US20170333406A1 - Therapeutic compounds and uses thereof - Google Patents
Therapeutic compounds and uses thereof Download PDFInfo
- Publication number
- US20170333406A1 US20170333406A1 US15/667,227 US201715667227A US2017333406A1 US 20170333406 A1 US20170333406 A1 US 20170333406A1 US 201715667227 A US201715667227 A US 201715667227A US 2017333406 A1 US2017333406 A1 US 2017333406A1
- Authority
- US
- United States
- Prior art keywords
- alkyl
- independently selected
- optionally substituted
- membered
- carbocyclyl
- 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.)
- Abandoned
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 192
- 230000001225 therapeutic effect Effects 0.000 title description 4
- 102100038885 Histone acetyltransferase p300 Human genes 0.000 claims abstract description 126
- 101000882390 Homo sapiens Histone acetyltransferase p300 Proteins 0.000 claims abstract description 126
- 239000003112 inhibitor Substances 0.000 claims abstract description 87
- 150000003839 salts Chemical class 0.000 claims abstract description 76
- 238000000034 method Methods 0.000 claims abstract description 34
- 230000001404 mediated effect Effects 0.000 claims abstract description 33
- -1 —N(Rd)2 Chemical group 0.000 claims description 358
- 125000000623 heterocyclic group Chemical group 0.000 claims description 224
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 164
- 125000004452 carbocyclyl group Chemical group 0.000 claims description 143
- 125000004043 oxo group Chemical group O=* 0.000 claims description 135
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 85
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 83
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 67
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 52
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 52
- 229910052739 hydrogen Inorganic materials 0.000 claims description 50
- 229910052757 nitrogen Inorganic materials 0.000 claims description 45
- 208000035475 disorder Diseases 0.000 claims description 41
- 239000001257 hydrogen Substances 0.000 claims description 38
- 150000002431 hydrogen Chemical group 0.000 claims description 36
- 125000001246 bromo group Chemical group Br* 0.000 claims description 33
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 33
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 33
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 33
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 32
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 28
- 230000003176 fibrotic effect Effects 0.000 claims description 27
- 201000010099 disease Diseases 0.000 claims description 26
- 125000001072 heteroaryl group Chemical group 0.000 claims description 26
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 23
- 241001465754 Metazoa Species 0.000 claims description 19
- 208000005069 pulmonary fibrosis Diseases 0.000 claims description 18
- 229910052717 sulfur Inorganic materials 0.000 claims description 14
- 208000019693 Lung disease Diseases 0.000 claims description 13
- 125000006706 (C3-C6) carbocyclyl group Chemical group 0.000 claims description 12
- 229910052760 oxygen Inorganic materials 0.000 claims description 11
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 7
- 201000003883 Cystic fibrosis Diseases 0.000 claims description 6
- 201000009794 Idiopathic Pulmonary Fibrosis Diseases 0.000 claims description 6
- 208000029523 Interstitial Lung disease Diseases 0.000 claims description 6
- 229910052799 carbon Inorganic materials 0.000 claims description 6
- 208000019425 cirrhosis of liver Diseases 0.000 claims description 6
- 208000036971 interstitial lung disease 2 Diseases 0.000 claims description 6
- 208000011231 Crohn disease Diseases 0.000 claims description 5
- 208000008439 Biliary Liver Cirrhosis Diseases 0.000 claims description 4
- 208000033222 Biliary cirrhosis primary Diseases 0.000 claims description 4
- 206010008609 Cholangitis sclerosing Diseases 0.000 claims description 4
- 208000012654 Primary biliary cholangitis Diseases 0.000 claims description 4
- 230000001684 chronic effect Effects 0.000 claims description 4
- 208000010157 sclerosing cholangitis Diseases 0.000 claims description 4
- 206010058029 Arthrofibrosis Diseases 0.000 claims description 3
- 208000024934 IgG4-related mediastinitis Diseases 0.000 claims description 3
- 208000014919 IgG4-related retroperitoneal fibrosis Diseases 0.000 claims description 3
- 208000002260 Keloid Diseases 0.000 claims description 3
- 206010023330 Keloid scar Diseases 0.000 claims description 3
- 208000002805 Mediastinal fibrosis Diseases 0.000 claims description 3
- 208000003510 Nephrogenic Fibrosing Dermopathy Diseases 0.000 claims description 3
- 206010067467 Nephrogenic systemic fibrosis Diseases 0.000 claims description 3
- 206010036805 Progressive massive fibrosis Diseases 0.000 claims description 3
- 206010064911 Pulmonary arterial hypertension Diseases 0.000 claims description 3
- 206010038748 Restrictive cardiomyopathy Diseases 0.000 claims description 3
- 206010038979 Retroperitoneal fibrosis Diseases 0.000 claims description 3
- 201000010001 Silicosis Diseases 0.000 claims description 3
- 201000009594 Systemic Scleroderma Diseases 0.000 claims description 3
- 206010042953 Systemic sclerosis Diseases 0.000 claims description 3
- 125000005605 benzo group Chemical group 0.000 claims description 3
- 201000010048 endomyocardial fibrosis Diseases 0.000 claims description 3
- 210000001117 keloid Anatomy 0.000 claims description 3
- 206010028537 myelofibrosis Diseases 0.000 claims description 3
- 208000010125 myocardial infarction Diseases 0.000 claims description 3
- 201000004071 non-specific interstitial pneumonia Diseases 0.000 claims description 3
- 230000000414 obstructive effect Effects 0.000 claims description 3
- 201000000742 primary sclerosing cholangitis Diseases 0.000 claims description 3
- 230000002685 pulmonary effect Effects 0.000 claims description 3
- 201000002793 renal fibrosis Diseases 0.000 claims description 3
- 125000001475 halogen functional group Chemical group 0.000 claims 19
- 239000000203 mixture Substances 0.000 abstract description 45
- 238000011282 treatment Methods 0.000 abstract description 26
- 239000008194 pharmaceutical composition Substances 0.000 abstract description 4
- 125000005843 halogen group Chemical group 0.000 description 112
- 235000002639 sodium chloride Nutrition 0.000 description 72
- 230000014509 gene expression Effects 0.000 description 48
- 239000005557 antagonist Substances 0.000 description 46
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 46
- 102100040678 Programmed cell death protein 1 Human genes 0.000 description 43
- 101710089372 Programmed cell death protein 1 Proteins 0.000 description 41
- 206010028980 Neoplasm Diseases 0.000 description 40
- 125000003118 aryl group Chemical group 0.000 description 35
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 32
- 229940125763 bromodomain inhibitor Drugs 0.000 description 31
- 102000004887 Transforming Growth Factor beta Human genes 0.000 description 30
- 108090001012 Transforming Growth Factor beta Proteins 0.000 description 30
- 229940127089 cytotoxic agent Drugs 0.000 description 30
- 201000011510 cancer Diseases 0.000 description 29
- 239000003795 chemical substances by application Substances 0.000 description 29
- 125000001424 substituent group Chemical group 0.000 description 29
- 102000001805 Bromodomains Human genes 0.000 description 27
- 102100024213 Programmed cell death 1 ligand 2 Human genes 0.000 description 27
- 210000001744 T-lymphocyte Anatomy 0.000 description 27
- 108050009021 Bromodomains Proteins 0.000 description 25
- 108090000623 proteins and genes Proteins 0.000 description 25
- 108010006654 Bleomycin Proteins 0.000 description 21
- OYVAGSVQBOHSSS-UAPAGMARSA-O bleomycin A2 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C OYVAGSVQBOHSSS-UAPAGMARSA-O 0.000 description 21
- 125000004400 (C1-C12) alkyl group Chemical group 0.000 description 20
- 101000978776 Mus musculus Neurogenic locus notch homolog protein 1 Proteins 0.000 description 20
- 101100407308 Mus musculus Pdcd1lg2 gene Proteins 0.000 description 20
- 108700030875 Programmed Cell Death 1 Ligand 2 Proteins 0.000 description 20
- 229960001561 bleomycin Drugs 0.000 description 20
- 241000699670 Mus sp. Species 0.000 description 19
- 230000000694 effects Effects 0.000 description 19
- 108010033040 Histones Proteins 0.000 description 18
- 101001117317 Homo sapiens Programmed cell death 1 ligand 1 Proteins 0.000 description 18
- 102100024216 Programmed cell death 1 ligand 1 Human genes 0.000 description 17
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 17
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 17
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 17
- 108010077544 Chromatin Proteins 0.000 description 16
- 210000003483 chromatin Anatomy 0.000 description 16
- GLVAUDGFNGKCSF-UHFFFAOYSA-N mercaptopurine Chemical compound S=C1NC=NC2=C1NC=N2 GLVAUDGFNGKCSF-UHFFFAOYSA-N 0.000 description 16
- 125000003566 oxetanyl group Chemical group 0.000 description 16
- 125000005936 piperidyl group Chemical group 0.000 description 16
- 230000011664 signaling Effects 0.000 description 16
- 239000002246 antineoplastic agent Substances 0.000 description 15
- 239000002254 cytotoxic agent Substances 0.000 description 15
- 231100000599 cytotoxic agent Toxicity 0.000 description 15
- 125000006736 (C6-C20) aryl group Chemical group 0.000 description 14
- 210000004072 lung Anatomy 0.000 description 14
- 229960003301 nivolumab Drugs 0.000 description 14
- 239000003981 vehicle Substances 0.000 description 14
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 13
- 102000000589 Interleukin-1 Human genes 0.000 description 13
- 108010002352 Interleukin-1 Proteins 0.000 description 13
- 238000011529 RT qPCR Methods 0.000 description 13
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 13
- 239000003814 drug Substances 0.000 description 13
- 102000052116 epidermal growth factor receptor activity proteins Human genes 0.000 description 13
- 108700015053 epidermal growth factor receptor activity proteins Proteins 0.000 description 13
- YOHYSYJDKVYCJI-UHFFFAOYSA-N n-[3-[[6-[3-(trifluoromethyl)anilino]pyrimidin-4-yl]amino]phenyl]cyclopropanecarboxamide Chemical compound FC(F)(F)C1=CC=CC(NC=2N=CN=C(NC=3C=C(NC(=O)C4CC4)C=CC=3)C=2)=C1 YOHYSYJDKVYCJI-UHFFFAOYSA-N 0.000 description 13
- 125000004076 pyridyl group Chemical group 0.000 description 13
- 101000946843 Homo sapiens T-cell surface glycoprotein CD8 alpha chain Proteins 0.000 description 12
- 102100034922 T-cell surface glycoprotein CD8 alpha chain Human genes 0.000 description 12
- 230000003993 interaction Effects 0.000 description 12
- 239000011593 sulfur Substances 0.000 description 12
- 208000024891 symptom Diseases 0.000 description 12
- 102000008096 B7-H1 Antigen Human genes 0.000 description 11
- 229940121878 P300 inhibitor Drugs 0.000 description 11
- 230000015572 biosynthetic process Effects 0.000 description 11
- 210000004027 cell Anatomy 0.000 description 11
- 230000006698 induction Effects 0.000 description 11
- 108010074708 B7-H1 Antigen Proteins 0.000 description 10
- 239000002253 acid Substances 0.000 description 10
- 230000003247 decreasing effect Effects 0.000 description 10
- 210000002950 fibroblast Anatomy 0.000 description 10
- 125000003226 pyrazolyl group Chemical group 0.000 description 10
- 210000003289 regulatory T cell Anatomy 0.000 description 10
- QFJCIRLUMZQUOT-HPLJOQBZSA-N sirolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 QFJCIRLUMZQUOT-HPLJOQBZSA-N 0.000 description 10
- 239000002904 solvent Substances 0.000 description 10
- OQANPHBRHBJGNZ-FYJGNVAPSA-N (3e)-6-oxo-3-[[4-(pyridin-2-ylsulfamoyl)phenyl]hydrazinylidene]cyclohexa-1,4-diene-1-carboxylic acid Chemical compound C1=CC(=O)C(C(=O)O)=C\C1=N\NC1=CC=C(S(=O)(=O)NC=2N=CC=CC=2)C=C1 OQANPHBRHBJGNZ-FYJGNVAPSA-N 0.000 description 9
- 102100036732 Actin, aortic smooth muscle Human genes 0.000 description 9
- 102100031611 Collagen alpha-1(III) chain Human genes 0.000 description 9
- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 description 9
- 108010036949 Cyclosporine Proteins 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- 108090000246 Histone acetyltransferases Proteins 0.000 description 9
- 102000003893 Histone acetyltransferases Human genes 0.000 description 9
- 101000929319 Homo sapiens Actin, aortic smooth muscle Proteins 0.000 description 9
- 101000993285 Homo sapiens Collagen alpha-1(III) chain Proteins 0.000 description 9
- 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 9
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 9
- 239000000427 antigen Substances 0.000 description 9
- 108091007433 antigens Proteins 0.000 description 9
- 102000036639 antigens Human genes 0.000 description 9
- 125000002618 bicyclic heterocycle group Chemical group 0.000 description 9
- 125000004432 carbon atom Chemical group C* 0.000 description 9
- 239000003246 corticosteroid Substances 0.000 description 9
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 9
- 229960001428 mercaptopurine Drugs 0.000 description 9
- 229960000485 methotrexate Drugs 0.000 description 9
- 230000004044 response Effects 0.000 description 9
- 125000006413 ring segment Chemical group 0.000 description 9
- 230000019491 signal transduction Effects 0.000 description 9
- 229960001940 sulfasalazine Drugs 0.000 description 9
- 238000003786 synthesis reaction Methods 0.000 description 9
- OTTXCOAOKOEENK-UHFFFAOYSA-N 2,2-difluoroethenone Chemical group FC(F)=C=O OTTXCOAOKOEENK-UHFFFAOYSA-N 0.000 description 8
- YWPMKTWUFVOFPL-UHFFFAOYSA-N 3,4-dihydro-2h-isoquinolin-1-one Chemical group C1=CC=C2C(=O)NCCC2=C1 YWPMKTWUFVOFPL-UHFFFAOYSA-N 0.000 description 8
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 8
- 108020004414 DNA Proteins 0.000 description 8
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 8
- UETNIIAIRMUTSM-UHFFFAOYSA-N Jacareubin Natural products CC1(C)OC2=CC3Oc4c(O)c(O)ccc4C(=O)C3C(=C2C=C1)O UETNIIAIRMUTSM-UHFFFAOYSA-N 0.000 description 8
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 8
- LMEKQMALGUDUQG-UHFFFAOYSA-N azathioprine Chemical compound CN1C=NC([N+]([O-])=O)=C1SC1=NC=NC2=C1NC=N2 LMEKQMALGUDUQG-UHFFFAOYSA-N 0.000 description 8
- 229960002170 azathioprine Drugs 0.000 description 8
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 8
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 8
- 229960001265 ciclosporin Drugs 0.000 description 8
- 125000006255 cyclopropyl carbonyl group Chemical group [H]C1([H])C([H])([H])C1([H])C(*)=O 0.000 description 8
- 239000002552 dosage form Substances 0.000 description 8
- 231100000673 dose–response relationship Toxicity 0.000 description 8
- AAKJLRGGTJKAMG-UHFFFAOYSA-N erlotinib Chemical group C=12C=C(OCCOC)C(OCCOC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 AAKJLRGGTJKAMG-UHFFFAOYSA-N 0.000 description 8
- 229960002949 fluorouracil Drugs 0.000 description 8
- 238000009472 formulation Methods 0.000 description 8
- YLMAHDNUQAMNNX-UHFFFAOYSA-N imatinib methanesulfonate Chemical compound CS(O)(=O)=O.C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 YLMAHDNUQAMNNX-UHFFFAOYSA-N 0.000 description 8
- 230000005764 inhibitory process Effects 0.000 description 8
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical group C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 description 8
- BCFGMOOMADDAQU-UHFFFAOYSA-N lapatinib Chemical compound O1C(CNCCS(=O)(=O)C)=CC=C1C1=CC=C(N=CN=C2NC=3C=C(Cl)C(OCC=4C=C(F)C=CC=4)=CC=3)C2=C1 BCFGMOOMADDAQU-UHFFFAOYSA-N 0.000 description 8
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 8
- 125000004458 methylaminocarbonyl group Chemical group [H]N(C(*)=O)C([H])([H])[H] 0.000 description 8
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 8
- 238000010606 normalization Methods 0.000 description 8
- 239000001301 oxygen Substances 0.000 description 8
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 8
- ZAHRKKWIAAJSAO-UHFFFAOYSA-N rapamycin Natural products COCC(O)C(=C/C(C)C(=O)CC(OC(=O)C1CCCCN1C(=O)C(=O)C2(O)OC(CC(OC)C(=CC=CC=CC(C)CC(C)C(=O)C)C)CCC2C)C(C)CC3CCC(O)C(C3)OC)C ZAHRKKWIAAJSAO-UHFFFAOYSA-N 0.000 description 8
- 229960002930 sirolimus Drugs 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- NCEXYHBECQHGNR-UHFFFAOYSA-N sulfasalazine Natural products C1=C(O)C(C(=O)O)=CC(N=NC=2C=CC(=CC=2)S(=O)(=O)NC=2N=CC=CC=2)=C1 NCEXYHBECQHGNR-UHFFFAOYSA-N 0.000 description 8
- 125000005329 tetralinyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 8
- VLLMWSRANPNYQX-UHFFFAOYSA-N thiadiazole Chemical group C1=CSN=N1.C1=CSN=N1 VLLMWSRANPNYQX-UHFFFAOYSA-N 0.000 description 8
- WYWHKKSPHMUBEB-UHFFFAOYSA-N tioguanine Chemical compound N1C(N)=NC(=S)C2=C1N=CN2 WYWHKKSPHMUBEB-UHFFFAOYSA-N 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 239000005541 ACE inhibitor Substances 0.000 description 7
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 7
- 102000008186 Collagen Human genes 0.000 description 7
- 108010035532 Collagen Proteins 0.000 description 7
- 102000006947 Histones Human genes 0.000 description 7
- 101001117312 Homo sapiens Programmed cell death 1 ligand 2 Proteins 0.000 description 7
- 101000611183 Homo sapiens Tumor necrosis factor Proteins 0.000 description 7
- 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 7
- 102100040247 Tumor necrosis factor Human genes 0.000 description 7
- 239000002671 adjuvant Substances 0.000 description 7
- 229920001436 collagen Polymers 0.000 description 7
- 229960004397 cyclophosphamide Drugs 0.000 description 7
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 description 7
- 229930182912 cyclosporin Natural products 0.000 description 7
- 230000007423 decrease Effects 0.000 description 7
- 239000012636 effector Substances 0.000 description 7
- 230000002708 enhancing effect Effects 0.000 description 7
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 7
- 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 7
- 125000005842 heteroatom Chemical group 0.000 description 7
- JZZFDCXSFTVOJY-UHFFFAOYSA-N n-[4-(3-chloro-4-fluoroanilino)-7-(3-morpholin-4-ylpropoxy)quinazolin-6-yl]prop-2-enamide;hydron;dichloride Chemical compound Cl.Cl.C1=C(Cl)C(F)=CC=C1NC1=NC=NC2=CC(OCCCN3CCOCC3)=C(NC(=O)C=C)C=C12 JZZFDCXSFTVOJY-UHFFFAOYSA-N 0.000 description 7
- 229960002621 pembrolizumab Drugs 0.000 description 7
- 229920001223 polyethylene glycol Polymers 0.000 description 7
- 125000000714 pyrimidinyl group Chemical group 0.000 description 7
- 239000003826 tablet Substances 0.000 description 7
- 229940124597 therapeutic agent Drugs 0.000 description 7
- XRASPMIURGNCCH-UHFFFAOYSA-N zoledronic acid Chemical compound OP(=O)(O)C(P(O)(O)=O)(O)CN1C=CN=C1 XRASPMIURGNCCH-UHFFFAOYSA-N 0.000 description 7
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 6
- 102000004127 Cytokines Human genes 0.000 description 6
- 108090000695 Cytokines Proteins 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 102100027581 Forkhead box protein P3 Human genes 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- 101000861452 Homo sapiens Forkhead box protein P3 Proteins 0.000 description 6
- 229930012538 Paclitaxel Natural products 0.000 description 6
- 108091000080 Phosphotransferase Proteins 0.000 description 6
- 102100033479 RAF proto-oncogene serine/threonine-protein kinase Human genes 0.000 description 6
- 102100030086 Receptor tyrosine-protein kinase erbB-2 Human genes 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- RJURFGZVJUQBHK-UHFFFAOYSA-N actinomycin D Natural products CC1OC(=O)C(C(C)C)N(C)C(=O)CN(C)C(=O)C2CCCN2C(=O)C(C(C)C)NC(=O)C1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)NC4C(=O)NC(C(N5CCCC5C(=O)N(C)CC(=O)N(C)C(C(C)C)C(=O)OC4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-UHFFFAOYSA-N 0.000 description 6
- 239000002585 base Substances 0.000 description 6
- 229950002826 canertinib Drugs 0.000 description 6
- 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 6
- 239000003937 drug carrier Substances 0.000 description 6
- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 description 6
- 239000012634 fragment Substances 0.000 description 6
- 230000006870 function Effects 0.000 description 6
- 230000036737 immune function Effects 0.000 description 6
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 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
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 6
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 6
- 125000002971 oxazolyl group Chemical group 0.000 description 6
- 125000006299 oxetan-3-yl group Chemical group [H]C1([H])OC([H])([H])C1([H])* 0.000 description 6
- 229960001592 paclitaxel Drugs 0.000 description 6
- 102000020233 phosphotransferase Human genes 0.000 description 6
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 6
- 235000018102 proteins Nutrition 0.000 description 6
- 102000004169 proteins and genes Human genes 0.000 description 6
- 230000002829 reductive effect Effects 0.000 description 6
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 6
- 125000000335 thiazolyl group Chemical group 0.000 description 6
- 125000001425 triazolyl group Chemical group 0.000 description 6
- 229960004276 zoledronic acid Drugs 0.000 description 6
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 description 5
- XRYJULCDUUATMC-CYBMUJFWSA-N 4-[4-[[(1r)-1-phenylethyl]amino]-7h-pyrrolo[2,3-d]pyrimidin-6-yl]phenol Chemical compound N([C@H](C)C=1C=CC=CC=1)C(C=1C=2)=NC=NC=1NC=2C1=CC=C(O)C=C1 XRYJULCDUUATMC-CYBMUJFWSA-N 0.000 description 5
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 5
- 206010006187 Breast cancer Diseases 0.000 description 5
- 208000026310 Breast neoplasm Diseases 0.000 description 5
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 5
- 108010008165 Etanercept Proteins 0.000 description 5
- 101001012157 Homo sapiens Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 description 5
- 108010050904 Interferons Proteins 0.000 description 5
- 102000014150 Interferons Human genes 0.000 description 5
- 102100030694 Interleukin-11 Human genes 0.000 description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 5
- 239000005551 L01XE03 - Erlotinib Substances 0.000 description 5
- 239000002136 L01XE07 - Lapatinib Substances 0.000 description 5
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 description 5
- 108091005735 TGF-beta receptors Proteins 0.000 description 5
- 102000016715 Transforming Growth Factor beta Receptors Human genes 0.000 description 5
- 238000010521 absorption reaction Methods 0.000 description 5
- 125000000217 alkyl group Chemical group 0.000 description 5
- SHGAZHPCJJPHSC-YCNIQYBTSA-N all-trans-retinoic acid Chemical compound OC(=O)\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-YCNIQYBTSA-N 0.000 description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 5
- 229960001334 corticosteroids Drugs 0.000 description 5
- 235000014113 dietary fatty acids Nutrition 0.000 description 5
- 229960004679 doxorubicin Drugs 0.000 description 5
- 229930195729 fatty acid Natural products 0.000 description 5
