哌嗪-1-基)乙-1-酮;1-(2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)乙醯基)哌啶-4-甲醯胺;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)-N-(2-氰基丙-2-基)-N-甲基乙醯胺;1-(2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)乙醯基)-N-甲基哌啶-4-甲醯胺;N-(1-(2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)乙醯基)哌啶-3-基)乙醯胺;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)-1-(4-(哌啶-1-羰基)哌啶-1-基)乙-1-酮;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)-1-(4-(氮雜環庚烷-1-羰基)哌啶-1-基)乙-1-酮;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-
基)-N-(1,1-二氧離子基四氫噻吩-3-基)-N-(2-甲氧基乙基)乙醯胺;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)-1-(4-(3-甲基哌啶-1-羰基)哌啶-1-基)乙-1-酮;1-(4-乙醯基哌嗪-1-基)-2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)乙-1-酮;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)-N-(1,1-二氧離子基四氫噻吩-3-基)-N-((四氫呋喃-2-基)甲基)乙醯胺;1-(2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)乙醯基)-N-異丙基-N-甲基哌啶-4-甲醯胺;2-(2-((3R,4R)-3-胺基-4-甲氧基哌啶-1-基)-6-氟-1H-苯并[d]咪唑-1-基)-N-甲基-N-(2,2,2-三氟乙基)乙醯胺;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5-氟-7-甲氧基-1H-苯并[d]咪唑-1-基)-N-甲基-N-(2,2,2-三氟乙基)乙醯胺;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-6-氟-4-甲氧基-1H-苯并[d]咪唑-1-基)-1-嗎啉基乙-1-酮;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5-氟-7-甲氧基-1H-苯并[d]咪唑-1-基)-1-嗎啉基乙-1-酮;(R)-3-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)-1-環丙基吡咯啶-2-酮;(S)-3-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)-1-(四氫-2H-哌喃-4-基)吡咯啶-2-酮;(S)-3-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪
唑-1-基)-1-環丙基吡咯啶-2-酮;(R)-3-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)-1-(四氫-2H-哌喃-4-基)吡咯啶-2-酮;(3R,4R)-1-(5,6-二氟-1-((5-甲基噻唑-2-基)甲基)-1H-苯并[d]咪唑-2-基)-4-氟哌啶-3-胺;(3R,4R)-1-(4,6-二氟-1-((5-甲基-1,3,4-噻二唑-2-基)甲基)-1H-苯并[d]咪唑-2-基)-4-氟哌啶-3-胺;(3R,4R)-1-(5,6-二氟-1-((5-甲基-1,3,4-噻二唑-2-基)甲基)-1H-苯并[d]咪唑-2-基)-4-氟哌啶-3-胺;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-6-(三氟甲基)-1H-苯并[d]咪唑-1-基)-N-甲基-N-(2,2,2-三氟乙基)乙醯胺;(3R,4R)-1-(1-((5-氯嘧啶-2-基)甲基)-6-氟-1H-咪唑并[4,5-b]吡啶-2-基)-4-氟哌啶-3-胺;(3R,4R)-1-(4,6-二氟-1-((5-(甲基磺醯基)吡啶-2-基)甲基)-1H-苯并[d]咪唑-2-基)-4-氟哌啶-3-胺;(3R,4R)-1-(1-((5-(二氟甲基)-1,3,4-噻二唑-2-基)甲基)-4,6-二氟-1H-苯并[d]咪唑-2-基)-4-氟哌啶-3-胺;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-4,6-二氟-1H-苯并[d]咪唑-1-基)-N-甲基-N-(2,2,2-三氟乙基)乙醯胺;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-6-氯-1H-苯并[d]咪唑-1-基)-N-甲基-N-(2,2,2-三氟乙基)乙醯胺;(3R,4R)-1-(1-((5-(二氟甲基)-1,3,4-噻二唑-2-基)甲基)-5,6-二氟-1H-苯并[d]咪唑-2-基)-4-氟哌啶-3-胺;
(3R,4R)-4-氟-1-(6-氟-1-((5-甲基-1,3,4-噻二唑-2-基)甲基)-1H-苯并[d]咪唑-2-基)哌啶-3-胺;(3R,4R)-1-(5,6-二氟-1-((5-(甲基磺醯基)吡啶-2-基)甲基)-1H-苯并[d]咪唑-2-基)-4-氟哌啶-3-胺;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-6-(三氟甲基)-1H-苯并[d]咪唑-1-基)-N,N-二甲基乙醯胺;(3R,4R)-1-(5,6-二氟-1-((5-甲基異噁唑-3-基)甲基)-1H-苯并[d]咪唑-2-基)-4-氟哌啶-3-胺;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-4,6-二氟-1H-苯并[d]咪唑-1-基)-N,N-二甲基乙醯胺;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-6-氟-1H-苯并[d]咪唑-1-基)-N,N-二甲基乙醯胺;(3R,4R)-1-(5,6-二氟-1-((5-甲基噁唑-2-基)甲基)-1H-苯并[d]咪唑-2-基)-4-氟哌啶-3-胺;(3R,4R)-1-(5,6-二氟-1-((4-甲基噻唑-2-基)甲基)-1H-苯并[d]咪唑-2-基)-4-氟哌啶-3-胺;(3R,4R)-4-氟-1-(6-氟-1-((3-(三氟甲基)-1,2,4-噁二唑-5-基)甲基)-1H-苯并[d]咪唑-2-基)哌啶-3-胺;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5-氯-1H-苯并[d]咪唑-1-基)-N-甲基-N-(2,2,2-三氟乙基)乙醯胺;(3R,4R)-1-(5,6-二氟-1-((5-甲基-1,3,4-噁二唑-2-基)甲基)-1H-苯并[d]咪唑-2-基)-4-氟哌啶-3-胺;(3R,4R)-1-(5,6-二氟-1-((5-甲基-1,2,4-噁二唑-3-基)甲基)-1H-苯并
[d]咪唑-2-基)-4-氟哌啶-3-胺;(3R,4R)-1-(1-((5-(二氟甲基)-1,3,4-噻二唑-2-基)甲基)-6-氟-1H-苯并[d]咪唑-2-基)-4-氟哌啶-3-胺;(3R,4R)-4-氟-1-(6-氟-1-((5-甲基-1,3,4-噻二唑-2-基)甲基)-1H-咪唑并[4,5-b]吡啶-2-基)哌啶-3-胺;(3R,4R)-1-(1-((4,5-二甲基噁唑-2-基)甲基)-5,6-二氟-1H-苯并[d]咪唑-2-基)-4-氟哌啶-3-胺;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5-氟-1H-苯并[d]咪唑-1-基)-N,N-二甲基乙醯胺;(3R,4R)-1-(1-((5-乙基-1,2,4-噁二唑-3-基)甲基)-5,6-二氟-1H-苯并[d]咪唑-2-基)-4-氟哌啶-3-胺;(3R,4R)-1-(1-((5-環丙基-1,2,4-噁二唑-3-基)甲基)-5,6-二氟-1H-苯并[d]咪唑-2-基)-4-氟哌啶-3-胺;(3R,4R)-1-(5,6-二氟-1-((3-甲基異噁唑-5-基)甲基)-1H-苯并[d]咪唑-2-基)-4-氟哌啶-3-胺;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5-(三氟甲基)-1H-苯并[d]咪唑-1-基)-N-甲基-N-(2,2,2-三氟乙基)乙醯胺;(3R,4R)-1-(1-((5-環丙基-1,3,4-噁二唑-2-基)甲基)-5,6-二氟-1H-苯并[d]咪唑-2-基)-4-氟哌啶-3-胺;(3R,4R)-4-氟-1-(5-氟-1-((5-甲基-1,3,4-噻二唑-2-基)甲基)-1H-苯并[d]咪唑-2-基)哌啶-3-胺;(3R,4R)-1-(3-((5-氯嘧啶-2-基)甲基)-6-氟-3H-咪唑并[4,5-b]吡啶-2-基)-4-氟哌啶-3-胺;
(3R,4R)-4-氟-1-(5-氟-1-((3-(三氟甲基)-1,2,4-噁二唑-5-基)甲基)-1H-苯并[d]咪唑-2-基)哌啶-3-胺;(3R,4R)-4-氟-1-(6-氟-1-((4-甲基-2-苯基噻唑-5-基)甲基)-1H-苯并[d]咪唑-2-基)哌啶-3-胺;(3R,4R)-1-(1-((4,5-二甲基-4H-1,2,4-三唑-3-基)甲基)-5,6-二氟-1H-苯并[d]咪唑-2-基)-4-氟哌啶-3-胺;(3R,4R)-1-(1-((5-(二氟甲基)-1,3,4-噻二唑-2-基)甲基)-5-氟-1H-苯并[d]咪唑-2-基)-4-氟哌啶-3-胺;(R)-4,4-二氟-1-(6-氟-1-((5-甲基-1,3,4-噻二唑-2-基)甲基)-1H-苯并[d]咪唑-2-基)哌啶-3-胺;(3R,4R)-1-(1-((2,4-二甲基噻唑-5-基)甲基)-6-氟-1H-苯并[d]咪唑-2-基)-4-氟哌啶-3-胺;(3R,4R)-4-氟-1-(6-氟-3-((5-甲基-1,3,4-噻二唑-2-基)甲基)-3H-咪唑并[4,5-b]吡啶-2-基)哌啶-3-胺;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,7-二氟-1H-苯并[d]咪唑-1-基)-N-甲基-N-(2,2,2-三氟乙基)乙醯胺;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5-(三氟甲基)-1H-苯并[d]咪唑-1-基)-N,N-二甲基乙醯胺;(3R,4R)-4-氟-1-(5-氟-1-((4-甲基-2-苯基噻唑-5-基)甲基)-1H-苯并[d]咪唑-2-基)哌啶-3-胺;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,7-二氟-1H-苯并[d]咪唑-1-基)-N,N-二甲基乙醯胺;(3R,4R)-1-(5,7-二氟-1-((5-(甲基磺醯基)吡啶-2-基)甲基)-1H-苯并
[d]咪唑-2-基)-4-氟哌啶-3-胺;(3R,4R)-1-(1-((2,4-二甲基噻唑-5-基)甲基)-5-氟-1H-苯并[d]咪唑-2-基)-4-氟哌啶-3-胺;(R)-4,4-二氟-1-(5-氟-1-((5-甲基-1,3,4-噻二唑-2-基)甲基)-1H-苯并[d]咪唑-2-基)哌啶-3-胺;(3R,4R)-1-(1-((5-(二氟甲基)-1,3,4-噻二唑-2-基)甲基)-5,7-二氟-1H-苯并[d]咪唑-2-基)-4-氟哌啶-3-胺;(3R,4R)-1-(5,7-二氟-1-((5-甲基-1,3,4-噻二唑-2-基)甲基)-1H-苯并[d]咪唑-2-基)-4-氟哌啶-3-胺;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)-1-(2-甲基氮雜環丁-1-基)乙酮;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)-N-(2,2-二氟乙基)-N-甲基乙醯胺;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)-N-環丙基-N-甲基乙醯胺;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)-N-((R)-1-氰基乙基)-N-甲基乙醯胺;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)-N-甲基-N-((R)-1-(吡啶-2-基)乙基)乙醯胺;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)-N-乙基-N-甲基乙醯胺;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)-N-(2-氟乙基)-N-甲基乙醯胺;
2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)-1-((1R,5S)-3-氮雜二環[3.1.0]己-3-基)乙酮;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)-N-甲基-N-(1-(吡啶-2-基)乙基)乙醯胺;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)-1-(2-氮雜二環[3.1.0]己-2-基)乙酮;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)-N-((S)-1-氰基乙基)-N-甲基乙醯胺;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)-N-甲基-N-(四氫呋喃-3-基)乙醯胺;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)-N-(1-氰基丙-2-基)-N-甲基乙醯胺;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)-N-甲基-N-(1-(吡啶-4-基)乙基)乙醯胺;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)-N-甲基-N-(1,1,1-三氟丙-2-基)乙醯胺;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)-N-(氰基甲基)-N-甲基乙醯胺;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)-N-甲基-N-丙基乙醯胺;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)-N-環丙基-N-(2-羥基乙基)乙醯胺;1-(2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑
-1-基)乙醯基)-3-氟吡咯啶-3-甲腈;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)-1-(2-氧雜-5-氮雜二環[2.2.1]庚-5-基)乙酮;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)-1-(六氫哌喃并[4,3-b][1,4]噁嗪-4(7H)-基)乙酮;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)-N-(2-氰基丙基)-N-甲基乙醯胺;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)-N-甲基-N-(3,3,3-三氟丙基)乙醯胺;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)-1-((1R,5S)-6,6-二氟-3-氮雜二環[3.1.0]己-3-基)乙酮;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)-1-(4-(嘧啶-2-基)哌嗪-1-基)乙酮;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)-1-(2-異丙基氮雜環丁-1-基)乙酮;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)-1-(3-(二氟甲氧基)吡咯啶-1-基)乙酮;4-(2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)乙醯基)嗎啉-2-甲腈;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)-1-(3-羥基哌啶-1-基)乙酮;1-(2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)乙醯基)-4-甲基哌啶-4-甲腈;
2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)-1-(3,4-二氫-1,8-萘啶-1(2H)-基)乙酮;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)-N-環丙基-N-(2,2-二氟乙基)乙醯胺;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)-1-(5H-吡咯并[3,4-b]吡啶-6(7H)-基)乙酮;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)-N-甲基-N-((四氫呋喃-3-基)甲基)乙醯胺;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)-N-(2,2-二氟乙基)-N-甲基乙醯胺;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)-N-甲基-N-(2,2,2-三氟乙基)乙醯胺;(R)-1-(2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)乙醯基)吡咯啶-2-甲腈;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)-N-((1r,4R)-4-羥基環己基)-N-甲基乙醯胺;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)-N-甲基-N-((S)-1-(吡啶-2-基)乙基)乙醯胺;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)-1-(八氫-1H-哌喃并[4,3-b]吡啶-1-基)乙酮;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)-1-(4-羥基哌啶-1-基)乙酮;1-(3-(1H-1,2,4-三唑-1-基)氮雜環丁-1-基)-2-(2-((3R,4R)-3-胺基-4-
氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)乙酮;7-(2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)乙醯基)六氫咪唑并[1,5-a]吡嗪-3(2H)-酮;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)-N-(2-氰基乙基)-N-((四氫呋喃-3-基)甲基)乙醯胺;4-(2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)乙醯基)-N-甲基嗎啉-2-甲醯胺;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)-1-(3-((甲基磺醯基)甲基)吡咯啶-1-基)乙酮;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)-1-(5,6-二氫-[1,2,4]三唑并[1,5-a]吡嗪-7(8H)-基)乙酮;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)-1-(2-(甲氧基甲基)嗎啉基)乙酮;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)-1-(3-羥基-3-甲基吡咯啶-1-基)乙酮;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)-1-(4-(甲基磺醯基)哌嗪-1-基)乙酮;N-((1-乙醯基吡咯啶-3-基)甲基)-2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)-N-乙基乙醯胺;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)-N-(1,1-二氧離子基四氫-2H-硫哌喃-4-基)-N-甲基乙醯胺;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)-N-((1,1-二氧離子基四氫噻吩-3-基)甲基)-N-甲基乙醯胺;
2-(1-(2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)乙醯基)哌啶-4-基)-2-甲基丙腈;1-(2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)乙醯基)-N-甲基哌啶-3-甲醯胺;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)-N-(2-羥基乙基)-N-(吡啶-3-基甲基)乙醯胺;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)-N-(2-氰基乙基)-N-(四氫-2H-哌喃-4-基)乙醯胺;1-(2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)乙醯基)-N,N-二甲基哌啶-3-甲醯胺;1-(2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)乙醯基)-4-(甲氧基甲基)哌啶-4-甲腈;7-(2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)乙醯基)四氫-1H-噁唑并[3,4-a]吡嗪-3(5H)-酮;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-6-氟-1H-苯并[d]咪唑-1-基)-N-(噻唑-2-基)乙醯胺;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-6-氟-1H-苯并[d]咪唑-1-基)-N-(2,2,2-三氟乙基)乙醯胺;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-6-氟-1H-苯并[d]咪唑-1-基)-N-環丙基-N-(2,2,2-三氟乙基)乙醯胺;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-6-氟-1H-苯并[d]咪唑-1-基)-N-(2-甲氧基乙基)-N-甲基乙醯胺;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-6-氟-1H-苯并[d]咪唑-1-基)-
N-甲基-N-((S)-四氫呋喃-3-基)乙醯胺;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-6-氟-1H-苯并[d]咪唑-1-基)-N-甲基-N-((R)-四氫呋喃-3-基)乙醯胺;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-6-氟-1H-苯并[d]咪唑-1-基)-N-((S)-1-(吡啶-2-基)乙基)乙醯胺;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-6-氟-1H-苯并[d]咪唑-1-基)-N-((S)-四氫呋喃-3-基)-N-(2,2,2-三氟乙基)乙醯胺;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-6-氟-1H-苯并[d]咪唑-1-基)-N-環丁基乙醯胺;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-6-氟-1H-苯并[d]咪唑-1-基)-N-((S)-1-氰基丙-2-基)乙醯胺;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-6-氟-1H-苯并[d]咪唑-1-基)-N-((R)-1-氰基丙-2-基)乙醯胺;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-6-氟-1H-苯并[d]咪唑-1-基)-N-乙基-N-(2-甲氧基乙基)乙醯胺;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-6-氟-1H-苯并[d]咪唑-1-基)-N-((R)-四氫呋喃-3-基)-N-(2,2,2-三氟乙基)乙醯胺;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-6-氟-1H-苯并[d]咪唑-1-基)-N-(3,3,3-三氟丙基)乙醯胺;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-6-氟-1H-苯并[d]咪唑-1-基)-N-((R)-1-(吡啶-2-基)乙基)乙醯胺;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-6-氟-1H-苯并[d]咪唑-1-基)-N-((S)-四氫呋喃-3-基)乙醯胺;
2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-6-氟-1H-苯并[d]咪唑-1-基)-N-((R)-四氫呋喃-3-基)乙醯胺;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-6-氟-1H-苯并[d]咪唑-1-基)-1-(2-甲基氮雜環丁-1-基)乙-1-酮;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-6-氟-1H-苯并[d]咪唑-1-基)-1-((S)-3-甲基嗎啉基)乙-1-酮;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-6-氟-1H-苯并[d]咪唑-1-基)-1-((R)-2-甲基吡咯啶-1-基)乙-1-酮;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-6-氟-1H-苯并[d]咪唑-1-基)-1-((R)-3-(甲氧基甲基)嗎啉基)乙-1-酮;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-6-氟-1H-苯并[d]咪唑-1-基)-1-((R)-3-甲基嗎啉基)乙-1-酮;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-6-氟-1H-苯并[d]咪唑-1-基)-1-((S)-2-甲基吡咯啶-1-基)乙-1-酮;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-6-氟-1H-苯并[d]咪唑-1-基)-1-(3,5-二甲基嗎啉基)乙-1-酮;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-6-氟-1H-苯并[d]咪唑-1-基)-1-(3-乙基嗎啉基)乙-1-酮;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-6-氟-1H-苯并[d]咪唑-1-基)-1-((S)-3-環丙基嗎啉基)乙-1-酮;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-6-氟-1H-苯并[d]咪唑-1-基)-1-((R)-3-(羥基甲基)嗎啉基)乙-1-酮;及2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-6-氟-1H-苯并[d]咪唑-1-基)-
1-(3,3-二甲基嗎啉基)乙-1-酮。
在第三十九實施例中,本發明提供第一或第二實施例之化合物,其中該化合物列舉於下表B中:表B 6-((2-((3R,4S)-3-胺基-4-氟哌啶-1-基)-6-氯-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-1-((5-氰基吡啶-2-基)甲基)-1H-苯并[d]咪唑-4-甲腈;6-((2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5-(三氟甲基)-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;6-((2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-6-(三氟甲氧基)-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-1-((5-氯嘧啶-2-基)甲基)-6-氟-1H-苯并[d]咪唑-4-甲腈;(3R,4R)-1-(4,6-二氟-1-((5-氟吡啶-2-基)甲基)-1H-苯并[d]咪唑-2-基)-4-氟哌啶-3-胺;(3R,4R)-1-(4,6-二氟-1-((5-氟嘧啶-2-基)甲基)-1H-苯并[d]咪唑-2-基)-4-氟哌啶-3-胺;2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-6-氟-1-((5-氟嘧啶-2-基)甲基)-1H-苯并[d]咪唑-4-甲腈;6-((2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;6-((2-((3R,4S)-3-胺基-4-氟哌啶-1-基)-5-氟-1H-苯并[d]咪唑-1-基)
甲基)菸鹼腈鹽酸鹽;6-((2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5-氟-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈鹽酸鹽;6-((2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-4,6-二氟-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;(R)-6-((2-(3-胺基-4,4-二氟哌啶-1-基)-4,6-二氟-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈鹽酸鹽;(R)-6-((2-(3-胺基-4,4-二氟哌啶-1-基)-6-氟-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;6-((2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-6-氯-1H-咪唑并[4,5-b]吡啶-1-基)甲基)菸鹼腈;6-((2-((3R)-3-胺基-4,4-二氟-1-哌啶基)-6-(三氟甲基)-1H-苯并咪唑-1-基)甲基)-3-吡啶甲腈;6-((2-((3R,4R)-3-胺基-4-氟-1-哌啶基)-5-(二氟甲氧基)-1H-苯并咪唑-1-基)甲基)-3-吡啶甲腈;6-((2-((3R,4R)-3-胺基-4-氟-1-哌啶基)-4-甲氧基-1H-苯并咪唑-1-基)甲基)-3-吡啶甲腈;6-((2-((3R)-3-胺基-4,4-二氟-1-哌啶基)-6-甲氧基-1H-苯并咪唑-1-基)甲基)-3-吡啶甲腈;6-((2-((3R,4S)-3-胺基-4-氟哌啶-1-基)-6-甲氧基-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈鹽酸鹽;2-((3R,4S)-3-胺基-4-氟哌啶-1-基)-1-((5-氯嘧啶-2-基)甲基)-6-氟-1H-苯并[d]咪唑-4-甲腈;
