CN109415346A - 作为alk5抑制剂的新型吡唑衍生物及其用途 - Google Patents
作为alk5抑制剂的新型吡唑衍生物及其用途 Download PDFInfo
- Publication number
- CN109415346A CN109415346A CN201780041502.0A CN201780041502A CN109415346A CN 109415346 A CN109415346 A CN 109415346A CN 201780041502 A CN201780041502 A CN 201780041502A CN 109415346 A CN109415346 A CN 109415346A
- Authority
- CN
- China
- Prior art keywords
- base
- picoline
- pyrazole
- carboxamide
- benzo
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 150000003217 pyrazoles Chemical class 0.000 title abstract description 5
- 239000003112 inhibitor Substances 0.000 title description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 106
- 201000010099 disease Diseases 0.000 claims abstract description 45
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 45
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 39
- 201000011510 cancer Diseases 0.000 claims abstract description 30
- ZRKFYGHZFMAOKI-QMGMOQQFSA-N tgfbeta Chemical compound C([C@H](NC(=O)[C@H](C(C)C)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CCSC)C(C)C)[C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)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)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O)C1=CC=C(O)C=C1 ZRKFYGHZFMAOKI-QMGMOQQFSA-N 0.000 claims abstract description 20
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 18
- 102000004887 Transforming Growth Factor beta Human genes 0.000 claims abstract description 17
- 108090001012 Transforming Growth Factor beta Proteins 0.000 claims abstract description 17
- 230000003176 fibrotic effect Effects 0.000 claims abstract description 13
- 208000015181 infectious disease Diseases 0.000 claims abstract description 6
- 230000002265 prevention Effects 0.000 claims abstract description 4
- WKGHUAZJNBXABN-UHFFFAOYSA-N 3-bromo-2-chloro-6-methyl-5-nitropyridine Chemical compound CC1=NC(Cl)=C(Br)C=C1[N+]([O-])=O WKGHUAZJNBXABN-UHFFFAOYSA-N 0.000 claims description 418
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 329
- -1 Carbonyl Chemical group 0.000 claims description 229
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical compound C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 claims description 201
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 164
- NSPMIYGKQJPBQR-UHFFFAOYSA-N 4H-1,2,4-triazole Chemical compound C=1N=CNN=1 NSPMIYGKQJPBQR-UHFFFAOYSA-N 0.000 claims description 159
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 66
- 206010016654 Fibrosis Diseases 0.000 claims description 35
- 230000004761 fibrosis Effects 0.000 claims description 33
- 150000003839 salts Chemical class 0.000 claims description 33
- 239000000126 substance Substances 0.000 claims description 27
- 238000000034 method Methods 0.000 claims description 26
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 21
- 150000001408 amides Chemical class 0.000 claims description 21
- 229910052760 oxygen Inorganic materials 0.000 claims description 20
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 15
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 claims description 14
- 239000003814 drug Substances 0.000 claims description 14
- 239000001257 hydrogen Substances 0.000 claims description 14
- 229910052739 hydrogen Inorganic materials 0.000 claims description 14
- 150000003222 pyridines Chemical class 0.000 claims description 14
- BCMCBBGGLRIHSE-UHFFFAOYSA-N 1,3-benzoxazole Chemical compound C1=CC=C2OC=NC2=C1 BCMCBBGGLRIHSE-UHFFFAOYSA-N 0.000 claims description 12
- 208000019425 cirrhosis of liver Diseases 0.000 claims description 12
- 229940079593 drug Drugs 0.000 claims description 12
- 229910052717 sulfur Inorganic materials 0.000 claims description 12
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 11
- FTNJQNQLEGKTGD-UHFFFAOYSA-N 1,3-benzodioxole Chemical compound C1=CC=C2OCOC2=C1 FTNJQNQLEGKTGD-UHFFFAOYSA-N 0.000 claims description 10
- IWTFOFMTUOBLHG-UHFFFAOYSA-N 2-methoxypyridine Chemical compound COC1=CC=CC=N1 IWTFOFMTUOBLHG-UHFFFAOYSA-N 0.000 claims description 10
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical class C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 claims description 10
- 125000003118 aryl group Chemical group 0.000 claims description 10
- 239000007787 solid Substances 0.000 claims description 10
- DXFBKDSQMUFYLD-UHFFFAOYSA-N 2-pyrazol-1-ylethanol Chemical class OCCN1C=CC=N1 DXFBKDSQMUFYLD-UHFFFAOYSA-N 0.000 claims description 9
- MAQAGRJURDEYDQ-UHFFFAOYSA-N 6-methylpyridine Chemical compound CC1=C=CC=C[N]1 MAQAGRJURDEYDQ-UHFFFAOYSA-N 0.000 claims description 9
- 230000001404 mediated effect Effects 0.000 claims description 9
- 208000005069 pulmonary fibrosis Diseases 0.000 claims description 9
- 208000027418 Wounds and injury Diseases 0.000 claims description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 239000011737 fluorine Substances 0.000 claims description 8
- 229910052731 fluorine Inorganic materials 0.000 claims description 8
- 125000005842 heteroatom Chemical group 0.000 claims description 8
- 125000003367 polycyclic group Chemical group 0.000 claims description 8
- AWBOSXFRPFZLOP-UHFFFAOYSA-N 2,1,3-benzoxadiazole Chemical class C1=CC=CC2=NON=C21 AWBOSXFRPFZLOP-UHFFFAOYSA-N 0.000 claims description 7
- 206010052428 Wound Diseases 0.000 claims description 7
- 206010069351 acute lung injury Diseases 0.000 claims description 7
- 229910052736 halogen Inorganic materials 0.000 claims description 7
- 150000002367 halogens Chemical class 0.000 claims description 7
- 210000003734 kidney Anatomy 0.000 claims description 7
- 201000010260 leiomyoma Diseases 0.000 claims description 7
- 229910052757 nitrogen Inorganic materials 0.000 claims description 7
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 claims description 6
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 claims description 6
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 6
- AULWPXHFRBLPAE-UHFFFAOYSA-N 6-chloropyridine Chemical compound ClC1=C=CC=C[N]1 AULWPXHFRBLPAE-UHFFFAOYSA-N 0.000 claims description 6
- 208000032612 Glial tumor Diseases 0.000 claims description 6
- 206010018338 Glioma Diseases 0.000 claims description 6
- 206010023421 Kidney fibrosis Diseases 0.000 claims description 6
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 6
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 6
- 206010060862 Prostate cancer Diseases 0.000 claims description 6
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 6
- 208000019065 cervical carcinoma Diseases 0.000 claims description 6
- 239000000835 fiber Substances 0.000 claims description 6
- 201000010536 head and neck cancer Diseases 0.000 claims description 6
- 208000014829 head and neck neoplasm Diseases 0.000 claims description 6
- 210000004185 liver Anatomy 0.000 claims description 6
- 201000007270 liver cancer Diseases 0.000 claims description 6
- 208000014018 liver neoplasm Diseases 0.000 claims description 6
- 201000005202 lung cancer Diseases 0.000 claims description 6
- 208000020816 lung neoplasm Diseases 0.000 claims description 6
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 6
- XSCHRSMBECNVNS-UHFFFAOYSA-N quinoxaline Chemical compound N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 claims description 6
- 125000004204 2-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C([H])=C1[H] 0.000 claims description 5
- 206010006187 Breast cancer Diseases 0.000 claims description 5
- 208000026310 Breast neoplasm Diseases 0.000 claims description 5
- 208000007342 Diabetic Nephropathies Diseases 0.000 claims description 5
- 206010020772 Hypertension Diseases 0.000 claims description 5
- 206010028594 Myocardial fibrosis Diseases 0.000 claims description 5
- 206010029164 Nephrotic syndrome Diseases 0.000 claims description 5
- 230000008859 change Effects 0.000 claims description 5
- UKJLNMAFNRKWGR-UHFFFAOYSA-N cyclohexatrienamine Chemical group NC1=CC=C=C[CH]1 UKJLNMAFNRKWGR-UHFFFAOYSA-N 0.000 claims description 5
- 208000033679 diabetic kidney disease Diseases 0.000 claims description 5
- 125000001072 heteroaryl group Chemical group 0.000 claims description 5
- 230000002401 inhibitory effect Effects 0.000 claims description 5
- 208000009928 nephrosis Diseases 0.000 claims description 5
- 231100001027 nephrosis Toxicity 0.000 claims description 5
- 230000019491 signal transduction Effects 0.000 claims description 5
- UEMGWPRHOOEKTA-UHFFFAOYSA-N 1,3-difluorobenzene Chemical compound FC1=CC=CC(F)=C1 UEMGWPRHOOEKTA-UHFFFAOYSA-N 0.000 claims description 4
- XKUCYXXFXDCXFO-UHFFFAOYSA-N 1-ethoxypyrazole Chemical class CCON1C=CC=N1 XKUCYXXFXDCXFO-UHFFFAOYSA-N 0.000 claims description 4
- WLPACIZIAIUYDM-UHFFFAOYSA-N 1-methylsulfonylpyrazole Chemical class CS(=O)(=O)N1C=CC=N1 WLPACIZIAIUYDM-UHFFFAOYSA-N 0.000 claims description 4
- PKDPUENCROCRCH-UHFFFAOYSA-N 1-piperazin-1-ylethanone Chemical compound CC(=O)N1CCNCC1 PKDPUENCROCRCH-UHFFFAOYSA-N 0.000 claims description 4
- AOKYJAAYDKAMJZ-UHFFFAOYSA-N 2-methylpyridine;pyridine Chemical compound C1=CC=NC=C1.CC1=CC=CC=N1 AOKYJAAYDKAMJZ-UHFFFAOYSA-N 0.000 claims description 4
- 125000004208 3-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C([H])C(*)=C1[H] 0.000 claims description 4
- 125000004203 4-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 claims description 4
- VAZNJOLLULMJGT-UHFFFAOYSA-N 6-bromopyridine Chemical compound BrC1=C=CC=C[N]1 VAZNJOLLULMJGT-UHFFFAOYSA-N 0.000 claims description 4
- 208000024827 Alzheimer disease Diseases 0.000 claims description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 4
- 201000009030 Carcinoma Diseases 0.000 claims description 4
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims description 4
- 206010009944 Colon cancer Diseases 0.000 claims description 4
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 4
- 206010018364 Glomerulonephritis Diseases 0.000 claims description 4
- 201000009794 Idiopathic Pulmonary Fibrosis Diseases 0.000 claims description 4
- 208000002260 Keloid Diseases 0.000 claims description 4
- 206010023330 Keloid scar Diseases 0.000 claims description 4
- 210000004027 cell Anatomy 0.000 claims description 4
- 206010016629 fibroma Diseases 0.000 claims description 4
- 208000005017 glioblastoma Diseases 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- 208000036971 interstitial lung disease 2 Diseases 0.000 claims description 4
- 210000001117 keloid Anatomy 0.000 claims description 4
- 201000001441 melanoma Diseases 0.000 claims description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 4
- 210000000056 organ Anatomy 0.000 claims description 4
- 231100000241 scar Toxicity 0.000 claims description 4
- 230000029663 wound healing Effects 0.000 claims description 4
- PCLKVJBRTCQNDU-UHFFFAOYSA-N 2-methylsulfonylpyridine Chemical compound CS(=O)(=O)C1=CC=CC=N1 PCLKVJBRTCQNDU-UHFFFAOYSA-N 0.000 claims description 3
- 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 0.000 claims description 3
- 125000004801 4-cyanophenyl group Chemical group [H]C1=C([H])C(C#N)=C([H])C([H])=C1* 0.000 claims description 3
- 206010001233 Adenoma benign Diseases 0.000 claims description 3
- 206010004593 Bile duct cancer Diseases 0.000 claims description 3
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 3
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 3
- 201000008808 Fibrosarcoma Diseases 0.000 claims description 3
- 208000005777 Lupus Nephritis Diseases 0.000 claims description 3
- 206010027476 Metastases Diseases 0.000 claims description 3
- 206010034665 Peritoneal fibrosis Diseases 0.000 claims description 3
- 201000009594 Systemic Scleroderma Diseases 0.000 claims description 3
- 206010042953 Systemic sclerosis Diseases 0.000 claims description 3
- 201000004471 adenofibroma Diseases 0.000 claims description 3
- 208000026900 bile duct neoplasm Diseases 0.000 claims description 3
- 230000009401 metastasis Effects 0.000 claims description 3
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 3
- 125000004076 pyridyl group Chemical group 0.000 claims description 3
- 125000004434 sulfur atom Chemical group 0.000 claims description 3
- DGAKOGDJXIUBGF-UHFFFAOYSA-N 1-cyclopropylsulfonylpyrazole Chemical class C1(CC1)S(=O)(=O)N1N=CC=C1 DGAKOGDJXIUBGF-UHFFFAOYSA-N 0.000 claims description 2
- 125000006276 2-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C(*)C([H])=C1[H] 0.000 claims description 2
- 125000006282 2-chlorobenzyl group Chemical group [H]C1=C([H])C(Cl)=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- OKDGRDCXVWSXDC-UHFFFAOYSA-N 2-chloropyridine Chemical compound ClC1=CC=CC=N1 OKDGRDCXVWSXDC-UHFFFAOYSA-N 0.000 claims description 2
- 125000004189 3,4-dichlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(Cl)C([H])=C1* 0.000 claims description 2
- 125000004211 3,5-difluorophenyl group Chemical group [H]C1=C(F)C([H])=C(*)C([H])=C1F 0.000 claims description 2
- LJGHYPLBDBRCRZ-UHFFFAOYSA-N 3-(3-aminophenyl)sulfonylaniline Chemical group NC1=CC=CC(S(=O)(=O)C=2C=C(N)C=CC=2)=C1 LJGHYPLBDBRCRZ-UHFFFAOYSA-N 0.000 claims description 2
- 125000006275 3-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C([H])C(*)=C1[H] 0.000 claims description 2
- 125000003852 3-chlorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C(Cl)=C1[H])C([H])([H])* 0.000 claims description 2
- 125000006497 3-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C(OC([H])([H])[H])=C1[H])C([H])([H])* 0.000 claims description 2
- 125000006283 4-chlorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Cl)C([H])([H])* 0.000 claims description 2
- 208000007122 AIDS-Associated Nephropathy Diseases 0.000 claims description 2
- 206010004146 Basal cell carcinoma Diseases 0.000 claims description 2
- 206010005003 Bladder cancer Diseases 0.000 claims description 2
- 208000003174 Brain Neoplasms Diseases 0.000 claims description 2
- 208000017897 Carcinoma of esophagus Diseases 0.000 claims description 2
- 206010010356 Congenital anomaly Diseases 0.000 claims description 2
- 206010056370 Congestive cardiomyopathy Diseases 0.000 claims description 2
- 201000010046 Dilated cardiomyopathy Diseases 0.000 claims description 2
- 208000000461 Esophageal Neoplasms Diseases 0.000 claims description 2
- DGICIFQPMFLZQY-UHFFFAOYSA-N FC1=C(C=CC=C1)NC(=O)C1=NN(C(=C1)C=1C=C2N=CC=NC2=CC=1)C1=CC(=CC=C1)C Chemical compound FC1=C(C=CC=C1)NC(=O)C1=NN(C(=C1)C=1C=C2N=CC=NC2=CC=1)C1=CC(=CC=C1)C DGICIFQPMFLZQY-UHFFFAOYSA-N 0.000 claims description 2
- 208000022072 Gallbladder Neoplasms Diseases 0.000 claims description 2
- 206010017711 Gangrene Diseases 0.000 claims description 2
- 206010070737 HIV associated nephropathy Diseases 0.000 claims description 2
- 206010019280 Heart failures Diseases 0.000 claims description 2
- 206010019728 Hepatitis alcoholic Diseases 0.000 claims description 2
- 206010061523 Lip and/or oral cavity cancer Diseases 0.000 claims description 2
- 208000009525 Myocarditis Diseases 0.000 claims description 2
- UQFQONCQIQEYPJ-UHFFFAOYSA-N N-methylpyrazole Chemical class CN1C=CC=N1 UQFQONCQIQEYPJ-UHFFFAOYSA-N 0.000 claims description 2
- 206010029216 Nervousness Diseases 0.000 claims description 2
- 208000001132 Osteoporosis Diseases 0.000 claims description 2
- 208000009565 Pharyngeal Neoplasms Diseases 0.000 claims description 2
- 206010035664 Pneumonia Diseases 0.000 claims description 2
- 208000002158 Proliferative Vitreoretinopathy Diseases 0.000 claims description 2
- 206010038934 Retinopathy proliferative Diseases 0.000 claims description 2
- 206010039491 Sarcoma Diseases 0.000 claims description 2
- 208000034189 Sclerosis Diseases 0.000 claims description 2
- 235000018259 Solanum vestissimum Nutrition 0.000 claims description 2
- 240000002825 Solanum vestissimum Species 0.000 claims description 2
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 2
- 208000007536 Thrombosis Diseases 0.000 claims description 2
- 208000024770 Thyroid neoplasm Diseases 0.000 claims description 2
- 206010062129 Tongue neoplasm Diseases 0.000 claims description 2
- 208000025865 Ulcer Diseases 0.000 claims description 2
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 claims description 2
- 208000002495 Uterine Neoplasms Diseases 0.000 claims description 2
- 206010047571 Visual impairment Diseases 0.000 claims description 2
- 208000002353 alcoholic hepatitis Diseases 0.000 claims description 2
- 229910021529 ammonia Inorganic materials 0.000 claims description 2
- 206010003246 arthritis Diseases 0.000 claims description 2
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 claims description 2
- 229940092714 benzenesulfonic acid Drugs 0.000 claims description 2
- BNBQRQQYDMDJAH-UHFFFAOYSA-N benzodioxan Chemical compound C1=CC=C2OCCOC2=C1 BNBQRQQYDMDJAH-UHFFFAOYSA-N 0.000 claims description 2
- 210000003445 biliary tract Anatomy 0.000 claims description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 2
- 230000009787 cardiac fibrosis Effects 0.000 claims description 2
- 239000000084 colloidal system Substances 0.000 claims description 2
- 210000004087 cornea Anatomy 0.000 claims description 2
- 125000004802 cyanophenyl group Chemical group 0.000 claims description 2
- 201000001981 dermatomyositis Diseases 0.000 claims description 2