- 239000000194 fatty acid Substances 0.000 description 5
- 239000012458 free base Substances 0.000 description 5
- 229960003685 imatinib mesylate Drugs 0.000 description 5
- 229940047124 interferons Drugs 0.000 description 5
- 125000000842 isoxazolyl group Chemical group 0.000 description 5
- HPJKCIUCZWXJDR-UHFFFAOYSA-N letrozole Chemical compound C1=CC(C#N)=CC=C1C(N1N=CN=C1)C1=CC=C(C#N)C=C1 HPJKCIUCZWXJDR-UHFFFAOYSA-N 0.000 description 5
- 201000001441 melanoma Diseases 0.000 description 5
- KKZJGLLVHKMTCM-UHFFFAOYSA-N mitoxantrone Chemical compound O=C1C2=C(O)C=CC(O)=C2C(=O)C2=C1C(NCCNCCO)=CC=C2NCCNCCO KKZJGLLVHKMTCM-UHFFFAOYSA-N 0.000 description 5
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 5
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 5
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 5
- 238000011275 oncology therapy Methods 0.000 description 5
- 239000006186 oral dosage form Substances 0.000 description 5
- 229960001972 panitumumab Drugs 0.000 description 5
- 239000000546 pharmaceutical excipient Substances 0.000 description 5
- 229960005205 prednisolone Drugs 0.000 description 5
- 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 5
- 150000003254 radicals Chemical class 0.000 description 5
- 150000003384 small molecules Chemical class 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 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 5
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 5
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 5
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 5
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 4
- IAKHMKGGTNLKSZ-INIZCTEOSA-N (S)-colchicine Chemical compound C1([C@@H](NC(C)=O)CC2)=CC(=O)C(OC)=CC=C1C1=C2C=C(OC)C(OC)=C1OC IAKHMKGGTNLKSZ-INIZCTEOSA-N 0.000 description 4
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 4
- 125000001731 2-cyanoethyl group Chemical group [H]C([H])(*)C([H])([H])C#N 0.000 description 4
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 4
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 4
- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 description 4
- 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 4
- 206010009944 Colon cancer Diseases 0.000 description 4
- 102000036364 Cullin Ring E3 Ligases Human genes 0.000 description 4
- 108091007045 Cullin Ring E3 Ligases Proteins 0.000 description 4
- 229930105110 Cyclosporin A Natural products 0.000 description 4
- 108010092160 Dactinomycin Proteins 0.000 description 4
- 102000004190 Enzymes Human genes 0.000 description 4
- 108090000790 Enzymes Proteins 0.000 description 4
- 102100039620 Granulocyte-macrophage colony-stimulating factor Human genes 0.000 description 4
- 206010061218 Inflammation Diseases 0.000 description 4
- 108010078049 Interferon alpha-2 Proteins 0.000 description 4
- 102000003816 Interleukin-13 Human genes 0.000 description 4
- 108090000176 Interleukin-13 Proteins 0.000 description 4
- 102100034671 L-lactate dehydrogenase A chain Human genes 0.000 description 4
- 108010088350 Lactate Dehydrogenase 5 Proteins 0.000 description 4
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 description 4
- PMDCZENCAXMSOU-UHFFFAOYSA-N N-ethylacetamide Chemical group CCNC(C)=O PMDCZENCAXMSOU-UHFFFAOYSA-N 0.000 description 4
- 108010038807 Oligopeptides Proteins 0.000 description 4
- 102000015636 Oligopeptides Human genes 0.000 description 4
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 4
- 101150035628 Serpine1 gene Proteins 0.000 description 4
- 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 4
- NAVMQTYZDKMPEU-UHFFFAOYSA-N Targretin Chemical compound CC1=CC(C(CCC2(C)C)(C)C)=C2C=C1C(=C)C1=CC=C(C(O)=O)C=C1 NAVMQTYZDKMPEU-UHFFFAOYSA-N 0.000 description 4
- FOCVUCIESVLUNU-UHFFFAOYSA-N Thiotepa Chemical compound C1CN1P(N1CC1)(=S)N1CC1 FOCVUCIESVLUNU-UHFFFAOYSA-N 0.000 description 4
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 4
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 4
- 150000007513 acids Chemical class 0.000 description 4
- 229940100198 alkylating agent Drugs 0.000 description 4
- 239000002168 alkylating agent Substances 0.000 description 4
- 230000003110 anti-inflammatory effect Effects 0.000 description 4
- 125000004429 atom Chemical group 0.000 description 4
- 125000000319 biphenyl-4-yl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 4
- GXJABQQUPOEUTA-RDJZCZTQSA-N bortezomib Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)B(O)O)NC(=O)C=1N=CC=NC=1)C1=CC=CC=C1 GXJABQQUPOEUTA-RDJZCZTQSA-N 0.000 description 4
- RYYVLZVUVIJVGH-UHFFFAOYSA-N caffeine Chemical compound CN1C(=O)N(C)C(=O)C2=C1N=CN2C RYYVLZVUVIJVGH-UHFFFAOYSA-N 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 4
- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 description 4
- 229960003957 dexamethasone Drugs 0.000 description 4
- 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 4
- 229960003668 docetaxel Drugs 0.000 description 4
- 229940088598 enzyme Drugs 0.000 description 4
- 229960001433 erlotinib Drugs 0.000 description 4
- 229960000403 etanercept Drugs 0.000 description 4
- 235000019441 ethanol Nutrition 0.000 description 4
- 150000004665 fatty acids Chemical class 0.000 description 4
- 235000019152 folic acid Nutrition 0.000 description 4
- 239000011724 folic acid Substances 0.000 description 4
- 108020001507 fusion proteins Proteins 0.000 description 4
- 102000037865 fusion proteins Human genes 0.000 description 4
- 229960002584 gefitinib Drugs 0.000 description 4
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 4
- 229940088597 hormone Drugs 0.000 description 4
- 239000005556 hormone Substances 0.000 description 4
- 230000001965 increasing effect Effects 0.000 description 4
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 4
- 229960000598 infliximab Drugs 0.000 description 4
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 4
- KBOPZPXVLCULAV-UHFFFAOYSA-N mesalamine Chemical compound NC1=CC=C(O)C(C(O)=O)=C1 KBOPZPXVLCULAV-UHFFFAOYSA-N 0.000 description 4
- 229960004963 mesalazine Drugs 0.000 description 4
- VAOCPAMSLUNLGC-UHFFFAOYSA-N metronidazole Chemical compound CC1=NC=C([N+]([O-])=O)N1CCO VAOCPAMSLUNLGC-UHFFFAOYSA-N 0.000 description 4
- 229960000282 metronidazole Drugs 0.000 description 4
- 229960001156 mitoxantrone Drugs 0.000 description 4
- 230000004048 modification Effects 0.000 description 4
- 238000012986 modification Methods 0.000 description 4
- 231100000252 nontoxic Toxicity 0.000 description 4
- 230000003000 nontoxic effect Effects 0.000 description 4
- WRUUGTRCQOWXEG-UHFFFAOYSA-N pamidronate Chemical compound NCCC(O)(P(O)(O)=O)P(O)(O)=O WRUUGTRCQOWXEG-UHFFFAOYSA-N 0.000 description 4
- 201000002528 pancreatic cancer Diseases 0.000 description 4
- 208000008443 pancreatic carcinoma Diseases 0.000 description 4
- 125000004351 phenylcyclohexyl group Chemical group C1(=CC=CC=C1)C1(CCCCC1)* 0.000 description 4
- 229920000642 polymer Polymers 0.000 description 4
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 4
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 4
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 4
- 230000002285 radioactive effect Effects 0.000 description 4
- 230000009467 reduction Effects 0.000 description 4
- 229960004641 rituximab Drugs 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 229960003989 tocilizumab Drugs 0.000 description 4
- 230000002103 transcriptional effect Effects 0.000 description 4
- 229960005486 vaccine Drugs 0.000 description 4
- 229950000578 vatalanib Drugs 0.000 description 4
- YCOYDOIWSSHVCK-UHFFFAOYSA-N vatalanib Chemical compound C1=CC(Cl)=CC=C1NC(C1=CC=CC=C11)=NN=C1CC1=CC=NC=C1 YCOYDOIWSSHVCK-UHFFFAOYSA-N 0.000 description 4
- 229960004528 vincristine Drugs 0.000 description 4
- 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 4
- 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 4
- VVIAGPKUTFNRDU-UHFFFAOYSA-N 6S-folinic acid Natural products C1NC=2NC(N)=NC(=O)C=2N(C=O)C1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 VVIAGPKUTFNRDU-UHFFFAOYSA-N 0.000 description 3
- OGSPWJRAVKPPFI-UHFFFAOYSA-N Alendronic Acid Chemical compound NCCCC(O)(P(O)(O)=O)P(O)(O)=O OGSPWJRAVKPPFI-UHFFFAOYSA-N 0.000 description 3
- BFYIZQONLCFLEV-DAELLWKTSA-N Aromasine Chemical compound O=C1C=C[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CC(=C)C2=C1 BFYIZQONLCFLEV-DAELLWKTSA-N 0.000 description 3
- 208000023275 Autoimmune disease Diseases 0.000 description 3
- MLDQJTXFUGDVEO-UHFFFAOYSA-N BAY-43-9006 Chemical compound C1=NC(C(=O)NC)=CC(OC=2C=CC(NC(=O)NC=3C=C(C(Cl)=CC=3)C(F)(F)F)=CC=2)=C1 MLDQJTXFUGDVEO-UHFFFAOYSA-N 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- 102000017420 CD3 protein, epsilon/gamma/delta subunit Human genes 0.000 description 3
- 108050005493 CD3 protein, epsilon/gamma/delta subunit Proteins 0.000 description 3
- GAGWJHPBXLXJQN-UORFTKCHSA-N Capecitabine Chemical compound C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1[C@H]1[C@H](O)[C@H](O)[C@@H](C)O1 GAGWJHPBXLXJQN-UORFTKCHSA-N 0.000 description 3
- 239000004215 Carbon black (E152) Substances 0.000 description 3
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 3
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 description 3
- 102100039498 Cytotoxic T-lymphocyte protein 4 Human genes 0.000 description 3
- 229940122558 EGFR antagonist Drugs 0.000 description 3
- 102100036089 Fascin Human genes 0.000 description 3
- VWUXBMIQPBEWFH-WCCTWKNTSA-N Fulvestrant Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3[C@H](CCCCCCCCCS(=O)CCCC(F)(F)C(F)(F)F)CC2=C1 VWUXBMIQPBEWFH-WCCTWKNTSA-N 0.000 description 3
- 102100031181 Glyceraldehyde-3-phosphate dehydrogenase Human genes 0.000 description 3
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 3
- 101000889276 Homo sapiens Cytotoxic T-lymphocyte protein 4 Proteins 0.000 description 3
- 101000611936 Homo sapiens Programmed cell death protein 1 Proteins 0.000 description 3
- 101000914514 Homo sapiens T-cell-specific surface glycoprotein CD28 Proteins 0.000 description 3
- PMMYEEVYMWASQN-DMTCNVIQSA-N Hydroxyproline Chemical class O[C@H]1CN[C@H](C(O)=O)C1 PMMYEEVYMWASQN-DMTCNVIQSA-N 0.000 description 3
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 3
- 102000051628 Interleukin-1 receptor antagonist Human genes 0.000 description 3
- 108700021006 Interleukin-1 receptor antagonist Proteins 0.000 description 3
- 108090000177 Interleukin-11 Proteins 0.000 description 3
- 102000004889 Interleukin-6 Human genes 0.000 description 3
- 108090001005 Interleukin-6 Proteins 0.000 description 3
- 239000005517 L01XE01 - Imatinib Substances 0.000 description 3
- 239000005411 L01XE02 - Gefitinib Substances 0.000 description 3
- 239000002147 L01XE04 - Sunitinib Substances 0.000 description 3
- 239000005511 L01XE05 - Sorafenib Substances 0.000 description 3
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 3
- 102000018697 Membrane Proteins Human genes 0.000 description 3
- 108010052285 Membrane Proteins Proteins 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 241000699666 Mus <mouse, genus> Species 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 239000002202 Polyethylene glycol Substances 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- IIDJRNMFWXDHID-UHFFFAOYSA-N Risedronic acid Chemical compound OP(=O)(O)C(P(O)(O)=O)(O)CC1=CC=CN=C1 IIDJRNMFWXDHID-UHFFFAOYSA-N 0.000 description 3
- 229930006000 Sucrose Natural products 0.000 description 3
- 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 3
- 102100027213 T-cell-specific surface glycoprotein CD28 Human genes 0.000 description 3
- 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 3
- 229940123237 Taxane Drugs 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 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 3
- RJURFGZVJUQBHK-IIXSONLDSA-N actinomycin D Chemical compound C[C@H]1OC(=O)[C@H](C(C)C)N(C)C(=O)CN(C)C(=O)[C@@H]2CCCN2C(=O)[C@@H](C(C)C)NC(=O)[C@H]1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)N[C@@H]4C(=O)N[C@@H](C(N5CCC[C@H]5C(=O)N(C)CC(=O)N(C)[C@@H](C(C)C)C(=O)O[C@@H]4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-IIXSONLDSA-N 0.000 description 3
- 230000001154 acute effect Effects 0.000 description 3
- 229960002964 adalimumab Drugs 0.000 description 3
- 108700025316 aldesleukin Proteins 0.000 description 3
- 229960000548 alemtuzumab Drugs 0.000 description 3
- 125000003342 alkenyl group Chemical group 0.000 description 3
- 150000001413 amino acids Chemical class 0.000 description 3
- 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 3
- 229940044094 angiotensin-converting-enzyme inhibitor Drugs 0.000 description 3
- 230000000340 anti-metabolite Effects 0.000 description 3
- 239000002256 antimetabolite Substances 0.000 description 3
- 229940100197 antimetabolite Drugs 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- 208000006673 asthma Diseases 0.000 description 3
- 229960002938 bexarotene Drugs 0.000 description 3
- 230000003115 biocidal effect Effects 0.000 description 3
- 230000004071 biological effect Effects 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 229960001467 bortezomib Drugs 0.000 description 3
- 229960000590 celecoxib Drugs 0.000 description 3
- RZEKVGVHFLEQIL-UHFFFAOYSA-N celecoxib Chemical compound C1=CC(C)=CC=C1C1=CC(C(F)(F)F)=NN1C1=CC=C(S(N)(=O)=O)C=C1 RZEKVGVHFLEQIL-UHFFFAOYSA-N 0.000 description 3
- 229960003115 certolizumab pegol Drugs 0.000 description 3
- 229960005395 cetuximab Drugs 0.000 description 3
- JCKYGMPEJWAADB-UHFFFAOYSA-N chlorambucil Chemical compound OC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 JCKYGMPEJWAADB-UHFFFAOYSA-N 0.000 description 3
- 229960004630 chlorambucil Drugs 0.000 description 3
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 3
- 229960004316 cisplatin Drugs 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
- ACSIXWWBWUQEHA-UHFFFAOYSA-N clodronic acid Chemical compound OP(O)(=O)C(Cl)(Cl)P(O)(O)=O ACSIXWWBWUQEHA-UHFFFAOYSA-N 0.000 description 3
- 125000004122 cyclic group Chemical group 0.000 description 3
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 3
- 229960000640 dactinomycin Drugs 0.000 description 3
- 229960000975 daunorubicin Drugs 0.000 description 3
- CYQFCXCEBYINGO-IAGOWNOFSA-N delta1-THC Chemical compound C1=C(C)CC[C@H]2C(C)(C)OC3=CC(CCCCC)=CC(O)=C3[C@@H]21 CYQFCXCEBYINGO-IAGOWNOFSA-N 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 229940031098 ethanolamine Drugs 0.000 description 3
- 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 3
- 239000000945 filler Substances 0.000 description 3
- VVIAGPKUTFNRDU-ABLWVSNPSA-N folinic acid Chemical compound C1NC=2NC(N)=NC(=O)C=2N(C=O)C1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 VVIAGPKUTFNRDU-ABLWVSNPSA-N 0.000 description 3
- 235000008191 folinic acid Nutrition 0.000 description 3
- 239000011672 folinic acid Substances 0.000 description 3
- 235000013305 food Nutrition 0.000 description 3
- 229960003297 gemtuzumab ozogamicin Drugs 0.000 description 3
- 229940080856 gleevec Drugs 0.000 description 3
- 108020004445 glyceraldehyde-3-phosphate dehydrogenase Proteins 0.000 description 3
- 239000003102 growth factor Substances 0.000 description 3
- 229930195733 hydrocarbon Natural products 0.000 description 3
- 229960001680 ibuprofen Drugs 0.000 description 3
- HOMGKSMUEGBAAB-UHFFFAOYSA-N ifosfamide Chemical compound ClCCNP1(=O)OCCCN1CCCl HOMGKSMUEGBAAB-UHFFFAOYSA-N 0.000 description 3
- 229960001101 ifosfamide Drugs 0.000 description 3
- 208000026278 immune system disease Diseases 0.000 description 3
- 208000027866 inflammatory disease Diseases 0.000 description 3
- 230000004054 inflammatory process Effects 0.000 description 3
- 229940100601 interleukin-6 Drugs 0.000 description 3
- 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 3
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 3
- 229940043355 kinase inhibitor Drugs 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 229960001375 lactose Drugs 0.000 description 3
- 229960004891 lapatinib Drugs 0.000 description 3
- 229960000681 leflunomide Drugs 0.000 description 3
- 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 3
- 229960003881 letrozole Drugs 0.000 description 3
- 229960001691 leucovorin Drugs 0.000 description 3
- 239000003446 ligand Substances 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 208000014018 liver neoplasm Diseases 0.000 description 3
- 201000005202 lung cancer Diseases 0.000 description 3
- 208000020816 lung neoplasm Diseases 0.000 description 3
- 235000018977 lysine Nutrition 0.000 description 3
- 235000019359 magnesium stearate Nutrition 0.000 description 3
- 238000004949 mass spectrometry Methods 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 201000006417 multiple sclerosis Diseases 0.000 description 3
- RTGDFNSFWBGLEC-SYZQJQIISA-N mycophenolate mofetil Chemical compound COC1=C(C)C=2COC(=O)C=2C(O)=C1C\C=C(/C)CCC(=O)OCCN1CCOCC1 RTGDFNSFWBGLEC-SYZQJQIISA-N 0.000 description 3
- 229960004866 mycophenolate mofetil Drugs 0.000 description 3
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 description 3
- 229960004110 olsalazine Drugs 0.000 description 3
- QQBDLJCYGRGAKP-FOCLMDBBSA-N olsalazine Chemical compound C1=C(O)C(C(=O)O)=CC(\N=N\C=2C=C(C(O)=CC=2)C(O)=O)=C1 QQBDLJCYGRGAKP-FOCLMDBBSA-N 0.000 description 3
- 229960001756 oxaliplatin Drugs 0.000 description 3
- DWAFYCQODLXJNR-BNTLRKBRSA-L oxaliplatin Chemical compound O1C(=O)C(=O)O[Pt]11N[C@@H]2CCCC[C@H]2N1 DWAFYCQODLXJNR-BNTLRKBRSA-L 0.000 description 3
- 125000004430 oxygen atom Chemical group O* 0.000 description 3
- 229940046231 pamidronate Drugs 0.000 description 3
- WVUNYSQLFKLYNI-AATRIKPKSA-N pelitinib Chemical compound C=12C=C(NC(=O)\C=C\CN(C)C)C(OCC)=CC2=NC=C(C#N)C=1NC1=CC=C(F)C(Cl)=C1 WVUNYSQLFKLYNI-AATRIKPKSA-N 0.000 description 3
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 3
- 239000006187 pill Substances 0.000 description 3
- 229910052697 platinum Inorganic materials 0.000 description 3
- 230000004481 post-translational protein modification Effects 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 230000000770 proinflammatory effect Effects 0.000 description 3
- 230000035755 proliferation Effects 0.000 description 3
- 125000002098 pyridazinyl group Chemical group 0.000 description 3
- 230000001105 regulatory effect Effects 0.000 description 3
- 206010039073 rheumatoid arthritis Diseases 0.000 description 3
- 229960000371 rofecoxib Drugs 0.000 description 3
- RZJQGNCSTQAWON-UHFFFAOYSA-N rofecoxib Chemical compound C1=CC(S(=O)(=O)C)=CC=C1C1=C(C=2C=CC=CC=2)C(=O)OC1 RZJQGNCSTQAWON-UHFFFAOYSA-N 0.000 description 3
- HXCHCVDVKSCDHU-PJKCJEBCSA-N s-[(2r,3s,4s,6s)-6-[[(2r,3s,4s,5r,6r)-5-[(2s,4s,5s)-5-(ethylamino)-4-methoxyoxan-2-yl]oxy-4-hydroxy-6-[[(2s,5z,9r,13e)-9-hydroxy-12-(methoxycarbonylamino)-13-[2-(methyltrisulfanyl)ethylidene]-11-oxo-2-bicyclo[7.3.1]trideca-1(12),5-dien-3,7-diynyl]oxy]-2-m Chemical compound C1[C@H](OC)[C@@H](NCC)CO[C@H]1O[C@H]1[C@H](O[C@@H]2C\3=C(NC(=O)OC)C(=O)C[C@@](C/3=C/CSSSC)(O)C#C\C=C/C#C2)O[C@H](C)[C@@H](NO[C@@H]2O[C@H](C)[C@@H](SC(=O)C=3C(=C(OC)C(O[C@H]4[C@@H]([C@H](OC)[C@@H](O)[C@H](C)O4)O)=C(I)C=3C)OC)[C@@H](O)C2)[C@@H]1O HXCHCVDVKSCDHU-PJKCJEBCSA-N 0.000 description 3
- 239000000523 sample Substances 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 230000000638 stimulation Effects 0.000 description 3
- 239000005720 sucrose Substances 0.000 description 3
- 230000004083 survival effect Effects 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 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 3
- 239000000454 talc Substances 0.000 description 3
- 229910052623 talc Inorganic materials 0.000 description 3
- 229940033134 talc Drugs 0.000 description 3
- 235000012222 talc Nutrition 0.000 description 3
- 229960001278 teniposide Drugs 0.000 description 3
- 229960001196 thiotepa Drugs 0.000 description 3
- 229960003087 tioguanine Drugs 0.000 description 3
- 229960000303 topotecan Drugs 0.000 description 3
- 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 3
- 229960005267 tositumomab Drugs 0.000 description 3
- 239000003053 toxin Substances 0.000 description 3
- 231100000765 toxin Toxicity 0.000 description 3
- 108700012359 toxins Proteins 0.000 description 3
- 229960001727 tretinoin Drugs 0.000 description 3
- 229960003048 vinblastine Drugs 0.000 description 3
- 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 3
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 3
- 239000001993 wax Substances 0.000 description 3
- 239000000080 wetting agent Substances 0.000 description 3
- BMKDZUISNHGIBY-ZETCQYMHSA-N (+)-dexrazoxane Chemical compound C([C@H](C)N1CC(=O)NC(=O)C1)N1CC(=O)NC(=O)C1 BMKDZUISNHGIBY-ZETCQYMHSA-N 0.000 description 2
- VDPLLINNMXFNQX-UHFFFAOYSA-N (1-aminocyclohexyl)methanol Chemical compound OCC1(N)CCCCC1 VDPLLINNMXFNQX-UHFFFAOYSA-N 0.000 description 2
- HMLGSIZOMSVISS-ONJSNURVSA-N (7r)-7-[[(2z)-2-(2-amino-1,3-thiazol-4-yl)-2-(2,2-dimethylpropanoyloxymethoxyimino)acetyl]amino]-3-ethenyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid Chemical compound N([C@@H]1C(N2C(=C(C=C)CSC21)C(O)=O)=O)C(=O)\C(=N/OCOC(=O)C(C)(C)C)C1=CSC(N)=N1 HMLGSIZOMSVISS-ONJSNURVSA-N 0.000 description 2
- FPVKHBSQESCIEP-UHFFFAOYSA-N (8S)-3-(2-deoxy-beta-D-erythro-pentofuranosyl)-3,6,7,8-tetrahydroimidazo[4,5-d][1,3]diazepin-8-ol Natural products C1C(O)C(CO)OC1N1C(NC=NCC2O)=C2N=C1 FPVKHBSQESCIEP-UHFFFAOYSA-N 0.000 description 2
- 125000001506 1,2,3-triazol-5-yl group Chemical group [H]N1N=NC([H])=C1[*] 0.000 description 2
- 125000004505 1,2,4-oxadiazol-5-yl group Chemical group O1N=CN=C1* 0.000 description 2
- 125000004510 1,3,4-oxadiazol-5-yl group Chemical group O1C=NN=C1* 0.000 description 2
- 125000004522 1,3,4-thiadiazol-5-yl group Chemical group S1C=NN=C1* 0.000 description 2
- HJTAZXHBEBIQQX-UHFFFAOYSA-N 1,5-bis(chloromethyl)naphthalene Chemical compound C1=CC=C2C(CCl)=CC=CC2=C1CCl HJTAZXHBEBIQQX-UHFFFAOYSA-N 0.000 description 2
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- 125000004343 1-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C([H])([H])[H] 0.000 description 2
- TXQPXJKRNHJWAX-UHFFFAOYSA-N 2-(3-aminopropylamino)ethylsulfanylphosphonic acid;trihydrate Chemical compound O.O.O.NCCCNCCSP(O)(O)=O TXQPXJKRNHJWAX-UHFFFAOYSA-N 0.000 description 2
- QXLQZLBNPTZMRK-UHFFFAOYSA-N 2-[(dimethylamino)methyl]-1-(2,4-dimethylphenyl)prop-2-en-1-one Chemical compound CN(C)CC(=C)C(=O)C1=CC=C(C)C=C1C QXLQZLBNPTZMRK-UHFFFAOYSA-N 0.000 description 2
- 125000000143 2-carboxyethyl group Chemical group [H]OC(=O)C([H])([H])C([H])([H])* 0.000 description 2
- 125000004398 2-methyl-2-butyl group Chemical group CC(C)(CC)* 0.000 description 2
- 125000004918 2-methyl-2-pentyl group Chemical group CC(C)(CCC)* 0.000 description 2
- 125000004922 2-methyl-3-pentyl group Chemical group CC(C)C(CC)* 0.000 description 2
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 2
- 125000006479 2-pyridyl methyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 description 2
- QGJZLNKBHJESQX-UHFFFAOYSA-N 3-Epi-Betulin-Saeure Natural products C1CC(O)C(C)(C)C2CCC3(C)C4(C)CCC5(C(O)=O)CCC(C(=C)C)C5C4CCC3C21C QGJZLNKBHJESQX-UHFFFAOYSA-N 0.000 description 2