(R)-2-(3-胺基-4,4-二氟哌啶-1-基)-1-((5-氯嘧啶-2-基)甲基)-6-氟-1H-苯并[d]咪唑-4-甲腈;4-((2-((3R,4R)-3-胺基-4-氟-1-哌啶基)-4,6-二氟-1H-苯并咪唑-1-基)甲基)苯甲腈;4-((2-((3S,4S)-3-胺基-4-氟哌啶-1-基)-1H-苯并[d]咪唑-1-基)甲基)苯甲腈;4-((2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-1H-苯并[d]咪唑-1-基)甲基)苯甲腈;(R)-4-((2-(3-胺基哌啶-1-基)-6-甲氧基-1H-苯并[d]咪唑-1-基)甲基)苯甲腈;2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-1-((5-氯嘧啶-2-基)甲基)-1H-苯并[d]咪唑-6-甲腈;(3R,4R)-4-氟-1-(1-((5-氟嘧啶-2-基)甲基)-1H-苯并[d]咪唑-2-基)哌啶-3-胺;2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-1-((5-氟嘧啶-2-基)甲基)-1H-苯并[d]咪唑-6-甲腈;2-((3R,4S)-3-胺基-4-氟哌啶-1-基)-1-((5-氯嘧啶-2-基)甲基)-1H-苯并[d]咪唑-6-甲腈;(3R,4R)-3-胺基-1-(1-((5-氯嘧啶-2-基)甲基)-6-氟-1H-苯并[d]咪唑-2-基)哌啶-4-醇;(R)-1-(1-((5-氯吡啶-2-基)甲基)-4,6-二氟-1H-苯并[d]咪唑-2-基)-4,4-二氟哌啶-3-胺鹽酸鹽;(3R,4R)-1-(1-((5-氯-2-嘧啶基)甲基)-4,6-二氟-1H-苯并咪唑-2-基)-
4-氟-3-哌啶胺;2-(2-((3R,4R)-3-胺基-4-氟-1-哌啶基)-5,6-二氟-1H-苯并咪唑-1-基)-1-(1-哌啶基)乙酮;2-(2-((3R,4R)-3-胺基-4-氟-1-哌啶基)-6-氯-1H-苯并咪唑-1-基)-1-(1-氮雜環丁基)乙酮;(3R,4R)-1-(1-((5-氯嘧啶-2-基)甲基)-6-氟-1H-苯并[d]咪唑-2-基)-4-氟哌啶-3-胺;(3R,4R)-1-(1-((5-氯嘧啶-2-基)甲基)-5-氟-1H-苯并[d]咪唑-2-基)-4-氟哌啶-3-胺;(3R,4R)-1-(5,6-二氟-1-((5-氟嘧啶-2-基)甲基)-1H-苯并[d]咪唑-2-基)-4-氟哌啶-3-胺;(3R,4S)-4-氟-1-(1-((5-氟嘧啶-2-基)甲基)-6-(三氟甲基)-1H-苯并[d]咪唑-2-基)哌啶-3-胺;及4-((2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-6-氯-1H-苯并[d]咪唑-1-基)甲基)苯甲腈鹽酸鹽。
在第四十實施例中,本發明提供第一或第二實施例之化合物,其中該化合物列舉於下表C中:表C 6-((2-((3R,4S)-3-胺基-4-氟哌啶-1-基)-6-氯-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;6-((2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-6-(三氟甲氧基)-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-1-((5-氯嘧啶-2-基)甲基)-6-氟-
1H-苯并[d]咪唑-4-甲腈;(3R,4R)-1-(4,6-二氟-1-((5-氟吡啶-2-基)甲基)-1H-苯并[d]咪唑-2-基)-4-氟哌啶-3-胺;(3R,4R)-1-(4,6-二氟-1-((5-氟嘧啶-2-基)甲基)-1H-苯并[d]咪唑-2-基)-4-氟哌啶-3-胺;6-((2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;6-((2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5-氟-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈鹽酸鹽;6-((2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-4,6-二氟-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;(R)-6-((2-(3-胺基-4,4-二氟哌啶-1-基)-4,6-二氟-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈鹽酸鹽;(R)-6-((2-(3-胺基-4,4-二氟哌啶-1-基)-6-氟-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;6-((2-((3R,4R)-3-胺基-4-氟-1-哌啶基)-4-甲氧基-1H-苯并咪唑-1-基)甲基)-3-吡啶甲腈;6-((2-((3R)-3-胺基-4,4-二氟-1-哌啶基)-6-甲氧基-1H-苯并咪唑-1-基)甲基)-3-吡啶甲腈;2-((3R,4S)-3-胺基-4-氟哌啶-1-基)-1-((5-氯嘧啶-2-基)甲基)-6-氟-1H-苯并[d]咪唑-4-甲腈;(R)-2-(3-胺基-4,4-二氟哌啶-1-基)-1-((5-氯嘧啶-2-基)甲基)-6-氟-1H-苯并[d]咪唑-4-甲腈;
2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-1-((5-氯嘧啶-2-基)甲基)-1H-苯并[d]咪唑-6-甲腈;(3R,4R)-4-氟-1-(1-((5-氟嘧啶-2-基)甲基)-1H-苯并[d]咪唑-2-基)哌啶-3-胺;2-((3R,4S)-3-胺基-4-氟哌啶-1-基)-1-((5-氯嘧啶-2-基)甲基)-1H-苯并[d]咪唑-6-甲腈;(R)-1-(1-((5-氯吡啶-2-基)甲基)-4,6-二氟-1H-苯并[d]咪唑-2-基)-4,4-二氟哌啶-3-胺鹽酸鹽;(3R,4R)-1-(1-((5-氯-2-嘧啶基)甲基)-4,6-二氟-1H-苯并咪唑-2-基)-4-氟-3-哌啶胺;及(3R,4R)-1-(1-((5-氯嘧啶-2-基)甲基)-6-氟-1H-苯并[d]咪唑-2-基)-4-氟哌啶-3-胺。
在第四十一實施例中,本發明提供第一或第二實施例之化合物,其中該化合物列舉於下表D中:表D 6-((2-((3R,4S)-3-胺基-4-氟哌啶-1-基)-6-氯-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-1-((5-氯嘧啶-2-基)甲基)-6-氟-1H-苯并[d]咪唑-4-甲腈;(3R,4R)-1-(4,6-二氟-1-((5-氟嘧啶-2-基)甲基)-1H-苯并[d]咪唑-2-基)-4-氟哌啶-3-胺;6-((2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;
(R)-6-((2-(3-胺基-4,4-二氟哌啶-1-基)-4,6-二氟-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈鹽酸鹽;(R)-6-((2-(3-胺基-4,4-二氟哌啶-1-基)-6-氟-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;6-((2-((3R,4R)-3-胺基-4-氟-1-哌啶基)-4-甲氧基-1H-苯并咪唑-1-基)甲基)-3-吡啶甲腈;2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-1-((5-氯嘧啶-2-基)甲基)-1H-苯并[d]咪唑-6-甲腈;(3R,4R)-4-氟-1-(1-((5-氟嘧啶-2-基)甲基)-1H-苯并[d]咪唑-2-基)哌啶-3-胺;及(3R,4R)-1-(1-((5-氯嘧啶-2-基)甲基)-6-氟-1H-苯并[d]咪唑-2-基)-4-氟哌啶-3-胺。
在又一實施例中,本文揭示之化合物中之每一者係以醫藥學上可接受之鹽形式提供。
在第四十二實施例中,本發明提供6-((2-((3R,4S)-3-胺基-4-氟哌啶-1-基)-6-氯-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈。在第四十二實施例之某些態樣中,本發明提供6-((2-((3R,4S)-3-胺基-4-氟哌啶-1-基)-6-氯-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈之醫藥學上可接受之鹽。
在第四十三實施例中,本發明提供2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-1-((5-氯嘧啶-2-基)甲基)-6-氟-1H-苯并[d]咪唑-4-甲腈。在第四十三實施例之某些態樣中,本發明提供2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-1-((5-氯嘧啶-2-基)甲基)-6-氟-1H-苯并[d]咪唑-4-甲腈
之醫藥學上可接受之鹽。
在第四十四實施例,本發明提供(3R,4R)-1-(4,6-二氟-1-((5-氟嘧啶-2-基)甲基)-1H-苯并[d]咪唑-2-基)-4-氟哌啶-3-胺。在第四十四實施例之某些態樣中,本發明提供(3R,4R)-1-(4,6-二氟-1-((5-氟嘧啶-2-基)甲基)-1H-苯并[d]咪唑-2-基)-4-氟哌啶-3-胺之醫藥學上可接受之鹽。
在第四十五實施例中,本發明提供6-((2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈。在第四十五實施例之某些態樣中,本發明提供6-((2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈之醫藥學上可接受之鹽。
在第四十六實施例中,本發明提供(R)-6-((2-(3-胺基-4,4-二氟哌啶-1-基)-4,6-二氟-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈。在第四十六實施例之某些態樣中,本發明提供(R)-6-((2-(3-胺基-4,4-二氟哌啶-1-基)-6-氟-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈之醫藥學上可接受之鹽。鹽酸鹽係第四十六實施例之尤佳態樣,例如(R)-6-((2-(3-胺基-4,4-二氟哌啶-1-基)-6-氟-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈鹽酸鹽。
在第四十七實施例中,本發明提供(R)-6-((2-(3-胺基-4,4-二氟哌啶-1-基)-6-氟-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈。在第四十七實施例之某些態樣中,本發明提供(R)-6-((2-(3-胺基-4,4-二氟哌啶-1-基)-6-氟-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈之醫藥學上可接受之鹽。
在第四十八實施例中,本發明提供6-((2-((3R,4R)-3-胺
基-4-氟-1-哌啶基)-4-甲氧基-1H-苯并咪唑-1-基)甲基)-3-吡啶甲腈。在第四十八實施例之某些態樣中,本發明提供6-((2-((3R,4R)-3-胺基-4-氟-1-哌啶基)-4-甲氧基-1H-苯并咪唑-1-基)甲基)-3-吡啶甲腈之醫藥學上可接受之鹽。
在第四十九實施例中,本發明提供2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-1-((5-氯嘧啶-2-基)甲基)-1H-苯并[d]咪唑-6-甲腈。在第四十九實施例之某些態樣中,本發明提供2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-1-((5-氯嘧啶-2-基)甲基)-1H-苯并[d]咪唑-6-甲腈之醫藥學上可接受之鹽。
在第五十實施例中,本發明提供(3R,4R)-4-氟-1-(1-((5-氟嘧啶-2-基)甲基)-1H-苯并[d]咪唑-2-基)哌啶-3-胺。在第五十實施例之某些態樣中,本發明提供(3R,4R)-4-氟-1-(1-((5-氟嘧啶-2-基)甲基)-1H-苯并[d]咪唑-2-基)哌啶-3-胺之醫藥學上可接受之鹽。
在第五十一實施例中,本發明提供(3R,4R)-1-(1-((5-氯嘧啶-2-基)甲基)-6-氟-1H-苯并[d]咪唑-2-基)-4-氟哌啶-3-胺。在第五十一實施例之某些態樣中,本發明提供(3R,4R)-1-(1-((5-氯嘧啶-2-基)甲基)-6-氟-1H-苯并[d]咪唑-2-基)-4-氟哌啶-3-胺之醫藥學上可接受之鹽。
在第四十二至第五十一實施例中之每一者之又一態樣中,其中提供之化合物及醫藥學上可接受之鹽中的每一者可用於製備用於治療由TRPC6活性介導之疾病的藥劑。在某些態樣中,第四十二至第五十一實施例中提供之化合物或其醫藥學上可接受之鹽可用於製造用於治療選自以下之疾病或病症的藥劑:腎病症候群、微小變化
病、局灶性節段性腎小球硬化症、塌陷性腎小球病、膜性腎病變、膜增殖性腎小球性腎炎、IGA腎病變、急性腎衰竭、慢性腎衰竭、糖尿病腎病變、敗血症、肺高血壓、急性肺病症、急性呼吸窘迫症候群(ARDS)、心臟衰竭、中風、惡性腫瘤或肌肉營養不良症。在其他態樣中,第四十二至第五十一實施例之化合物或其醫藥學上可接受之鹽可用於製備用於治療腎病症候群、膜性腎病變及急性腎衰竭之藥劑。
在第五十二實施例中,提供治療需要療法之患者之疾病或病症的方法,該方法包括投與包含第四十二至第五十一實施例中任一實施例之化合物或其醫藥學上可接受之鹽的醫藥學上可接受之組合物之步驟,其中該疾病或病症係選自腎病症候群、微小變化病、局灶性節段性腎小球硬化症、塌陷性腎小球病、膜性腎病變、膜增殖性腎小球性腎炎、IGA腎病變、急性腎衰竭、慢性腎衰竭、糖尿病腎病變、敗血症、肺高血壓、急性肺病症、急性呼吸窘迫症候群(ARDS)、心臟衰竭、中風、惡性腫瘤或肌肉營養不良症。在第五十一實施例之某些態樣中,該疾病或病症係選自腎病症候群、膜性腎病變及急性腎衰竭。
在又一實施例中,本發明提供製備式IIIb或其子式之化合物之方法
其中X係氯、溴或碘且Q係氯、溴、碘、C1-C6烷基磺酸酯或視情況經取代苯基磺酸酯;(b)使步驟(a)中生成之烷基化鹵化苯并咪唑與具有下式之經保護哌啶在有助於親核芳族取代之條件下偶合:
,其中PG係對於親核芳族取代穩定之醯胺保
護基團(諸如烷氧基羰基保護基團),以生成具有下式之烷基化2-(哌啶
-1-基)苯并咪唑化合物:
(c)自步驟(b)中形成之烷基化2-(哌啶-1-基)苯并咪唑化合物移除PG,以生成式(IIIb)化合物,其中變數X1、X2、X3、Z4、R1a、R2、R3、R4、R7、R11、R12、R13及R15具有第三十實施例中所提供之定義。
在合成方法之較佳態樣中,步驟(a)之鹼性條件包括使鹵化苯并咪唑與親電子部分在諸如碳酸鉀或更佳碳酸銫等碳酸鹽鹼存在下接觸。
在又一實施例中,本發明提供製備式IIIb或其子式之化合物之方法
其中Q係氯、溴、碘、C1-C6烷基磺酸酯或視情況經取代苯基磺酸酯;(c)自步驟(b)中生成之烷基化2-(哌啶-1-基)苯并咪唑化合物移除PG,以生成式(IIIb)化合物,其中變數X1、X2、X3、Z4、R1a、R2、R3、R4、R7、R11、R12、R13及R15具有第三十實施例中所提供之定義。
在又一實施例中,本發明提供製備式IIIb或其子式之化合物之方法
該方法包括以下合成步驟:
(a)使具有式之溴化異硫氰酸酯化合物與具有
式之經保護哌啶化合物在有助於硫脲形成之條件下偶
合,以生成具有式之N,N'-二取代之硫脲化合
物,其中PG係醯胺保護基團,諸如烷氧基羰基保護基團;(b)使步驟(a)中生成之N,N'-二取代之硫脲化合物與具有式
之胺化合物在適於胍形成之條件下縮合,以提供具有
下式之N,N',N"-三取代之胍化合物:;
(c)在過渡金屬觸媒存在下分子內環化步驟(b)中生成之N,N',N"-三取代之胍化合物,以形成具有下式之烷基化2-(哌啶-1-基)苯并咪唑
化合物:
(d)自步驟(c)中生成之烷基化2-(哌啶-1-基)苯并咪唑化合物移除PG,以提供式(IIIb)化合物,其中變數X1、X2、X3、Z4、R1a、R2、R3、R4、R7、R11、R12、R13及R15具有第三十實施例中所提供之定義。
在又一實施例中,本發明提供製備式IIId或其子式之化合物之方法
b)藉由以下方式生成具有下式之烷基化-2-氯苯并咪唑化合物:
:還原步驟(a)中生成之二級胺化合物中之硝基取代
基以原位形成二苯胺化合物、用羰基來源環化該二苯胺及氯化(利用氯來源,諸如P(O)Cl3)以生成烷基化-2-氯苯并咪唑化合物;c)使步驟(b)中生成之烷基化-2-氯苯并咪唑化合物與具有下式之
經保護哌啶:,在適於親核芳族取代之條件下偶合,
以生成具有下式之烷基化2-(哌啶-1-基)苯并咪唑化合物:
d)自步驟(c)中生成之烷基化2-(哌啶-1-基)苯并咪唑化合物移除PG,以生成式(IIId)化合物,其中變數X1、X2、X3、R1a、R2、R3、R4、R7、R11、R12、R13、R14及R15具有第三十實施例中所提供之定義。
在又一實施例中,本發明提供製備式VII或其子式之化合物之方法
其中X係氯、溴或碘且PG係對親核芳族取代穩定之醯胺保護基團,諸如烷氧基羰基保護基團;
(b)用鹵基酯烷基化步驟(a)中生成之2-(哌啶-1-基)苯并
咪唑化合物,其中Y係氯、溴或碘且R係C1-C6烷基,以生成具有下式之經取代1-乙醯基-2-(哌啶-1-基)苯并咪唑化合物:
(c)皂化步驟(b)中生成之經取代1-乙醯基-2-(哌啶-1-基)苯并咪唑化合物以提供游離酸,之後在有助於醯胺鍵形成之條件下用胺HNR9R10胺化以提供1-[(2-哌啶-1-基)苯并咪唑)]乙醯胺化合物;(d)自步驟(c)中生成之1-[(2-哌啶-1-基)苯并咪唑)]乙醯胺化合物移除PG,以生成式(VII)化合物,其中變數X1、X2、X3、Z4、R1a、R2、R3、R4、R7、R11、R12、R13及R15具有第三十四實施例中提供之定義。
在另一實施例中,提供醫藥組合物,其包含一或多種醫藥學上可接受之載劑及治療有效量的式I或其子式中之任一者之化合物。在一些態樣中,以選自由以下組成之群之形式調配組合物:可注射流體、氣溶膠、錠劑、丸劑、膠囊、糖漿、乳霜、凝膠及經皮貼
劑。
在另一實施例中,提供組合,具體而言醫藥組合,其包含治療有效量的式I或其子式中之任一者之化合物。
在另一實施例中,提供調節個體之TRPC蛋白活性之方法,該等方法包括向個體投與治療有效量之式I或其子式。在實施例之較佳態樣中,提供抑制個體之TRPC6活性之方法,該等方法包括向個體投與治療有效量之式I或其子式之化合物。在實施例之某些態樣中,提供抑制個體之TRPC6活性之方法,該等方法包括向個體投與治療有效量之式I或其子式之化合物。
在其他實施例中,提供治療個體之由TRPC蛋白活性介導之病症或疾病的方法,具體而言提供治療由TRPC6蛋白活性介導之疾病或病症的方法。該等方法包括向個體投與治療有效量之式I或其子式之化合物。
在另一實施例中,提供治療或預防疾病或病症之方法,其中該疾病或病症係選自腎病症候群、微小變化病、局灶性節段性腎小球硬化症、塌陷性腎小球病、膜性腎病變、膜增殖性腎小球性腎炎、IGA腎病變、急性腎衰竭、慢性腎衰竭、糖尿病腎病變、敗血症、肺高血壓、急性肺病症、急性呼吸窘迫症候群(ARDS)、心臟衰竭、中風、惡性腫瘤或肌肉營養不良症,該方法包括向需要療法之個體投與治療有效量之式I或其子式之化合物或鹽的步驟。在此實施例之某些態樣中,該方法包括治療選自以下之疾病或病症:腎病症候群、微小變化病、局灶性節段性腎小球硬化症、塌陷性腎小球病、膜性腎病變、膜增殖性腎小球性腎炎、IGA腎病變、急性腎衰竭、慢性
腎衰竭、糖尿病腎病變、敗血症、肺高血壓、急性肺病症、急性呼吸窘迫症候群(ARDS)、心臟衰竭、中風、惡性腫瘤或肌肉營養不良症。在某些情況下,治療方法及/或預防方法適於治療及或預防腎病症候群、膜性腎病變及急性腎衰竭。
在另一態樣中,本發明提供式I或其子式之化合物之用途,其用於製備藥劑或用於製造用於治療個體之由TRPC蛋白活性介導之病症或疾病的藥劑。在某些其他態樣中,本發明提供根據式I或其子式之化合物之用途,其用於治療腎病症候群、微小變化病、局灶性節段性腎小球硬化症、塌陷性腎小球病、膜性腎病變、膜增殖性腎小球性腎炎、IGA腎病變、急性腎衰竭、慢性腎衰竭、糖尿病腎病變、敗血症、肺高血壓、急性肺病症、急性呼吸窘迫症候群(ARDS)、心臟衰竭、中風、惡性腫瘤或肌肉營養不良症。在某些情況下,本發明提供式I或其子式之化合物之用途,其用於製備藥劑或用於製造用於治療個體之選自腎病症候群、膜性腎病變及急性腎衰竭之疾病或病症的藥劑。
出於闡釋本說明書之目的,將使用以下定義,且若適宜,以單數使用之術語亦可包括複數且反之亦然。
如本文所用,術語「烷基」係指具有高達20個碳原子之完全飽和具支鏈或無支鏈烴部分。除非另外提供,否則烷基係指具有1至20個碳原子、1至16個碳原子、1至10個碳原子、1至7個碳原子或1至4個碳原子之烴部分。烷基之代表性實例包括(但不限於)甲基、乙基、正丙基、異丙基、正丁基、第二丁基、異丁基、第三丁基、正戊基、異戊基、新戊基、正己基、3-甲基己基、2,2-二甲基戊基、
2,3-二甲基戊基、正庚基、正辛基、正壬基、正癸基及諸如此類。
如本文所用,術語「伸烷基」係指如上文所定義之具有1至20個碳原子之二價烷基。除非另外提供,否則伸烷基係指具有1至20個碳原子、1至16個碳原子、1至10個碳原子、1至7個碳原子或1至4個碳原子之部分。伸烷基之代表性實例包括(但不限於)亞甲基、伸乙基、伸正丙基、伸異丙基、伸正丁基、伸第二丁基、伸第三丁基、伸正戊基、伸異戊基、伸新戊基、伸正己基、3-甲基伸己基、2,2-二甲基伸戊基、2,3-二甲基伸戊基、伸正庚基、伸正辛基、伸正壬基、伸正癸基及諸如此類。
如本文所用,術語「鹵代烷基」係指經一或多個如本文定義之鹵基取代的如本文所定義之烷基。鹵代烷基可為單鹵代烷基、二鹵代烷基或多鹵代烷基,包括全鹵代烷基。單鹵代烷基可在烷基內具有一個碘、溴、氯或氟。二鹵代烷基及多鹵代烷基可在烷基內具有兩個或更多個相同鹵基原子或不同鹵基之組合。通常,多鹵代烷基含有高達12或10或8或6或4或3或2個鹵基。鹵代烷基之非限制性實例包括氟甲基、二氟甲基、三氟甲基、氯甲基、二氯甲基、三氯甲基、五氟乙基、七氟丙基、二氟氯甲基、二氯氟甲基、二氟乙基、二氟丙基、二氯乙基及二氯丙基。全鹵代烷基係指所有氫原子皆經鹵基原子置換之烷基。
如本文所用,術語「羥基烷基」係指經一或多個羥基取代之如本文所定義之烷基。術語「羥基環烷基-烷基」係指如本文所定義之經環烷基取代且進一步經羥基取代之烷基。羥基可在烷基、環烷基上或在烷基及環烷基中之每一者上。
術語「芳基」係指在環部分中具有6至20個碳原子之芳族烴基團。通常,芳基係具有6至20個碳原子之單環、雙環或三環芳基。此外,如本文所用,術語「芳基」係指芳族取代基,其可為單一芳族環或稠合一起之多個芳族環。非限制性實例包括苯基、萘基或四氫萘基,其各自可視情況經1至4個取代基取代,諸如烷基、三氟甲基、環烷基、鹵素、羥基、烷氧基、醯基、烷基-C(O)-O-、芳基-O-、雜芳基-O-、胺基、硫醇、烷基-S-、芳基-S-硝基、氰基、羧基、烷基-O-C(O)-、胺甲醯基、烷基-S(O)-、磺醯基、磺醯胺基、苯基及雜環基。
如本文所用,術語「雜環」、「雜環基(heterocyclyl)」、「雜環烷基」或「雜環基(heterocyclo)」係指飽和或不飽和非芳族環或環系統,例如,其係4-、5-、6-或7-員單環、7-、8-、9-、10-、11-或12-員雙環或10--11-、12-、13-、14-或15-員三環系統且含有至少一個選自O、S及N之雜原子,其中N及S亦可視情況經氧化成各個氧化態。雜環基可在雜原子或碳原子連接。雜環基可包括稠合或橋接環以及螺環。雜環之實例包括四氫呋喃、二氫呋喃、1,4-二噁烷、嗎啉、1,4-二噻烷、哌嗪、哌啶、1,3-二氧雜環戊烷、咪唑啶、咪唑啉、吡咯啉、吡咯啶、四氫哌喃、二氫哌喃、氧硫雜環戊烷、二硫雜環戊烷、1,3-二噁烷、1,3-二噻烷、氧硫雜環己烷、硫嗎啉、氮雜環丁烷、噻唑啶、嗎啉及諸如此類。
如本文所用,術語「氮雜環」係指包含至少一個環氮原子且可視情況包含0、1或2個選自N、O或S之額外環雜原子的雜環。
如本文所用,術語「環烷基」係指3至12個碳原子之飽和或部分不飽和單環、雙環或三環烴基團。為免生疑問,環烷基並不意欲包括芳族基團,諸如萘基或苯基。除非另外提供,否則環烷基係指具有介於3個與9個之間的環碳原子或介於3個與7個之間的環碳原子之環狀烴基團,其各自可視情況經一個或兩個或三個或更多個獨立地選自由以下組成之群之取代基取代:烷基、鹵基、側氧基、羥基、烷氧基、烷基-C(O)-、醯基胺基、胺甲醯基、烷基-NH-、(烷基)2N-、硫醇、烷基-S-、硝基、氰基、羧基、烷基-O-C(O)-、磺醯基、磺醯胺基、胺磺醯基及雜環基。例示性單環烴基團包括(但不限於)環丙基、環丁基、環戊基、環戊烯基、環己基及環己烯基及諸如此類。例示性雙環烴基團包括冰片基、吲哚基、六氫吲哚基、四氫萘基、十氫萘基、二環[2.1.1]己基、二環[2.2.1]庚基、二環[2.2.1]庚烯基、6,6-二甲基二環[3.1.1]庚基、2,6,6-三甲基二環[3.1.1]庚基、二環[2.2.2]辛基及諸如此類。例示性三環烴基團包括金剛烷基及諸如此類。術語「羥基環烷基」特定而言係指經一或多個羥基取代之環烷基。
如本文所用,術語「烷氧基」係指烷基-O-,其中烷基係如上文中所定義。烷氧基之代表性實例包括(但不限於)甲氧基、乙氧基、丙氧基、2-丙氧基、丁氧基、第三丁氧基、戊基氧基、己基氧基、環丙基氧基-、環己基氧基-及諸如此類。通常,烷氧基具有約1至7、更佳約1至4個碳。
如本文所用,術語「環烷氧基」係指環烷基-O-及環烷基-烷基-O,其中環烷基及烷基係如上文中所定義。環烷氧基之代表性實例包括(但不限於)環丙基氧基、環丁基氧基、環戊基氧基、1-甲
基環丙基氧基、環丙基甲氧基、1-甲基環丁基氧基及諸如此類。通常,環烷氧基具有約3至7、更佳約3至6個碳原子。
二價取代基用「二基」後綴表示。因此,二價烷基連接基團稱作烷二基且二價環烷烴基團稱作環烷二基(例如,環丙二基)。
如本文所用,術語「雜芳基」係指具有1至8個選自N、O及S之雜原子之5至14員單環-或雙環-或三環-芳族環系統。在某些較佳態樣中,雜芳基係5至10員環系統(例如,5至7員單環或8至10員雙環)或5至7員環系統。例示性單環雜芳基包括2-或3-噻吩基、2-或3-呋喃基、2-或3-吡咯基、2-、4-或5-咪唑基、3-、4-或5-吡唑基、2-、4-或5-噻唑基、3-、4-或5-異噻唑基、2-、4-或5-噁唑基、3-、4-或5-異噁唑基、3-或5-1,2,4-三唑基、4-或5-1,2,3-三唑基、四唑基、2-、3-或4-吡啶基、3-或4-噠嗪基、3-、4-或5-吡嗪基、2-吡嗪基及2-、4-及5-嘧啶基。例示性雙環雜芳基包括1-、3-、4-、5-、6-、7-或8-異喹啉基、2-、3-、4-、5-、6-、7-或8-喹啉基、1-、3-、4-、5-、6-、7-或8-異喹啉基、1-、2-、4-、5-、6-、7-或8-苯并咪唑基及1-、2-、3-、4-、5-、6-、7-或8-吲哚基。
術語「雜芳基」亦係指其中雜芳族環稠合至一或多個芳基、環脂族或雜環基環之基團,其中連接之基團或點在雜芳族環上。
術語「雙環」及「雙環基」係指具有兩個稠合環之環系統,每一環可為碳環或雜環且每一環可為飽和、不飽和或芳族。
如本文所用,術語「鹵素」或「鹵基」係指氟、氯、
溴及碘。
如本文所用,術語「視情況經取代」除非另外規定否則係指未經取代或經一或多個、通常1、2、3或4個適宜非氫取代基取代的基團。若「視情況存在之取代基」之身分在視情況經取代基團之上下文中未明確定義,則每一視情況存在之取代基獨立地選自由以下組成之群:烷基、羥基、鹵素、側氧基、胺基、烷基胺基、二烷基胺基、烷氧基、環烷基、CO2H、雜環烷基氧基(其表示經由氧橋鍵結之雜環基)、-CO2烷基、巰基、硝基、氰基、胺磺醯基、磺醯胺、芳基、-OC(O)烷基、-OC(O)芳基、芳基-S-、芳基氧基;烷基硫基、甲醯基(亦即,HC(O)-)、-C(O)NH2、芳烷基(經芳基取代之烷基)、芳基及經烷基取代之芳基、環烷基、烷氧基、羥基、胺基、烷基-C(O)-NH-、烷基胺基、二烷基胺基或鹵素。應理解,若基團指示為視情況經取代,則本發明包括其中該基團未經取代之實施例以及其中該基團經取代之實施例。
如本文所用,術語「異構物」係指具有相同分子式但原子佈置及組態不同之不同化合物。同樣,如本文所用,術語「光學異構物」或「立體異構物」係指本發明給定化合物中可存在之各種立體異構組態的任一者且包括幾何異構物。應理解,取代基可連接至碳原子之對掌性中心。因此,本發明包括化合物之對映異構物、非對映異構物或外消旋物。「對映異構物」係一對彼此不可重疊鏡像之立體異構物。對映異構物對之1:1混合物為「外消旋」混合物。若適宜,該術語用於指示外消旋混合物。使用「rel」指示已知非對映異構取向但未知絕對立體化學。在絕對立體化學尚未確定之情形下,旋光性及
/或對掌性層析情況將指示存在何種異構物。
「非對映異構物」係具有至少兩個不對稱原子但彼此並非鏡像之立體異構物。根據Cahn-Ingold-Prelog R-S系統來指定絕對立體化學。當化合物係純淨對映異構物時,每一對掌性碳之立體化學可指定為R或S。絕對組態未知之拆分化合物可端視其在鈉D線波長下旋轉平面偏振光之方向(右旋或左旋)或對掌性層析分離上之滯留時間而指定為(+)或(-)。本文所述之某些化合物含有一或多個不對稱中心或軸且可由此產生對映異構物、非對映異構物及其他立體異構形式,該等形式可根據絕對立體化學定義為(R)-或(S)-或用(+)或(-)符號定義。本發明意欲包括所有此類可能之異構物,包括外消旋混合物、光學純形式及中間體混合物。可使用對掌性合成子或對掌性試劑來製備光學活性(R)-及(S)-異構物或使用習用技術來進行拆分。若化合物含有雙鍵,則取代基可為E或Z組態。若化合物含有二取代之環烷基,則環烷基取代基可具有順式-或反式-組態。
應理解,對於本文提供之任何化合物,包括任何式(I)化合物或其任何實施例或表A、B或C之任何化合物或上述中任一者之鹽,化合物可以任何立體化學形式存在,諸如單一對映異構物、非對映異構物或互變異構物或一或多種對映異構物、非對映異構物及互變異構物以任何比率之混合物。
如本文所用,術語「鹽」(「salt」或「salts」)係指本發明化合物之酸加成鹽或鹼加成鹽。「鹽」具體而言包括「醫藥學上可接受之鹽」。術語「醫藥學上可接受之鹽」係指保留有本發明化合物之生物有效性及性質且通常在生物上或在其他方面合意之鹽。在許
多情形下,本發明化合物由於存在胺基及/或羧基或相似基團而能夠形成酸性及/或鹼性鹽。
醫藥學上可接受之酸加成鹽可利用無機酸及有機酸形成。
可自其衍生鹽之無機酸包括(例如)鹽酸、氫溴酸、硫酸、硝酸、磷酸及諸如此類。
可自其衍生鹽之有機酸包括(例如)乙酸、丙酸、乙醇酸、草酸、順丁烯二酸、丙二酸、丁二酸、反丁烯二酸、酒石酸、檸檬酸、苯甲酸、杏仁酸、甲磺酸、乙磺酸、苯磺酸、甲苯磺酸、磺柳酸及諸如此類。
醫藥學上可接受之鹼加成鹽可用無機鹼及有機鹼形成。
可自其衍生鹽之無機鹼包括(例如)銨鹽及來自週期表第I欄至第XII欄之金屬。在某些實施例中,鹽係衍生自鈉、鉀、銨、鈣、鎂、鐵、銀、鋅及銅。在某些其他實施例中,鹽係選自銨鹽、鉀鹽、鈉鹽、鈣鹽及鎂鹽。
可自其衍生鹽之有機鹼包括(例如)一級、二級及三級胺、包括天然存在經取代胺在內之經取代胺、環狀胺、鹼性離子交換樹脂及諸如此類。特定有機胺包括異丙基胺、苄星青黴素、膽酸鹽、二乙醇胺、二乙胺、離胺酸、葡甲胺、哌嗪及緩血酸胺。
在另一態樣中,本發明提供呈以下形式之如本文揭示之化合物:乙酸鹽、抗壞血酸鹽、己二酸鹽、天冬胺酸鹽、苯甲酸鹽、苯磺酸鹽、溴化物/氫溴酸鹽、碳酸氫鹽/碳酸鹽、硫酸氫鹽/硫酸
鹽、樟腦磺酸鹽、癸酸鹽、氯化物/鹽酸鹽、氯茶鹼鹽、檸檬酸鹽、乙二磺酸鹽、反丁烯二酸鹽、葡庚糖酸鹽、葡萄糖酸鹽、葡萄糖醛酸鹽、麩胺酸鹽、戊二酸鹽、羥乙酸鹽、馬尿酸鹽、氫碘酸鹽/碘化物、羥乙磺酸鹽、乳酸鹽、乳糖酸鹽、月桂基硫酸鹽、蘋果酸鹽、順丁烯二酸鹽、丙二酸鹽、杏仁酸鹽、甲磺酸鹽、甲基硫酸鹽、黏酸鹽、萘甲酸鹽、萘磺酸鹽、菸鹼酸鹽、硝酸鹽、十八烷酸鹽、油酸鹽、草酸鹽、棕櫚酸鹽、雙羥萘酸鹽、磷酸鹽/磷酸氫鹽/磷酸二氫鹽、聚半乳糖醛酸鹽、丙酸鹽、癸二酸鹽、硬脂酸鹽、丁二酸鹽、磺基柳酸鹽、硫酸鹽、酒石酸鹽、甲苯磺酸鹽、三苯乙酸鹽(trifenatate)、三氟乙酸鹽或羥萘甲酸鹽。在另一態樣中,本發明提供呈C1-C4烷基磺酸、苯磺酸或單-、二-或三-C1-C4烷基取代之苯磺酸加成鹽形式的如本文中揭示之化合物。
本文所給出任一式亦欲表示該等化合物之未經標記形式以及經同位素標記形式。經同位素標記之化合物具有由本文所給出式繪示的結構,只是一或多個原子由具有所選原子質量或質量數的原子置換。可納入本發明化合物中之同位素的實例包括氫、碳、氮、氧、磷、氟及氯之同位素,諸如分別為2H、3H、11C、13C、14C、15N、18F、31P、32P、35S、36Cl、124I、125I。本發明包括各種如本文所定義經同位素標記之化合物,例如,存在諸如3H、13C及14C等放射性同位素之彼等。此等經同位素標記之化合物可用於代謝研究(利用14C)、反應動力學研究(利用例如2H或3H)、偵測或成像技術(諸如正電子發射斷層攝影術(PET)或單光子發射電腦斷層攝影術(SPECT),包括藥物或受質組織分佈分析驗)或用於患者之放射性治療。具體而言,
18F或經標記化合物可為PET或SPECT研究尤其需要。經同位素標記之本發明化合物及其鹽通常可藉由實施在流程中或在下文所述實例及製備中所揭示程序藉由用易於獲得之經同位素標記之試劑取代未經同位素標記之試劑來製備。