- 201000010175 gallbladder cancer Diseases 0.000 claims description 2
- 206010017758 gastric cancer Diseases 0.000 claims description 2
- 230000001771 impaired effect Effects 0.000 claims description 2
- 201000001881 impotence Diseases 0.000 claims description 2
- 230000006698 induction Effects 0.000 claims description 2
- 125000000040 m-tolyl group Chemical group [H]C1=C([H])C(*)=C([H])C(=C1[H])C([H])([H])[H] 0.000 claims description 2
- 208000002780 macular degeneration Diseases 0.000 claims description 2
- 230000001394 metastastic effect Effects 0.000 claims description 2
- 206010061289 metastatic neoplasm Diseases 0.000 claims description 2
- 208000021971 neovascular inflammatory vitreoretinopathy Diseases 0.000 claims description 2
- 208000020717 oral cavity carcinoma Diseases 0.000 claims description 2
- 125000006505 p-cyanobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C#N)C([H])([H])* 0.000 claims description 2
- 201000008006 pharynx cancer Diseases 0.000 claims description 2
- 208000005987 polymyositis Diseases 0.000 claims description 2
- 230000000750 progressive effect Effects 0.000 claims description 2
- 230000006785 proliferative vitreoretinopathy Effects 0.000 claims description 2
- 230000005855 radiation Effects 0.000 claims description 2
- 201000001275 rectum cancer Diseases 0.000 claims description 2
- 230000029058 respiratory gaseous exchange Effects 0.000 claims description 2
- 208000037803 restenosis Diseases 0.000 claims description 2
- 241000894007 species Species 0.000 claims description 2
- 210000000952 spleen Anatomy 0.000 claims description 2
- 201000011549 stomach cancer Diseases 0.000 claims description 2
- 208000011580 syndromic disease Diseases 0.000 claims description 2
- 230000009885 systemic effect Effects 0.000 claims description 2
- 210000001550 testis Anatomy 0.000 claims description 2
- 201000002510 thyroid cancer Diseases 0.000 claims description 2
- 210000001685 thyroid gland Anatomy 0.000 claims description 2
- 201000006134 tongue cancer Diseases 0.000 claims description 2
- 231100000419 toxicity Toxicity 0.000 claims description 2
- 230000001988 toxicity Effects 0.000 claims description 2
- 231100000397 ulcer Toxicity 0.000 claims description 2
- 201000005112 urinary bladder cancer Diseases 0.000 claims description 2
- 206010046766 uterine cancer Diseases 0.000 claims description 2
- 230000002792 vascular Effects 0.000 claims description 2
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims 3
- XPDWGBQVDMORPB-UHFFFAOYSA-N Fluoroform Chemical compound FC(F)F XPDWGBQVDMORPB-UHFFFAOYSA-N 0.000 claims 2
- GOYLFWMKCLRPBJ-UHFFFAOYSA-N 1-(6-methylpyridin-2-yl)pyrazole-3-carboxamide Chemical compound CC1=CC=CC(=N1)N1N=C(C=C1)C(=O)N GOYLFWMKCLRPBJ-UHFFFAOYSA-N 0.000 claims 1
- MREIFUWKYMNYTK-UHFFFAOYSA-N 1H-pyrrole Chemical class C=1C=CNC=1.C=1C=CNC=1 MREIFUWKYMNYTK-UHFFFAOYSA-N 0.000 claims 1
- BNYCHCAYYYRJSH-UHFFFAOYSA-N 1h-pyrazole-5-carboxamide Chemical compound NC(=O)C1=CC=NN1 BNYCHCAYYYRJSH-UHFFFAOYSA-N 0.000 claims 1
- 125000004861 4-isopropyl phenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims 1
- 206010007559 Cardiac failure congestive Diseases 0.000 claims 1
- 208000028006 Corneal injury Diseases 0.000 claims 1
- 201000003741 Gastrointestinal carcinoma Diseases 0.000 claims 1
- 206010061216 Infarction Diseases 0.000 claims 1
- 208000003782 Raynaud disease Diseases 0.000 claims 1
- 208000012322 Raynaud phenomenon Diseases 0.000 claims 1
- PPBRXRYQALVLMV-UHFFFAOYSA-N Styrene Chemical compound C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 claims 1
- 210000001367 artery Anatomy 0.000 claims 1
- WLJVXDMOQOGPHL-UHFFFAOYSA-N benzyl-alpha-carboxylic acid Natural products OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 claims 1
- 210000000013 bile duct Anatomy 0.000 claims 1
- 210000001174 endocardium Anatomy 0.000 claims 1
- 210000000232 gallbladder Anatomy 0.000 claims 1
- 230000007574 infarction Effects 0.000 claims 1
- 230000002458 infectious effect Effects 0.000 claims 1
- 201000002313 intestinal cancer Diseases 0.000 claims 1
- 210000005229 liver cell Anatomy 0.000 claims 1
- 208000019423 liver disease Diseases 0.000 claims 1
- BEARMXYKACECDH-UHFFFAOYSA-N methylsulfonylmethylbenzene Chemical compound CS(=O)(=O)CC1=CC=CC=C1 BEARMXYKACECDH-UHFFFAOYSA-N 0.000 claims 1
- 210000004165 myocardium Anatomy 0.000 claims 1
- HVOYZOQVDYHUPF-UHFFFAOYSA-N n,n',n'-trimethylethane-1,2-diamine Chemical compound CNCCN(C)C HVOYZOQVDYHUPF-UHFFFAOYSA-N 0.000 claims 1
- 210000004303 peritoneum Anatomy 0.000 claims 1
- 229960003424 phenylacetic acid Drugs 0.000 claims 1
- 239000003279 phenylacetic acid Substances 0.000 claims 1
- 210000002784 stomach Anatomy 0.000 claims 1
- UPGBQYFXKAKWQC-UHFFFAOYSA-N trifluoromethylsulfonylbenzene Chemical compound FC(F)(F)S(=O)(=O)C1=CC=CC=C1 UPGBQYFXKAKWQC-UHFFFAOYSA-N 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 7
- 239000000470 constituent Substances 0.000 abstract description 5
- 208000023275 Autoimmune disease Diseases 0.000 abstract description 3
- 208000027866 inflammatory disease Diseases 0.000 abstract description 3
- 101001059454 Homo sapiens Serine/threonine-protein kinase MARK2 Proteins 0.000 abstract description 2
- 102100028904 Serine/threonine-protein kinase MARK2 Human genes 0.000 abstract description 2
- 208000024172 Cardiovascular disease Diseases 0.000 abstract 1
- 208000035473 Communicable disease Diseases 0.000 abstract 1
- 208000016097 disease of metabolism Diseases 0.000 abstract 1
- 208000030159 metabolic disease Diseases 0.000 abstract 1
- 230000004770 neurodegeneration Effects 0.000 abstract 1
- 208000015122 neurodegenerative disease Diseases 0.000 abstract 1
- 230000007781 signaling event Effects 0.000 abstract 1
- 201000008827 tuberculosis Diseases 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 82
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 81
- 238000006243 chemical reaction Methods 0.000 description 72
- 239000000243 solution Substances 0.000 description 66
- 238000002360 preparation method Methods 0.000 description 65
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 51
- 239000000706 filtrate Substances 0.000 description 44
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 41
- 238000005481 NMR spectroscopy Methods 0.000 description 41
- 238000004440 column chromatography Methods 0.000 description 35
- 239000000047 product Substances 0.000 description 35
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 32
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 30
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 24
- 239000012044 organic layer Substances 0.000 description 23
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 22
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 22
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 21
- 235000019441 ethanol Nutrition 0.000 description 21
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 18
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 15
- 238000003756 stirring Methods 0.000 description 15
- 238000001914 filtration Methods 0.000 description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- 238000005160 1H NMR spectroscopy Methods 0.000 description 11
- 239000002253 acid Substances 0.000 description 11
- 239000007821 HATU Substances 0.000 description 10
- 125000004494 ethyl ester group Chemical group 0.000 description 10
- QLJACZBEDWORHA-UHFFFAOYSA-N (6-methylpyridin-2-yl)hydrazine;hydrochloride Chemical compound Cl.CC1=CC=CC(NN)=N1 QLJACZBEDWORHA-UHFFFAOYSA-N 0.000 description 9
- 108091000080 Phosphotransferase Proteins 0.000 description 9
- 102000020233 phosphotransferase Human genes 0.000 description 9
- 239000006227 byproduct Substances 0.000 description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 8
- 239000004615 ingredient Substances 0.000 description 8
- 239000000203 mixture Substances 0.000 description 8
- 239000007864 aqueous solution Substances 0.000 description 7
- BHAAPTBBJKJZER-UHFFFAOYSA-N p-anisidine Chemical compound COC1=CC=C(N)C=C1 BHAAPTBBJKJZER-UHFFFAOYSA-N 0.000 description 7
- 238000010992 reflux Methods 0.000 description 7
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 101000799189 Homo sapiens Activin receptor type-1B Proteins 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 6
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 150000002148 esters Chemical class 0.000 description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- VQMSRUREDGBWKT-UHFFFAOYSA-N quinoline-4-carboxylic acid Chemical compound C1=CC=C2C(C(=O)O)=CC=NC2=C1 VQMSRUREDGBWKT-UHFFFAOYSA-N 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- MKYRMMMSZSVIGD-UHFFFAOYSA-N thieno[3,2-c]pyridine Chemical compound N1=CC=C2SC=CC2=C1 MKYRMMMSZSVIGD-UHFFFAOYSA-N 0.000 description 6
- KAESVJOAVNADME-UHFFFAOYSA-N 1H-pyrrole Natural products C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 5
- FTZQXOJYPFINKJ-UHFFFAOYSA-N 2-fluoroaniline Chemical group NC1=CC=CC=C1F FTZQXOJYPFINKJ-UHFFFAOYSA-N 0.000 description 5
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 5
- 150000001412 amines Chemical class 0.000 description 5
- 238000007796 conventional method Methods 0.000 description 5
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 5
- 238000009472 formulation Methods 0.000 description 5
- 238000002347 injection Methods 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 description 5
- 239000001301 oxygen Substances 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 4
- 102100034134 Activin receptor type-1B Human genes 0.000 description 4
- 206010001052 Acute respiratory distress syndrome Diseases 0.000 description 4
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 4
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 4
- 208000013616 Respiratory Distress Syndrome Diseases 0.000 description 4
- 208000011341 adult acute respiratory distress syndrome Diseases 0.000 description 4
- 201000000028 adult respiratory distress syndrome Diseases 0.000 description 4
- 125000002619 bicyclic group Chemical group 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 230000006378 damage Effects 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- NXPHGHWWQRMDIA-UHFFFAOYSA-M magnesium;carbanide;bromide Chemical compound [CH3-].[Mg+2].[Br-] NXPHGHWWQRMDIA-UHFFFAOYSA-M 0.000 description 4
- 229960000485 methotrexate Drugs 0.000 description 4
- 230000002062 proliferating effect Effects 0.000 description 4
- 108020003175 receptors Proteins 0.000 description 4
- 102000005962 receptors Human genes 0.000 description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 3
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 3
- 229920002261 Corn starch Polymers 0.000 description 3
- 206010017993 Gastrointestinal neoplasms Diseases 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
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- 229910052786 argon Inorganic materials 0.000 description 3
- 150000003851 azoles Chemical class 0.000 description 3
- 150000001721 carbon Chemical group 0.000 description 3
- 239000011203 carbon fibre reinforced carbon Substances 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
- 239000008120 corn starch Substances 0.000 description 3
- 229940099112 cornstarch Drugs 0.000 description 3
- 230000006870 function Effects 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- 230000014509 gene expression Effects 0.000 description 3
- AMWRITDGCCNYAT-UHFFFAOYSA-L hydroxy(oxo)manganese;manganese Chemical compound [Mn].O[Mn]=O.O[Mn]=O AMWRITDGCCNYAT-UHFFFAOYSA-L 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 208000014674 injury Diseases 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 210000004072 lung Anatomy 0.000 description 3
- 235000019359 magnesium stearate Nutrition 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 230000020477 pH reduction Effects 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- 210000003491 skin Anatomy 0.000 description 3
- JXTGICXCHWMCPM-UHFFFAOYSA-N (methylsulfinyl)benzene Chemical compound CS(=O)C1=CC=CC=C1 JXTGICXCHWMCPM-UHFFFAOYSA-N 0.000 description 2
- UZKWTJUDCOPSNM-UHFFFAOYSA-N 1-ethenoxybutane Chemical compound CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 2
- FUFLCEKSBBHCMO-UHFFFAOYSA-N 11-dehydrocorticosterone Natural products O=C1CCC2(C)C3C(=O)CC(C)(C(CC4)C(=O)CO)C4C3CCC2=C1 FUFLCEKSBBHCMO-UHFFFAOYSA-N 0.000 description 2
- JCCCMAAJYSNBPR-UHFFFAOYSA-N 2-ethylthiophene Chemical compound CCC1=CC=CS1 JCCCMAAJYSNBPR-UHFFFAOYSA-N 0.000 description 2
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 2
- PVMNPAUTCMBOMO-UHFFFAOYSA-N 4-chloropyridine Chemical compound ClC1=CC=NC=C1 PVMNPAUTCMBOMO-UHFFFAOYSA-N 0.000 description 2
- 200000000007 Arterial disease Diseases 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- MFYSYFVPBJMHGN-ZPOLXVRWSA-N Cortisone Chemical compound O=C1CC[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 MFYSYFVPBJMHGN-ZPOLXVRWSA-N 0.000 description 2
- MFYSYFVPBJMHGN-UHFFFAOYSA-N Cortisone Natural products O=C1CCC2(C)C3C(=O)CC(C)(C(CC4)(O)C(=O)CO)C4C3CCC2=C1 MFYSYFVPBJMHGN-UHFFFAOYSA-N 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 208000020564 Eye injury Diseases 0.000 description 2
- 208000004930 Fatty Liver Diseases 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 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 2
- 206010019708 Hepatic steatosis Diseases 0.000 description 2
- 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 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- ATUOYWHBWRKTHZ-UHFFFAOYSA-N Propane Chemical compound CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 description 2
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 108091005735 TGF-beta receptors Proteins 0.000 description 2
- NKANXQFJJICGDU-QPLCGJKRSA-N Tamoxifen Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 NKANXQFJJICGDU-QPLCGJKRSA-N 0.000 description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
- 102000016715 Transforming Growth Factor beta Receptors Human genes 0.000 description 2
- 102100023345 Tyrosine-protein kinase ITK/TSK Human genes 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- IAQRGUVFOMOMEM-UHFFFAOYSA-N butene Natural products CC=CC IAQRGUVFOMOMEM-UHFFFAOYSA-N 0.000 description 2
- 230000005907 cancer growth Effects 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 210000003169 central nervous system Anatomy 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 208000006990 cholangiocarcinoma Diseases 0.000 description 2
- 208000003167 cholangitis Diseases 0.000 description 2
- 230000007882 cirrhosis Effects 0.000 description 2
- 208000018631 connective tissue disease Diseases 0.000 description 2
- 229960004544 cortisone Drugs 0.000 description 2
- LDHQCZJRKDOVOX-NSCUHMNNSA-N crotonic acid Chemical compound C\C=C\C(O)=O LDHQCZJRKDOVOX-NSCUHMNNSA-N 0.000 description 2
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 2
- 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 2
- LPIQUOYDBNQMRZ-UHFFFAOYSA-N cyclopentene Chemical compound C1CC=CC1 LPIQUOYDBNQMRZ-UHFFFAOYSA-N 0.000 description 2
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 2
- 239000003995 emulsifying agent Substances 0.000 description 2
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 2
- 208000010706 fatty liver disease Diseases 0.000 description 2
- 125000002541 furyl group Chemical group 0.000 description 2
- 125000004415 heterocyclylalkyl group Chemical group 0.000 description 2
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 208000032839 leukemia Diseases 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- 201000006417 multiple sclerosis Diseases 0.000 description 2
- KRKPYFLIYNGWTE-UHFFFAOYSA-N n,o-dimethylhydroxylamine Chemical class CNOC KRKPYFLIYNGWTE-UHFFFAOYSA-N 0.000 description 2
- KSBMLBBPMOTYRO-UHFFFAOYSA-N n-methyl-1,3-benzothiazole-6-carboxamide Chemical class CNC(=O)C1=CC=C2N=CSC2=C1 KSBMLBBPMOTYRO-UHFFFAOYSA-N 0.000 description 2
- SVDVKEBISAOWJT-UHFFFAOYSA-N n-methylbenzenesulfonamide Chemical compound CNS(=O)(=O)C1=CC=CC=C1 SVDVKEBISAOWJT-UHFFFAOYSA-N 0.000 description 2
- IFDWCRYLTTWCCU-UHFFFAOYSA-N n-methylquinoline-4-carboxamide Chemical class C1=CC=C2C(C(=O)NC)=CC=NC2=C1 IFDWCRYLTTWCCU-UHFFFAOYSA-N 0.000 description 2
- 230000001537 neural effect Effects 0.000 description 2
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- ABOYDMHGKWRPFD-UHFFFAOYSA-N phenylmethanesulfonamide Chemical compound NS(=O)(=O)CC1=CC=CC=C1 ABOYDMHGKWRPFD-UHFFFAOYSA-N 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 230000035755 proliferation Effects 0.000 description 2
- 125000003226 pyrazolyl group Chemical group 0.000 description 2
- 239000000700 radioactive tracer Substances 0.000 description 2
- 230000000306 recurrent effect Effects 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 230000002784 sclerotic effect Effects 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 206010041823 squamous cell carcinoma Diseases 0.000 description 2