- UZFPOOOQHWICKY-UHFFFAOYSA-N 3-[13-[1-[1-[8,12-bis(2-carboxyethyl)-17-(1-hydroxyethyl)-3,7,13,18-tetramethyl-21,24-dihydroporphyrin-2-yl]ethoxy]ethyl]-18-(2-carboxyethyl)-8-(1-hydroxyethyl)-3,7,12,17-tetramethyl-22,23-dihydroporphyrin-2-yl]propanoic acid Chemical compound N1C(C=C2C(=C(CCC(O)=O)C(C=C3C(=C(C)C(C=C4N5)=N3)CCC(O)=O)=N2)C)=C(C)C(C(C)O)=C1C=C5C(C)=C4C(C)OC(C)C1=C(N2)C=C(N3)C(C)=C(C(O)C)C3=CC(C(C)=C3CCC(O)=O)=NC3=CC(C(CCC(O)=O)=C3C)=NC3=CC2=C1C UZFPOOOQHWICKY-UHFFFAOYSA-N 0.000 description 2
- QOXOZONBQWIKDA-UHFFFAOYSA-N 3-hydroxypropyl Chemical group [CH2]CCO QOXOZONBQWIKDA-UHFFFAOYSA-N 0.000 description 2
- 125000004917 3-methyl-2-butyl group Chemical group CC(C(C)*)C 0.000 description 2
- 125000004919 3-methyl-2-pentyl group Chemical group CC(C(C)*)CC 0.000 description 2
- 125000004921 3-methyl-3-pentyl group Chemical group CC(CC)(CC)* 0.000 description 2
- CLOUCVRNYSHRCF-UHFFFAOYSA-N 3beta-Hydroxy-20(29)-Lupen-3,27-oic acid Natural products C1CC(O)C(C)(C)C2CCC3(C)C4(C(O)=O)CCC5(C)CCC(C(=C)C)C5C4CCC3C21C CLOUCVRNYSHRCF-UHFFFAOYSA-N 0.000 description 2
- AOJJSUZBOXZQNB-VTZDEGQISA-N 4'-epidoxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-VTZDEGQISA-N 0.000 description 2
- 125000004920 4-methyl-2-pentyl group Chemical group CC(CC(C)*)C 0.000 description 2
- DGHJKOUXAHNRAP-UHFFFAOYSA-N 4-methyloxadiazole Chemical compound CC1=CON=N1 DGHJKOUXAHNRAP-UHFFFAOYSA-N 0.000 description 2
- OFFFOVCCGHKJES-UHFFFAOYSA-N 4-methylthiadiazole Chemical compound CC1=CSN=N1 OFFFOVCCGHKJES-UHFFFAOYSA-N 0.000 description 2
- IDPUKCWIGUEADI-UHFFFAOYSA-N 5-[bis(2-chloroethyl)amino]uracil Chemical compound ClCCN(CCCl)C1=CNC(=O)NC1=O IDPUKCWIGUEADI-UHFFFAOYSA-N 0.000 description 2
- NMUSYJAQQFHJEW-KVTDHHQDSA-N 5-azacytidine Chemical compound O=C1N=C(N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 NMUSYJAQQFHJEW-KVTDHHQDSA-N 0.000 description 2
- SHGAZHPCJJPHSC-ZVCIMWCZSA-N 9-cis-retinoic acid Chemical compound OC(=O)/C=C(\C)/C=C/C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-ZVCIMWCZSA-N 0.000 description 2
- LRFVTYWOQMYALW-UHFFFAOYSA-N 9H-xanthine Chemical compound O=C1NC(=O)NC2=C1NC=N2 LRFVTYWOQMYALW-UHFFFAOYSA-N 0.000 description 2
- 208000024827 Alzheimer disease Diseases 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 2
- 229930183010 Amphotericin Natural products 0.000 description 2
- QGGFZZLFKABGNL-UHFFFAOYSA-N Amphotericin A Natural products OC1C(N)C(O)C(C)OC1OC1C=CC=CC=CC=CCCC=CC=CC(C)C(O)C(C)C(C)OC(=O)CC(O)CC(O)CCC(O)C(O)CC(O)CC(O)(CC(O)C2C(O)=O)OC2C1 QGGFZZLFKABGNL-UHFFFAOYSA-N 0.000 description 2
- 101710129690 Angiotensin-converting enzyme inhibitor Proteins 0.000 description 2
- 206010002556 Ankylosing Spondylitis Diseases 0.000 description 2
- 108010024976 Asparaginase Proteins 0.000 description 2
- 102000015790 Asparaginase Human genes 0.000 description 2
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 2
- 102100022414 Axin interactor, dorsalization-associated protein Human genes 0.000 description 2
- DIZWSDNSTNAYHK-XGWVBXMLSA-N Betulinic acid Natural products CC(=C)[C@@H]1C[C@H]([C@H]2CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@@]34C)[C@@H]12)C(=O)O DIZWSDNSTNAYHK-XGWVBXMLSA-N 0.000 description 2
- 229940122361 Bisphosphonate Drugs 0.000 description 2
- 101710086378 Bradykinin-potentiating and C-type natriuretic peptides Proteins 0.000 description 2
- 108091005575 Bromodomain-containing proteins Proteins 0.000 description 2
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 2
- 101710149863 C-C chemokine receptor type 4 Proteins 0.000 description 2
- 102100032976 CCR4-NOT transcription complex subunit 6 Human genes 0.000 description 2
- 102100024263 CD160 antigen Human genes 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- KLWPJMFMVPTNCC-UHFFFAOYSA-N Camptothecin Natural products CCC1(O)C(=O)OCC2=C1C=C3C4Nc5ccccc5C=C4CN3C2=O KLWPJMFMVPTNCC-UHFFFAOYSA-N 0.000 description 2
- GAGWJHPBXLXJQN-UHFFFAOYSA-N Capecitabine Natural products C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1C1C(O)C(O)C(C)O1 GAGWJHPBXLXJQN-UHFFFAOYSA-N 0.000 description 2
- 201000009030 Carcinoma Diseases 0.000 description 2
- DLGOEMSEDOSKAD-UHFFFAOYSA-N Carmustine Chemical compound ClCCNC(=O)N(N=O)CCCl DLGOEMSEDOSKAD-UHFFFAOYSA-N 0.000 description 2
- JWBOIMRXGHLCPP-UHFFFAOYSA-N Chloditan Chemical compound C=1C=CC=C(Cl)C=1C(C(Cl)Cl)C1=CC=C(Cl)C=C1 JWBOIMRXGHLCPP-UHFFFAOYSA-N 0.000 description 2
- 229920001268 Cholestyramine Polymers 0.000 description 2
- PTOAARAWEBMLNO-KVQBGUIXSA-N Cladribine Chemical compound C1=NC=2C(N)=NC(Cl)=NC=2N1[C@H]1C[C@H](O)[C@@H](CO)O1 PTOAARAWEBMLNO-KVQBGUIXSA-N 0.000 description 2
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 2
- 229940124073 Complement inhibitor Drugs 0.000 description 2
- XZMCDFZZKTWFGF-UHFFFAOYSA-N Cyanamide Chemical compound NC#N XZMCDFZZKTWFGF-UHFFFAOYSA-N 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- 229940123780 DNA topoisomerase I inhibitor Drugs 0.000 description 2
- 229940124087 DNA topoisomerase II inhibitor Drugs 0.000 description 2
- 108010019673 Darbepoetin alfa Proteins 0.000 description 2
- 201000004624 Dermatitis Diseases 0.000 description 2
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical compound C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 2
- 206010061818 Disease progression Diseases 0.000 description 2
- 102000001301 EGF receptor Human genes 0.000 description 2
- 108060006698 EGF receptor Proteins 0.000 description 2
- 102100030751 Eomesodermin homolog Human genes 0.000 description 2
- HTIJFSOGRVMCQR-UHFFFAOYSA-N Epirubicin Natural products COc1cccc2C(=O)c3c(O)c4CC(O)(CC(OC5CC(N)C(=O)C(C)O5)c4c(O)c3C(=O)c12)C(=O)CO HTIJFSOGRVMCQR-UHFFFAOYSA-N 0.000 description 2
- 108010074604 Epoetin Alfa Proteins 0.000 description 2
- 101000755748 Escherichia coli AIDA-I autotransporter Proteins 0.000 description 2
- 102000003972 Fibroblast growth factor 7 Human genes 0.000 description 2
- 108090000385 Fibroblast growth factor 7 Proteins 0.000 description 2
- 108010029961 Filgrastim Proteins 0.000 description 2
- WJOHZNCJWYWUJD-IUGZLZTKSA-N Fluocinonide Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@H]3OC(C)(C)O[C@@]3(C(=O)COC(=O)C)[C@@]2(C)C[C@@H]1O WJOHZNCJWYWUJD-IUGZLZTKSA-N 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-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
- 206010018364 Glomerulonephritis Diseases 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 108010069236 Goserelin Proteins 0.000 description 2
- 201000005569 Gout Diseases 0.000 description 2
- 102100039619 Granulocyte colony-stimulating factor Human genes 0.000 description 2
- 102000001398 Granzyme Human genes 0.000 description 2
- 108060005986 Granzyme Proteins 0.000 description 2
- 102100034458 Hepatitis A virus cellular receptor 2 Human genes 0.000 description 2
- 102000003964 Histone deacetylase Human genes 0.000 description 2
- 108090000353 Histone deacetylase Proteins 0.000 description 2
- 101000755749 Homo sapiens Axin interactor, dorsalization-associated protein Proteins 0.000 description 2
- 101000761938 Homo sapiens CD160 antigen Proteins 0.000 description 2
- 101001064167 Homo sapiens Eomesodermin homolog Proteins 0.000 description 2
- 101000599951 Homo sapiens Insulin-like growth factor I Proteins 0.000 description 2
- 101000945371 Homo sapiens Killer cell immunoglobulin-like receptor 2DL2 Proteins 0.000 description 2
- 101001137987 Homo sapiens Lymphocyte activation gene 3 protein Proteins 0.000 description 2
- 101001013797 Homo sapiens Metallothionein-1L Proteins 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 239000003458 I kappa b kinase inhibitor Substances 0.000 description 2
- XDXDZDZNSLXDNA-TZNDIEGXSA-N Idarubicin Chemical compound C1[C@H](N)[C@H](O)[C@H](C)O[C@H]1O[C@@H]1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2C[C@@](O)(C(C)=O)C1 XDXDZDZNSLXDNA-TZNDIEGXSA-N 0.000 description 2
- XDXDZDZNSLXDNA-UHFFFAOYSA-N Idarubicin Natural products C1C(N)C(O)C(C)OC1OC1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2CC(O)(C(C)=O)C1 XDXDZDZNSLXDNA-UHFFFAOYSA-N 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
- 208000022559 Inflammatory bowel disease Diseases 0.000 description 2
- 102100037852 Insulin-like growth factor I Human genes 0.000 description 2
- 108010005716 Interferon beta-1a Proteins 0.000 description 2
- 108010047761 Interferon-alpha Proteins 0.000 description 2
- 102000006992 Interferon-alpha Human genes 0.000 description 2
- 108010074328 Interferon-gamma Proteins 0.000 description 2
- 102100026018 Interleukin-1 receptor antagonist protein Human genes 0.000 description 2
- 108010065805 Interleukin-12 Proteins 0.000 description 2
- 102000013462 Interleukin-12 Human genes 0.000 description 2
- 108010002350 Interleukin-2 Proteins 0.000 description 2
- 102000000588 Interleukin-2 Human genes 0.000 description 2
- 102100036705 Interleukin-23 subunit alpha Human genes 0.000 description 2
- 108090000978 Interleukin-4 Proteins 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- 241000764238 Isis Species 0.000 description 2
- LPHGQDQBBGAPDZ-UHFFFAOYSA-N Isocaffeine Natural products CN1C(=O)N(C)C(=O)C2=C1N(C)C=N2 LPHGQDQBBGAPDZ-UHFFFAOYSA-N 0.000 description 2
- RRHGJUQNOFWUDK-UHFFFAOYSA-N Isoprene Chemical compound CC(=C)C=C RRHGJUQNOFWUDK-UHFFFAOYSA-N 0.000 description 2
- 102100033599 Killer cell immunoglobulin-like receptor 2DL2 Human genes 0.000 description 2
- 102000017578 LAG3 Human genes 0.000 description 2
- JLERVPBPJHKRBJ-UHFFFAOYSA-N LY 117018 Chemical compound C1=CC(O)=CC=C1C1=C(C(=O)C=2C=CC(OCCN3CCCC3)=CC=2)C2=CC=C(O)C=C2S1 JLERVPBPJHKRBJ-UHFFFAOYSA-N 0.000 description 2
- 108090000581 Leukemia inhibitory factor Proteins 0.000 description 2
- 108010000817 Leuprolide Proteins 0.000 description 2
- HLFSDGLLUJUHTE-SNVBAGLBSA-N Levamisole Chemical compound C1([C@H]2CN3CCSC3=N2)=CC=CC=C1 HLFSDGLLUJUHTE-SNVBAGLBSA-N 0.000 description 2
- GQYIWUVLTXOXAJ-UHFFFAOYSA-N Lomustine Chemical compound ClCCN(N=O)C(=O)NC1CCCCC1 GQYIWUVLTXOXAJ-UHFFFAOYSA-N 0.000 description 2
- 208000005777 Lupus Nephritis Diseases 0.000 description 2
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 2
- 239000004472 Lysine Substances 0.000 description 2
- 229940122696 MAP kinase inhibitor Drugs 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- ZRVUJXDFFKFLMG-UHFFFAOYSA-N Meloxicam Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC1=NC=C(C)S1 ZRVUJXDFFKFLMG-UHFFFAOYSA-N 0.000 description 2
- XOGTZOOQQBDUSI-UHFFFAOYSA-M Mesna Chemical compound [Na+].[O-]S(=O)(=O)CCS XOGTZOOQQBDUSI-UHFFFAOYSA-M 0.000 description 2
- 101710170181 Metalloproteinase inhibitor Proteins 0.000 description 2
- 102100031782 Metallothionein-1L Human genes 0.000 description 2
- 206010027476 Metastases Diseases 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- QXKHYNVANLEOEG-UHFFFAOYSA-N Methoxsalen Chemical compound C1=CC(=O)OC2=C1C=C1C=COC1=C2OC QXKHYNVANLEOEG-UHFFFAOYSA-N 0.000 description 2
- 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 2
- OVBPIULPVIDEAO-UHFFFAOYSA-N N-Pteroyl-L-glutaminsaeure Natural products C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-UHFFFAOYSA-N 0.000 description 2
- OHLUUHNLEMFGTQ-UHFFFAOYSA-N N-methylacetamide Chemical group CNC(C)=O OHLUUHNLEMFGTQ-UHFFFAOYSA-N 0.000 description 2
- BTYYWOYVBXILOJ-UHFFFAOYSA-N N-{4-[(3-bromophenyl)amino]quinazolin-6-yl}but-2-ynamide Chemical compound C12=CC(NC(=O)C#CC)=CC=C2N=CN=C1NC1=CC=CC(Br)=C1 BTYYWOYVBXILOJ-UHFFFAOYSA-N 0.000 description 2
- FTFRZXFNZVCRSK-UHFFFAOYSA-N N4-(3-chloro-4-fluorophenyl)-N6-(1-methyl-4-piperidinyl)pyrimido[5,4-d]pyrimidine-4,6-diamine Chemical compound C1CN(C)CCC1NC1=NC=C(N=CN=C2NC=3C=C(Cl)C(F)=CC=3)C2=N1 FTFRZXFNZVCRSK-UHFFFAOYSA-N 0.000 description 2
- 201000004253 NUT midline carcinoma Diseases 0.000 description 2
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 2
- CMWTZPSULFXXJA-UHFFFAOYSA-N Naproxen Natural products C1=C(C(C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-UHFFFAOYSA-N 0.000 description 2
- 206010033128 Ovarian cancer Diseases 0.000 description 2
- 206010061535 Ovarian neoplasm Diseases 0.000 description 2
- 102000004503 Perforin Human genes 0.000 description 2
- 108010056995 Perforin Proteins 0.000 description 2
- KHGNFPUMBJSZSM-UHFFFAOYSA-N Perforine Natural products COC1=C2CCC(O)C(CCC(C)(C)O)(OC)C2=NC2=C1C=CO2 KHGNFPUMBJSZSM-UHFFFAOYSA-N 0.000 description 2
- 229940099471 Phosphodiesterase inhibitor Drugs 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- 206010035226 Plasma cell myeloma Diseases 0.000 description 2
- 206010035664 Pneumonia Diseases 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 description 2
- 206010060862 Prostate cancer Diseases 0.000 description 2
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 2
- 229940079156 Proteasome inhibitor Drugs 0.000 description 2
- 201000001263 Psoriatic Arthritis Diseases 0.000 description 2
- 208000036824 Psoriatic arthropathy Diseases 0.000 description 2
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 description 2
- REFJWTPEDVJJIY-UHFFFAOYSA-N Quercetin Chemical compound C=1C(O)=CC(O)=C(C(C=2O)=O)C=1OC=2C1=CC=C(O)C(O)=C1 REFJWTPEDVJJIY-UHFFFAOYSA-N 0.000 description 2
- 101710141955 RAF proto-oncogene serine/threonine-protein kinase Proteins 0.000 description 2
- 208000006265 Renal cell carcinoma Diseases 0.000 description 2
- 206010039491 Sarcoma Diseases 0.000 description 2
- 206010040047 Sepsis Diseases 0.000 description 2
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- CYQFCXCEBYINGO-UHFFFAOYSA-N THC Natural products C1=C(C)CCC2C(C)(C)OC3=CC(CCCCC)=CC(O)=C3C21 CYQFCXCEBYINGO-UHFFFAOYSA-N 0.000 description 2
- BPEGJWRSRHCHSN-UHFFFAOYSA-N Temozolomide Chemical compound O=C1N(C)N=NC2=C(C(N)=O)N=CN21 BPEGJWRSRHCHSN-UHFFFAOYSA-N 0.000 description 2
- 208000024313 Testicular Neoplasms Diseases 0.000 description 2
- DKJJVAGXPKPDRL-UHFFFAOYSA-N Tiludronic acid Chemical compound OP(O)(=O)C(P(O)(O)=O)SC1=CC=C(Cl)C=C1 DKJJVAGXPKPDRL-UHFFFAOYSA-N 0.000 description 2
- 239000000365 Topoisomerase I Inhibitor Substances 0.000 description 2
- 239000000317 Topoisomerase II Inhibitor Substances 0.000 description 2
- 108010009583 Transforming Growth Factors Proteins 0.000 description 2
- 102000009618 Transforming Growth Factors Human genes 0.000 description 2
- PCWZKQSKUXXDDJ-UHFFFAOYSA-N Xanthotoxin Natural products COCc1c2OC(=O)C=Cc2cc3ccoc13 PCWZKQSKUXXDDJ-UHFFFAOYSA-N 0.000 description 2
- DGYIJVNZSDYBOE-UHFFFAOYSA-N [CH2]C1=CC=NC=C1 Chemical group [CH2]C1=CC=NC=C1 DGYIJVNZSDYBOE-UHFFFAOYSA-N 0.000 description 2
- IBXPAFBDJCXCDW-MHFPCNPESA-A [Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].Cc1cn([C@H]2C[C@H](O)[C@@H](COP([S-])(=O)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3CO)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3cnc4c3nc(N)[nH]c4=O)n3ccc(N)nc3=O)n3cnc4c3nc(N)[nH]c4=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c3nc(N)[nH]c4=O)n3ccc(N)nc3=O)n3cnc4c3nc(N)[nH]c4=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)O2)c(=O)[nH]c1=O Chemical compound [Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].Cc1cn([C@H]2C[C@H](O)[C@@H](COP([S-])(=O)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3CO)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3cnc4c3nc(N)[nH]c4=O)n3ccc(N)nc3=O)n3cnc4c3nc(N)[nH]c4=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c3nc(N)[nH]c4=O)n3ccc(N)nc3=O)n3cnc4c3nc(N)[nH]c4=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)O2)c(=O)[nH]c1=O IBXPAFBDJCXCDW-MHFPCNPESA-A 0.000 description 2
- AIWRTTMUVOZGPW-HSPKUQOVSA-N abarelix Chemical compound C([C@@H](C(=O)N[C@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCNC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N[C@H](C)C(N)=O)N(C)C(=O)[C@H](CO)NC(=O)[C@@H](CC=1C=NC=CC=1)NC(=O)[C@@H](CC=1C=CC(Cl)=CC=1)NC(=O)[C@@H](CC=1C=C2C=CC=CC2=CC=1)NC(C)=O)C1=CC=C(O)C=C1 AIWRTTMUVOZGPW-HSPKUQOVSA-N 0.000 description 2
- 108010023617 abarelix Proteins 0.000 description 2
- 229960002184 abarelix Drugs 0.000 description 2
- 229960003697 abatacept Drugs 0.000 description 2
- 235000011054 acetic acid Nutrition 0.000 description 2
- 230000021736 acetylation Effects 0.000 description 2
- 229960001138 acetylsalicylic acid Drugs 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 239000008186 active pharmaceutical agent Substances 0.000 description 2
- 208000009956 adenocarcinoma Diseases 0.000 description 2
- 239000000464 adrenergic agent Substances 0.000 description 2
- 239000000556 agonist Substances 0.000 description 2
- NDAUXUAQIAJITI-UHFFFAOYSA-N albuterol Chemical compound CC(C)(C)NCC(O)C1=CC=C(O)C(CO)=C1 NDAUXUAQIAJITI-UHFFFAOYSA-N 0.000 description 2
- 229960005310 aldesleukin Drugs 0.000 description 2
- 235000010443 alginic acid Nutrition 0.000 description 2
- 229920000615 alginic acid Polymers 0.000 description 2
- 229960001445 alitretinoin Drugs 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- 125000000304 alkynyl group Chemical group 0.000 description 2
- OFCNXPDARWKPPY-UHFFFAOYSA-N allopurinol Chemical compound OC1=NC=NC2=C1C=NN2 OFCNXPDARWKPPY-UHFFFAOYSA-N 0.000 description 2
- 229960003459 allopurinol Drugs 0.000 description 2
- 230000004075 alteration Effects 0.000 description 2
- 229960000473 altretamine Drugs 0.000 description 2
- 229960001097 amifostine Drugs 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 125000000539 amino acid group Chemical group 0.000 description 2
- ROBVIMPUHSLWNV-UHFFFAOYSA-N aminoglutethimide Chemical compound C=1C=C(N)C=CC=1C1(CC)CCC(=O)NC1=O ROBVIMPUHSLWNV-UHFFFAOYSA-N 0.000 description 2
- 229960003437 aminoglutethimide Drugs 0.000 description 2
- 229940009444 amphotericin Drugs 0.000 description 2
- APKFDSVGJQXUKY-INPOYWNPSA-N amphotericin B Chemical compound O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1/C=C/C=C/C=C/C=C/C=C/C=C/C=C/[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 APKFDSVGJQXUKY-INPOYWNPSA-N 0.000 description 2
- 229960004238 anakinra Drugs 0.000 description 2
- 229960002932 anastrozole Drugs 0.000 description 2
- 239000004037 angiogenesis inhibitor Substances 0.000 description 2
- 229940121369 angiogenesis inhibitor Drugs 0.000 description 2
- RWZYAGGXGHYGMB-UHFFFAOYSA-N anthranilic acid Chemical compound NC1=CC=CC=C1C(O)=O RWZYAGGXGHYGMB-UHFFFAOYSA-N 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 229940044684 anti-microtubule agent Drugs 0.000 description 2
- 230000000692 anti-sense effect Effects 0.000 description 2
- 229940088710 antibiotic agent Drugs 0.000 description 2
- 239000003146 anticoagulant agent Substances 0.000 description 2
- 229960004676 antithrombotic agent Drugs 0.000 description 2
- GOLCXWYRSKYTSP-UHFFFAOYSA-N arsenic trioxide Inorganic materials O1[As]2O[As]1O2 GOLCXWYRSKYTSP-UHFFFAOYSA-N 0.000 description 2
- 229960002594 arsenic trioxide Drugs 0.000 description 2
- 229960003272 asparaginase Drugs 0.000 description 2
- DCXYFEDJOCDNAF-UHFFFAOYSA-M asparaginate Chemical compound [O-]C(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-M 0.000 description 2
- 208000010668 atopic eczema Diseases 0.000 description 2
- 229960002756 azacitidine Drugs 0.000 description 2
- VSRXQHXAPYXROS-UHFFFAOYSA-N azanide;cyclobutane-1,1-dicarboxylic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OC(=O)C1(C(O)=O)CCC1 VSRXQHXAPYXROS-UHFFFAOYSA-N 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 2
- SESFRYSPDFLNCH-UHFFFAOYSA-N benzyl benzoate Chemical compound C=1C=CC=CC=1C(=O)OCC1=CC=CC=C1 SESFRYSPDFLNCH-UHFFFAOYSA-N 0.000 description 2
- QZPQTZZNNJUOLS-UHFFFAOYSA-N beta-lapachone Chemical compound C12=CC=CC=C2C(=O)C(=O)C2=C1OC(C)(C)CC2 QZPQTZZNNJUOLS-UHFFFAOYSA-N 0.000 description 2
- 229960002537 betamethasone Drugs 0.000 description 2
- 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 2
- QGJZLNKBHJESQX-FZFNOLFKSA-N betulinic acid Chemical compound C1C[C@H](O)C(C)(C)[C@@H]2CC[C@@]3(C)[C@]4(C)CC[C@@]5(C(O)=O)CC[C@@H](C(=C)C)[C@@H]5[C@H]4CC[C@@H]3[C@]21C QGJZLNKBHJESQX-FZFNOLFKSA-N 0.000 description 2
- 229960000397 bevacizumab Drugs 0.000 description 2
- 125000002619 bicyclic group Chemical group 0.000 description 2
- 229920002988 biodegradable polymer Polymers 0.000 description 2
- 239000004621 biodegradable polymer Substances 0.000 description 2
- 230000033228 biological regulation Effects 0.000 description 2
- 239000000090 biomarker Substances 0.000 description 2
- 150000004663 bisphosphonates Chemical class 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 229960002092 busulfan Drugs 0.000 description 2
- 235000019437 butane-1,3-diol Nutrition 0.000 description 2
- KVNRLNFWIYMESJ-UHFFFAOYSA-N butyronitrile Chemical compound CCCC#N KVNRLNFWIYMESJ-UHFFFAOYSA-N 0.000 description 2
- 229960001948 caffeine Drugs 0.000 description 2
- VJEONQKOZGKCAK-UHFFFAOYSA-N caffeine Natural products CN1C(=O)N(C)C(=O)C2=C1C=CN2C VJEONQKOZGKCAK-UHFFFAOYSA-N 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 229960005069 calcium Drugs 0.000 description 2
- 229930195731 calicheamicin Natural products 0.000 description 2
- IVFYLRMMHVYGJH-PVPPCFLZSA-N calusterone Chemical compound C1C[C@]2(C)[C@](O)(C)CC[C@H]2[C@@H]2[C@@H](C)CC3=CC(=O)CC[C@]3(C)[C@H]21 IVFYLRMMHVYGJH-PVPPCFLZSA-N 0.000 description 2
- 229950009823 calusterone Drugs 0.000 description 2
- 229940127093 camptothecin Drugs 0.000 description 2
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical compound C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 description 2
- 229960004117 capecitabine Drugs 0.000 description 2
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 2
- 229960004562 carboplatin Drugs 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 2
- 229960005243 carmustine Drugs 0.000 description 2
- 230000022131 cell cycle Effects 0.000 description 2
- 230000003915 cell function Effects 0.000 description 2
- 230000022534 cell killing Effects 0.000 description 2
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 2
- 229960001231 choline Drugs 0.000 description 2
- 238000002487 chromatin immunoprecipitation Methods 0.000 description 2
- MYSWGUAQZAJSOK-UHFFFAOYSA-N ciprofloxacin Chemical compound C12=CC(N3CCNCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 MYSWGUAQZAJSOK-UHFFFAOYSA-N 0.000 description 2
- 229960002436 cladribine Drugs 0.000 description 2
- 229960002286 clodronic acid Drugs 0.000 description 2
- 229960000928 clofarabine Drugs 0.000 description 2
- WDDPHFBMKLOVOX-AYQXTPAHSA-N clofarabine Chemical compound C1=NC=2C(N)=NC(Cl)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1F WDDPHFBMKLOVOX-AYQXTPAHSA-N 0.000 description 2
- 238000011260 co-administration Methods 0.000 description 2
- 229960001338 colchicine Drugs 0.000 description 2
- 210000001072 colon Anatomy 0.000 description 2
- 208000029742 colonic neoplasm Diseases 0.000 description 2
- 239000004074 complement inhibitor Substances 0.000 description 2
- 229940111134 coxibs Drugs 0.000 description 2
- 235000012754 curcumin Nutrition 0.000 description 2
- VFLDPWHFBUODDF-FCXRPNKRSA-N curcumin Chemical compound C1=C(O)C(OC)=CC(\C=C\C(=O)CC(=O)\C=C\C=2C=C(OC)C(O)=CC=2)=C1 VFLDPWHFBUODDF-FCXRPNKRSA-N 0.000 description 2