此外,使用較重同位素,尤其氘(亦即,2H或D)取代可提供某些治療優點,此歸因於較大代謝穩定性,例如活體內半衰期延長或劑量需求降低或治療指數改善。應瞭解,在此上下文中氘被視為式(I)化合物之取代基。此一較重同位素(特定而言氘)之濃度可定義為同位素富集因子。如本文所用,術語「同位素富集因子」意指指定同位素之同位素豐度與天然豐度之間的比率。若本發明化合物中之取代基表示為氘,則此化合物在每一指定氘原子處納入至少50%氘、納入60%氘、納入至少75%氘、納入至少90%氘、納入至少95%氘、納入至少99%氘或納入至少99.5%氘。
本發明化合物可固有地或藉由設計與溶劑(包括水)形成溶劑合物。因此,本發明意欲涵蓋溶劑化及非溶劑化形式。術語「溶劑合物」係指本發明化合物(包括其鹽)與一或多種溶劑分子之分子複合物。該等溶劑分子係在醫藥領域中常用且已知對接受者無害之彼等,例如水、乙醇、二甲基亞碸、丙酮及其他常見有機溶劑。術語「水合物」係指包含本發明化合物及水之分子複合物。本發明之醫藥學上可接受之溶劑合物包括其中結晶之溶劑可經同位素取代之彼等,例如D2O、d6-丙酮、d6-DMSO。
術語本發明化合物之「治療有效量」係指將引發個體之生物或醫學反應(例如,降低或抑制酶或蛋白活性)或改善症狀、緩
和病況、減緩或延遲疾病進展或預防疾病等之本發明化合物的量。在一個非限制性實施例中,術語「治療有效量」係指當投與個體時對以下有效之本發明化合物的量:(1)至少部分緩和、抑制、預防及/或改善(i)由TRPC6活性介導或(ii)與TRPC6活性相關之病況或病症或疾病或生物過程;或(2)抑制TRPC6之活性。在另一非限制性實施例中,術語「治療有效量」係指當投與細胞或組織或非細胞生物材料或培養基時可有效地至少部分抑制TRPC6活性之本發明化合物的量。
如本文所用,術語「個體」係指動物。通常,動物係哺乳動物。個體亦係指(例如)靈長類動物(例如,人類)、牛、綿羊、山羊、馬、狗、貓、兔、大鼠、小鼠、魚、鳥及諸如此類。在某些實施例中,個體係靈長類動物。在又一些實施例中,該個體係人類。
如本文所用,術語「抑制(inhibit、inhibition或inhibiting)」係指減輕或抑制給定之病況、症狀或病症或疾病,或顯著降低生物活性或過程之基線活性。
在一個實施例中,如本文所用,術語「治療(treat、treating或treatment)」任一疾病或病症係指改善該疾病或病症(亦即,減緩或阻止或減慢該疾病或其至少一種臨床症狀的發展)。在另一實施例中,「治療(treat、treating或treatment)」係指減輕或改善包括患者不能感受到之彼等物理參數的至少一個物理參數。在又一實施例中,「治療(treat、treating或treatment)」係指在物理方面調節疾病或病症(例如,穩定可辨別症狀)、在生理學方面調節疾病或病症(例如,穩定物理參數)或二者均有。
在一個實施例中,如本文所用,術語「預防(prevent、
preventing或prevention)」任一疾病或病症係指延遲或避免疾病或病症發作(亦即,在易於發生疾病或病症之患者中減慢或預防疾病或病症發作)。
如本文所用,若個體可在生物學方面、醫學方面或生命品質方面受益於治療,則該個體「需要」該治療。
如本文所用,除非本文另外指明或上下文明顯矛盾,否則,在本發明上下文(尤其在申請專利範圍之上下文)中所用之術語「一(a、an)」、「該(the)」及類似術語皆理解為涵蓋單數與複數二者。
本發明化合物之任一不對稱原子(例如,碳或諸如此類)可以外消旋性或對映異構性富集形式存在,例如(R)-、(S)-或(R,S)-組態。在某些實施例中,每一不對稱原子在(R)-或(S)-組態中至少50%對映異構物過量、至少60%對映異構物過量、至少70%對映異構物過量、至少80%對映異構物過量、至少90%對映異構物過量、至少95%對映異構物過量或至少99%對映異構物過量。原子上具有不飽和鍵之取代基若可能則可以順-(Z)-或反-(E)-形式存在。
因此,如本文所用,本發明化合物可以可能之異構物、旋轉異構物、滯轉異構物、互變異構物或其混合物中的一種形式存在,舉例而言,為實質上純淨之幾何(順式或反式)異構物、非對映異構物、光學異構物(對映體)、外消旋物或其混合物。
任何所得異構物之混合物皆可基於其成分之物理化學差異(例如)藉由層析法及/或分步結晶分離成純淨或實質上純淨之幾何或光學異構物、非對映異構物、外消旋物。
可藉由已知方法將最終產物或中間體之任何所得外消
旋物拆分成光學對映體,例如,藉由分離使用光學活性酸或鹼獲得之其非對映異構鹽且釋放光學活性酸性或鹼性化合物。具體而言,由此可採用鹼性部分藉由(例如)對用光學活性酸(例如酒石酸、二苯甲醯基酒石酸、二乙醯基酒石酸、二-O,O'-對-甲苯甲醯基酒石酸、杏仁酸、蘋果酸或樟腦-10-磺酸)所形成之鹽進行分步結晶將本發明化合物拆分成其光學對映體。亦可使用對掌性吸附劑藉由對掌性層析(例如,高效液相層析(HPLC)或超臨界流體層析(SFC))來拆分外消旋產物。
可根據本發明獲得之異構物之混合物可以彼等熟習此項技術者已知之方式分離成個別異構物;非對映異構物可藉由例如在多相溶劑混合物之間分配、重結晶及/或例如矽膠上之層析分離或藉由例如反相管柱上之中壓液相層析來分離,且外消旋物可例如藉由以下方式來分離:使用光學純淨之鹽形成試劑形成鹽,且可藉助例如分步結晶或光學活性管柱材料上之層析分離由此獲得之非對映異構物混合物。
在本文範疇內,除非上下文另外指明,否則僅將不為本發明化合物之具體期望最終產物之成分且易於移除之基團稱為「保護基團」。該等保護基團對官能基之保護、保護基團本身及其裂解反應闡述於(例如)標準參考著作中,諸如J.F.W.McOmie,「Protective Groups in Organic Chemistry」,Plenum Press,London and New York 1973;T.W.Greene及P.G.M.Wuts,「Protective Groups in Organic Synthesis」,第3版,Wiley,New York 1999;「The Peptides」,第3卷(編者:E.Gross及J.Meienhofer),Academic Press,London and New York 1981;「Methoden der organischen Chemie」(Methods of Organic
Chemistry),Houben Weyl,第4版,第15/I卷,Georg Thieme Verlag,Stuttgart 1974;H.-D.Jakubke及H.Jeschkeit,「Aminosauren,Peptide,Proteine」(Amino acids,Peptides,Proteins),Verlag Chemie,Weinheim,Deerfield Beach,and Basel 1982;及Jochen Lehmann,「Chemie der Kohlenhydrate:Monosaccharide and Derivate」(Chemistry of Carbohydrates:Monosaccharides and Derivatives),Georg Thieme Verlag,Stuttgart 1974。保護基團之特徵在於其可易於藉由(例如)溶劑分解、還原、光解或另一選擇為在生理學條件下(例如藉由酶裂解)移除(亦即,並不發生不期望之二級反應)。
可根據標準方法(例如,使用層析方法、分佈方法、(重)結晶及諸如此類)對中間體及最終產物實施處理及/或純化。
除非本文另有說明或上下文另外明顯矛盾,否則本文所述之所有方法皆可以任何適宜順序實施。本文所提供之任何及所有實例或例示性語言(例如「諸如」)的使用僅意欲更好地闡釋本發明且並非對本發明之範疇加以限制,除非另有聲明。
本文揭示之任何製程步驟可在彼等熟習此項技術者已知之反應條件下實施,該等條件包括特定提及之彼等:在溶劑或稀釋劑不存在或(習慣上)存在下,該等溶劑或稀釋劑包括(例如)對所用試劑呈惰性且使其溶解之溶劑或稀釋劑;在觸媒、縮合劑或中和劑(例如離子交換劑,諸如陽離子交換劑,例如,呈H+形式,此端視反應及/或反應物之性質而定)不存在或存在下;在低溫、常溫或高溫下(例如約-100℃至約250℃之溫度範圍內,包括(例如)約-80℃至約250℃,例如在-80℃至-60℃下,在室溫下,在-20℃至40℃下或在回流溫度
下);在常壓下或在密閉容器中,若適宜,在壓力下及/或在惰性氛圍中,例如在氬或氮氣氛圍中。
除非在闡述該等製程時另外指明,否則可自其選擇彼等適用於任一特定反應之溶劑的溶劑包括特定提及之彼等,或(例如)水、酯(諸如低碳鏈烷酸低碳烷基酯,例如乙酸乙酯)、醚(諸如脂族醚,例如乙醚)或環醚(例如四氫呋喃或二噁烷)、液體芳族烴(諸如苯或甲苯)、醇(諸如甲醇、乙醇或1-丙醇或2-丙醇)、腈(諸如乙腈)、鹵化烴(諸如二氯甲烷或氯仿)、醯胺(諸如二甲基甲醯胺或二甲基乙醯胺)、鹼(諸如雜環氮鹼,例如吡啶或N-甲基吡咯啶-2-酮)、羧酸酐(諸如低碳烷酸酐,例如乙酸酐)、環狀、直鏈或具支鏈烴(諸如環己烷、己烷或異戊烷、甲基環己烷)或彼等溶劑之混合物(例如水溶液)。該等溶劑混合物亦可藉由(例如)層析或分配用於處理中。
在另一態樣中,本發明提供包含本發明化合物或其醫藥學上可接受之鹽及醫藥學上可接受之載劑的醫藥組合物。在又一實施例中,該組合物包含至少兩種醫藥學上可接受之載劑,諸如本文所述之彼等。出於本發明之目的,除非另外指明,否則溶劑合物及水合物通常被視為組合物。較佳地,醫藥學上可接受之載劑係無菌的。醫藥組合物可經調配用以特定投與途徑,諸如,經口投與、非經腸投與及直腸投與等。另外,本發明之醫藥組合物可以固體形式(包括但不限於膠囊、錠劑、丸劑、顆粒、粉劑或栓劑)或以液體形式(包括但不限於溶液、懸浮液或乳液)製備。醫藥組合物可經受習用醫藥操作(諸如殺菌)及/或可含有習用惰性稀釋劑、潤滑劑或緩衝劑,以及佐劑,諸如防腐劑、穩定劑、潤濕劑、乳化劑及緩衝劑等。
如本文所用,術語「醫藥學上可接受之載劑」包括如熟習此項技術者已知之任一及所有溶劑、分散介質、包衣、界面活性劑、抗氧化劑、防腐劑(例如,抗細菌劑、抗真菌劑)、等滲劑、吸收延遲劑、鹽、防腐劑、藥物、藥物穩定劑、黏合劑、賦形劑、崩解劑、潤滑劑、甜味劑、矯味劑、染料及諸如此類及其組合(例如,參見Remington's Pharmaceutical Sciences,第18版,Mack Printing公司,1990,第1289-1329頁)。除任何與活性成分不相容之習用載劑之外,本發明涵蓋其於治療或醫藥組合物中之使用。
通常,醫藥組合物係包含活性成分及以下中之一或多者之錠劑或明膠膠囊:a)稀釋劑,例如乳糖、右旋糖、蔗糖、甘露醇、山梨醇、纖維素及/或甘胺酸;b)潤滑劑,例如二氧化矽、滑石粉、硬脂酸、其鎂鹽或鈣鹽及/或聚乙二醇;對於錠劑亦有c)黏合劑,例如矽酸鎂鋁、澱粉糊、明膠、黃蓍膠、甲基纖維素、羧甲基纖維素鈉及/或聚乙烯基吡咯啶酮;(若需要)d)崩解劑,例如澱粉、瓊脂、海藻酸或其鈉鹽或起泡混合物;及e)吸收劑、著色劑、矯味劑及甜味劑。錠劑可根據業內已知之方法進行膜包衣或腸溶包衣。適用於經口投與之組合物包括有效量之呈錠劑、口含錠、水性或油性懸浮液、可分散粉劑或顆粒、乳液、硬或軟膠囊或糖漿或酏劑形式的本發明化合物。意欲經口使用之組合物可根據業內已知用於製造醫藥組合物之任一方法來製備且該等組合物可含有一或多種選自由甜味劑、矯味劑、著色劑及防腐劑組成之群的試劑以提供醫藥學上美觀且可口之製劑。錠劑可含有活性成分與適於製造錠劑且醫藥學上可接受之無毒賦形劑的混合物。舉例而言,該等賦形劑為惰性稀釋劑,諸如,碳酸
鈣、碳酸鈉、乳糖、磷酸鈣或磷酸鈉;造粒劑及崩解劑,例如,玉米澱粉或海藻酸;黏合劑,例如,澱粉、明膠或阿拉伯膠;及潤滑劑,例如,硬脂酸鎂、硬脂酸或滑石。該等錠劑係未經包衣或藉由已知技術包衣以延遲在胃腸道中之崩解及吸收且藉此提供較長時間段之持續作用。例如,可採用諸如單硬脂酸甘油酯或二硬脂酸甘油酯等延時物質。用於經口使用之調配物可提供為硬明膠膠囊形式,其中將活性成分與惰性固體稀釋劑(例如,碳酸鈣、磷酸鈣或高嶺土)混合;或其可為軟明膠膠囊形式,其中將活性成分與水或油介質(例如,花生油、液體石蠟或橄欖油)混合。某些可注射組合物係等滲水溶液或懸浮液,且栓劑有利地係自脂肪乳液或懸浮液製備。該等組合物可經滅菌及/或含有佐劑,諸如防腐劑、穩定劑、潤濕劑或乳化劑、溶液促進劑、調控滲透壓之鹽及/或緩衝劑。另外,其亦可含有其他治療上有價值之物質。該等組合物分別係根據習用混和、造粒或包衣方法來製備且含有約0.1-75%,或含有約1-50%之活性成分。適於經皮施用之組合物包括有效量之本發明化合物與適宜載劑。適於經皮遞送之載劑包括可吸收之藥理學上可接受之溶劑以有助於通過宿主之皮膚。舉例而言,經皮裝置係呈繃帶形式,該繃帶包含背襯元件;含有該化合物(視情況具有載劑)之儲液器;視情況包含速度控制障壁以便以受控之預定速度長時間遞送化合物至宿主皮膚;及將裝置固定至皮膚之構件。適用於局部施用(例如,施用至皮膚及眼睛)之組合物包括水溶液、懸浮液、軟膏劑、乳霜、凝膠或可噴霧調配物,(例如)藉由氣溶膠或諸如此類遞送。該等局部遞送系統尤其適用於皮膚施用以(例如)治療皮膚癌,用以(例如)防曬霜、洗劑、噴霧劑及諸如此類之預防用
途。因此,其尤其適用於業內熟知之局部用(包括化妝品用)調配物。此類調配物可含有增溶劑、穩定劑、張力增強劑、緩衝劑及防腐劑。如本文所用,局部施用亦可係關於吸入或鼻內施用。其可以乾粉形式(單獨;呈混合物形式,例如與乳糖之乾燥摻合物;或呈混合組分粒子形式,例如與磷脂之混合組分粒子)自乾粉吸入器方便地遞送,或以氣溶膠噴霧劑形式自加壓容器、幫浦、噴射器、霧化器或噴霧器呈遞,其中使用或不使用適宜推進劑。
本發明進一步提供包含本發明化合物作為活性成分之無水醫藥組合物及劑型,此乃因水可有利於某些化合物降解。
可使用無水或含低水分之成分在低水分或低濕氣條件下製備本發明之無水醫藥組合物及劑型。無水醫藥組合物可製備且儲存以維持其無水性質。因此,使用已知材料包裝無水組合物以防止曝露於水以便其可納入適宜配方套組中。適宜包裝之實例包括(但不限於)氣密性密封箔、塑膠、單位劑量容器(例如,小瓶)、泡罩包及條帶包。
本發明進一步提供包含一或多種可降低作為活性成分之本發明化合物分解速率之試劑的醫藥組合物及劑型。本文稱作「穩定劑」之該等試劑包括(但不限於)抗氧化劑(諸如抗壞血酸)、pH緩衝劑或鹽緩衝劑等。
預防性及治療性用途
呈游離形式或呈醫藥學上可接受之鹽形式的本文揭示之化合物展現有價值之藥理學特性,例如TRPC蛋白調節性質且更具體而言抑制TRPC6蛋白活性,例如如以下部分中提供之活體外及活體
內測試中所指示且因此指示可用於療法。
本發明提供藉由向有需要之個體投與有效量之本文揭示之化合物治療與TRPC6蛋白活性相關之疾病或病症的方法。在某些態樣中,適於藉由投與本發明化合物之療法之疾病或病症包括(但不限於)腎病症候群、微小變化病、局灶性節段性腎小球硬化症、塌陷性腎小球病、膜性腎病變、膜增殖性腎小球性腎炎、IGA腎病變、急性腎衰竭、慢性腎衰竭、糖尿病腎病變、敗血症、肺高血壓、急性肺病症、急性呼吸窘迫症候群(ARDS)、心臟衰竭、中風、惡性腫瘤或肌肉營養不良症。在某些情況下,患者患有腎病症候群、膜性腎病變及急性腎衰竭。
在具體實施例中,本發明提供藉由向有需要之個體投與有效量之本文揭示之化合物治療或預防腎病的方法。在某些實施例中,目前無症狀但處於發生腎病之風險下之患者適於投與本發明化合物。治療或預防腎病之方法包括(但不限於)治療或預防腎病症候群、膜性腎病變、急性腎衰竭、敗血症、慢性腎衰竭及糖尿病腎病變之方法。
本發明之醫藥組合物或組合針對約50-70kg之個體可呈約1-1000mg活性成分或約1-500mg或約1-250mg或約1-150mg或約0.5-100mg或約1-50mg活性成分的單位劑量。化合物、醫藥組合物或其組合之治療有效劑量端視個體物種、體重、年齡及個體狀態、所治療病症或疾病或其嚴重程度而定。熟習此項技術之內科醫師、臨床醫師或獸醫師可容易地確定預防、治療或抑制病症或疾病進程所必需各活性成分的有效量。
可有利地使用哺乳動物(例如,小鼠、大鼠、狗、猴)或其經分離器官、組織及製劑在活體外及活體內測試中證明上述劑量性質。本發明化合物可以溶液(例如,水溶液)形式於活體外施用及經腸、非經腸(有利地靜脈內)(例如)作為懸浮液或於水溶液中於活體內施用。活體外劑量可介於約10-3莫耳濃度與10-9莫耳濃度之間。端視投與途徑,活體內之治療有效量可介於約0.1mg/kg與500mg/kg之間,或約1mg/kg與100mg/kg之間。
本發明化合物之活性可藉由活體外及活體內方法,諸如以下實例中所述之彼等方法進行評定。
本發明化合物可在投與一或多種其他治療劑的同時或之前或之後投與。本發明化合物可藉由與其他藥劑相同或不同投與途徑單獨投與,或以相同醫藥組合物一起投與。
在一個實施例中,本發明提供包含本文揭示之化合物及至少一種另一治療劑之產物,其作為組合製劑同時、分開或依序用於療法中。在一個實施例中,療法係治療由TRPC蛋白活性介導之疾病或病況。在較佳態樣中,療法係治療腎病症候群、微小變化病、局灶性節段性腎小球硬化症、塌陷性腎小球病、膜性腎病變、膜增殖性腎小球性腎炎、IGA腎病變、急性腎衰竭、慢性腎衰竭、糖尿病腎病變、敗血症、肺高血壓、急性肺病症、急性呼吸窘迫症候群(ARDS)、心臟衰竭、中風、惡性腫瘤或肌肉營養不良症。
以組合製劑形式提供之產物包括包含一起存於相同醫藥組合物中之本文揭示之化合物及其他治療劑,或呈分開形式(例如呈套組形式)之本文揭示之化合物及其他治療劑的組合物。
在一個實施例中,本發明提供包含如本文揭示之化合物及另一(另外的)治療劑之醫藥組合物。視情況,醫藥組合物可包含如上文所述醫藥學上可接受之載劑。
在一個實施例中,本發明提供包含兩種或更多種單獨醫藥組合物之套組,其中至少一種醫藥組合物含有本文揭示之化合物。在一個實施例中,該套組包含用於單獨地保留該等組合物之構件,諸如容器、分立式瓶或分立式箔片包。此套組之實例係泡罩包,通常用於包裝錠劑、膠囊及諸如此類。
本發明套組可用於投與不同的劑型(例如,經口及非經腸劑型),以不同的劑量間隔投與單獨的組合物,或滴定單獨的組合物相對於彼此之劑量。為有助於順從性,本發明套組通常包含投與說明書。
在本發明之組合療法中,本發明化合物與其他治療劑可由相同的或不同的生產商生產及/或調配。此外,可在如下情形下將本發明化合物與另一治療劑一起帶入組合療法中:(i)在對內科醫師發放組合產品之前(例如,在包含本發明化合物及另一治療劑之套組情形中);(ii)在即將投與前由內科醫師自身(或在內科醫師指導下);(iii)由患者自身,例如,在依序投與本發明化合物與另一治療劑期間。
因此,本發明提供如本文揭示之化合物之用途,其用於治療由TRPC蛋白活性介導之疾病或病況,其中製備藥劑用於與另一治療劑一起投與。本發明亦提供另一治療劑之用途,其用於治療由TRPC蛋白活性介導之疾病或病況,其中投與藥劑與如本文揭示之化
合物。在另一態樣中,本發明提供如本文揭示之化合物之用途,其用於治療選自以下之疾病或病症:腎病症候群、微小變化病、局灶性節段性腎小球硬化症、塌陷性腎小球病、膜性腎病變、膜增殖性腎小球性腎炎、IGA腎病變、急性腎衰竭、慢性腎衰竭、糖尿病腎病變、敗血症、肺高血壓、急性肺病症、急性呼吸窘迫症候群(ARDS)、心臟衰竭、中風、惡性腫瘤或肌肉營養不良症,其中製備藥劑用於與另一治療劑一起投與。本發明亦提供另一治療劑之用途,其用於治療選自以下之疾病或病症:腎病症候群、微小變化病、局灶性節段性腎小球硬化症、塌陷性腎小球病、膜性腎病變、膜增殖性腎小球性腎炎、IGA腎病變、急性腎衰竭、慢性腎衰竭、糖尿病腎病變、敗血症、肺高血壓、急性肺病症、急性呼吸窘迫症候群(ARDS)、心臟衰竭、中風、惡性腫瘤或肌肉營養不良症,其中投與藥劑與如本文揭示之化合物。
本發明亦提供如本文揭示之化合物,其用於治療由TRPC蛋白活性介導之疾病或病況的方法中,其中製備化合物與另一治療劑一起投與。本發明亦提供另一治療劑,其用於治療由TRPC蛋白活性介導之疾病或病況的方法中,其中製備另一治療劑用於與如本文揭示之化合物一起投與。本發明亦提供如本文揭示之化合物,其用於治療由TRPC蛋白活性介導之疾病或病況的方法中,其中化合物與另一治療劑一起投與。本發明亦提供另一治療劑,其用於治療由TRPC蛋白活性介導之疾病或病況的方法中,其中另一治療劑與如本文揭示之化合物一起投與。
本發明亦提供如本文揭示之化合物之用途,其用於治
療由TRPC蛋白活性介導之疾病或病況,其中患者先前(例如在24小時內)已經另一治療劑治療。本發明亦提供另一治療劑之用途,其用於治療由TRPC蛋白活性介導之疾病或病況,其中患者先前(例如在24小時內)已經如本文揭示之化合物治療。
醫藥組合物可單獨投與或與已知在腎病之治療中或更具體而言在FSGS、腎病症候群、微小變化病或糖尿病性腎病之治療中具有有益效應的其他分子組合投與。組合療法方案可為加性的或其可產生協同結果(例如,腎功能改善超出組合使用兩種藥劑所預期)。在一些實施例中,本發明提供利用本發明化合物與選自由以下組成之群之第二治療劑的用於預防及/或治療腎病或更具體而言FSGS、腎病症候群或微小變化病之組合療法:ACE/ARB(諸如卡托普利(captopril)、賴諾普利(lisinopril)或氯沙坦(losartan))、類固醇療法(諸如普賴松(prednisone))、免疫調節劑(諸如嗎替麥考酚酯(mycophenolate mofetil)、他克莫司(tacrolimus)或環孢素A(cyclosporine A))、促腎上腺皮質激素類似物(諸如促皮質素凝膠)、抗CD20抗體(諸如利妥昔單抗(rituximab))、鈣通道阻斷劑(諸如胺氯地平(amlodipine))、利尿劑(諸如氫氯噻嗪(hydrochlorothiazide))、抗血小板劑(諸如雙嘧達莫(dipyridamole))、抗凝劑(諸如肝素)、DPP-4抑制劑(諸如西他列汀(sitagliptin))、SGLT2抑制劑(諸如達格列淨(dapagliflozin))、抗高脂血症藥(諸如瑞舒伐他汀(rosuvastatin))、貧血治療藥(阿法達貝伯汀(darbepoetin alfa))或抗高尿酸血症藥(非布司他(febxostat))。
在一個實施例中,本發明提供在個體中抑制TRPC蛋白
之活性或更佳抑制TRPC6蛋白之活性的方法,其中該方法包括向個體投與治療有效量之根據式(I)之定義之化合物。本發明進一步提供藉由投與如本文揭示之化合物在個體中抑制TRPC蛋白之活性或更佳更佳抑制TRPC6蛋白之活性的方法,其中該方法包括向個體投與治療有效量之如本文揭示之化合物。
在一個實施例中,本發明提供如本文揭示之化合物,其用作藥劑。
在一個實施例中,本發明提供如本文揭示之化合物之用途,其用於治療個體之以TRPC蛋白之活性或更佳TRPC6蛋白之活性為特徵的病症或疾病。具體而言,本發明提供如本文揭示之化合物之用途,其用於治療由TRPC蛋白之活性或更佳TRPC6蛋白之活性介導之病症或疾病,例如腎病症候群、微小變化病、局灶性節段性腎小球硬化症、塌陷性腎小球病、膜性腎病變、膜增殖性腎小球性腎炎、IGA腎病變、急性腎衰竭、慢性腎衰竭、糖尿病腎病變、敗血症、肺高血壓、急性肺病症、急性呼吸窘迫症候群(ARDS)、心臟衰竭、中風、惡性腫瘤或肌肉營養不良症。在某些較佳態樣中,本發明提供如本文揭示之化合物之用途,其用於治療由TRPC6蛋白之活性介導之病症或疾病,其選自腎病症候群、膜性腎病變及急性腎衰竭。
在一個實施例中,本發明提供如本文揭示之化合物之用途,其用於製造用於治療個體之以TRPC蛋白之活性或更佳TRPC6蛋白之活性為特徵的病症或疾病之藥劑。更具體而言,用於製造用於治療個體之以TRPC蛋白之活性或更佳TRPC6蛋白之活性為特徵的病症或疾病之藥劑,該疾病或病症例如腎病症候群、微小變化病、局灶
性節段性腎小球硬化症、塌陷性腎小球病、膜性腎病變、膜增殖性腎小球性腎炎、IGA腎病變、急性腎衰竭、慢性腎衰竭、糖尿病腎病變、敗血症、肺高血壓、急性肺病症、急性呼吸窘迫症候群(ARDS)、心臟衰竭、中風、惡性腫瘤或肌肉營養不良症。在某些較佳態樣中,本發明提供如本文揭示之化合物之用途,其用於製造用於治療腎病症候群、膜性腎病變及急性腎衰竭之藥劑。
在一個實施例中,本發明提供如本文揭示之化合物之用途,其用於治療個體之以TRPC蛋白之活性或更佳TRPC6蛋白之活性為特徵的病症或疾病。更具體而言,本發明提供本文提供之化合物之用途,其用於治療以TRPC蛋白之活性或更佳TRPC6蛋白之活性為特徵之疾病或病症,例如腎病症候群、微小變化病、局灶性節段性腎小球硬化症、塌陷性腎小球病、膜性腎病變、膜增殖性腎小球性腎炎、IGA腎病變、急性腎衰竭、慢性腎衰竭、糖尿病腎病變、敗血症、肺高血壓、急性肺病症、急性呼吸窘迫症候群(ARDS)、心臟衰竭、中風、惡性腫瘤或肌肉營養不良症。在某些實施例中,本文提供之化合物之用途係用於治療選自腎病症候群、膜性腎病變及急性腎衰竭之疾病或病症。
在具體實施例中,本發明提供本發明化合物之用途,其用於治療或預防腎病症候群、膜性腎病變、急性腎衰竭、敗血症、慢性腎衰竭、糖尿病腎病變、肺高血壓、急性肺病症、急性呼吸窘迫症候群(ARDS)、心臟衰竭、中風、惡性腫瘤或肌肉營養不良症。在某些實施例中,目前無症狀但處於發生症狀性腎病症候群、膜性腎病變、急性腎衰竭、敗血症、慢性腎衰竭、糖尿病腎病變、肺高血壓、
急性肺病症、急性呼吸窘迫症候群(ARDS)、心臟衰竭、中風、惡性腫瘤或肌肉營養不良症風險下之患者適於投與本發明化合物。在治療或預防腎病症候群、膜性腎病變、急性腎衰竭、敗血症、慢性腎衰竭、糖尿病腎病變、肺高血壓、急性肺病症、急性呼吸窘迫症候群(ARDS)、心臟衰竭、中風、惡性腫瘤或肌肉營養不良症中之用途包括(但不限於)用於治療或預防腎病症候群、膜性腎病變、急性腎衰竭、敗血症、慢性腎衰竭、糖尿病腎病變、肺高血壓、急性肺病症、急性呼吸窘迫症候群(ARDS)、心臟衰竭、中風、惡性腫瘤或肌肉營養不良症之一或多種症狀或態樣。
本發明進一步包括本發明製程之任何變化形式,其中使用在其任一階段獲得之中間產物作為起始物質且實施其餘步驟,或其中起始物質係在反應條件下原位形成,或其中反應組分係以其鹽或光學純物質形式使用。
以下實例意欲闡釋本發明且不應理解為對其進行限制。溫度係以攝氏度(℃)給出。若無另外說明,則所有蒸發皆係在通常介於約15mm Hg與100mm Hg(=20-133毫巴)之低壓下實施。最終產物、中間體及起始物質之結構皆係藉由標準分析方法來證實,例如微量分析法及光譜特徵分析法(例如MS、IR、NMR)。所用縮寫係業內習用之彼等。
本發明亦係關於以下製程之彼等形式:其中在該製程任一階段作為中間體獲得之化合物係用作起始物質且實施其餘製程步驟,或其中起始物質係在反應條件下形成或以衍生物形式(例如以受保護形式或以鹽形式)使用,或可藉由本發明方法獲得之化合物係在
製程條件下產生且進一步經受原位處理。
用於合成本發明化合物之所有起始物質、結構單元、試劑、酸、鹼、脫水劑、溶劑及觸媒皆市面有售,或可藉由業內普通技術人員已知之有機合成方法產生。
實驗
除非另有說明,否則所有材料皆自商業供應商獲得且無需進一步純化即使用。除非另外指明,否則所有份數皆係以重量計且溫度係以℃表示。所有微波輔助之反應皆係利用Biotage之Smith合成器實施。質譜數據係藉由電噴射離子化技術測定。將所有實例純化至>95%純度,如藉由高效液相層析所測定。除非另外指明,否則反應係在室溫下運行。
市售材料係自Sigma Aldrich、HDH Pharma、Pharmablock、Alfa Aesar、Enovation Chemicals及Combi-Blocks購得。
本申請案中所述之化合物之化合物名稱(亦即IUPAC名稱)係使用ChemDraw化合物命名軟體生成。
使用以下縮寫:CDI- 1,1'-羰基二咪唑
DCM- 二氯甲烷
DMSO- 二甲基亞碸
DMF- N,N-二甲基甲醯胺
THF- 四氫呋喃
Et2O- 乙醚
EtOAc- 乙酸乙酯
EtOH- 乙醇
Ms- 甲磺酸鹽
MeCN- 乙腈
MeOH- 甲醇
SFC- 超臨界流體層析
TFA- 三氟乙酸
tmp- 2,2,6,6-四甲基哌啶
h- 小時
min- 分鐘
rt- 室溫(22-25℃)
mL 毫升
μL 微升
g 公克
μg 微克
mg 毫克
μmoL 毫莫耳濃度
本文所述之化合物係使用彼等熟習此項技術者已知之技術經由流程1至6中繪示之反應順序以及藉由其他方法製備。此外,在以下流程中,若提及特定酸、鹼、試劑、偶合劑、溶劑等,則應理解,可使用其他適宜酸、鹼、試劑、偶合劑、溶劑等且包括於本發明範疇內。
本發明所選化合物之合成係如流程1中所述製備。期望雙-苯胺之CDI偶合提供相應苯并咪唑酮。經受回流POCl3,從而遞送氯苯并咪唑。該等中間體可用各種親電子劑烷基化,接著經受SnAr條件以提供Boc保護之次末端中間體。曝露於各種酸,實現Boc去保護,以供給最終產物。
流程1
用於合成本發明中之額外化合物之苯并咪唑中間體的替代方法示於流程2中。期望雙-苯胺之CDI偶合提供相應苯并咪唑酮。經受回流POCl3,從而遞送氯苯并咪唑。將該等中間體與鹼及親核劑一起加熱以提供SnAr產物。用各種親電子劑烷基化,之後酸性Boc去保護,從而供給最終化合物。
流程2
另外,本發明中之實例可藉由流程3-6中所示之方法合成。
流程3
異硫氰酸酯形成係使用各種試劑完成。添加二級胺,之後與一級胺縮合,從而提供相應經取代之胍。使用銅催化完成分子內環化。最終酸性Boc去保護供給期望化合物。
流程4
使經取代之哌啶經受溴化氰,從而提供相應哌啶-1-甲腈。該等物質易受各種苯胺親核劑之親核劑攻擊,該等苯胺親核劑接著由苄基親電子劑捕獲。相應胍在鈀及銅催化下進行分子內交叉偶合。酸性條件下之最終Boc去保護供給期望化合物。
流程5
用各種親電子劑及鹼使苯并咪唑烷基化。該等中間體經受Zn(tmp)2、銅催化及苯甲醯基羥基胺,以供給胺化產物。最終經受酸性Boc去保護條件,從而產生期望產物。
流程6
在經取代氟-硝基苯上使用一級苄胺及鹼完成SnAr轉變。用鐵或鋅還原相應硝基中間體,接著經受CDI偶合及POCl3氯化反應。使該等中間體再經受SnAr條件,接著在酸性條件下Boc去保護,以供給最終化合物。
流程7. 烷基化中間體之通用合成
中間體1:6-((2-氯-5,7-二氟-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈及中間體2:6-((2-氯-4,6-二氟-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈
步驟1. 4,6-二氟-1H-苯并[d]咪唑-2(3H)-酮
將3,5-二氟苯-1,2-二胺(210.0g,1.457mol,1.0當量)及CDI(236.0g,1.457mol,1.0當量)溶解於無水THF(2.5L,11.9mL/g)中且於室溫下攪拌12h。LCMS指示反應完成。將反應混合物用水(6.0L)稀釋且用乙酸乙酯(2×6.0L)萃取。將合併之有機層經硫酸鈉乾燥,過濾且在減壓下濃縮,以提供黑色固體狀粗製4,6-二氟-1H-苯并[d]咪唑-2(3H)-酮,其不經進一步純化即用於下一步驟。1H NMR(400MHz,DMSO-d 6):δ 11.20(s,1H),11.05(s,1H),6.85(td,J=10.7,2.2Hz,1H),6.69(dd,J=8.6,2.2Hz,1H)。MS(ESI,陽離子)m/z:171.0[M+1]
步驟2. 2-氯-4,6-二氟-1H-苯并[d]咪唑
將4,6-二氟-1H-苯并[d]咪唑-2(3H)-酮(180.0g,1.058mol,1.0當量)懸浮於POCl3(2.0L)中且在攪拌下於110℃下加熱2h,此時LCMS指示反應完成。經由真空蒸餾移除過量POCl3且將剩餘殘餘物用乙腈(1.0L)及飽和碳酸氫鈉水溶液(1.0L)稀釋,接著用乙酸乙酯(2×4.0L)萃取。將合併之有機層經硫酸鈉乾燥,過濾且在減壓下濃縮,以提供褐色固體狀2-氯-4,6-二氟-1H-苯并[d]咪唑,其不經進一步純化即用於下一反應。1H NMR(400MHz,DMSO-d 6):13.40(bs,1H),7.31-7.03(m,2H)。MS(ESI,陽離子)m/z:189.0[M+1]。
步驟3. 6-(羥基甲基)菸鹼腈
將(5-溴吡啶-2-基)甲醇(75.0g,399.0mmol,1.0當量)、氰化鋅(141.0g,1.197mol,3.0當量)及肆(三苯基膦)鈀(0)(46.1g,39.9mmol,0.1當量)溶解於N,N-二甲基甲醯胺(750.0mL,10.0mL/g)中且用氮脫氣30分鐘。將反應混合物於110℃下加熱2h。LCMS指示形成產物。反應完成後,使混合物冷卻至室溫,用水(700mL)稀釋且用乙酸乙酯(3×700mL)萃取。將合併之有機層經硫酸鈉乾燥,過濾且在減壓下濃縮。將粗物質吸附至矽膠塞(230-400網目)上且通過Biotage Isolera-one預填充之矽膠管柱,使用含於己烷中之40%乙酸乙酯之梯度溶析,進行純化,以提供白色固體狀6-(羥基甲基)菸鹼腈。1H NMR(400MHz,DMSO-d 6)δ 8.93(dt,J=1.8,0.8Hz,1H),8.32-8.28(m,1H),7.66(dt,J=8.3,0.9Hz,1H),5.68(td,J=5.9,0.8Hz,1H),4.64(d,J=5.8Hz,2H)。MS(ESI,陽離子)m/z:135.0[M+1]
步驟4. 6-(氯甲基)菸鹼腈及甲烷磺酸(5-氰基吡啶-2-基)甲基酯
將6-(羥基甲基)菸鹼腈(25.0g,186.0mmol,1.0當量)溶解於二氯甲烷(360.0mL,14.4mL/g)中且冷卻至0℃。添加N,N-二異丙基乙胺(48.8mL,280.0mmol,1.5當量),之後經15分鐘逐滴添加甲磺醯氯(16.0g,205.0mmol,1.1當量)。使反應混合物升溫至室溫且攪拌45min。LCMS指示形成產物。將反應混合物用水(500mL)稀釋且用DCM(2×250mL)萃取。將合併之有機層經硫酸鈉乾燥,過濾且在減壓下濃縮,以得到粗物質,將其吸附至矽膠塞(230-400網目)上且通過Biotage Isolera-one預填充之矽膠管柱,使用含於己烷中之15%乙酸乙酯之梯度溶析,進行層析而純化,以得到微黃色固體狀6-(氯甲基)菸鹼腈(VI)。1H NMR(400MHz,DMSO-d 6)δ 9.03(dd,J=2.2,1.0Hz,1H),8.38(dd,J=8.1,2.2Hz,1H),7.77(dd,J=8.1,0.9Hz,1H),4.88(s,2H)。使用含於己烷中之50%乙酸乙酯之梯度進一步溶析管柱,提供褐色固體狀甲烷磺酸(5-氰基吡啶-2-基)甲基酯。1H NMR(400MHz,DMSO-d 6)δ 9.06(dt,J=2.1,1.0Hz,1H),8.41(dt,J=8.2,1.7Hz,1H),7.73(dd,J=8.2,1.0Hz,1H),5.42(d,J=1.1Hz,2H),3.34(s,3H)。MS(ESI,陽離子)m/z:213.2[M+1]。兩種化合物皆係適用於烷基化(步驟5)中之親電子劑。