- 231100000240 steatosis hepatitis Toxicity 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- VKOINCMQZKBKHH-UHFFFAOYSA-N thieno[3,2-c]pyridine-2-carboxylic acid Chemical class N1=CC=C2SC(C(=O)O)=CC2=C1 VKOINCMQZKBKHH-UHFFFAOYSA-N 0.000 description 2
- IAQRGUVFOMOMEM-ONEGZZNKSA-N trans-but-2-ene Chemical compound C\C=C\C IAQRGUVFOMOMEM-ONEGZZNKSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 230000008733 trauma Effects 0.000 description 2
- PYOKUURKVVELLB-UHFFFAOYSA-N trimethyl orthoformate Chemical compound COC(OC)OC PYOKUURKVVELLB-UHFFFAOYSA-N 0.000 description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- 231100000216 vascular lesion Toxicity 0.000 description 2
- 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 1
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 1
- ITOFPJRDSCGOSA-KZLRUDJFSA-N (2s)-2-[[(4r)-4-[(3r,5r,8r,9s,10s,13r,14s,17r)-3-hydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]pentanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H](CC[C@]13C)[C@@H]2[C@@H]3CC[C@@H]1[C@H](C)CCC(=O)N[C@H](C(O)=O)CC1=CNC2=CC=CC=C12 ITOFPJRDSCGOSA-KZLRUDJFSA-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
- UWYVPFMHMJIBHE-OWOJBTEDSA-N (e)-2-hydroxybut-2-enedioic acid Chemical compound OC(=O)\C=C(\O)C(O)=O UWYVPFMHMJIBHE-OWOJBTEDSA-N 0.000 description 1
- KTZQTRPPVKQPFO-UHFFFAOYSA-N 1,2-benzoxazole Chemical compound C1=CC=C2C=NOC2=C1 KTZQTRPPVKQPFO-UHFFFAOYSA-N 0.000 description 1
- DMPZJACLHDWUFS-UHFFFAOYSA-N 1,3-benzothiazole-6-carboxylic acid Chemical compound OC(=O)C1=CC=C2N=CSC2=C1 DMPZJACLHDWUFS-UHFFFAOYSA-N 0.000 description 1
- FRNTUFQKHQMLSE-UHFFFAOYSA-N 1,3-benzoxazole-6-carboxylic acid Chemical compound OC(=O)C1=CC=C2N=COC2=C1 FRNTUFQKHQMLSE-UHFFFAOYSA-N 0.000 description 1
- RTBFRGCFXZNCOE-UHFFFAOYSA-N 1-methylsulfonylpiperidin-4-one Chemical compound CS(=O)(=O)N1CCC(=O)CC1 RTBFRGCFXZNCOE-UHFFFAOYSA-N 0.000 description 1
- BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical compound C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 description 1
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Natural products C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-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
- ZKLPARSLTMPFCP-OAQYLSRUSA-N 2-[2-[4-[(R)-(4-chlorophenyl)-phenylmethyl]-1-piperazinyl]ethoxy]acetic acid Chemical compound C1CN(CCOCC(=O)O)CCN1[C@@H](C=1C=CC(Cl)=CC=1)C1=CC=CC=C1 ZKLPARSLTMPFCP-OAQYLSRUSA-N 0.000 description 1
- SOHDPICLICFSOP-UHFFFAOYSA-N 2-bromo-6-methylpyridine Chemical compound CC1=CC=CC(Br)=N1 SOHDPICLICFSOP-UHFFFAOYSA-N 0.000 description 1
- WLJVXDMOQOGPHL-PPJXEINESA-N 2-phenylacetic acid Chemical compound O[14C](=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-PPJXEINESA-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
- FJKROLUGYXJWQN-UHFFFAOYSA-M 4-hydroxybenzoate Chemical compound OC1=CC=C(C([O-])=O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-M 0.000 description 1
- HHIZISRHAQPAMY-UHFFFAOYSA-N 5-bromo-1h-1,2,4-triazole Chemical compound BrC1=NC=NN1 HHIZISRHAQPAMY-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 206010000117 Abnormal behaviour Diseases 0.000 description 1
- 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 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- ZKLPARSLTMPFCP-UHFFFAOYSA-N Cetirizine Chemical compound C1CN(CCOCC(=O)O)CCN1C(C=1C=CC(Cl)=CC=1)C1=CC=CC=C1 ZKLPARSLTMPFCP-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- PMPVIKIVABFJJI-UHFFFAOYSA-N Cyclobutane Chemical compound C1CCC1 PMPVIKIVABFJJI-UHFFFAOYSA-N 0.000 description 1
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 1
- 201000003066 Diffuse Scleroderma Diseases 0.000 description 1
- 108010008165 Etanercept Proteins 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- 102000010834 Extracellular Matrix Proteins Human genes 0.000 description 1
- 108010037362 Extracellular Matrix Proteins Proteins 0.000 description 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
- 239000001828 Gelatine Substances 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 102000015696 Interleukins Human genes 0.000 description 1
- 108010063738 Interleukins Proteins 0.000 description 1
- ZCVMWBYGMWKGHF-UHFFFAOYSA-N Ketotifene Chemical compound C1CN(C)CCC1=C1C2=CC=CC=C2CC(=O)C2=C1C=CS2 ZCVMWBYGMWKGHF-UHFFFAOYSA-N 0.000 description 1
- 239000005411 L01XE02 - Gefitinib Substances 0.000 description 1
- 239000005551 L01XE03 - Erlotinib Substances 0.000 description 1
- 108010000817 Leuprolide Proteins 0.000 description 1
- 208000004852 Lung Injury Diseases 0.000 description 1
- FQISKWAFAHGMGT-SGJOWKDISA-M Methylprednisolone sodium succinate Chemical compound [Na+].C([C@@]12C)=CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2[C@@H](O)C[C@]2(C)[C@@](O)(C(=O)COC(=O)CCC([O-])=O)CC[C@H]21 FQISKWAFAHGMGT-SGJOWKDISA-M 0.000 description 1
- 229940121849 Mitotic inhibitor Drugs 0.000 description 1
- 102100025751 Mothers against decapentaplegic homolog 2 Human genes 0.000 description 1
- 101710143123 Mothers against decapentaplegic homolog 2 Proteins 0.000 description 1
- 102100025748 Mothers against decapentaplegic homolog 3 Human genes 0.000 description 1
- 101710143111 Mothers against decapentaplegic homolog 3 Proteins 0.000 description 1
- 102100025725 Mothers against decapentaplegic homolog 4 Human genes 0.000 description 1
- 101710143112 Mothers against decapentaplegic homolog 4 Proteins 0.000 description 1
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 1
- JOTDIFJUZPGAJU-UHFFFAOYSA-N N1=CC=C2SC(C(=O)NC)=CC2=C1 Chemical class N1=CC=C2SC(C(=O)NC)=CC2=C1 JOTDIFJUZPGAJU-UHFFFAOYSA-N 0.000 description 1
- RQQDJYROSYLPPK-UHFFFAOYSA-N N1=CC=CC2=CC=CC=C21.N1=CC=CC2=CC=CC=C21 Chemical compound N1=CC=CC2=CC=CC=C21.N1=CC=CC2=CC=CC=C21 RQQDJYROSYLPPK-UHFFFAOYSA-N 0.000 description 1
- 206010029113 Neovascularisation Diseases 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 239000004793 Polystyrene Substances 0.000 description 1
- 102000001253 Protein Kinase Human genes 0.000 description 1
- 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 1
- 206010038748 Restrictive cardiomyopathy Diseases 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 102000007374 Smad Proteins Human genes 0.000 description 1
- 108010007945 Smad Proteins Proteins 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 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
- 102000043168 TGF-beta family Human genes 0.000 description 1
- 108091085018 TGF-beta family Proteins 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
- GUGOEEXESWIERI-UHFFFAOYSA-N Terfenadine Chemical compound C1=CC(C(C)(C)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 GUGOEEXESWIERI-UHFFFAOYSA-N 0.000 description 1
- 101710183280 Topoisomerase Proteins 0.000 description 1
- JXLYSJRDGCGARV-WWYNWVTFSA-N Vinblastine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-WWYNWVTFSA-N 0.000 description 1
- AHIBWURJLGCHAY-UHFFFAOYSA-N [S].C1=CC=CC=C1 Chemical compound [S].C1=CC=CC=C1 AHIBWURJLGCHAY-UHFFFAOYSA-N 0.000 description 1
- KWKGMWRBLLAJNV-UHFFFAOYSA-N [S]C1CC1 Chemical compound [S]C1CC1 KWKGMWRBLLAJNV-UHFFFAOYSA-N 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N acrylic acid group Chemical group C(C=C)(=O)O NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- 150000003855 acyl compounds Chemical class 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 229960002964 adalimumab Drugs 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 125000002947 alkylene group Chemical group 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 description 1
- XCPGHVQEEXUHNC-UHFFFAOYSA-N amsacrine Chemical compound COC1=CC(NS(C)(=O)=O)=CC=C1NC1=C(C=CC=C2)C2=NC2=CC=CC=C12 XCPGHVQEEXUHNC-UHFFFAOYSA-N 0.000 description 1
- 229960001220 amsacrine Drugs 0.000 description 1
- 229960002932 anastrozole Drugs 0.000 description 1
- YBBLVLTVTVSKRW-UHFFFAOYSA-N anastrozole Chemical compound N#CC(C)(C)C1=CC(C(C)(C#N)C)=CC(CN2N=CN=C2)=C1 YBBLVLTVTVSKRW-UHFFFAOYSA-N 0.000 description 1
- JFCQEDHGNNZCLN-UHFFFAOYSA-N anhydrous glutaric acid Natural products OC(=O)CCCC(O)=O JFCQEDHGNNZCLN-UHFFFAOYSA-N 0.000 description 1
- 230000001387 anti-histamine Effects 0.000 description 1
- 230000003388 anti-hormonal effect Effects 0.000 description 1
- 230000000340 anti-metabolite Effects 0.000 description 1
- 239000000739 antihistaminic agent Substances 0.000 description 1
- 229940100197 antimetabolite Drugs 0.000 description 1
- 239000002256 antimetabolite Substances 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 230000003305 autocrine Effects 0.000 description 1
- 239000011324 bead Substances 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 125000005605 benzo group Chemical group 0.000 description 1
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- QRUDEWIWKLJBPS-UHFFFAOYSA-N benzotriazole Chemical compound C1=CC=C2N[N][N]C2=C1 QRUDEWIWKLJBPS-UHFFFAOYSA-N 0.000 description 1
- 239000012964 benzotriazole Substances 0.000 description 1
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 229960002537 betamethasone Drugs 0.000 description 1
- UREBDLICKHMUKA-DVTGEIKXSA-N betamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-DVTGEIKXSA-N 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 229960002092 busulfan Drugs 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
- SKKTUOZKZKCGTB-UHFFFAOYSA-N butyl carbamate Chemical compound CCCCOC(N)=O SKKTUOZKZKCGTB-UHFFFAOYSA-N 0.000 description 1
- ZZHGIUCYKGFIPV-UHFFFAOYSA-N butylcarbamic acid Chemical compound CCCCNC(O)=O ZZHGIUCYKGFIPV-UHFFFAOYSA-N 0.000 description 1
- 229940046731 calcineurin inhibitors Drugs 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 235000012241 calcium silicate Nutrition 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 125000002837 carbocyclic group Chemical group 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 238000004177 carbon cycle Methods 0.000 description 1
- JYYOBHFYCIDXHH-UHFFFAOYSA-N carbonic acid;hydrate Chemical compound O.OC(O)=O JYYOBHFYCIDXHH-UHFFFAOYSA-N 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 230000012292 cell migration Effects 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 230000036755 cellular response Effects 0.000 description 1
- 230000004715 cellular signal transduction Effects 0.000 description 1
- 230000005754 cellular signaling Effects 0.000 description 1
- 229960001803 cetirizine Drugs 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 208000020832 chronic kidney disease Diseases 0.000 description 1
- 238000010835 comparative analysis Methods 0.000 description 1
- 229940125810 compound 20 Drugs 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 208000035250 cutaneous malignant susceptibility to 1 melanoma Diseases 0.000 description 1
- 125000000392 cycloalkenyl group Chemical group 0.000 description 1
- 125000001047 cyclobutenyl group Chemical group C1(=CCC1)* 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001162 cycloheptenyl group Chemical group C1(=CCCCCC1)* 0.000 description 1
- URYYVOIYTNXXBN-UPHRSURJSA-N cyclooctene Chemical compound C1CCC\C=C/CC1 URYYVOIYTNXXBN-UPHRSURJSA-N 0.000 description 1
- 239000004913 cyclooctene Substances 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 229960004397 cyclophosphamide Drugs 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 229960003957 dexamethasone Drugs 0.000 description 1
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- WYACBZDAHNBPPB-UHFFFAOYSA-N diethyl oxalate Chemical compound CCOC(=O)C(=O)OCC WYACBZDAHNBPPB-UHFFFAOYSA-N 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- OBISXEJSEGNNKL-UHFFFAOYSA-N dinitrogen-n-sulfide Chemical compound [N-]=[N+]=S OBISXEJSEGNNKL-UHFFFAOYSA-N 0.000 description 1
- 150000002012 dioxanes Chemical class 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 229940020485 elidel Drugs 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 201000010048 endomyocardial fibrosis Diseases 0.000 description 1
- 239000002532 enzyme inhibitor Substances 0.000 description 1
- 229940125532 enzyme inhibitor Drugs 0.000 description 1
- AAKJLRGGTJKAMG-UHFFFAOYSA-N erlotinib Chemical compound C=12C=C(OCCOC)C(OCCOC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 AAKJLRGGTJKAMG-UHFFFAOYSA-N 0.000 description 1
- 229960001433 erlotinib Drugs 0.000 description 1
- 229960000403 etanercept Drugs 0.000 description 1
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 description 1
- 229960005420 etoposide Drugs 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 210000002744 extracellular matrix Anatomy 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 229960003592 fexofenadine Drugs 0.000 description 1
- RWTNPBWLLIMQHL-UHFFFAOYSA-N fexofenadine Chemical compound 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
- 239000003205 fragrance Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- XGALLCVXEZPNRQ-UHFFFAOYSA-N gefitinib Chemical compound C=12C=C(OCCCN3CCOCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 XGALLCVXEZPNRQ-UHFFFAOYSA-N 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 229960005277 gemcitabine Drugs 0.000 description 1
- SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 239000003292 glue Substances 0.000 description 1
- 125000005456 glyceride group Chemical group 0.000 description 1
- 210000002216 heart Anatomy 0.000 description 1
- 230000002008 hemorrhagic effect Effects 0.000 description 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 1
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 1
- DKAGJZJALZXOOV-UHFFFAOYSA-N hydrate;hydrochloride Chemical compound O.Cl DKAGJZJALZXOOV-UHFFFAOYSA-N 0.000 description 1
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
- 125000000717 hydrazino group Chemical group [H]N([*])N([H])[H] 0.000 description 1
- 150000002430 hydrocarbons Chemical group 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- ZQDWXGKKHFNSQK-UHFFFAOYSA-N hydroxyzine Chemical compound C1CN(CCOCCO)CCN1C(C=1C=CC(Cl)=CC=1)C1=CC=CC=C1 ZQDWXGKKHFNSQK-UHFFFAOYSA-N 0.000 description 1
- 229960000930 hydroxyzine Drugs 0.000 description 1
- 125000002632 imidazolidinyl group Chemical group 0.000 description 1
- 230000008629 immune suppression Effects 0.000 description 1
- 239000002955 immunomodulating agent Substances 0.000 description 1
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 229960000598 infliximab Drugs 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 229940084651 iressa Drugs 0.000 description 1
- UWKQSNNFCGGAFS-XIFFEERXSA-N irinotecan Chemical compound C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 UWKQSNNFCGGAFS-XIFFEERXSA-N 0.000 description 1
- 229960004768 irinotecan Drugs 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000005956 isoquinolyl group Chemical group 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 229960004958 ketotifen Drugs 0.000 description 1
- 229940043355 kinase inhibitor Drugs 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- VHOGYURTWQBHIL-UHFFFAOYSA-N leflunomide Chemical compound O1N=CC(C(=O)NC=2C=CC(=CC=2)C(F)(F)F)=C1C VHOGYURTWQBHIL-UHFFFAOYSA-N 0.000 description 1
- 229960000681 leflunomide Drugs 0.000 description 1
- GFIJNRVAKGFPGQ-LIJARHBVSA-N leuprolide Chemical compound CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)CC1=CC=C(O)C=C1 GFIJNRVAKGFPGQ-LIJARHBVSA-N 0.000 description 1
- 229960004338 leuprorelin Drugs 0.000 description 1
- 229960001508 levocetirizine Drugs 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 230000003908 liver function Effects 0.000 description 1
- JCCNYMKQOSZNPW-UHFFFAOYSA-N loratadine Chemical compound C1CN(C(=O)OCC)CCC1=C1C2=NC=CC=C2CCC2=CC(Cl)=CC=C21 JCCNYMKQOSZNPW-UHFFFAOYSA-N 0.000 description 1
- 229960003088 loratadine Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 210000005075 mammary gland Anatomy 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 210000002752 melanocyte Anatomy 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 229960004584 methylprednisolone Drugs 0.000 description 1
- 239000004530 micro-emulsion Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 206010028537 myelofibrosis Diseases 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 230000018791 negative regulation of catalytic activity Effects 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 125000004365 octenyl group Chemical group C(=CCCCCCC)* 0.000 description 1
- 238000006384 oligomerization reaction Methods 0.000 description 1
- 239000007935 oral tablet Substances 0.000 description 1
- 229940096978 oral tablet Drugs 0.000 description 1
- 150000004866 oxadiazoles Chemical class 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 230000003076 paracrine Effects 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- RGSFGYAAUTVSQA-UHFFFAOYSA-N pentamethylene Natural products C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- HKOOXMFOFWEVGF-UHFFFAOYSA-N phenylhydrazine Chemical compound NNC1=CC=CC=C1 HKOOXMFOFWEVGF-UHFFFAOYSA-N 0.000 description 1
- 229940067157 phenylhydrazine Drugs 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 1
- IBBMAWULFFBRKK-UHFFFAOYSA-N picolinamide Chemical class NC(=O)C1=CC=CC=N1 IBBMAWULFFBRKK-UHFFFAOYSA-N 0.000 description 1