- RMRCNWBMXRMIRW-BYFNXCQMSA-M cyanocobalamin Chemical compound N#C[Co+]N([C@]1([H])[C@H](CC(N)=O)[C@]\2(CCC(=O)NC[C@H](C)OP(O)(=O)OC3[C@H]([C@H](O[C@@H]3CO)N3C4=CC(C)=C(C)C=C4N=C3)O)C)C/2=C(C)\C([C@H](C/2(C)C)CCC(N)=O)=N\C\2=C\C([C@H]([C@@]/2(CC(N)=O)C)CCC(N)=O)=N\C\2=C(C)/C2=N[C@]1(C)[C@@](C)(CC(N)=O)[C@@H]2CCC(N)=O RMRCNWBMXRMIRW-BYFNXCQMSA-M 0.000 description 2
- 239000003255 cyclooxygenase 2 inhibitor Substances 0.000 description 2
- 229960000684 cytarabine Drugs 0.000 description 2
- 230000016396 cytokine production Effects 0.000 description 2
- 102000003675 cytokine receptors Human genes 0.000 description 2
- 108010057085 cytokine receptors Proteins 0.000 description 2
- 230000001461 cytolytic effect Effects 0.000 description 2
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical compound NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 description 2
- 229960005029 darbepoetin alfa Drugs 0.000 description 2
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 230000003111 delayed effect Effects 0.000 description 2
- 229960000605 dexrazoxane Drugs 0.000 description 2
- 229960001259 diclofenac Drugs 0.000 description 2
- DCOPUUMXTXDBNB-UHFFFAOYSA-N diclofenac Chemical compound OC(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl DCOPUUMXTXDBNB-UHFFFAOYSA-N 0.000 description 2
- 229960001193 diclofenac sodium Drugs 0.000 description 2
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 2
- VFLDPWHFBUODDF-UHFFFAOYSA-N diferuloylmethane Natural products C1=C(O)C(OC)=CC(C=CC(=O)CC(=O)C=CC=2C=C(OC)C(O)=CC=2)=C1 VFLDPWHFBUODDF-UHFFFAOYSA-N 0.000 description 2
- PZXJOHSZQAEJFE-UHFFFAOYSA-N dihydrobetulinic acid Natural products C1CC(O)C(C)(C)C2CCC3(C)C4(C)CCC5(C(O)=O)CCC(C(C)C)C5C4CCC3C21C PZXJOHSZQAEJFE-UHFFFAOYSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical group C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- 230000005750 disease progression Effects 0.000 description 2
- NYDXNILOWQXUOF-UHFFFAOYSA-L disodium;2-[[4-[2-(2-amino-4-oxo-1,7-dihydropyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]amino]pentanedioate Chemical compound [Na+].[Na+].C=1NC=2NC(N)=NC(=O)C=2C=1CCC1=CC=C(C(=O)NC(CCC([O-])=O)C([O-])=O)C=C1 NYDXNILOWQXUOF-UHFFFAOYSA-L 0.000 description 2
- 239000002270 dispersing agent Substances 0.000 description 2
- AUZONCFQVSMFAP-UHFFFAOYSA-N disulfiram Chemical compound CCN(CC)C(=S)SSC(=S)N(CC)CC AUZONCFQVSMFAP-UHFFFAOYSA-N 0.000 description 2
- VSJKWCGYPAHWDS-UHFFFAOYSA-N dl-camptothecin Natural products C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-UHFFFAOYSA-N 0.000 description 2
- NOTIQUSPUUHHEH-UXOVVSIBSA-N dromostanolone propionate Chemical compound C([C@@H]1CC2)C(=O)[C@H](C)C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H](OC(=O)CC)[C@@]2(C)CC1 NOTIQUSPUUHHEH-UXOVVSIBSA-N 0.000 description 2
- 229950004683 drostanolone propionate Drugs 0.000 description 2
- 230000004064 dysfunction Effects 0.000 description 2
- 229940121647 egfr inhibitor Drugs 0.000 description 2
- 229940120655 eloxatin Drugs 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 230000001973 epigenetic effect Effects 0.000 description 2
- 229960001904 epirubicin Drugs 0.000 description 2
- 229960003388 epoetin alfa Drugs 0.000 description 2
- 229960001842 estramustine Drugs 0.000 description 2
- FRPJXPJMRWBBIH-RBRWEJTLSA-N estramustine Chemical compound ClCCN(CCCl)C(=O)OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 FRPJXPJMRWBBIH-RBRWEJTLSA-N 0.000 description 2
- 235000019439 ethyl acetate Nutrition 0.000 description 2
- 229960005293 etodolac Drugs 0.000 description 2
- XFBVBWWRPKNWHW-UHFFFAOYSA-N etodolac Chemical compound C1COC(CC)(CC(O)=O)C2=N[C]3C(CC)=CC=CC3=C21 XFBVBWWRPKNWHW-UHFFFAOYSA-N 0.000 description 2
- 229960005420 etoposide Drugs 0.000 description 2
- 229960004945 etoricoxib Drugs 0.000 description 2
- MNJVRJDLRVPLFE-UHFFFAOYSA-N etoricoxib Chemical compound C1=NC(C)=CC=C1C1=NC=C(Cl)C=C1C1=CC=C(S(C)(=O)=O)C=C1 MNJVRJDLRVPLFE-UHFFFAOYSA-N 0.000 description 2
- 229960000255 exemestane Drugs 0.000 description 2
- 229940087476 femara Drugs 0.000 description 2
- 229960004177 filgrastim Drugs 0.000 description 2
- 229960000961 floxuridine Drugs 0.000 description 2
- ODKNJVUHOIMIIZ-RRKCRQDMSA-N floxuridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(F)=C1 ODKNJVUHOIMIIZ-RRKCRQDMSA-N 0.000 description 2
- 229960000390 fludarabine Drugs 0.000 description 2
- GIUYCYHIANZCFB-FJFJXFQQSA-N fludarabine phosphate Chemical compound C1=NC=2C(N)=NC(F)=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@@H]1O GIUYCYHIANZCFB-FJFJXFQQSA-N 0.000 description 2
- 229960000785 fluocinonide Drugs 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 229940014144 folate Drugs 0.000 description 2
- 229960000304 folic acid Drugs 0.000 description 2
- 229960002258 fulvestrant Drugs 0.000 description 2
- CHPZKNULDCNCBW-UHFFFAOYSA-N gallium nitrate Chemical compound [Ga+3].[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O CHPZKNULDCNCBW-UHFFFAOYSA-N 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- 239000007903 gelatin capsule Substances 0.000 description 2
- 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 2
- 229960005277 gemcitabine Drugs 0.000 description 2
- KWIUHFFTVRNATP-UHFFFAOYSA-N glycine betaine Chemical compound C[N+](C)(C)CC([O-])=O KWIUHFFTVRNATP-UHFFFAOYSA-N 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 229940093915 gynecological organic acid Drugs 0.000 description 2
- LNEPOXFFQSENCJ-UHFFFAOYSA-N haloperidol Chemical compound C1CC(O)(C=2C=CC(Cl)=CC=2)CCN1CCCC(=O)C1=CC=C(F)C=C1 LNEPOXFFQSENCJ-UHFFFAOYSA-N 0.000 description 2
- UUVWYPNAQBNQJQ-UHFFFAOYSA-N hexamethylmelamine Chemical compound CN(C)C1=NC(N(C)C)=NC(N(C)C)=N1 UUVWYPNAQBNQJQ-UHFFFAOYSA-N 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 239000003276 histone deacetylase inhibitor Substances 0.000 description 2
- HHXHVIJIIXKSOE-QILQGKCVSA-N histrelin Chemical compound CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](NC(=O)[C@H](CC=1C=CC(O)=CC=1)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)CC(N=C1)=CN1CC1=CC=CC=C1 HHXHVIJIIXKSOE-QILQGKCVSA-N 0.000 description 2
- 229960003911 histrelin acetate Drugs 0.000 description 2
- 230000003054 hormonal effect Effects 0.000 description 2
- 229960002764 hydrocodone bitartrate Drugs 0.000 description 2
- JYGXADMDTFJGBT-VWUMJDOOSA-N hydrocortisone Chemical compound O=C1CC[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 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 description 2
- 229960000908 idarubicin Drugs 0.000 description 2
- 125000002883 imidazolyl group Chemical group 0.000 description 2
- 239000002955 immunomodulating agent Substances 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 125000001041 indolyl group Chemical group 0.000 description 2
- 229960000905 indomethacin Drugs 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 239000007972 injectable composition Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 229960003521 interferon alfa-2a Drugs 0.000 description 2
- 229960003507 interferon alfa-2b Drugs 0.000 description 2
- 229940117681 interleukin-12 Drugs 0.000 description 2
- 238000007918 intramuscular administration Methods 0.000 description 2
- 230000002601 intratumoral effect Effects 0.000 description 2
- 229940084651 iressa Drugs 0.000 description 2
- 229960004768 irinotecan Drugs 0.000 description 2
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-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
- 229960004942 lenalidomide Drugs 0.000 description 2
- GOTYRUGSSMKFNF-UHFFFAOYSA-N lenalidomide Chemical compound C1C=2C(N)=CC=CC=2C(=O)N1C1CCC(=O)NC1=O GOTYRUGSSMKFNF-UHFFFAOYSA-N 0.000 description 2
- 208000032839 leukemia Diseases 0.000 description 2
- 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 2
- 229960004338 leuprorelin Drugs 0.000 description 2
- 229960001614 levamisole Drugs 0.000 description 2
- 229960002247 lomustine Drugs 0.000 description 2
- DHMTURDWPRKSOA-RUZDIDTESA-N lonafarnib Chemical compound C1CN(C(=O)N)CCC1CC(=O)N1CCC([C@@H]2C3=C(Br)C=C(Cl)C=C3CCC3=CC(Br)=CN=C32)CC1 DHMTURDWPRKSOA-RUZDIDTESA-N 0.000 description 2
- 125000000040 m-tolyl group Chemical group [H]C1=C([H])C(*)=C([H])C(=C1[H])C([H])([H])[H] 0.000 description 2
- 230000036210 malignancy Effects 0.000 description 2
- 229950008001 matuzumab Drugs 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- RQZAXGRLVPAYTJ-GQFGMJRRSA-N megestrol acetate Chemical compound C1=C(C)C2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(C)=O)(OC(=O)C)[C@@]1(C)CC2 RQZAXGRLVPAYTJ-GQFGMJRRSA-N 0.000 description 2
- 229960004296 megestrol acetate Drugs 0.000 description 2
- 229960001929 meloxicam Drugs 0.000 description 2
- SGDBTWWWUNNDEQ-LBPRGKRZSA-N melphalan Chemical compound OC(=O)[C@@H](N)CC1=CC=C(N(CCCl)CCCl)C=C1 SGDBTWWWUNNDEQ-LBPRGKRZSA-N 0.000 description 2
- 229960001924 melphalan Drugs 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 229960000901 mepacrine Drugs 0.000 description 2
- 229960004635 mesna Drugs 0.000 description 2
- 230000004060 metabolic process Effects 0.000 description 2
- 229940126170 metalloproteinase inhibitor Drugs 0.000 description 2
- 239000003475 metalloproteinase inhibitor Substances 0.000 description 2
- 230000009401 metastasis Effects 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 229960004469 methoxsalen Drugs 0.000 description 2
- OJLOPKGSLYJEMD-URPKTTJQSA-N methyl 7-[(1r,2r,3r)-3-hydroxy-2-[(1e)-4-hydroxy-4-methyloct-1-en-1-yl]-5-oxocyclopentyl]heptanoate Chemical compound CCCCC(C)(O)C\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1CCCCCCC(=O)OC OJLOPKGSLYJEMD-URPKTTJQSA-N 0.000 description 2
- VQJHOPSWBGJHQS-UHFFFAOYSA-N metoprine, methodichlorophen Chemical compound CC1=NC(N)=NC(N)=C1C1=CC=C(Cl)C(Cl)=C1 VQJHOPSWBGJHQS-UHFFFAOYSA-N 0.000 description 2
- 239000004530 micro-emulsion Substances 0.000 description 2
- 229960005249 misoprostol Drugs 0.000 description 2
- CFCUWKMKBJTWLW-BKHRDMLASA-N mithramycin Chemical compound O([C@@H]1C[C@@H](O[C@H](C)[C@H]1O)OC=1C=C2C=C3C[C@H]([C@@H](C(=O)C3=C(O)C2=C(O)C=1C)O[C@@H]1O[C@H](C)[C@@H](O)[C@H](O[C@@H]2O[C@H](C)[C@H](O)[C@H](O[C@@H]3O[C@H](C)[C@@H](O)[C@@](C)(O)C3)C2)C1)[C@H](OC)C(=O)[C@@H](O)[C@@H](C)O)[C@H]1C[C@@H](O)[C@H](O)[C@@H](C)O1 CFCUWKMKBJTWLW-BKHRDMLASA-N 0.000 description 2
- 239000002829 mitogen activated protein kinase inhibitor Substances 0.000 description 2
- 229960004857 mitomycin Drugs 0.000 description 2
- 229960000350 mitotane Drugs 0.000 description 2
- 125000002950 monocyclic group Chemical group 0.000 description 2
- 230000035772 mutation Effects 0.000 description 2
- LBWFXVZLPYTWQI-IPOVEDGCSA-N n-[2-(diethylamino)ethyl]-5-[(z)-(5-fluoro-2-oxo-1h-indol-3-ylidene)methyl]-2,4-dimethyl-1h-pyrrole-3-carboxamide;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.CCN(CC)CCNC(=O)C1=C(C)NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C1C LBWFXVZLPYTWQI-IPOVEDGCSA-N 0.000 description 2
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 2
- 229960004719 nandrolone Drugs 0.000 description 2
- NPAGDVCDWIYMMC-IZPLOLCNSA-N nandrolone Chemical compound O=C1CC[C@@H]2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 NPAGDVCDWIYMMC-IZPLOLCNSA-N 0.000 description 2
- 229960002009 naproxen Drugs 0.000 description 2
- CMWTZPSULFXXJA-VIFPVBQESA-M naproxen(1-) Chemical compound C1=C([C@H](C)C([O-])=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-VIFPVBQESA-M 0.000 description 2
- IXOXBSCIXZEQEQ-UHTZMRCNSA-N nelarabine Chemical compound C1=NC=2C(OC)=NC(N)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1O IXOXBSCIXZEQEQ-UHTZMRCNSA-N 0.000 description 2
- 229960000801 nelarabine Drugs 0.000 description 2
- QZGIWPZCWHMVQL-UIYAJPBUSA-N neocarzinostatin chromophore Chemical compound O1[C@H](C)[C@H](O)[C@H](O)[C@@H](NC)[C@H]1O[C@@H]1C/2=C/C#C[C@H]3O[C@@]3([C@@H]3OC(=O)OC3)C#CC\2=C[C@H]1OC(=O)C1=C(O)C=CC2=C(C)C=C(OC)C=C12 QZGIWPZCWHMVQL-UIYAJPBUSA-N 0.000 description 2
- MQYXUWHLBZFQQO-UHFFFAOYSA-N nepehinol Natural products C1CC(O)C(C)(C)C2CCC3(C)C4(C)CCC5(C)CCC(C(=C)C)C5C4CCC3C21C MQYXUWHLBZFQQO-UHFFFAOYSA-N 0.000 description 2
- 102000037979 non-receptor tyrosine kinases Human genes 0.000 description 2
- 108091008046 non-receptor tyrosine kinases Proteins 0.000 description 2
- 239000000346 nonvolatile oil Substances 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 235000019198 oils Nutrition 0.000 description 2
- 229960000381 omeprazole Drugs 0.000 description 2
- SBQLYHNEIUGQKH-UHFFFAOYSA-N omeprazole Chemical compound N1=C2[CH]C(OC)=CC=C2N=C1S(=O)CC1=NC=C(C)C(OC)=C1C SBQLYHNEIUGQKH-UHFFFAOYSA-N 0.000 description 2
- 229960001840 oprelvekin Drugs 0.000 description 2
- 108010046821 oprelvekin Proteins 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 235000005985 organic acids Nutrition 0.000 description 2
- 201000008482 osteoarthritis Diseases 0.000 description 2
- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical compound C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 description 2
- 125000001715 oxadiazolyl group Chemical group 0.000 description 2
- 229960002739 oxaprozin Drugs 0.000 description 2
- OFPXSFXSNFPTHF-UHFFFAOYSA-N oxaprozin Chemical compound O1C(CCC(=O)O)=NC(C=2C=CC=CC=2)=C1C1=CC=CC=C1 OFPXSFXSNFPTHF-UHFFFAOYSA-N 0.000 description 2
- 125000003551 oxepanyl group Chemical group 0.000 description 2
- 229960002404 palifermin Drugs 0.000 description 2
- 229960005489 paracetamol Drugs 0.000 description 2
- 230000037361 pathway Effects 0.000 description 2
- HQQSBEDKMRHYME-UHFFFAOYSA-N pefloxacin mesylate Chemical compound [H+].CS([O-])(=O)=O.C1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCN(C)CC1 HQQSBEDKMRHYME-UHFFFAOYSA-N 0.000 description 2
- 229960001218 pegademase Drugs 0.000 description 2
- 108010027841 pegademase bovine Proteins 0.000 description 2
- 229960001744 pegaspargase Drugs 0.000 description 2
- 108010001564 pegaspargase Proteins 0.000 description 2
- 229960001373 pegfilgrastim Drugs 0.000 description 2
- 108010044644 pegfilgrastim Proteins 0.000 description 2
- 229960003349 pemetrexed disodium Drugs 0.000 description 2
- 229960001639 penicillamine Drugs 0.000 description 2
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 2
- 229960002340 pentostatin Drugs 0.000 description 2
- FPVKHBSQESCIEP-JQCXWYLXSA-N pentostatin Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(N=CNC[C@H]2O)=C2N=C1 FPVKHBSQESCIEP-JQCXWYLXSA-N 0.000 description 2
- 229930192851 perforin Natural products 0.000 description 2
- 229960002087 pertuzumab Drugs 0.000 description 2
- 239000002571 phosphodiesterase inhibitor Substances 0.000 description 2
- 229910052698 phosphorus Inorganic materials 0.000 description 2
- 239000011574 phosphorus Substances 0.000 description 2
- 229960000952 pipobroman Drugs 0.000 description 2
- NJBFOOCLYDNZJN-UHFFFAOYSA-N pipobroman Chemical compound BrCCC(=O)N1CCN(C(=O)CCBr)CC1 NJBFOOCLYDNZJN-UHFFFAOYSA-N 0.000 description 2
- 229960002702 piroxicam Drugs 0.000 description 2
- QYSPLQLAKJAUJT-UHFFFAOYSA-N piroxicam Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC1=CC=CC=N1 QYSPLQLAKJAUJT-UHFFFAOYSA-N 0.000 description 2
- 150000003057 platinum Chemical class 0.000 description 2
- 229960003171 plicamycin Drugs 0.000 description 2
- 229960004293 porfimer sodium Drugs 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 229960004618 prednisone Drugs 0.000 description 2
- 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 2
- 239000003755 preservative agent Substances 0.000 description 2
- 230000000861 pro-apoptotic effect Effects 0.000 description 2
- CPTBDICYNRMXFX-UHFFFAOYSA-N procarbazine Chemical compound CNNCC1=CC=C(C(=O)NC(C)C)C=C1 CPTBDICYNRMXFX-UHFFFAOYSA-N 0.000 description 2
- 229960000624 procarbazine Drugs 0.000 description 2
- 238000004393 prognosis Methods 0.000 description 2
- QLNJFJADRCOGBJ-UHFFFAOYSA-N propionamide Chemical compound CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 description 2
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 description 2
- 239000003207 proteasome inhibitor Substances 0.000 description 2
- 239000003528 protein farnesyltransferase inhibitor Substances 0.000 description 2
- 150000003212 purines Chemical class 0.000 description 2
- RXWNCPJZOCPEPQ-NVWDDTSBSA-N puromycin Chemical compound C1=CC(OC)=CC=C1C[C@H](N)C(=O)N[C@H]1[C@@H](O)[C@H](N2C3=NC=NC(=C3N=C2)N(C)C)O[C@@H]1CO RXWNCPJZOCPEPQ-NVWDDTSBSA-N 0.000 description 2
- 125000003373 pyrazinyl group Chemical group 0.000 description 2
- LXNHXLLTXMVWPM-UHFFFAOYSA-N pyridoxine Chemical compound CC1=NC=C(CO)C(CO)=C1O LXNHXLLTXMVWPM-UHFFFAOYSA-N 0.000 description 2
- GPKJTRJOBQGKQK-UHFFFAOYSA-N quinacrine Chemical compound C1=C(OC)C=C2C(NC(C)CCCN(CC)CC)=C(C=CC(Cl)=C3)C3=NC2=C1 GPKJTRJOBQGKQK-UHFFFAOYSA-N 0.000 description 2
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 2
- 229960004622 raloxifene Drugs 0.000 description 2
- GZUITABIAKMVPG-UHFFFAOYSA-N raloxifene Chemical compound C1=CC(O)=CC=C1C1=C(C(=O)C=2C=CC(OCCN3CCCCC3)=CC=2)C2=CC=C(O)C=C2S1 GZUITABIAKMVPG-UHFFFAOYSA-N 0.000 description 2
- 229940099538 rapamune Drugs 0.000 description 2
- 229960000424 rasburicase Drugs 0.000 description 2
- 108010084837 rasburicase Proteins 0.000 description 2
- 230000004043 responsiveness Effects 0.000 description 2
- 229960002052 salbutamol Drugs 0.000 description 2
- WVYADZUPLLSGPU-UHFFFAOYSA-N salsalate Chemical compound OC(=O)C1=CC=CC=C1OC(=O)C1=CC=CC=C1O WVYADZUPLLSGPU-UHFFFAOYSA-N 0.000 description 2
- 229960002530 sargramostim Drugs 0.000 description 2
- 108010038379 sargramostim Proteins 0.000 description 2
- 229940095743 selective estrogen receptor modulator Drugs 0.000 description 2
- 239000000333 selective estrogen receptor modulator Substances 0.000 description 2
- 229910052710 silicon Inorganic materials 0.000 description 2
- 239000010703 silicon Substances 0.000 description 2
- 210000003491 skin Anatomy 0.000 description 2
- 208000000587 small cell lung carcinoma Diseases 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- JGMJQSFLQWGYMQ-UHFFFAOYSA-M sodium;2,6-dichloro-n-phenylaniline;acetate Chemical compound [Na+].CC([O-])=O.ClC1=CC=CC(Cl)=C1NC1=CC=CC=C1 JGMJQSFLQWGYMQ-UHFFFAOYSA-M 0.000 description 2
- MIXCUJKCXRNYFM-UHFFFAOYSA-M sodium;diiodomethanesulfonate;n-propyl-n-[2-(2,4,6-trichlorophenoxy)ethyl]imidazole-1-carboxamide Chemical compound [Na+].[O-]S(=O)(=O)C(I)I.C1=CN=CN1C(=O)N(CCC)CCOC1=C(Cl)C=C(Cl)C=C1Cl MIXCUJKCXRNYFM-UHFFFAOYSA-M 0.000 description 2
- 239000007909 solid dosage form Substances 0.000 description 2
- 229960003787 sorafenib Drugs 0.000 description 2
- 239000007921 spray Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- PVYJZLYGTZKPJE-UHFFFAOYSA-N streptonigrin Chemical compound C=1C=C2C(=O)C(OC)=C(N)C(=O)C2=NC=1C(C=1N)=NC(C(O)=O)=C(C)C=1C1=CC=C(OC)C(OC)=C1O PVYJZLYGTZKPJE-UHFFFAOYSA-N 0.000 description 2
- 229960001052 streptozocin Drugs 0.000 description 2
- ZSJLQEPLLKMAKR-GKHCUFPYSA-N streptozocin Chemical compound O=NN(C)C(=O)N[C@H]1[C@@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O ZSJLQEPLLKMAKR-GKHCUFPYSA-N 0.000 description 2
- MLKXDPUZXIRXEP-MFOYZWKCSA-N sulindac Chemical compound CC1=C(CC(O)=O)C2=CC(F)=CC=C2\C1=C/C1=CC=C(S(C)=O)C=C1 MLKXDPUZXIRXEP-MFOYZWKCSA-N 0.000 description 2
- 229960000894 sulindac Drugs 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 239000000375 suspending agent Substances 0.000 description 2
- 229940034785 sutent Drugs 0.000 description 2
- 229960001603 tamoxifen Drugs 0.000 description 2
- FQZYTYWMLGAPFJ-OQKDUQJOSA-N tamoxifen citrate Chemical compound [H+].[H+].[H+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O.C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 FQZYTYWMLGAPFJ-OQKDUQJOSA-N 0.000 description 2
- 229940120982 tarceva Drugs 0.000 description 2
- DKPFODGZWDEEBT-QFIAKTPHSA-N taxane Chemical class C([C@]1(C)CCC[C@@H](C)[C@H]1C1)C[C@H]2[C@H](C)CC[C@@H]1C2(C)C DKPFODGZWDEEBT-QFIAKTPHSA-N 0.000 description 2
- 229960004964 temozolomide Drugs 0.000 description 2
- 229960005353 testolactone Drugs 0.000 description 2
- BPEWUONYVDABNZ-DZBHQSCQSA-N testolactone Chemical compound O=C1C=C[C@]2(C)[C@H]3CC[C@](C)(OC(=O)CC4)[C@@H]4[C@@H]3CCC2=C1 BPEWUONYVDABNZ-DZBHQSCQSA-N 0.000 description 2
- 125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 description 2
- 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 2
- 125000003831 tetrazolyl group Chemical group 0.000 description 2
- YAPQBXQYLJRXSA-UHFFFAOYSA-N theobromine Chemical compound CN1C(=O)NC(=O)C2=C1N=CN2C YAPQBXQYLJRXSA-UHFFFAOYSA-N 0.000 description 2
- ZFXYFBGIUFBOJW-UHFFFAOYSA-N theophylline Chemical compound O=C1N(C)C(=O)N(C)C2=C1NC=N2 ZFXYFBGIUFBOJW-UHFFFAOYSA-N 0.000 description 2
- 125000001113 thiadiazolyl group Chemical group 0.000 description 2
- PLHJCIYEEKOWNM-HHHXNRCGSA-N tipifarnib Chemical compound CN1C=NC=C1[C@](N)(C=1C=C2C(C=3C=C(Cl)C=CC=3)=CC(=O)N(C)C2=CC=1)C1=CC=C(Cl)C=C1 PLHJCIYEEKOWNM-HHHXNRCGSA-N 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- XFCLJVABOIYOMF-QPLCGJKRSA-N toremifene Chemical compound C1=CC(OCCN(C)C)=CC=C1C(\C=1C=CC=CC=1)=C(\CCCl)C1=CC=CC=C1 XFCLJVABOIYOMF-QPLCGJKRSA-N 0.000 description 2
- 229960005026 toremifene Drugs 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
- 238000013518 transcription Methods 0.000 description 2
- 230000035897 transcription Effects 0.000 description 2
- 229960000575 trastuzumab Drugs 0.000 description 2
- 238000011269 treatment regimen Methods 0.000 description 2
- 229960002117 triamcinolone acetonide Drugs 0.000 description 2
- YNDXUCZADRHECN-JNQJZLCISA-N triamcinolone acetonide Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]1(C)C[C@@H]2O YNDXUCZADRHECN-JNQJZLCISA-N 0.000 description 2
- 125000004306 triazinyl group Chemical group 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- NOYPYLRCIDNJJB-UHFFFAOYSA-N trimetrexate Chemical compound COC1=C(OC)C(OC)=CC(NCC=2C(=C3C(N)=NC(N)=NC3=CC=2)C)=C1 NOYPYLRCIDNJJB-UHFFFAOYSA-N 0.000 description 2
- 229960001099 trimetrexate Drugs 0.000 description 2
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 2
- 229960000281 trometamol Drugs 0.000 description 2
- 229940094060 tykerb Drugs 0.000 description 2
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 2
- 150000004917 tyrosine kinase inhibitor derivatives Chemical class 0.000 description 2
- 229960001055 uracil mustard Drugs 0.000 description 2
- 229960002004 valdecoxib Drugs 0.000 description 2
- LNPDTQAFDNKSHK-UHFFFAOYSA-N valdecoxib Chemical compound CC=1ON=C(C=2C=CC=CC=2)C=1C1=CC=C(S(N)(=O)=O)C=C1 LNPDTQAFDNKSHK-UHFFFAOYSA-N 0.000 description 2
- 229960000653 valrubicin Drugs 0.000 description 2
- ZOCKGBMQLCSHFP-KQRAQHLDSA-N valrubicin Chemical compound O([C@H]1C[C@](CC2=C(O)C=3C(=O)C4=CC=CC(OC)=C4C(=O)C=3C(O)=C21)(O)C(=O)COC(=O)CCCC)[C@H]1C[C@H](NC(=O)C(F)(F)F)[C@H](O)[C@H](C)O1 ZOCKGBMQLCSHFP-KQRAQHLDSA-N 0.000 description 2
- 229960000241 vandetanib Drugs 0.000 description 2
- UHTHHESEBZOYNR-UHFFFAOYSA-N vandetanib Chemical compound COC1=CC(C(/N=CN2)=N/C=3C(=CC(Br)=CC=3)F)=C2C=C1OCC1CCN(C)CC1 UHTHHESEBZOYNR-UHFFFAOYSA-N 0.000 description 2
- GBABOYUKABKIAF-IELIFDKJSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-IELIFDKJSA-N 0.000 description 2
- 229960002066 vinorelbine Drugs 0.000 description 2