步驟5. 6-((2-氯-4,6-二氟-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈及6-((2-氯-5,7-二氟-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈
於室溫下將2-氯-4,6-二氟-1H-苯并[d]咪唑(50.0g,265.0mmol,1.0當量)及6-(氯甲基)菸鹼腈(40.5g,265.0mmol,1.0當量)溶解於乙腈(500.0mL,10.0mL/g)中。添加碳酸銫(138.0g,427.0mmol,1.6當量)且將混合物於室溫下攪拌12h。將反應混合物用水(200mL)稀釋且用乙酸乙酯(2×200mL)萃取。將合併之有機層經硫酸鈉乾燥,過濾且在減壓下濃縮。將粗物質吸附至矽膠塞(60-120網目)上且藉由管柱層析,使用含於己烷中之25%乙酸乙酯之梯度溶析來純化,以提供呈異構物之混合物(淺黃色固體)形式之6-((2-氯-4,6-二氟-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈及6-((2-氯-5,7-二氟-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈。在一些情況下,異構物之混合物表經分離即繼續使用,在其他情況下則在此階段分離異構物。
步驟6. 6-((2-氯-5,7-二氟-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈(中間體1)及6-((2-氯-4,6-二氟-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈(中間體2)之分離
將1.0g樣品溶解於20mL甲醇中,管柱Lux C4(250×50mm,5μm),移動相:70:30(A:B),A:液體CO2,B:甲醇,流速:120mL/min,波長:220nm,樣品負載:100mg/注射,入口壓力:200-210巴,循環時間:3.5,運行時間:10。總之,藉由SFC分離(51.0g異構物之混合物),以得到黃色固體狀6-((2-氯-5,7-二氟-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈(中間體1,峰1)及6-((2-氯-4,6-二氟-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈(中間體2,峰2)。峰1:1H NMR(400MHz,DMSO-d 6):δ 8.90(d,J=2.0Hz,1H),8.37(dd,J=8.2,2.1Hz,1H),7.70(d,J=8.2Hz,1H),7.42(dd,J=9.0,2.2Hz,1H),7.22(ddd,J=11.9,10.3,2.2Hz,1H),5.79(s,2H)。MS(ESI,陽離子)m/z:304.0[M+1]。峰2:1H NMR(400MHz,DMSO-d 6):δ 8.91(t,J=3.0Hz,1H),8.37(ddd,J=8.2,4.4,2.1Hz,1H),7.67(dd,J=8.4,4.2Hz,1H),7.49(dt,J=8.7,3.0Hz,1H),7.20(tdd,J=10.7,4.5,2.1Hz,1H),5.79(d,J=3.8Hz,2H)。MS(ESI,陽離子)m/z:304.0[M+1]。
以下中間體係使用與用於合成中間體1及2之順序類似之順序及上述通用流程7來合成:
[a]經由非選擇性苄化形成之異構物之混合物,其在最終產物或次末端中間體經分離
流程8. 烷基化中間體至最終產物之推進
實例38:6-((2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈
步驟1. ((3R,4R)-1-(1-((5-氰基吡啶-2-基)甲基)-1H-苯并[d]咪唑-2-基)-4-氟哌啶-3-基)胺基甲酸第三丁基酯
將1,1'-二甲基三乙胺(1.300ml,7.44mmol)、((3R,4R)-4-氟哌啶-3-基)胺基甲酸第三丁基酯(0.975g,4.47mmol)、6-((2-氯-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈(中間體7,1g,3.72mmol)及二甲基亞碸(7.44ml)組合於燒瓶中且加熱至130℃,持續36小時。將混合物冷卻,倒入水中,接著用EtOAc(3×)萃取。合併有機物,經Na2SO4乾燥,過濾且濃縮。將粗物質裝載至80g RediSep ISCO柱上,用庚烷中之10-50% EtOAc溶析,以提供淺橙色泡沫狀((3R,4R)-1-(1-((5-氰基吡啶-2-基)甲基)-1H-苯并[d]咪唑-2-基)-4-氟哌啶-3-基)胺基甲酸第三丁基酯。MS(ESI,陽離子)m/z:451.2[M+1]
注意:正丁醇為DMSO之合適替代物。二氟化哌啶需要加熱至150℃。
利用TFA之Boc去保護程序(程序B)
步驟2. 6-((2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈(實例43)
將((3R,4R)-1-(1-((5-氰基吡啶-2-基)甲基)-1H-苯并[d]咪唑-2-基)-4-氟哌啶-3-基)胺基甲酸第三丁基酯(1.31g,2.91mmol,1當量)溶解於DCM(10mL)中且緩慢滴入冷卻(0℃)TFA(約10mL)之燒瓶中。1小時後,去保護完成。將混合物傾倒至SCX管柱(用MeOH預潤濕)上,用MeOH沖洗,接著用甲醇氨溶析。將甲醇氨濃縮,且將淺橙色油再溶解於MeCN/水中,冷凍,且凍乾,以提供淺黃色固體狀標題化合物。1H NMR(500MHz,MeOD)δ 8.81-8.92(m,1 H),8.23(dd,J=8.30,2.08Hz,1 H),7.49-7.66(m,2H),7.17-7.39(m,3H),5.64(s,2H),4.69-4.86(m,1H),3.92-4.06(m,1H),3.61-3.79(m,2H),3.20-3.32(m,2H),2.24-2.41(m,1H),1.92-2.14(m,1H)。(ESI,陽離子)m/z:351.2[M+1]
實例45:6-((2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈鹽酸鹽
步驟1. (S)-(1-(1-((5-氰基吡啶-2-基)甲基)-5-氟-1H-苯并[d]咪唑-2-基)哌啶-3-基)胺基甲酸第三丁基酯
向6-((2-氯-6-氟-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈(150mg,0.523mmol)及休尼格鹼(hunig’s base)(137μl,0.785mmol)於1-丁醇(2093μl)中之懸浮液中添加(S)-哌啶-3-基胺基甲酸第三丁基酯(115mg,0.576mmol)。將反應物於130℃下攪拌隔夜。24小時後,將反應混合物濃縮且藉由管柱層析,用庚烷中之20-100%乙酸乙酯溶析而純化,以提供灰白色固體狀標題化合物。(ESI,陽離子)m/z:451.2[M+1]
利用HCl之Boc去保護(程序A)
(S)-6-((2-(3-胺基哌啶-1-基)-5-氟-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈鹽酸鹽(實例51)
步驟2. 將(S)-(1-(1-((5-氰基吡啶-2-基)甲基)-5-氟-1H-苯并[d]咪唑-2-基)哌啶-3-基)胺基甲酸第三丁基酯(77mg)溶解於二噁
烷(2mL)中,且添加二噁烷中之4N HCl(585μL,2.340mmol)。將反應物於環境溫度下攪拌。16小時後,LC/MS分析顯示反應完成。在真空中濃縮反應混合物,以提供灰白色固體狀標題化合物。1H NMR(400MHz,d 6-DMSO)δ 8.94(s,1H),8.48(br s,2H),8.40(dd,J=2.18,8.19Hz,1H),7.77(d,J=8.19Hz,1H),7.40(dd,J=2.85,8.66Hz,2H),7.14(dt,J=2.38,9.33Hz,1H),5.65-5.84(m,2H),3.89(br d,J=10.57Hz,1H),3.28-3.52(m,3H),3.18(br t,J=9.80Hz,1H),1.94-2.02(m,1H),1.81-1.93(m,1H),1.47-1.72(m,2H)。(ESI,陽離子)m/z:351.0[M+1]。
注意 :使用水性處理或使用離子交換層析有時將HCl鹽轉化呈游離鹼形式。在表中指定鹽或游離鹼之分離。
實例8:6-((2-((3R,4S)-3-胺基-4-氟哌啶-1-基)-6-氯-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈
以1mmol規模遵循與上文所概述類似之順序之程序使用TFA Boc去保護(程序B)合成6-((2-((3R,4S)-3-胺基-4-氟哌啶-1-基)-6-氯-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈。將其在Boc中間體分離:Chiralcel OD-H,25% IPA,峰1。1H NMR(500MHz,MeOD)δ 8.86(d,J=1.30Hz,1H),8.14-8.20(m,1H),7.47(d,J=8.56Hz,1H),7.44(d,J=8.30Hz,1H),7.23(d,J=2.08Hz,1H),7.19(dd,J=1.95,8.43Hz,1H),
5.53(s,2H),4.33-4.50(m,1H),3.53-3.61(m,1H),3.43-3.50(m,1H),3.02-3.20(m,2H),2.95(dd,J=8.69,12.33Hz,1H),2.12-2.24(m,1H),1.82-1.94(m,1H)。(ESI,陽離子)m/z:387.2[M+1]。
實例93:(R)-6-((2-(3-胺基-4,4-二氟哌啶-1-基)-6-氟-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈
以1.9mmol規模遵循與上文所概述之順序類似之程序使用TFA Boc去保護(程序B)合成(R)-6-((2-(3-胺基-4,4-二氟哌啶-1-基)-6-氟-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈。將其在氯苯并咪唑中間體分離(YMC Amyose SA,甲醇THF(70:30)40%;峰1)。1H NMR(500MHz,MeOD)δ 8.84(d,J=1.82Hz,1H),8.15(dd,J=2.08,8.30Hz,1H),7.40-7.52(m,2H),6.91-7.00(m,2H),5.47-5.62(m,2H),3.34-3.54(m,2H),3.08-3.28(m,3H),2.21-2.36(m,1H),2.00-2.21(m,1H)。(ESI,陽離子)m/z:351.0[M+1]。
表2中之實例係使用與用於合成實例38、45、8及88之順序類似之順序及上述通用流程8來合成:
[a]在SnAr期間出現腈水解[b]在Boc去保護期間觀察到Ritter反應性[c]未指定之立體化學命名對映異構物或非對映異構物之混合物
表3. 遵循流程8製得之化合物之表徵數據。
「分離階段」欄指示在該製程步驟後,在製表之最終化合物製備期間分離由於流程8中R 1 處之不對稱苯并咪唑取代形成的區位異構物(I=在製備烷基化中間體1-59(其中至少一個R 1 不為氫)之 後;B=在boc去保護之前;或F=最終化合物)。
流程9
中間體60:((3R,4R)-1-(6-氰基-1H-苯并[d]咪唑-2-基)-4-氟哌啶-3-基)胺基甲酸第三丁基酯
步驟1. 2-側氧基-2,3-二氫-1H-苯并[d]咪唑-5-甲腈
向1,2-二胺基-4-氰基苯(1.00mL,7.51mmol)於四氫呋喃(5mL)中之溶液中添加1,1'-羰基二咪唑(1.22g,7.51mmol)。將反應物於環境溫度下攪拌1小時,濃縮,接著用水濕磨。藉由真空過濾收集褐色沈澱,以提供褐色粉末狀2-側氧基-2,3-二氫-1H-苯并[d]咪唑-
5-甲腈。MS(ESI,陽離子)m/z:160.2[M+1]
步驟2. 2-氯-1H-苯并[d]咪唑-6-甲腈
向2-側氧基-2,3-二氫-1H-苯并[d]咪唑-5-甲腈(XVIII,1.19g,7.48mmol,1當量)於乙腈(5mL)中之懸浮液中添加氧氯化磷(v)(1.398mL,14.95mmol)。將反應物於110℃下攪拌16小時,接著冷卻至室溫。將其用乙腈稀釋且接著緩慢添加至冷的快速攪拌之飽和碳酸氫鈉水溶液(50mL)的燒杯中。將混合物用乙酸乙酯萃取;將其經無水硫酸鎂乾燥,過濾且濃縮,以提供黃褐色粉末狀2-氯-1H-苯并[d]咪唑-6-甲腈。(ESI,陽離子)m/z:178.2[M+1]
步驟3. ((3R,4R)-1-(6-氰基-1H-苯并[d]咪唑-2-基)-4-氟哌啶-3-基)胺基甲酸第三丁基酯(中間體60)
將N,N-二異丙基乙胺(3.93mL,22.52mmol)、2-氯-1H-苯并[d]咪唑-6-甲腈(2g,11.26mmol)、((3R,4R)-4-氟哌啶-3-基)胺基甲酸第三丁基酯(2.95g,13.51mmol)及1-丁醇(25mL)組合於燒瓶中且加熱至130℃,持續48小時。將混合物濃縮,接著裝載至125g RediSep ISCO柱上,用DCM中之0-4% MeOH溶析,以提供淺褐色泡沫狀標題化合物。(ESI,陽離子)m/z:360.2[M+1]
以下中間體係使用與針對中間體60所述之順序類似之順序及上述通用流程9來合成:
流程10. SnAr中間體至最終產物之推進
實例187:2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-1-((5-氯嘧啶-2-基)甲基)-1H-苯并[d]咪唑-6-甲腈
步驟1. ((3R,4R)-1-(1-((5-氯嘧啶-2-基)甲基)-6-氰基-1H-苯并[d]咪唑-2-基)-4-氟哌啶-3-基)胺基甲酸第三丁基酯
將碳酸銫(0.707mg,2.170mmol)、((3R,4R)-1-(6-氰基-1H-苯并[d]咪唑-2-基)-4-氟哌啶-3-基)胺基甲酸第三丁基酯(390mg,1.085mmol)、甲烷磺酸(5-氯嘧啶-2-基)甲基酯(290mg,1.302mmol)及乙腈(10mL)組合於小瓶中且攪拌隔夜。將混合物傾倒至水中並用DCM(3×)萃取。合併有機物,經Na2SO4乾燥,過濾且濃縮。將褐色
固體溶解於DCM中,裝載至20g二氧化矽塞上且用EtOAc(約4管柱體積)沖洗。濃縮EtOAc以提供呈異構物之混合物形式之((3R,4R)-1-(1-((5-氯嘧啶-2-基)甲基)-6-氰基-1H-苯并[d]咪唑-2-基)-4-氟哌啶-3-基)胺基甲酸第三丁基酯及((3R,4R)-1-(1-((5-氯嘧啶-2-基)甲基)-5-氰基-1H-苯并[d]咪唑-2-基)-4-氟哌啶-3-基)胺基甲酸第三丁基酯。使用對掌性SFC(Chiralcel AD,25% IPA, 峰1 )分離異構物。(ESI,陽離子)m/z:486.2[M+1]
使用TFA之Boc去保護(程序B)
步驟2. 2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-1-((5-氯嘧啶-2-基)甲基)-1H-苯并[d]咪唑-6-甲腈(實例187)
將((3R,4R)-1-(1-((5-氯嘧啶-2-基)甲基)-6-氰基-1H-苯并[d]咪唑-2-基)-4-氟哌啶-3-基)胺基甲酸第三丁基酯(150mg,0.309mmol)裝載至小瓶中。添加DCM(5mL),接著添加TFA(2mL)。1小時後,將混合物傾倒至SCX管柱上,該管柱用甲醇預潤濕,用甲醇沖洗,接著用甲醇氨溶析。將殘餘物再溶解於MeCN/H2O中,冷凍且凍乾,以提供白色固體狀標題化合物。1H NMR(500MHz,MeOD)δ 8.80(s,2H),7.65-7.69(m,1H),7.54-7.61(m,1H),7.49(d,J=8.30Hz,1H),5.57(s,2H),4.42-4.60(m,1H),3.72-3.80(m,1H),3.64(br d,J=13.23Hz,1H),3.15-3.27(m,2H),3.06(dd,J=9.21,12.59Hz,1H),2.13-2.27(m,1H),1.80-1.99(m,1H)。(ESI,陽離子)m/z:386.2[M+1]
注意:在一些情形下,將游離鹼再溶解於DCM中,且添加HCl以析出HCl鹽。此在表中闡述為TFA去保護,但HCl產物除外。
利用HCl之替代性Boc去保護(程序A)
步驟2. 2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-1-((5-甲氧基嘧啶-2-基)甲基)-1H-苯并[d]咪唑-6-甲腈鹽酸鹽(實例242)
將((3R,4R)-1-(6-氰基-1-((5-甲氧基嘧啶-2-基)甲基)-1H-苯并[d]咪唑-2-基)-4-氟哌啶-3-基)胺基甲酸第三丁基酯(69mg)溶解於二噁烷(2mL)中,且添加二噁烷中之4N HCl(500uL)。將反應物於環境溫度下攪拌隔夜,接著在真空中濃縮,以提供白色固體狀標題化合物。1H NMR(500MHz,MeOD)δ 8.52(s,2H),7.94(s,1H),7.66-7.74(m,2H),5.54-5.67(m,2H),4.77-4.93(m,1H),4.21-4.30(m,1H),4.01(br d,J=12.98Hz,1H),3.96(s,3H),3.71-3.78(m,1H),3.43-3.50(m,2H),2.32-2.46(m,1H),1.98-2.14(m,1H)。(ESI,陽離子)m/z:382.2[M+1]。
注意:使用水性處理或使用離子交換層析,HCl鹽有時係游離鹼化。在表中指定鹽或游離鹼之分離。
實例188:以0.3mmol規模遵循與上述類似之順序合成(3R,4R)-4-氟-1-(1-((5-氟嘧啶-2-基)甲基)-1H-苯并[d]咪唑-2-基)哌啶-3-胺。使用TFA程序完成Boc去保護。1H NMR(500MHz,MeOD)δ 8.68-8.74(s,2H),7.47-7.52(m,1H),7.14-7.20(m,2H),7.08-7.13(m,1H),5.53(s,2H),4.34-4.52(m,1H),3.64(dtd,J=1.95,4.14,12.36Hz,1H),3.48-3.57(m,1H),3.04-3.21(m,2H),2.98(dd,J=8.82,12.20Hz,1H),2.12-2.25(m,1H),1.82-1.92(m,1H)。(ESI,陽離子)m/z:345.2[M+1]。
以下實例係使用與針對實例239-240所述之順序類似之順序及上述通用流程9-10來合成:
[a]使用TFA移除Boc。將游離鹼再溶解於DCM中,且添加HCl以析出HCl鹽。[b]未指定之立體化學表示對映異構物或非對映異構物之混合物。
表6. 遵循流程9-10製得之化合物之表徵數據
「分離階段」欄指示在該製程步驟後,在製表之最終化合物製備期間分離由於流程10中R 1 處之不對稱苯并咪唑取代形成的區位異構物(I=在製備流程10之第一步驟中之N-芳烷基-2-哌啶基-苯并咪唑中間體(其中至少一個R 1 不為氫)之後;B=在boc去保護之前;或F=最終化合物)。
流程11. 獲得氯苯并咪唑選擇性
中間體86:4-((2,6-二氯-1H-苯并[d]咪唑-1-基)甲基)苯甲腈
步驟1. 4-(((5-氯-2-硝基苯基)胺基)甲基)苯甲腈
向4-氯-2-氟-1-硝基苯(8.0g,45.6mmol,1當量)於乙醇(104.0mL)及水(80.0mL)中之經攪拌溶液中添加4-(胺基甲基)苯甲腈鹽酸鹽(8.45g,50.1mmol,1.1當量),之後添加碳酸鉀(11.34g,82.0mmol,1.8當量)。將反應混合物加熱至85℃,持續10h,接著於環境溫度下攪拌8h。完成(藉由TLC監測)後,將反應混合物用水(100mL)稀釋且過濾固體。將所得固體在高真空下乾燥,以提供黃色固體狀4-(((5-氯-2-硝基苯基)胺基)甲基)苯甲腈(9g,68.6%產率)。1H NMR(400MHz,DMSO-d6):δ 8.85(t,J=6.3Hz,1H),8.08-8.13(m,1H),7.86-7.79(m,2H),7.56(d,J=8.0Hz,2H),6.90(t,J=2.4Hz,1H),6.77-6.66(m,1H),4.76(d,J=6.3Hz,2H)。
步驟2. 4-(((2-胺基-5-氯苯基)胺基)甲基)苯甲腈
向4-(((5-氯-2-硝基苯基)胺基)甲基)苯甲腈(9.0g,31.3mmol,1.0當量)於四氫呋喃(90.0mL)、甲醇(90.0mL)及水(60.0mL)之混合物中之經攪拌溶液中添加鐵粉(7.51g,135.0mmol,4.3當量),之後添加氯化銨(7.53g,141.0mmol,4.5當量)。將所得反應混合物加熱至60℃,持續2h。完成(藉由TLC監測)後,將反應混合物經由矽藻土墊過濾,且用乙酸乙酯(100mL)洗滌。將濾液用水(100mL)稀釋且分
離各層,用乙酸乙酯(2×200mL)洗滌水層。將合併之有機層用水(2×200mL)、鹽水(2×200mL)洗滌,經硫酸鈉乾燥,過濾且在減壓下濃縮,以提供淺黃色固體狀4-(((2-胺基-5-氯苯基)胺基)甲基)苯甲腈(7.5g,93%產率),其足夠純以用於下一步驟。1H NMR(400MHz,DMSO-d6):δ 7.81(dd,J=8.3,2.3Hz,2H),7.65-7.45(m,2H),6.53(dd,J=8.2,2.2Hz,1H),6.40(dt,J=8.1,2.4Hz,1H),6.19(d,J=2.4Hz,1H),5.58(t,J=7.2Hz,1H),4.75(s,2H),4.54-4.28(m,2H)。
步驟3. 4-((6-氯-2-側氧基-2,3-二氫-1H-苯并[d]咪唑-1-基)甲基)苯甲腈
向4-(((2-胺基-5-氯苯基)胺基)甲基)苯甲腈(7.5g,29.1mmol,1.0當量)於1,4-二噁烷(120.0mL)中之經攪拌溶液中逐份添加DIPEA(7.62mL,43.7mmol,1.5當量)及CDI(11.80g,72.8mmol,2.5當量)。將所得反應混合物加熱至100℃,持續1h。完成(藉由TLC監測)後,將反應混合物冷卻至環境溫度且用冰冷水(100mL)緩慢淬滅。將反應混合物用乙酸乙酯(2×150mL)萃取。將合併之有機層用水(2×150mL)及鹽水溶液(2×100mL)洗滌,經硫酸鈉乾燥,過濾且在減壓下濃縮,以提供淺褐色固體狀4-((6-氯-2-側氧基-2,3-二氫-1H-苯并[d]咪唑-1-基)甲基)苯甲腈(6g,72.7%產率),其足夠純以原樣用於下一步驟。1H NMR(400MHz,DMSO-d6):δ 11.21(s,1H),7.86-7.79(m,2H),7.54-7.40(m,2H),7.23(d,J=1.7Hz,1H),7.06-6.97(m,2H),
5.12(s,2H)。MS:(ESI陰離子)m/z:282[M-1]
步驟4. 4-((2,6-二氯-1H-苯并[d]咪唑-1-基)甲基)苯甲腈
將4-((6-氯-2-側氧基-2,3-二氫-1H-苯并[d]咪唑-1-基)甲基)苯甲腈(6.0g,21.15mmol,1.0當量)於POCl3(60.0mL)中之經攪拌溶液加熱至110℃,持續5h。完成(藉由TLC監測)後,在高真空壓力下濃縮反應混合物。將所得殘餘物用DCM稀釋且於0℃下用10%碳酸氫鈉水溶液緩慢中和。分離各層且用DCM(2×150mL)萃取水層。將合併之有機層用水(200mL)、鹽水(200mL)洗滌,經硫酸鈉乾燥,過濾且在減壓下濃縮。所得粗製物在230-400網目矽膠上,使用石油醚及乙酸乙酯作為溶析液(15-20%)純化,以得到灰白色固體狀4-((2,6-二氯-1H-苯并[d]咪唑-1-基)甲基)苯甲腈(2.5g,39.1%產率)。1H NMR(400MHz,DMSO-d6):δ 7.91-7.79(m,3H),7.68(d,J=8.7Hz,1H),7.39-7.28(m,3H),5.67(s,2H)。MS:(ESI陽離子)m/z:302.0[M+1]
流程12. 苄基化中間體至最終產物之推進
步驟1. 4-((2,6-二氯-1H-苯并[d]咪唑-1-基)甲基)苯甲腈
向微波小瓶中之4-((2,6-二氯-1H-苯并[d]咪唑-1-基)甲基)苯甲腈(50mg,0.165mmol,1當量)及((3R,4R)-4-氟哌啶-3-基)胺基甲酸第三丁基酯(72.2mg,0.331mmol,2當量)於1-丁醇(662μl,0.25
M)中之懸浮液中添加DIEA(43.4μl,0.248mmol,1.5當量)。將小瓶加熱至130℃,持續12小時。將反應混合物冷卻至室溫,濃縮,且裝載至用庚烷中之20-80%乙酸乙酯溶析之12g RediSep ISCO柱上,以提供白色固體狀((3R,4R)-1-(6-氯-1-(4-氰基苄基)-1H-苯并[d]咪唑-2-基)-4-氟哌啶-3-基)胺基甲酸第三丁基酯(40mg,49.9%產率)。MS(ESI陽離子)m/z:484.0(M+H)。
步驟2. 4-((2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-6-氯-1H-苯并[d]咪唑-1-基)甲基)苯甲腈
向((3R,4R)-1-(6-氯-1-(4-氰基苄基)-1H-苯并[d]咪唑-2-基)-4-氟哌啶-3-基)胺基甲酸第三丁基酯(40mg,0.083mmol,1當量)於1,4-二噁烷(1mL)中之溶液中添加二噁烷中之4N HCl(0.517mL,2.066mmol,25當量)。將反應物於環境溫度下攪拌6小時,此時濃縮反應混合物,以提供白色固體狀4-((2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-6-氯-1H-苯并[d]咪唑-1-基)甲基)苯甲腈鹽酸鹽。NMR(400MHz,DMSO-d6)8.78(br s,2H),7.87-7.80(m,2H),7.55(d,J=8.5Hz,1H),7.49-7.35(m,3H),7.31-7.21(m,1H),5.65-5.49(m,2H),5.05-4.91(m,1H),3.95(br d,J=12.3Hz,1H),3.79-3.61(m,1H),3.52-3.44(m,1H),3.35-3.22(m,1H),3.12(br t,J=11.5Hz,1H),2.32-2.15(m,1H),1.99-1.79(m,1H)。MS(ESI陽離子)m/z:384.0(M+H)。
表9. 遵循流程11-12之化合物之表徵數據。
流程13. 甲磺酸鹽轉移化學
實例425:(3R,4R)-4-氟-1-(1-((5-甲氧基吡啶-2-基)甲基)-1H-苯并[d]咪唑-2-基)哌啶-3-胺
步驟1. ((3R,4R)-4-氟-1-(1-(甲基磺醯基)-1H-苯并[d]咪唑-2-基)哌啶-3-基)胺基甲酸第三丁基酯
將((3R,4R)-1-(1H-苯并[d]咪唑-2-基)-4-氟哌啶-3-基)胺基甲酸第三丁基酯(中間體54,156mg,0.467mmol)溶解於DCM(2.3
mL)中。將混合物用甲磺醯氯(100μl,0.700mmol,2當量)及無水三乙胺(197μl,1.400mmol)處理。將所得黃色溶液攪拌隔夜。將反應物用NH4Cl(水溶液)淬滅,用DCM稀釋,萃取至DCM中,經MgSO4乾燥,過濾且濃縮,從而產生油狀粗製物。在管柱層析(25g SiO2,庚烷中之0-45%乙酸乙酯)上純化該油,以產生無色固體狀((3R,4R)-4-氟-1-(1-(甲基磺醯基)-1H-苯并[d]咪唑-2-基)哌啶-3-基)胺基甲酸第三丁基酯。(ESI,陽離子)m/z:413.2[M+1]。
步驟2. ((3R,4R)-4-氟-1-(1-((5-甲氧基吡啶-2-基)甲基)-1H-苯并[d]咪唑-2-基)哌啶-3-基)胺基甲酸第三丁基酯
向小瓶中裝入(S)-1-(1-(甲基磺醯基)-1H-苯并[d]咪唑-2-基)哌啶-3-胺(150mg,0.38mmol)、1-羥基-2,3-二氫-1H-茚-5-甲腈(67mg,1.1當量)及Cs2CO3(150mg,1.2當量)。向小瓶配備攪拌棒,加蓋,且添加MeCN(1.3ml)。於90℃下將混合物放置於加熱塊中持續18h。將反應物用EtOAc及NH4Cl(水溶液)稀釋,將混合物萃取至EtOAc中。將合併之有機萃取物經MgSO4乾燥,過濾且濃縮,從而產生粗製反應物。在管柱層析(4g SiO2,庚烷中之0-30% EtOAc)純化粗物質,以得到無色油狀((3R,4R)-4-氟-1-(1-((5-甲氧基吡啶-2-基)甲基)-1H-苯并[d]咪唑-2-基)哌啶-3-基)胺基甲酸第三丁基酯。(ESI,陽離子)m/z:456.2[M+1]。
步驟3. (3R,4R)-4-氟-1-(1-((5-甲氧基吡啶-2-基)甲基)-1H-苯并[d]咪唑-2-基)哌啶-3-胺(實例425)
將((3R,4R)-4-氟-1-(1-((5-甲氧基吡啶-2-基)甲基)-1H-苯并[d]咪唑-2-基)哌啶-3-基)胺基甲酸第三丁基酯(32mg,1當量)溶解於DCM(5mL)中。添加二噁烷中之HCl(10當量),且將混合物攪拌隔夜。濃縮溶液,接著使用反相HPLC純化,以提供標題化合物。1H NMR(600MHz,d6-DMSO)δ 7.79(s,1H),7.50(t,J=7.53Hz,2H),7.11(t,J=7.66Hz,1H),6.96(d,J=7.79Hz,1H),6.88-6.94(m,1H),6.39-6.49(m,1H),6.19(t,J=8.95Hz,1H),3.54-3.62(m,1H),3.36-3.43(m,1H),3.18-3.24(m,3H),3.00-3.13(m,2H),2.74-2.87(m,1H),2.52-2.63(m,1H),1.91-2.12(m,2H),1.77-1.89(m,1H),1.47-1.56(m,1H)。(ESI,陽離子)m/z:356.2[M+1]。
流程14. 經由肽偶合製得之化合物
實例426:1-(2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)乙醯基)氮雜環丁烷-3-甲腈
步驟1. 2-(2-((3R,4R)-3-((第三丁氧基羰基)胺基)-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)乙酸甲基酯
向小瓶中裝入((3R,4R)-1-(5,6-二氟-1H-苯并[d]咪唑-2-基)-4-氟哌啶-3-基)胺基甲酸第三丁基酯(0.3g,0.810mmol)、乙腈(2.70ml)中之Cs2CO3(0.792g,2.430mmol)及2-溴乙酸甲基酯(0.149g,0.972mmol)且在J-Kem塊上振盪16h。將反應混合物經由Celite®牌過濾劑塞過濾且藉由反相HPLC純化,以獲得2-(2-((3R,4R)-3-((第三丁氧基羰基)胺基)-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)乙酸甲基酯。1H NMR(600MHz,DMSO-d6)δ 7.56(t,J=9.06Hz,1H),7.51(t,J=8.85Hz,1H),7.19(br d,J=8.25Hz,1H),4.94-5.03(m,2H),4.51-4.59(dt,J=4.63,9.01Hz,1H),3.68-3.77(m,3H),3.35-3.46(m,2H),3.24-3.30(m,1H),2.95(br t,J=10.63Hz,1H),2.73-2.89(m,1H),2.13-
2.21(m,1H),1.79-1.89(m,1H),1.39(s,9H)。MS:(ESI陽離子)m/z:443.2[M+1]。
步驟2. 2-(2-((3R,4R)-3-((第三丁氧基羰基)胺基)-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)乙酸
使用二噁烷(1mL)及水(1mL)中之LiOH(0.097g,4.05mmol)皂化2-(2-((3R,4R)-3-((第三丁氧基羰基)胺基)-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)乙酸甲基酯。將反應混合物於環境溫度下攪拌1h。使用乙酸酸化反應混合物且過濾所得灰白色沈澱,以獲得2-(2-((3R,4R)-3-((第三丁氧基羰基)胺基)-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)乙酸。MS:(ESI陽離子)m/z:429.2[M+1]。
步驟3. ((3R,4R)-1-(1-(2-(3-氰基氮雜環丁-1-基)-2-側氧基乙基)-5,6-二氟-1H-苯并[d]咪唑-2-基)-4-氟哌啶-3-基)胺基甲酸第三丁基酯