- 229940023488 pill Drugs 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- KASDHRXLYQOAKZ-XDSKOBMDSA-N pimecrolimus Chemical compound C/C([C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@]2(O)O[C@@H]([C@H](C[C@H]2C)OC)[C@@H](OC)C[C@@H](C)C/C(C)=C/[C@H](C(C[C@H](O)[C@H]1C)=O)CC)=C\[C@@H]1CC[C@H](Cl)[C@H](OC)C1 KASDHRXLYQOAKZ-XDSKOBMDSA-N 0.000 description 1
- 125000005936 piperidyl group Chemical group 0.000 description 1
- 229940068918 polyethylene glycol 400 Drugs 0.000 description 1
- 229920002223 polystyrene Polymers 0.000 description 1
- 238000010837 poor prognosis Methods 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 229960005205 prednisolone Drugs 0.000 description 1
- OIGNJSKKLXVSLS-VWUMJDOOSA-N prednisolone Chemical compound O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OIGNJSKKLXVSLS-VWUMJDOOSA-N 0.000 description 1
- 229960004618 prednisone Drugs 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
- 230000001737 promoting effect Effects 0.000 description 1
- 239000001294 propane Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000000159 protein binding assay Methods 0.000 description 1
- 108060006633 protein kinase Proteins 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 229940107700 pyruvic acid Drugs 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000013049 sediment Substances 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 239000004575 stone Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 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
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 229960001603 tamoxifen Drugs 0.000 description 1
- NRUKOCRGYNPUPR-QBPJDGROSA-N teniposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@@H](OC[C@H]4O3)C=3SC=CC=3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 NRUKOCRGYNPUPR-QBPJDGROSA-N 0.000 description 1
- 229960001278 teniposide Drugs 0.000 description 1
- QCIWZIYBBNEPKB-UHFFFAOYSA-N tert-butyl(dimethyl)silane Chemical compound C[SiH](C)C(C)(C)C QCIWZIYBBNEPKB-UHFFFAOYSA-N 0.000 description 1
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- UCFGDBYHRUNTLO-QHCPKHFHSA-N topotecan Chemical compound C1=C(O)C(CN(C)C)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 UCFGDBYHRUNTLO-QHCPKHFHSA-N 0.000 description 1
- 229960000303 topotecan Drugs 0.000 description 1
- 230000026683 transduction Effects 0.000 description 1
- 238000010361 transduction Methods 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 229910000404 tripotassium phosphate Inorganic materials 0.000 description 1
- 235000019798 tripotassium phosphate Nutrition 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 150000003673 urethanes Chemical class 0.000 description 1
- 229960003048 vinblastine Drugs 0.000 description 1
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 1
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
- 229960004528 vincristine Drugs 0.000 description 1
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- UGOMMVLRQDMAQQ-UHFFFAOYSA-N xphos Chemical compound CC(C)C1=CC(C(C)C)=CC(C(C)C)=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 UGOMMVLRQDMAQQ-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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
-
- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
- A61K31/4155—1,2-Diazoles non condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/428—Thiazoles condensed with carbocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—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
- A61K31/47—Quinolines; Isoquinolines
- A61K31/472—Non-condensed isoquinolines, e.g. papaverine
- A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
- C07D233/58—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring nitrogen atoms
-
- 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
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- 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
- C07D403/14—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 three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/04—Drugs for skeletal disorders for non-specific disorders of the connective tissue
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Physical Education & Sports Medicine (AREA)
- Diabetes (AREA)
- Rheumatology (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Pulmonology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Hematology (AREA)
- Endocrinology (AREA)
- Urology & Nephrology (AREA)
- Hospice & Palliative Care (AREA)
- Reproductive Health (AREA)
- Dermatology (AREA)
- Oncology (AREA)
- Ophthalmology & Optometry (AREA)
- Gynecology & Obstetrics (AREA)
- Psychiatry (AREA)
- Immunology (AREA)
- Gastroenterology & Hepatology (AREA)
- Vascular Medicine (AREA)
- Emergency Medicine (AREA)
Abstract
本发明涉及一种具有抑制TGF‑β的受体ALK5的丝氨酸/苏氨酸激酶活性的功能的新型的吡唑衍生物,并且涉及一种药物组合物,所述药物组合物包含本发明的化合物作为其活性成分,可用于预防和/或治疗癌症、自身免疫疾病、纤维化疾病、炎性疾病、神经退行性疾病、传染病、肺病、心血管疾病或代谢疾病或与TGF家族信号传导活性降低有关的其他疾病。
Description
技术领域
本发明涉及新型吡唑衍生物化合物及其用途,特别是涉及具有ALK5活性抑制作用的新型吡唑衍生物、其药学上可接受的盐或溶剂合物,含有该化合物作为有效成分的药物组合物,及其用途。
背景技术
转化生长因子-β(TGF-β)信号以各种方式调节发展阶段和细胞活性,从而调节各种细胞应答,例如细胞增殖、分化、细胞迁移和细胞死亡。TGF-β具有至少3种亚型,名为TGF-β1、TGF-β2和TGF-β3。并且TGF-β1可被分为两种高度保守的单膜丝氨酸/苏氨酸激酶I型(ALK5)和制剂TGF-β受体。当通过配体诱导寡聚化时,制剂受体通过使ALK5的丝氨酸/苏氨酸残基过度磷酸化并产生Smad蛋白质结合位点来诱导ALK5的活化。活化的ALK5使Smad2和Smad3磷酸化以与Smad4形成复合物,并迁移到细胞核中以调节基因表达(Pennison,M.Pasche,B.,Curr Opin Oncol(2007)19,579-85,Attisano,L.,Wrana,JL.Science(2002)296,1646-47)。因此,TGF-β信号传导功能的异常引起许多人类疾病(例如,细胞外基质的沉积、炎症反应、纤维化功能障碍和晚期癌症)。
同时,TGF-β在癌症早期对癌症的形成有响应,并促进癌症生长和晚期肿瘤阶段的转移形成。对于癌细胞,TGF-β促进增殖、上皮间质转化(EMT)、穿透和转移,是癌症和癌症周围微环境之间的自分泌和旁分泌的主要调节剂,并且作用于微环境、新血管形成和免疫抑制的变化,其可有效抑制肿瘤增殖和癌转移。TGF-β在促进癌症生长中发挥的重要作用也表明有效的TGF-β表达与不良预后之间的相关性。
此外,器官和组织的纤维化被认为是TGF-β与疾病之间的相关因素。已知EMT活性是迄今为止引起纤维化的主要机制。细胞间信号传导途径的抑制剂是纤维素增生的有用治疗剂。已知其与肾脏、肝脏、肺、心脏、骨髓和皮肤等器官的纤维化高度相关。从这一点可以明显看出,抑制TGF-β可用于预防和治疗伴随纤维化的所有疾病,包括慢性肾病。
已发现本发明提供的化合物及其盐具有非常重要的药理学性质,同时具有高度耐受性。特别是,这些表现出TGF-β受体I激酶(ALK5)抑制特性。相应地,对于TGF-β家族的信号传导途径成分,已经需要开发抑制剂来治疗或预防与该信号传导途径的异常行为相关的疾病。
公开
技术问题
本发明涉及提供一种能够选择性地且有效地抑制ALK5和/或ALK4的化合物,或其药学上可接受的盐。
本发明还涉及提供一种包括所述化合物作为活性成分的药物组合物。
本发明还涉及提供一种药物组合物,所述药物组合物能够通过包括所述化合物作为活性成分,选择性地和有效地抑制ALK5和/或ALK4,从而预防或治疗由此介导的各种疾病。
技术方案
鉴于以上所述,本发明的一个实施方式提供由以下化学式1表示的化合物或其药学上可接受的盐:
[化学式1]
在化学式1中,
X是N或CH;
环A是C3-6亚环烷基、C6-10亚芳基、含有1至4个选自N、O和S的杂原子的C5-10亚杂芳基,或含有1至4个选自N,O和S的杂原子的非芳族稠合杂多环;
各个R1各自独立地为氢、卤素,或直链或支链C1-6烷基或卤代C1-6烷基,并且当存在多个R1时,它们彼此相同或不同;
各个R2各自独立地为
R3是氢、卤素、直链或支链C1-6烷基、直链或支链卤代C1-6烷基、C3-10环烷基、未取代或被R4取代的C3-10杂环烷基、C6-10杂双环烷基、直链或支链C2-6烯基、C2-6炔基、-(CH2)a-R4、-(CH2)a-OR4、-(CH2)a-O-(CH2)a-R4、-(CH2)a-S-(CH2)a-R4、-(CH2)a-O-(CH2)a-OR4、-(CH2)a-NR4R5、-(CH2)a-NO2、-(CH2)a-CN、-(CH2)a-COR4、-(CH2)a-CO2R4、-(CH2)a-CONR4R5、-(CH2)a-NHCOR4、-(CH2)a-SR4、-(CH2)a-NHSO2R4、-(CH2)aSOR6、-(CH2)a-SO2R6、-(CH2)a-SO2NHR6、-(CH2)a-SO(NH)R6或-(CH2)a-SO2NR4R5,或者当存在多个R3并且它们彼此相邻时,它们可以彼此连接以形成具有环A的5元或6元环,其中包括一个或多个选自N、O和S原子的杂原子,并且所述杂原子可以进一步被氧化;
R4和R5各自独立地为氢、直链或支链C1-6烷基、直链或支链卤代C1-6烷基、C3-10环烷基、C3-6环烯基、C1-6羰基、C6-12芳基、-(CH2)b-NR6R7,或饱和或部分不饱和的5元至10元含有1至4个选自N、O和S的杂原子的单环或双环的杂环烷基或杂芳基;
R6和R7各自独立地为氢、羟基、C1-6烷基、卤代C1-6烷基或C3-6环烷基;
a和b是0至4的整数;和
l、m和n各自独立地为0至4的整数。
本发明的另一个实施方式提供了药物组合物用于由ALK5和/或ALK4受体介导的疾病的预防或治疗的用途,所述药物组合物包括化学式1所示的化合物或其药学上可接受的盐,作为活性成分。
所述疾病特别优选地选自下组:纤维化疾病(例如,硬皮病、狼疮性肾炎、结缔组织病、伤口愈合、手术创伤、脊柱外伤、CNS损伤、急性肺损伤、特发性肺纤维化、慢性阻塞性肺病、成人呼吸窘迫综合征、急性肺损伤、药物性肺损伤、肾小球肾炎、糖尿病肾病、高血压引起的肾病、肝或胆纤维化、肝硬化、原发性胆汁硬化、脂肪肝、原发性硬化性胆管炎、复发性狭窄、心肌纤维化、眼损伤、纤维硬化、纤维性癌、纤维肌瘤、纤维瘤、纤维腺瘤、纤维肉瘤、嫁接动脉疾病和瘢痕疙瘩);神经多发性硬化脱水;阿尔茨海默氏病;大窦血管病变;和肿瘤细胞(例如,鳞状细胞癌、多发性骨髓瘤、黑素瘤、神经胶质瘤、胶质母细胞瘤、白血病,以及肺癌、乳腺癌、卵巢癌、宫颈癌、肝癌、胆管癌、胃肠道癌、胰腺癌、前列腺癌和头颈癌)。
优势效果
本发明所述的新型吡唑衍生物能够选择性地或同时地抑制由TGF-β介导的,特别是ALK5和/或ALK4介导的各种疾病。因此,本发明所述的新型衍生物可用于治疗或预防纤维化疾病(例如,硬皮病、狼疮性肾炎、结缔组织病、伤口愈合、手术创伤、脊柱外伤、CNS损伤、急性肺损伤、特发性肺纤维化、慢性阻塞性肺病、成人呼吸窘迫综合征、急性肺损伤、药物性肺损伤、肾小球肾炎、糖尿病肾病、高血压引起的肾病、肝或胆纤维化、肝硬化、原发性胆汁硬化、脂肪肝、原发性硬化性胆管炎、复发性狭窄、心肌纤维化、眼损伤、纤维硬化、纤维性癌、纤维肌瘤、纤维瘤、纤维腺瘤、纤维肉瘤、嫁接动脉疾病和瘢痕疙瘩);神经多发性硬化脱水;阿尔茨海默氏病;大窦血管病变;和肿瘤细胞(例如,鳞状细胞癌、多发性骨髓瘤、黑素瘤、神经胶质瘤、胶质母细胞瘤、白血病,以及肺癌、乳腺癌、卵巢癌、宫颈癌、肝癌、胆管癌、胃肠道癌、胰腺癌、前列腺癌和头颈癌)。
发明方式
下面列出的定义是用于描述本发明的各种术语的定义。除非另有限制,这些定义在整个说明书中单独使用或作为包括这些的术语的一部分使用。
除非另有说明,本说明书中使用的术语“卤素”是指氟、氯、溴、碘中的任何一种或全部。
除非另有说明,本说明书中使用的术语“烷基”是指由CnH2n+1表示的饱和直链或支链烃基,具体地,是指饱和的直链或支链烃基,各自包括碳原子数在1至6、1至8、1至10或1至20之间。这些基团的实例包括甲基、乙基、丙基、异丙基、正丁基、叔丁基、新戊基、正己基、庚基和辛基,但不限于此。
除非另有说明,本说明书中使用的术语“烯基”是指衍生自具有至少一个碳碳双键的不饱和直链或支链烃部分的单价基团,具体地,是指不饱和的直链或支链单价基团,各自包括碳原子数在2至6、2至8、2至10或2至20之间。其实例包括乙烯基、丙烯基、丁烯基、1-甲基-2-丁烯-1-基、庚烯基和辛烯基,但不限于此。
除非另有说明,本说明书中使用的术语“环烷基”是指衍生自单环或多环饱和或部分不饱和碳环化合物的单价基团。例如,C3-C8-环烷基的实例包括但不限于环丙基、环丁基、环戊基、环己基、环戊基和环辛基;C3-C12-环烷基的实例包括但不限于环丙基、环丁基、环戊基、环己基、双环[2.2.1]庚基和双环[2.2.2]辛基。还包括衍生自通过将至少一个碳碳双键取代氢原子而获得的单环或多环的碳环化合物的单价基团。这类基团的实例包括但不限于环丙烯基、环丁烯基、环戊烯基、环己烯基和环庚烯基、环辛烯基等。
除非另有说明,本说明书中使用的术语“环烯基”是指含有3至6个碳原子且在环中具有碳碳双键的部分不饱和碳环。这类基团的实例包括但不限于环戊烯基、环己烯基等。
除非另有说明,本说明书中使用的术语“芳基”是指具有稠合或非稠合的一个或多个芳环的单环或多环碳环系统,但不限于此,包括苯基、萘基、四氢萘基、茚基、壬基等。
除非另有说明,本说明书中使用的术语“杂环烷基”是指饱和或部分不饱和的3元至10元单环或多环取代基,其含有一个或多个,例如,1至4个选自N、O和S的杂原子。单环杂环烷基的实例可包括哌啶基、吗啉基、硫代吗啉基、吡咯烷基、咪唑烷基、四氢呋喃基、哌嗪基和与其类似的基团,但不限于此。
除非另有说明,本说明书中使用的术语“杂芳基”是指含有一个或多个,例如,1至4个选自O、N和S的杂原子的5元至12元单环或双环或更高芳族基团。单环杂芳基的实例可包括噻唑基、恶唑基、苯硫基、呋喃基、吡咯基、咪唑基、异恶唑基、吡唑基、三唑基、噻二唑基、四唑基、恶二唑基、吡啶基、哒嗪基、嘧啶基、吡嗪基和与其类似的基团,但不限于此。双环杂芳基的实例可包括吲哚基、苯并噻吩基、苯并呋喃基、苯并咪唑基、苯并恶唑基、苯并异恶唑基、苯并噻唑基、苯并噻二唑基、苯并三唑基、喹啉基、异喹啉基、呋喃基、呋喃吡啶基和与其类似的基团,但不限于此。
本说明书中使用的术语“非芳族稠合杂多环”是指具有两个或多个彼此稠合的环的基团,包括选自N、O和S的杂原子作为除碳之外的成环原子,并且使整个分子表现出非芳香性(例如,具有5至10个核心原子)。非芳族稠合杂多环的实例可包括苯并[d][1,3]二氧杂环戊烯等,但不限于此。
在下文中,将更详细地描述本发明。
本发明的一个实施方式提供了一种以下化学式1的化合物或其药学上可接受的盐:
[化学式1]
在化学式1中,
X是N或CH;
环A是C3-6亚环烷基、C6-10亚芳基、含有1至4个选自N、O和S的杂原子的C5-10亚杂芳基,或含有1至4个选自N,O和S的杂原子的非芳族稠合杂多环;
各个R1各自独立地为氢、卤素,或直链或支链C1-6烷基或卤代C1-6烷基,并且当存在多个R1时,它们彼此相同或不同;
各个R2各自独立地为
R3是氢、卤素、直链或支链C1-6烷基、直链或支链卤代C1-6烷基、C3-10环烷基、未取代或被R4取代的C3-10杂环烷基、C6-10杂双环烷基、直链或支链C2-6烯基、C2-6炔基、-(CH2)a-R4、-(CH2)a-OR4、-(CH2)a-O-(CH2)a-R4、-(CH2)a-S-(CH2)a-R4、-(CH2)a-O-(CH2)a-OR4、-(CH2)a-NR4R5、-(CH2)a-NO2、-(CH2)a-CN、-(CH2)a-COR4、-(CH2)a-CO2R4、-(CH2)a-CONR4R5、-(CH2)a-NHCOR4、-(CH2)a-SR4、-(CH2)a-NHSO2R4、-(CH2)aSOR6、-(CH2)a-SO2R6、-(CH2)a-SO2NHR6、-(CH2)a-SO(NH)R6或-(CH2)a-SO2NR4R5,或者当存在多个R3并且它们彼此相邻时,它们可以彼此连接以形成具有环A的5元或6元环,其中包括一个或多个选自N、O和S原子的杂原子,并且所述杂原子可以进一步被氧化;
R4和R5各自独立地为氢、直链或支链C1-6烷基、直链或支链卤代C1-6烷基、C3-10环烷基、C3-6环烯基、C1-6羰基、C6-12芳基、-(CH2)b-NR6R7,或饱和或部分不饱和的5元至10元含有1至4个选自N、O和S的杂原子的单环或双环的杂环烷基或杂芳基;
R6和R7各自独立地为氢、羟基、C1-6烷基、卤代C1-6烷基或C3-6环烷基;
a和b是0至4的整数;和
l、m和n各自独立地为0至4的整数。
在本发明的一个具体实施方式中,X可以是N,R1可以是C1-6烷基。
在本发明的一个具体实施方式中,环A可以是苯基、吡唑基、吡啶基或苯并[d][1,3]二氧杂环戊烯。
在本发明的一个具体实施方式中,化学式1的化合物可以是选自下组的化合物,但不限于此:
(1)5-(苯并[d]噻唑-6-基)-N-(4-甲氧基苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(2)5-(苯并[d]噻唑-6-基)-N-(4-乙氧基苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(3)5-(苯并[d]噻唑-6-基)-N-(4-(环丙基甲氧基)苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(4)5-(苯并[d]噻唑-6-基)-N-(4-(2-甲氧基乙氧基)苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(5)5-(苯并[d]噻唑-6-基)-1-(6-甲基吡啶-2-基)-N-(4-(三氟甲氧基)苯基)-1H-吡唑-3-羧酰胺;
(6)5-(苯并[d]噻唑-6-基)-N-(4-(苄氧基)苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(7)N-(苯并[d][1,3]二氧杂环戊烯-5-基)-5-(苯并[d]噻唑-6-基)-1-(6-甲基吡啶-2-基)-1-H-吡唑-3-羧酰胺;
(8)5-(苯并[d]噻唑-6-基)-N-(4-氟-3-甲氧基苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(9)5-(苯并[d]噻唑-6-基)-N-(2-氟-4-甲氧基苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(10)5-(苯并[d]噻唑-6-基)-N-(3-氟-4-甲氧基苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(11)5-(苯并[d]噻唑-6-基)-N-(3-氨基苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(12)5-(苯并[d]噻唑-6-基)-N-(3-(甲基氨基)苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(13)5-(苯并[d]噻唑-6-基)-N-(4-(二甲基氨基)苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(14)5-(苯并[d]噻唑-6-基)-1-(6-甲基吡啶-2-基)-N-(4-硝基苯基)-1H-吡唑-3-羧酰胺;
(15)5-(苯并[d]噻唑-6-基)-N-(4-((2-(二甲基氨基)乙基)(甲基)氨基)苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(16)5-(苯并[d]噻唑-6-基)-N-(4-(3-(二甲基氨基)吡咯烷-1-基)苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(17)5-(苯并[d]噻唑-6-基)-N-(3-氯-4-(八氢-6H-吡咯并[3,4-b]吡啶-6-基)苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(18)5-(苯并[d]噻唑-6-基)-1-(6-甲基吡啶-2-基)-N-苯基-1H-吡唑-3-羧酰胺;
(19)5-(苯并[d]噻唑-6-基)-N-(3-甲苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(20)5-(苯并[d]噻唑-6-基)-1-(6-甲基吡啶-2-基)-N-(3-乙烯基苯基)-1H-吡唑-3-羧酰胺;
(21)5-(苯并[d]噻唑-6-基)-N-(3-(三氟甲基)苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(22)5-(苯并[d]噻唑-6-基)-N-(3-(氰基苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(23)5-(苯并[d]噻唑-6-基)-N-(3-乙酰基苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(24)3-(5-(苯并[d]噻唑-6-基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺)苯乙酸酯;
(25)5-(苯并[d]噻唑-6-基)-N-(4-(甲基氨基甲酰基)苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(26)5-(苯并[d]噻唑-6-基)-N-(4-乙酰氨基苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(27)5-(苯并[d]噻唑-6-基)-N-(2-氟苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(28)5-(苯并[d]噻唑-6-基)-N-(3-氟苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(29)5-(苯并[d]噻唑-6-基)-N-(4-氟苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(30)5-(苯并[d]噻唑-6-基)-N-(3,4-二氟苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(31)5-(苯并[d]噻唑-6-基)-N-(2-氯苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(32)5-(苯并[d]噻唑-6-基)-N-(3-氯苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(33)5-(苯并[d]噻唑-6-基)-N-(4-氯苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(34)5-(苯并[d]噻唑-6-基)-N-(4-溴苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(35)5-(苯并[d]噻唑-6-基)-1-(6-甲基吡啶-2-基)-N-(3-(甲硫基)苯基)-1H-吡唑-3-羧酰胺;
(36)5-(苯并[d]噻唑-6-基)-1-(6-甲基吡啶-2-基)-N-(4-(甲硫基)苯基)-1H-吡唑-3-羧酰胺;
(37)5-(苯并[d]噻唑-6-基)-N-(4-(环丙基硫基)苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(38)5-(苯并[d]噻唑-6-基)-1-(6-甲基吡啶-2-基)-N-(3-(甲基亚磺酰基)苯基)-1H-吡唑-3-羧酰胺;
(39)5-(苯并[d]噻唑-6-基)-1-(6-甲基吡啶-2-基)-N-(4-(甲基亚磺酰基)苯基)-1H-吡唑-3-羧酰胺;
(40)5-(苯并[d]噻唑-6-基)-1-(6-甲基吡啶-2-基)-N-(3-(甲基磺酰基)苯基)-1H-吡唑-3-羧酰胺;
(41)5-(苯并[d]噻唑-6-基)-1-(6-甲基吡啶-2-基)-N-(4-(甲基磺酰基)苯基)-1H-吡唑-3-羧酰胺;
(42)5-(苯并[d]噻唑-6-基)-1-(6-甲基吡啶-2-基)-N-(4-(丙基磺酰基)苯基)-1H-吡唑-3-羧酰胺;
(43)5-(苯并[d]噻唑-6-基)-N-(4-(环丙基磺酰基)苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(44)5-(苯并[d]噻唑-6-基)-N-(2-氟-4-(甲基磺酰基)苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(45)5-(苯并[d]噻唑-6-基)-1-(6-甲基吡啶-2-基)-N-(3-氨磺酰基苯基)-1H-吡唑-3-羧酰胺;
(46)5-(苯并[d]噻唑-6-基)-1-(6-甲基吡啶-2-基)-N-(4-氨磺酰基苯基)-1H-吡唑-3-羧酰胺;
(47)5-(苯并[d]噻唑-6-基)-1-(6-甲基吡啶-2-基)-N-(3-(N-甲基氨磺酰基)苯基)-1H-吡唑-3-羧酰胺;
(48)5-(苯并[d]噻唑-6-基)-1-(6-甲基吡啶-2-基)-N-(4-(N-甲基氨磺酰基)苯基)-1H-吡唑-3-羧酰胺;
(49)5-(苯并[d]噻唑-6-基)-N-(3-(N-环丙基氨磺酰基)苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(50)5-(苯并[d]噻唑-6-基)-N-(4-(N-环丙基氨磺酰基)苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(51)5-(苯并[d]噻唑-6-基)-N-(3-(N,N-二甲基氨磺酰基)苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(52)5-(苯并[d]噻唑-6-基)-N-(4-(N,N-二甲基氨磺酰基)苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(53)5-(苯并[d]噻唑-6-基)-1-(6-甲基吡啶-2-基)-N-(3-(甲基磺酰氨基)苯基)-1H-吡唑-3-羧酰胺;
(54)5-(苯并[d]噻唑-6-基)-N-(3-(环丙烷磺酰氨基)苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(55)5-(苯并[d]噻唑-6-基)-N-(4-(环丙烷磺酰氨基)苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(56)4-(5-(苯并[d]噻唑-6-基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺)苯磺酸;
(57)5-(苯并[d]噻唑-6-基)-1-(6-甲基吡啶-2-基)-N-(4-((三氟甲基)磺酰基)苯基)-1H-吡唑-3-羧酰胺;
(58)5-(苯并[d]噻唑-6-基)-1-(6-甲基吡啶-2-基)-N-(4-(N-(2,2,2-)三氟乙基)氨磺酰基)苯基)-1H-吡唑-3-羧酰胺;
(59)5-(苯并[d]噻唑-6-基)-1-(6-甲基吡啶-2-基)-N-(4-((甲基磺酰基)甲基)苯基)-1H-吡唑-3-羧酰胺;
(60)5-(苯并[d]噻唑-6-基)-1-(6-甲基吡啶-2-基)-N-(3-(氨磺酰基甲基)苯基)-1H-吡唑-3-羧酰胺;
(61)5-(苯并[d]噻唑-6-基)-1-(6-甲基吡啶-2-基)-N-(4-(氨磺酰基甲基)苯基)-1H-吡唑-3-羧酰胺;
(62)5-(苯并[d]噻唑-6-基)-N-(4-氟-3-(氨磺酰基甲基)苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(63)5-(苯并[d]噻唑-6-基)-N-(4-((1,1-二氧代四氢噻吩-3-基)氨基)苯基)-1-(6-甲基吡啶-吡啶-2-基)-1H-吡唑-3-羧酰胺;
(64)5-(苯并[d]噻唑-6-基)-1-(6-甲基吡啶-2-基)-N-(吡啶-4-基)-1H-吡唑-3-羧酰胺;
(65)5-(苯并[d]噻唑-6-基)-N-(6-甲氧基吡啶-3-基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(66)5-(苯并[d]噻唑-6-基)-N-(2-甲氧基吡啶-4-基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(67)5-(苯并[d]噻唑-6-基)-N-(6-(甲硫基)吡啶-3-基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(68)5-(苯并[d]噻唑-6-基)-1-(6-甲基吡啶-2-基)-N-(6-(甲基磺酰基)吡啶-2-基)-1H-吡唑-3-羧酰胺;
(69)5-(苯并[d]噻唑-6-基)-N-(6-(甲基磺酰基)吡啶-3-基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(70)5-(苯并[d]噻唑-6-基)-1-(6-甲基吡啶-2-基)-N-(2-(甲基磺酰基)吡啶-4-基)-1H-吡唑-3-羧酰胺;
(71)5-(苯并[d]噻唑-6-基)-N-(6-氟吡啶-3-基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(72)5-(苯并[d]噻唑-6-基)-N-(2-氟吡啶-4-基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(73)5-(苯并[d]噻唑-6-基)-N-(6-氯吡啶-3-基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(74)5-(苯并[d]噻唑-6-基)-N-(2-氯吡啶-4-基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(75)5-(苯并[d]噻唑-6-基)-1-(6-甲基吡啶-2-基)-N-(噻唑-2-基)-1H-吡唑-3-羧酰胺;
(76)5-(苯并[d]噻唑-6-基)-N-苄基-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(77)5-(苯并[d]噻唑-6-基)-N-(2-氟苄基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(78)5-(苯并[d]噻唑-6-基)-N-(3-氟苄基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(79)5-(苯并[d]噻唑-6-基)-N-(4-氟苄基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(80)5-(苯并[d]噻唑-6-基)-1-(6-甲基吡啶-2-基)-N-(1-(甲基磺酰基)-1H-吡唑-4-基)-1H-吡唑-3-羧酰胺;
(81)5-(苯并[d]噻唑-6-基)-N-(1-(环丙基磺酰基)-1H-吡唑-4-基)-1-(6-甲基吡啶-2-基))-1H-吡唑-3-羧酰胺;
(82)5-(苯并[d]噻唑-6-基)-N-(3-羟基苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(83)5-(苯并[d]噻唑-6-基)-N-(4-羟基苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(84)5-(苯并[d]噻唑-6-基)-N-(3-(羟甲基)苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(85)5-(苯并[d]噻唑-6-基)-N-(4-(羟甲基)苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(86)N-(4-氨基苯基)-5-(苯并[d]噻唑-6-基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(87)5-(苯并[d]噻唑-6-基)-N-(4-(丁基氨基)苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(88)5-(苯并[d]噻唑-6-基)-N-(4-(环丙基氨基)苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(89)5-(苯并[d]噻唑-6-基)-1-(6-甲基吡啶-2-基)-N-(4-(S-甲基磺酰亚胺基)苯基)-1H-吡唑-3-羧酰胺;