- DNXHEGUUPJUMQT-UHFFFAOYSA-N (+)-estrone Natural products OC1=CC=C2C3CCC(C)(C(CC4)=O)C4C3CCC2=C1 DNXHEGUUPJUMQT-UHFFFAOYSA-N 0.000 description 1
- XWTYSIMOBUGWOL-UHFFFAOYSA-N (+-)-Terbutaline Chemical compound CC(C)(C)NCC(O)C1=CC(O)=CC(O)=C1 XWTYSIMOBUGWOL-UHFFFAOYSA-N 0.000 description 1
- WMBWREPUVVBILR-WIYYLYMNSA-N (-)-Epigallocatechin-3-o-gallate Chemical compound O([C@@H]1CC2=C(O)C=C(C=C2O[C@@H]1C=1C=C(O)C(O)=C(O)C=1)O)C(=O)C1=CC(O)=C(O)C(O)=C1 WMBWREPUVVBILR-WIYYLYMNSA-N 0.000 description 1
- NNJPGOLRFBJNIW-HNNXBMFYSA-N (-)-demecolcine Chemical compound C1=C(OC)C(=O)C=C2[C@@H](NC)CCC3=CC(OC)=C(OC)C(OC)=C3C2=C1 NNJPGOLRFBJNIW-HNNXBMFYSA-N 0.000 description 1
- ZIUSSTSXXLLKKK-KOBPDPAPSA-N (1e,4z,6e)-5-hydroxy-1,7-bis(4-hydroxy-3-methoxyphenyl)hepta-1,4,6-trien-3-one Chemical compound C1=C(O)C(OC)=CC(\C=C\C(\O)=C\C(=O)\C=C\C=2C=C(OC)C(O)=CC=2)=C1 ZIUSSTSXXLLKKK-KOBPDPAPSA-N 0.000 description 1
- 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
- JNYAEWCLZODPBN-JGWLITMVSA-N (2r,3r,4s)-2-[(1r)-1,2-dihydroxyethyl]oxolane-3,4-diol Chemical compound OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O JNYAEWCLZODPBN-JGWLITMVSA-N 0.000 description 1
- RIWLPSIAFBLILR-WVNGMBSFSA-N (2s)-1-[(2s)-2-[[(2s,3s)-2-[[(2s)-2-[[(2s,3r)-2-[[(2r,3s)-2-[[(2s)-2-[[2-[[2-[acetyl(methyl)amino]acetyl]amino]acetyl]amino]-3-methylbutanoyl]amino]-3-methylpentanoyl]amino]-3-hydroxybutanoyl]amino]pentanoyl]amino]-3-methylpentanoyl]amino]-5-(diaminomethy Chemical compound CC(=O)N(C)CC(=O)NCC(=O)N[C@@H](C(C)C)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N1CCC[C@H]1C(=O)NCC RIWLPSIAFBLILR-WVNGMBSFSA-N 0.000 description 1
- RDJGLLICXDHJDY-NSHDSACASA-N (2s)-2-(3-phenoxyphenyl)propanoic acid Chemical compound OC(=O)[C@@H](C)C1=CC=CC(OC=2C=CC=CC=2)=C1 RDJGLLICXDHJDY-NSHDSACASA-N 0.000 description 1
- YXTKHLHCVFUPPT-YYFJYKOTSA-N (2s)-2-[[4-[(2-amino-5-formyl-4-oxo-1,6,7,8-tetrahydropteridin-6-yl)methylamino]benzoyl]amino]pentanedioic acid;(1r,2r)-1,2-dimethanidylcyclohexane;5-fluoro-1h-pyrimidine-2,4-dione;oxalic acid;platinum(2+) Chemical compound [Pt+2].OC(=O)C(O)=O.[CH2-][C@@H]1CCCC[C@H]1[CH2-].FC1=CNC(=O)NC1=O.C1NC=2NC(N)=NC(=O)C=2N(C=O)C1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 YXTKHLHCVFUPPT-YYFJYKOTSA-N 0.000 description 1
- FLWWDYNPWOSLEO-HQVZTVAUSA-N (2s)-2-[[4-[1-(2-amino-4-oxo-1h-pteridin-6-yl)ethyl-methylamino]benzoyl]amino]pentanedioic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1C(C)N(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FLWWDYNPWOSLEO-HQVZTVAUSA-N 0.000 description 1
- LJRDOKAZOAKLDU-UDXJMMFXSA-N (2s,3s,4r,5r,6r)-5-amino-2-(aminomethyl)-6-[(2r,3s,4r,5s)-5-[(1r,2r,3s,5r,6s)-3,5-diamino-2-[(2s,3r,4r,5s,6r)-3-amino-4,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-6-hydroxycyclohexyl]oxy-4-hydroxy-2-(hydroxymethyl)oxolan-3-yl]oxyoxane-3,4-diol;sulfuric ac Chemical compound OS(O)(=O)=O.N[C@@H]1[C@@H](O)[C@H](O)[C@H](CN)O[C@@H]1O[C@H]1[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](N)C[C@@H](N)[C@@H]2O)O[C@@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)N)O[C@@H]1CO LJRDOKAZOAKLDU-UDXJMMFXSA-N 0.000 description 1
- OTHYPAMNTUGKDK-UHFFFAOYSA-N (3-acetylphenyl) acetate Chemical compound CC(=O)OC1=CC=CC(C(C)=O)=C1 OTHYPAMNTUGKDK-UHFFFAOYSA-N 0.000 description 1
- CGMTUJFWROPELF-YPAAEMCBSA-N (3E,5S)-5-[(2S)-butan-2-yl]-3-(1-hydroxyethylidene)pyrrolidine-2,4-dione Chemical compound CC[C@H](C)[C@@H]1NC(=O)\C(=C(/C)O)C1=O CGMTUJFWROPELF-YPAAEMCBSA-N 0.000 description 1
- CVCQAQVBOPNTFI-AAONGDSNSA-N (3r,4r,5s,6r)-3-amino-6-(hydroxymethyl)oxane-2,4,5-triol;sulfuric acid Chemical compound OS(O)(=O)=O.N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O.N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O CVCQAQVBOPNTFI-AAONGDSNSA-N 0.000 description 1
- TVIRNGFXQVMMGB-OFWIHYRESA-N (3s,6r,10r,13e,16s)-16-[(2r,3r,4s)-4-chloro-3-hydroxy-4-phenylbutan-2-yl]-10-[(3-chloro-4-methoxyphenyl)methyl]-6-methyl-3-(2-methylpropyl)-1,4-dioxa-8,11-diazacyclohexadec-13-ene-2,5,9,12-tetrone Chemical compound C1=C(Cl)C(OC)=CC=C1C[C@@H]1C(=O)NC[C@@H](C)C(=O)O[C@@H](CC(C)C)C(=O)O[C@H]([C@H](C)[C@@H](O)[C@@H](Cl)C=2C=CC=CC=2)C/C=C/C(=O)N1 TVIRNGFXQVMMGB-OFWIHYRESA-N 0.000 description 1
- CXAGHAZMQSCAKJ-WAHHBDPQSA-N (4s,7s)-n-[(2r,3s)-2-ethoxy-5-oxooxolan-3-yl]-7-(isoquinoline-1-carbonylamino)-6,10-dioxo-2,3,4,7,8,9-hexahydro-1h-pyridazino[1,2-a]diazepine-4-carboxamide Chemical compound CCO[C@@H]1OC(=O)C[C@@H]1NC(=O)[C@H]1N(C(=O)[C@H](CCC2=O)NC(=O)C=3C4=CC=CC=C4C=CN=3)N2CCC1 CXAGHAZMQSCAKJ-WAHHBDPQSA-N 0.000 description 1
- XRBSKUSTLXISAB-XVVDYKMHSA-N (5r,6r,7r,8r)-8-hydroxy-7-(hydroxymethyl)-5-(3,4,5-trimethoxyphenyl)-5,6,7,8-tetrahydrobenzo[f][1,3]benzodioxole-6-carboxylic acid Chemical compound COC1=C(OC)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@H](O)[C@@H](CO)[C@@H]2C(O)=O)=C1 XRBSKUSTLXISAB-XVVDYKMHSA-N 0.000 description 1
- PQMFVUNERGGBPG-UHFFFAOYSA-N (6-bromopyridin-2-yl)hydrazine Chemical compound NNC1=CC=CC(Br)=N1 PQMFVUNERGGBPG-UHFFFAOYSA-N 0.000 description 1
- XRBSKUSTLXISAB-UHFFFAOYSA-N (7R,7'R,8R,8'R)-form-Podophyllic acid Natural products COC1=C(OC)C(OC)=CC(C2C3=CC=4OCOC=4C=C3C(O)C(CO)C2C(O)=O)=C1 XRBSKUSTLXISAB-UHFFFAOYSA-N 0.000 description 1
- AESVUZLWRXEGEX-DKCAWCKPSA-N (7S,9R)-7-[(2S,4R,5R,6R)-4-amino-5-hydroxy-6-methyloxan-2-yl]oxy-6,9,11-trihydroxy-9-(2-hydroxyacetyl)-4-methoxy-8,10-dihydro-7H-tetracene-5,12-dione iron(3+) Chemical compound [Fe+3].COc1cccc2C(=O)c3c(O)c4C[C@@](O)(C[C@H](O[C@@H]5C[C@@H](N)[C@@H](O)[C@@H](C)O5)c4c(O)c3C(=O)c12)C(=O)CO AESVUZLWRXEGEX-DKCAWCKPSA-N 0.000 description 1
- JXVAMODRWBNUSF-KZQKBALLSA-N (7s,9r,10r)-7-[(2r,4s,5s,6s)-5-[[(2s,4as,5as,7s,9s,9ar,10ar)-2,9-dimethyl-3-oxo-4,4a,5a,6,7,9,9a,10a-octahydrodipyrano[4,2-a:4',3'-e][1,4]dioxin-7-yl]oxy]-4-(dimethylamino)-6-methyloxan-2-yl]oxy-10-[(2s,4s,5s,6s)-4-(dimethylamino)-5-hydroxy-6-methyloxan-2 Chemical compound O([C@@H]1C2=C(O)C=3C(=O)C4=CC=CC(O)=C4C(=O)C=3C(O)=C2[C@@H](O[C@@H]2O[C@@H](C)[C@@H](O[C@@H]3O[C@@H](C)[C@H]4O[C@@H]5O[C@@H](C)C(=O)C[C@@H]5O[C@H]4C3)[C@H](C2)N(C)C)C[C@]1(O)CC)[C@H]1C[C@H](N(C)C)[C@H](O)[C@H](C)O1 JXVAMODRWBNUSF-KZQKBALLSA-N 0.000 description 1
- INAUWOVKEZHHDM-PEDBPRJASA-N (7s,9s)-6,9,11-trihydroxy-9-(2-hydroxyacetyl)-7-[(2r,4s,5s,6s)-5-hydroxy-6-methyl-4-morpholin-4-yloxan-2-yl]oxy-4-methoxy-8,10-dihydro-7h-tetracene-5,12-dione;hydrochloride Chemical compound Cl.N1([C@H]2C[C@@H](O[C@@H](C)[C@H]2O)O[C@H]2C[C@@](O)(CC=3C(O)=C4C(=O)C=5C=CC=C(C=5C(=O)C4=C(O)C=32)OC)C(=O)CO)CCOCC1 INAUWOVKEZHHDM-PEDBPRJASA-N 0.000 description 1
- RCFNNLSZHVHCEK-IMHLAKCZSA-N (7s,9s)-7-(4-amino-6-methyloxan-2-yl)oxy-6,9,11-trihydroxy-9-(2-hydroxyacetyl)-4-methoxy-8,10-dihydro-7h-tetracene-5,12-dione;hydrochloride Chemical compound [Cl-].O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)C1CC([NH3+])CC(C)O1 RCFNNLSZHVHCEK-IMHLAKCZSA-N 0.000 description 1
- NOPNWHSMQOXAEI-PUCKCBAPSA-N (7s,9s)-7-[(2r,4s,5s,6s)-4-(2,3-dihydropyrrol-1-yl)-5-hydroxy-6-methyloxan-2-yl]oxy-6,9,11-trihydroxy-9-(2-hydroxyacetyl)-4-methoxy-8,10-dihydro-7h-tetracene-5,12-dione Chemical compound N1([C@H]2C[C@@H](O[C@@H](C)[C@H]2O)O[C@H]2C[C@@](O)(CC=3C(O)=C4C(=O)C=5C=CC=C(C=5C(=O)C4=C(O)C=32)OC)C(=O)CO)CCC=C1 NOPNWHSMQOXAEI-PUCKCBAPSA-N 0.000 description 1
- IEXUMDBQLIVNHZ-YOUGDJEHSA-N (8s,11r,13r,14s,17s)-11-[4-(dimethylamino)phenyl]-17-hydroxy-17-(3-hydroxypropyl)-13-methyl-1,2,6,7,8,11,12,14,15,16-decahydrocyclopenta[a]phenanthren-3-one Chemical compound C1=CC(N(C)C)=CC=C1[C@@H]1C2=C3CCC(=O)C=C3CC[C@H]2[C@H](CC[C@]2(O)CCCO)[C@@]2(C)C1 IEXUMDBQLIVNHZ-YOUGDJEHSA-N 0.000 description 1
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 1
- FDKXTQMXEQVLRF-ZHACJKMWSA-N (E)-dacarbazine Chemical compound CN(C)\N=N\c1[nH]cnc1C(N)=O FDKXTQMXEQVLRF-ZHACJKMWSA-N 0.000 description 1
- LKJPYSCBVHEWIU-KRWDZBQOSA-N (R)-bicalutamide Chemical compound C([C@@](O)(C)C(=O)NC=1C=C(C(C#N)=CC=1)C(F)(F)F)S(=O)(=O)C1=CC=C(F)C=C1 LKJPYSCBVHEWIU-KRWDZBQOSA-N 0.000 description 1
- MHFRGQHAERHWKZ-HHHXNRCGSA-N (R)-edelfosine Chemical compound CCCCCCCCCCCCCCCCCCOC[C@@H](OC)COP([O-])(=O)OCC[N+](C)(C)C MHFRGQHAERHWKZ-HHHXNRCGSA-N 0.000 description 1
- PPKXEPBICJTCRU-XMZRARIVSA-N (R,R)-tramadol hydrochloride Chemical compound Cl.COC1=CC=CC([C@]2(O)[C@H](CCCC2)CN(C)C)=C1 PPKXEPBICJTCRU-XMZRARIVSA-N 0.000 description 1
- WHTVZRBIWZFKQO-AWEZNQCLSA-N (S)-chloroquine Chemical compound ClC1=CC=C2C(N[C@@H](C)CCCN(CC)CC)=CC=NC2=C1 WHTVZRBIWZFKQO-AWEZNQCLSA-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
- AGNGYMCLFWQVGX-AGFFZDDWSA-N (e)-1-[(2s)-2-amino-2-carboxyethoxy]-2-diazonioethenolate Chemical compound OC(=O)[C@@H](N)CO\C([O-])=C\[N+]#N AGNGYMCLFWQVGX-AGFFZDDWSA-N 0.000 description 1
- XGQXULJHBWKUJY-LYIKAWCPSA-N (z)-but-2-enedioic acid;n-[2-(diethylamino)ethyl]-5-[(z)-(5-fluoro-2-oxo-1h-indol-3-ylidene)methyl]-2,4-dimethyl-1h-pyrrole-3-carboxamide Chemical compound OC(=O)\C=C/C(O)=O.CCN(CC)CCNC(=O)C1=C(C)NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C1C XGQXULJHBWKUJY-LYIKAWCPSA-N 0.000 description 1
- WBYWAXJHAXSJNI-VOTSOKGWSA-M .beta-Phenylacrylic acid Natural products [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
- 125000005988 1,1-dioxo-thiomorpholinyl group Chemical group 0.000 description 1
- 125000004516 1,2,4-thiadiazol-5-yl group Chemical group S1N=CN=C1* 0.000 description 1
- 125000001414 1,2,4-triazol-5-yl group Chemical group [H]N1N=C([H])N=C1[*] 0.000 description 1
- ZHYMGSPDEVXULU-UHFFFAOYSA-N 1,2-benzodiazepin-3-one Chemical compound N1=NC(=O)C=CC2=CC=CC=C21 ZHYMGSPDEVXULU-UHFFFAOYSA-N 0.000 description 1
- FONKWHRXTPJODV-DNQXCXABSA-N 1,3-bis[2-[(8s)-8-(chloromethyl)-4-hydroxy-1-methyl-7,8-dihydro-3h-pyrrolo[3,2-e]indole-6-carbonyl]-1h-indol-5-yl]urea Chemical compound C1([C@H](CCl)CN2C(=O)C=3NC4=CC=C(C=C4C=3)NC(=O)NC=3C=C4C=C(NC4=CC=3)C(=O)N3C4=CC(O)=C5NC=C(C5=C4[C@H](CCl)C3)C)=C2C=C(O)C2=C1C(C)=CN2 FONKWHRXTPJODV-DNQXCXABSA-N 0.000 description 1
- 229940058015 1,3-butylene glycol Drugs 0.000 description 1
- WNXJIVFYUVYPPR-UHFFFAOYSA-N 1,3-dioxolane Chemical compound C1COCO1 WNXJIVFYUVYPPR-UHFFFAOYSA-N 0.000 description 1
- JPRPJUMQRZTTED-UHFFFAOYSA-N 1,3-dioxolanyl Chemical group [CH]1OCCO1 JPRPJUMQRZTTED-UHFFFAOYSA-N 0.000 description 1
- 125000005960 1,4-diazepanyl group Chemical group 0.000 description 1
- 125000004973 1-butenyl group Chemical group C(=CCC)* 0.000 description 1
- 125000004972 1-butynyl group Chemical group [H]C([H])([H])C([H])([H])C#C* 0.000 description 1
- VSNHCAURESNICA-NJFSPNSNSA-N 1-oxidanylurea Chemical compound N[14C](=O)NO VSNHCAURESNICA-NJFSPNSNSA-N 0.000 description 1
- GAJBWMUZVXJIBO-UHFFFAOYSA-N 1-oxidopyridazin-1-ium Chemical class [O-][N+]1=CC=CC=N1 GAJBWMUZVXJIBO-UHFFFAOYSA-N 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- 102100036506 11-beta-hydroxysteroid dehydrogenase 1 Human genes 0.000 description 1
- 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 1
- ABEXEQSGABRUHS-UHFFFAOYSA-N 16-methylheptadecyl 16-methylheptadecanoate Chemical compound CC(C)CCCCCCCCCCCCCCCOC(=O)CCCCCCCCCCCCCCC(C)C ABEXEQSGABRUHS-UHFFFAOYSA-N 0.000 description 1
- RAXXELZNTBOGNW-UHFFFAOYSA-N 1H-imidazole Chemical compound C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 1
- APXRHPDHORGIEB-UHFFFAOYSA-N 1H-pyrazolo[4,3-d]pyrimidine Chemical class N1=CN=C2C=NNC2=C1 APXRHPDHORGIEB-UHFFFAOYSA-N 0.000 description 1
- BTOTXLJHDSNXMW-POYBYMJQSA-N 2,3-dideoxyuridine Chemical compound O1[C@H](CO)CC[C@@H]1N1C(=O)NC(=O)C=C1 BTOTXLJHDSNXMW-POYBYMJQSA-N 0.000 description 1
- CHHHXKFHOYLYRE-UHFFFAOYSA-M 2,4-Hexadienoic acid, potassium salt (1:1), (2E,4E)- Chemical compound [K+].CC=CC=CC([O-])=O CHHHXKFHOYLYRE-UHFFFAOYSA-M 0.000 description 1
- BOMZMNZEXMAQQW-UHFFFAOYSA-N 2,5,11-trimethyl-6h-pyrido[4,3-b]carbazol-2-ium-9-ol;acetate Chemical compound CC([O-])=O.C[N+]1=CC=C2C(C)=C(NC=3C4=CC(O)=CC=3)C4=C(C)C2=C1 BOMZMNZEXMAQQW-UHFFFAOYSA-N 0.000 description 1
- ZAVJTSLIGAGALR-UHFFFAOYSA-N 2-(2,2,2-trifluoroacetyl)cyclooctan-1-one Chemical compound FC(F)(F)C(=O)C1CCCCCCC1=O ZAVJTSLIGAGALR-UHFFFAOYSA-N 0.000 description 1
- YMZPQKXPKZZSFV-CPWYAANMSA-N 2-[3-[(1r)-1-[(2s)-1-[(2s)-2-[(1r)-cyclohex-2-en-1-yl]-2-(3,4,5-trimethoxyphenyl)acetyl]piperidine-2-carbonyl]oxy-3-(3,4-dimethoxyphenyl)propyl]phenoxy]acetic acid Chemical compound C1=C(OC)C(OC)=CC=C1CC[C@H](C=1C=C(OCC(O)=O)C=CC=1)OC(=O)[C@H]1N(C(=O)[C@@H]([C@H]2C=CCCC2)C=2C=C(OC)C(OC)=C(OC)C=2)CCCC1 YMZPQKXPKZZSFV-CPWYAANMSA-N 0.000 description 1
- GXAFMKJFWWBYNW-OWHBQTKESA-N 2-[3-[(1r)-1-[(2s)-1-[(2s)-3-cyclopropyl-2-(3,4,5-trimethoxyphenyl)propanoyl]piperidine-2-carbonyl]oxy-3-(3,4-dimethoxyphenyl)propyl]phenoxy]acetic acid Chemical compound C1=C(OC)C(OC)=CC=C1CC[C@H](C=1C=C(OCC(O)=O)C=CC=1)OC(=O)[C@H]1N(C(=O)[C@@H](CC2CC2)C=2C=C(OC)C(OC)=C(OC)C=2)CCCC1 GXAFMKJFWWBYNW-OWHBQTKESA-N 0.000 description 1
- RQVKVJIRFKVPBF-VWLOTQADSA-N 2-[[(2s)-2-amino-3-phenylpropyl]amino]-3-methyl-5-naphthalen-2-yl-6-pyridin-4-ylpyrimidin-4-one Chemical compound C([C@H](N)CNC=1N(C(C(C=2C=C3C=CC=CC3=CC=2)=C(C=2C=CN=CC=2)N=1)=O)C)C1=CC=CC=C1 RQVKVJIRFKVPBF-VWLOTQADSA-N 0.000 description 1
- QCXJFISCRQIYID-IAEPZHFASA-N 2-amino-1-n-[(3s,6s,7r,10s,16s)-3-[(2s)-butan-2-yl]-7,11,14-trimethyl-2,5,9,12,15-pentaoxo-10-propan-2-yl-8-oxa-1,4,11,14-tetrazabicyclo[14.3.0]nonadecan-6-yl]-4,6-dimethyl-3-oxo-9-n-[(3s,6s,7r,10s,16s)-7,11,14-trimethyl-2,5,9,12,15-pentaoxo-3,10-di(propa Chemical compound C[C@H]1OC(=O)[C@H](C(C)C)N(C)C(=O)CN(C)C(=O)[C@@H]2CCCN2C(=O)[C@H](C(C)C)NC(=O)[C@H]1NC(=O)C1=C(N=C2C(C(=O)N[C@@H]3C(=O)N[C@H](C(N4CCC[C@H]4C(=O)N(C)CC(=O)N(C)[C@@H](C(C)C)C(=O)O[C@@H]3C)=O)[C@@H](C)CC)=C(N)C(=O)C(C)=C2O2)C2=C(C)C=C1 QCXJFISCRQIYID-IAEPZHFASA-N 0.000 description 1
- MSWZFWKMSRAUBD-IVMDWMLBSA-N 2-amino-2-deoxy-D-glucopyranose Chemical compound N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O MSWZFWKMSRAUBD-IVMDWMLBSA-N 0.000 description 1
- CPJAOFOWDGRJQD-NJVNFBHUSA-N 2-aminoacetic acid;(2s)-2-amino-3-phenylpropanoic acid;(2s)-2,5-diamino-5-oxopentanoic acid Chemical compound NCC(O)=O.OC(=O)[C@@H](N)CCC(N)=O.OC(=O)[C@@H](N)CC1=CC=CC=C1 CPJAOFOWDGRJQD-NJVNFBHUSA-N 0.000 description 1
- 125000004174 2-benzimidazolyl group Chemical group [H]N1C(*)=NC2=C([H])C([H])=C([H])C([H])=C12 0.000 description 1
- 125000004974 2-butenyl group Chemical group C(C=CC)* 0.000 description 1
- 125000000069 2-butynyl group Chemical group [H]C([H])([H])C#CC([H])([H])* 0.000 description 1
- FDAYLTPAFBGXAB-UHFFFAOYSA-N 2-chloro-n,n-bis(2-chloroethyl)ethanamine Chemical compound ClCCN(CCCl)CCCl FDAYLTPAFBGXAB-UHFFFAOYSA-N 0.000 description 1
- VNBAOSVONFJBKP-UHFFFAOYSA-N 2-chloro-n,n-bis(2-chloroethyl)propan-1-amine;hydrochloride Chemical compound Cl.CC(Cl)CN(CCCl)CCCl VNBAOSVONFJBKP-UHFFFAOYSA-N 0.000 description 1
- BFSVOASYOCHEOV-UHFFFAOYSA-N 2-diethylaminoethanol Chemical compound CCN(CC)CCO BFSVOASYOCHEOV-UHFFFAOYSA-N 0.000 description 1
- 229940013085 2-diethylaminoethanol Drugs 0.000 description 1
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 description 1
- JIZRGGUCOQKGQD-UHFFFAOYSA-N 2-nitrothiophene Chemical group [O-][N+](=O)C1=CC=CS1 JIZRGGUCOQKGQD-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
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 1
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 1
- 125000001698 2H-pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- YIMDLWDNDGKDTJ-QLKYHASDSA-N 3'-deamino-3'-(3-cyanomorpholin-4-yl)doxorubicin Chemical compound N1([C@H]2C[C@@H](O[C@@H](C)[C@H]2O)O[C@H]2C[C@@](O)(CC=3C(O)=C4C(=O)C=5C=CC=C(C=5C(=O)C4=C(O)C=32)OC)C(=O)CO)CCOCC1C#N YIMDLWDNDGKDTJ-QLKYHASDSA-N 0.000 description 1
- NDMPLJNOPCLANR-UHFFFAOYSA-N 3,4-dihydroxy-15-(4-hydroxy-18-methoxycarbonyl-5,18-seco-ibogamin-18-yl)-16-methoxy-1-methyl-6,7-didehydro-aspidospermidine-3-carboxylic acid methyl ester Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 NDMPLJNOPCLANR-UHFFFAOYSA-N 0.000 description 1
- SIVJKYRAPQKLIM-UHFFFAOYSA-N 3-(3,4-difluorophenyl)-n-(3-fluoro-5-morpholin-4-ylphenyl)propanamide Chemical compound C=1C(N2CCOCC2)=CC(F)=CC=1NC(=O)CCC1=CC=C(F)C(F)=C1 SIVJKYRAPQKLIM-UHFFFAOYSA-N 0.000 description 1
- DDYUBCCTNHWSQM-UHFFFAOYSA-N 3-(3-cyclopentyloxy-4-methoxyphenyl)-3-(1,3-dioxoisoindol-2-yl)propanamide Chemical compound COC1=CC=C(C(CC(N)=O)N2C(C3=CC=CC=C3C2=O)=O)C=C1OC1CCCC1 DDYUBCCTNHWSQM-UHFFFAOYSA-N 0.000 description 1
- PWMYMKOUNYTVQN-UHFFFAOYSA-N 3-(8,8-diethyl-2-aza-8-germaspiro[4.5]decan-2-yl)-n,n-dimethylpropan-1-amine Chemical compound C1C[Ge](CC)(CC)CCC11CN(CCCN(C)C)CC1 PWMYMKOUNYTVQN-UHFFFAOYSA-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
- 125000004975 3-butenyl group Chemical group C(CC=C)* 0.000 description 1
- 125000000474 3-butynyl group Chemical group [H]C#CC([H])([H])C([H])([H])* 0.000 description 1
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 description 1
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 125000004364 3-pyrrolinyl group Chemical group [H]C1=C([H])C([H])([H])N(*)C1([H])[H] 0.000 description 1
- NBUHTTJGQKIBMR-UHFFFAOYSA-N 4,6-dimethylpyrimidin-5-amine Chemical compound CC1=NC=NC(C)=C1N NBUHTTJGQKIBMR-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- CLPFFLWZZBQMAO-UHFFFAOYSA-N 4-(5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-5-yl)benzonitrile Chemical compound C1=CC(C#N)=CC=C1C1N2C=NC=C2CCC1 CLPFFLWZZBQMAO-UHFFFAOYSA-N 0.000 description 1
- AKJHMTWEGVYYSE-AIRMAKDCSA-N 4-HPR Chemical compound C=1C=C(O)C=CC=1NC(=O)/C=C(\C)/C=C/C=C(C)C=CC1=C(C)CCCC1(C)C AKJHMTWEGVYYSE-AIRMAKDCSA-N 0.000 description 1
- DODQJNMQWMSYGS-QPLCGJKRSA-N 4-[(z)-1-[4-[2-(dimethylamino)ethoxy]phenyl]-1-phenylbut-1-en-2-yl]phenol Chemical compound C=1C=C(O)C=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 DODQJNMQWMSYGS-QPLCGJKRSA-N 0.000 description 1
- TVZGACDUOSZQKY-LBPRGKRZSA-N 4-aminofolic acid Chemical compound C1=NC2=NC(N)=NC(N)=C2N=C1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 TVZGACDUOSZQKY-LBPRGKRZSA-N 0.000 description 1
- WUBBRNOQWQTFEX-UHFFFAOYSA-N 4-aminosalicylic acid Chemical compound NC1=CC=C(C(O)=O)C(O)=C1 WUBBRNOQWQTFEX-UHFFFAOYSA-N 0.000 description 1
- NFBCSWGEYDCCDW-UHFFFAOYSA-N 4-n-(3-methylphenyl)quinazoline-4,6-diamine Chemical compound CC1=CC=CC(NC=2C3=CC(N)=CC=C3N=CN=2)=C1 NFBCSWGEYDCCDW-UHFFFAOYSA-N 0.000 description 1
- OBKXEAXTFZPCHS-UHFFFAOYSA-N 4-phenylbutyric acid Chemical compound OC(=O)CCCC1=CC=CC=C1 OBKXEAXTFZPCHS-UHFFFAOYSA-N 0.000 description 1
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 1
- 125000001826 4H-pyranyl group Chemical group O1C(=CCC=C1)* 0.000 description 1
- 125000002471 4H-quinolizinyl group Chemical group C=1(C=CCN2C=CC=CC12)* 0.000 description 1
- RONQPWQYDRPRGG-UHFFFAOYSA-N 5,6-bis(4-fluoroanilino)isoindole-1,3-dione Chemical compound C1=CC(F)=CC=C1NC(C(=C1)NC=2C=CC(F)=CC=2)=CC2=C1C(=O)NC2=O RONQPWQYDRPRGG-UHFFFAOYSA-N 0.000 description 1
- MJZJYWCQPMNPRM-UHFFFAOYSA-N 6,6-dimethyl-1-[3-(2,4,5-trichlorophenoxy)propoxy]-1,6-dihydro-1,3,5-triazine-2,4-diamine Chemical compound CC1(C)N=C(N)N=C(N)N1OCCCOC1=CC(Cl)=C(Cl)C=C1Cl MJZJYWCQPMNPRM-UHFFFAOYSA-N 0.000 description 1
- FYSRKRZDBHOFAY-UHFFFAOYSA-N 6-(N-carbamoyl-2,6-difluoroanilino)-2-(2,4-difluorophenyl)-3-pyridinecarboxamide Chemical compound FC=1C=CC=C(F)C=1N(C(=O)N)C(N=1)=CC=C(C(N)=O)C=1C1=CC=C(F)C=C1F FYSRKRZDBHOFAY-UHFFFAOYSA-N 0.000 description 1
- WYXSYVWAUAUWLD-SHUUEZRQSA-N 6-azauridine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C=N1 WYXSYVWAUAUWLD-SHUUEZRQSA-N 0.000 description 1
- YCWQAMGASJSUIP-YFKPBYRVSA-N 6-diazo-5-oxo-L-norleucine Chemical compound OC(=O)[C@@H](N)CCC(=O)C=[N+]=[N-] YCWQAMGASJSUIP-YFKPBYRVSA-N 0.000 description 1
- 229960005538 6-diazo-5-oxo-L-norleucine Drugs 0.000 description 1
- YPWFNLSXQIGJCK-UHFFFAOYSA-N 7-oxabicyclo[2.2.1]heptane Chemical compound C1CC2CCC1O2 YPWFNLSXQIGJCK-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- ZGXJTSGNIOSYLO-UHFFFAOYSA-N 88755TAZ87 Chemical compound NCC(=O)CCC(O)=O ZGXJTSGNIOSYLO-UHFFFAOYSA-N 0.000 description 1
- FUXVKZWTXQUGMW-FQEVSTJZSA-N 9-Aminocamptothecin Chemical compound C1=CC(N)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 FUXVKZWTXQUGMW-FQEVSTJZSA-N 0.000 description 1
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
- HDZZVAMISRMYHH-UHFFFAOYSA-N 9beta-Ribofuranosyl-7-deazaadenin Natural products C1=CC=2C(N)=NC=NC=2N1C1OC(CO)C(O)C1O HDZZVAMISRMYHH-UHFFFAOYSA-N 0.000 description 1
- 208000030507 AIDS Diseases 0.000 description 1
- 208000007122 AIDS-Associated Nephropathy Diseases 0.000 description 1
- 208000030090 Acute Disease Diseases 0.000 description 1
- 208000009304 Acute Kidney Injury Diseases 0.000 description 1
- 206010000830 Acute leukaemia Diseases 0.000 description 1
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 description 1
- 208000014697 Acute lymphocytic leukaemia Diseases 0.000 description 1
- 208000031261 Acute myeloid leukaemia Diseases 0.000 description 1
- 208000026872 Addison Disease Diseases 0.000 description 1
- 102100031934 Adhesion G-protein coupled receptor G1 Human genes 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- 102100033407 Alpha-amylase 2B Human genes 0.000 description 1
- CEIZFXOZIQNICU-UHFFFAOYSA-N Alternaria alternata Crofton-weed toxin Natural products CCC(C)C1NC(=O)C(C(C)=O)=C1O CEIZFXOZIQNICU-UHFFFAOYSA-N 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- 201000003076 Angiosarcoma Diseases 0.000 description 1
- 108090000644 Angiozyme Proteins 0.000 description 1
- 102100033307 Ankyrin repeat domain-containing protein 37 Human genes 0.000 description 1
- 108020000948 Antisense Oligonucleotides Proteins 0.000 description 1
- 235000003276 Apios tuberosa Nutrition 0.000 description 1
- 101150094024 Apod gene Proteins 0.000 description 1
- 102100022954 Apolipoprotein D Human genes 0.000 description 1
- 244000105624 Arachis hypogaea Species 0.000 description 1
- 235000010777 Arachis hypogaea Nutrition 0.000 description 1
- 235000010744 Arachis villosulicarpa Nutrition 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 102000014654 Aromatase Human genes 0.000 description 1
- 108010078554 Aromatase Proteins 0.000 description 1
- 208000036487 Arthropathies Diseases 0.000 description 1
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Natural products OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 1
- 206010003571 Astrocytoma Diseases 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- NOWKCMXCCJGMRR-UHFFFAOYSA-N Aziridine Chemical class C1CN1 NOWKCMXCCJGMRR-UHFFFAOYSA-N 0.000 description 1
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 description 1
- 239000012664 BCL-2-inhibitor Substances 0.000 description 1
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 description 1
- 102100021621 BEN domain-containing protein 5 Human genes 0.000 description 1
- 206010004146 Basal cell carcinoma Diseases 0.000 description 1
- 229940123711 Bcl2 inhibitor Drugs 0.000 description 1
- 208000009137 Behcet syndrome Diseases 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- VGGGPCQERPFHOB-MCIONIFRSA-N Bestatin Chemical compound CC(C)C[C@H](C(O)=O)NC(=O)[C@@H](O)[C@H](N)CC1=CC=CC=C1 VGGGPCQERPFHOB-MCIONIFRSA-N 0.000 description 1
- 229940121786 Beta 2 adrenoreceptor agonist Drugs 0.000 description 1
- 206010004593 Bile duct cancer Diseases 0.000 description 1