於環境溫度下振盪2-(2-((3R,4R)-3-((第三丁氧基羰基)胺基)-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)乙酸(0.015g,0.035mmol)、3-氰基氮雜環丁烷鹽酸鹽(4.15mg,0.035mmol)及六氟磷酸2-(1h-苯并三唑-1-基)-1,1,3,3-四甲基鎓鹽(0.013g,0.035mmol)於
二甲基亞碸(0.117ml)及DIPEA(0.024ml,0.140mmol)中之溶液。藉由反相HPLC純化反應混合物,以獲得((3R,4R)-1-(1-(2-(3-氰基氮雜環丁-1-基)-2-側氧基乙基)-5,6-二氟-1H-苯并[d]咪唑-2-基)-4-氟哌啶-3-基)胺基甲酸第三丁基酯。MS:(ESI陽離子)m/z:493.2[M+1]。
步驟4. 1-(2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)乙醯基)氮雜環丁烷-3-甲腈(實例426)
將((3R,4R)-1-(1-(2-(3-氰基氮雜環丁-1-基)-2-側氧基乙基)-5,6-二氟-1H-苯并[d]咪唑-2-基)-4-氟哌啶-3-基)胺基甲酸第三丁基酯用DCM(0.5mL)中之TFA(0.5mL)處理。濃縮混合物且使用反相HPLC純化,以獲得標題化合物。1H NMR(600MHz,DMSO-d6)δ 7.34-7.60(m,2H),4.73-4.80(m,2H),4.48-4.60(m,2H),4.31-4.48(m,1H),4.17-4.28(m,1H),4.06-4.15(m,1H),3.82-3.94(m,1H),2.96-3.06(m,2H),2.74-2.84(m,1H),2.06-2.17(m,1H),1.64-1.88(m,3H)。MS:(ESI陽離子)m/z:393.2[M+1]。
實例432:(R)-6-((2-(4,4-二氟-3-(甲基胺基)哌啶-1-基)-6-氟-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈
向小瓶中裝入(R)-6-((2-(3-胺基-4,4-二氟哌啶-1-基)-6-氟-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈(100mg,0.259mmol)。向小瓶裝配攪拌棒且添加DMF(1.3mL)。添加碳酸鉀(53.7mg,0.388mmol),之後添加碘甲烷(40.4mg,0.285mmol)。將混合物於室溫下攪拌2小時。藉由LCMS觀察單甲基化及雙甲基化胺之形成。藉由用EtOAc及NH4Cl(水溶液)稀釋處理反應物。將混合物用EtOAc萃取,合併有機萃取物,經MgSO4乾燥,過濾且濃縮,從而產生粗製混合物。在HPLC上純化粗製物,以得到標題化合物。MS:(ESI陽離子)m/z:401.2[M+1];1H NMR(600MHz,d6-DMSO)δ 8.95(dd,J=0.62,2.18Hz,1H),8.33(dd,J=2.18,8.10Hz,1H),7.51(d,J=8.10Hz,1H),7.46(dd,J=4.98,8.72Hz,1H),7.11(dd,J=2.49,9.03Hz,1H),6.95(ddd,J=2.49,8.72,9.96Hz,1H),5.54(s,2H),3.35-3.41(m,1H),3.28-3.32(m,1H),3.10-3.16(m,1H),2.91-2.96(m,1H),2.88(td,J=3.66,13.23Hz,1H),2.25(s,3H),2.13-2.23(m,1H),2.01-2.13(m,1H)。
實例433:(R)-6-((2-(4,4-二氟-3-((2-羥基乙基)胺基)哌啶-1-基)-6-氟-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈
步驟1. (R)-6-((2-(3-((2-((第三丁基二甲基矽基)氧基)乙基)胺基)-4,4-二氟哌啶-1-基)-6-氟-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈
將(R)-6-((2-(3-胺基-4,4-二氟哌啶-1-基)-6-氟-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈(89.4mg,0.231mmol)與(第三丁基二甲基矽基氧基)乙醛(63.7μl,0.301mmol)組合在小瓶中。添加四氫呋喃(2.3mL)及氰基硼氫化鈉(24.2μl,0.463mmol)。將混合物於室溫下攪拌2小時,此時起始物質完全消耗。將反應物用NH4Cl(水溶液)淬滅,萃取至EtOAc中,用鹽水洗滌,經MgSO4乾燥,過濾且濃縮,從而產生(R)-6-((2-(3-((2-((第三丁基二甲基矽基)氧基)乙基)胺基)-4,4-二氟哌啶-1-基)-6-氟-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈,其不經進一步純化即用於下一步驟。
步驟2. (R)-6-((2-(4,4-二氟-3-((2-羥基乙基)胺基)哌啶-1-基)-6-氟-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈(實例433)
將(R)-6-((2-(3-((2-((第三丁基二甲基矽基)氧基)乙基)胺基)-4,4-二氟哌啶-1-基)-6-氟-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈溶解於THF(2.3mL)中,且添加四丁基氟化銨(THF中之1.0M溶液,301μl,0.301mmol)。將混合物於室溫下攪拌16h。藉由LCMS觀察到澈底去保護。藉由用水及EtOAc稀釋、萃取至EtOAc中、經MgSO4乾燥、過濾及濃縮處理所得混合物。藉由管柱層析(4g SiO2,庚烷中之0-70% EtOAc)純化粗製物,以供給標題化合物。MS:(ESI陽離子)m/z:431.2[M+1]。1H NMR(500MHz,d4-MeOH)δ 8.82(br s,1H),8.13-8.25(m,1H),7.59(d,J=8.30Hz,1H),7.55(dd,J=4.67,8.30Hz,1H),6.98-7.06(m,2H),5.58(s,2H),4.17(dtd,J=4.80,8.63,12.98Hz,1H),4.06(br d,J=13.23Hz,1H),3.84-3.95(m,2H),3.53-3.66(m,2H),3.38-3.47(m,1H),3.32-3.37(m,2H),2.25-2.42(m,2H)。
實例434:(S)-6-((2-(3-胺基哌啶-1-基)-1H-苯并[d]咪唑-1-基)甲基)菸鹼酸
向小瓶中裝入(S)-6-((2-(3-胺基哌啶-1-基)-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈(0.03g,0.09mmol)及1,4-二噁烷(0.301ml)中之3.99N鹽酸水溶液(0.075ml,0.451mmol),且於環境溫度下振盪1h。濃縮反應混合物且藉由反相HPLC純化。1H NMR(600MHz,DMSO-d6)δ 13.23-13.65(br s,1H),8.98(d,J=1.40Hz,1H),8.29(br d,J=6.85Hz,1H),8.12-8.19(m,1H),8.11(br s,1H),7.51(br d,J=7.71Hz,1H),7.21(br s,1H),7.15(br s,1H),5.57-5.61(br s,2H),3.58-3.76(m,1H),3.44-3.57(m,1H),3.16-3.29(m,2H),3.06(br s,1H),2.52-2.55(m,1H),1.95(br s,1H),1.83(br s,1H),1.53-1.64(m,1H)。MS:(ESI陽離子)m/z:352.2[M+1]。
實例435:(S)-6-((2-(3-胺基哌啶-1-基)-1H-苯并[d]咪唑-1-基)甲基)菸鹼醯胺
將含有甲醇(0.30mL)中之(S)-6-((2-(3-胺基哌啶-1-基)-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈(0.03g,0.090mmol)及NaOH(1M,於水中)(0.271ml,0.271mmol)之小瓶於室溫下振盪3h。將反應
混合物用EtOAc稀釋,過濾,濃縮,且藉由反相HPLC純化,以得到標題化合物。1H NMR(600MHz,DMSO-d6)δ 8.94(s,1H),8.16(dd,J=2.22,8.14Hz,1H),8.11(br s,1H),7.56(br s,1H),7.43(d,J=7.79Hz,1H),7.18(d,J=8.17Hz,1H),6.98-7.11(m,3H),5.38-5.44(m,2H),3.37-3.43(m,1H),2.76-2.89(m,2H),2.57-2.66(m,1H),2.52-2.56(m,1H),1.78-1.84(m,1H),1.65-1.74(m,1H),1.50-1.58(m,1H),1.14-1.28(m,1H)。MS:(ESI陽離子)m/z:351.2[M+1]。
實例436:6-((2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-1H-苯并[d]咪唑-1-基)甲基)菸鹼醯胺
將含有甲醇(0.301ml)中之6-((2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈(0.03g,0.090mmol)及NaOH(1M,於水中)(0.271ml,0.271mmol)之小瓶於環境溫度下振盪3h。將反應混合物用EtOAc稀釋,過濾,濃縮且藉由反相HPLC純化,以得到標題化合物。1H NMR(500MHz,MeOH-d4)δ 8.84-9.04(m,1H),8.08-8.27(m,1H),7.48-7.58(m,1H),7.06-7.34(m,4H),5.51(br d,J=6.75Hz,3H),4.29-4.50(m,1H),3.61(br dd,J=3.89,7.79Hz,
1H),3.39-3.50(m,1H),2.87-3.19(m,3H),2.10-2.27(m,1H),1.78-1.97(m,1H),0.79-0.98(m,1H)。MS:(ESI陽離子)m/z:369.2[M+1]。
實例437:2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)乙酸
將2-(2-((3R,4R)-3-((第三丁氧基羰基)胺基)-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)乙酸用DCM(1mL)中之TFA(0.5mL)處理且於室溫下攪拌1h。濃縮反應混合物且經由反相HPLC純化,以獲得標題化合物。1H NMR(600MHz,DMSO-d6)δ 7.47-7.60(m,2H),4.82-4.92(m,2H),4.51-4.59(dt,J=4.63,9.01Hz,1H),3.35-3.46(m,2H),3.24-3.30(m,1H),2.95(br t,J=10.63Hz,1H),2.73-2.89(m,1H),2.13-2.21(m,1H),1.79-1.89(m,1H)。MS:(ESI陽離子)m/z:329.0[M+1]。
實例438-441:6-((R)-1-(4,6-二氟-2-((3R,4R)-4-氟-3-(甲基胺基)哌啶-1-基)-1H-苯并[d]咪唑-1-基)乙基)菸鹼腈(實例438)及6-((S)-1- (4,6-二氟-2-((3R,4R)-4-氟-3-(甲基胺基)哌啶-1-基)-1H-苯并[d]咪唑-1-基)乙基)菸鹼腈(實例439)及6-((R)-1-(5,7-二氟-2-((3R,4R)-4-氟-3-(甲基胺基)哌啶-1-基)-1H-苯并[d]咪唑-1-基)乙基)菸鹼腈(實例440)及6-((S)-1-(5,7-二氟-2-((3R,4R)-4-氟-3-(甲基胺基)哌啶-1-基)-1H-苯并[d]咪唑-1-基)乙基)菸鹼腈(實例441)
步驟1. 將((3R,4R)-1-(1-(1-(5-氰基吡啶-2-基)乙基)-4,6-二氟-1H-苯并[d]咪唑-2-基)-4-氟哌啶-3-基)胺基甲酸第三丁基酯(1.05g,2.098mmol,4種異構物之混合物)及碘甲烷(0.144ml,2.308mmol)溶解於THF中且冷卻至0℃。緩慢添加四氫呋喃中之1m雙(三甲基矽基)醯胺鉀溶液(2.203ml,2.203mmol),且將反應攪拌1小時。轉化停止,因此將反應物用氯化銨淬滅,接著用DCM(3×)萃取。合併有機物,經Na2SO4乾燥,過濾且濃縮,以提供甲基化及N-H產物之混合物。
步驟2. 使用對掌性SFC分離異構物:Chiralpak Cel2,15% MeOH,0.2% DEA。
步驟3. 將每一個別異構物(100mg,1當量)溶解於DCM(5mL)中,接著添加TFA(0.5mL)。1小時後,將溶液傾倒至預潤濕之
SCX管柱上且用甲醇沖洗。用甲醇氨溶析產物。
峰1:6-((R)-1-(4,6-二氟-2-((3R,4R)-4-氟-3-(甲基胺基)哌啶-1-基)-1H-苯并[d]咪唑-1-基)乙基)菸鹼腈(實例438): 1H NMR(500MHz,甲醇-d4)δ ppm 1.88-2.08(m,4 H)2.22-2.33(m,1 H)2.41-2.50(m,3 H)2.99(dd,J=12.72,9.34Hz,1 H)3.16-3.30(m,2 H)3.50-3.64(m,1 H)3.77-3.95(m,1 H)4.53-4.76(m,1 H)5.97(q,J=7.01Hz,1 H)6.63-6.78(m,1 H)7.04-7.16(m,1 H)7.62(d,J=8.30Hz,1 H)8.19(dd,J=8.30,2.08Hz,1 H)8.84(d,J=1.56Hz,1 H)。MS:(ESI陽離子)m/z:415.2[M+1]。
峰2:6-((S)-1-(4,6-二氟-2-((3R,4R)-4-氟-3-(甲基胺基)哌啶-1-基)-1H-苯并[d]咪唑-1-基)乙基)菸鹼腈(實例439): 1H NMR(500MHz,甲醇-d4)δ ppm 1.97(d,J=7.01Hz,3 H)2.03-2.28(m,2 H)2.52(s,3 H)2.99-3.21(m,3 H)3.59(br d,J=12.98Hz,1 H)3.71-3.80(m,1 H)4.54-4.75(m,1 H)5.97(q,J=7.01Hz,1 H)6.64-6.75(m,1 H)7.10(dd,J=8.82,2.08Hz,1 H)7.58(d,J=8.30Hz,1 H)8.18(dd,J=8.30,2.08Hz,1 H)8.76-8.87(m,1 H)。MS:(ESI陽離子)m/z:415.2[M+1]。
峰3:6-((R)-1-(5,7-二氟-2-((3R,4R)-4-氟-3-(甲基胺基)哌啶-1-基)-1H-苯并[d]咪唑-1-基)乙基)菸鹼腈(實例440): 1H NMR(500MHz,甲醇-d4)δ ppm 2.01(d,J=7.27Hz,4 H)2.18-2.33(m,1 H)2.49(s,3 H)2.98(dd,J=12.46,9.34Hz,1 H)3.14-3.28(m,2 H)3.47(br dd,J=12.85,1.95Hz,1 H)3.79(dtd,J=8.40,4.04,4.04,2.47Hz,1 H)4.57-4.76(m,1 H)5.91-6.04(m,1 H)6.67-6.85(m,2 H)
7.63(d,J=8.30Hz,1 H)8.13-8.25(m,1 H)8.84-8.96(m,1 H)。MS:(ESI陽離子)m/z:415.2[M+1]。
峰4:6-((S)-1-(5,7-二氟-2-((3R,4R)-4-氟-3-(甲基胺基)哌啶-1-基)-1H-苯并[d]咪唑-1-基)乙基)菸鹼腈(實例441): 1H NMR(500MHz,甲醇-d4)δ ppm 2.02(d,J=7.01Hz,3 H)2.16-2.35(m,1 H)2.51-2.68(m,3 H)2.98-3.20(m,3 H)3.46-3.60(m,1 H)3.65-3.78(m,1 H)4.54-4.78(m,1 H)5.99(q,J=7.27Hz,1 H)6.64-6.85(m,2 H)7.58(d,J=8.30Hz,1 H)8.19(dd,J=8.17,2.21Hz,1 H)8.83-8.96(m,1 H)。MS:(ESI陽離子)m/z:415.2[M+1]。
流程15. 經由混合酸酐製得之化合物
實例607:2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)-1-((1R,5S)-3-氮雜二環[3.1.0]己-3-基)乙酮
步驟1. 2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)-1-((1R,5S)-3-氮雜二環[3.1.0]己-3-基)乙酮
將2-(2-((3R,4R)-3-((第三丁氧基羰基)胺基)-4-氟哌啶-
1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)乙酸(110mg,0.257mmol)、1,1'-二甲基三乙胺(135μl,0.770mmol)及四氫呋喃(1284μl)組合於小瓶中且冷卻至0℃。逐滴添加三甲基乙醯氯(24.12μl,0.282mmol)且將混合物攪拌15分鐘。LCMS顯示完全轉化成混合酸酐(藉由LCMS自MeOH置換以甲基酯形式出現)。添加3-氮雜二環[3.1.0]己烷(1.5當量)且將其攪拌1小時。濃縮混合物,接著再溶解於DCM/TFA(1:1)中且攪拌1小時。再濃縮混合物,接著再溶解於1mL DMSO中,過濾,且藉由反相HPLC純化,以提供期望產物。
表15. 表14中製表之化合物之表徵數據
「分離階段」欄指示在該製程步驟後,在製表之最終化合物製備期間分離由於流程15中R 1 處之不對稱苯并咪唑取代形成的區位異構物(I=在製備乙酸中間體(其中至少一個R 1 不為氫)之後;B=在boc去保護之前;或F=最終化合物)。
生物實例1 TRPC6鈣流量分析
TRPC6(瞬時受體電位通道家族C6)抑制劑之功效係使用FLIPR tetra系統藉由其抑制由經人類TRPC6穩定轉染之HEK293細胞上OAG(1-油醯基-2-乙醯基-sn-甘油,Millipore Sigma,O6754)刺激觸發的鈣流量來量測。使用具有以下選擇性試劑之生長培養基(杜貝克氏改良鷹氏培養基(Dulbecco's Modified Eagle's Medium,DMEM)使細胞在37℃、5% CO2下在加濕環境中生長:高葡萄糖、10%胎牛血清、1XPSGlu(青黴素-鏈黴素麩醯胺酸)、1X NEAA(非必需胺基酸)、1X丙酮酸鈉及200ug/ml潮黴素)。對於一般傳代,使細胞生長至70-90%匯合;且移除培養基,且用不含鈣及鎂之PBS(磷酸鹽緩衝鹽水)輕輕洗滌細胞2次。在37℃下施加胰蛋白酶(3mL),持續5分鐘。藉由用手之基部敲擊燒瓶移出細胞,且添加7mL生長培養基以使胰
蛋白酶失活且重新懸浮細胞。通常之分裂時間表係每2-3天1:5。
在分析前一天將細胞接種,接種細胞密度係在聚-D-離胺酸(PDL)塗佈之384孔盤中1.0-1.5×104個/25μl/孔,使用多通道吸量管或multidrop進行。將該等細胞首先於室溫下與螢光染料一起培育90-120分鐘,之後使其在PDL塗佈之384孔黑色盤上生長隔夜(染料上樣緩衝液10ml實例:9mL分析緩衝液,1mL,10X PBX信號增強子,10μL鈣指示劑)。在用TRPC6激動劑OAG刺激之前,將細胞與一定劑量之化合物一起培育25分鐘。藉由將OAG添加至分析緩衝液(Ca林格氏溶液鹼:10mM HEPES(4-(2-羥基乙基)-1-哌嗪-乙磺酸)、4mM MgCl2、120mM NaCl、5mM KCl,pH=7.2,於25℃下)+0.1% BSA+2mM CaCl2)至0.2mM/2% DMSO之濃度(此達到50uM/0.5% DMSO之最終細胞上濃度)製備OAG溶液。添加12.5uL OAG混合物,且藉由FLIPR terra系統上之細胞內鈣含量之變化量測TRPC6通道之活化。
藉由量測在180秒成像幀期間自背景中減去之螢光峰信號來獲取數據。將每一數據點進一步正規化至相對於緩衝液之100% OAG觸發之信號。表16提供每一化合物之IC50,該數據係藉由針對化合物劑量繪製峰信號而獲得的。
前述內容僅僅係本發明之說明,且並不意欲將本發明限制於所揭示之化合物。對於熟習此項技術者顯而易見之變化及改變意欲落入在隨附申請專利範圍中界定之本發明之範疇及性質內。
根據前面之說明,熟習此項技術者可容易地確定本發明之基本特徵,且在不脫離其精神及範疇之情況下,可對本發明進行各種改變及修飾以使其適應各種用途及條件。
Claims (29)
- 一種根據式I之化合物或其醫藥學上可接受之鹽,
- 一種根據式I之化合物或其醫藥學上可接受之鹽, 其中 p係0或1;當p係0時,則R1係氫、C1-C6烷基、鹵素或羥基;R2係胺基或胺基C1-C4烷基;R3係氫;且R4係氫、C1-C6烷基或苯基;或當p係0時,則R1及R3組合起來形成稠合C3-C6環烷基環或具有1或2個獨立地選自N、O或S之環雜原子之稠合4至6員雜環,該環烷基或雜環視情況經胺基取代;R2係氫、C1-C6烷基或胺基C1-C4烷基;且R4係氫;或當p係1時,則R1係NHR1a;R1a係氫、C1-C4烷基、C3-C7環烷基、羥基C1-C4烷基或具有一個選自N、O或S之環雜原子之4至6員雜環烷基;R2係氫、C1-C4烷基、羥基C1-C4烷基或C(O)NH2;R3係氫、鹵素、C1-C4烷基、C1-C4烷氧基或羥基;且R4係氫、C1-C4烷基或鹵素;或當p係0或1時,則C(NHR1a)R2組合起來形成螺環4至6員雜環烷基;R3係氫、鹵素、C1-C4烷基、C1-C4烷氧基或羥基;且R4係氫或鹵素;或當p係1時,則R1及R3組合起來形成稠合4至6員雜環或稠合3至7員碳環,該雜環包含環氮原子及視情況0或1個選自N、O及S之額外環雜原子,且該碳環經胺基取代;且R2係氫;且R4係氫、鹵素或羥基;R5表示1或2個獨立地選自氫、鹵素、羥基、胺基、C1-C6烷基或 C1-C6烷氧基之取代基;R6係-(CR7R8)-A;或R6係4至7員內醯胺,其視情況經一個或兩個獨立地選自由以下組成之群之取代基取代:羥基、C1-C6烷基、C2-C6烯基、C2-C6炔基、鹵基C1-C6烷基、C1-C6烷氧基、鹵基C1-C6烷氧基、羥基C1-C6烷基、C1-C6烷氧基C1-C6烷基、苯基或具有一個選自N、O或S之環雜原子及0或1個額外環氮原子之5或6員雜芳基,其中該雜芳基或苯基係視情況經0、1或2個C1-C6烷基或鹵素取代;或R6係部分不飽和9或10員雙環碳環,其視情況經1或2個獨立地選自以下之取代基取代:鹵素、氰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、鹵基C1-C6烷基、C1-C6烷氧基、鹵基C1-C6烷氧基、C(O)NH2及C(O)NHC1-C6烷基;A係5或6員雜芳基,該雜芳基包含一個選自N、O或S之環雜原子及0、1或2個額外環氮原子,該雜芳基視情況經0、1、2、3或4個獨立地選自以下之基團取代:鹵素、氰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、鹵基C1-C6烷基、C1-C6烷氧基、鹵基C1-C6烷氧基、C(O)NH2、C(O)NHC1-C6烷基、苯基或具有一個選自N、O或S之環雜原子及0、1或2個額外環氮原子之5或6員雜芳基,其中該視情況存在之雜芳基或苯基取代基進一步經0、1或2個C1-C6烷基取代;或A係經1、2或3個獨立地選自以下之取代基取代之苯基:鹵素、C1-C6烷基、C2-C6烯基、C2-C6炔基、鹵基C1-C6烷基、氰基C1-C6烷基、C1-C6烷氧基、鹵基C1-C6烷氧基、氰基C1-C6烷氧基、S(O)qC1-C6烷基、S(O)2NH2、S(O)2NHC1-C6烷基、S(O)2N(C1-C6烷基)2、 C(O)NH2、C(O)NHC1-C6烷基、C(O)N(C1-C6烷基)2、羥基、氰基或具有一個選自N、O或S之環雜原子及0、1或2個額外環氮原子之5或6員雜芳基,該雜芳基進一步經0、1或2個C1-C6烷基取代;或A係C(O)OR9或C(O)NR9R10;或A係具有0、1或2個環氮原子及0或1個選自N、O或S之額外環雜原子的視情況經取代之9或10員芳族或部分不飽和雙環基,該雙環基經0、1或2個獨立地選自由以下組成之群之取代基取代:鹵素、氰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、鹵基C1-C6烷基、C1-C6烷氧基、鹵基C1-C6烷氧基、C(O)NH2、C(O)OH或C(O)NHC1-C6烷基;R7係氫、C1-C4烷基或胺基;R8係氫或C1-C4烷基;或CR7R8組合起來形成3至6員環烷二基;R9係氫、C1-C6烷基、羥基C1-C6烷基、鹵基C1-C6烷基或氰基C1-C6烷基;R10係氫、C1-C6烷基、C2-C6烯基、C2-C6炔基、鹵基C1-C6烷基、C3-C7環烷基或4至7員雜環,該雜環具有1或2個選自N、O或S之環雜原子,該硫可視情況經氧化,且其中每一烷基或環烷基視情況經以下取代:氰基、鹵素、羥基、C1-C6烷氧基、S(O)qC1-C6烷基、具有1或2個選自N、O或S之環雜原子之4至6員雜環或具有1個選自N、O或S之環雜原子及0、1或2個額外環氮原子之5或6員雜芳基;或NR9R10組合起來形成具有一個環氮原子及0或1個選自N、O或S之額外環雜原子之單環或雙環4至9員雜環,該環硫可視情況經氧化,該雜環視情況經0、1或2個選自以下之取代基取代:鹵素、側氧基、羥 基、氰基、C1-C6烷基、鹵基C1-C6烷基、羥基C1-C6烷基、C1-C6烷氧基、S(O)qC1-C6烷基、CO2H、C(O)C1-C6烷基或C(O)NH2;q係0、1或2;Z1係N或CR11;Z2係N或CR12;Z3係N或CR13;Z4係N或CR14,Z5及Z6各自獨立地係N或C;其中Z1、Z2、Z3、Z4、Z5及Z6中之0、1或2者係N;R11、R12、R13及R14中之每一者獨立地選自由以下組成之群:氫、鹵素、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6烷氧基、鹵基C1-C6烷基、鹵基C1-C6烷氧基、C3-C7環烷基、氰基、SO2C1-C6烷基、苯基及具有1或2個獨立地選自N、O及S之環雜原子之飽和、部分不飽和或芳族5或6員雜環,該雜環視情況經1或2個獨立地選自C1-C6烷基及鹵素之取代基取代;且前提條件係式I化合物不包括1-[7-氟-6-甲氧基-1-[[2-(三氟甲基)苯基]甲基]-1H-苯并咪唑-2-基]-3-哌啶胺。
- 如請求項1或2之化合物或其醫藥學上可接受之鹽,其中p係0;R1及R3組合起來形成稠合C3-C6環烷基環或稠合4至6員氮雜環,該環烷基或氮雜環視情況經胺基取代;且R2及R4係氫。
- 如請求項1或2之化合物或其醫藥學上可接受之鹽,其中p係1,R1係NHR1a;R1a係氫、C1-C4烷基、C3-C7環烷基或具有一個選自N、O或 S之環雜原子之4至6員雜環烷基;R2係氫或C1-C4烷基;R3係氫、鹵素、C1-C4烷基、C1-C4烷氧基或羥基;且R4係氫、鹵素或C1-C4烷基。
- 如請求項4之化合物或其醫藥學上可接受之鹽,其中R1係NHR1a;R1a係氫、甲基、乙基、丙基、異丙基或環丙基;R2係氫或甲基;R3係氫、鹵素、甲基、乙基、甲氧基、乙氧基或羥基;且R4係氫、鹵素、甲基或乙基。
- 如請求項4或5之化合物或其醫藥學上可接受之鹽,其中R1係NH2;R2係氫;R3係氫、氟、甲基或羥基;且R4係氫、氟或甲基。
- 如請求項1至6中任一項之化合物或其醫藥學上可接受之鹽,其中R6係-(CR7R8)-A。
- 如請求項7之化合物,其中R7係氫或甲基;且R8係氫。
- 如請求項7或8之化合物或其醫藥學上可接受之鹽,其中A係5或6員雜芳基,該雜芳基包含一個選自N、O或S之環雜原子及0、1或2個額外環氮原子,該雜芳基視情況經0、1或2個獨立地選自以下之基團取代:鹵素、氰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、鹵基C1-C6烷基、C1-C6烷氧基、鹵基C1-C6烷氧基、C(O)NH2、C(O)NHC1-C6烷基、苯基或具有一個選自N、O或S之環雜原子及0、1或2個額外環氮原子之5或6員雜芳基,其中該視情況存在之雜芳基或苯基取代基進一 步經0、1或2個C1-C6烷基取代。
- 如請求項9之化合物或其醫藥學上可接受之鹽,其中A係吡啶-2-基、吡啶-3-基、嘧啶-2-基或吡嗪-2-基,其各自經1至3個獨立地選自由以下組成之群之基團取代:鹵素、氰基、C1-C4烷基、鹵基C1-C4烷基、C1-C4烷氧基、鹵基C1-C4烷氧基、C(O)NH2、C(O)NHC1-C4烷基、苯基或具有一個選自N、O或S之環雜原子及0、1或2個額外環氮原子之5員雜芳基,其中該視情況存在之雜芳基或苯基取代基進一步經0、1或2個C1-C6烷基取代。
- 如請求項7或8之化合物或其醫藥學上可接受之鹽,其中A係經一個選自由以下組成之群之取代基取代的苯基:鹵素、C1-C4烷基、鹵基C1-C4烷基、C1-C4烷氧基、鹵基C1-C4烷氧基、羥基、氰基或具有一個選自N、O或S之環雜原子及0、1或2個額外環氮原子之5員雜芳基,且其中該苯基視情況進一步經鹵素、C1-C4烷基、C1-C4烷氧基、鹵基C1-C4烷基或鹵基C1-C4烷氧基取代。
- 如請求項7或8之化合物或其醫藥學上可接受之鹽,其中A係C(O)NR9R10;R9係氫或C1-C4烷基;R10係C1-C4烷基、鹵基C1-C4烷基、C3-C7環烷基或4至7員雜環,該雜環具有1或2個選自N、O或S之環雜原子,該硫可視情況經氧化,且其中每一烷基或環烷基視情況經氰基、鹵素、羥基、C1-C6烷氧 基、S(O)qC1-C6烷基取代;或NR9R10組合起來形成具有一個環氮原子及0或1個選自N、O或S之額外環雜原子之單環或雙環4至9員氮雜環,該環硫可視情況經氧化,該氮雜環視情況經0、1或2個選自以下之取代基取代:鹵素、側氧基、羥基、氰基、C1-C6烷基、鹵基C1-C6烷基、羥基C1-C6烷基、C1-C6烷氧基、S(O)2C1-C6烷基、CO2H、C(O)C1-C6烷基或C(O)NH2。
- 如請求項12之化合物或其醫藥學上可接受之鹽,其中R9係氫、甲基或乙基;且R10係C1-C4烷基或鹵基C1-C4烷基,其中每一烷基視情況經氰基、鹵素、羥基、C1-C6烷氧基或S(O)qC1-C6烷基取代。
- 如請求項12之化合物或其醫藥學上可接受之鹽,其中NR9R10組合起來形成4至6員單環氮雜環或7至9員雙環氮雜環,其各自具有一個環氮原子及0或1個選自N、O或S之額外環雜原子,該環硫可視情況經氧化,其中每一氮雜環視情況經0、1或2個選自以下之取代基取代:鹵素、側氧基、羥基、氰基、C1-C6烷基、鹵基C1-C6烷基、羥基C1-C6烷基、C1-C6烷氧基、S(O)2C1-C6烷基、CO2H、C(O)C1-C6烷基或C(O)NH2。
- 如請求項1至14中任一項之化合物或其醫藥學上可接受之鹽,其中Z1係CR11;Z2係CR12; Z3係CR13;Z4係N或CR14,Z5及Z6各自係C;R11係氫、鹵素、氰基或C1-C4烷基;R12及R13各自獨立地選自由以下組成之群:氫、鹵素、氰基、C1-C4烷基、鹵基C1-C4烷基、C1-C4烷氧基、鹵基C1-C4烷氧基、C3-C6環烷基或具有1或2個獨立地選自N、O及S之環雜原子之5員飽和、部分不飽和或芳族5或6員雜環;且R14係氫、鹵素、氰基或C1-C4烷基。
- 如請求項1或2之化合物或其醫藥學上可接受之鹽,其係式III化合物:
- 如請求項1或2之化合物或其醫藥學上可接受之鹽,其係式VI化合物:
- 如請求項1或2之化合物或其醫藥學上可接受之鹽,其係式VII化合物: 其中 R1a係氫或C1-C4烷基;R3係氫或鹵素;R4係氫或鹵素;R7係氫、甲基或乙基;R9係氫、甲基或乙基;R10係C1-C4烷基或鹵基C1-C4烷基,其中每一烷基視情況經氰基、鹵素、羥基、C1-C6烷氧基或S(O)qC1-C6烷基取代;或NR9R10組合起來形成4至6員單環氮雜環或7至9員雙環氮雜環,其各自具有一個環氮原子及0或1個選自N、O或S之額外環雜原子,該環硫可視情況經氧化,其中每一氮雜環視情況經0、1或2個選自以下之取代基取代:鹵素、側氧基、羥基、氰基、C1-C6烷基、鹵基C1-C6烷基、羥基C1-C6烷基、C1-C6烷氧基、S(O)2C1-C6烷基、CO2H、C(O)C1-C6烷基或C(O)NH2;R11係氫、鹵素、氰基或C1-C4烷基; R12及R13各自獨立地選自由以下組成之群:氫、鹵素、氰基、C1-C4烷基、鹵基C1-C4烷基、C1-C4烷氧基或鹵基C1-C4烷氧基;且R14係氫、鹵素、氰基或C1-C4烷基。
- 如請求項16至18中任一項之化合物或其醫藥學上可接受之鹽,其中R11係氫。
- 如請求項16至19中任一項之化合物或其醫藥學上可接受之鹽,其中R1a係氫或甲基;R3係氫或氟;且R4係氫或氟。