(90)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-N-(2-甲氧基苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(91)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-N-(3-甲氧基苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(92)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-N-(2-甲氧基苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(93)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-N-(4-羟基苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(94)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-N-(4-异丙基苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(95)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-N-(4-(2-甲氧基乙氧基)苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(96)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-N-(苯并[d][1,3]二氧杂环戊烯-5-基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(97)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-N-(2-氟-4-甲氧基苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(98)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-N-(3-氟-4-甲氧基苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(99)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-1-(6-甲基吡啶-2-基)-N-(2-(三氟甲氧基)苯基)-1H-吡唑-3-羧酰胺;
(100)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-1-(6-甲基吡啶-2-基)-N-(3-(三氟甲氧基)苯基)-1H-吡唑-3-羧酰胺;
(101)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-1-(6-甲基吡啶-2-基)-N-(4-(三氟甲氧基)苯基)-1H-吡唑-3-羧酰胺;
(102)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-N-(3-(二甲基氨基)苯基)-1-(6-甲基吡啶-2-基)-1-H-吡唑-3-羧酰胺;
(103)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-N-(4-氨基苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(104)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-N-(4-(二甲基氨基)苯基)-1-(6-甲基吡啶-2-基)-1-H-吡唑-3-羧酰胺;
(105)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-N-(4-(吡咯烷-1-基)苯基)1-(6甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(106)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-N-(4-((2-(二甲基氨基)乙基)(甲基)氨基)苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(107)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-N-(4-(4-甲基哌嗪-1-基)苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(108)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-N-(4-(4-乙酰基哌嗪-1-基)苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(109)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-N-(4-((1,1-二氧代四氢噻吩-3-基)氨基)苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(110)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-N-(4-乙酰氨基苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(111)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-N-(4-((二甲基氨基)甲基)苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(112)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-N-(2-(甲基氨基甲酰基)苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(113)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-N-(4-(甲基氨基甲酰基)苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(114)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-1-(6-甲基吡啶-2-基)-N-苯基-1H-吡唑-3-羧酰胺;
(115)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-1-(6-甲基吡啶-2-基)-N-(邻-甲苯基)-1H-吡唑-3-羧酰胺;
(116)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-1-(6-甲基吡啶-2-基)-N-(间-甲苯基)-1H-吡唑-3-羧酰胺;
(117)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-1-(6-甲基吡啶-2-基)-N-(对-甲苯基)-1H-吡唑-3-羧酰胺;
(118)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-1-(6-甲基吡啶-2-基)-N-(3-(三氟甲基)苯基)-1H-吡唑-3-羧酰胺;
(119)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-1-(6-甲基吡啶-2-基)-N-(4-乙烯基苯基)-1H-吡唑-3-羧酰胺;
(120)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-N-(3-氰基苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(121)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-N-(4-氰基苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(122)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-N-(3-乙酰基苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(123)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-N-(4-乙酰基苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(124)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-N-(2-氟苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(125)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-N-(3-氟苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(126)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-N-(4-氟苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(127)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-N-(2-氯苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(128)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-N-(3-氯苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(129)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-N-(4-氯苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(130)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-N-(2-溴苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(131)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-N-(3-溴苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(132)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-N-(4-溴苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(133)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-N-(2,3-二氟苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(134)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-N-(2,4-二氟苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(135)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-N-(2,5-二氟苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(136)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-N-(3,4-二氟苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(137)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-N-(3,5-二氟苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(138)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-N-(3-氯-2-氟苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(139)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-N-(4-氯-2-氟苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(140)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-N-(3-氯-4-氟苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(141)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-N-(3,4-二氯苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(142)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-N-(2-溴-4-氟苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(143)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-N-(3-(甲氧基硫基)苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(144)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-N-(4-(甲氧基硫基)苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(145)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-N-(3-(甲基亚磺酰基)苯基)-1-(6-甲基吡啶-吡啶-2-基)-1H-吡唑-3-羧酰胺;
(146)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-N-(4-(甲基亚磺酰基)苯基)-1-(6-甲基吡啶-吡啶-2-基)-1H-吡唑-3-羧酰胺;
(147)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-N-(4-(甲基磺酰基)苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(148)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-N-(4-氨磺酰基苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(149)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-N-(4-(S-甲基磺亚胺酰基)苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(150)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-N-(4-(丙基磺酰基)苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(151)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-N-(4-(丙基磺酰基)苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(152)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-N-(6-氟吡啶-3-基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(153)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-N-(6-氯吡啶-3-基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(154)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-N-(6-甲氧基吡啶-3-基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(155)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-N-(2-氟苄基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(156)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-N-(3-氟苄基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(157)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-N-(4-氟苄基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(158)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-N-(3-甲氧基苄基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(159)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-N-(4-甲氧基苄基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(160)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-N-(4-(二甲基氨基)苄基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(161)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-N-(-乙酰氨基苄基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(162)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-1-(6-甲基吡啶-2-基)-N-(1-(甲基磺酰基)-1H-吡唑-4-基)-1H-吡唑-3-羧酰胺;
(163)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-N-(1-环丙基磺酰基)-1H-吡唑-4-基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(164)N-(4-甲氧基苯基)-1-(6-甲基吡啶-2-基)-5-(喹喔啉-6-基)-1H-吡唑-3-羧酰胺;
(165)N-(3-甲氧基苯基)-1-(6-甲基吡啶-2-基)-5-(喹喔啉-6-基)-1H-吡唑-3-羧酰胺;
(166)N-(2-甲氧基苯基)-1-(6-甲基吡啶-2-基)-5-(喹喔啉-6-基)-1H-吡唑-3-羧酰胺;
(167)N-(4-(2-甲氧基乙氧基)苯基)-1-(6-甲基吡啶-2-基)-5-(喹喔啉-6-基)-1H-吡唑-3-羧酰胺;
(168)N-(苯并[d][1,3]二氧杂环戊烯-5-基)-1-(6-甲基吡啶-2-基)-5-(喹喔啉-6-基)-1H-吡唑-3-羧酰胺;
(169)N-(2,3-二氢苯并[b][1,4]二恶英-6-基)-1-(6-甲基吡啶-2-基)-5-(喹喔啉-6-基)-1H-吡唑-3-羧酰胺;
(170)N-(4-(二甲基氨基)苯基)-1-(6-甲基吡啶-2-基)-5-(喹喔啉-6-基)-1H-吡唑-3-羧酰胺;
(171)1-(6-甲基吡啶-2-基)-N-(4-吗啉代苯基)-5-(喹喔啉-6-基)-1H-吡唑-3-羧酰胺;
(172)N-(4-(4-甲基哌嗪-1-基)苯基)-1-(6-甲基吡啶-2-基)-5-(喹喔啉-6-基)-1H-吡唑-3-羧酰胺;
(173)N-(4-(4-乙酰基哌嗪-1-基)苯基)-1-(6-甲基吡啶-2-基)-5-(喹喔啉-6-基)-1H-吡唑-3-羧酰胺;
(174)N-(4-氰基苯基)-1-(6-甲基吡啶-2-基)-5-(喹喔啉-6-基)-1H-吡唑-3-羧酰胺;
(175)N-(3-氰基苯基)-1-(6-甲基吡啶-2-基)-5-(喹喔啉-6-基)-1H-吡唑-3-羧酰胺;
(176)N-(2-氰基苯基)-1-(6-甲基吡啶-2-基)-5-(喹喔啉-6-基)-1H-吡唑-3-羧酰胺;
(177)1-(6-甲基吡啶-2-基)-N-(4-(吗啉代甲基)苯基)-5-(喹喔啉-6-基)-1H-吡唑-3-羧酰胺;
(178)N-(4-乙酰基苯基)-1-(6-甲基吡啶-2-基)-5-(喹喔啉-6-基)-1H-吡唑-3-羧酰胺;
(179)N-(3-乙酰基苯基)-1-(6-甲基吡啶-2-基)-5-(喹喔啉-6-基)-1H-吡唑-3-羧酰胺;
(180)1-(6-甲基吡啶-2-基)-5-(喹喔啉-6-基)-N-(4-(三氟甲基)苯基)-1H-吡唑-3-羧酰胺;
(181)1-(6-甲基吡啶-2-基)-5-(喹喔啉-6-基)-N-(3-(三氟甲基)苯基)-1H-吡唑-3-羧酰胺;
(182)N-(4-(甲基氨基甲酰基)苯基)-1-(6-甲基吡啶-2-基)-5-(喹喔啉-6-基)-1H-吡唑-3-羧酰胺;
(183)N-(4-氟苯基)-1-(6-甲基吡啶-2-基)-5-(喹喔啉-6-基)-1H-吡唑-3-羧酰胺;
(184)N-(3-氟苯基)-1-(6-甲基吡啶-2-基)-5-(喹喔啉-6-基)-1H-吡唑-3-羧酰胺;
(185)N-(2-氟苯基)-1-(6-甲基吡啶-2-基)-5-(喹喔啉-6-基)-1H-吡唑-3-羧酰胺;
(186)N-(3,4-二氟苯基)-1-(6-甲基吡啶-2-基)-5-(喹喔啉-6-基)-1H-吡唑-3-羧酰胺;
(187)N-(2,4-二氟苯基)-1-(6-甲基吡啶-2-基)-5-(喹喔啉-6-基)-1H-吡唑-3-羧酰胺;
(188)N-(2,3-二氟苯基)-1-(6-甲基吡啶-2-基)-5-(喹喔啉-6-基)-1H-吡唑-3-羧酰胺;
(189)N-(4-氯苯基)-1-(6-甲基吡啶-2-基)-5-(喹喔啉-6-基)-1H-吡唑-3-羧酰胺;
(190)N-(2-氯苯基)-1-(6-甲基吡啶-2-基)-5-(喹喔啉-6-基)-1H-吡唑-3-羧酰胺;
(191)N-(4-溴苯基)-1-(6-甲基吡啶-2-基)-5-(喹喔啉-6-基)-1H-吡唑-3-羧酰胺;
(192)N-(6-甲氧基吡啶-3-基)-1-(6-甲基吡啶-2-基)-5-(喹喔啉-6-基)-1H-吡唑-3-羧酰胺;
(193)N-(4-甲氧基苄基)-1-(6-甲基吡啶-2-基)-5-(喹喔啉-6-基)-1H-吡唑-3-羧酰胺;
(194)N-(4-氰基苄基)-1-(6-甲基吡啶-2-基)-5-(喹喔啉-6-基)-1H-吡唑-3-羧酰胺;
(195)N-(3-乙酰基苄基)-1-(6-甲基吡啶-2-基)-5-(喹喔啉-6-基)-1H-吡唑-3-羧酰胺;
(196)N-(4-氟苄基)-1-(6-甲基吡啶-2-基)-5-(喹喔啉-6-基)-1H-吡唑-3-羧酰胺;
(197)N-(3-氟苄基)-1-(6-甲基吡啶-2-基)-5-(喹喔啉-6-基)-1H-吡唑-3-羧酰胺;
(198)N-(2-氟苄基)-1-(6-甲基吡啶-2-基)-5-(喹喔啉-6-基)-1H-吡唑-3-羧酰胺;
(199)N-(4-氯苄基)-1-(6-甲基吡啶-2-基)-5-(喹喔啉-6-基)-1H-吡唑-3-羧酰胺;
(200)N-(3-氯苄基)-1-(6-甲基吡啶-2-基)-5-(喹喔啉-6-基)-1H-吡唑-3-羧酰胺;
(201)N-(2-氯苄基)-1-(6-甲基吡啶-2-基)-5-(喹喔啉-6-基)-1H-吡唑-3-羧酰胺;
(202)N-(2-氟苯基)-5-(喹喔啉-6-基)-1-(m-甲苯基)-1H-吡唑-3-羧酰胺;
(203)1-(5-氯-2-氟苯基)-N-(4-甲氧基苯基)-5-(喹喔啉-6-基)-1H-吡唑-3-羧酰胺;
(204)1-(5-氯-2-氟苯基)-N-(4-(二甲基氨基)苯基)-5-(喹喔啉-6-基)-1H-吡唑-3-羧酰胺;
(205)N-(4-甲氧基苯基)-5-(喹喔啉-6-基)-1-(6-三氟甲基)吡啶-2-基)-1H-吡唑-3-羧酰胺;
(206)N-(4-(二甲基氨基)苯基)-5-(喹喔啉-6-基)-1-(6-三氟甲基)吡啶-2-基)-1H-吡唑-3-羧酰胺;
(207)1-(6-溴吡啶-2-基)-N-(4-甲氧基苯基)-5-(喹喔啉-6-基)-1H-吡唑-3-羧酰胺;
(208)1-(6-溴吡啶-2-基)-N-(4-(二甲基氨基)苯基)-5-(喹喔啉-6-基)-1H-吡唑-3-羧酰胺;
(209)N-(2-氟苯基)-1-(6-甲基吡啶-2-基)-5-(喹啉-4-基)-1H-吡唑-3-羧酰胺;
(210)N-(4-甲氧基苯基)-1-(6-甲基吡啶-2-基)-5-(喹啉-4-基)-1H-吡唑-3-羧酰胺;
(211)1-(6-甲基吡啶-2-基)-N-(4-(甲基磺酰基)苯基)-5-(喹啉-4-基)-1H-吡唑-3-羧酰胺;
(212)N-(6-甲氧基吡啶-3-基)-1-(6-甲基吡啶-2-基)-5-(喹啉-4-基)-1H-吡唑-3-羧酰胺;
(213)N-(6-氯吡啶-3-基)-1-(6-甲基吡啶-2-基)-5-(喹啉-4-基)-1H-吡唑-3-羧酰胺;
(214)N-(苯并[d][1,3]二氧杂环戊烯-5-基)-1-(6-甲基吡啶-2-基)-5-(喹啉-4-基)-1H-吡唑-3-羧酰胺;
(215)N-(3-氟-4-甲氧基苯基)-1-(6-甲基吡啶-2-基)-5-(喹啉-4-基)-1H-吡唑-3-羧酰胺;
(216)N-(2-氟-4-甲氧基苯基)-1-(6-甲基吡啶-2-基)-5-(喹啉-4-基)-1H-吡唑-3-羧酰胺;
(217)N-(4-(2-甲氧基乙氧基)苯基)-1-(6-甲基吡啶-2-基)-5-(喹啉-4-基)-1H-吡唑-3-羧酰胺;
(218)5-(苯并[c][1,2,5]恶二唑-5-基)-N-(4-(环丙基磺酰基)苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(219)5-(苯并[d]恶唑-6-基)-N-(2-氟苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(220)5-(苯并[d]恶唑-6-基)-N-(4-(环丙基磺酰基)苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3羧酰胺;
(221)N-环丙基-5-(4-氟-3-(1-(2-羟基乙基)-1H-吡唑-4-基)苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(222)N-(1H-吡唑-4-基)-5-(4-氟-3-(1-(2-羟基乙基)-1H-吡唑-4-基)苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(223)N-(1-甲基-1H-吡唑-4-基)-5-(4-氟-3-(1-(2-羟乙基)-1H-吡唑-4基)苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(224)N-(1-(甲基磺酰基)-1H-吡唑-4-基)-5-(4-氟-3-(1-(2-羟基乙基)-1H-吡唑-4-基)苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(225)N-(4-氯苯基)-5-(4-氟-3-(1-(2-羟基乙基)-1H-吡唑-4-基)苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(226)N-(4-(甲基磺酰基)苯基)-5-(4-氟-3-(1-(2-羟基乙基)-1H-吡唑-4-基)苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;和
(227)N-(2-氟苯基)-5-(噻吩并[3,2,c]吡啶-2-基)-1-(间-甲苯基)-1H-吡唑-3-羧酰胺。
可以使用以下反应式1中代表性说明的方法制备本发明所述的化学式1的化合物:
<反应式1>
在反应式1中,
R1、R2、R3、A、l、m和n各自具有与化学式1中相同的定义。
当参考反应式1更详细地描述反应时,将具有R2、草酸二乙酯和乙氧基钠溶液的乙酰基化合物在有机溶剂(例如乙醇)中回流,得到化合物(4)。将化合物(4)与具有(R1)1基团等的肼基原料一起回流,得到化合物(3),并将其与1,4-二恶烷和氢氧化锂搅拌,得到中间体化合物(2)。接下来,化合物(2)可以与具有R3基团的苯胺衍生物以及HATU和DIPEA在N,N-二甲基甲酰胺中反应,以获得本发明的化学式1的目标化合物。
可以将本发明所述的化学式1的化合物制备成添加有无机酸或有机酸的药学上可接受的盐的形式,并且在本文中,优选的盐的实例可以包括:衍生自盐酸、氢溴酸、硫酸、磷酸、硝酸、乙酸、乙醇酸、乳酸、丙酮酸、丙二酸、丁二酸、戊二酸、富马酸、苹果酸、扁桃酸、酒石酸、柠檬酸、抗坏血酸、棕榈酸、马来酸、羟基马来酸、苯甲酸、羟基苯甲酸、苯乙酸、肉桂酸、水杨酸、甲磺酸、苯磺酸、甲苯磺酸等的盐。
具体地,本发明所述的药学上可接受的盐可以通过将化学式1的化合物溶解在有机溶剂如丙酮,甲醇,乙醇或乙腈中,向其中加入有机酸或无机酸,并过滤其所得的晶体沉淀来制备。或者,可以通过在加酸的反应混合物中抽真空溶剂或过量的酸来干燥残余物来制备药学上可接受的盐,或者通过过滤由于加入其它有机溶剂产生的盐沉淀来制备药学上可接受的盐。
本发明所述的化学式1的化合物或其药学上可接受的盐可以具有水合物或溶剂合物的形式,并且这些化合物也包括在本发明中。
本发明所述的化学式1的化合物或其药学上可接受的盐可以有效地抑制蛋白激酶。在一个实施方式中,本发明的化合物可以有效地预防或治疗由ALK5受体或ALK4受体,或ALK5受体和ALK4受体共同介导的疾病。具体地,所述疾病可选自下组:肾、肝或肺纤维化、肾小球肾炎、糖尿病肾病、红斑性肾炎、高血压引起的肾病、肾间质纤维化、源自药物暴露并发症的肾纤维化、HIV相关性肾病、器官移植坏疽、各种疾病引起的肝纤维化、感染引起的肝功能障碍、酒精性肝炎、胆道疾病、肺纤维化、急性肺损伤、成人呼吸疼痛综合征、特发性肺纤维化、慢性阻塞性肺疾病、由感染或毒性因素引起的肺纤维化、心肌梗塞后心肌纤维化、充血性心力衰竭、扩张型心肌病、心肌炎、血管狭窄、再狭窄、动脉粥样硬化、视觉障碍、角膜损伤、增生性玻璃体视网膜病变、外伤或手术伤口的伤口愈合期间发生的真皮中形成过度或加重瘢痕或瘢痕疙瘩、腹膜和皮下粘连、皮肤硬化、纤维硬化、进行性系统性硬化、皮肌炎、多发性肌炎、关节炎、骨质疏松症、溃疡、神经功能受损、男性阳痿、阿尔茨海默病、雷诺氏病、纤维性癌、转移性肿瘤生长、放射诱导的纤维化和血栓形成,但不限于此。
在本公开的一个具体实施方式中,所述化学式1的化合物或其药学上可接受的盐可以预防或治疗纤维化疾病或纤维化病症。本文中,所述纤维化疾病或纤维化病症可选自下组:肝纤维化、肾纤维化、肺纤维化、过敏性肺炎、间质纤维化、系统性硬皮病、黄斑变性、胰腺纤维化、脾纤维化、心脏纤维化、物种脓毒性纤维化、骨髓纤维化、血管纤维化、皮肤纤维化、眼纤维化、关节纤维化、肌纤维化、甲状腺纤维化、心内膜心肌纤维化、腹膜纤维化、后腹膜纤维化、进行性先天性滋养细胞纤维化、异体系统性纤维化、手术纤维化并发症和感染性纤维化,但不限于此。
在本发明的一个具体实施方式中,所述化学式1的化合物或其药学上可接受的盐可以有效地预防或治疗癌症或肿瘤,并且还可以进一步有效地抑制癌细胞转移。本文中,所述癌症可选自肝癌、肝细胞癌、甲状腺癌、结肠直肠癌、睾丸癌、骨癌、口腔癌、基底细胞癌、卵巢癌、脑肿瘤、胆囊癌、胆道癌、头颈癌、结直肠癌、膀胱癌、舌癌、食道癌、胶质瘤、胶质母细胞瘤、肾癌、恶性黑色素瘤、胃癌、乳腺癌、肉瘤、咽癌、子宫癌、宫颈癌、前列腺癌、直肠癌、胰腺癌、肺癌、皮肤癌和其他实体癌症,但不限于此。
在本发明的一个具体实施方式中,所述化学式1的化合物或其药学上可接受的盐可以有效地预防或治疗由TGFβ过表达介导的癌。本文中,所述癌可以选自下组:肺癌、乳腺癌、肝癌、胆道癌、胃肠道癌、头颈癌、胰腺癌、前列腺癌和宫颈癌、多发性骨髓瘤、黑素瘤、神经胶质瘤和胶质母细胞瘤,但不限于此。
本发明所述的化学式1的化合物或其药学上可接受的盐可以通过与用于治疗纤维化疾病、癌症或肿瘤、炎性疾病、自身免疫疾病、增殖性疾病、过度增殖性疾病或免疫介导的疾病的其他药物共同施用来增强治疗效果。
用于治疗癌症或肿瘤的其他药物的实例可包括例如细胞信号传导抑制剂(格列卫、易瑞沙、特罗凯等)、有丝分裂抑制剂(长春新碱、长春花碱等)、烷化剂(环磷酰胺、噻替派、白消安等)、抗代谢物(基于tergaflor的、甲氨蝶呤、吉西他滨等)、拓扑异构酶抑制剂(伊立替康、拓扑替康、安吖啶、依托泊苷、替尼泊苷等)、免疫治疗剂(干扰素α、β、γ、白细胞介素等)或抗激素(他莫昔芬、亮丙瑞林、阿那曲唑等),但不限于此,并且选自这其中的一种或多种药物可包括在本发明的药物组合物中。
用于治疗炎性疾病、自身免疫疾病、增殖性疾病、过度增殖性疾病或免疫介导的疾病的其他药物的实例可包括例如类固醇药物(泼尼松、泼尼松龙、甲基强的松龙、可的松、羟基可的松、倍他米松、地塞米松等)、甲氨蝶呤、来氟米特、抗TNFα药物(依那西普、英夫利昔单抗、阿达木单抗等)、钙调神经磷酸酶抑制剂(他克莫司、吡美莫司等)和抗组胺药(苯海拉明、羟嗪(hydroxygene)、氯雷他定、阿瓦斯汀、酮替芬、西替利嗪、左西替利嗪、非索非那定等),但不限于此,并且选自这其中的一种或多种药物可以包括在本发明的药物组合物中。
本发明所述的化学式1的化合物,其药学上可接受的盐等可以施用于对象以预防或治疗上述疾病。本文中,剂量可以根据待治疗的对象、疾病或病症的严重程度、给药速率和处方医师的判断而变化,然而,所述化学式1的化合物作为活性成分施用于人通常可以通过口服或肠胃外的途径,基于70kg的体重,每天0.1mg至2,000mg,优选地1mg至1,000mg,每天1至4次或开/关时间表。在某些情况下,低于上述范围的剂量可能更合适,并且高于上述范围的剂量不会引起有害的副作用。可以在一天内将更多剂量以几个较小剂量分次施用。
本发明所述的药物组合物可以使用常规方法配制,并且可以以各种口服制剂的形式制备,例如片剂、丸剂、粉剂、胶囊剂、糖浆剂、乳剂或微乳剂,或肠胃外给药制剂的形式,例如肌肉内、静脉内或皮下给药。
当本发明所述的药物组合物以口服制剂的形式制备时,可使用的载体的实例可包括纤维素、硅酸钙、玉米淀粉、乳糖、蔗糖、右旋糖、磷酸钙、硬脂酸、硬脂酸镁、硬脂酸钙、明胶、滑石、表面活性剂、悬浮液、乳化剂、稀释剂等。当以注射剂形式制备本发明所述的药物组合物时,载体可是水、盐水溶液、葡萄糖水溶液、假糖水溶液、乙醇、乙二醇、醚(例如:聚乙二醇400)、油、脂肪酸、脂肪酸酯、甘油酯、表面活性剂、悬浮液、乳化剂等。
本发明的化学式1的化合物可用于研究激酶的生物学和病理学现象、由激酶介导的细胞内信号传导途径,以及对新型激酶抑制剂的比较评价。
在下文中,将参考实施例详细描述本发明。然而,以下实施例仅用于说明目的,并且本发明不限于以下实施例。
<反应式2>
[制备实施例1]5-(苯并[d]噻唑-6-基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酸
步骤1 N-甲氧基-N-甲基苯并[d]噻唑-6-羧酰胺的制备
将苯并噻唑-6-羧酸(5.0g,27.9mmol)、HATU(15.9g,41.9mmol)和DIPEA(11.7mL,83.7mmol)加入二氯甲烷(87mL)和N,N-二甲基甲酰胺(加入22mL),搅拌30分钟。向反应溶液中加入N,O-二甲基羟胺盐(3.0g,30.7mmol),在室温下搅拌12小时。终止反应后,除去反应溶液,并向其中加入乙酸乙酯。将产物用水和盐水洗涤,然后用无水硫酸镁干燥,过滤。浓缩滤液,使用柱色谱法纯化,得到目标化合物(6.2g)。
1H NMR谱(300MHz,CDCl3)δ9.13(s,1H),8.36(d,1H),8.16(d,1H),7.87(dd,1H),3.57(s,3H),3.42(s,3H)。
步骤2 1-(苯并[d]噻唑-6-基)乙-1-酮
将在步骤1中合成的N-甲氧基-N-甲基苯并[d]噻唑-6-羧酰胺(6.2g,27.9mmol)在氩气下溶解于无水四氢呋喃(84mL)后,在0℃下向其中滴加溶解于乙醚中的3M甲基溴化镁(13.9mL,41.8mmol)。将反应溶液温热至室温并搅拌12小时。通过向其中加入饱和氯化铵溶液终止反应后,加入乙酸乙酯,并萃取产物。用无水硫酸镁干燥有机层,然后过滤。浓缩滤液,然后使用柱色谱法纯化,得到目标化合物(3.1g)。
1H NMR谱(300MHz,CDCl3)δ9.17(s,1H),8.62(s,1H),8.16(q,2H),2.71(s,3H)。
步骤3(Z)-4-(苯并[d]噻唑-6-基)-4-羟基-2-氧代-3-丁烯酸乙酯
将步骤2中合成的1-(苯并[d]噻唑-6-基)乙-1-酮(1.0g,5.6mmol)和草酸二乙酯(1.5mL,11.3mmol)溶解于乙醇(2mL)溶液后,在50℃下向其中缓慢滴加2M乙氧基钠溶液(5.6mL,11.3mmol),并将产物回流2小时。产物冷却至室温后,真空浓缩,并通过向其中滴加2M HCl酸化产物。向其中加入二氯甲烷用于萃取,并使用无水硫酸镁干燥有机层,然后过滤。浓缩滤液,使用柱色谱法纯化,得到目标化合物(597mg)。
1H NMR谱(300MHz,CDCl3)δ9.19(s,1H),8.68(s,1H),8.20(q,2H),7.17(s,1H),4.43(q,2H),1.43(t,3H)。
步骤4 5-(苯并[d]噻唑-6-基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酸乙酯