- 206010005003 Bladder cancer Diseases 0.000 description 1
- 102000004506 Blood Proteins Human genes 0.000 description 1
- 108010017384 Blood Proteins Proteins 0.000 description 1
- 208000019838 Blood disease Diseases 0.000 description 1
- 208000003174 Brain Neoplasms Diseases 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- VOVIALXJUBGFJZ-KWVAZRHASA-N Budesonide Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1C[C@H]3OC(CCC)O[C@@]3(C(=O)CO)[C@@]1(C)C[C@@H]2O VOVIALXJUBGFJZ-KWVAZRHASA-N 0.000 description 1
- MBABCNBNDNGODA-LTGLSHGVSA-N Bullatacin Natural products O=C1C(C[C@H](O)CCCCCCCCCC[C@@H](O)[C@@H]2O[C@@H]([C@@H]3O[C@H]([C@@H](O)CCCCCCCCCC)CC3)CC2)=C[C@H](C)O1 MBABCNBNDNGODA-LTGLSHGVSA-N 0.000 description 1
- KGGVWMAPBXIMEM-ZRTAFWODSA-N Bullatacinone Chemical compound O1[C@@H]([C@@H](O)CCCCCCCCCC)CC[C@@H]1[C@@H]1O[C@@H]([C@H](O)CCCCCCCCCC[C@H]2OC(=O)[C@H](CC(C)=O)C2)CC1 KGGVWMAPBXIMEM-ZRTAFWODSA-N 0.000 description 1
- KGGVWMAPBXIMEM-JQFCFGFHSA-N Bullatacinone Natural products O=C(C[C@H]1C(=O)O[C@H](CCCCCCCCCC[C@H](O)[C@@H]2O[C@@H]([C@@H]3O[C@@H]([C@@H](O)CCCCCCCCCC)CC3)CC2)C1)C KGGVWMAPBXIMEM-JQFCFGFHSA-N 0.000 description 1
- 108010037003 Buserelin Proteins 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 1
- 102100036848 C-C motif chemokine 20 Human genes 0.000 description 1
- 102100028990 C-X-C chemokine receptor type 3 Human genes 0.000 description 1
- 102100031658 C-X-C chemokine receptor type 5 Human genes 0.000 description 1
- 125000000041 C6-C10 aryl group Chemical group 0.000 description 1
- 108091058555 C7orf68 Proteins 0.000 description 1
- 125000006519 CCH3 Chemical group 0.000 description 1
- 102100037917 CD109 antigen Human genes 0.000 description 1
- 102100038077 CD226 antigen Human genes 0.000 description 1
- 101150013553 CD40 gene Proteins 0.000 description 1
- 102100024119 CDK5 and ABL1 enzyme substrate 1 Human genes 0.000 description 1
- LLVZBTWPGQVVLW-SNAWJCMRSA-N CP-724714 Chemical compound C12=CC(/C=C/CNC(=O)COC)=CC=C2N=CN=C1NC(C=C1C)=CC=C1OC1=CC=C(C)N=C1 LLVZBTWPGQVVLW-SNAWJCMRSA-N 0.000 description 1
- 229940127291 Calcium channel antagonist Drugs 0.000 description 1
- 239000005461 Canertinib Substances 0.000 description 1
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 1
- SHHKQEUPHAENFK-UHFFFAOYSA-N Carboquone Chemical compound O=C1C(C)=C(N2CC2)C(=O)C(C(COC(N)=O)OC)=C1N1CC1 SHHKQEUPHAENFK-UHFFFAOYSA-N 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- AOCCBINRVIKJHY-UHFFFAOYSA-N Carmofur Chemical compound CCCCCCNC(=O)N1C=C(F)C(=O)NC1=O AOCCBINRVIKJHY-UHFFFAOYSA-N 0.000 description 1
- 108090000994 Catalytic RNA Proteins 0.000 description 1
- 102000053642 Catalytic RNA Human genes 0.000 description 1
- 206010008342 Cervix carcinoma Diseases 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- MKQWTWSXVILIKJ-LXGUWJNJSA-N Chlorozotocin Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](C=O)NC(=O)N(N=O)CCCl MKQWTWSXVILIKJ-LXGUWJNJSA-N 0.000 description 1
- 108010066551 Cholestenone 5 alpha-Reductase Proteins 0.000 description 1
- 229920002567 Chondroitin Polymers 0.000 description 1
- 208000005243 Chondrosarcoma Diseases 0.000 description 1
- 201000009047 Chordoma Diseases 0.000 description 1
- 208000006332 Choriocarcinoma Diseases 0.000 description 1
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 description 1
- WBYWAXJHAXSJNI-SREVYHEPSA-N Cinnamic acid Chemical compound OC(=O)\C=C/C1=CC=CC=C1 WBYWAXJHAXSJNI-SREVYHEPSA-N 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 102100040836 Claudin-1 Human genes 0.000 description 1
- FBRAWBYQGRLCEK-AVVSTMBFSA-N Clobetasone butyrate 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)CCl)(OC(=O)CCC)[C@@]1(C)CC2=O FBRAWBYQGRLCEK-AVVSTMBFSA-N 0.000 description 1
- 206010009900 Colitis ulcerative Diseases 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 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 1
- ITRJWOMZKQRYTA-RFZYENFJSA-N Cortisone acetate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)COC(=O)C)(O)[C@@]1(C)CC2=O ITRJWOMZKQRYTA-RFZYENFJSA-N 0.000 description 1
- 208000009798 Craniopharyngioma Diseases 0.000 description 1
- 229930188224 Cryptophycin Natural products 0.000 description 1
- 108010025468 Cyclin-Dependent Kinase 6 Proteins 0.000 description 1
- 102100026804 Cyclin-dependent kinase 6 Human genes 0.000 description 1
- 102100028188 Cystatin-F Human genes 0.000 description 1
- 102100036194 Cytochrome P450 2A6 Human genes 0.000 description 1
- 102100038800 Cytochrome c oxidase assembly protein COX20, mitochondrial Human genes 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 1
- VVNCNSJFMMFHPL-VKHMYHEASA-N D-penicillamine Chemical compound CC(C)(S)[C@@H](N)C(O)=O VVNCNSJFMMFHPL-VKHMYHEASA-N 0.000 description 1
- 230000004543 DNA replication Effects 0.000 description 1
- WEAHRLBPCANXCN-UHFFFAOYSA-N Daunomycin Natural products CCC1(O)CC(OC2CC(N)C(O)C(C)O2)c3cc4C(=O)c5c(OC)cccc5C(=O)c4c(O)c3C1 WEAHRLBPCANXCN-UHFFFAOYSA-N 0.000 description 1
- XXGMIHXASFDFSM-UHFFFAOYSA-N Delta9-tetrahydrocannabinol Natural products CCCCCc1cc2OC(C)(C)C3CCC(=CC3c2c(O)c1O)C XXGMIHXASFDFSM-UHFFFAOYSA-N 0.000 description 1
- NNJPGOLRFBJNIW-UHFFFAOYSA-N Demecolcine Natural products C1=C(OC)C(=O)C=C2C(NC)CCC3=CC(OC)=C(OC)C(OC)=C3C2=C1 NNJPGOLRFBJNIW-UHFFFAOYSA-N 0.000 description 1
- 108010002156 Depsipeptides Proteins 0.000 description 1
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 208000007342 Diabetic Nephropathies Diseases 0.000 description 1
- 206010012689 Diabetic retinopathy Diseases 0.000 description 1
- AUGQEEXBDZWUJY-ZLJUKNTDSA-N Diacetoxyscirpenol Chemical compound C([C@]12[C@]3(C)[C@H](OC(C)=O)[C@@H](O)[C@H]1O[C@@H]1C=C(C)CC[C@@]13COC(=O)C)O2 AUGQEEXBDZWUJY-ZLJUKNTDSA-N 0.000 description 1
- AUGQEEXBDZWUJY-UHFFFAOYSA-N Diacetoxyscirpenol Natural products CC(=O)OCC12CCC(C)=CC1OC1C(O)C(OC(C)=O)C2(C)C11CO1 AUGQEEXBDZWUJY-UHFFFAOYSA-N 0.000 description 1
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 1
- 102100034108 DnaJ homolog subfamily C member 12 Human genes 0.000 description 1
- 102100031133 Docking protein 5 Human genes 0.000 description 1
- SNRUBQQJIBEYMU-UHFFFAOYSA-N Dodecane Natural products CCCCCCCCCCCC SNRUBQQJIBEYMU-UHFFFAOYSA-N 0.000 description 1
- OFDNQWIFNXBECV-UHFFFAOYSA-N Dolastatin 10 Natural products CC(C)C(N(C)C)C(=O)NC(C(C)C)C(=O)N(C)C(C(C)CC)C(OC)CC(=O)N1CCCC1C(OC)C(C)C(=O)NC(C=1SC=CN=1)CC1=CC=CC=C1 OFDNQWIFNXBECV-UHFFFAOYSA-N 0.000 description 1
- MWWSFMDVAYGXBV-RUELKSSGSA-N Doxorubicin hydrochloride Chemical compound Cl.O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 MWWSFMDVAYGXBV-RUELKSSGSA-N 0.000 description 1
- ZQZFYGIXNQKOAV-OCEACIFDSA-N Droloxifene Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=C(O)C=CC=1)\C1=CC=C(OCCN(C)C)C=C1 ZQZFYGIXNQKOAV-OCEACIFDSA-N 0.000 description 1
- CYQFCXCEBYINGO-DLBZAZTESA-N Dronabinol Natural products C1=C(C)CC[C@H]2C(C)(C)OC3=CC(CCCCC)=CC(O)=C3[C@H]21 CYQFCXCEBYINGO-DLBZAZTESA-N 0.000 description 1
- 208000030453 Drug-Related Side Effects and Adverse reaction Diseases 0.000 description 1
- 229930193152 Dynemicin Natural products 0.000 description 1
- 208000032928 Dyslipidaemia Diseases 0.000 description 1
- 206010013935 Dysmenorrhoea Diseases 0.000 description 1
- 206010058314 Dysplasia Diseases 0.000 description 1
- 102100025027 E3 ubiquitin-protein ligase TRIM69 Human genes 0.000 description 1
- 102100025137 Early activation antigen CD69 Human genes 0.000 description 1
- 229940122858 Elastase inhibitor Drugs 0.000 description 1
- 201000009051 Embryonal Carcinoma Diseases 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 206010014733 Endometrial cancer Diseases 0.000 description 1
- 206010014759 Endometrial neoplasm Diseases 0.000 description 1
- 102400000792 Endothelial monocyte-activating polypeptide 2 Human genes 0.000 description 1
- AFMYMMXSQGUCBK-UHFFFAOYSA-N Endynamicin A Natural products C1#CC=CC#CC2NC(C=3C(=O)C4=C(O)C=CC(O)=C4C(=O)C=3C(O)=C3)=C3C34OC32C(C)C(C(O)=O)=C(OC)C41 AFMYMMXSQGUCBK-UHFFFAOYSA-N 0.000 description 1
- SAMRUMKYXPVKPA-VFKOLLTISA-N Enocitabine Chemical compound O=C1N=C(NC(=O)CCCCCCCCCCCCCCCCCCCCC)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 SAMRUMKYXPVKPA-VFKOLLTISA-N 0.000 description 1
- 102100033482 Enolase-phosphatase E1 Human genes 0.000 description 1
- 206010014967 Ependymoma Diseases 0.000 description 1
- 102400001368 Epidermal growth factor Human genes 0.000 description 1
- 101800003838 Epidermal growth factor Proteins 0.000 description 1
- 102100033183 Epithelial membrane protein 1 Human genes 0.000 description 1
- OBMLHUPNRURLOK-XGRAFVIBSA-N Epitiostanol Chemical compound C1[C@@H]2S[C@@H]2C[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CC[C@H]21 OBMLHUPNRURLOK-XGRAFVIBSA-N 0.000 description 1
- 208000031637 Erythroblastic Acute Leukemia Diseases 0.000 description 1
- 208000036566 Erythroleukaemia Diseases 0.000 description 1
- 208000000461 Esophageal Neoplasms Diseases 0.000 description 1
- 229930189413 Esperamicin Natural products 0.000 description 1
- 208000032027 Essential Thrombocythemia Diseases 0.000 description 1
- JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- DBVJJBKOTRCVKF-UHFFFAOYSA-N Etidronic acid Chemical compound OP(=O)(O)C(O)(C)P(O)(O)=O DBVJJBKOTRCVKF-UHFFFAOYSA-N 0.000 description 1
- 108010022894 Euchromatin Proteins 0.000 description 1
- 102100027327 Eukaryotic translation initiation factor 2 subunit 2 Human genes 0.000 description 1
- 208000006168 Ewing Sarcoma Diseases 0.000 description 1
- 101150021185 FGF gene Proteins 0.000 description 1
- 102100023589 Fibroblast growth factor-binding protein 2 Human genes 0.000 description 1
- 201000008808 Fibrosarcoma Diseases 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- 239000004606 Fillers/Extenders Substances 0.000 description 1
- CITFYDYEWQIEPX-UHFFFAOYSA-N Flavanol Natural products O1C2=CC(OCC=C(C)C)=CC(O)=C2C(=O)C(O)C1C1=CC=C(O)C=C1 CITFYDYEWQIEPX-UHFFFAOYSA-N 0.000 description 1
- WHZRCUIISKRTJL-YTZKRAOUSA-N Fluocortolone caproate Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2C[C@@H](C)[C@H](C(=O)COC(=O)CCCCC)[C@@]2(C)C[C@@H]1O WHZRCUIISKRTJL-YTZKRAOUSA-N 0.000 description 1
- 102100038025 Forkhead box protein D4-like 3 Human genes 0.000 description 1
- 102100031389 Formin-binding protein 1-like Human genes 0.000 description 1
- 102100021245 G-protein coupled receptor 183 Human genes 0.000 description 1
- 102100038407 G-protein coupled receptor 87 Human genes 0.000 description 1
- WMBWREPUVVBILR-UHFFFAOYSA-N GCG Natural products C=1C(O)=C(O)C(O)=CC=1C1OC2=CC(O)=CC(O)=C2CC1OC(=O)C1=CC(O)=C(O)C(O)=C1 WMBWREPUVVBILR-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- JRZJKWGQFNTSRN-UHFFFAOYSA-N Geldanamycin Natural products C1C(C)CC(OC)C(O)C(C)C=C(C)C(OC(N)=O)C(OC)CCC=C(C)C(=O)NC2=CC(=O)C(OC)=C1C2=O JRZJKWGQFNTSRN-UHFFFAOYSA-N 0.000 description 1
- 208000007465 Giant cell arteritis Diseases 0.000 description 1
- 108010072051 Glatiramer Acetate Proteins 0.000 description 1
- 208000032612 Glial tumor Diseases 0.000 description 1
- 206010018338 Glioma Diseases 0.000 description 1
- 102100039632 Glioma pathogenesis-related protein 1 Human genes 0.000 description 1
- 206010018374 Glomerulonephritis minimal lesion Diseases 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 102100036636 Glucose 1,6-bisphosphate synthase Human genes 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 102100021018 Golgin subfamily A member 6-like protein 1 Human genes 0.000 description 1
- BLCLNMBMMGCOAS-URPVMXJPSA-N Goserelin Chemical compound C([C@@H](C(=O)N[C@H](COC(C)(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N1[C@@H](CCC1)C(=O)NNC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 BLCLNMBMMGCOAS-URPVMXJPSA-N 0.000 description 1
- 108010017213 Granulocyte-Macrophage Colony-Stimulating Factor Proteins 0.000 description 1
- 206010072579 Granulomatosis with polyangiitis Diseases 0.000 description 1
- 102100030385 Granzyme B Human genes 0.000 description 1
- 102100038393 Granzyme H Human genes 0.000 description 1
- 102100035910 Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 Human genes 0.000 description 1
- 102100023954 Guanine nucleotide-binding protein subunit alpha-15 Human genes 0.000 description 1
- 229940125497 HER2 kinase inhibitor Drugs 0.000 description 1
- 206010070737 HIV associated nephropathy Diseases 0.000 description 1
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 1
- 206010019233 Headaches Diseases 0.000 description 1
- 102100040352 Heat shock 70 kDa protein 1A Human genes 0.000 description 1
- 102100040407 Heat shock 70 kDa protein 1B Human genes 0.000 description 1
- 208000001258 Hemangiosarcoma Diseases 0.000 description 1
- 206010019708 Hepatic steatosis Diseases 0.000 description 1
- 108010007707 Hepatitis A Virus Cellular Receptor 2 Proteins 0.000 description 1
- 101710083479 Hepatitis A virus cellular receptor 2 homolog Proteins 0.000 description 1
- 108010034791 Heterochromatin Proteins 0.000 description 1
- 239000004705 High-molecular-weight polyethylene Substances 0.000 description 1
- 102100030649 Histone H2B type 1-J Human genes 0.000 description 1
- 102100021639 Histone H2B type 1-K Human genes 0.000 description 1
- 102100039869 Histone H2B type F-S Human genes 0.000 description 1
- 102100034535 Histone H3.1 Human genes 0.000 description 1
- 101000928753 Homo sapiens 11-beta-hydroxysteroid dehydrogenase 1 Proteins 0.000 description 1
- 101000775042 Homo sapiens Adhesion G-protein coupled receptor G1 Proteins 0.000 description 1
- 101000732641 Homo sapiens Alpha-amylase 2B Proteins 0.000 description 1
- 101000732539 Homo sapiens Ankyrin repeat domain-containing protein 37 Proteins 0.000 description 1
- 101000971247 Homo sapiens BEN domain-containing protein 5 Proteins 0.000 description 1
- 101000713099 Homo sapiens C-C motif chemokine 20 Proteins 0.000 description 1
- 101000916050 Homo sapiens C-X-C chemokine receptor type 3 Proteins 0.000 description 1
- 101000922405 Homo sapiens C-X-C chemokine receptor type 5 Proteins 0.000 description 1
- 101000738399 Homo sapiens CD109 antigen Proteins 0.000 description 1
- 101000884298 Homo sapiens CD226 antigen Proteins 0.000 description 1
- 101000910461 Homo sapiens CDK5 and ABL1 enzyme substrate 1 Proteins 0.000 description 1
- 101000749331 Homo sapiens Claudin-1 Proteins 0.000 description 1
- 101000916688 Homo sapiens Cystatin-F Proteins 0.000 description 1
- 101000875170 Homo sapiens Cytochrome P450 2A6 Proteins 0.000 description 1
- 101000957223 Homo sapiens Cytochrome c oxidase assembly protein COX20, mitochondrial Proteins 0.000 description 1
- 101000870234 Homo sapiens DnaJ homolog subfamily C member 12 Proteins 0.000 description 1
- 101000845689 Homo sapiens Docking protein 5 Proteins 0.000 description 1
- 101000830203 Homo sapiens E3 ubiquitin-protein ligase TRIM69 Proteins 0.000 description 1
- 101000934374 Homo sapiens Early activation antigen CD69 Proteins 0.000 description 1
- 101000850450 Homo sapiens Enolase-phosphatase E1 Proteins 0.000 description 1
- 101000851181 Homo sapiens Epidermal growth factor receptor Proteins 0.000 description 1
- 101000850989 Homo sapiens Epithelial membrane protein 1 Proteins 0.000 description 1
- 101001081893 Homo sapiens Eukaryotic translation initiation factor 2 subunit 2 Proteins 0.000 description 1
- 101001021925 Homo sapiens Fascin Proteins 0.000 description 1
- 101000827770 Homo sapiens Fibroblast growth factor-binding protein 2 Proteins 0.000 description 1
- 101001025071 Homo sapiens Forkhead box protein D4-like 3 Proteins 0.000 description 1
- 101000846884 Homo sapiens Formin-binding protein 1-like Proteins 0.000 description 1
- 101001040801 Homo sapiens G-protein coupled receptor 183 Proteins 0.000 description 1
- 101001033052 Homo sapiens G-protein coupled receptor 87 Proteins 0.000 description 1
- 101000888759 Homo sapiens Glioma pathogenesis-related protein 1 Proteins 0.000 description 1
- 101001072892 Homo sapiens Glucose 1,6-bisphosphate synthase Proteins 0.000 description 1
- 101001075382 Homo sapiens Golgin subfamily A member 6-like protein 1 Proteins 0.000 description 1
- 101000746373 Homo sapiens Granulocyte-macrophage colony-stimulating factor Proteins 0.000 description 1
- 101001009603 Homo sapiens Granzyme B Proteins 0.000 description 1
- 101001033000 Homo sapiens Granzyme H Proteins 0.000 description 1
- 101001073272 Homo sapiens Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 Proteins 0.000 description 1
- 101000904080 Homo sapiens Guanine nucleotide-binding protein subunit alpha-15 Proteins 0.000 description 1
- 101001037759 Homo sapiens Heat shock 70 kDa protein 1A Proteins 0.000 description 1
- 101001037968 Homo sapiens Heat shock 70 kDa protein 1B Proteins 0.000 description 1
- 101001084678 Homo sapiens Histone H2B type 1-J Proteins 0.000 description 1
- 101000898898 Homo sapiens Histone H2B type 1-K Proteins 0.000 description 1
- 101001035372 Homo sapiens Histone H2B type F-S Proteins 0.000 description 1
- 101001067844 Homo sapiens Histone H3.1 Proteins 0.000 description 1
- 101000902205 Homo sapiens Inactive cytidine monophosphate-N-acetylneuraminic acid hydroxylase Proteins 0.000 description 1
- 101001076680 Homo sapiens Insulin-induced gene 1 protein Proteins 0.000 description 1
- 101001034834 Homo sapiens Interferon alpha-17 Proteins 0.000 description 1
- 101001002470 Homo sapiens Interferon lambda-1 Proteins 0.000 description 1
- 101000959664 Homo sapiens Interferon-induced protein 44-like Proteins 0.000 description 1
- 101001082058 Homo sapiens Interferon-induced protein with tetratricopeptide repeats 2 Proteins 0.000 description 1
- 101001082060 Homo sapiens Interferon-induced protein with tetratricopeptide repeats 3 Proteins 0.000 description 1
- 101001057504 Homo sapiens Interferon-stimulated gene 20 kDa protein Proteins 0.000 description 1
- 101001076407 Homo sapiens Interleukin-1 receptor antagonist protein Proteins 0.000 description 1
- 101001076418 Homo sapiens Interleukin-1 receptor type 1 Proteins 0.000 description 1
- 101001003138 Homo sapiens Interleukin-12 receptor subunit beta-2 Proteins 0.000 description 1
- 101001019615 Homo sapiens Interleukin-18 receptor accessory protein Proteins 0.000 description 1
- 101001055144 Homo sapiens Interleukin-2 receptor subunit alpha Proteins 0.000 description 1
- 101000853012 Homo sapiens Interleukin-23 receptor Proteins 0.000 description 1
- 101000852980 Homo sapiens Interleukin-23 subunit alpha Proteins 0.000 description 1
- 101001047047 Homo sapiens Kelch repeat and BTB domain-containing protein 8 Proteins 0.000 description 1
- 101000944960 Homo sapiens Keratin-associated protein 2-2 Proteins 0.000 description 1
- 101001007044 Homo sapiens Keratin-associated protein 4-5 Proteins 0.000 description 1
- 101001050565 Homo sapiens Kinesin-like protein KIF3A Proteins 0.000 description 1
- 101001006892 Homo sapiens Krueppel-like factor 10 Proteins 0.000 description 1
- 101000874532 Homo sapiens Lactosylceramide 1,3-N-acetyl-beta-D-glucosaminyltransferase Proteins 0.000 description 1
- 101000627851 Homo sapiens Matrix metalloproteinase-23 Proteins 0.000 description 1
- 101000978418 Homo sapiens Melanocortin receptor 4 Proteins 0.000 description 1
- 101001023037 Homo sapiens Myoferlin Proteins 0.000 description 1
- 101000906927 Homo sapiens N-chimaerin Proteins 0.000 description 1
- 101000998596 Homo sapiens NADH-cytochrome b5 reductase 2 Proteins 0.000 description 1
- 101000589307 Homo sapiens Natural cytotoxicity triggering receptor 3 Proteins 0.000 description 1
- 101000577555 Homo sapiens Neuritin Proteins 0.000 description 1
- 101000594426 Homo sapiens Olfactory receptor 10H4 Proteins 0.000 description 1
- 101000611343 Homo sapiens Olfactory receptor 1D2 Proteins 0.000 description 1
- 101000611363 Homo sapiens Olfactory receptor 4N2 Proteins 0.000 description 1
- 101000982741 Homo sapiens Olfactory receptor 52E5 Proteins 0.000 description 1
- 101000990744 Homo sapiens Olfactory receptor 52N4 Proteins 0.000 description 1
- 101000583474 Homo sapiens Phosphatidylinositol-binding clathrin assembly protein Proteins 0.000 description 1
- 101000690940 Homo sapiens Pro-adrenomedullin Proteins 0.000 description 1
- 101001014654 Homo sapiens Probable G-protein coupled receptor 171 Proteins 0.000 description 1
- 101001117509 Homo sapiens Prostaglandin E2 receptor EP4 subtype Proteins 0.000 description 1
- 101001062760 Homo sapiens Protein FAM13A Proteins 0.000 description 1
- 101000796015 Homo sapiens Protein turtle homolog B Proteins 0.000 description 1
- 101000982554 Homo sapiens Putative oncomodulin-2 Proteins 0.000 description 1
- 101000870953 Homo sapiens RAS guanyl-releasing protein 4 Proteins 0.000 description 1
- 101000711577 Homo sapiens RING finger protein 122 Proteins 0.000 description 1
- 101000668168 Homo sapiens RNA-binding motif, single-stranded-interacting protein 3 Proteins 0.000 description 1
- 101000848727 Homo sapiens Rap guanine nucleotide exchange factor 2 Proteins 0.000 description 1
- 101000738771 Homo sapiens Receptor-type tyrosine-protein phosphatase C Proteins 0.000 description 1
- 101001111656 Homo sapiens Retinol dehydrogenase 10 Proteins 0.000 description 1
- 101000825432 Homo sapiens SHC-transforming protein 4 Proteins 0.000 description 1
- 101000633784 Homo sapiens SLAM family member 7 Proteins 0.000 description 1
- 101000984753 Homo sapiens Serine/threonine-protein kinase B-raf Proteins 0.000 description 1
- 101000729945 Homo sapiens Serine/threonine-protein kinase PLK2 Proteins 0.000 description 1
- 101000826116 Homo sapiens Single-stranded DNA-binding protein 3 Proteins 0.000 description 1
- 101000832685 Homo sapiens Small ubiquitin-related modifier 2 Proteins 0.000 description 1
- 101000693265 Homo sapiens Sphingosine 1-phosphate receptor 1 Proteins 0.000 description 1
- 101000648207 Homo sapiens Striatin-interacting protein 2 Proteins 0.000 description 1
- 101000934346 Homo sapiens T-cell surface antigen CD2 Proteins 0.000 description 1
- 101000716102 Homo sapiens T-cell surface glycoprotein CD4 Proteins 0.000 description 1
- 101000914484 Homo sapiens T-lymphocyte activation antigen CD80 Proteins 0.000 description 1
- 101000714920 Homo sapiens Taste receptor type 2 member 13 Proteins 0.000 description 1
- 101000835745 Homo sapiens Teratocarcinoma-derived growth factor 1 Proteins 0.000 description 1
- 101000800116 Homo sapiens Thy-1 membrane glycoprotein Proteins 0.000 description 1
- 101000851376 Homo sapiens Tumor necrosis factor receptor superfamily member 8 Proteins 0.000 description 1
- 101000982054 Homo sapiens Unconventional myosin-Ib Proteins 0.000 description 1
- 101000997307 Homo sapiens Voltage-gated potassium channel subunit beta-2 Proteins 0.000 description 1
- 101000818605 Homo sapiens Zinc finger and BTB domain-containing protein 32 Proteins 0.000 description 1
- 101000976225 Homo sapiens Zinc finger protein 705A Proteins 0.000 description 1
- 101000991029 Homo sapiens [F-actin]-monooxygenase MICAL2 Proteins 0.000 description 1
- 108090000144 Human Proteins Proteins 0.000 description 1
- 102000003839 Human Proteins Human genes 0.000 description 1
- 108091006905 Human Serum Albumin Proteins 0.000 description 1