- 一種化合物,其係如以下所列舉:(S)-6-((2-(3-胺基哌啶-1-基)-6-氯-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;(S)-6-((2-(3-胺基哌啶-1-基)-5-氯-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;(S)-6-((2-(3-胺基哌啶-1-基)-4-氯-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;6-((2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-4-氯-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;6-((2-((3R,4S)-3-胺基-4-氟哌啶-1-基)-4-氯-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;6-((2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-6-氯-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈; 6-((2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5-氯-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;6-((2-((3R,4S)-3-胺基-4-氟哌啶-1-基)-6-氯-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;6-((2-((3R,4S)-3-胺基-4-氟哌啶-1-基)-5-氯-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;(R)-6-((2-(3-胺基-4,4-二氟哌啶-1-基)-4-氯-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-1-((5-氰基吡啶-2-基)甲基)-1H-苯并[d]咪唑-4-甲腈;(R)-6-((2-(3-胺基-4,4-二氟哌啶-1-基)-6-氯-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;(R)-6-((2-(3-胺基-4,4-二氟哌啶-1-基)-5-氯-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;6-((2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-6-(三氟甲基)-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;6-((2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5-(三氟甲基)-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;6-((2-((3S,4S)-3-胺基-4-氟哌啶-1-基)-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;(S)-6-((2-(5-胺基-3,3-二氟哌啶-1-基)-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-1-((5-氰基吡啶-2-基)甲基)-6- 氟-1H-苯并[d]咪唑-4-甲腈;6-((2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-6-(三氟甲氧基)-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;6-((2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5-(三氟甲氧基)-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;6-((2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-6-氟-5-(三氟甲基)-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;6-((2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5-氟-6-(三氟甲基)-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;6-((2-((3aR,7aR)-六氫-1H-吡咯并[2,3-c]吡啶-6(2H)-基)-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;6-((2-((3aR,7aS)-六氫-1H-吡咯并[2,3-c]吡啶-6(2H)-基)-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;6-((2-((3aS,7aS)-六氫-1H-吡咯并[2,3-c]吡啶-6(2H)-基)-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;6-((2-((3aS,7aR)-六氫-1H-吡咯并[2,3-c]吡啶-6(2H)-基)-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;(R)-6-((2-(1,6-二氮雜螺[3.5]壬-6-基)-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;(S)-6-((2-(1,6-二氮雜螺[3.5]壬-6-基)-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;(3R,4R)-1-(1-((5-氯吡啶-2-基)甲基)-6-(甲基磺醯基)-1H-苯并[d]咪唑-2-基)-4-氟哌啶-3-胺; (3R,4R)-1-(1-((5-氯吡啶-2-基)甲基)-5-(甲基磺醯基)-1H-苯并[d]咪唑-2-基)-4-氟哌啶-3-胺;2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-1-((5-氯嘧啶-2-基)甲基)-6-氟-1H-苯并[d]咪唑-4-甲腈;(3R,4R)-1-(5,7-二氟-1-((5-氟吡啶-2-基)甲基)-1H-苯并[d]咪唑-2-基)-4-氟哌啶-3-胺;(3R,4R)-1-(4,6-二氟-1-((5-氟吡啶-2-基)甲基)-1H-苯并[d]咪唑-2-基)-4-氟哌啶-3-胺;(3R,4R)-1-(5,7-二氟-1-((5-氟嘧啶-2-基)甲基)-1H-苯并[d]咪唑-2-基)-4-氟哌啶-3-胺;(3R,4R)-1-(4,6-二氟-1-((5-氟嘧啶-2-基)甲基)-1H-苯并[d]咪唑-2-基)-4-氟哌啶-3-胺;2-((3R,4S)-3-胺基-4-氟哌啶-1-基)-6-氟-1-((5-氟嘧啶-2-基)甲基)-1H-苯并[d]咪唑-4-甲腈;2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-6-氟-1-((5-氟嘧啶-2-基)甲基)-1H-苯并[d]咪唑-4-甲腈;6-((2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;(3R,4S)-1-(1-((5-氯嘧啶-2-基)甲基)-6-氟-1H-苯并[d]咪唑-2-基)-4-氟哌啶-3-胺;(3R,4S)-1-(1-((5-氯嘧啶-2-基)甲基)-5-氟-1H-苯并[d]咪唑-2-基)-4-氟哌啶-3-胺;(R)-2-(3-胺基-4,4-二氟哌啶-1-基)-1-((5-氯嘧啶-2-基)甲基)-1H-苯 并[d]咪唑-6-甲腈;(R)-2-(3-胺基-4,4-二氟哌啶-1-基)-1-((5-氯嘧啶-2-基)甲基)-1H-苯并[d]咪唑-5-甲腈;6-((2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氯-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;((3R,4R)-1-(1-((5-氰基吡啶-2-基)甲基)-5,6-二甲基-1H-苯并[d]咪唑-2-基)-4-氟哌啶-3-基)胺基甲酸第三丁基酯;(S)-6-((2-(3-胺基哌啶-1-基)-6-氟-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈鹽酸鹽;(S)-6-((2-(3-胺基哌啶-1-基)-5-氟-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈鹽酸鹽;6-((2-((3R,4S)-3-胺基-4-氟哌啶-1-基)-6-氟-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈鹽酸鹽;6-((2-((3R,4S)-3-胺基-4-氟哌啶-1-基)-5-氟-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈鹽酸鹽;6-((2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5-氟-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈鹽酸鹽;6-((2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-6-氟-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈鹽酸鹽;(S)-2-(3-胺基哌啶-1-基)-1-((5-氰基吡啶-2-基)甲基)-1H-苯并[d]咪唑-6-甲腈;(S)-2-(3-胺基哌啶-1-基)-1-((5-氰基吡啶-2-基)甲基)-1H-苯并[d]咪唑-5-甲腈; 2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-1-((5-氰基吡啶-2-基)甲基)-1H-苯并[d]咪唑-6-甲腈;2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-1-((5-氰基吡啶-2-基)甲基)-1H-苯并[d]咪唑-5-甲腈;(R)-2-(3-胺基-4,4-二氟哌啶-1-基)-1-((5-氰基吡啶-2-基)甲基)-1H-苯并[d]咪唑-6-甲腈;(R)-2-(3-胺基-4,4-二氟哌啶-1-基)-1-((5-氰基吡啶-2-基)甲基)-1H-苯并[d]咪唑-5-甲腈;(S)-6-((2-(3-胺基哌啶-1-基)-4,6-二氯-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;6-((2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-4,6-二氯-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;6-((2-((3R,4S)-3-胺基-4-氟哌啶-1-基)-4,6-二氯-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;(R)-6-((2-(3-胺基-4,4-二氟哌啶-1-基)-4,6-二氯-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;(S)-6-((2-(3-胺基哌啶-1-基)-4,6-二氟-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;(S)-6-((2-(3-胺基哌啶-1-基)-5,7-二氟-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;6-((2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-4,6-二氟-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;6-((2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,7-二氟-1H-苯并[d]咪唑- 1-基)甲基)菸鹼腈;6-((2-((3R,4S)-3-胺基-4-氟哌啶-1-基)-4,6-二氟-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;6-((2-((3R,4S)-3-胺基-4-氟哌啶-1-基)-5,7-二氟-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;(R)-6-((2-(3-胺基-4,4-二氟哌啶-1-基)-5,7-二氟-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;2-((3R,4S)-3-胺基-4-氟哌啶-1-基)-1-((5-氰基吡啶-2-基)甲基)-1H-苯并[d]咪唑-6-甲腈;2-((3R,4S)-3-胺基-4-氟哌啶-1-基)-1-((5-氰基吡啶-2-基)甲基)-1H-苯并[d]咪唑-5-甲腈;(S)-6-((2-(3-胺基哌啶-1-基)-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;(R)-6-((2-(3-胺基-4,4-二氟哌啶-1-基)-5-氟-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈鹽酸鹽;6-((2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;6-((2-((3R,4S)-3-胺基-4-氟哌啶-1-基)-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;6-((2-((1R,5S)-1-(胺基甲基)-3-氮雜二環[3.1.0]己-3-基)-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈鹽酸鹽;6-((2-((1S,5R)-1-(胺基甲基)-3-氮雜二環[3.1.0]己-3-基)-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈鹽酸鹽;6-((2-((3aR,4R,6aS)-4-胺基六氫環戊[c]吡咯-2(1H)-基)-1H-苯并 [d]咪唑-1-基)甲基)菸鹼腈鹽酸鹽;6-((2-((3aS,4S,6aR)-4-胺基六氫環戊[c]吡咯-2(1H)-基)-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈鹽酸鹽;6-((2-((3aR,4S,6aS)-4-胺基六氫環戊[c]吡咯-2(1H)-基)-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈鹽酸鹽;6-((2-((3aS,4R,6aR)-4-胺基六氫環戊[c]吡咯-2(1H)-基)-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈鹽酸鹽;(R)-6-((2-(3-(胺基甲基)吡咯啶-1-基)-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈鹽酸鹽;(S)-6-((2-(3-(胺基甲基)吡咯啶-1-基)-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈鹽酸鹽;6-((2-((3R,4S)-3-胺基-4-氟哌啶-1-基)-5,6-二氯-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈鹽酸鹽;6-((2-((3R,4S)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈鹽酸鹽;(R)-6-((2-(3-胺基-4,4-二氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈鹽酸鹽;(R)-1-(1-((5-氯吡啶-2-基)甲基)-1H-苯并[d]咪唑-2-基)-4,4-二氟哌啶-3-胺鹽酸鹽;(3R,4S)-1-(1-((5-氯吡啶-2-基)甲基)-1H-苯并[d]咪唑-2-基)-4-氟哌啶-3-胺鹽酸鹽;(R)-6-((2-(3-胺基-4,4-二氟哌啶-1-基)-4,6-二氟-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈鹽酸鹽; (R)-6-((2-(3-胺基-4,4-二氟哌啶-1-基)-6-氟-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;(R)-6-((2-(3-胺基-4,4-二氟哌啶-1-基)-4-(三氟甲基)-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;6-((2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-4-(三氟甲基)-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;6-((2-((3R,4S)-3-胺基-4-氟哌啶-1-基)-4-(三氟甲基)-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;6-((2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-6-氯-3H-咪唑并[4,5-b]吡啶-3-基)甲基)菸鹼腈;6-((2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-6-氯-1H-咪唑并[4,5-b]吡啶-1-基)甲基)菸鹼腈;6-((2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-6-氯-1H-咪唑并[4,5-b]吡啶-1-基)甲基)-N-(第三丁基)菸鹼醯胺;6-((2-((3R,4R)-3-胺基-4-羥基哌啶-1-基)-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;6-((2-((3S,4S)-3-胺基-4-羥基哌啶-1-基)-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;6-((2-(2,6-二氮雜螺[3.4]辛-6-基)-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;6-((2-((4aR,7aS)-六氫吡咯并[3,4-b][1,4]噁嗪-6(2H)-基)-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈鹽酸鹽;6-((2-((4aS,7aR)-六氫吡咯并[3,4-b][1,4]噁嗪-6(2H)-基)-1H-苯并 [d]咪唑-1-基)甲基)菸鹼腈鹽酸鹽;6-((2-((4aR,7aR)-六氫吡咯并[3,4-b][1,4]噁嗪-6(2H)-基)-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;6-((2-((4aS,7aS)-六氫吡咯并[3,4-b][1,4]噁嗪-6(2H)-基)-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;(S)-3-胺基-1-(1-((5-氰基吡啶-2-基)甲基)-1H-苯并[d]咪唑-2-基)哌啶-3-甲醯胺;(R)-3-胺基-1-(1-((5-氰基吡啶-2-基)甲基)-1H-苯并[d]咪唑-2-基)哌啶-3-甲醯胺;(S)-6-((2-(3-胺基-3-(羥基甲基)哌啶-1-基)-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;(R)-6-((2-(3-胺基-3-(羥基甲基)哌啶-1-基)-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;6-((2-((3R,4S)-3-胺基-4-氟-1-哌啶基)-6-(三氟甲基)-1H-苯并咪唑-1-基)甲基)-3-吡啶甲腈;6-((2-((3R,4S)-3-胺基-4-氟-1-哌啶基)-5-(三氟甲基)-1H-苯并咪唑-1-基)甲基)-3-吡啶甲腈;6-((2-((3R)-3-胺基-4,4-二氟-1-哌啶基)-6-(三氟甲基)-1H-苯并咪唑-1-基)甲基)-3-吡啶甲腈;6-((2-((3R)-3-胺基-4,4-二氟-1-哌啶基)-5-(三氟甲基)-1H-苯并咪唑-1-基)甲基)-3-吡啶甲腈;6-((2-((3R,4R)-3-胺基-4-氟-1-哌啶基)-5-甲基-1H-苯并咪唑-1-基)甲基)-3-吡啶甲腈; 6-((2-((3R,4R)-3-胺基-4-氟-1-哌啶基)-6-甲基-1H-苯并咪唑-1-基)甲基)-3-吡啶甲腈;6-((2-((3R,4R)-3-胺基-4-氟-1-哌啶基)-6-氯-5-甲基-1H-苯并咪唑-1-基)甲基)-3-吡啶甲腈;6-((2-((3R,4R)-3-胺基-4-氟-1-哌啶基)-5-氯-6-甲基-1H-苯并咪唑-1-基)甲基)-3-吡啶甲腈;6-((2-((3R,4R)-3-胺基-4-氟-1-哌啶基)-6-氟-5-甲基-1H-苯并咪唑-1-基)甲基)-3-吡啶甲腈;6-((2-((3R,4R)-3-胺基-4-氟-1-哌啶基)-5-氟-6-甲基-1H-苯并咪唑-1-基)甲基)-3-吡啶甲腈;6-((2-((3S)-3-(甲基胺基)-1-哌啶基)-1H-苯并咪唑-1-基)甲基)-3-吡啶甲腈;6-((2-((3R)-3-(甲基胺基)-1-哌啶基)-1H-苯并咪唑-1-基)甲基)-3-吡啶甲腈;6-((2-((3R,4R)-3-胺基-4-氟-1-哌啶基)-6-(二氟甲氧基)-1H-苯并咪唑-1-基)甲基)-3-吡啶甲腈;6-((2-((3R,4R)-3-胺基-4-氟-1-哌啶基)-5-(二氟甲氧基)-1H-苯并咪唑-1-基)甲基)-3-吡啶甲腈;6-((2-((3R,4R)-3-胺基-4-氟-1-哌啶基)-4-甲氧基-1H-苯并咪唑-1-基)甲基)-3-吡啶甲腈;6-((2-((3R,4R)-3-胺基-4-氟-1-哌啶基)-4-甲基-1H-苯并咪唑-1-基)甲基)-3-吡啶甲腈;5-((2-((3R,4S)-3-胺基-4-氟-1-哌啶基)-6-(三氟甲基)-1H-苯并咪唑 -1-基)甲基)-2-吡嗪甲醯胺;5-((2-((3R,4S)-3-胺基-4-氟-1-哌啶基)-5-(三氟甲基)-1H-苯并咪唑-1-基)甲基)-2-吡嗪甲醯胺;6-((2-((3R,4R)-3-胺基-4-氟-1-哌啶基)-6-氯-5-(三氟甲氧基)-1H-苯并咪唑-1-基)甲基)-3-吡啶甲腈;6-((2-((3R,4R)-3-胺基-4-氟-1-哌啶基)-5-氯-6-(三氟甲氧基)-1H-苯并咪唑-1-基)甲基)-3-吡啶甲腈;6-((2-((3R,4R)-3-胺基-4-氟-1-哌啶基)-6-氯-5-(三氟甲基)-1H-苯并咪唑-1-基)甲基)-3-吡啶甲腈;6-((2-((3R,4R)-3-胺基-4-氟-1-哌啶基)-5-氯-6-(三氟甲基)-1H-苯并咪唑-1-基)甲基)-3-吡啶甲腈;6-((2-((5R)-1,7-二氮雜螺[4.5]癸-7-基)-1H-苯并咪唑-1-基)甲基)-3-吡啶甲腈,6-((2-((5S)-1,7-二氮雜螺[4.5]癸-7-基)-1H-苯并咪唑-1-基)甲基)-3-吡啶甲腈;6-((2-((6R)-1,8-二氮雜螺[5.5]十一-8-基)-1H-苯并咪唑-1-基)甲基)-3-吡啶甲腈;6-((2-((6S)-1,8-二氮雜螺[5.5]十一-8-基)-1H-苯并咪唑-1-基)甲基)-3-吡啶甲腈;6-((2-((4aR,8aR)-六氫-2H-吡啶并[4,3-b][1,4]噁嗪-6(5H)-基)-1H-苯并咪唑-1-基)甲基)-3-吡啶甲腈;6-((2-((4aS,8aS)-六氫-2H-吡啶并[4,3-b][1,4]噁嗪-6(5H)-基)-1H-苯并咪唑-1-基)甲基)-3-吡啶甲腈;5-((2-((3R,4R)-3-胺基-4-氟-1-哌啶基)-5,6-二氟-1H-苯并咪唑-1- 基)甲基)-2-吡嗪甲醯胺;5-((2-((3R,4R)-3-胺基-4-氟-1-哌啶基)-6-(三氟甲基)-1H-苯并咪唑-1-基)甲基)-2-吡嗪甲醯胺;6-((2-((5R)-1,7-二氮雜螺[4.5]癸-7-基)-1H-苯并咪唑-1-基)甲基)-3-吡啶甲腈;6-((2-((5S)-1,7-二氮雜螺[4.5]癸-7-基)-1H-苯并咪唑-1-基)甲基)-3-吡啶甲腈;6-((2-((3R)-3-胺基-4,4-二氟-1-哌啶基)-5-甲氧基-1H-苯并咪唑-1-基)甲基)-3-吡啶甲腈;6-((2-((3R)-3-胺基-4,4-二氟-1-哌啶基)-6-甲氧基-1H-苯并咪唑-1-基)甲基)-3-吡啶甲腈;6-((2-((3S)-3-(甲基胺基)-1-哌啶基)-6-(三氟甲基)-1H-苯并咪唑-1-基)甲基)-3-吡啶甲腈;6-((2-((3S)-3-(甲基胺基)-1-哌啶基)-5-(三氟甲基)-1H-苯并咪唑-1-基)甲基)-3-吡啶甲腈;6-((2-((3S)-3-胺基-3-甲基-1-哌啶基)-1H-苯并咪唑-1-基)甲基)-3-吡啶甲腈;(S)-6-((2-(3-胺基哌啶-1-基)-6-甲氧基-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈2,2,2-三氟乙酸鹽;(S)-6-((2-(3-胺基哌啶-1-基)-5-甲氧基-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈2,2,2-三氟乙酸鹽;6-((2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-4-氯-6-氟-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈2,2,2-三氟乙酸鹽; 6-((2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5-甲氧基-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈鹽酸鹽;6-((2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-6-甲氧基-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈鹽酸鹽;6-((2-((3R,4S)-3-胺基-4-氟哌啶-1-基)-6-甲氧基-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈鹽酸鹽;6-((2-((3R,4S)-3-胺基-4-氟哌啶-1-基)-5-甲氧基-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈鹽酸鹽;2-((3R,4S)-3-胺基-4-氟哌啶-1-基)-1-((5-氯嘧啶-2-基)甲基)-6-氟-1H-苯并[d]咪唑-4-甲腈;(R)-2-(3-胺基-4,4-二氟哌啶-1-基)-1-((5-氯嘧啶-2-基)甲基)-5-氟-1H-苯并[d]咪唑-7-甲腈;(R)-2-(3-胺基-4,4-二氟哌啶-1-基)-1-((5-氯嘧啶-2-基)甲基)-6-氟-1H-苯并[d]咪唑-4-甲腈;6-((2-((3R,4R)-3-胺基-4-羥基哌啶-1-基)-6-氯-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;6-((2-((3R,4S)-3-胺基-4-羥基哌啶-1-基)-6-氯-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;(R)-4-((2-(3-胺基-4,4-二氟哌啶-1-基)-1H-苯并[d]咪唑-1-基)甲基)苯甲腈;4-((2-((3R,4R)-3-胺基-4-羥基哌啶-1-基)-1H-苯并[d]咪唑-1-基)甲基)苯甲腈化合物與4-((2-((3S,4S)-3-胺基-4-羥基哌啶-1-基)-1H-苯并[d]咪唑-1-基)甲基)苯甲腈(1:1)二鹽酸鹽; 4-((2-((3R,4R)-3-胺基-4-氟-1-哌啶基)-5,7-二氟-1H-苯并咪唑-1-基)甲基)苯甲腈;4-((2-((3R,4R)-3-胺基-4-氟-1-哌啶基)-4,6-二氟-1H-苯并咪唑-1-基)甲基)苯甲腈;2-((3R,4R)-3-胺基-4-氟-1-哌啶基)-1-(4-氰基苄基)-1H-苯并咪唑-6-甲腈;2-((3R,4R)-3-胺基-4-氟-1-哌啶基)-1-(4-氰基苄基)-1H-苯并咪唑-5-甲腈;2-((3R)-3-胺基-4,4-二氟-1-哌啶基)-1-(4-氰基苄基)-1H-苯并咪唑-6-甲腈;2-((3R)-3-胺基-4,4-二氟-1-哌啶基)-1-(4-氰基苄基)-1H-苯并咪唑-5-甲腈;(R)-4-((2-(3-胺基哌啶-1-基)-1H-苯并[d]咪唑-1-基)甲基)苯甲腈;4-((2-((3R,4R)-3-胺基-4-甲基哌啶-1-基)-1H-苯并[d]咪唑-1-基)甲基)苯甲腈;4-((2-(3-(胺基甲基)-3-甲基吡咯啶-1-基)-1H-苯并[d]咪唑-1-基)甲基)苯甲腈;4-((2-((3S,4R)-3-胺基-4-苯基吡咯啶-1-基)-1H-苯并[d]咪唑-1-基)甲基)苯甲腈及4-((2-((3R,4S)-3-胺基-4-苯基吡咯啶-1-基)-1H-苯并[d]咪唑-1-基)甲基)苯甲腈;(S)-4-((2-(3-胺基吡咯啶-1-基)-1H-苯并[d]咪唑-1-基)甲基)苯甲腈;(S)-4-((2-(3-胺基哌啶-1-基)-1H-苯并[d]咪唑-1-基)甲基)苯甲腈; 4-((2-(6-胺基-2-氮雜螺[4.4]壬-2-基)-1H-苯并[d]咪唑-1-基)甲基)苯甲腈;4-((2-(4-胺基六氫環戊[c]吡咯-2(1H)-基)-1H-苯并[d]咪唑-1-基)甲基)苯甲腈;4-((2-((3S,4S)-3-胺基-4-氟哌啶-1-基)-1H-苯并[d]咪唑-1-基)甲基)苯甲腈;4-((2-((3S,4R)-3-胺基-4-氟哌啶-1-基)-1H-苯并[d]咪唑-1-基)甲基)苯甲腈;4-((2-((3R,4S)-3-胺基-4-氟哌啶-1-基)-1H-苯并[d]咪唑-1-基)甲基)苯甲腈;4-((2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-1H-苯并[d]咪唑-1-基)甲基)苯甲腈;(R)-4-((2-(3-(胺基甲基)-3-氟吡咯啶-1-基)-1H-苯并[d]咪唑-1-基)甲基)苯甲腈2,2,2-三氟乙酸鹽;(S)-4-((2-(3-(胺基甲基)-3-氟吡咯啶-1-基)-1H-苯并[d]咪唑-1-基)甲基)苯甲腈2,2,2-三氟乙酸鹽;(R)-4-((2-(3-(胺基甲基)-3-羥基吡咯啶-1-基)-1H-苯并[d]咪唑-1-基)甲基)苯甲腈2,2,2-三氟乙酸鹽;(S)-4-((2-(3-(胺基甲基)-3-羥基吡咯啶-1-基)-1H-苯并[d]咪唑-1-基)甲基)苯甲腈2,2,2-三氟乙酸鹽;(S)-4-((2-(3-(胺基甲基)吡咯啶-1-基)-1H-苯并[d]咪唑-1-基)甲基)苯甲腈; (R)-4-((2-(3-(胺基甲基)吡咯啶-1-基)-1H-苯并[d]咪唑-1-基)甲基)苯甲腈;4-((2-((3S,4S)-3-胺基-4-甲基哌啶-1-基)-1H-苯并[d]咪唑-1-基)甲基)苯甲腈2,2,2-三氟乙酸鹽;4-((2-((3S,4R)-3-胺基-4-甲基哌啶-1-基)-1H-苯并[d]咪唑-1-基)甲基)苯甲腈2,2,2-三氟乙酸鹽;4-((2-((3R,4S)-3-胺基-4-甲基哌啶-1-基)-1H-苯并[d]咪唑-1-基)甲基)苯甲腈2,2,2-三氟乙酸鹽;4-((2-((1S,5R)-1-(胺基甲基)-3-氮雜二環[3.1.0]己-3-基)-1H-苯并[d]咪唑-1-基)甲基)苯甲腈;4-((2-((1R,5S)-1-(胺基甲基)-3-氮雜二環[3.1.0]己-3-基)-1H-苯并[d]咪唑-1-基)甲基)苯甲腈;(R)-4-((2-(3-胺基哌啶-1-基)-6-甲氧基-1H-苯并[d]咪唑-1-基)甲基)苯甲腈;(R)-4-((2-(3-胺基哌啶-1-基)-5-甲氧基-1H-苯并[d]咪唑-1-基)甲基)苯甲腈;2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-1-((5-氯嘧啶-2-基)甲基)-1H-苯并[d]咪唑-6-甲腈;(3R,4R)-4-氟-1-(1-((5-氟嘧啶-2-基)甲基)-1H-苯并[d]咪唑-2-基)哌啶-3-胺;(3R,4R)-4-氟-1-(1-((5-氟吡啶-2-基)甲基)-1H-苯并[d]咪唑-2-基)哌啶-3-胺; 