将步骤3中合成的(Z)-4-(苯并[d]噻唑-6-基)-4-羟基-2-氧代-3-丁烯酸乙酯(580mg,2.1mmol)和2-肼基-6-甲基吡啶盐酸(350mg,2.2mmol)溶解于乙醇(10mL)溶液,回流2小时。终止反应后,在真空下除去反应溶液,并向其中加入乙酸乙酯。用盐水洗涤有机层,然后用无水硫酸镁干燥,过滤后浓缩滤液。使用柱色谱法纯化滤液,得到目标化合物(525mg)。
1H NMR谱(300MHz,CDCl3)δ9.04(s,1H),8.04(d,1H),7.97(d,1H),7.67(t,1H),7.41-7.33(m,2H),7.14-7.10(m,2H),7.47(q,2H),2.32(s,3H),1.43(t,3H)。
步骤5 5-(苯并[d]噻唑-6-基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酸
将步骤4合成的5-(苯并[d]噻唑-6-基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酸乙酯(520mg,1.4mmol)溶解于1,4-二恶烷(11mL)中,向其中加入2N氢氧化锂水溶液,并在70℃下搅拌2小时。终止反应后,在真空下除去反应溶液。向其中加入12N盐酸以酸化产物,然后通过向其中引入氯仿/异丙醇(3:1)进行萃取。用无水硫酸镁干燥有机层,过滤后浓缩滤液。使用柱色谱法纯化滤液,得到中间体1(394mg)。
1H NMR谱(300MHz,CDCl3)δ9.34(s,1H),8.09(d,1H),8.05(s,1H),7.75(t,1H),7.44-7.39(m,2H),7.21(d,1H),7.13(s,1H),2.36(s,3H)。
<反应式3>
[制备实施例2]5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酸的制备
步骤1 2-肼基-6-甲基吡啶盐酸盐的制备
将水合肼(60mL)加入到2-溴-6-甲基吡啶(10.0g,58.1mmol)中,并将产物加热回流4小时。终止反应后,用乙酸乙酯萃取,将得到的有机层真空浓缩,用4N盐酸/二恶烷(30mL)酸化。过滤生成的固体,干燥得到的固体,得到目标化合物(9.3g)。
1H NMR(300MHz,DMSO-d6)δ9.65(brs,3H),7.60(t,1H),6.75(d,1H),6.69(d,1H),2.41(s,3H)。
MS(ESI+):m/z 124[M+H]+。
步骤2 1-([1,2,4]三唑并[1,5-α]吡啶-6-基)乙-1-酮的制备
将1-溴-[1,2,4]三唑并[1,5-α]吡啶(1.1g,5.6mmol)溶解于密封管中的N,N-二甲基甲酰胺(15mL)后,向其中加入n-丁基乙烯基醚(3.6mL,27.8mmol)、1,3-双(二苯基膦基)丙烷(161mg,0.4mmol)、乙酸钯(II)(37mg,0.2mmol)、碳酸钾(922mg,6.7mmol)和水(1.6mL),加热回流16小时。将温度降至室温后,加入2N盐酸水溶液(10mL),在室温下搅拌30分钟。终止反应后,用乙酸乙酯萃取产物,用无水硫酸镁干燥得到的有机层,然后过滤。浓缩滤液,使用柱色谱法纯化,得到目标化合物(410mg)。
1H NMR(300MHz,CDCl3)δ9.23(s,1H),8.46(s,1H),8.09(d,1H),7.81(d,1H),2.67(s,3H)。
MS(ESI+):m/z 162[M+H]+。
步骤3(Z)-乙基-4-([1,2,4]三唑并[1,5-α]吡啶-6-基)-2-羟基-4-氧-2-丁烯酸
酯的制备
向2M乙氧基钠溶液(5.0mL,9.9mmol)中加入草酸二乙酯(1.3mL,9.9mmol)后,向其中加入步骤1中合成的1-([1,2,4]三唑并[1,5-α]吡啶-6-基)乙-1-酮(400mg,2.5mmol)的乙醇(3mL)溶液,并在室温下搅拌2小时。将产物真空浓缩,并在0℃下向其中滴加2N盐酸水溶液酸化。产物用乙酸乙酯萃取,所得有机层用无水硫酸镁干燥,然后过滤。浓缩滤液,用乙醚重结晶,得到目标化合物(444mg)。
1H NMR(300MHz,DMSO-d6)δ9.95(s,1H),8.69(s,1H),8.16(d,1H),7.95(d,1H),7.30(brs,1H),4.30(q,2H),1.31(t,3H)。
MS(ESI+):m/z 262[M+H]+。
步骤4 5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-1-(6-甲基吡啶-2-基)-1H-吡唑-
3-羧酸乙酯的制备
将步骤3中合成的(Z)-乙基-4-([1,2,4]三唑并[1,5-α]吡啶-6-基)-2-羟基-4-氧-2-丁烯酸酯(440mg,1.7mmol)和步骤1中合成的2-肼基-6-甲基吡啶盐酸盐(268mg,1.7mmol)溶解于乙醇(6mL),在50℃下搅拌2小时。将产物真空浓缩,用乙酸乙酯萃取,并将得到的有机层用无水硫酸镁干燥,然后过滤。浓缩滤液,使用柱色谱法纯化,得到目标化合物(446mg)。
1H NMR(300MHz,CDCl3)δ8.73(s,1H),8.39(s,1H),7.77-7.67(m,3H),7.47(d,1H),7.18-7.09(m,2H),4.46(q,2H),2.26(s,3H),1.45(t,3H)。
MS(ESI+):m/z 349[M+H]+。
步骤5 5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-1-(6-甲基吡啶-2-基)-1H-吡唑-
3-羧酸的制备
将50%乙醇水溶液(5mL)加入到步骤4中合成的乙基5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酸酯(440mg,1.3mmol)后,在50℃下搅拌1小时。将产物真空浓缩并用2N盐酸水溶液酸化,过滤产生的固体并干燥,得到中间体2(386mg)。
1H NMR(300MHz,DMSO-d6)δ13.2(brs,1H),9.15(s,1H),8.52(s,1H),7.91(t,1H),7.78(d,1H),7.73(d,1H),7.29(d,1H),2.13(s,3H)。
MS(ESI+):m/z 321[M+H]+。
<反应式4>
[制备实施例3]1-(6-甲基吡啶-2-基)-5-(喹喔啉-6-基)-1H-吡唑-3-羧酸的合成
步骤1 1-(喹喔啉-6-基)乙-1-酮的制备
将6-溴喹喔啉(3.8g,18.2mmol)、n-丁基乙烯基醚(12.3mL,95.2mmol)、碳酸钾(3.1g,22.8mmol)、1,3-双(二苯基膦基)丙烷(504mg,1.3mmol)和乙酸钯(II)(124mg,0.5mmol)加入到N,N-二甲基甲酰胺(47mL)和水(6mL)中,搅拌并回流6小时。终止反应后,将产物冷却至室温,加入2N盐酸,搅拌0.5小时。向其中加入乙酸乙酯,用水和碳酸氢钠洗涤有机层,用无水硫酸镁干燥,并过滤。浓缩滤液,使用柱色谱法纯化,得到目标化合物(2.4g)。
1H NMR谱(300MHz,DMSO-d6)δ10.05(d,1H),9.73(t,1H),8.71(s,1H),7.97(d,1H),3.16(s,3H)。
步骤2(Z)-4-羟基-2-氧-4-(喹喔啉-6-基)-3-丁烯酸乙酯的制备
将步骤1中合成的6-(喹喔啉-6-基)乙-1-酮(4.6g,27.0mmol)和草酸二乙酯(7.3mL,53.9mmol)溶解在乙醇(9mL)中后,在50℃下向其中缓慢滴加2M乙氧基钠溶液(26.9mL,53.9mmol),并回流2小时。产物冷却至室温后,真空浓缩,并通过向其中滴加2MHCl酸化产物。向其中加入二氯甲烷用于萃取,并使用无水硫酸镁干燥有机层,然后过滤。浓缩滤液,使用柱色谱法纯化,得到目标化合物(6.7g)。
1H NMR谱(300MHz,CDCl3)δ8.96(s,2H),8.78(s,1H),8.35(dd,1H),8.24(d,1H),7.27(s,1H),4.44(q,2H),1.45(t,3H)。
步骤3 1-(6-甲基吡啶-2-基)-5-(喹喔啉-6-基)-1H-吡唑-3-羧酸乙酯的制备
将步骤2中合成的(Z)-4-羟基-2-氧-4-(喹喔啉-6-基)-3-丁烯酸酯(2.7g,10.1mmol)和2-肼基-6-甲基吡啶盐酸(1.3g,10.6mmol)溶解于乙醇溶液,回流2小时。终止反应后,在真空下除去反应溶液,并向其中加入乙酸乙酯。用碳酸氢钠洗涤有机层,用无水硫酸镁干燥,过滤。浓缩滤液,使用柱色谱法纯化,得到目标化合物(2.7g)。
1H NMR谱(300MHz,CDCl3)δ8.86(s,2H),8.09(d,1H),8.01(d,1H),7.73-7.62(m,1H),7.55(d,1H),7.20(s,1H),7.13(d,1H),4.48(q,2H),2.24(s,3H),1.45(s,3H)。
步骤4 1-(6-甲基吡啶-2-基)-5-(喹喔啉-6-基)-1H-吡唑-3-羧酸的制备
将步骤3中合成的乙基1-(6-甲基吡啶-2-基)-5-(喹喔啉-6-基)-1H-吡唑-3-羧酸酯(2.6g,7.2mmol)溶解于1,4-二恶烷(40mL),加入2N氢氧化锂水溶液,并在70℃下搅拌3小时。终止反应后,在真空下除去反应溶液,并向其中加入水。向其中加入乙酸乙酯进行萃取,将水层酸化至pH为2至3,并在室温下搅拌1小时。过滤生成的固体,用水洗涤并干燥,得到中间体3(2.3g)。
1H NMR谱(300MHz,DMSO-d6)δ13.17(br,1H),8.96(s,2H),8.06-7.92(m,3H),7.72(dd,1H),7.60(d,1H),7.35-7.32(m,2H),2.15(s,3H)。
<反应式5>
[制备实施例4]1-(6-甲基吡啶-2-基)-5-(喹啉-4-基)-1H-吡唑-3-羧酸
步骤1 N-甲氧基-N-甲基喹啉-4-羧酰胺的制备
在将喹啉-4-羧酸(2.2g,12.8mmol)、HATU(5.8g,15.3mmol)和DIPEA(6.7mL,38.4mmol)加入二氯甲烷(25mL)后,搅拌30分钟。向反应溶液中加入N,O-二甲基羟胺盐(1.9g,19.2mmol),在室温下搅拌12小时。终止反应后,除去反应溶液,并向其中加入乙酸乙酯。将产物用水和盐水洗涤,然后用无水硫酸镁干燥,过滤。浓缩滤液,使用柱色谱法纯化,得到目标化合物(2.8g)。
1H NMR谱(300MHz,CDCl3)δ8.96(d,1H),8.15(d,1H),7.86(d,1H),7.76(t,1H),7.59(t,1H),7.39(d,1H),3.48-3.40(m,6H)。
步骤2 1-(喹啉-4-基)乙-1-酮的制备
在氩气下将步骤1中合成的N-甲氧基-N-甲基喹啉-4-羧酰胺(2.8g,12.9mmol)溶于无水四氢呋喃(100mL)中后,在0℃下向其中滴加溶解于乙醚中的溶液3M甲基溴化镁(6.5mL,19.4mmol)。将反应溶液温热至室温,并搅拌3小时。在0℃下进一步滴加溶解在乙醚中的3M甲基溴化镁(3.0mL,9.0mmol)。将反应溶液温热至室温并搅拌12小时。通过向其中加入饱和氯化铵溶液终止反应后,加入乙酸乙酯,并萃取产物。用无水硫酸镁干燥有机层,然后过滤。浓缩滤液,然后使用柱色谱法纯化,得到目标化合物(1.8g)。
1H NMR谱(300MHz,CDCl3)δ9.03(d,1H),8.46(d,1H),8.17(d,1H),7.77(t,1H),7.67-7.61(m,2H),2.75(s,3H)。
步骤3(Z)-2-羟基-4-氧-4-(喹啉-4-基)丁-2-烯酸乙酯的制备
将步骤2中合成的1-(喹啉-4-基)乙-1-酮(1.0g,5.8mmol)和草酸二乙酯(1.6mL,11.7mmol)溶解于乙醇(3mL)中后,在50℃下向其中缓慢滴加2M乙氧基钠溶液(5.8mL,11.7mmol),并回流1小时。将产物冷却至室温后,将溶剂真空浓缩,并通过向其中滴加2M盐酸酸化产物。向其中加入二氯甲烷用于萃取,并使用无水硫酸镁干燥有机层,然后过滤。浓缩滤液,然后使用己烷和乙醚的1:1混合溶液结晶,得到目标化合物(1.1g)。
1H NMR谱(300MHz,CDCl3)δ9.06(d,1H),8.40(d,1H),8.20(d,1H),7.81(t,1H),7.70-7.63(m,2H),6.95(s,1H),4.42(q,2H),1.41(t,3H)。
步骤4 1-(6-甲基吡啶-2-基)-5-(喹啉-4-基)-1H-吡唑-3-羧酸乙酯的制备
将步骤3中合成的(Z)-2-羟基-4-氧-4-(喹啉-4-基)丁-2-烯酸乙酯(1.1g,4.2mmol)和2-肼基-6-甲基吡啶盐酸(677mg,4.2mmol)溶解于乙醇(12mL)中,将产物回流3小时。终止反应后,在真空下除去反应溶液,并向其中加入乙酸乙酯。用水和盐水洗涤有机层,然后用无水硫酸镁干燥,过滤后浓缩滤液。使用柱色谱法纯化滤液,得到目标化合物(1.1g)。
1H NMR谱(300MHz,CDCl3)δ8.92(d,1H),8.13(d,1H),7.70-7.56(m,4H),7.39(t,1H),7.31(t,1H),7.13(s,1H),6.89(d,1H),4.50(q,2H),1.79(s,3H),1.46(t,3H)。
步骤5 1-(6-甲基吡啶-2-基)-5-(喹啉-4-基)-1H-吡唑-3-羧酸的制备
将步骤4中合成的1-(6-甲基吡啶-2-基)-5-(喹啉-4-基)-1H-吡唑-3-羧酸乙酯(1.1g,3.2mmol)溶解于1,4-二恶烷(11mL),加入2N氢氧化锂水溶液(4.8mL,9.5mmol)中,在45℃下搅拌2小时。终止反应后,在真空下除去反应溶液,通过向其中加入2N盐酸将产物酸化至pH为2至3,然后在室温下搅拌1小时。将产物真空过滤,得到中间体4(960mg)。
1H NMR谱(300MHz,DMSO-d6)δ13.0(bs,1H),8.92(d,1H),8.07(d,1H),7.81(t,1H),7.71-7.65(m,2H),7.50-7.44(m,3H),7.06(s,1H),7.05(d,1H),1.64(t,3H)。
<反应式6>
[制备实施例5]5-(苯并[c][1,2,5]恶二唑-5-基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酸
步骤5 5-(苯并[c][1,2,5]恶二唑-5-基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧
酸的制备
通过制备实施例4的步骤1至步骤5的方法获得中间体5(30mg),其中,在步骤1中,用苯并[c][1,2,5]恶二唑-5-羧酸代替喹啉-4-羧酸。
1H NMR谱(300MHz,DMSO-d6)δ8.14(s,1H),7.97-7.92(m,2H),7.71(d,1H),7.40(d,1H),7.31-7.28(m,2H),2.10(s,3H)。
<反应式7>
[制备实施例6]5-(苯并[d]恶唑-6-基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酸
步骤3(Z)-4-(苯并[d]恶唑-6-基)-2-羟基-4-氧代丁-2-烯酸乙酯的制备
通过制备实施例4的步骤1至步骤3的方法获得目标化合物(1.2g),其中,在步骤1中,使用苯并[d]恶唑-6-羧酸代替喹啉-4-羧酸。
1H NMR谱(300MHz,CDCl3)δ8.28-8.26(m,2H),8.06(d,1H),7.90(d,1H),7.27(s,1H),7.14(s,1H),4.42(q,2H),1.44(t,3H)。
步骤4 5-(4-氨基-3-羟基苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酸乙酯的
制备
将步骤3中合成的(Z)-4-(苯并[d]恶唑-6-基)-2-羟基-4-氧代丁-2-烯酸乙酯(1.2g,4.8mmol)和2-肼基-6-甲基吡啶盐酸(915mg,5.7mmol)溶解于乙醇(15mL)溶液,回流2小时。终止反应后,真空除去反应溶液,并向其中加入饱和碳酸氢钠溶液。将产物在室温下搅拌1小时,然后真空过滤。将获得的固体用二氯甲烷结晶并真空过滤,得到目标化合物(1.5g)。
1H NMR谱(300MHz,DMSO-d6)δ9.11(s,1H),7.84(t,1H),7.37(d,1H),7.20(d,1H),6.83(s,1H),6.49-6.41(m,3H),4.79(bs,2H),4.31(q,2H),1.33(t,3H)。
步骤5 5-(苯并[d]恶唑-6-基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酸乙酯的制
备
将步骤4中合成的乙基5-(4-氨基-3-羟基苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酸酯(1.0g,3.0mmol)溶解于原甲酸三甲酯(1.5mL),在100℃下搅拌2小时。终止反应后,真空除去反应溶液,用柱色谱法纯化,得到目标化合物(930mg)。
1H NMR谱(300MHz,CDCl3)δ8.12(s,1H),7.72-7.63(m,2H),7.55(d,1H),7.36(d,1H),7.25(m,1H),7.13(d,1H),7.07(s,1H),4.46(q,2H),2.33(s,3H),1.43(t,3H)。
步骤6 5-(苯并[d]恶唑-6-基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酸的制备
将步骤5合成的5-(苯并[d]恶唑-6-基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酸乙酯(300mg,0.9mmol)溶解于1,4-二恶烷(3mL)中,向其中加入1N氢氧化锂水溶液(1.5mL,1.5mmol),并将产物在室温下搅拌2小时。终止反应后,在真空下除去反应溶液,通过向其中加入1N盐酸将产物酸化至pH为2至3,然后在室温下搅拌1小时。将产物真空过滤,然后使用柱色谱法纯化,得到中间体6(100mg)。
1H NMR谱(300MHz,DMSO-d6)δ8.75(s,1H),7.85(t,1H),7.72-7.68(m,2H),7.45(d,1H),7.24-7.17(m,2H),6.84(s,1H),2.14(s,3H)。
<反应式8>
[制备实施例7]1-(6-甲基吡啶-2-基)-5-(4-氟-3-(1-(2-羟基乙基)-1H-吡唑-4-基)-1H-吡唑-3-羧酸
步骤1 t-丁基4-(5-乙酰基-2-氟苯基)-1H-吡唑-1-羧酸酯的制备
将1-(3-溴-4-氟苯基)乙-1-酮(1.0g,4.6mmol)溶解于1,4-二恶烷(20mL)和水(4mL)中后,在氮气下向其中加入t-丁基4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-1H-吡唑-1-羧酸酯(2.0g,6.9mmol)、磷酸三钾(2.0g,9.2mmol)和XPhos(156mg,0.2mmol),并将产物在100℃下回流加热5小时。将产物冷却至室温,然后用乙酸乙酯萃取,干燥并浓缩。使用柱色谱法纯化结果,得到目标化合物(960mg)。
1H NMR(300MHz,CDCl3)δ8.51(s,1H),8.21(d,1H),8.14(s,1H),7.23(d,1H),2.64(s,3H),1.70(s,9H)。
MS(ESI+):[M+H]+m/z 305
步骤2 4-(4-氟-3-(1H-吡唑-4-基)苯基)-2-羟基-4-氧代丁-2-酮酸乙酯的制备
向草酸二乙酯(1.7mL,12.6mmol)中加入乙醇(15mL)后,加入2M乙氧基钠溶液(6.3mL,12.6mmol)。向其中缓慢加入t-丁基4-(5-乙酰基-2-氟苯基)-1H-吡唑-1-羧酸盐(1.0g,4.6mmol),在室温下搅拌3小时。将溶剂真空浓缩,并通过向其中滴加2N盐酸酸化产物。用乙酸乙酯萃取产物,有机层用无水硫酸镁干燥,然后过滤。浓缩滤液,得到目标化合物(958mg)。
1H NMR(300MHz,CDCl3)δ8.24(d,1H),8.07(s,2H),7.90-7.84(m,1H),7.29-7.23(m,1H),7.07(s,1H),4.42(q,2H),1.43(t,3H)。
MS(ESI+):[M+H]+m/z 305
步骤3 5-(4-氟-3-(1H-吡唑-4-基)苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧
酸乙酯的制备
将乙基4-(4-氟-3-(1H-吡唑-4-基)苯基)-2-羟基-4-氧代丁-2-酮(955mg,3.1mmol)和2-肼基-6-甲基吡啶盐酸盐(751mg,4.7mmol)溶解于乙醇(15mL)溶液,在50℃下搅拌2小时。终止反应后,在真空下除去反应溶液。用乙酸乙酯萃取产物,用无水硫酸镁干燥,然后过滤。浓缩滤液,使用柱色谱法纯化,得到目标化合物(658mg)。
1H NMR(300MHz,CDCl3)δ7.90(s,2H),7.72(t,1H),7.53(d,1H),7.40(d,1H),7.18(d,1H),7.12-7.09(m,3H),4.49(q,2H),2.42(s,3H),1.46(t,3H)。
MS(ESI+):[M+H]+m/z 392
步骤4 5-(3-(1-(2-((t-丁基二甲基甲硅烷基)氧基)乙基)-1H-吡唑-4-基)-4-氟
苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酸酯的制备
将5-(4-氟-3-(1H-吡唑-4-基)苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酸乙酯(650mg,1.7mmol)、(2-溴乙氧基)(t-丁基)二甲基硅烷(477mg,2.0mmol)和碳酸钾(688mg,5.0mmol)溶解于N,N-二甲基甲酰胺(15mL),在80℃下搅拌16小时。将产物冷却至室温,然后用乙酸乙酯萃取,用无水硫酸镁干燥,并过滤。浓缩滤液,使用柱色谱法纯化,得到目标化合物(740mg)。
1H NMR(300MHz,CDCl3)δ7.88(s,1H),7.75-7.70(m,2H),7.51(d,1H),7.41(d,1H),7.19(d,1H),7.11-7.08(m,3H),4.51(q,2H),4.29(t,2H),4.00(t,2H),2.44(s,3H),1.47(t,3H),0.88(s,9H),0.02(s,6H)。
MS(ESI+):[M+H]+m/z 550
步骤5 5-(4-氟-3-(1-(2-羟乙基)-1H-吡唑-4-基)苯基)-1-(6-甲基吡啶-2-基)-
1H-吡唑-3-羧酸的制备
向5-(3-(1-(2-((t-丁基二甲基甲硅烷基)氧基)乙基)-1H-吡唑-4-基)-4-氟苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酸乙酯(700mg,1.3mmol)中加入50%乙醇水溶液(8mL),在50℃下搅拌2小时。将产物真空浓缩并用2N盐酸酸化,然后过滤产生的固体并干燥,得到中间体7(460mg)。
1H NMR(300MHz,CDCl3)δ7.84(s,1H),7.74-7.69(m,2H),7.50(d,1H),7.40(d,1H),7.18(d,1H),7.08-7.05(m,3H),4.32(t,2H),4.06(t,2H),2.40(s,3H)。
MS(ESI+):m/z 408[M+H]+。
<反应式9>
[制备实施例8]1-(6-甲基吡啶-2-基)-5-(噻吩并[3,2-c]吡啶-2-基)-1H-吡唑-3-羧酸
步骤1(4-氯吡啶-3-基)甲醇的制备
将4-氯烟酸(7.0g,44.4mmol)溶解于四氢呋喃(500mL)后,向其中加入氢化铝锂(1.68g,44.4mmol),在室温下搅拌1小时。终止反应后,在真空下除去反应溶液,并通过向其中加入乙酸乙酯和水来萃取产物。用无水硫酸镁干燥有机层,过滤后浓缩滤液。使用柱色谱法纯化滤液,得到中间体(2.6g)。
1H NMR谱(300MHz,CDCl3)δ8.62(s,1H),8.42(s,1H),7.48(s,1H),7.53(s,2H)。
步骤2 4-氯代烟碱的制备
将步骤1中合成的(4-氯吡啶-3-基)甲醇(2.6g,18.0mmol)溶解于二氯甲烷(26mL)中后,向其中加入氧化锰(IV)(23.5g,270.5mmol),在50℃下搅拌12小时。终止反应后,通过向其中加入水来萃取产物。用无水硫酸镁干燥有机层,过滤后浓缩滤液。使用柱色谱法纯化滤液,得到中间体(1.37g)。
1H NMR谱(300MHz,CDCl3)δ10.51(s,1H),9.05(s,1H),8.67(s,1H),7.42(s,1H)。
步骤3制备乙基噻吩并[3,2,c]吡啶-2-羧酸酯
将步骤2中合成的4-氯代烟碱(3.3g,23.3mmol)溶于N,N-二甲基甲酰胺(33mL)和水(3.3mL)后,向其中加入碳酸钾(3.1g,23.3mmol),将产物在室温下搅拌5分钟。向其中滴加2-巯基乙酸盐(2.8g,23.3mmol)后,在50℃下搅拌12小时。反应完成后,向其中滴加水,搅拌1小时,过滤固体,得到中间体(2.3g)。
1H NMR谱(300MHz,CDCl3)δ9.26(s,1H),8.54(s,1H),8.32(s,1H),13(s,1H),4.39(q,2H),1.33(t,3H)。
步骤4噻吩并[3,2-c]吡啶-2-羧酸的制备
将步骤3中合成的乙基噻吩并[3,2,c]吡啶-2-羧酸酯(2.3g,11.0mmol)溶解于甲醇(25mL)中后,向其中加入2N氢氧化锂溶液,在70℃下搅拌2小时。终止反应后,在真空下除去反应溶液。向其中加入12N盐酸以酸化产物,然后通过向其中引入氯仿/异丙醇(3:1)进行萃取。用无水硫酸镁干燥有机层,过滤后浓缩滤液。使用柱色谱法纯化滤液,得到中间体(1.89g)。
1H NMR谱(300MHz,CDCl3)δ9.24(s,1H),8.52(s,1H),8.23(s,1H),8.10(s,1H)。
步骤5 N-甲氧基-N-甲基噻吩并[3,2-c]吡啶-2-羧酰胺的制备
将噻吩并[3,2-c]吡啶-2-羧酸(1.9g,10.5mmol)、HATU(6.0g,15.8mmol)和TEA(3.2g,31.6mmol)加入二氯甲烷(38mL)和N,N-二甲基甲酰胺(7.5mL)中后,搅拌30分钟。向反应溶液中加入N,O-二甲基羟胺盐(1.1g,11.6mmol),在室温下搅拌12小时。终止反应后,除去反应溶液,并向其中加入乙酸乙酯。将产物用水和盐水洗涤,然后用无水硫酸镁干燥,过滤。浓缩滤液,使用柱色谱法纯化,得到目标化合物(1.4g)。
1H NMR谱(300MHz,CDCl3)δ9.19(s,1H),8.50(s,1H),8.27(s,1H),7.80(s,1H),3.83(s,3H),3.42(s,3H)。
步骤6 1-(噻吩并[3,2-c]吡啶-2-基)乙-1-酮的制备
在氩气下,将步骤5中合成的N-甲氧基-N-甲基噻吩并[3,2-c]吡啶-2-羧酰胺(0.4g,1.7mmol)溶于无水四氢呋喃(5.1mL)中,在0℃下向其中滴加3M甲基溴化镁(2.8mL,2.5mmol)的乙醚溶液。通过向其中加入饱和氯化铵溶液终止反应后,加入乙酸乙酯,并萃取产物。用无水硫酸镁干燥有机层,然后过滤。浓缩滤液,然后使用柱色谱法纯化,得到目标化合物(250mg)。
1H NMR谱(300MHz,CDCl3)δ9.19(s,1H),8.54(s,1H),7.80(s,1H),7.78(s,1H),2.68(s,3H)。
步骤7(Z)-乙基2-羟基-4-氧-4-(噻吩并[3,2-c]吡啶-2-基)2-丁烯酸酯的制备
将步骤6中合成的1-(噻吩并[3,2-c]吡啶-2-基)乙-1-酮(0.3g,1.4mmol)和草酸二乙酯(0.8g,5.6mmol)溶解于乙醇溶液(2.5mL),在50℃下向其中缓慢滴加乙氧基钠(0.4g,5.6mmol),并回流2小时。将产物冷却至室温后,将溶剂真空浓缩,并通过向其中滴加2M盐酸酸化产物。向其中加入二氯甲烷用于萃取,并使用无水硫酸镁干燥有机层,然后过滤。浓缩滤液,使用柱色谱法纯化,得到目标化合物(0.2g)。
1H NMR谱(300MHz,CDCl3)δ9.51(s,1H),8.43(s,1H),8.16(s,1H),7.38(s,1H),7.38(s,1H),4.23(q,2H),1.21(t,3H)。
步骤8 1-(6-甲基吡啶-2-基)-5-(噻吩并[3,2,c]吡啶-2-基)-1H-吡唑-3-羧酸乙
酯的制备
将步骤7中合成的(Z)-乙基2-羟基-4-氧-4-(噻吩并[3,2-c]吡啶-2-基)2-丁烯酸酯(0.2g,0.6mmol)和2-肼基-6-甲基吡啶盐酸(0.1g,0.6mmol)溶解于乙醇(1.5mL)溶液中,回流2小时。终止反应后,在真空下除去反应溶液,并向其中加入乙酸乙酯。用盐水洗涤有机层,然后用无水硫酸镁干燥,过滤后浓缩滤液。使用柱色谱法纯化滤液,得到目标化合物(98mg)。
1H NMR谱(300MHz,CDCl3)δ9.02(s,1H),8.45(s,1H),7.84-7.70(m,2H),7.61(t,1H),7.52(s,1H),7.39-7.20(m,2H),4.50(q,2H),2.32(s,3H),1.43(t,3H)。
步骤9 1-(6-甲基吡啶-2-基)-5-(噻吩并[3,2-c]吡啶-2-基)-1H-吡唑-3-羧酸的
制备
将步骤8中合成的1-(6-甲基吡啶-2-基)-5-(噻吩并[3,2,c]吡啶-2-基)-1H-吡唑-3-羧酸酯(98mg,0.3)溶解于1,4-二恶烷(1mL)中,向其中加入2N氢氧化锂水溶液,并在70℃下搅拌2小时。终止反应后,在真空下除去反应溶液。向其中加入12N盐酸以酸化产物,然后通过向其中引入氯仿/异丙醇(3:1)进行萃取。用无水硫酸镁干燥有机层,过滤后浓缩滤液。使用柱色谱法纯化滤液,得到中间体8(82mg)。
1H NMR谱(300MHz,CDCl3)δ9.50(s,1H),8.69(d,2H),8.06(s,1H),7.99(t,1H),7.64-7.61(m,2H),7.43(d,1H),2.37(s,3H)。
[实施例1]5-(苯并[d]噻唑-6-基)-N-(4-甲氧基苯基)-1-(6-甲基吡啶-2-基)- 1H-吡唑-3-羧酰胺
将制备实施例1的步骤5中合成的1-(6-甲基吡啶-2-基)-5-(喹喔啉-6-基)-1H-吡唑-3-羧酸(40mg,0.1mmol)溶解于二氯甲烷中,向其中加入HATU(54mg,0.1mmol)和DIPEA(60μL,0.4mmol),并在室温下搅拌20分钟。向反应溶液中加入p-茴香胺(16mg,0.1mmol),在室温下搅拌12小时。终止反应后,向其中加入乙酸乙酯。用碳酸氢钠洗涤,然后用无水硫酸镁干燥,过滤后浓缩滤液。使用柱色谱法纯化滤液,得到目标化合物(22mg)。
1H NMR谱(300MHz,CDCl3)δ9.05(s,1H),8.76(s,1H),8.05(d,1H),7.98(d,1H),7.66-7.63(m,3H),7.35(dd,1H),7.20(t,3H),7.20(dd,2H),3.82(s,3H),2.43(s,3H)。
MS(ESI+):[M+H]+m/z 442.1
[实施例2至81]
以与实施例1的步骤1)相同的方法获得以下[表1]中列出的实施例2至79的化合物,其中,用各种胺衍生物代替p-茴香胺。
【表1】
[实施例82]5-(苯并[d]噻唑-6-基)-N-(3-羟基苯基)-1-(6-甲基吡啶-2-基)-1H- 吡唑-3-羧酰胺
步骤1 5-(苯并[d]噻唑-6-基)-N-(3-((叔丁基二甲基甲硅烷基)氧基)苯基)-1-
(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺
以与实施例1中相同的方法获得目标化合物(140mg),其中,使用3-((叔丁基二甲基甲硅烷基)氧基)苯胺代替p-茴香胺之外。
1H NMR谱(300MHz,CDCl3)δ9.04(s,1H),8.79(s,1H),8.05(d,1H),7.97(d,1H),7.66(t,1H),7.40(d,1H),7.34(d,1H),7.26-7.17(m,5H),6.64-6.61(m,1H),2.43(s,3H),1.01(s,9H),0.25(S,6H)。
步骤2 5-(苯并[d]噻唑-6-基)-N-(3-羟基苯基)-1-(6-甲基吡啶-2-基)-1H-吡
唑-3-羧酰胺
将步骤1中合成的5-(苯并[d]噻唑-6-基)-N-(3-((叔丁基二甲基甲硅烷基)氧基)苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺(140mg,0.26mmol)溶解于四氢呋喃(2.5mL)后,在室温下向其中滴加1.0M TBAF(0.78mL,0.78mmol),并且搅拌反应溶液1小时。真空除去反应溶液,然后向其中加入乙酸乙酯。用碳酸氢钠洗涤有机层,然后用无水硫酸镁干燥,过滤后,将滤液真空浓缩。使用柱色谱法纯化滤液,得到目标化合物(23mg)。
1H NMR谱(300MHz,CDCl3)δ9.06(s,1H),8.93(s,1H),8.05(d,1H),8.00(d,2H),7.67(t,1H),7.38-7.18(m,5H),6.90(d,1H),6.68(d,1H),2.44(s,3H)。
MS(ESI+):[M+H]+m/z 428.1
[实施例83至85]
以与实施例82的步骤2)相同的方法获得以下[表2]中列出的实施例83至85的化合物。
【表2】
[实施例86]N-(4-氨基苯基)-5-(苯并[d]噻唑-6-基)-1-(6-甲基吡啶-2-基)-1H- 吡唑-3-羧酰胺
将实施例14中合成的5-(苯并[d]噻唑-6-基)-1-(6-甲基吡啶-2-基)-N-(4-硝基苯基)-1H-吡唑-3-羧酰胺(65mg,0.14mmol)溶解于乙醇(1.5mL)和二氯甲烷(3mL)后,在室温下向其中加入20%PdOH/C(20mg,30%w/w),并且在氢气下搅拌反应溶液13小时。将反应溶液通过硅藻土真空过滤,并将溶剂真空浓缩。使用柱色谱法纯化结果,得到目标化合物(20mg)。
1H NMR谱(300MHz,CDCl3)δ9.09(s,1H),8.05(d,1H),8.00(d,1H),7.63(t,1H),7.52(d,2H),7.36(d,1H),7.21(d,1H),7.18(s,1H),7.05(d,1H),6.74(d,2H),3.38(s,2H),2.51(s,3H)。
MS(ESI+):[M+H]+m/z 427.1
[实施例87]5-(苯并[d]噻唑-6-基)-N-(4-(丁基氨基)苯基)-1-(6-甲基吡啶-2- 基)-1H-吡唑-3-羧酰胺
步骤1叔丁基(4-(5-(苯并[d]噻唑-6-基))-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧
酰胺)苯基)(丁基)氨基甲酸酯
与实施例1相同的方法得到目标化合物(110mg),其中,用叔丁基(4-氨基苯基)(丁基)氨基甲酸酯代替p-茴香胺。
1H NMR谱(300MHz,CDCl3)δ9.05(s,1H),8.85(s,1H),8.05(d,1H),7.98(d,1H),7.71-7.64(m,3H),7.36(d,1H),7.20(td,5H),3.61(t,2H),2.44(s,3H),1.56-1.50(m,2H),1.43(s,9H),1.37-1.25(m,2H),0.90(t,3H)。
步骤2 5-(苯并[d]噻唑-6-基)-N-(4-(丁基氨基)苯基)-1-(6-甲基吡啶-2-基)-
1H-吡唑-3-羧酰胺
将步骤1中合成的叔丁基(4-(5-(苯并[d]噻唑-6-基))-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺)苯基)(丁基)-氨基甲酸酯(110mg,0.19mmol)溶解于二氯甲烷(1.5mL)后,在室温下向其中滴加4.0M盐酸1,4-二恶烷溶液(0.28mL,1.13mmol),将反应溶液在室温下搅拌13小时。向反应溶液中加入二氯甲烷后,用碳酸氢钠洗涤有机层,用无水硫酸镁干燥,过滤后,将滤液真空浓缩。使用柱色谱法纯化滤液,得到目标化合物(70mg)。
1H NMR谱(300MHz,CDCl3)δ9.05(s,1H),8.67(s,1H),8.06(d,1H),7.99(d,1H),7.67(t,1H),7.53(d,2H),7.36(d,1H),7.20(t,3H),6.64(d,2H),3.13(t,2H),2.44(s,3H),1.65-1.51(m,2H),1.51-1.41(m,2H),0.98(t,3H)。
MS(ESI+):[M+H]+m/z 483.2
[实施例88]
以与实施例87的步骤2)相同的方法获得以下[表3]中列出的实施例88的化合物。
【表3】
[实施例89]5-(苯并[d]噻唑-6-基)-1-(6-甲基吡啶-2-基)-N-(4-(S-甲基磺酰亚 胺基)苯基)-1H-吡唑-3-羧酰胺
步骤1乙基-((4-(5-(苯并[d]噻唑-6-基))-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧
酰胺)苯基)(甲基)(氧代)-λ6-硫烷基)氨基甲酸酯
以与实施例1相同的方式得到目标化合物(50mg),其中,用乙基((4-氨基苯基)(甲基)(氧代)-λ6-硫烷基)氨基甲酸乙酯代替p-茴香胺。
1H NMR谱(300MHz,CDCl3)δ9.16(s,1H),9.06(s,1H),8.06(d,1H),8.00-7.98(m,5H),7.67(t,1H),7.35(d,1H),7.23-7.17(m,3H),4.15-4.07(m,2H),3.33(s,3H),2.46(s,3H),1.24(t,3H)。
步骤2 5-(苯并[d]噻唑-6-基)-1-(6-甲基吡啶-2-基)-N-(4-(S-甲基磺酰亚胺
基)苯基)-1H-吡唑-3-羧酰胺
将步骤1中合成的乙基-((4-(5-(苯并[d]噻唑-6-基))-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺)苯基)(甲基)(氧代)-λ6-硫烷基)氨基甲酸酯(50mg,0.09mmol)溶解于乙醇(1.0mL)后,在室温下向其中逐滴加入1.5M乙醇钠乙醇溶液(0.30mL,0.45mmol),将反应溶液在60℃下搅拌5小时。向反应溶液中加入盐水后,使用二氯甲烷和甲醇的混合溶液萃取产物。用无水硫酸镁干燥有机层,过滤后,将滤液真空浓缩。使用柱色谱法纯化滤液,得到目标化合物(10mg)。
1H NMR谱(300MHz,CDCl3)δ9.16(s,1H),9.06(s,1H),8.08-7.92(m,6H),7.67(t,1H),7.35(d,1H),7.23-7.15(m,3H),3.13(t,2H),2.47(s,3H)。
MS(ESI+):[M+H]+m/z 489.1
[实施例90]5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-N-(2-甲氧基苯基)-1-(6-甲 基吡啶-2-基)-1H-吡唑-3-羧酰胺的制备
步骤1 5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-N-(4-甲氧基苯基)-1-(6-甲基吡
啶-2-基)-1H-吡唑-3-羧酰胺的制备