- 102000008100 Human Serum Albumin Human genes 0.000 description 1
- VSNHCAURESNICA-UHFFFAOYSA-N Hydroxyurea Chemical compound NC(=O)NO VSNHCAURESNICA-UHFFFAOYSA-N 0.000 description 1
- 208000035150 Hypercholesterolemia Diseases 0.000 description 1
- 206010055171 Hypertensive nephropathy Diseases 0.000 description 1
- 206010062767 Hypophysitis Diseases 0.000 description 1
- 102100028891 Hypoxia-inducible lipid droplet-associated protein Human genes 0.000 description 1
- 101150027484 ILI3 gene Proteins 0.000 description 1
- MPBVHIBUJCELCL-UHFFFAOYSA-N Ibandronate Chemical compound CCCCCN(C)CCC(O)(P(O)(O)=O)P(O)(O)=O MPBVHIBUJCELCL-UHFFFAOYSA-N 0.000 description 1
- 208000010159 IgA glomerulonephritis Diseases 0.000 description 1
- 206010021263 IgA nephropathy Diseases 0.000 description 1
- 208000029462 Immunodeficiency disease Diseases 0.000 description 1
- 108060003951 Immunoglobulin Proteins 0.000 description 1
- 102100022247 Inactive cytidine monophosphate-N-acetylneuraminic acid hydroxylase Human genes 0.000 description 1
- 206010022489 Insulin Resistance Diseases 0.000 description 1
- 102100025887 Insulin-induced gene 1 protein Human genes 0.000 description 1
- 102100039730 Interferon alpha-17 Human genes 0.000 description 1
- 102100020990 Interferon lambda-1 Human genes 0.000 description 1
- 108090000467 Interferon-beta Proteins 0.000 description 1
- 102000003996 Interferon-beta Human genes 0.000 description 1
- 102100039953 Interferon-induced protein 44-like Human genes 0.000 description 1
- 102100027303 Interferon-induced protein with tetratricopeptide repeats 2 Human genes 0.000 description 1
- 102100027302 Interferon-induced protein with tetratricopeptide repeats 3 Human genes 0.000 description 1
- 102100027268 Interferon-stimulated gene 20 kDa protein Human genes 0.000 description 1
- 101710144554 Interleukin-1 receptor antagonist protein Proteins 0.000 description 1
- 102100026016 Interleukin-1 receptor type 1 Human genes 0.000 description 1
- 102100020792 Interleukin-12 receptor subunit beta-2 Human genes 0.000 description 1
- 102000003812 Interleukin-15 Human genes 0.000 description 1
- 108090000172 Interleukin-15 Proteins 0.000 description 1
- 102000049772 Interleukin-16 Human genes 0.000 description 1
- 101800003050 Interleukin-16 Proteins 0.000 description 1
- 102100035010 Interleukin-18 receptor accessory protein Human genes 0.000 description 1
- 108010065637 Interleukin-23 Proteins 0.000 description 1
- 102100036672 Interleukin-23 receptor Human genes 0.000 description 1
- 108010002586 Interleukin-7 Proteins 0.000 description 1
- 102000000704 Interleukin-7 Human genes 0.000 description 1
- 108090001007 Interleukin-8 Proteins 0.000 description 1
- 102000004890 Interleukin-8 Human genes 0.000 description 1
- 108090000862 Ion Channels Proteins 0.000 description 1
- 102000004310 Ion Channels Human genes 0.000 description 1
- 208000012659 Joint disease Diseases 0.000 description 1
- 208000011200 Kawasaki disease Diseases 0.000 description 1
- 102100022830 Kelch repeat and BTB domain-containing protein 8 Human genes 0.000 description 1
- 102100033540 Keratin-associated protein 2-2 Human genes 0.000 description 1
- 102100028350 Keratin-associated protein 4-5 Human genes 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
- 102100023425 Kinesin-like protein KIF3A Human genes 0.000 description 1
- 102100027798 Krueppel-like factor 10 Human genes 0.000 description 1
- WTDRDQBEARUVNC-LURJTMIESA-N L-DOPA Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-LURJTMIESA-N 0.000 description 1
- WTDRDQBEARUVNC-UHFFFAOYSA-N L-Dopa Natural products OC(=O)C(N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-UHFFFAOYSA-N 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- 102100035655 Lactosylceramide 1,3-N-acetyl-beta-D-glucosaminyltransferase Human genes 0.000 description 1
- 208000031671 Large B-Cell Diffuse Lymphoma Diseases 0.000 description 1
- 208000018142 Leiomyosarcoma Diseases 0.000 description 1
- 241000222722 Leishmania <genus> Species 0.000 description 1
- 229920001491 Lentinan Polymers 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 102100032352 Leukemia inhibitory factor Human genes 0.000 description 1
- 208000017170 Lipid metabolism disease Diseases 0.000 description 1
- 208000004883 Lipoid Nephrosis Diseases 0.000 description 1
- 108010013563 Lipoprotein Lipase Proteins 0.000 description 1
- 102100022119 Lipoprotein lipase Human genes 0.000 description 1
- 239000000867 Lipoxygenase Inhibitor Substances 0.000 description 1
- 229940122142 Lipoxygenase inhibitor Drugs 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- MEPSBMMZQBMKHM-UHFFFAOYSA-N Lomatiol Natural products CC(=C/CC1=C(O)C(=O)c2ccccc2C1=O)CO MEPSBMMZQBMKHM-UHFFFAOYSA-N 0.000 description 1
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- 108091054455 MAP kinase family Proteins 0.000 description 1
- 102000043136 MAP kinase family Human genes 0.000 description 1
- 239000013214 MOP-1 Substances 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 240000003183 Manihot esculenta Species 0.000 description 1
- 235000016735 Manihot esculenta subsp esculenta Nutrition 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- VJRAUFKOOPNFIQ-UHFFFAOYSA-N Marcellomycin Natural products C12=C(O)C=3C(=O)C4=C(O)C=CC(O)=C4C(=O)C=3C=C2C(C(=O)OC)C(CC)(O)CC1OC(OC1C)CC(N(C)C)C1OC(OC1C)CC(O)C1OC1CC(O)C(O)C(C)O1 VJRAUFKOOPNFIQ-UHFFFAOYSA-N 0.000 description 1
- 102100024130 Matrix metalloproteinase-23 Human genes 0.000 description 1
- 229930126263 Maytansine Natural products 0.000 description 1
- SBDNJUWAMKYJOX-UHFFFAOYSA-N Meclofenamic Acid Chemical compound CC1=CC=C(Cl)C(NC=2C(=CC=CC=2)C(O)=O)=C1Cl SBDNJUWAMKYJOX-UHFFFAOYSA-N 0.000 description 1
- 208000007054 Medullary Carcinoma Diseases 0.000 description 1
- 208000000172 Medulloblastoma Diseases 0.000 description 1
- 102100023724 Melanocortin receptor 4 Human genes 0.000 description 1
- IVDYZAAPOLNZKG-KWHRADDSSA-N Mepitiostane Chemical compound O([C@@H]1[C@]2(CC[C@@H]3[C@@]4(C)C[C@H]5S[C@H]5C[C@@H]4CC[C@H]3[C@@H]2CC1)C)C1(OC)CCCC1 IVDYZAAPOLNZKG-KWHRADDSSA-N 0.000 description 1
- 206010027406 Mesothelioma Diseases 0.000 description 1
- 208000001145 Metabolic Syndrome Diseases 0.000 description 1
- 206010054949 Metaplasia Diseases 0.000 description 1
- 208000036631 Metastatic pain Diseases 0.000 description 1
- 208000019695 Migraine disease Diseases 0.000 description 1
- VFKZTMPDYBFSTM-KVTDHHQDSA-N Mitobronitol Chemical compound BrC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CBr VFKZTMPDYBFSTM-KVTDHHQDSA-N 0.000 description 1
- 229930192392 Mitomycin Natural products 0.000 description 1
- HRHKSTOGXBBQCB-UHFFFAOYSA-N Mitomycin E Natural products O=C1C(N)=C(C)C(=O)C2=C1C(COC(N)=O)C1(OC)C3N(C)C3CN12 HRHKSTOGXBBQCB-UHFFFAOYSA-N 0.000 description 1
- 208000003445 Mouth Neoplasms Diseases 0.000 description 1
- 208000034578 Multiple myelomas Diseases 0.000 description 1
- 101100523539 Mus musculus Raf1 gene Proteins 0.000 description 1
- 206010062207 Mycobacterial infection Diseases 0.000 description 1
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 description 1
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 description 1
- 208000009525 Myocarditis Diseases 0.000 description 1
- 102100035083 Myoferlin Human genes 0.000 description 1
- 201000002481 Myositis Diseases 0.000 description 1
- HRNLUBSXIHFDHP-UHFFFAOYSA-N N-(2-aminophenyl)-4-[[[4-(3-pyridinyl)-2-pyrimidinyl]amino]methyl]benzamide Chemical compound NC1=CC=CC=C1NC(=O)C(C=C1)=CC=C1CNC1=NC=CC(C=2C=NC=CC=2)=N1 HRNLUBSXIHFDHP-UHFFFAOYSA-N 0.000 description 1
- WVUNYSQLFKLYNI-UHFFFAOYSA-N N-[4-(3-chloro-4-fluoroanilino)-3-cyano-7-ethoxy-6-quinolinyl]-4-(dimethylamino)-2-butenamide Chemical compound C=12C=C(NC(=O)C=CCN(C)C)C(OCC)=CC2=NC=C(C#N)C=1NC1=CC=C(F)C(Cl)=C1 WVUNYSQLFKLYNI-UHFFFAOYSA-N 0.000 description 1
- 102100023648 N-chimaerin Human genes 0.000 description 1
- HTLZVHNRZJPSMI-UHFFFAOYSA-N N-ethylpiperidine Chemical compound CCN1CCCCC1 HTLZVHNRZJPSMI-UHFFFAOYSA-N 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- 102100033168 NADH-cytochrome b5 reductase 2 Human genes 0.000 description 1
- 108010072915 NAc-Sar-Gly-Val-(d-allo-Ile)-Thr-Nva-Ile-Arg-ProNEt Proteins 0.000 description 1
- BLXXJMDCKKHMKV-UHFFFAOYSA-N Nabumetone Chemical compound C1=C(CCC(C)=O)C=CC2=CC(OC)=CC=C21 BLXXJMDCKKHMKV-UHFFFAOYSA-N 0.000 description 1
- 102100032852 Natural cytotoxicity triggering receptor 3 Human genes 0.000 description 1
- 108010025020 Nerve Growth Factor Proteins 0.000 description 1
- 102000007072 Nerve Growth Factors Human genes 0.000 description 1
- 208000012902 Nervous system disease Diseases 0.000 description 1
- 102100028749 Neuritin Human genes 0.000 description 1
- 206010029260 Neuroblastoma Diseases 0.000 description 1
- 208000008457 Neurologic Manifestations Diseases 0.000 description 1
- 208000025966 Neurological disease Diseases 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- SYNHCENRCUAUNM-UHFFFAOYSA-N Nitrogen mustard N-oxide hydrochloride Chemical compound Cl.ClCC[N+]([O-])(C)CCCl SYNHCENRCUAUNM-UHFFFAOYSA-N 0.000 description 1
- KGTDRFCXGRULNK-UHFFFAOYSA-N Nogalamycin Natural products COC1C(OC)(C)C(OC)C(C)OC1OC1C2=C(O)C(C(=O)C3=C(O)C=C4C5(C)OC(C(C(C5O)N(C)C)O)OC4=C3C3=O)=C3C=C2C(C(=O)OC)C(C)(O)C1 KGTDRFCXGRULNK-UHFFFAOYSA-N 0.000 description 1
- 108010047956 Nucleosomes Proteins 0.000 description 1
- 208000008589 Obesity Diseases 0.000 description 1
- 206010030155 Oesophageal carcinoma Diseases 0.000 description 1
- 208000035327 Oestrogen receptor positive breast cancer Diseases 0.000 description 1
- 240000007817 Olea europaea Species 0.000 description 1
- 239000005642 Oleic acid Substances 0.000 description 1
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 1
- 102100035610 Olfactory receptor 10H4 Human genes 0.000 description 1
- 102100040776 Olfactory receptor 1D2 Human genes 0.000 description 1
- 102100040740 Olfactory receptor 4N2 Human genes 0.000 description 1
- 102100026989 Olfactory receptor 52E5 Human genes 0.000 description 1
- 102100030600 Olfactory receptor 52N4 Human genes 0.000 description 1
- 201000010133 Oligodendroglioma Diseases 0.000 description 1
- 229930187135 Olivomycin Natural products 0.000 description 1
- HVRLZEKDTUEKQH-NOILCQHBSA-N Olopatadine hydrochloride Chemical compound Cl.C1OC2=CC=C(CC(O)=O)C=C2C(=C/CCN(C)C)\C2=CC=CC=C21 HVRLZEKDTUEKQH-NOILCQHBSA-N 0.000 description 1
- BRUQQQPBMZOVGD-XFKAJCMBSA-N Oxycodone Chemical compound O=C([C@@H]1O2)CC[C@@]3(O)[C@H]4CC5=CC=C(OC)C2=C5[C@@]13CCN4C BRUQQQPBMZOVGD-XFKAJCMBSA-N 0.000 description 1
- 239000012826 P38 inhibitor Substances 0.000 description 1
- 239000012828 PI3K inhibitor Substances 0.000 description 1
- 102000042846 PKC family Human genes 0.000 description 1
- 108091082203 PKC family Proteins 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- VREZDOWOLGNDPW-ALTGWBOUSA-N Pancratistatin Chemical compound C1=C2[C@H]3[C@@H](O)[C@H](O)[C@@H](O)[C@@H](O)[C@@H]3NC(=O)C2=C(O)C2=C1OCO2 VREZDOWOLGNDPW-ALTGWBOUSA-N 0.000 description 1
- VREZDOWOLGNDPW-MYVCAWNPSA-N Pancratistatin Natural products O=C1N[C@H]2[C@H](O)[C@H](O)[C@H](O)[C@H](O)[C@@H]2c2c1c(O)c1OCOc1c2 VREZDOWOLGNDPW-MYVCAWNPSA-N 0.000 description 1
- 206010033645 Pancreatitis Diseases 0.000 description 1
- 208000030852 Parasitic disease Diseases 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- 108010057150 Peplomycin Proteins 0.000 description 1
- 102100031014 Phosphatidylinositol-binding clathrin assembly protein Human genes 0.000 description 1
- 229940123932 Phosphodiesterase 4 inhibitor Drugs 0.000 description 1
- IIXHQGSINFQLRR-UHFFFAOYSA-N Piceatannol Natural products Oc1ccc(C=Cc2c(O)c(O)c3CCCCc3c2O)cc1O IIXHQGSINFQLRR-UHFFFAOYSA-N 0.000 description 1
- 208000007641 Pinealoma Diseases 0.000 description 1
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 1
- KMSKQZKKOZQFFG-HSUXVGOQSA-N Pirarubicin Chemical compound O([C@H]1[C@@H](N)C[C@@H](O[C@H]1C)O[C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1CCCCO1 KMSKQZKKOZQFFG-HSUXVGOQSA-N 0.000 description 1
- 206010035742 Pneumonitis Diseases 0.000 description 1
- 229920002732 Polyanhydride Polymers 0.000 description 1
- 229920000954 Polyglycolide Polymers 0.000 description 1
- 229920001710 Polyorthoester Polymers 0.000 description 1
- 208000004550 Postoperative Pain Diseases 0.000 description 1
- 208000009052 Precursor T-Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 description 1
- HFVNWDWLWUCIHC-GUPDPFMOSA-N Prednimustine Chemical compound O=C([C@@]1(O)CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)[C@@H](O)C[C@@]21C)COC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 HFVNWDWLWUCIHC-GUPDPFMOSA-N 0.000 description 1
- 102100026651 Pro-adrenomedullin Human genes 0.000 description 1
- 102100033237 Pro-epidermal growth factor Human genes 0.000 description 1
- 102100032555 Probable G-protein coupled receptor 171 Human genes 0.000 description 1
- CWEZAWNPTYBADX-UHFFFAOYSA-N Procyanidin Natural products OC1C(OC2C(O)C(Oc3c2c(O)cc(O)c3C4C(O)C(Oc5cc(O)cc(O)c45)c6ccc(O)c(O)c6)c7ccc(O)c(O)c7)c8c(O)cc(O)cc8OC1c9ccc(O)c(O)c9 CWEZAWNPTYBADX-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 102100024450 Prostaglandin E2 receptor EP4 subtype Human genes 0.000 description 1
- 108090000459 Prostaglandin-endoperoxide synthases Proteins 0.000 description 1
- 102000004005 Prostaglandin-endoperoxide synthases Human genes 0.000 description 1
- 108010007568 Protamines Proteins 0.000 description 1
- 102000007327 Protamines Human genes 0.000 description 1
- 102100030557 Protein FAM13A Human genes 0.000 description 1
- 102100024924 Protein kinase C alpha type Human genes 0.000 description 1
- 101710109947 Protein kinase C alpha type Proteins 0.000 description 1
- 102100031337 Protein turtle homolog B Human genes 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- 102100026730 Putative oncomodulin-2 Human genes 0.000 description 1
- 206010037660 Pyrexia Diseases 0.000 description 1
- ZVOLCUVKHLEPEV-UHFFFAOYSA-N Quercetagetin Natural products C1=C(O)C(O)=CC=C1C1=C(O)C(=O)C2=C(O)C(O)=C(O)C=C2O1 ZVOLCUVKHLEPEV-UHFFFAOYSA-N 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
- 102100033445 RAS guanyl-releasing protein 4 Human genes 0.000 description 1
- 102100034117 RING finger protein 122 Human genes 0.000 description 1
- 102100039689 RNA-binding motif, single-stranded-interacting protein 3 Human genes 0.000 description 1
- 102100034585 Rap guanine nucleotide exchange factor 2 Human genes 0.000 description 1
- 229940127361 Receptor Tyrosine Kinase Inhibitors Drugs 0.000 description 1
- 101710100968 Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 description 1
- 102100037422 Receptor-type tyrosine-protein phosphatase C Human genes 0.000 description 1
- 208000015634 Rectal Neoplasms Diseases 0.000 description 1
- 208000033464 Reiter syndrome Diseases 0.000 description 1
- 206010038419 Renal colic Diseases 0.000 description 1
- 208000033626 Renal failure acute Diseases 0.000 description 1
- QNVSXXGDAPORNA-UHFFFAOYSA-N Resveratrol Natural products OC1=CC=CC(C=CC=2C=C(O)C(O)=CC=2)=C1 QNVSXXGDAPORNA-UHFFFAOYSA-N 0.000 description 1
- 201000000582 Retinoblastoma Diseases 0.000 description 1
- 102100023918 Retinol dehydrogenase 10 Human genes 0.000 description 1
- OWPCHSCAPHNHAV-UHFFFAOYSA-N Rhizoxin Natural products C1C(O)C2(C)OC2C=CC(C)C(OC(=O)C2)CC2CC2OC2C(=O)OC1C(C)C(OC)C(C)=CC=CC(C)=CC1=COC(C)=N1 OWPCHSCAPHNHAV-UHFFFAOYSA-N 0.000 description 1
- HWTZYBCRDDUBJY-UHFFFAOYSA-N Rhynchosin Natural products C1=C(O)C(O)=CC=C1C1=C(O)C(=O)C2=CC(O)=C(O)C=C2O1 HWTZYBCRDDUBJY-UHFFFAOYSA-N 0.000 description 1
- 235000004443 Ricinus communis Nutrition 0.000 description 1
- FTALBRSUTCGOEG-UHFFFAOYSA-N Riluzole Chemical compound C1=C(OC(F)(F)F)C=C2SC(N)=NC2=C1 FTALBRSUTCGOEG-UHFFFAOYSA-N 0.000 description 1
- XSVMFMHYUFZWBK-NSHDSACASA-N Rivastigmine Chemical compound CCN(C)C(=O)OC1=CC=CC([C@H](C)N(C)C)=C1 XSVMFMHYUFZWBK-NSHDSACASA-N 0.000 description 1
- NSFWWJIQIKBZMJ-YKNYLIOZSA-N Roridin A Chemical compound C([C@]12[C@]3(C)[C@H]4C[C@H]1O[C@@H]1C=C(C)CC[C@@]13COC(=O)[C@@H](O)[C@H](C)CCO[C@H](\C=C\C=C/C(=O)O4)[C@H](O)C)O2 NSFWWJIQIKBZMJ-YKNYLIOZSA-N 0.000 description 1
- 102100022333 SHC-transforming protein 4 Human genes 0.000 description 1
- CIEYTVIYYGTCCI-UHFFFAOYSA-N SJ000286565 Natural products C1=CC=C2C(=O)C(CC=C(C)C)=C(O)C(=O)C2=C1 CIEYTVIYYGTCCI-UHFFFAOYSA-N 0.000 description 1
- 102100029198 SLAM family member 7 Human genes 0.000 description 1
- 206010039705 Scleritis Diseases 0.000 description 1
- 229940124639 Selective inhibitor Drugs 0.000 description 1
- 201000010208 Seminoma Diseases 0.000 description 1
- 206010040070 Septic Shock Diseases 0.000 description 1
- 102100027103 Serine/threonine-protein kinase B-raf Human genes 0.000 description 1
- 102100031462 Serine/threonine-protein kinase PLK2 Human genes 0.000 description 1
- 102100023085 Serine/threonine-protein kinase mTOR Human genes 0.000 description 1
- 108010074687 Signaling Lymphocytic Activation Molecule Family Member 1 Proteins 0.000 description 1
- 102100029215 Signaling lymphocytic activation molecule Human genes 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 102100023008 Single-stranded DNA-binding protein 3 Human genes 0.000 description 1
- 208000000453 Skin Neoplasms Diseases 0.000 description 1
- 206010041067 Small cell lung cancer Diseases 0.000 description 1
- 102100024542 Small ubiquitin-related modifier 2 Human genes 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 244000061456 Solanum tuberosum Species 0.000 description 1
- 235000002595 Solanum tuberosum Nutrition 0.000 description 1
- 102100025750 Sphingosine 1-phosphate receptor 1 Human genes 0.000 description 1
- SSZBUIDZHHWXNJ-UHFFFAOYSA-N Stearinsaeure-hexadecylester Natural products CCCCCCCCCCCCCCCCCC(=O)OCCCCCCCCCCCCCCCC SSZBUIDZHHWXNJ-UHFFFAOYSA-N 0.000 description 1
- 208000005718 Stomach Neoplasms Diseases 0.000 description 1
- 102100028805 Striatin-interacting protein 2 Human genes 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 230000006044 T cell activation Effects 0.000 description 1
- 230000020385 T cell costimulation Effects 0.000 description 1
- 230000037453 T cell priming Effects 0.000 description 1
- 230000006052 T cell proliferation Effects 0.000 description 1
- BXFOFFBJRFZBQZ-QYWOHJEZSA-N T-2 toxin Chemical compound C([C@@]12[C@]3(C)[C@H](OC(C)=O)[C@@H](O)[C@H]1O[C@H]1[C@]3(COC(C)=O)C[C@@H](C(=C1)C)OC(=O)CC(C)C)O2 BXFOFFBJRFZBQZ-QYWOHJEZSA-N 0.000 description 1
- 208000029052 T-cell acute lymphoblastic leukemia Diseases 0.000 description 1
- 229940126547 T-cell immunoglobulin mucin-3 Drugs 0.000 description 1
- 102100025237 T-cell surface antigen CD2 Human genes 0.000 description 1
- 102100036011 T-cell surface glycoprotein CD4 Human genes 0.000 description 1
- 102100027222 T-lymphocyte activation antigen CD80 Human genes 0.000 description 1
- 229940126624 Tacatuzumab tetraxetan Drugs 0.000 description 1
- 208000001106 Takayasu Arteritis Diseases 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 102100036737 Taste receptor type 2 member 13 Human genes 0.000 description 1
- WFWLQNSHRPWKFK-UHFFFAOYSA-N Tegafur Chemical compound O=C1NC(=O)C(F)=CN1C1OCCC1 WFWLQNSHRPWKFK-UHFFFAOYSA-N 0.000 description 1
- CBPNZQVSJQDFBE-FUXHJELOSA-N Temsirolimus Chemical compound C1C[C@@H](OC(=O)C(C)(CO)CO)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 CBPNZQVSJQDFBE-FUXHJELOSA-N 0.000 description 1
- CGMTUJFWROPELF-UHFFFAOYSA-N Tenuazonic acid Natural products CCC(C)C1NC(=O)C(=C(C)/O)C1=O CGMTUJFWROPELF-UHFFFAOYSA-N 0.000 description 1
- 102100026404 Teratocarcinoma-derived growth factor 1 Human genes 0.000 description 1
- 206010057644 Testis cancer Diseases 0.000 description 1
- 102100033523 Thy-1 membrane glycoprotein Human genes 0.000 description 1
- 208000024770 Thyroid neoplasm Diseases 0.000 description 1
- 239000004012 Tofacitinib Substances 0.000 description 1
- 101710183280 Topoisomerase Proteins 0.000 description 1
- IWEQQRMGNVVKQW-OQKDUQJOSA-N Toremifene citrate Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O.C1=CC(OCCN(C)C)=CC=C1C(\C=1C=CC=CC=1)=C(\CCCl)C1=CC=CC=C1 IWEQQRMGNVVKQW-OQKDUQJOSA-N 0.000 description 1
- 206010044248 Toxic shock syndrome Diseases 0.000 description 1
- 231100000650 Toxic shock syndrome Toxicity 0.000 description 1
- 206010070863 Toxicity to various agents Diseases 0.000 description 1
- LUKBXSAWLPMMSZ-OWOJBTEDSA-N Trans-resveratrol Chemical compound C1=CC(O)=CC=C1\C=C\C1=CC(O)=CC(O)=C1 LUKBXSAWLPMMSZ-OWOJBTEDSA-N 0.000 description 1
- 102400001320 Transforming growth factor alpha Human genes 0.000 description 1
- 101800004564 Transforming growth factor alpha Proteins 0.000 description 1
- 206010052779 Transplant rejections Diseases 0.000 description 1
- UMILHIMHKXVDGH-UHFFFAOYSA-N Triethylene glycol diglycidyl ether Chemical compound C1OC1COCCOCCOCCOCC1CO1 UMILHIMHKXVDGH-UHFFFAOYSA-N 0.000 description 1
- FYAMXEPQQLNQDM-UHFFFAOYSA-N Tris(1-aziridinyl)phosphine oxide Chemical compound C1CN1P(N1CC1)(=O)N1CC1 FYAMXEPQQLNQDM-UHFFFAOYSA-N 0.000 description 1
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 1
- 102100040245 Tumor necrosis factor receptor superfamily member 5 Human genes 0.000 description 1
- 102100036857 Tumor necrosis factor receptor superfamily member 8 Human genes 0.000 description 1
- 208000035896 Twin-reversed arterial perfusion sequence Diseases 0.000 description 1
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 1
- 201000006704 Ulcerative Colitis Diseases 0.000 description 1
- 102100026776 Unconventional myosin-Ib Human genes 0.000 description 1
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 1
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 1
- 208000002495 Uterine Neoplasms Diseases 0.000 description 1
- 206010046851 Uveitis Diseases 0.000 description 1
- 108091008605 VEGF receptors Proteins 0.000 description 1
- 102000009484 Vascular Endothelial Growth Factor Receptors Human genes 0.000 description 1
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 description 1
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 1
- 206010047115 Vasculitis Diseases 0.000 description 1
- 208000014070 Vestibular schwannoma Diseases 0.000 description 1
- 229940122803 Vinca alkaloid Drugs 0.000 description 1
- 206010047642 Vitiligo Diseases 0.000 description 1
- 102100034074 Voltage-gated potassium channel subunit beta-2 Human genes 0.000 description 1
- 208000033559 Waldenström macroglobulinemia Diseases 0.000 description 1
- 208000008383 Wilms tumor Diseases 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 102100021135 Zinc finger and BTB domain-containing protein 32 Human genes 0.000 description 1
- 102100023887 Zinc finger protein 705A Human genes 0.000 description 1
- 239000001089 [(2R)-oxolan-2-yl]methanol Substances 0.000 description 1
- SPJCRMJCFSJKDE-ZWBUGVOYSA-N [(3s,8s,9s,10r,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1h-cyclopenta[a]phenanthren-3-yl] 2-[4-[bis(2-chloroethyl)amino]phenyl]acetate Chemical compound O([C@@H]1CC2=CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)C(=O)CC1=CC=C(N(CCCl)CCCl)C=C1 SPJCRMJCFSJKDE-ZWBUGVOYSA-N 0.000 description 1