2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-1-((5-氟吡啶-2-基)甲基)-1H-苯并[d]咪唑-6-甲腈;2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-1-((5-氟吡啶-2-基)甲基)-1H-苯并[d]咪唑-5-甲腈;(3R,4R)-1-(1-((5-溴嘧啶-2-基)甲基)-1H-苯并[d]咪唑-2-基)-4-氟哌啶-3-胺;(3R,4R)-4-氟-1-(1-((5-(三氟甲基)嘧啶-2-基)甲基)-1H-苯并[d]咪唑-2-基)哌啶-3-胺;(3R,4R)-4-氟-1-(1-((5-甲氧基嘧啶-2-基)甲基)-1H-苯并[d]咪唑-2-基)哌啶-3-胺;(3R,4R)-1-(1-((5-氯嘧啶-2-基)甲基)-1H-苯并[d]咪唑-2-基)-4-氟哌啶-3-胺;2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-1-((5-氟嘧啶-2-基)甲基)-1H-苯并[d]咪唑-6-甲腈;2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-1-((5-氟嘧啶-2-基)甲基)-1H-苯并[d]咪唑-5-甲腈;2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-1-((5-氰基嘧啶-2-基)甲基)-1H-苯并[d]咪唑-5-甲腈;2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-1-((5-氯嘧啶-2-基)甲基)-1H-苯并[d]咪唑-5-甲腈;2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-1-((5-溴嘧啶-2-基)甲基)-1H-苯并[d]咪唑-6-甲腈;2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-1-((5-溴嘧啶-2-基)甲基)-1H- 苯并[d]咪唑-5-甲腈;5-((2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-1H-苯并[d]咪唑-1-基)甲基)吡嗪-2-甲腈;2-((3R,4S)-3-胺基-4-氟哌啶-1-基)-1-((5-氯嘧啶-2-基)甲基)-1H-苯并[d]咪唑-6-甲腈;2-((3R,4S)-3-胺基-4-氟哌啶-1-基)-1-((5-氯嘧啶-2-基)甲基)-1H-苯并[d]咪唑-5-甲腈;(3R,4R)-3-胺基-1-(1-((5-氯嘧啶-2-基)甲基)-6-氟-1H-苯并[d]咪唑-2-基)哌啶-4-醇;(3R,4R)-3-胺基-1-(1-((5-氯嘧啶-2-基)甲基)-5-氟-1H-苯并[d]咪唑-2-基)哌啶-4-醇;6-((2-((3R,4R)-3-胺基-4-羥基哌啶-1-基)-6-氟-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;6-((2-((3R,4R)-3-胺基-4-羥基哌啶-1-基)-5-氟-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;(S)-1-(1-((5-氯吡啶-2-基)甲基)-1H-苯并[d]咪唑-2-基)哌啶-3-胺;(S)-5-((2-(3-胺基哌啶-1-基)-1H-苯并[d]咪唑-1-基)甲基)吡啶甲腈;(3R,4R)-1-(1-((5-氯吡啶-2-基)甲基)-1H-苯并[d]咪唑-2-基)-4-氟哌啶-3-胺鹽酸鹽;(R)-6-((2-(3-胺基-4,4-二氟哌啶-1-基)-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈鹽酸鹽; 2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-1-((5-氯吡啶-2-基)甲基)-1H-苯并[d]咪唑-6-甲腈鹽酸鹽;2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-1-((5-氯吡啶-2-基)甲基)-1H-苯并[d]咪唑-5-甲腈鹽酸鹽;(3R,4R)-1-(1-((R)-1-(5-氯吡啶-2-基)乙基)-1H-苯并[d]咪唑-2-基)-4-氟哌啶-3-胺鹽酸鹽;(3R,4R)-1-(1-((S)-1-(5-氯吡啶-2-基)乙基)-1H-苯并[d]咪唑-2-基)-4-氟哌啶-3-胺鹽酸鹽;(3R,4R)-1-(1-((R)-1-(5-氯吡啶-2-基)乙基)-5,6-二氟-1H-苯并[d]咪唑-2-基)-4-氟哌啶-3-胺鹽酸鹽;(3R,4R)-1-(1-((S)-1-(5-氯吡啶-2-基)乙基)-5,6-二氟-1H-苯并[d]咪唑-2-基)-4-氟哌啶-3-胺鹽酸鹽;(3R,4R)-1-(5-氯-1-((R)-1-(5-氯吡啶-2-基)乙基)-1H-苯并[d]咪唑-2-基)-4-氟哌啶-3-胺鹽酸鹽;(3R,4R)-1-(5-氯-1-((S)-1-(5-氯吡啶-2-基)乙基)-1H-苯并[d]咪唑-2-基)-4-氟哌啶-3-胺鹽酸鹽;(3R,4R)-1-(6-氯-1-((R)-1-(5-氯吡啶-2-基)乙基)-1H-苯并[d]咪唑-2-基)-4-氟哌啶-3-胺鹽酸鹽;(3R,4R)-1-(6-氯-1-((S)-1-(5-氯吡啶-2-基)乙基)-1H-苯并[d]咪唑-2-基)-4-氟哌啶-3-胺鹽酸鹽;2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-1-((R)-1-(5-氰基吡啶-2-基)乙基)-1H-苯并[d]咪唑-6-甲腈鹽酸鹽;2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-1-((R)-1-(5-氰基吡啶-2-基)乙 基)-1H-苯并[d]咪唑-5-甲腈鹽酸鹽;2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-1-((S)-1-(5-氰基吡啶-2-基)乙基)-1H-苯并[d]咪唑-6-甲腈鹽酸鹽;2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-1-((S)-1-(5-氰基吡啶-2-基)乙基)-1H-苯并[d]咪唑-5-甲腈鹽酸鹽;(3R,4R)-1-(1-((5-氯吡啶-2-基)甲基)-5,6-二氟-1H-苯并[d]咪唑-2-基)-4-氟哌啶-3-胺鹽酸鹽;(3R,4R)-1-(5,6-二氟-1-((5-氟吡啶-2-基)甲基)-1H-苯并[d]咪唑-2-基)-4-氟哌啶-3-胺鹽酸鹽;(R)-1-(1-((5-氯吡啶-2-基)甲基)-5,7-二氟-1H-苯并[d]咪唑-2-基)-4,4-二氟哌啶-3-胺鹽酸鹽;(R)-1-(1-((5-氯吡啶-2-基)甲基)-4,6-二氟-1H-苯并[d]咪唑-2-基)-4,4-二氟哌啶-3-胺鹽酸鹽;(R)-1-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-1H-苯并[d]咪唑-1-基)-2,3-二氫-1H-茚-5-甲腈鹽酸鹽;(S)-1-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-1H-苯并[d]咪唑-1-基)-2,3-二氫-1H-茚-5-甲腈鹽酸鹽;(R)-5-((2-(3-胺基-4,4-二氟哌啶-1-基)-6-氯-1H-苯并[d]咪唑-1-基)甲基)吡嗪-2-甲腈;(R)-5-((2-(3-胺基-4,4-二氟哌啶-1-基)-5-氯-1H-苯并[d]咪唑-1-基)甲基)吡嗪-2-甲腈;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)-N-異丙基乙醯胺; 2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)-1-(氮雜環丁-1-基)乙酮;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)-N-(2-氰基丙基)-N-乙基乙醯胺;3-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)-1-甲基吡咯啶-2-酮;3-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)-1-苯基哌啶-2-酮;3-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)-1-(4-氯苯基)吡咯啶-2-酮;2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-1-((5-甲氧基嘧啶-2-基)甲基)-1H-苯并[d]咪唑-5-甲腈鹽酸鹽;2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-1-((5-甲氧基嘧啶-2-基)甲基)-1H-苯并[d]咪唑-6-甲腈鹽酸鹽;2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-1-((6-(三氟甲基)吡啶-3-基)甲基)-1H-苯并[d]咪唑-6-甲腈鹽酸鹽;2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-1-((6-(三氟甲基)吡啶-3-基)甲基)-1H-苯并[d]咪唑-5-甲腈鹽酸鹽;(S)-3-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)-1-甲基吡咯啶-2-酮;(R)-3-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)-1-甲基吡咯啶-2-酮;(S)-3-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪 唑-1-基)-1-(4-氯苯基)吡咯啶-2-酮;(R)-3-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)-1-(4-氯苯基)吡咯啶-2-酮;2-((3R,4R)-3-胺基-4-氟-1-哌啶基)-1-((5-氰基-2-吡嗪基)甲基)-1H-苯并咪唑-6-甲腈;2-((3R,4R)-3-胺基-4-氟-1-哌啶基)-1-((5-氰基-2-吡嗪基)甲基)-1H-苯并咪唑-5-甲腈;5-((2-((3R,4R)-3-胺基-4-氟-1-哌啶基)-4,6-二氟-1H-苯并咪唑-1-基)甲基)-2-吡嗪甲腈;5-((2-((3R,4R)-3-胺基-4-氟-1-哌啶基)-5,7-二氟-1H-苯并咪唑-1-基)甲基)-2-吡嗪甲腈;(3S)-1-(1-((5-氟-2-吡啶基)甲基)-1H-苯并咪唑-2-基)-N-甲基-3-哌啶胺;(3S)-1-(1-((5-氯-2-吡啶基)甲基)-1H-苯并咪唑-2-基)-N-甲基-3-哌啶胺;6-((1R)-1-(2-((3S)-3-(甲基胺基)-1-哌啶基)-1H-苯并咪唑-1-基)乙基)-3-吡啶甲腈;6-((1S)-1-(2-((3S)-3-(甲基胺基)-1-哌啶基)-1H-苯并咪唑-1-基)乙基)-3-吡啶甲腈;(3R,4R)-1-(1-((5-氯-2-嘧啶基)甲基)-5,7-二氟-1H-苯并咪唑-2-基)-4-氟-3-哌啶胺;(3R,4R)-1-(1-((5-氯-2-嘧啶基)甲基)-4,6-二氟-1H-苯并咪唑-2-基)-4-氟-3-哌啶胺; (3R,4R)-1-(5,6-二氟-1-((1-甲基-1H-吲唑-4-基)甲基)-1H-苯并咪唑-2-基)-4-氟-3-哌啶胺;(3R,4R)-1-(5,6-二氟-1-(5-喹啉基甲基)-1H-苯并咪唑-2-基)-4-氟-3-哌啶胺;(3R,4R)-1-(5,6-二氟-1-((1R)-1-(8-喹啉基)乙基)-1H-苯并咪唑-2-基)-4-氟-3-哌啶胺;(3R,4R)-1-(5,6-二氟-1-((1S)-1-(8-喹啉基)乙基)-1H-苯并咪唑-2-基)-4-氟-3-哌啶胺;(3R,4R)-1-(1-((3-(3-氯苯基)-1,2-噁唑-5-基)甲基)-5,6-二氟-1H-苯并咪唑-2-基)-4-氟-3-哌啶胺;(3R,4R)-1-(5,6-二氟-1-((1-甲基-1H-吲唑-7-基)甲基)-1H-苯并咪唑-2-基)-4-氟-3-哌啶胺;(3R,4R)-1-(1-(2,6-二氯苄基)-5,6-二氟-1H-苯并咪唑-2-基)-4-氟-3-哌啶胺;1-(1-氮雜環丁基)-2-(2-((3S)-3-(甲基胺基)-1-哌啶基)-1H-苯并咪唑-1-基)乙酮;6-((1R)-1-(4,6-二氟-2-((4aR,8aR)-六氫-2H-吡啶并[4,3-b][1,4]噁嗪-6(5H)-基)-1H-苯并咪唑-1-基)乙基)-3-吡啶甲腈;6-((1R)-1-(4,6-二氟-2-((4aS,8aS)-六氫-2H-吡啶并[4,3-b][1,4]噁嗪-6(5H)-基)-1H-苯并咪唑-1-基)乙基)-3-吡啶甲腈;6-((1S)-1-(4,6-二氟-2-((4aS,8aS)-六氫-2H-吡啶并[4,3-b][1,4]噁嗪-6(5H)-基)-1H-苯并咪唑-1-基)乙基)-3-吡啶甲腈;6-((1S)-1-(4,6-二氟-2-((4aR,8aR)-六氫-2H-吡啶并[4,3-b][1,4]噁 嗪-6(5H)-基)-1H-苯并咪唑-1-基)乙基)-3-吡啶甲腈;6-((1R)-1-(5,7-二氟-2-((4aR,8aR)-六氫-2H-吡啶并[4,3-b][1,4]噁嗪-6(5H)-基)-1H-苯并咪唑-1-基)乙基)-3-吡啶甲腈;6-((1R)-1-(5,7-二氟-2-((4aS,8aS)-六氫-2H-吡啶并[4,3-b][1,4]噁嗪-6(5H)-基)-1H-苯并咪唑-1-基)乙基)-3-吡啶甲腈;6-((1S)-1-(5,7-二氟-2-((4aS,8aS)-六氫-2H-吡啶并[4,3-b][1,4]噁嗪-6(5H)-基)-1H-苯并咪唑-1-基)乙基)-3-吡啶甲腈;6-((1S)-1-(5,7-二氟-2-((4aR,8aR)-六氫-2H-吡啶并[4,3-b][1,4]噁嗪-6(5H)-基)-1H-苯并咪唑-1-基)乙基)-3-吡啶甲腈;2-(2-((3R,4R)-3-胺基-4-氟-1-哌啶基)-5,6-二氟-1H-苯并咪唑-1-基)-N-甲基乙醯胺;2-(2-((3R,4R)-3-胺基-4-氟-1-哌啶基)-5,6-二氟-1H-苯并咪唑-1-基)-1-(4-嗎啉基)乙酮;2-(2-((3R,4R)-3-胺基-4-氟-1-哌啶基)-5,6-二氟-1H-苯并咪唑-1-基)-1-(1-吡咯啶基)乙酮;2-(2-((3R,4R)-3-胺基-4-氟-1-哌啶基)-5,6-二氟-1H-苯并咪唑-1-基)-N,N-二甲基乙醯胺;(2R)-2-(2-((3R,4R)-3-胺基-4-氟-1-哌啶基)-5,6-二氟-1H-苯并咪唑-1-基)-N,N-二甲基丙醯胺;(2S)-2-(2-((3R,4R)-3-胺基-4-氟-1-哌啶基)-5,6-二氟-1H-苯并咪唑-1-基)-N,N-二甲基丙醯胺;2-(2-((3R,4R)-3-胺基-4-氟-1-哌啶基)-5,6-二氟-1H-苯并咪唑-1-基)-1-(1-哌啶基)乙酮; 2-(2-((3R,4R)-3-胺基-4-氟-1-哌啶基)-5,6-二氟-1H-苯并咪唑-1-基)-N-乙基乙醯胺;1-((5-氯-2-嘧啶基)甲基)-2-((3R,4R)-4-氟-3-(甲基胺基)-1-哌啶基)-1H-苯并咪唑-6-甲腈;1-((5-氯-2-嘧啶基)甲基)-2-((3R,4R)-4-氟-3-(甲基胺基)-1-哌啶基)-1H-苯并咪唑-5-甲腈;2-(2-((3R,4R)-3-胺基-4-氟-1-哌啶基)-6-氯-1H-苯并咪唑-1-基)-1-(1-氮雜環丁基)乙酮;2-(2-((3R,4R)-3-胺基-4-氟-1-哌啶基)-5-氯-1H-苯并咪唑-1-基)-1-(1-氮雜環丁基)乙酮;2-((3R,4S)-3-胺基-4-氟-1-哌啶基)-1-(2-(1-氮雜環丁基)-2-側氧基乙基)-1H-苯并咪唑-6-甲腈;2-((3R,4S)-3-胺基-4-氟-1-哌啶基)-1-(2-(1-氮雜環丁基)-2-側氧基乙基)-1H-苯并咪唑-5-甲腈;(3R,4R)-1-(1-((5-氯嘧啶-2-基)甲基)-6-氟-1H-苯并[d]咪唑-2-基)-4-氟哌啶-3-胺;(3R,4R)-1-(1-((5-氯嘧啶-2-基)甲基)-5-氟-1H-苯并[d]咪唑-2-基)-4-氟哌啶-3-胺;(R)-6-((2-(3-胺基哌啶-1-基)-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;(R)-5-((2-(3-胺基哌啶-1-基)-1H-苯并[d]咪唑-1-基)甲基)吡啶甲腈2,2,2-三氟乙酸鹽;(R)-1-(1-(異喹啉-7-基甲基)-1H-苯并[d]咪唑-2-基)哌啶-3-胺;(R)-1-(1-((1-甲基-1H-吲唑-7-基)甲基)-1H-苯并[d]咪唑-2-基)哌啶 -3-胺;6-((R)-1-(2-((S)-3-胺基哌啶-1-基)-1H-苯并[d]咪唑-1-基)乙基)菸鹼腈鹽酸鹽;6-((S)-1-(2-((S)-3-胺基哌啶-1-基)-1H-苯并[d]咪唑-1-基)乙基)菸鹼腈鹽酸鹽;6-((R)-1-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-1H-苯并[d]咪唑-1-基)乙基)菸鹼腈鹽酸鹽;6-((S)-1-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-1H-苯并[d]咪唑-1-基)乙基)菸鹼腈鹽酸鹽;6-((R)-1-(2-((S)-3-胺基哌啶-1-基)-1H-苯并[d]咪唑-1-基)丙基)菸鹼腈鹽酸鹽;6-((S)-1-(2-((S)-3-胺基哌啶-1-基)-1H-苯并[d]咪唑-1-基)丙基)菸鹼腈鹽酸鹽;(3R,4R)-1-(5,6-二氟-1-((5-氟嘧啶-2-基)甲基)-1H-苯并[d]咪唑-2-基)-4-氟哌啶-3-胺;3-(1-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)乙基)苯甲腈;(3R,4R)-1-(5,6-二氟-1-((5-氟嘧啶-2-基)甲基)-1H-苯并[d]咪唑-2-基)-4-氟哌啶-3-胺;(3R,4S)-1-(5,6-二氟-1-((5-氟吡啶-2-基)甲基)-1H-苯并[d]咪唑-2-基)-4-氟哌啶-3-胺;(3R,4S)-4-氟-1-(1-((5-氟嘧啶-2-基)甲基)-6-(三氟甲基)-1H-苯并[d]咪唑-2-基)哌啶-3-胺; (3R,4S)-4-氟-1-(1-((5-氟嘧啶-2-基)甲基)-5-(三氟甲基)-1H-苯并[d]咪唑-2-基)哌啶-3-胺;(R)-1-(5,6-二氟-1-((5-氟吡啶-2-基)甲基)-1H-苯并[d]咪唑-2-基)-4,4-二氟哌啶-3-胺;2-(2-((3R,4S)-3-胺基-4-氟哌啶-1-基)-6-(三氟甲基)-1H-苯并[d]咪唑-1-基)-1-(氮雜環丁-1-基)乙-1-酮;2-(2-((3R,4S)-3-胺基-4-氟哌啶-1-基)-5-(三氟甲基)-1H-苯并[d]咪唑-1-基)-1-(氮雜環丁-1-基)乙-1-酮;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)-1-(2,2-二甲基吡咯啶-1-基)乙-1-酮;6-((2-((3R,4S)-3-胺基-4-羥基哌啶-1-基)-6-氟-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;6-((2-((3R,4S)-3-胺基-4-羥基哌啶-1-基)-5-氟-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;4-((R)-1-(2-((S)-3-胺基哌啶-1-基)-1H-苯并[d]咪唑-1-基)乙基)苯甲腈鹽酸鹽;4-((S)-1-(2-((S)-3-胺基哌啶-1-基)-1H-苯并[d]咪唑-1-基)乙基)苯甲腈鹽酸鹽;(S)-4-((2-(3-胺基哌啶-1-基)-1H-苯并[d]咪唑-1-基)甲基)-3-氟苯甲腈鹽酸鹽;(S)-1-(1-(4-氯苄基)-1H-苯并[d]咪唑-2-基)哌啶-3-胺鹽酸鹽;4-((R)-1-(2-((3R,4S)-3-胺基-4-氟哌啶-1-基)-1H-苯并[d]咪唑-1-基)乙基)苯甲腈鹽酸鹽; 4-((S)-1-(2-((3R,4S)-3-胺基-4-氟哌啶-1-基)-1H-苯并[d]咪唑-1-基)乙基)苯甲腈鹽酸鹽;4-((R)-1-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-1H-苯并[d]咪唑-1-基)乙基)苯甲腈鹽酸鹽;4-((S)-1-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-1H-苯并[d]咪唑-1-基)乙基)苯甲腈鹽酸鹽;(S)-4-((2-(3-胺基哌啶-1-基)-1H-苯并[d]咪唑-1-基)甲基)-3-氯苯甲腈鹽酸鹽;(3R,4R)-1-(1-((1R)-1-(2,4-二氯苯基)乙基)-5,6-二氟-1H-苯并咪唑-2-基)-4-氟-3-哌啶胺;(3R,4R)-1-(1-((1S)-1-(2,4-二氯苯基)乙基)-5,6-二氟-1H-苯并咪唑-2-基)-4-氟-3-哌啶胺;(3R,4R)-1-(1-((1R)-1-(2-氯苯基)乙基)-5,6-二氟-1H-苯并咪唑-2-基)-4-氟-3-哌啶胺;(3R,4R)-1-(1-((1S)-1-(2-氯苯基)乙基)-5,6-二氟-1H-苯并咪唑-2-基)-4-氟-3-哌啶胺;(3R,4R)-1-(1-((1R)-1-(3-氯苯基)乙基)-5,6-二氟-1H-苯并咪唑-2-基)-4-氟-3-哌啶胺;(3R,4R)-1-(1-((1S)-1-(3-氯苯基)乙基)-5,6-二氟-1H-苯并咪唑-2-基)-4-氟-3-哌啶胺;(3R,4R)-1-(1-((1R)-1-(2,5-二氯苯基)乙基)-5,6-二氟-1H-苯并咪唑-2-基)-4-氟-3-哌啶胺;(3R,4R)-1-(1-((1S)-1-(2,5-二氯苯基)乙基)-5,6-二氟-1H-苯并咪唑- 2-基)-4-氟-3-哌啶胺;(3R,4R)-1-(1-((1R)-1-(2,4-二氟苯基)乙基)-5,6-二氟-1H-苯并咪唑-2-基)-4-氟-3-哌啶胺;(3R,4R)-1-(1-((1S)-1-(2,4-二氟苯基)乙基)-5,6-二氟-1H-苯并咪唑-2-基)-4-氟-3-哌啶胺;(3R,4R)-1-(1-((1R)-1-(3,4-二氯苯基)乙基)-5,6-二氟-1H-苯并咪唑-2-基)-4-氟-3-哌啶胺;(3R,4R)-1-(1-((1S)-1-(3,4-二氯苯基)乙基)-5,6-二氟-1H-苯并咪唑-2-基)-4-氟-3-哌啶胺;(3R,4R)-1-(1-((1R)-1-(2,5-二氟苯基)乙基)-5,6-二氟-1H-苯并咪唑-2-基)-4-氟-3-哌啶胺;(3R,4R)-1-(1-((1S)-1-(2,5-二氟苯基)乙基)-5,6-二氟-1H-苯并咪唑-2-基)-4-氟-3-哌啶胺;(3R,4R)-1-(5,6-二氟-1-((1R)-1-(4-(三氟甲基)苯基)乙基)-1H-苯并咪唑-2-基)-4-氟-3-哌啶胺;(3R,4R)-1-(5,6-二氟-1-((1R)-1-(4-(三氟甲氧基)苯基)乙基)-1H-苯并咪唑-2-基)-4-氟-3-哌啶胺;(3R,4R)-1-(1-(5-氯-2-(三氟甲氧基)苄基)-5,6-二氟-1H-苯并咪唑-2-基)-4-氟-3-哌啶胺;(3R,4R)-1-(5,6-二氟-1-(4-(1H-1,2,4-三唑-1-基)苄基)-1H-苯并咪唑-2-基)-4-氟-3-哌啶胺;2-((2-((3R,4R)-3-胺基-4-氟-1-哌啶基)-5,6-二氟-1H-苯并咪唑-1-基)甲基)-5-氯苯甲腈; (3R,4R)-1-(1-(2,4-二氯苄基)-5,6-二氟-1H-苯并咪唑-2-基)-4-氟-3-哌啶胺;4-((2-((3R,4R)-3-胺基-4-氟-1-哌啶基)-5,6-二氟-1H-苯并咪唑-1-基)甲基)-3-(二氟甲氧基)苯甲腈;(3R,4R)-1-(1-(2,5-二氯苄基)-5,6-二氟-1H-苯并咪唑-2-基)-4-氟-3-哌啶胺;(3R,4R)-1-(1-(4-(1,1-二氟乙基)苄基)-5,6-二氟-1H-苯并咪唑-2-基)-4-氟-3-哌啶胺;4-((2-((3R,4R)-3-胺基-4-氟-1-哌啶基)-5,6-二氟-1H-苯并咪唑-1-基)甲基)-2-甲基苯甲腈;4-((2-((3R,4R)-3-胺基-4-氟-1-哌啶基)-5,6-二氟-1H-苯并咪唑-1-基)甲基)-2-氯苯甲腈;2-((2-((3R,4R)-3-胺基-4-氟-1-哌啶基)-5,6-二氟-1H-苯并咪唑-1-基)甲基)-4-氯苯甲腈;(3R,4R)-1-(1-(2-(二氟甲氧基)苄基)-5,6-二氟-1H-苯并咪唑-2-基)-4-氟-3-哌啶胺;(3R,4R)-1-(1-(3-氯-4-氟苄基)-5,6-二氟-1H-苯并咪唑-2-基)-4-氟-3-哌啶胺;(3R,4R)-1-(1-(4-氯-2-甲氧基苄基)-5,6-二氟-1H-苯并咪唑-2-基)-4-氟-3-哌啶胺;(3R,4R)-1-(1-(2,4-二氟苄基)-5,6-二氟-1H-苯并咪唑-2-基)-4-氟-3-哌啶胺;(3R,4R)-1-(5,6-二氟-1-(2-(三氟甲基)苄基)-1H-苯并咪唑-2-基)-4- 氟-3-哌啶胺;2-((2-((3R,4R)-3-胺基-4-氟-1-哌啶基)-5,6-二氟-1H-苯并咪唑-1-基)甲基)苯甲腈;(3R,4R)-1-(1-(2-氯苄基)-5,6-二氟-1H-苯并咪唑-2-基)-4-氟-3-哌啶胺;(3R,4R)-1-(1-(2-氯-4-氟苄基)-5,6-二氟-1H-苯并咪唑-2-基)-4-氟-3-哌啶胺;(3R,4R)-1-(5,6-二氟-1-(4-氟-2-(三氟甲基)苄基)-1H-苯并咪唑-2-基)-4-氟-3-哌啶胺;(3R,4R)-1-(1-(3,4-二氟苄基)-5,6-二氟-1H-苯并咪唑-2-基)-4-氟-3-哌啶胺;(3R,4R)-1-(1-(4-氯-2-氟苄基)-5,6-二氟-1H-苯并咪唑-2-基)-4-氟-3-哌啶胺;(3R,4R)-1-(1-(3,4-二氯苄基)-5,6-二氟-1H-苯并咪唑-2-基)-4-氟-3-哌啶胺;(3R,4R)-1-(1-(4-氯-3-氟苄基)-5,6-二氟-1H-苯并咪唑-2-基)-4-氟-3-哌啶胺;(3R,4R)-1-(5,6-二氟-1-(4-(三氟甲基)苄基)-1H-苯并咪唑-2-基)-4-氟-3-哌啶胺;(3R,4R)-1-(5,6-二氟-1-(4-(三氟甲氧基)苄基)-1H-苯并咪唑-2-基)-4-氟-3-哌啶胺;(3R,4R)-1-(1-(4-(二氟甲基)苄基)-5,6-二氟-1H-苯并咪唑-2-基)-4-氟-3-哌啶胺; (3R,4R)-1-(5,6-二氟-1-(3-(三氟甲氧基)苄基)-1H-苯并咪唑-2-基)-4-氟-3-哌啶胺;(3R,4R)-1-(5,6-二氟-1-(3-(三氟甲基)苄基)-1H-苯并咪唑-2-基)-4-氟-3-哌啶胺;3-((2-((3R,4R)-3-胺基-4-氟-1-哌啶基)-5,6-二氟-1H-苯并咪唑-1-基)甲基)苯甲腈;(3R,4R)-1-(1-(3-氯苄基)-5,6-二氟-1H-苯并咪唑-2-基)-4-氟-3-哌啶胺;(S)-1-(1-(4-氟苄基)-1H-苯并[d]咪唑-2-基)哌啶-3-胺;(S)-1-(1-(4-(1,2,4-噁二唑-3-基)苄基)-1H-苯并[d]咪唑-2-基)哌啶-3-胺;(R)-1-(1-(4-(甲基磺醯基)苄基)-1H-苯并[d]咪唑-2-基)哌啶-3-胺;(R)-1-(1-(4-(1H-1,2,4-三唑-1-基)苄基)-1H-苯并[d]咪唑-2-基)哌啶-3-胺;(R)-2-((2-(3-胺基哌啶-1-基)-1H-苯并[d]咪唑-1-基)甲基)苯甲腈;(R)-1-(1-(2,6-二氯苄基)-1H-苯并[d]咪唑-2-基)哌啶-3-胺;(R)-1-(1-(2-氯苄基)-1H-苯并[d]咪唑-2-基)哌啶-3-胺;(R)-1-(1-(4-(三氟甲基)苄基)-1H-苯并[d]咪唑-2-基)哌啶-3-胺;(R)-1-(1-(4-(三氟甲氧基)苄基)-1H-苯并[d]咪唑-2-基)哌啶-3-胺;(R)-1-(1-(4-氯苄基)-1H-苯并[d]咪唑-2-基)哌啶-3-胺;(R)-1-(1-(3-氯苄基)-1H-苯并[d]咪唑-2-基)哌啶-3-胺;(R)-1-(1-(4-(1,1-二氟乙基)苄基)-1H-苯并[d]咪唑-2-基)哌啶-3-胺; (R)-2-(4-((2-(3-胺基哌啶-1-基)-1H-苯并[d]咪唑-1-基)甲基)苯基)-2-甲基丙腈;(R)-1-(1-(4-(二氟甲基)苄基)-1H-苯并[d]咪唑-2-基)哌啶-3-胺;(R)-4-((2-(3-胺基哌啶-1-基)-1H-苯并[d]咪唑-1-基)甲基)-N-甲基苯甲醯胺;(R)-4-((2-(3-胺基哌啶-1-基)-1H-苯并[d]咪唑-1-基)甲基)-3-氟苯甲腈;(R)-2-(4-((2-(3-胺基哌啶-1-基)-1H-苯并[d]咪唑-1-基)甲基)苯氧基)乙腈;(R)-4-((2-(3-胺基哌啶-1-基)-1H-苯并[d]咪唑-1-基)甲基)-N,N-二甲基苯磺醯胺;(R)-1-(1-(4-甲基苄基)-1H-苯并[d]咪唑-2-基)哌啶-3-胺;(R)-1-(1-(4-氟苄基)-1H-苯并[d]咪唑-2-基)哌啶-3-胺;(R)-1-(1-((1-甲基-1H-吲唑-7-基)甲基)-1H-苯并[d]咪唑-2-基)哌啶-3-胺;(R)-1-(1-(2,4-二氟苄基)-1H-苯并[d]咪唑-2-基)哌啶-3-胺;(R)-1-(1-(3,4-二氟苄基)-1H-苯并[d]咪唑-2-基)哌啶-3-胺;(R)-1-(1-(4-氯-3-氟苄基)-1H-苯并[d]咪唑-2-基)哌啶-3-胺;(R)-1-(1-((3-(3-氯苯基)異噁唑-5-基)甲基)-1H-苯并[d]咪唑-2-基)哌啶-3-胺;(R)-1-(1-(3-氯-4-甲氧基苄基)-1H-苯并[d]咪唑-2-基)哌啶-3-胺;(R)-4-((2-(3-胺基哌啶-1-基)-1H-苯并[d]咪唑-1-基)甲基)-3-氯苯甲腈; (R)-1-(1-(2,4-二氯苄基)-1H-苯并[d]咪唑-2-基)哌啶-3-胺;(R)-4-((2-(3-胺基哌啶-1-基)-1H-苯并[d]咪唑-1-基)甲基)-3-甲氧基苯甲腈;(R)-2-((2-(3-胺基哌啶-1-基)-1H-苯并[d]咪唑-1-基)甲基)-5-氯苯甲腈;4-((R)-1-(2-((R)-3-胺基哌啶-1-基)-1H-苯并[d]咪唑-1-基)乙基)苯甲腈;4-(1-(2-((S)-3-胺基哌啶-1-基)-1H-苯并[d]咪唑-1-基)乙基)苯甲腈;(R)-3-((2-(3-胺基哌啶-1-基)-1H-苯并[d]咪唑-1-基)甲基)苯甲腈;4-((2-((3R,4S)-3-胺基-4-氟哌啶-1-基)-6-氯-1H-苯并[d]咪唑-1-基)甲基)苯甲腈鹽酸鹽;(S)-4-((2-(3-胺基哌啶-1-基)-6-甲氧基-1H-苯并[d]咪唑-1-基)甲基)苯甲腈鹽酸鹽;4-((2-((3R,4S)-3-胺基-4-氟哌啶-1-基)-6-甲氧基-1H-苯并[d]咪唑-1-基)甲基)苯甲腈;(S)-4-((2-(3-胺基哌啶-1-基)-5-甲氧基-3H-咪唑并[4,5-b]吡啶-3-基)甲基)苯甲腈鹽酸鹽;(R)-4-((2-(3-胺基-4,4-二氟哌啶-1-基)-6-氯-1H-苯并[d]咪唑-1-基)甲基)苯甲腈;(R)-4-((2-(3-胺基-4,4-二氟哌啶-1-基)-6-甲氧基-1H-苯并[d]咪唑-1-基)甲基)苯甲腈;(R)-4-((2-(3-胺基-4,4-二氟哌啶-1-基)-4-氯-1H-苯并[d]咪唑-1-基) 甲基)苯甲腈;4-((2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-4-氯-1H-苯并[d]咪唑-1-基)甲基)苯甲腈;4-((2-((3R,4S)-3-胺基-4-氟哌啶-1-基)-4-氯-1H-苯并[d]咪唑-1-基)甲基)苯甲腈;(R)-4-((2-(3-胺基-4,4-二氟哌啶-1-基)-4-甲氧基-1H-苯并[d]咪唑-1-基)甲基)苯甲腈;4-((2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-4-甲氧基-1H-苯并[d]咪唑-1-基)甲基)苯甲腈;4-((2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-1H-咪唑并[4,5-c]吡啶-1-基)甲基)苯甲腈;4-((2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-3H-咪唑并[4,5-c]吡啶-3-基)甲基)苯甲腈;4-((2-((3R,4R)-3-胺基-4-氟-1-哌啶基)-6-乙氧基-1H-苯并咪唑-1-基)甲基)苯甲腈;4-((2-((3R,4S)-3-胺基-4-氟哌啶-1-基)-1H-咪唑并[4,5-b]吡啶-1-基)甲基)苯甲腈;4-((2-((3R)-3-胺基-4,4-二氟-1-哌啶基)-6-氟-1H-苯并咪唑-1-基)甲基)苯甲腈;4-((2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-1H-咪唑并[4,5-b]吡啶-1-基)甲基)苯甲腈;(S)-4-((2-(3-胺基哌啶-1-基)-4-氯-1H-苯并[d]咪唑-1-基)甲基)苯甲腈2,2,2-三氟乙酸鹽; (S)-4-((2-(3-胺基哌啶-1-基)-3H-咪唑并[4,5-b]吡啶-3-基)甲基)苯甲腈鹽酸鹽;4-((2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-6-氯-1H-苯并[d]咪唑-1-基)甲基)苯甲腈鹽酸鹽;(S)-4-((2-(3-胺基哌啶-1-基)-6-氯-1H-苯并[d]咪唑-1-基)甲基)苯甲腈;(S)-4-((2-(3-胺基哌啶-1-基)-5-氯-1H-苯并[d]咪唑-1-基)甲基)苯甲腈;(R)-1-(2-((S)-3-胺基哌啶-1-基)-1H-苯并[d]咪唑-1-基)-2,3-二氫-1H-茚-5-甲腈;(S)-1-(2-((S)-3-胺基哌啶-1-基)-1H-苯并[d]咪唑-1-基)-2,3-二氫-1H-茚-5-甲腈;(3R,4R)-4-氟-1-(1-((5-甲氧基吡啶-2-基)甲基)-1H-苯并[d]咪唑-2-基)哌啶-3-胺;1-(2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)乙醯基)氮雜環丁烷-3-甲腈;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)-1-(3-(第三丁氧基)氮雜環丁-1-基)乙-1-酮;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)-1-(3,3-二氟氮雜環丁-1-基)乙酮;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)-1-(3-異丙基氮雜環丁-1-基)乙酮;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1- 基)-1-(6,6-二氟-2-氮雜螺[3.3]庚-2-基)乙酮;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)-1-(7-氧雜-2-氮雜螺[3.5]壬-2-基)乙酮;(R)-6-((2-(4,4-二氟-3-(甲基胺基)哌啶-1-基)-6-氟-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;(R)-6-((2-(4,4-二氟-3-((2-羥基乙基)胺基)哌啶-1-基)-6-氟-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;(S)-6-((2-(3-胺基哌啶-1-基)-1H-苯并[d]咪唑-1-基)甲基)菸鹼酸;(S)-6-((2-(3-胺基哌啶-1-基)-1H-苯并[d]咪唑-1-基)甲基)菸鹼醯胺;6-((2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-1H-苯并[d]咪唑-1-基)甲基)菸鹼醯胺;2-(2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-5,6-二氟-1H-苯并[d]咪唑-1-基)乙酸;6-((R)-1-(4,6-二氟-2-((3R,4R)-4-氟-3-(甲基胺基)哌啶-1-基)-1H-苯并[d]咪唑-1-基)乙基)菸鹼腈;6-((S)-1-(4,6-二氟-2-((3R,4R)-4-氟-3-(甲基胺基)哌啶-1-基)-1H-苯并[d]咪唑-1-基)乙基)菸鹼腈;6-((R)-1-(5,7-二氟-2-((3R,4R)-4-氟-3-(甲基胺基)哌啶-1-基)-1H-苯并[d]咪唑-1-基)乙基)菸鹼腈;及6-((S)-1-(5,7-二氟-2-((3R,4R)-4-氟-3-(甲基胺基)哌啶-1-基)-1H-苯并[d]咪唑-1-基)乙基)菸鹼腈。