将制备实施例2的步骤4)中合成的5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酸(30mg,0.09mmol)溶解于N,N-二甲基甲酰胺(1mL)后,向其中加入HATU(42mg,0.11mmol)和DIPEA(34μL,0.28mmol),在室温下搅拌30分钟。向反应溶液中加入p-茴香胺(11μL,0.09mmol),在室温下搅拌12小时。产物用乙酸乙酯萃取,所得有机层用无水硫酸镁干燥,然后过滤。浓缩滤液,使用柱色谱法纯化,得到目标化合物(20mg,50%)。
1H NMR(300MHz,DMSO-d6)δ10.17(s,1H),9.18(s,1H),8.56(s,1H),7.96(m,1H),7.83-7.72(m,3H),7.54(m,1H),7.32(br,2H),6.96(d,2H),3.76(s,3H),2.17(s,3H)。
MS(ESI+):m/z 426[M+H]+。
[实施例91至163]
以与实施例4的步骤1)相同的方法获得以下[表1]中列出的实施例91至163的化合物,其中,用各种胺衍生物代替p-茴香胺。
【表4】
[实施例164]N-(4-甲氧基苯基)-1-(6-甲基吡啶-2-基)-5-(喹喔啉-6-基)-1H-吡
唑-3-羧酰胺的制备
将中间体3(50mg,0.15mmol)溶解于N,N-二甲基甲酰胺中后,向其中加入HATU(69mg,0.18mmol)和DIPEA(79μL,0.45mmol),并在室温下搅拌30分钟。向反应溶液中加入p-茴香胺(20mg,0.17mmol),在室温下搅拌12小时。过滤产生的固体,用乙酸乙酯洗涤,然后真空干燥,得到目标化合物(42mg)。
1H NMR谱(300MHz,DMSO-d6)δ10.1(s,1H),8.96(s,2H),8.07-7.93(m,3H),7.78-7.73(m,4H),7.37(br,2H),6.92(d,2H),3.75(s,3H),2.17(s,3H)。
MS(ESI+):[M+H]+m/z 437.1
[实施例165至201]
以与实施例160相同的方式获得以下[表5]中列出的实施例161至198的化合物,使用各种胺衍生物代替p-茴香胺。
【表5】
[实施例202]N-(2-氟苯基)-5-(喹喔啉-6-基)-1-(间甲苯基)-1H-吡唑-3-羧酰胺的制备
以与实施例160中相同的方法获得目标化合物(3mg),其中在制备实施例3的步骤3中使用苯肼代替2-肼基-6-甲基吡啶盐酸,并且在实施例160中用2-氟苯胺代替p-茴香胺。
1H NMR谱(300MHz,CDCl3)δ9.08(s,1H),8.87(s,2H),8.53(t,1H),8.07-8.03(m,2H),7.59(dd,1H),7.32(s,2H),7.24-7.07(m,6H),2.37(s,3H)。
MS(ESI+):[M+H]+m/z 424.2
[实施例203至208]
以与实施例202中相同的法获得以下[表6]中列出的实施例203至208的化合物。
【表6】
[实施例209]N-(2-氟苯基)-1-(6-甲基吡啶-2-基)-5-(喹啉-4-基)-1H-吡唑-3- 羧酰胺
将制备实施例4的步骤5中合成的1-(6-甲基吡啶-2-基)-5-(喹啉-4-基)-1H-吡唑-3-羧酸(40mg,0.1mmol)溶解于二氯甲烷中,向其中加入HATU(55mg,0.1mmol)和DIPEA(47μL,0.4mmol),并在室温下搅拌20分钟。向反应溶液中加入2-氟苯胺(13mg,0.1mmol),在室温下搅拌12小时。终止反应后,向其中加入乙酸乙酯。用碳酸氢钠洗涤,然后用无水硫酸镁干燥,过滤后浓缩滤液。使用柱色谱法纯化滤液,得到目标化合物(16mg)。
1H NMR谱(300MHz,CDCl3)δ9.17(s,1H),8.93(d,1H),8.55(t,1H),8.15(d,1H),7.69-7.60(m,4H),7.41(t,1H),7.33(d,1H),7.25-7.12(m,4H),6.95(d,1H),1.83(s,3H)。
MS(ESI+):[M+H]+m/z 424.2
[实施例210至217]
以与实施例209中相同的方式获得以下[表7]中列出的实施例210至217的化合物,使用各种胺衍生物代替2-氟苯胺。
【表7】
[实施例218]5-(苯并[c][1,2,5]恶二唑-5-基)-N-(4-(环丙基磺酰基)苯基)-1- (6-甲基吡啶-2-基))-1H-吡唑-3-羧酰胺
将制备实施例5的步骤5中合成的5-(苯并[c][1,2,5]恶二唑-5-基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酸(30mg,0.1mmol)溶解于二氯甲烷后,向其中加入HATU(43mg,0.1mmol)和DIPEA(48μL,0.3mmol),在室温下搅拌20分钟。向反应溶液中加入4-(环丙基磺酰基)苯胺(21mg,0.1mmol),在室温下搅拌12小时。终止反应后,向其中加入乙酸乙酯。用碳酸氢钠洗涤,然后用无水硫酸镁干燥,过滤后浓缩滤液。使用柱色谱法纯化滤液,得到目标化合物(5mg)。
1H NMR谱(300MHz,CDCl3)δ9.02(s,1H),7.93(s,4H),7.84-7.75(m,3H),7.60(s,1H),7.31-7.26(m,2H),7.18(d,1H),2.50-2.45(m,1H),2.28(s,3H),1.39-1.34(m,2H),1.06-1.03(m,2H)。
MS(ESI+):[M+H]+m/z 501
[实施例219]5-(苯并[d]恶唑-6-基)-N-(2-氟苯基)-1-(6-甲基吡啶-2-基)-1H- 吡唑-3-羧酰胺
将制备实施例6的步骤6合成的5-(苯并[d]恶唑-6-基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酸(50mg,0.2mmol)溶解于二氯甲烷后,加入HATU(71mg,0.2mmol)和DIPEA(81μL,0.5mmol),在室温下搅拌20分钟。向反应溶液中加入2-氟苯胺(17mg,0.2mmol),在室温下搅拌12小时。终止反应后,向其中加入乙酸乙酯。用碳酸氢钠洗涤,然后用无水硫酸镁干燥,过滤后浓缩滤液。使用柱色谱法纯化滤液,得到目标化合物(29mg)。
1H NMR谱(300MHz,CDCl3)δ9.09(s,1H),8.51(t,1H),8.13(s,1H),7.74-7.70(m,2H),7.58(d,1H),7.34-7.26(m,2H),7.18-7.11(m,5H),2.37(s,3H)。
MS(ESI+):[M+H]+m/z 414
[实施例220至227]
以与实施例219中相同的方法,其中,用各种胺代替2-氟苯胺,使用在制备实施例中制备的化合物,获得以下[表8]中列出的实施例220至227的化合物。
【表8】
配方实施例1:片剂的制备
根据常规方法,使用下表9的成分以相应的量制备含有实施例1至227中制备的每种化合物作为活性化合物的单一口服片剂。
【表9】
成分 | 每片的含量 |
活性化合物 | 100毫克 |
玉米淀粉 | 80毫克 |
乳糖 | 80毫克 |
硬脂酸镁 | 5毫克 |
配方实施例2:胶囊的制备
根据常规方法,使用下表10的成分以相应的量制备含有实施例1至227中制备的每种化合物作为活性化合物的用于口服给药的硬明胶胶囊。
【表10】
成分 | 每粒胶囊的含量 |
活性化合物 | 100毫克 |
玉米淀粉 | 80毫克 |
乳糖 | 80毫克 |
结晶纤维素 | 80毫克 |
硬脂酸镁 | 5毫克 |
配方实施例3:注射用制剂的制备
根据常规方法,使用下表11的成分以与其相应的量制备含有实施例1至227中制备的每种化合物作为活性化合物的注射用制剂。然而,当使用化学式1的化合物的盐作为活性化合物时,不调节pH。
【表11】
配方实施例4:注射用制剂的制备
根据常规方法,使用下表12的成分以与其相应的量制备含有实施例1至227中制备的每种化合物作为活性化合物的注射用制剂。
【表12】
成分 | 每个注射制剂的含量 |
活性化合物 | 20毫克 |
聚乙二醇400 | 2毫升 |
灭菌水 | 8毫升 |
实验实施例1:ALK5酶活性抑制试验
对于实施例1至227中获得的每种化合物,测量其对ALK5激酶的抑制活性。
为此,使用LanthaScreen Eu激酶结合测定的方法,并且ALK5激酶、激酶缓冲液、激酶示踪剂178和LanthaScreen Eu-GST结合抗体均购自Thermo Fisher ScientificSolutions。将每种化合物制成10mM DMSO溶液,并用含有4%DMSO的水溶液10倍稀释至1μM至0.0001μM的不等浓度。该试验在384孔板(聚苯乙烯低体积圆底板)中进行。首先,加入5μL稀释的化合物溶液,然后向其中加入5μL激酶/抗体混合物溶液,并向其中加入5μL示踪剂。在此,将这些加入到每个孔中,使得最终激酶浓度变为5nM,最终Eu-GST结合抗体浓度为2nM,激酶示踪物178浓度为10nM,并且在室温下在搅拌器中反应60分钟。然后使用荧光计(分子装置)(620nm激发滤光器,665nm发射滤光器)测量荧光值。在此,关于化合物抑制激酶反应的活性的程度,根据试剂盒中包含的实验方法,相对于对照组,磷酸化率计算为0%至100%,并且50%抑制浓度(IC50)值通过获得抑制50%活性的区域中的x轴浓度来计算。每种化合物的IC50结果如下表13所示。
【表13】
在上文中,已经参考实施例描述了本发明,然而,这些仅用于说明目的,并且应当理解,可以实现对于本领域技术人员显而易见的本发明的各种修改的和等同的其他实例,被包含在所附权利要求的范围内。
Claims (18)
1.如下式I所示的化合物或其药学上可接受的盐;
[化学式1]
其中,在化学式1中,
X是N或CH;
环A是C3-6亚环烷基、C6-10亚芳基、含有1至4个选自N、O和S的杂原子的C5-10亚杂芳基,或含有1至4个选自N,O和S的杂原子的非芳族稠合杂多环;
各个R1各自独立地为氢、卤素,或直链或支链C1-6烷基或卤代C1-6烷基,并且当存在多个R1时,它们彼此相同或不同;
各个R2各自独立地为
R3是氢、卤素、直链或支链C1-6烷基、直链或支链卤代C1-6烷基、C3-10环烷基、未取代或被R4取代的C3-10杂环烷基、C6-10杂双环烷基、直链或支链C2-6烯基、C2-6炔基、-(CH2)a-R4、-(CH2)a-OR4、-(CH2)a-O-(CH2)a-R4、-(CH2)a-S-(CH2)a-R4、-(CH2)a-O-(CH2)a-OR4、-(CH2)a-NR4R5、-(CH2)a-NO2、-(CH2)a-CN、-(CH2)a-COR4、-(CH2)a-CO2R4、-(CH2)a-CONR4R5、-(CH2)a-NHCOR4、-(CH2)a-SR4、-(CH2)a-NHSO2R4、-(CH2)aSOR6、-(CH2)a-SO2R6、-(CH2)a-SO2NHR6、-(CH2)a-SO(NH)R6或-(CH2)a-SO2NR4R5,或者当存在多个R3并且它们彼此相邻时,它们可以彼此连接以形成具有环A的5元或6元环,其中包括一个或多个选自N、O和S原子的杂原子,并且所述杂原子可以进一步被氧化;
R4和R5各自独立地为氢、直链或支链C1-6烷基、直链或支链卤代C1-6烷基、C3-10环烷基、C3-6环烯基、C1-6羰基、C6-12芳基、-(CH2)b-NR6R7,或饱和或部分不饱和的5元至10元含有1至4个选自N、O和S的杂原子的单环或双环的杂环烷基或杂芳基;
R6和R7各自独立地为氢、羟基、C1-6烷基、卤代C1-6烷基或C3-6环烷基;
a和b是0至4的整数;和
l、m和n各自独立地为0至4的整数。
2.如权利要求1所述的化合物或其药学上可接受的盐,其特征在于,其中X是N,并且R1是C1-6烷基。
3.如权利要求1所述的化合物或其药学上可接受的盐,其特征在于,其中环A是苯基、吡唑、吡啶基或苯并[d][1,3]二氧杂环戊烯。
4.如权利要求1所述的化合物或其药学上可接受的盐,其特征在于,所述如化学式1所示的化合物为选自下组的化合物:
(1)5-(苯并[d]噻唑-6-基)-N-(4-甲氧基苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(2)5-(苯并[d]噻唑-6-基)-N-(4-乙氧基苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(3)5-(苯并[d]噻唑-6-基)-N-(4-(环丙基甲氧基)苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(4)5-(苯并[d]噻唑-6-基)-N-(4-(2-甲氧基乙氧基)苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(5)5-(苯并[d]噻唑-6-基)-1-(6-甲基吡啶-2-基)-N-(4-(三氟甲氧基)苯基)-1H-吡唑-3-羧酰胺;
(6)5-(苯并[d]噻唑-6-基)-N-(4-(苄氧基)苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(7)N-(苯并[d][1,3]二氧杂环戊烯-5-基)-5-(苯并[d]噻唑-6-基)-1-(6-甲基吡啶-2-基)-1-H-吡唑-3-羧酰胺;
(8)5-(苯并[d]噻唑-6-基)-N-(4-氟-3-甲氧基苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(9)5-(苯并[d]噻唑-6-基)-N-(2-氟-4-甲氧基苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(10)5-(苯并[d]噻唑-6-基)-N-(3-氟-4-甲氧基苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(11)5-(苯并[d]噻唑-6-基)-N-(3-氨基苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(12)5-(苯并[d]噻唑-6-基)-N-(3-(甲基氨基)苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(13)5-(苯并[d]噻唑-6-基)-N-(4-(二甲基氨基)苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(14)5-(苯并[d]噻唑-6-基)-1-(6-甲基吡啶-2-基)-N-(4-硝基苯基)-1H-吡唑-3-羧酰胺;
(15)5-(苯并[d]噻唑-6-基)-N-(4-((2-(二甲基氨基)乙基)(甲基)氨基)苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(16)5-(苯并[d]噻唑-6-基)-N-(4-(3-(二甲基氨基)吡咯烷-1-基)苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(17)5-(苯并[d]噻唑-6-基)-N-(3-氯-4-(八氢-6H-吡咯并[3,4-b]吡啶-6-基)苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(18)5-(苯并[d]噻唑-6-基)-1-(6-甲基吡啶-2-基)-N-苯基-1H-吡唑-3-羧酰胺;
(19)5-(苯并[d]噻唑-6-基)-N-(3-甲苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(20)5-(苯并[d]噻唑-6-基)-1-(6-甲基吡啶-2-基)-N-(3-乙烯基苯基)-1H-吡唑-3-羧酰胺;
(21)5-(苯并[d]噻唑-6-基)-N-(3-(三氟甲基)苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(22)5-(苯并[d]噻唑-6-基)-N-(3-(氰基苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(23)5-(苯并[d]噻唑-6-基)-N-(3-乙酰基苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(24)3-(5-(苯并[d]噻唑-6-基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺)苯乙酸酯;
(25)5-(苯并[d]噻唑-6-基)-N-(4-(甲基氨基甲酰基)苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(26)5-(苯并[d]噻唑-6-基)-N-(4-乙酰氨基苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(27)5-(苯并[d]噻唑-6-基)-N-(2-氟苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(28)5-(苯并[d]噻唑-6-基)-N-(3-氟苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(29)5-(苯并[d]噻唑-6-基)-N-(4-氟苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(30)5-(苯并[d]噻唑-6-基)-N-(3,4-二氟苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(31)5-(苯并[d]噻唑-6-基)-N-(2-氯苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(32)5-(苯并[d]噻唑-6-基)-N-(3-氯苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(33)5-(苯并[d]噻唑-6-基)-N-(4-氯苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(34)5-(苯并[d]噻唑-6-基)-N-(4-溴苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(35)5-(苯并[d]噻唑-6-基)-1-(6-甲基吡啶-2-基)-N-(3-(甲硫基)苯基)-1H-吡唑-3-羧酰胺;
(36)5-(苯并[d]噻唑-6-基)-1-(6-甲基吡啶-2-基)-N-(4-(甲硫基)苯基)-1H-吡唑-3-羧酰胺;
(37)5-(苯并[d]噻唑-6-基)-N-(4-(环丙基硫基)苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(38)5-(苯并[d]噻唑-6-基)-1-(6-甲基吡啶-2-基)-N-(3-(甲基亚磺酰基)苯基)-1H-吡唑-3-羧酰胺;
(39)5-(苯并[d]噻唑-6-基)-1-(6-甲基吡啶-2-基)-N-(4-(甲基亚磺酰基)苯基)-1H-吡唑-3-羧酰胺;
(40)5-(苯并[d]噻唑-6-基)-1-(6-甲基吡啶-2-基)-N-(3-(甲基磺酰基)苯基)-1H-吡唑-3-羧酰胺;
(41)5-(苯并[d]噻唑-6-基)-1-(6-甲基吡啶-2-基)-N-(4-(甲基磺酰基)苯基)-1H-吡唑-3-羧酰胺;
(42)5-(苯并[d]噻唑-6-基)-1-(6-甲基吡啶-2-基)-N-(4-(丙基磺酰基)苯基)-1H-吡唑-3-羧酰胺;
(43)5-(苯并[d]噻唑-6-基)-N-(4-(环丙基磺酰基)苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(44)5-(苯并[d]噻唑-6-基)-N-(2-氟-4-(甲基磺酰基)苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(45)5-(苯并[d]噻唑-6-基)-1-(6-甲基吡啶-2-基)-N-(3-氨磺酰基苯基)-1H-吡唑-3-羧酰胺;
(46)5-(苯并[d]噻唑-6-基)-1-(6-甲基吡啶-2-基)-N-(4-氨磺酰基苯基)-1H-吡唑-3-羧酰胺;
(47)5-(苯并[d]噻唑-6-基)-1-(6-甲基吡啶-2-基)-N-(3-(N-甲基氨磺酰基)苯基)-1H-吡唑-3-羧酰胺;
(48)5-(苯并[d]噻唑-6-基)-1-(6-甲基吡啶-2-基)-N-(4-(N-甲基氨磺酰基)苯基)-1H-吡唑-3-羧酰胺;
(49)5-(苯并[d]噻唑-6-基)-N-(3-(N-环丙基氨磺酰基)苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(50)5-(苯并[d]噻唑-6-基)-N-(4-(N-环丙基氨磺酰基)苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(51)5-(苯并[d]噻唑-6-基)-N-(3-(N,N-二甲基氨磺酰基)苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(52)5-(苯并[d]噻唑-6-基)-N-(4-(N,N-二甲基氨磺酰基)苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(53)5-(苯并[d]噻唑-6-基)-1-(6-甲基吡啶-2-基)-N-(3-(甲基磺酰氨基)苯基)-1H-吡唑-3-羧酰胺;
(54)5-(苯并[d]噻唑-6-基)-N-(3-(环丙烷磺酰氨基)苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(55)5-(苯并[d]噻唑-6-基)-N-(4-(环丙烷磺酰氨基)苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(56)4-(5-(苯并[d]噻唑-6-基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺)苯磺酸;
(57)5-(苯并[d]噻唑-6-基)-1-(6-甲基吡啶-2-基)-N-(4-((三氟甲基)磺酰基)苯基)-1H-吡唑-3-羧酰胺;
(58)5-(苯并[d]噻唑-6-基)-1-(6-甲基吡啶-2-基)-N-(4-(N-(2,2,2-三氟乙基)氨磺酰基)苯基)-1H-吡唑-3-羧酰胺;
(59)5-(苯并[d]噻唑-6-基)-1-(6-甲基吡啶-2-基)-N-(4-((甲基磺酰基)甲基)苯基)-1H-吡唑-3-羧酰胺;
(60)5-(苯并[d]噻唑-6-基)-1-(6-甲基吡啶-2-基)-N-(3-(氨磺酰基甲基)苯基)-1H-吡唑-3-羧酰胺;
(61)5-(苯并[d]噻唑-6-基)-1-(6-甲基吡啶-2-基)-N-(4-(氨磺酰基甲基)苯基)-1H-吡唑-3-羧酰胺;
(62)5-(苯并[d]噻唑-6-基)-N-(4-氟-3-(氨磺酰基甲基)苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(63)5-(苯并[d]噻唑-6-基)-N-(4-((1,1-二氧代四氢噻吩-3-基)氨基)苯基)-1-(6-甲基吡啶-吡啶-2-基)-1H-吡唑-3-羧酰胺;
(64)5-(苯并[d]噻唑-6-基)-1-(6-甲基吡啶-2-基)-N-(吡啶-4-基)-1H-吡唑-3-羧酰胺;
(65)5-(苯并[d]噻唑-6-基)-N-(6-甲氧基吡啶-3-基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(66)5-(苯并[d]噻唑-6-基)-N-(2-甲氧基吡啶-4-基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(67)5-(苯并[d]噻唑-6-基)-N-(6-(甲硫基)吡啶-3-基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(68)5-(苯并[d]噻唑-6-基)-1-(6-甲基吡啶-2-基)-N-(6-(甲基磺酰基)吡啶-2-基)-1H-吡唑-3-羧酰胺;
(69)5-(苯并[d]噻唑-6-基)-N-(6-(甲基磺酰基)吡啶-3-基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(70)5-(苯并[d]噻唑-6-基)-1-(6-甲基吡啶-2-基)-N-(2-(甲基磺酰基)吡啶-4-基)-1H-吡唑-3-羧酰胺;
(71)5-(苯并[d]噻唑-6-基)-N-(6-氟吡啶-3-基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(72)5-(苯并[d]噻唑-6-基)-N-(2-氟吡啶-4-基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(73)5-(苯并[d]噻唑-6-基)-N-(6-氯吡啶-3-基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(74)5-(苯并[d]噻唑-6-基)-N-(2-氯吡啶-4-基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(75)5-(苯并[d]噻唑-6-基)-1-(6-甲基吡啶-2-基)-N-(噻唑-2-基)-1H-吡唑-3-羧酰胺;
(76)5-(苯并[d]噻唑-6-基)-N-苄基-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(77)5-(苯并[d]噻唑-6-基)-N-(2-氟苄基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(78)5-(苯并[d]噻唑-6-基)-N-(3-氟苄基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(79)5-(苯并[d]噻唑-6-基)-N-(4-氟苄基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(80)5-(苯并[d]噻唑-6-基)-1-(6-甲基吡啶-2-基)-N-(1-(甲基磺酰基)-1H-吡唑-4-基)-1H-吡唑-3-羧酰胺;
(81)5-(苯并[d]噻唑-6-基)-N-(1-(环丙基磺酰基)-1H-吡唑-4-基)-1-(6-甲基吡啶-2-基))-1H-吡唑-3-羧酰胺;
(82)5-(苯并[d]噻唑-6-基)-N-(3-羟基苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(83)5-(苯并[d]噻唑-6-基)-N-(4-羟基苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(84)5-(苯并[d]噻唑-6-基)-N-(3-(羟甲基)苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(85)5-(苯并[d]噻唑-6-基)-N-(4-(羟甲基)苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(86)N-(4-氨基苯基)-5-(苯并[d]噻唑-6-基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(87)5-(苯并[d]噻唑-6-基)-N-(4-(丁基氨基)苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(88)5-(苯并[d]噻唑-6-基)-N-(4-(环丙基氨基)苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(89)5-(苯并[d]噻唑-6-基)-1-(6-甲基吡啶-2-基)-N-(4-(S-甲基磺酰亚胺基)苯基)-1H-吡唑-3-羧酰胺;
(90)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-N-(2-甲氧基苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(91)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-N-(3-甲氧基苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(92)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-N-(2-甲氧基苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(93)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-N-(4-羟基苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(94)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-N-(4-异丙基苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(95)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-N-(4-(2-甲氧基乙氧基)苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(96)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-N-(苯并[d][1,3]二氧杂环戊烯-5-基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(97)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-N-(2-氟-4-甲氧基苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(98)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-N-(3-氟-4-甲氧基苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(99)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-1-(6-甲基吡啶-2-基)-N-(2-(三氟甲氧基)苯基)-1H-吡唑-3-羧酰胺;
(100)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-1-(6-甲基吡啶-2-基)-N-(3-(三氟甲氧基)苯基)-1H-吡唑-3-羧酰胺;
(101)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-1-(6-甲基吡啶-2-基)-N-(4-(三氟甲氧基)苯基)-1H-吡唑-3-羧酰胺;
(102)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-N-(3-(二甲基氨基)苯基)-1-(6-甲基吡啶-2-基)-1-H-吡唑-3-羧酰胺;
(103)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-N-(4-氨基苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(104)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-N-(4-(二甲基氨基)苯基)-1-(6-甲基吡啶-2-基)-1-H-吡唑-3-羧酰胺;
(105)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-N-(4-(吡咯烷-1-基)苯基)1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(106)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-N-(4-((2-(二甲基氨基)乙基)(甲基)氨基)苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(107)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-N-(4-(4-甲基哌嗪-1-基)苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(108)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-N-(4-(4-乙酰基哌嗪-1-基)苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(109)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-N-(4-((1,1-二氧代四氢噻吩-3-基)氨基)苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(110)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-N-(4-乙酰氨基苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(111)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-N-(4-((二甲基氨基)甲基)苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(112)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-N-(2-(甲基氨基甲酰基)苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(113)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-N-(4-(甲基氨基甲酰基)苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(114)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-1-(6-甲基吡啶-2-基)-N-苯基-1H-吡唑-3-羧酰胺;
(115)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-1-(6-甲基吡啶-2-基)-N-(邻-甲苯基)-1H-吡唑-3-羧酰胺;
(116)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-1-(6-甲基吡啶-2-基)-N-(间-甲苯基)-1H-吡唑-3-羧酰胺;
(117)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-1-(6-甲基吡啶-2-基)-N-(对-甲苯基)-1H-吡唑-3-羧酰胺;
(118)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-1-(6-甲基吡啶-2-基)-N-(3-(三氟甲基)苯基)-1H-吡唑-3-羧酰胺;
(119)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-1-(6-甲基吡啶-2-基)-N-(4-乙烯基苯基)-1H-吡唑-3-羧酰胺;