- 一種化合物,其係如以下所列舉:6-((2-((3R,4S)-3-胺基-4-氟哌啶-1-基)-6-氯-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-1-((5-氯嘧啶-2-基)甲基)-6-氟-1H-苯并[d]咪唑-4-甲腈;(3R,4R)-1-(4,6-二氟-1-((5-氟嘧啶-2-基)甲基)-1H-苯并[d]咪唑-2-基)-4-氟哌啶-3-胺;6-((2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;(R)-6-((2-(3-胺基-4,4-二氟哌啶-1-基)-4,6-二氟-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈鹽酸鹽;(R)-6-((2-(3-胺基-4,4-二氟哌啶-1-基)-6-氟-1H-苯并[d]咪唑-1-基)甲基)菸鹼腈;6-((2-((3R,4R)-3-胺基-4-氟-1-哌啶基)-4-甲氧基-1H-苯并咪唑-1-基)甲基)-3-吡啶甲腈;2-((3R,4R)-3-胺基-4-氟哌啶-1-基)-1-((5-氯嘧啶-2-基)甲基)-1H-苯并[d]咪唑-6-甲腈;(3R,4R)-4-氟-1-(1-((5-氟嘧啶-2-基)甲基)-1H-苯并[d]咪唑-2-基)哌啶-3-胺;及(3R,4R)-1-(1-((5-氯嘧啶-2-基)甲基)-6-氟-1H-苯并[d]咪唑-2-基)-4-氟哌啶-3-胺。
- 如請求項1至22中任一項之化合物或其醫藥學上可接受之鹽,其 呈醫藥學上可接受之鹽形式。
- 一種醫藥組合物,其包含醫藥學上可接受之賦形劑、載劑或佐劑,及至少一種如請求項1至23中任一項之化合物。
- 一種至少一種如請求項1至23中任一項之化合物或其醫藥鹽或其醫藥組合物之用途,其係用於製備治療哺乳動物之由TRPC6介導之疾病或病症的藥物。
- 如請求項25之用途,其中該由TRPC6介導之疾病或病症係選自由以下組成之群:腎病症候群、微小變化病、局灶性節段性腎小球硬化症、塌陷性腎小球病、膜性腎病變、膜增殖性腎小球性腎炎、IGA腎病變、急性腎衰竭、慢性腎衰竭、糖尿病腎病變、敗血症、肺高血壓、急性肺病症、急性呼吸窘迫症候群(ARDS)、心臟衰竭、中風、惡性腫瘤及肌肉營養不良症。
- 一種至少一種如請求項1至22中任一項之化合物或其醫藥鹽或其醫藥組合物之用途,其係用於製備調節哺乳動物中之TRPC6活性的藥物。
- 如請求項1至23中任一項之化合物或其醫藥學上可接受之鹽,其用作藥劑。
- 如請求項1至23中任一項之化合物或其醫藥學上可接受之鹽,其用於製造用於治療以下疾病之藥劑:腎病症候群、微小變化病、局灶性節段性腎小球硬化症、塌陷性腎小球病、膜性腎病變、膜增殖性腎小球性腎炎、IGA腎病變、急性腎衰竭、慢性腎衰竭、糖尿病腎病變、敗血症、肺高血壓、急性肺病症、急性呼吸窘迫症候群(ARDS)、心臟衰竭、中風、惡性腫瘤及肌肉營養不良症。
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201762574465P | 2017-10-19 | 2017-10-19 | |
US62/574,465 | 2017-10-19 | ||
US201862671090P | 2018-05-14 | 2018-05-14 | |
US62/671,090 | 2018-05-14 |
Publications (2)
Publication Number | Publication Date |
---|---|
TW201930284A TW201930284A (zh) | 2019-08-01 |
TWI816704B true TWI816704B (zh) | 2023-10-01 |
Family
ID=66173507
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
TW107137075A TWI816704B (zh) | 2017-10-19 | 2018-10-19 | 苯并咪唑衍生物及其用途 |
Country Status (19)
Country | Link |
---|---|
US (1) | US11332459B2 (zh) |
EP (1) | EP3697410A4 (zh) |
JP (1) | JP7450534B2 (zh) |
KR (1) | KR102697255B1 (zh) |
CN (1) | CN111417394B (zh) |
AU (1) | AU2018351059B2 (zh) |
BR (1) | BR112020007589A8 (zh) |
CA (1) | CA3079081A1 (zh) |
CL (1) | CL2020001020A1 (zh) |
CO (1) | CO2020004669A2 (zh) |
IL (1) | IL273839B (zh) |
MA (1) | MA50413A (zh) |
MX (1) | MX2020003993A (zh) |
PH (1) | PH12020550265A1 (zh) |
SA (1) | SA520411787B1 (zh) |
SG (1) | SG11202003502VA (zh) |
TW (1) | TWI816704B (zh) |
UY (1) | UY37941A (zh) |
WO (1) | WO2019079578A1 (zh) |
Families Citing this family (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP3793565B1 (en) | 2018-05-14 | 2022-01-05 | Gilead Sciences, Inc. | Mcl-1 inhibitors |
KR20210136106A (ko) * | 2019-04-11 | 2021-11-16 | 데이진 화-마 가부시키가이샤 | 벤즈이미다졸 유도체 및 이들의 용도 |
TWI778443B (zh) | 2019-11-12 | 2022-09-21 | 美商基利科學股份有限公司 | Mcl1抑制劑 |
AU2020391106B2 (en) | 2019-11-26 | 2024-03-21 | Gilead Sciences, Inc. | Processes and intermediates for preparing MCL1 inhibitors |
AR121846A1 (es) | 2020-04-16 | 2022-07-13 | Teijin Pharma Ltd | Derivado de arilo o heteroarilo |
CA3173616A1 (en) * | 2020-04-16 | 2021-10-21 | Boehringer Ingelheim International Gmbh | Use of pyridine carbonyl derivatives as inhibitors of trpc6 for treating respiratory conditions |
US20240307375A1 (en) * | 2021-06-29 | 2024-09-19 | Osaka University | Pharmaceutical composition for preventing and/or treating kidney injury, and autophagy activator |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2368876A1 (en) * | 2010-03-01 | 2011-09-28 | Sanofi | Derivatives of aminoindanes, their preparation and their application in therapeutics |
Family Cites Families (45)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2618435B1 (fr) | 1987-07-23 | 1989-10-27 | Synthelabo | Derives de benzimidazole, leur preparation et leur application en therapeutique |
US5670501A (en) | 1994-09-01 | 1997-09-23 | Discovery Therapeutics, Inc. | N-substituted 9-alkyladenines |
AU7775401A (en) * | 2000-08-10 | 2002-02-25 | Welfide Corp | Proline derivatives and use thereof as drugs |
UA76224C2 (en) | 2001-10-15 | 2006-07-17 | Janssen Pharmaceutica Nv | Substituted 4-phenyl 4-[1h-imidazol-2-yl]-piperidine derivatives and use thereof as selective non-peptide delta-opioid agonists |
PL370371A1 (en) | 2001-10-15 | 2005-05-16 | Janssen Pharmaceutica N.V. | Substituted 4-phenyl-4-(1h-imidazol-2-yl)-piperidine derivatives for reducing ischaemic damage |
AU2003252715B2 (en) | 2002-07-30 | 2009-06-04 | Banyu Pharmaceutical Co., Ltd. | Antagonist of melanin-concentrating hormone receptor comprising benzimidazole derivative as active ingredient |
WO2004035549A1 (en) * | 2002-10-17 | 2004-04-29 | Amgen Inc. | Benzimidazole derivatives and their use as vanilloid receptor ligands |
JPWO2005051949A1 (ja) | 2003-11-26 | 2007-06-21 | 住友製薬株式会社 | 新規縮合イミダゾール誘導体 |
DE102004017932A1 (de) | 2004-04-14 | 2005-11-03 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Neue Alkin-Verbindungen mit MCH-antagonistischer Wirkung und diese Verbindungen enthaltende Arzneimittel |
WO2006010283A1 (en) | 2004-07-28 | 2006-02-02 | Universität Zürich | Prevention and treatment of thrombus formation |
US7601745B2 (en) | 2004-09-27 | 2009-10-13 | 4Sc Ag | Heterocyclic NF-kB inhibitors |
US20100267717A1 (en) | 2005-07-29 | 2010-10-21 | 4Sc Ag | Novel Heterocyclic NF-kB Inhibitors |
DE102005012874A1 (de) | 2005-03-19 | 2006-09-21 | Sanofi-Aventis Deutschland Gmbh | Amid substituierte 8-N-Benzimidazole, Verfahren zu ihrer Herstellung und ihre Verwendung als Arzneimittel |
DE102005012875B4 (de) | 2005-03-19 | 2006-11-16 | Sanofi-Aventis Deutschland Gmbh | Verwendung von Amino substituierten 8-N-Benzimidazolen |
JP5167116B2 (ja) * | 2005-04-06 | 2013-03-21 | ノース・キャロライナ・ステイト・ユニヴァーシティ | 耐火材料の高密度成形品及びその製造方法 |
EP1739078A1 (de) | 2005-05-30 | 2007-01-03 | Jerini AG | C5a-Rezeptor-Antagonisten |
EP1951286A4 (en) | 2005-10-07 | 2009-11-04 | Waratah Pharmaceuticals Inc | COMBINED USE OF INHIBITORS OF DPP-IV AND GASTRIN COMPOUNDS |
AU2007271243A1 (en) | 2006-07-03 | 2008-01-10 | Neurosearch A/S | Combinations of monoamine reuptake inhibitors and potassium channel activators |
JP2010501540A (ja) | 2006-08-23 | 2010-01-21 | ファイザー・プロダクツ・インク | Gsk−3阻害剤としてのピリミドン化合物 |
US20080186971A1 (en) | 2007-02-02 | 2008-08-07 | Tarari, Inc. | Systems and methods for processing access control lists (acls) in network switches using regular expression matching logic |
WO2008100977A2 (en) | 2007-02-14 | 2008-08-21 | N.V. Organon | Carbamates therapeutic release agents as amidase inhibitors |
WO2008153701A1 (en) | 2007-05-24 | 2008-12-18 | Schering Corporation | Compounds for inhibiting ksp kinesin activity |
WO2009018280A2 (en) | 2007-07-30 | 2009-02-05 | Auspex Pharamaceuticals, Inc. | Substituted indoles |
WO2010144742A2 (en) | 2009-06-10 | 2010-12-16 | Nono, Inc. | Co-administration of an agent linked to an internalization peptide with an anti-inflammatory |
WO2009089234A2 (en) | 2008-01-07 | 2009-07-16 | Auspex Pharmaceuticals | Substituted dibenzhydrylpiperazines |
WO2010104307A2 (ko) | 2009-03-07 | 2010-09-16 | 주식회사 메디젠텍 | 세포핵에서 세포질로의 gsk3의 이동을 억제하는 화합물을 함유하는 세포핵에서 세포질로의 gsk3 이동에 의해 발생되는 질환의 치료 또는 예방용 약학적 조성물 |
WO2011023812A1 (en) | 2009-08-27 | 2011-03-03 | Novasaid Ab | Microsomal prostaglandin e synthase-1 (mpges1) inhibitors |
ES2650744T3 (es) | 2010-12-14 | 2018-01-22 | Electrophoretics Limited | Inhibidores de la caseína quinasa 1 delta (CK1delta) |
WO2012098281A2 (es) | 2011-01-19 | 2012-07-26 | Universidad Miguel Hernández De Elche | Péptidos moduladores de receptores trp y sus usos |
EP2681200A4 (en) | 2011-03-03 | 2015-05-27 | Zalicus Pharmaceuticals Ltd | INHIBITORS OF BENZIMIDAZOLE TYPE OF SODIUM CHANNEL |
WO2013171167A1 (en) | 2012-05-14 | 2013-11-21 | Boehringer Ingelheim International Gmbh | A xanthine derivative as dpp -4 inhibitor for use in the treatment of podocytes related disorders and/or nephrotic syndrome |
EP2698367A1 (en) | 2012-08-14 | 2014-02-19 | Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V. | Benzimidazoles for the treatment of cancer |
GB201223265D0 (en) | 2012-12-21 | 2013-02-06 | Selvita Sa | Novel benzimidazole derivatives as kinase inhibitors |
JP2016513112A (ja) | 2013-02-18 | 2016-05-12 | ザ スクリプス リサーチ インスティテュート | 治療的潜在能力を有するバソプレッシン受容体のモジュレーター |
WO2014160183A1 (en) | 2013-03-13 | 2014-10-02 | The United States Of America,As Represented By The Secretary,Department Of Health And Human Services | Methods for modulating chemotherapeutic cytotoxicity |
ES2806135T3 (es) | 2013-06-21 | 2021-02-16 | Zenith Epigenetics Ltd | Nuevos inhibidores de bromodominios bicíclicos |
US9828348B2 (en) | 2013-11-08 | 2017-11-28 | Purdue Pharma L.P. | Benzimidazole derivatives and use thereof |
US11447486B2 (en) | 2014-07-31 | 2022-09-20 | Institut Pasteur Korea | 2-amino-benzimidazole derivatives and their use as 5-lipoxygenase and/or prostaglandin E synthase inhibitors |
TW201643138A (zh) | 2015-04-17 | 2016-12-16 | 佛瑪治療公司 | 作為組蛋白脫乙醯基酶(hdac)抑制劑之3-螺-7-異羥肟酸四氫萘 |
WO2017052394A1 (en) | 2015-09-23 | 2017-03-30 | Uniwersytet Jagielloński | Imidazopyridine compounds and their use as 5-ht6 receptor ligands |
WO2017060488A1 (en) | 2015-10-09 | 2017-04-13 | Almirall, S.A. | New trpa1 antagonists |
WO2017064068A1 (en) | 2015-10-14 | 2017-04-20 | Almirall, S.A. | New trpa1 antagonists |
GB201603311D0 (en) | 2016-02-25 | 2016-04-13 | Jakobsson Per Johan | New uses and methods |
US11091482B2 (en) | 2016-08-23 | 2021-08-17 | Ardelyx, Inc. | Isoxazolyl-carbonyloxy azabicyclo[3.2.1]octanyl compounds as FXR activators |
US10501421B1 (en) * | 2017-01-27 | 2019-12-10 | Vanderbilt University | Substituted benzimidazoles as modulators of Ras signaling |
-
2018
- 2018-10-18 EP EP18867844.5A patent/EP3697410A4/en active Pending
- 2018-10-18 KR KR1020207013744A patent/KR102697255B1/ko active IP Right Grant
- 2018-10-18 JP JP2020521577A patent/JP7450534B2/ja active Active
- 2018-10-18 WO PCT/US2018/056484 patent/WO2019079578A1/en unknown
- 2018-10-18 US US16/754,349 patent/US11332459B2/en active Active
- 2018-10-18 CA CA3079081A patent/CA3079081A1/en active Pending
- 2018-10-18 SG SG11202003502VA patent/SG11202003502VA/en unknown
- 2018-10-18 IL IL273839A patent/IL273839B/en unknown
- 2018-10-18 CN CN201880077655.5A patent/CN111417394B/zh active Active
- 2018-10-18 BR BR112020007589A patent/BR112020007589A8/pt unknown
- 2018-10-18 MA MA050413A patent/MA50413A/fr unknown
- 2018-10-18 AU AU2018351059A patent/AU2018351059B2/en active Active
- 2018-10-18 MX MX2020003993A patent/MX2020003993A/es unknown
- 2018-10-19 UY UY0001037941A patent/UY37941A/es not_active Application Discontinuation
- 2018-10-19 TW TW107137075A patent/TWI816704B/zh active
-
2020
- 2020-04-14 PH PH12020550265A patent/PH12020550265A1/en unknown
- 2020-04-16 CL CL2020001020A patent/CL2020001020A1/es unknown
- 2020-04-16 CO CONC2020/0004669A patent/CO2020004669A2/es unknown
- 2020-04-17 SA SA520411787A patent/SA520411787B1/ar unknown
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2368876A1 (en) * | 2010-03-01 | 2011-09-28 | Sanofi | Derivatives of aminoindanes, their preparation and their application in therapeutics |
Also Published As
Publication number | Publication date |
---|---|
CN111417394B (zh) | 2023-11-07 |
JP7450534B2 (ja) | 2024-03-15 |
KR102697255B1 (ko) | 2024-08-23 |
PH12020550265A1 (en) | 2021-03-01 |
JP2021500332A (ja) | 2021-01-07 |
BR112020007589A2 (pt) | 2020-09-24 |
UY37941A (es) | 2019-04-30 |
SA520411787B1 (ar) | 2022-08-29 |
IL273839A (en) | 2020-05-31 |
AU2018351059A1 (en) | 2020-04-23 |
TW201930284A (zh) | 2019-08-01 |
AU2018351059B2 (en) | 2022-05-12 |
CO2020004669A2 (es) | 2020-05-05 |
CN111417394A (zh) | 2020-07-14 |
IL273839B (en) | 2022-09-01 |
US20200308145A1 (en) | 2020-10-01 |
KR20200074965A (ko) | 2020-06-25 |
CL2020001020A1 (es) | 2020-09-21 |
MA50413A (fr) | 2020-08-26 |
CA3079081A1 (en) | 2019-04-25 |
EP3697410A4 (en) | 2021-08-11 |
WO2019079578A1 (en) | 2019-04-25 |
SG11202003502VA (en) | 2020-05-28 |
MX2020003993A (es) | 2020-08-13 |
EP3697410A1 (en) | 2020-08-26 |
BR112020007589A8 (pt) | 2022-08-02 |
US11332459B2 (en) | 2022-05-17 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
TWI816704B (zh) | 苯并咪唑衍生物及其用途 | |
JP7216682B2 (ja) | Usp30阻害剤としての1-シアノ-ピロリジン化合物 | |
ES2866152T3 (es) | Derivados de tirosina amida como inhibidores de la Rho-quinasa | |
KR102493967B1 (ko) | 신규한 화합물 | |
AU2014304046B2 (en) | Benzimidazolyl-methyl urea derivatives as ALX receptor agonists | |
JP7434285B2 (ja) | N-シアノ-7-アザノルボルナン誘導体及びその使用 | |
KR20190012167A (ko) | 이소퀴놀린-3-일 카르복스아마이드 및 이의 제제와 용도 | |
US10703748B2 (en) | Diazanaphthalen-3-yl carboxamides and preparation and use thereof | |
KR20170075756A (ko) | 카르바졸 유도체 | |
KR20200078567A (ko) | P2x3 억제제로서의 신규 피라졸로-피롤로-피리미딘-디온 유도체 | |
JP2022532145A (ja) | 置換ベンズイミダゾロン化合物 | |
KR20160086930A (ko) | 피롤로피롤론 유도체 및 bet 억제제로서의 그의 용도 | |
ES2864948T3 (es) | Aparato de colocación de remaches ciegos y dispositivo de procesamiento de remaches ciegos con un aparato de colocación de remaches ciegos | |
CN104619707A (zh) | 稠环杂环化合物 | |
EP4255904A2 (en) | Novel par-2 inhibitors | |
EA043189B1 (ru) | Производные бензимидазола и их применение в качестве ингибиторов trpc6 | |
WO2023233033A1 (en) | Novel par-2 inhibitors | |
TW202417458A (zh) | 調節her2的化合物及方法 |