(120)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-N-(3-氰基苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(121)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-N-(4-氰基苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(122)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-N-(3-乙酰基苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(123)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-N-(4-乙酰基苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(124)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-N-(2-氟苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(125)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-N-(3-氟苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(126)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-N-(4-氟苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(127)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-N-(2-氯苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(128)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-N-(3-氯苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(129)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-N-(4-氯苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(130)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-N-(2-溴苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(131)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-N-(3-溴苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(132)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-N-(4-溴苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(133)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-N-(2,3-二氟苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(134)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-N-(2,4-二氟苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(135)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-N-(2,5-二氟苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(136)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-N-(3,4-二氟苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(137)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-N-(3,5-二氟苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(138)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-N-(3-氯-2-氟苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(139)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-N-(4-氯-2-氟苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(140)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-N-(3-氯-4-氟苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(141)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-N-(3,4-二氯苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(142)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-N-(2-溴-4-氟苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(143)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-N-(3-(甲氧基硫基)苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(144)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-N-(4-(甲氧基硫基)苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(145)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-N-(3-(甲基亚磺酰基)苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(146)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-N-(4-(甲基亚磺酰基)苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(147)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-N-(4-(甲基磺酰基)苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(148)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-N-(4-氨磺酰基苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(149)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-N-(4-(S-甲基磺亚胺酰基)苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(150)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-N-(4-(丙基磺酰基)苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(151)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-N-(4-(丙基磺酰基)苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(152)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-N-(6-氟吡啶-3-基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(153)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-N-(6-氯吡啶-3-基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(154)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-N-(6-甲氧基吡啶-3-基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(155)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-N-(2-氟苄基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(156)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-N-(3-氟苄基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(157)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-N-(4-氟苄基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(158)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-N-(3-甲氧基苄基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(159)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-N-(4-甲氧基苄基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(160)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-N-(4-(二甲基氨基)苄基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(161)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-N-(-乙酰氨基苄基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(162)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-1-(6-甲基吡啶-2-基)-N-(1-(甲基磺酰基)-1H-吡唑-4-基)-1H-吡唑-3-羧酰胺;
(163)5-([1,2,4]三唑并[1,5-α]吡啶-6-基)-N-(1-环丙基磺酰基)-1H-吡唑-4-基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(164)N-(4-甲氧基苯基)-1-(6-甲基吡啶-2-基)-5-(喹喔啉-6-基)-1H-吡唑-3-羧酰胺;
(165)N-(3-甲氧基苯基)-1-(6-甲基吡啶-2-基)-5-(喹喔啉-6-基)-1H-吡唑-3-羧酰胺;
(166)N-(2-甲氧基苯基)-1-(6-甲基吡啶-2-基)-5-(喹喔啉-6-基)-1H-吡唑-3-羧酰胺;
(167)N-(4-(2-甲氧基乙氧基)苯基)-1-(6-甲基吡啶-2-基)-5-(喹喔啉-6-基)-1H-吡唑-3-羧酰胺;
(168)N-(苯并[d][1,3]二氧杂环戊烯-5-基)-1-(6-甲基吡啶-2-基)-5-(喹喔啉-6-基)-1H-吡唑-3-羧酰胺;
(169)N-(2,3-二氢苯并[b][1,4]二恶英-6-基)-1-(6-甲基吡啶-2-基)-5-(喹喔啉-6-基)-1H-吡唑-3-羧酰胺;
(170)N-(4-(二甲基氨基)苯基)-1-(6-甲基吡啶-2-基)-5-(喹喔啉-6-基)-1H-吡唑-3-羧酰胺;
(171)1-(6-甲基吡啶-2-基)-N-(4-吗啉代苯基)-5-(喹喔啉-6-基)-1H-吡唑-3-羧酰胺;
(172)N-(4-(4-甲基哌嗪-1-基)苯基)-1-(6-甲基吡啶-2-基)-5-(喹喔啉-6-基)-1H-吡唑-3-羧酰胺;
(173)N-(4-(4-乙酰基哌嗪-1-基)苯基)-1-(6-甲基吡啶-2-基)-5-(喹喔啉-6-基)-1H-吡唑-3-羧酰胺;
(174)N-(4-氰基苯基)-1-(6-甲基吡啶-2-基)-5-(喹喔啉-6-基)-1H-吡唑-3-羧酰胺;
(175)N-(3-氰基苯基)-1-(6-甲基吡啶-2-基)-5-(喹喔啉-6-基)-1H-吡唑-3-羧酰胺;
(176)N-(2-氰基苯基)-1-(6-甲基吡啶-2-基)-5-(喹喔啉-6-基)-1H-吡唑-3-羧酰胺;
(177)1-(6-甲基吡啶-2-基)-N-(4-(吗啉代甲基)苯基)-5-(喹喔啉-6-基)-1H-吡唑-3-羧酰胺;
(178)N-(4-乙酰基苯基)-1-(6-甲基吡啶-2-基)-5-(喹喔啉-6-基)-1H-吡唑-3-羧酰胺;
(179)N-(3-乙酰基苯基)-1-(6-甲基吡啶-2-基)-5-(喹喔啉-6-基)-1H-吡唑-3-羧酰胺;
(180)1-(6-甲基吡啶-2-基)-5-(喹喔啉-6-基)-N-(4-(三氟甲基)苯基)-1H-吡唑-3-羧酰胺;
(181)1-(6-甲基吡啶-2-基)-5-(喹喔啉-6-基)-N-(3-(三氟甲基)苯基)-1H-吡唑-3-羧酰胺;
(182)N-(4-(甲基氨基甲酰基)苯基)-1-(6-甲基吡啶-2-基)-5-(喹喔啉-6-基)-1H-吡唑-3-羧酰胺;
(183)N-(4-氟苯基)-1-(6-甲基吡啶-2-基)-5-(喹喔啉-6-基)-1H-吡唑-3-羧酰胺;
(184)N-(3-氟苯基)-1-(6-甲基吡啶-2-基)-5-(喹喔啉-6-基)-1H-吡唑-3-羧酰胺;
(185)N-(2-氟苯基)-1-(6-甲基吡啶-2-基)-5-(喹喔啉-6-基)-1H-吡唑-3-羧酰胺;
(186)N-(3,4-二氟苯基)-1-(6-甲基吡啶-2-基)-5-(喹喔啉-6-基)-1H-吡唑-3-羧酰胺;
(187)N-(2,4-二氟苯基)-1-(6-甲基吡啶-2-基)-5-(喹喔啉-6-基)-1H-吡唑-3-羧酰胺;
(188)N-(2,3-二氟苯基)-1-(6-甲基吡啶-2-基)-5-(喹喔啉-6-基)-1H-吡唑-3-羧酰胺;
(189)N-(4-氯苯基)-1-(6-甲基吡啶-2-基)-5-(喹喔啉-6-基)-1H-吡唑-3-羧酰胺;
(190)N-(2-氯苯基)-1-(6-甲基吡啶-2-基)-5-(喹喔啉-6-基)-1H-吡唑-3-羧酰胺;
(191)N-(4-溴苯基)-1-(6-甲基吡啶-2-基)-5-(喹喔啉-6-基)-1H-吡唑-3-羧酰胺;
(192)N-(6-甲氧基吡啶-3-基)-1-(6-甲基吡啶-2-基)-5-(喹喔啉-6-基)-1H-吡唑-3-羧酰胺;
(193)N-(4-甲氧基苄基)-1-(6-甲基吡啶-2-基)-5-(喹喔啉-6-基)-1H-吡唑-3-羧酰胺;
(194)N-(4-氰基苄基)-1-(6-甲基吡啶-2-基)-5-(喹喔啉-6-基)-1H-吡唑-3-羧酰胺;
(195)N-(3-乙酰基苄基)-1-(6-甲基吡啶-2-基)-5-(喹喔啉-6-基)-1H-吡唑-3-羧酰胺;
(196)N-(4-氟苄基)-1-(6-甲基吡啶-2-基)-5-(喹喔啉-6-基)-1H-吡唑-3-羧酰胺;
(197)N-(3-氟苄基)-1-(6-甲基吡啶-2-基)-5-(喹喔啉-6-基)-1H-吡唑-3-羧酰胺;
(198)N-(2-氟苄基)-1-(6-甲基吡啶-2-基)-5-(喹喔啉-6-基)-1H-吡唑-3-羧酰胺;
(199)N-(4-氯苄基)-1-(6-甲基吡啶-2-基)-5-(喹喔啉-6-基)-1H-吡唑-3-羧酰胺;
(200)N-(3-氯苄基)-1-(6-甲基吡啶-2-基)-5-(喹喔啉-6-基)-1H-吡唑-3-羧酰胺;
(201)N-(2-氯苄基)-1-(6-甲基吡啶-2-基)-5-(喹喔啉-6-基)-1H-吡唑-3-羧酰胺;
(202)N-(2-氟苯基)-5-(喹喔啉-6-基)-1-(m-甲苯基)-1H-吡唑-3-羧酰胺;
(203)1-(5-氯-2-氟苯基)-N-(4-甲氧基苯基)-5-(喹喔啉-6-基)-1H-吡唑-3-羧酰胺;
(204)1-(5-氯-2-氟苯基)-N-(4-(二甲基氨基)苯基)-5-(喹喔啉-6-基)-1H-吡唑-3-羧酰胺;
(205)N-(4-甲氧基苯基)-5-(喹喔啉-6-基)-1-(6-三氟甲基)吡啶-2-基)-1H-吡唑-3-羧酰胺;
(206)N-(4-(二甲基氨基)苯基)-5-(喹喔啉-6-基)-1-(6-三氟甲基)吡啶-2-基)-1H-吡唑-3-羧酰胺;
(207)1-(6-溴吡啶-2-基)-N-(4-甲氧基苯基)-5-(喹喔啉-6-基)-1H-吡唑-3-羧酰胺;
(208)1-(6-溴吡啶-2-基)-N-(4-(二甲基氨基)苯基)-5-(喹喔啉-6-基)-1H-吡唑-3-羧酰胺;
(209)N-(2-氟苯基)-1-(6-甲基吡啶-2-基)-5-(喹啉-4-基)-1H-吡唑-3-羧酰胺;
(210)N-(4-甲氧基苯基)-1-(6-甲基吡啶-2-基)-5-(喹啉-4-基)-1H-吡唑-3-羧酰胺;
(211)1-(6-甲基吡啶-2-基)-N-(4-(甲基磺酰基)苯基)-5-(喹啉-4-基)-1H-吡唑-3-羧酰胺;
(212)N-(6-甲氧基吡啶-3-基)-1-(6-甲基吡啶-2-基)-5-(喹啉-4-基)-1H-吡唑-3-羧酰胺;
(213)N-(6-氯吡啶-3-基)-1-(6-甲基吡啶-2-基)-5-(喹啉-4-基)-1H-吡唑-3-羧酰胺;
(214)N-(苯并[d][1,3]二氧杂环戊烯-5-基)-1-(6-甲基吡啶-2-基)-5-(喹啉-4-基)-1H-吡唑-3-羧酰胺;
(215)N-(3-氟-4-甲氧基苯基)-1-(6-甲基吡啶-2-基)-5-(喹啉-4-基)-1H-吡唑-3-羧酰胺;
(216)N-(2-氟-4-甲氧基苯基)-1-(6-甲基吡啶-2-基)-5-(喹啉-4-基)-1H-吡唑-3-羧酰胺;
(217)N-(4-(2-甲氧基乙氧基)苯基)-1-(6-甲基吡啶-2-基)-5-(喹啉-4-基)-1H-吡唑-3-羧酰胺;
(218)5-(苯并[c][1,2,5]恶二唑-5-基)-N-(4-(环丙基磺酰基)苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(219)5-(苯并[d]恶唑-6-基)-N-(2-氟苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(220)5-(苯并[d]恶唑-6-基)-N-(4-(环丙基磺酰基)苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3羧酰胺;
(221)N-环丙基-5-(4-氟-3-(1-(2-羟基乙基)-1H-吡唑-4-基)苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(222)N-(1H-吡唑-4-基)-5-(4-氟-3-(1-(2-羟基乙基)-1H-吡唑-4-基)苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(223)N-(1-甲基-1H-吡唑-4-基)-5-(4-氟-3-(1-(2-羟乙基)-1H-吡唑-4基)苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(224)N-(1-甲基磺酰基-1H-吡唑-4-基)-5-(4-氟-3-(1-(2-羟乙基)-1H-吡唑-4基)苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(225)N-(4-氯苯基)-5-(4-氟-3-(1-(2-羟基乙基)-1H-吡唑-4-基)苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;
(226)N-(4-(甲基磺酰基)苯基)-5-(4-氟-3-(1-(2-羟基乙基)-1H-吡唑-4-基)苯基)-1-(6-甲基吡啶-2-基)-1H-吡唑-3-羧酰胺;和
(227)N-(2-氟苯基)-5-(噻吩并[3,2,c]吡啶-2-基)-1-(间-甲苯基)-1H-吡唑-3-羧酰胺。
5.一种药物组合物,其特征在于,包含药学有效量的权利要求1所述的化合物或其药学上可接受的盐。
6.一种药物组合物,其特征在于,包含药学有效量的权利要求4所述的化合物或其药学上可接受的盐。
7.一种抑制对象或细胞中TGF-β信号传导途径的方法,其特征在于,所述方法包括向有需要的对象施用药学有效量的权利要求1所述的化合物。
8.一种抑制对象或细胞中TGF-β信号传导途径的方法,其特征在于,所述方法包括向有需要的对象施用药学有效量的权利要求4所述的化合物。
9.一种治疗或预防受试者的纤维化疾病或纤维化病症的方法,其特征在于,所述方法包括向有需要的受试者施用药学有效量的权利要求1所述的化合物。
10.如权利要求9所述的方法,其特征在于,所述纤维化疾病或纤维化病症选自硬皮病、特发性肺纤维化、肾小球性肾炎、糖尿病肾病、狼疮肾病、高血压引起的肾病、眼瘢痕、角膜瘢痕、肝纤维化、胆管纤维化、肺纤维化、急性肺损伤、梗死后心肌纤维化、纤维硬化、纤维性癌、纤维瘤、胸膜纤维瘤、纤维腺瘤或纤维肉瘤。
11.一种抑制受试者中癌细胞转移的方法,其特征在于,所述方法包括向有需要的对象施用药学有效量的权利要求1所述的化合物。
12.一种治疗由TGFβ过表达介导的癌症的方法,其特征在于,所述方法包括向需要治疗由TGFβ过表达介导的癌症的受试者施用药学有效量的权利要求1所述的化合物。
13.如权利要求12所述的方法,其特征在于,所述癌选自肺癌、乳腺癌、肝癌、胆道癌、胃肠道癌、头颈癌、胰腺癌、前列腺癌和宫颈癌、多发性骨髓瘤、黑素瘤、神经胶质瘤和胶质母细胞瘤。
14.如权利要求5或6所述的药物组合物,其特征在于,用于预防或治疗纤维化疾病或纤维化病症。
15.如权利要求14所述的药物组合物,其特征在于,所述纤维化疾病或纤维化病症包括一种或多种选自下组的疾病:肝纤维化、肾纤维化、肺纤维化、过敏性肺炎、间质纤维化、系统性硬皮病、黄斑变性、胰腺纤维化、脾纤维化、心脏纤维化、物种脓毒性纤维化、骨髓纤维化、血管纤维化、皮肤纤维化、眼纤维化、关节纤维化、肌纤维化、甲状腺纤维化、心内膜心肌纤维化、腹膜纤维化、后腹膜纤维化、进行性先天性滋养细胞纤维化、异体系统性纤维化、手术纤维化并发症和感染性纤维化。
16.如权利要求5或6所述的药物组合物,其特征在于,用于预防或治疗癌症或肿瘤。
17.如权利要求16所述的药物组合物,其特征在于,所述癌症选自下组:肝癌、肝细胞癌、甲状腺癌、结肠直肠癌、睾丸癌、骨癌、口腔癌、基底细胞癌、卵巢癌、脑肿瘤、胆囊癌、胆道癌、头颈癌、结直肠癌、膀胱癌、舌癌、食道癌、胶质瘤、胶质母细胞瘤、肾癌、恶性黑色素瘤、胃癌、乳腺癌、肉瘤、咽癌、子宫癌、宫颈癌、前列腺癌、直肠癌、胰腺癌、肺癌、皮肤癌和其他实体癌症。
18.权利要求6或7所述的药物组合物,其特征在于,用于预防或治疗选自下组的疾病:肾、肝或肺纤维化、肾小球肾炎、糖尿病肾病、红斑性肾炎、高血压引起的肾病、肾间质纤维化、源自药物暴露并发症的肾纤维化、HIV相关性肾病、器官移植坏疽、各种疾病引起的肝纤维化、感染引起的肝功能障碍、酒精性肝炎、胆道疾病、肺纤维化、急性肺损伤、成人呼吸疼痛综合征、特发性肺纤维化、慢性阻塞性肺疾病、由感染或毒性因素引起的肺纤维化、心肌梗塞后心肌纤维化、充血性心力衰竭、扩张型心肌病、心肌炎、血管狭窄、再狭窄、动脉粥样硬化、视觉障碍、角膜损伤、增生性玻璃体视网膜病变、外伤或手术伤口的伤口愈合期间发生的真皮中形成过度或加重瘢痕或瘢痕疙瘩、腹膜和皮下粘连、皮肤硬化、纤维硬化、进行性系统性硬化、皮肌炎、多发性肌炎、关节炎、骨质疏松症、溃疡、神经功能受损、男性阳痿、阿尔茨海默病、雷诺氏病、纤维性癌、转移性肿瘤生长、放射诱导的纤维化和血栓形成。
Applications Claiming Priority (7)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KR10-2016-0082824 | 2016-06-30 | ||
KR20160082824 | 2016-06-30 | ||
KR10-2016-0180401 | 2016-12-27 | ||
KR20160180401 | 2016-12-27 | ||
KR10-2017-0082868 | 2017-06-29 | ||
KR1020170082868A KR102434226B1 (ko) | 2016-06-30 | 2017-06-29 | Alk5 억제제로서의 신규 피라졸 유도체 및 이의 용도 |
PCT/KR2017/006940 WO2018004290A1 (ko) | 2016-06-30 | 2017-06-30 | Alk5 억제제로서의 신규 피라졸 유도체 및 이의 용도 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN109415346A true CN109415346A (zh) | 2019-03-01 |
Family
ID=61000232
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201780041502.0A Pending CN109415346A (zh) | 2016-06-30 | 2017-06-30 | 作为alk5抑制剂的新型吡唑衍生物及其用途 |
Country Status (9)
Country | Link |
---|---|
US (1) | US10954232B2 (zh) |
EP (1) | EP3480193B1 (zh) |
JP (1) | JP6921877B2 (zh) |
KR (1) | KR102434226B1 (zh) |
CN (1) | CN109415346A (zh) |
AU (1) | AU2017289021B2 (zh) |
CA (1) | CA3029175C (zh) |
IL (1) | IL263930A (zh) |
ZA (1) | ZA201900606B (zh) |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN113876769A (zh) * | 2021-09-30 | 2022-01-04 | 延边大学 | 一种含吡啶结构的吡唑类衍生物在制备抗肝纤维化药物中的应用 |
WO2022063050A1 (zh) * | 2020-09-28 | 2022-03-31 | 四川科伦博泰生物医药股份有限公司 | 吡唑类化合物及其制备方法和用途 |
CN114787145A (zh) * | 2019-11-28 | 2022-07-22 | 奥里戈生物制药有限公司 | 作为转化生长因子-β受体I/ALK5抑制剂的苯甲酰胺衍生物 |
CN114929345A (zh) * | 2019-11-01 | 2022-08-19 | 百时美施贵宝公司 | 作为toll受体抑制剂的经取代的吡唑化合物 |
WO2022252391A1 (zh) * | 2021-06-01 | 2022-12-08 | 苏州大学 | 吡唑衍生物在制备p2y6r相关治疗动脉粥样硬化及抗炎药物中的应用 |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101062916A (zh) * | 2006-04-29 | 2007-10-31 | 中国人民解放军军事医学科学院毒物药物研究所 | 三取代1h-吡唑化合物、其制备方法、药物组合物及其制药用途 |
CN101528752A (zh) * | 2006-10-16 | 2009-09-09 | 辉瑞产品公司 | 治疗性吡唑基噻吩并吡啶 |
Family Cites Families (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8084467B2 (en) * | 1999-10-18 | 2011-12-27 | University Of Connecticut | Pyrazole derivatives as cannabinoid receptor antagonists |
CO5271680A1 (es) * | 2000-02-21 | 2003-04-30 | Smithkline Beecham Corp | Compuestos |
CL2004000234A1 (es) * | 2003-02-12 | 2005-04-15 | Biogen Idec Inc | Compuestos derivados 3-(piridin-2-il)-4-heteroaril-pirazol sustituidos, antagonistas de aik5 y/o aik4; composicion farmaceutica y uso del compuesto en el tratamiento de desordenes fibroticos como esclerodermia, lupus nefritico, cicatrizacion de herid |
GB0313914D0 (en) * | 2003-06-16 | 2003-07-23 | Smithkline Beecham Corp | Compounds |
AU2005219737B2 (en) * | 2004-03-05 | 2009-11-19 | Taisho Pharmaceutical Co., Ltd. | Thiazole derivative |
KR100749566B1 (ko) * | 2004-04-21 | 2007-08-16 | 이화여자대학교 산학협력단 | Alk5 및/또는 alk4 억제제로 유효한 2-피리딜이치환된 이미다졸 유도체 |
CN101031294A (zh) * | 2004-07-29 | 2007-09-05 | 先灵-普劳有限公司 | Alk5抑制剂在调节或抑制导致动物瘦肉组织添加生长增强的肌肉生长抑制素活性中的用途 |
MX2007008781A (es) | 2005-01-21 | 2007-09-11 | Astex Therapeutics Ltd | Compuestos farmaceuticos. |
CA2629432A1 (en) * | 2005-12-16 | 2007-06-21 | Alcon, Inc. | Control of intraocular pressure using alk5 modulation agents |
CN101544631B (zh) * | 2008-03-26 | 2012-05-23 | 中国科学院上海药物研究所 | 吡唑类5-脂氧酶小分子抑制剂及其制备方法、药物组合物和应用 |
AU2009288158B2 (en) * | 2008-09-05 | 2014-09-11 | Engineering Fitness International Corp. | Adjustable user support platform for an inclinable exercise device and method of use |
US8080568B1 (en) * | 2010-06-29 | 2011-12-20 | Ewha University - Industry Collaboration Foundation | 2-pyridyl substituted imidazoles as therapeutic ALK5 and/or ALK4 inhibitors |
-
2017
- 2017-06-29 KR KR1020170082868A patent/KR102434226B1/ko active IP Right Grant
- 2017-06-30 EP EP17820566.2A patent/EP3480193B1/en active Active
- 2017-06-30 AU AU2017289021A patent/AU2017289021B2/en not_active Ceased
- 2017-06-30 JP JP2018568418A patent/JP6921877B2/ja active Active
- 2017-06-30 US US16/313,948 patent/US10954232B2/en active Active
- 2017-06-30 CA CA3029175A patent/CA3029175C/en not_active Expired - Fee Related
- 2017-06-30 CN CN201780041502.0A patent/CN109415346A/zh active Pending
-
2018
- 2018-12-24 IL IL263930A patent/IL263930A/en unknown
-
2019
- 2019-01-29 ZA ZA2019/00606A patent/ZA201900606B/en unknown
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101062916A (zh) * | 2006-04-29 | 2007-10-31 | 中国人民解放军军事医学科学院毒物药物研究所 | 三取代1h-吡唑化合物、其制备方法、药物组合物及其制药用途 |
CN101528752A (zh) * | 2006-10-16 | 2009-09-09 | 辉瑞产品公司 | 治疗性吡唑基噻吩并吡啶 |
Non-Patent Citations (2)
Title |
---|
XIAN PING DAI,等: "Synthesis and Biological Evaluation of Novel 1, 5-diarylpyrazole-3-carboxamide Compounds as Inhibitors of ALK5", 《CHINESE CHEMICAL LETTERS》 * |
代现平,等: "1 , 5-二取代吡唑-3-甲酰胺类新化合物的合成及其生物活性", 《中国药物化学杂志》 * |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN114929345A (zh) * | 2019-11-01 | 2022-08-19 | 百时美施贵宝公司 | 作为toll受体抑制剂的经取代的吡唑化合物 |
CN114787145A (zh) * | 2019-11-28 | 2022-07-22 | 奥里戈生物制药有限公司 | 作为转化生长因子-β受体I/ALK5抑制剂的苯甲酰胺衍生物 |
CN114787145B (zh) * | 2019-11-28 | 2024-03-26 | 阿戈麦布西班牙股份有限公司 | 作为转化生长因子-β受体I/ALK5抑制剂的苯甲酰胺衍生物 |
WO2022063050A1 (zh) * | 2020-09-28 | 2022-03-31 | 四川科伦博泰生物医药股份有限公司 | 吡唑类化合物及其制备方法和用途 |
WO2022252391A1 (zh) * | 2021-06-01 | 2022-12-08 | 苏州大学 | 吡唑衍生物在制备p2y6r相关治疗动脉粥样硬化及抗炎药物中的应用 |
CN113876769A (zh) * | 2021-09-30 | 2022-01-04 | 延边大学 | 一种含吡啶结构的吡唑类衍生物在制备抗肝纤维化药物中的应用 |
Also Published As
Publication number | Publication date |
---|---|
IL263930A (en) | 2019-01-31 |
US20190194198A1 (en) | 2019-06-27 |
JP2019520366A (ja) | 2019-07-18 |
JP6921877B2 (ja) | 2021-08-18 |
ZA201900606B (en) | 2020-05-27 |
CA3029175A1 (en) | 2018-01-04 |
CA3029175C (en) | 2021-01-05 |
US10954232B2 (en) | 2021-03-23 |
AU2017289021B2 (en) | 2020-06-25 |
NZ749951A (en) | 2020-03-27 |
EP3480193B1 (en) | 2024-05-29 |
EP3480193A4 (en) | 2020-04-08 |
AU2017289021A1 (en) | 2019-01-31 |
EP3480193A1 (en) | 2019-05-08 |
KR102434226B1 (ko) | 2022-08-19 |
KR20180003470A (ko) | 2018-01-09 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN109415346A (zh) | 作为alk5抑制剂的新型吡唑衍生物及其用途 | |
KR102181915B1 (ko) | Trka 키나아제 억제제로서 n-피롤리디닐, n'-피라졸릴-우레아, 티오우레아, 구아니딘 및 시아노구아니딘 화합물 | |
TWI394749B (zh) | 具有激酶抑制劑活性之雜戊環 | |
KR102007056B1 (ko) | 과증식성 질환 치료시 Bub1 키나제 저해제로 사용하기 위한 치환된 벤질인다졸 | |
CN108697714A (zh) | 新型稠合嘧啶化合物或其盐 | |
EP2942349A1 (en) | Enzyme modulators and treatments | |
WO2016026445A1 (zh) | 作为fgfr激酶抑制剂的吲唑类化合物及其制备和应用 | |
JP7264906B2 (ja) | ファルネソイドx受容体モジュレーターとしてのアルケン化合物 | |
JP5608097B2 (ja) | キナーゼ阻害薬としてのピロロピリジン | |
WO2020200158A1 (zh) | 用于治疗癌症的氮杂芳环酰胺衍生物 | |
AU2005245386A1 (en) | Nitrogenated heterocyclic derivatives as protein kinase modulators and use for the treatment of angiogenesis and cancer | |
KR20190034620A (ko) | 피페리딘 cxcr7 수용체 조절제 | |
JP6353556B2 (ja) | ナフチルアミド系化合物、その製造方法および使用 | |
JP2014129379A (ja) | キナーゼ阻害薬としてのピラゾロピリジン | |
AU2017290705A1 (en) | Compounds and compositions for the treatment of cancer | |
JP2019504826A (ja) | ヘテロ−1,5,6,7−テトラヒドロ−4h−インドール−4−オン類 | |
TW202104212A (zh) | 以雜環化合物作為激酶抑制劑的治療用途 | |
CN106068263A (zh) | 用于治疗癌症和增殖性疾病的抗有丝分裂酰胺 | |
JP5303271B2 (ja) | キナーゼ阻害剤として有用な1H−チエノ[2,3−c]ピラゾール化合物 | |
CN110177784A (zh) | 一种含芳环化合物、其制备方法、药物组合物及应用 | |
KR20180088412A (ko) | 아미노아졸 유도체 | |
TW202417429A (zh) | 用於抑制yap-tead交互作用的新穎雜雙環化合物及包含其之藥學組成物 | |
NZ749951B (en) | Novel pyrazole derivative as alk5 inhibitor and uses thereof | |
TW202416958A (zh) | 用於抑制yap-tead交互作用的新穎雜雙環化合物及包含其之藥學組成物 | |
AU2022292903A1 (en) | 3-substituted 1h-pyrrolo[2,3-b]pyridine as grk5 modulators |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
REG | Reference to a national code |
Ref country code: HK Ref legal event code: DE Ref document number: 40005144 Country of ref document: HK |
|
RJ01 | Rejection of invention patent application after publication |
Application publication date: 20190301 |