- IFJUINDAXYAPTO-UUBSBJJBSA-N [(8r,9s,13s,14s,17s)-17-[2-[4-[4-[bis(2-chloroethyl)amino]phenyl]butanoyloxy]acetyl]oxy-13-methyl-6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta[a]phenanthren-3-yl] benzoate Chemical compound C([C@@H]1[C@@H](C2=CC=3)CC[C@]4([C@H]1CC[C@@H]4OC(=O)COC(=O)CCCC=1C=CC(=CC=1)N(CCCl)CCCl)C)CC2=CC=3OC(=O)C1=CC=CC=C1 IFJUINDAXYAPTO-UUBSBJJBSA-N 0.000 description 1
- IHGLINDYFMDHJG-UHFFFAOYSA-N [2-(4-methoxyphenyl)-3,4-dihydronaphthalen-1-yl]-[4-(2-pyrrolidin-1-ylethoxy)phenyl]methanone Chemical compound C1=CC(OC)=CC=C1C(CCC1=CC=CC=C11)=C1C(=O)C(C=C1)=CC=C1OCCN1CCCC1 IHGLINDYFMDHJG-UHFFFAOYSA-N 0.000 description 1
- XZSRRNFBEIOBDA-CFNBKWCHSA-N [2-[(2s,4s)-4-[(2r,4s,5s,6s)-4-amino-5-hydroxy-6-methyloxan-2-yl]oxy-2,5,12-trihydroxy-7-methoxy-6,11-dioxo-3,4-dihydro-1h-tetracen-2-yl]-2-oxoethyl] 2,2-diethoxyacetate Chemical compound O([C@H]1C[C@](CC2=C(O)C=3C(=O)C4=CC=CC(OC)=C4C(=O)C=3C(O)=C21)(O)C(=O)COC(=O)C(OCC)OCC)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 XZSRRNFBEIOBDA-CFNBKWCHSA-N 0.000 description 1
- 102100030295 [F-actin]-monooxygenase MICAL2 Human genes 0.000 description 1
- 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 description 1
- 230000001594 aberrant effect Effects 0.000 description 1
- 229940028652 abraxane Drugs 0.000 description 1
- 239000002250 absorbent Substances 0.000 description 1
- 230000002745 absorbent Effects 0.000 description 1
- 239000003655 absorption accelerator Substances 0.000 description 1
- ZOZKYEHVNDEUCO-XUTVFYLZSA-N aceglatone Chemical compound O1C(=O)[C@H](OC(C)=O)[C@@H]2OC(=O)[C@@H](OC(=O)C)[C@@H]21 ZOZKYEHVNDEUCO-XUTVFYLZSA-N 0.000 description 1
- 229950002684 aceglatone Drugs 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- FHEAIOHRHQGZPC-KIWGSFCNSA-N acetic acid;(2s)-2-amino-3-(4-hydroxyphenyl)propanoic acid;(2s)-2-aminopentanedioic acid;(2s)-2-aminopropanoic acid;(2s)-2,6-diaminohexanoic acid Chemical compound CC(O)=O.C[C@H](N)C(O)=O.NCCCC[C@H](N)C(O)=O.OC(=O)[C@@H](N)CCC(O)=O.OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 FHEAIOHRHQGZPC-KIWGSFCNSA-N 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 108091005646 acetylated proteins Proteins 0.000 description 1
- 238000006640 acetylation reaction Methods 0.000 description 1
- 208000004064 acoustic neuroma Diseases 0.000 description 1
- 208000017733 acquired polycythemia vera Diseases 0.000 description 1
- 125000000641 acridinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3C=C12)* 0.000 description 1
- 229930183665 actinomycin Natural products 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 229940037127 actonel Drugs 0.000 description 1
- 201000011186 acute T cell leukemia Diseases 0.000 description 1
- 208000021841 acute erythroid leukemia Diseases 0.000 description 1
- 201000011040 acute kidney failure Diseases 0.000 description 1
- 229950004955 adozelesin Drugs 0.000 description 1
- BYRVKDUQDLJUBX-JJCDCTGGSA-N adozelesin Chemical compound C1=CC=C2OC(C(=O)NC=3C=C4C=C(NC4=CC=3)C(=O)N3C[C@H]4C[C@]44C5=C(C(C=C43)=O)NC=C5C)=CC2=C1 BYRVKDUQDLJUBX-JJCDCTGGSA-N 0.000 description 1
- 210000004100 adrenal gland Anatomy 0.000 description 1
- 229940009456 adriamycin Drugs 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- JZMHCANOTJFLQJ-IEQBYLOXSA-A affinitac Chemical compound [Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](COP([O-])(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(N=C(N)C=C2)=O)COP([O-])(=S)O[C@@H]2[C@H](O[C@H](C2)N2C3=C(C(NC(N)=N3)=O)N=C2)COP([O-])(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(N=C(N)C=C2)=O)COP([O-])(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(NC(=O)C(C)=C2)=O)COP([O-])(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(N=C(N)C=C2)=O)COP([O-])(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(NC(=O)C(C)=C2)=O)COP([O-])(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(NC(=O)C(C)=C2)=O)COP([O-])(=S)O[C@@H]2[C@H](O[C@H](C2)N2C3=C(C(NC(N)=N3)=O)N=C2)CO)[C@@H](OP([S-])(=O)OC[C@@H]2[C@H](C[C@@H](O2)N2C3=C(C(NC(N)=N3)=O)N=C2)OP([O-])(=S)OC[C@@H]2[C@H](C[C@@H](O2)N2C3=C(C(NC(N)=N3)=O)N=C2)OP([O-])(=S)OC[C@@H]2[C@H](C[C@@H](O2)N2C(NC(=O)C(C)=C2)=O)OP([O-])(=S)OC[C@@H]2[C@H](C[C@@H](O2)N2C3=C(C(NC(N)=N3)=O)N=C2)OP([O-])(=S)OC[C@@H]2[C@H](C[C@@H](O2)N2C3=NC=NC(N)=C3N=C2)OP([O-])(=S)OC[C@@H]2[C@H](C[C@@H](O2)N2C3=C(C(NC(N)=N3)=O)N=C2)OP([O-])(=S)OC[C@@H]2[C@H](C[C@@H](O2)N2C(NC(=O)C(C)=C2)=O)OP([O-])(=S)OC[C@@H]2[C@H](C[C@@H](O2)N2C(NC(=O)C(C)=C2)=O)OP([O-])(=S)OC[C@@H]2[C@H](C[C@@H](O2)N2C(NC(=O)C(C)=C2)=O)OP([O-])(=S)OC[C@@H]2[C@H](C[C@@H](O2)N2C(N=C(N)C=C2)=O)OP([O-])(=S)OC[C@@H]2[C@H](C[C@@H](O2)N2C3=NC=NC(N)=C3N=C2)O)C1 JZMHCANOTJFLQJ-IEQBYLOXSA-A 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 235000010419 agar Nutrition 0.000 description 1
- FJXOGVLKCZQRDN-PHCHRAKRSA-N alclometasone Chemical compound C([C@H]1Cl)C2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O FJXOGVLKCZQRDN-PHCHRAKRSA-N 0.000 description 1
- 229940062527 alendronate Drugs 0.000 description 1
- 229960004343 alendronic acid Drugs 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 229940045714 alkyl sulfonate alkylating agent Drugs 0.000 description 1
- 150000008052 alkyl sulfonates Chemical class 0.000 description 1
- 230000000172 allergic effect Effects 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 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
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- CEGOLXSVJUTHNZ-UHFFFAOYSA-K aluminium tristearate Chemical compound [Al+3].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CEGOLXSVJUTHNZ-UHFFFAOYSA-K 0.000 description 1
- 229940063655 aluminum stearate Drugs 0.000 description 1
- DKNWSYNQZKUICI-UHFFFAOYSA-N amantadine Chemical compound C1C(C2)CC3CC2CC1(N)C3 DKNWSYNQZKUICI-UHFFFAOYSA-N 0.000 description 1
- 229960003805 amantadine Drugs 0.000 description 1
- ILKJAFIWWBXGDU-MOGDOJJUSA-N amcinonide Chemical compound O([C@@]1([C@H](O2)C[C@@H]3[C@@]1(C[C@H](O)[C@]1(F)[C@@]4(C)C=CC(=O)C=C4CC[C@H]13)C)C(=O)COC(=O)C)C12CCCC1 ILKJAFIWWBXGDU-MOGDOJJUSA-N 0.000 description 1
- 229960003099 amcinonide Drugs 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 229960002749 aminolevulinic acid Drugs 0.000 description 1
- FQPFAHBPWDRTLU-UHFFFAOYSA-N aminophylline Chemical compound NCCN.O=C1N(C)C(=O)N(C)C2=C1NC=N2.O=C1N(C)C(=O)N(C)C2=C1NC=N2 FQPFAHBPWDRTLU-UHFFFAOYSA-N 0.000 description 1
- 229960003556 aminophylline Drugs 0.000 description 1
- 229960003896 aminopterin Drugs 0.000 description 1
- 229940113720 aminosalicylate Drugs 0.000 description 1
- 229960000836 amitriptyline Drugs 0.000 description 1
- KRMDCWKBEZIMAB-UHFFFAOYSA-N amitriptyline Chemical compound C1CC2=CC=CC=C2C(=CCCN(C)C)C2=CC=CC=C21 KRMDCWKBEZIMAB-UHFFFAOYSA-N 0.000 description 1
- 229960001220 amsacrine Drugs 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
- 230000000202 analgesic effect Effects 0.000 description 1
- BBDAGFIXKZCXAH-CCXZUQQUSA-N ancitabine Chemical compound N=C1C=CN2[C@@H]3O[C@H](CO)[C@@H](O)[C@@H]3OC2=N1 BBDAGFIXKZCXAH-CCXZUQQUSA-N 0.000 description 1
- 229950000242 ancitabine Drugs 0.000 description 1
- 239000003098 androgen Substances 0.000 description 1
- 229940030486 androgens Drugs 0.000 description 1
- 229960004977 anhydrous lactose Drugs 0.000 description 1
- 229940045799 anthracyclines and related substance Drugs 0.000 description 1
- 230000002280 anti-androgenic effect Effects 0.000 description 1
- 230000001773 anti-convulsant effect Effects 0.000 description 1
- 229940046836 anti-estrogen Drugs 0.000 description 1
- 230000001833 anti-estrogenic effect Effects 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 230000001028 anti-proliverative effect Effects 0.000 description 1
- 230000001754 anti-pyretic effect Effects 0.000 description 1
- 230000005809 anti-tumor immunity Effects 0.000 description 1
- 239000000051 antiandrogen Substances 0.000 description 1
- 229940030495 antiandrogen sex hormone and modulator of the genital system Drugs 0.000 description 1
- 239000000611 antibody drug conjugate Substances 0.000 description 1
- 229940049595 antibody-drug conjugate Drugs 0.000 description 1
- 229940125681 anticonvulsant agent Drugs 0.000 description 1
- 239000001961 anticonvulsive agent Substances 0.000 description 1
- 239000013059 antihormonal agent Substances 0.000 description 1
- 229940082992 antihypertensives mao inhibitors Drugs 0.000 description 1
- 229940111131 antiinflammatory and antirheumatic product propionic acid derivative Drugs 0.000 description 1
- 239000000063 antileukemic agent Substances 0.000 description 1
- 229940045687 antimetabolites folic acid analogs Drugs 0.000 description 1
- 229940045719 antineoplastic alkylating agent nitrosoureas Drugs 0.000 description 1
- 229940045988 antineoplastic drug protein kinase inhibitors Drugs 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 239000000939 antiparkinson agent Substances 0.000 description 1
- 239000002221 antipyretic Substances 0.000 description 1
- 239000003435 antirheumatic agent Substances 0.000 description 1
- 239000000074 antisense oligonucleotide Substances 0.000 description 1
- 238000012230 antisense oligonucleotides Methods 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 229950003145 apolizumab Drugs 0.000 description 1
- NMYKBZSMOUFOJV-FJSWQEPZSA-N aprinocarsen Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C3=C(C(NC(N)=N3)=O)N=C2)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C3=C(C(NC(N)=N3)=O)N=C2)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(NC(=O)C(C)=C2)=O)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(N=C(N)C=C2)=O)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C3=C(C(NC(N)=N3)=O)N=C2)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(N=C(N)C=C2)=O)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(NC(=O)C(C)=C2)=O)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(N=C(N)C=C2)=O)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(NC(=O)C(C)=C2)=O)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(NC(=O)C(C)=C2)=O)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C3=C(C(NC(N)=N3)=O)N=C2)CO)[C@@H](OP(O)(=S)OC[C@@H]2[C@H](C[C@@H](O2)N2C3=C(C(NC(N)=N3)=O)N=C2)OP(O)(=S)OC[C@@H]2[C@H](C[C@@H](O2)N2C3=NC=NC(N)=C3N=C2)OP(O)(=S)OC[C@@H]2[C@H](C[C@@H](O2)N2C3=C(C(NC(N)=N3)=O)N=C2)OP(O)(=S)OC[C@@H]2[C@H](C[C@@H](O2)N2C(NC(=O)C(C)=C2)=O)OP(O)(=S)OC[C@@H]2[C@H](C[C@@H](O2)N2C(NC(=O)C(C)=C2)=O)OP(O)(=S)OC[C@@H]2[C@H](C[C@@H](O2)N2C(NC(=O)C(C)=C2)=O)OP(O)(=S)OC[C@@H]2[C@H](C[C@@H](O2)N2C(N=C(N)C=C2)=O)OP(O)(=S)OC[C@@H]2[C@H](C[C@@H](O2)N2C3=NC=NC(N)=C3N=C2)O)C1 NMYKBZSMOUFOJV-FJSWQEPZSA-N 0.000 description 1
- 150000008209 arabinosides Chemical class 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 229960003121 arginine Drugs 0.000 description 1
- 229940078010 arimidex Drugs 0.000 description 1
- 229940087620 aromasin Drugs 0.000 description 1
- 239000003886 aromatase inhibitor Substances 0.000 description 1
- 229940046844 aromatase inhibitors Drugs 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- 125000002102 aryl alkyloxo group Chemical group 0.000 description 1
- 125000005160 aryl oxy alkyl group Chemical group 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229950002882 aselizumab Drugs 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 229940009100 aurothiomalate Drugs 0.000 description 1
- XJHSMFDIQHVMCY-UHFFFAOYSA-M aurothiomalic acid Chemical compound OC(=O)CC(S[Au])C(O)=O XJHSMFDIQHVMCY-UHFFFAOYSA-M 0.000 description 1
- 230000001363 autoimmune Effects 0.000 description 1
- 239000012822 autophagy inhibitor Substances 0.000 description 1
- 229940120638 avastin Drugs 0.000 description 1
- 229940003504 avonex Drugs 0.000 description 1
- 229950011321 azaserine Drugs 0.000 description 1
- 125000003725 azepanyl group Chemical group 0.000 description 1
- 125000002393 azetidinyl group Chemical group 0.000 description 1
- 150000001541 aziridines Chemical class 0.000 description 1
- 125000004069 aziridinyl group Chemical group 0.000 description 1
- 210000003719 b-lymphocyte Anatomy 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 229960004168 balsalazide Drugs 0.000 description 1
- IPOKCKJONYRRHP-FMQUCBEESA-N balsalazide Chemical compound C1=CC(C(=O)NCCC(=O)O)=CC=C1\N=N\C1=CC=C(O)C(C(O)=O)=C1 IPOKCKJONYRRHP-FMQUCBEESA-N 0.000 description 1
- 229950001863 bapineuzumab Drugs 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 239000000440 bentonite Substances 0.000 description 1
- 229910000278 bentonite Inorganic materials 0.000 description 1
- SVPXDRXYRYOSEX-UHFFFAOYSA-N bentoquatam Chemical compound O.O=[Si]=O.O=[Al]O[Al]=O SVPXDRXYRYOSEX-UHFFFAOYSA-N 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000004618 benzofuryl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 125000005874 benzothiadiazolyl group Chemical group 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000003354 benzotriazolyl group Chemical group N1N=NC2=C1C=CC=C2* 0.000 description 1
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- 229960002903 benzyl benzoate Drugs 0.000 description 1
- 239000002876 beta blocker Substances 0.000 description 1
- 229940097320 beta blocking agent Drugs 0.000 description 1
- MSWZFWKMSRAUBD-UHFFFAOYSA-N beta-D-galactosamine Natural products NC1C(O)OC(CO)C(O)C1O MSWZFWKMSRAUBD-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 229960003237 betaine Drugs 0.000 description 1
- 229960001102 betamethasone dipropionate Drugs 0.000 description 1
- CIWBQSYVNNPZIQ-XYWKZLDCSA-N betamethasone dipropionate 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)COC(=O)CC)(OC(=O)CC)[C@@]1(C)C[C@@H]2O CIWBQSYVNNPZIQ-XYWKZLDCSA-N 0.000 description 1
- PLCQGRYPOISRTQ-LWCNAHDDSA-L betamethasone sodium phosphate Chemical compound [Na+].[Na+].C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)COP([O-])([O-])=O)(O)[C@@]1(C)C[C@@H]2O PLCQGRYPOISRTQ-LWCNAHDDSA-L 0.000 description 1
- 229960005354 betamethasone sodium phosphate Drugs 0.000 description 1
- 229960004311 betamethasone valerate Drugs 0.000 description 1
- SNHRLVCMMWUAJD-SUYDQAKGSA-N betamethasone valerate 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)(OC(=O)CCCC)[C@@]1(C)C[C@@H]2O SNHRLVCMMWUAJD-SUYDQAKGSA-N 0.000 description 1
- 229960000997 bicalutamide Drugs 0.000 description 1
- GPRLTFBKWDERLU-UHFFFAOYSA-N bicyclo[2.2.2]octane Chemical compound C1CC2CCC1CC2 GPRLTFBKWDERLU-UHFFFAOYSA-N 0.000 description 1
- GNTFBMAGLFYMMZ-UHFFFAOYSA-N bicyclo[3.2.2]nonane Chemical compound C1CC2CCC1CCC2 GNTFBMAGLFYMMZ-UHFFFAOYSA-N 0.000 description 1
- 201000007180 bile duct carcinoma Diseases 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 238000004166 bioassay Methods 0.000 description 1
- 239000003124 biologic agent Substances 0.000 description 1
- 238000000225 bioluminescence resonance energy transfer Methods 0.000 description 1
- 229940126587 biotherapeutics Drugs 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 239000004305 biphenyl Chemical group 0.000 description 1
- 229950008548 bisantrene Drugs 0.000 description 1
- 229960005522 bivatuzumab mertansine Drugs 0.000 description 1
- 229950006844 bizelesin Drugs 0.000 description 1
- 230000036760 body temperature Effects 0.000 description 1
- 239000004327 boric acid Substances 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- OZVBMTJYIDMWIL-AYFBDAFISA-N bromocriptine Chemical compound C1=CC(C=2[C@H](N(C)C[C@@H](C=2)C(=O)N[C@]2(C(=O)N3[C@H](C(N4CCC[C@H]4[C@]3(O)O2)=O)CC(C)C)C(C)C)C2)=C3C2=C(Br)NC3=C1 OZVBMTJYIDMWIL-AYFBDAFISA-N 0.000 description 1
- 229960002802 bromocriptine Drugs 0.000 description 1
- 208000003362 bronchogenic carcinoma Diseases 0.000 description 1
- 229960005520 bryostatin Drugs 0.000 description 1
- MJQUEDHRCUIRLF-TVIXENOKSA-N bryostatin 1 Chemical compound C([C@@H]1CC(/[C@@H]([C@@](C(C)(C)/C=C/2)(O)O1)OC(=O)/C=C/C=C/CCC)=C\C(=O)OC)[C@H]([C@@H](C)O)OC(=O)C[C@H](O)C[C@@H](O1)C[C@H](OC(C)=O)C(C)(C)[C@]1(O)C[C@@H]1C\C(=C\C(=O)OC)C[C@H]\2O1 MJQUEDHRCUIRLF-TVIXENOKSA-N 0.000 description 1
- MUIWQCKLQMOUAT-AKUNNTHJSA-N bryostatin 20 Natural products COC(=O)C=C1C[C@@]2(C)C[C@]3(O)O[C@](C)(C[C@@H](O)CC(=O)O[C@](C)(C[C@@]4(C)O[C@](O)(CC5=CC(=O)O[C@]45C)C(C)(C)C=C[C@@](C)(C1)O2)[C@@H](C)O)C[C@H](OC(=O)C(C)(C)C)C3(C)C MUIWQCKLQMOUAT-AKUNNTHJSA-N 0.000 description 1
- 229960004436 budesonide Drugs 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- MBABCNBNDNGODA-LUVUIASKSA-N bullatacin Chemical compound O1[C@@H]([C@@H](O)CCCCCCCCCC)CC[C@@H]1[C@@H]1O[C@@H]([C@H](O)CCCCCCCCCC[C@@H](O)CC=2C(O[C@@H](C)C=2)=O)CC1 MBABCNBNDNGODA-LUVUIASKSA-N 0.000 description 1
- 208000019748 bullous skin disease Diseases 0.000 description 1
- CUWODFFVMXJOKD-UVLQAERKSA-N buserelin Chemical compound CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](COC(C)(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=1NC=NC=1)NC(=O)[C@H]1NC(=O)CC1)CC1=CC=C(O)C=C1 CUWODFFVMXJOKD-UVLQAERKSA-N 0.000 description 1
- 229960002719 buserelin 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
- 108700002839 cactinomycin Proteins 0.000 description 1
- 229950009908 cactinomycin Drugs 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 235000010216 calcium carbonate Nutrition 0.000 description 1
- 239000000480 calcium channel blocker Substances 0.000 description 1
- 239000001506 calcium phosphate Substances 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
- 229940112129 campath Drugs 0.000 description 1
- OMZCMEYTWSXEPZ-UHFFFAOYSA-N canertinib Chemical compound C1=C(Cl)C(F)=CC=C1NC1=NC=NC2=CC(OCCCN3CCOCC3)=C(NC(=O)C=C)C=C12 OMZCMEYTWSXEPZ-UHFFFAOYSA-N 0.000 description 1
- 229950007296 cantuzumab mertansine Drugs 0.000 description 1
- 125000000609 carbazolyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3NC12)* 0.000 description 1
- 229960004205 carbidopa Drugs 0.000 description 1
- TZFNLOMSOLWIDK-JTQLQIEISA-N carbidopa (anhydrous) Chemical compound NN[C@@](C(O)=O)(C)CC1=CC=C(O)C(O)=C1 TZFNLOMSOLWIDK-JTQLQIEISA-N 0.000 description 1
- 125000002837 carbocyclic group Chemical group 0.000 description 1
- 150000001722 carbon compounds Chemical class 0.000 description 1
- 229960002115 carboquone Drugs 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- BLMPQMFVWMYDKT-NZTKNTHTSA-N carfilzomib Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC(C)C)C(=O)[C@]1(C)OC1)NC(=O)CN1CCOCC1)CC1=CC=CC=C1 BLMPQMFVWMYDKT-NZTKNTHTSA-N 0.000 description 1
- 108010021331 carfilzomib Proteins 0.000 description 1
- 229960002438 carfilzomib Drugs 0.000 description 1
- 229960003261 carmofur Drugs 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000012876 carrier material Substances 0.000 description 1
- BBZDXMBRAFTCAA-AREMUKBSSA-N carzelesin Chemical compound C1=2NC=C(C)C=2C([C@H](CCl)CN2C(=O)C=3NC4=CC=C(C=C4C=3)NC(=O)C3=CC4=CC=C(C=C4O3)N(CC)CC)=C2C=C1OC(=O)NC1=CC=CC=C1 BBZDXMBRAFTCAA-AREMUKBSSA-N 0.000 description 1
- 229950007509 carzelesin Drugs 0.000 description 1
- 108010047060 carzinophilin Proteins 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 229950006754 cedelizumab Drugs 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 230000024245 cell differentiation Effects 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 230000003833 cell viability Effects 0.000 description 1
- 230000005754 cellular signaling Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 201000010881 cervical cancer Diseases 0.000 description 1
- 229960000541 cetyl alcohol Drugs 0.000 description 1
- XMEVHPAGJVLHIG-FMZCEJRJSA-N chembl454950 Chemical compound [Cl-].C1=CC=C2[C@](O)(C)[C@H]3C[C@H]4[C@H]([NH+](C)C)C(O)=C(C(N)=O)C(=O)[C@@]4(O)C(O)=C3C(=O)C2=C1O XMEVHPAGJVLHIG-FMZCEJRJSA-N 0.000 description 1
- 229910052729 chemical element Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 229960003677 chloroquine Drugs 0.000 description 1
- WHTVZRBIWZFKQO-UHFFFAOYSA-N chloroquine Natural products ClC1=CC=C2C(NC(C)CCCN(CC)CC)=CC=NC2=C1 WHTVZRBIWZFKQO-UHFFFAOYSA-N 0.000 description 1
- 229960001480 chlorozotocin Drugs 0.000 description 1
- 239000000544 cholinesterase inhibitor Substances 0.000 description 1
- DLGJWSVWTWEWBJ-HGGSSLSASA-N chondroitin Chemical compound CC(O)=N[C@@H]1[C@H](O)O[C@H](CO)[C@H](O)[C@@H]1OC1[C@H](O)[C@H](O)C=C(C(O)=O)O1 DLGJWSVWTWEWBJ-HGGSSLSASA-N 0.000 description 1
- 108091006090 chromatin-associated proteins Proteins 0.000 description 1
- 210000000349 chromosome Anatomy 0.000 description 1
- 208000020832 chronic kidney disease Diseases 0.000 description 1
- 208000024207 chronic leukemia Diseases 0.000 description 1
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 description 1
- 208000025302 chronic primary adrenal insufficiency Diseases 0.000 description 1
- 229940090100 cimzia Drugs 0.000 description 1
- 235000013985 cinnamic acid Nutrition 0.000 description 1
- 229930016911 cinnamic acid Natural products 0.000 description 1
- 125000000259 cinnolinyl group Chemical group N1=NC(=CC2=CC=CC=C12)* 0.000 description 1
- 229960003405 ciprofloxacin Drugs 0.000 description 1
- DIOIOSKKIYDRIQ-UHFFFAOYSA-N ciprofloxacin hydrochloride Chemical compound Cl.C12=CC(N3CCNCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 DIOIOSKKIYDRIQ-UHFFFAOYSA-N 0.000 description 1
- 229960001229 ciprofloxacin hydrochloride Drugs 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 239000004927 clay Substances 0.000 description 1
- 229960004703 clobetasol propionate Drugs 0.000 description 1
- CBGUOGMQLZIXBE-XGQKBEPLSA-N clobetasol propionate 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)CCl)(OC(=O)CC)[C@@]1(C)C[C@@H]2O CBGUOGMQLZIXBE-XGQKBEPLSA-N 0.000 description 1
- 229960005465 clobetasone butyrate Drugs 0.000 description 1
- HJKBJIYDJLVSAO-UHFFFAOYSA-L clodronic acid disodium salt Chemical compound [Na+].[Na+].OP([O-])(=O)C(Cl)(Cl)P(O)([O-])=O HJKBJIYDJLVSAO-UHFFFAOYSA-L 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 239000008119 colloidal silica Substances 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 239000000356 contaminant Substances 0.000 description 1
- 239000002872 contrast media Substances 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- BMCQMVFGOVHVNG-TUFAYURCSA-N cortisol 17-butyrate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)CO)(OC(=O)CCC)[C@@]1(C)C[C@@H]2O BMCQMVFGOVHVNG-TUFAYURCSA-N 0.000 description 1
- FZCHYNWYXKICIO-FZNHGJLXSA-N cortisol 17-valerate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)CO)(OC(=O)CCCC)[C@@]1(C)C[C@@H]2O FZCHYNWYXKICIO-FZNHGJLXSA-N 0.000 description 1
- ALEXXDVDDISNDU-JZYPGELDSA-N cortisol 21-acetate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)COC(=O)C)(O)[C@@]1(C)C[C@@H]2O ALEXXDVDDISNDU-JZYPGELDSA-N 0.000 description 1
- 229960004544 cortisone Drugs 0.000 description 1
- 229960003290 cortisone acetate Drugs 0.000 description 1
- 235000012343 cottonseed oil Nutrition 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 229940109248 cromoglycate Drugs 0.000 description 1
- IMZMKUWMOSJXDT-UHFFFAOYSA-N cromoglycic acid Chemical compound O1C(C(O)=O)=CC(=O)C2=C1C=CC=C2OCC(O)COC1=CC=CC2=C1C(=O)C=C(C(O)=O)O2 IMZMKUWMOSJXDT-UHFFFAOYSA-N 0.000 description 1
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 1
- 108010089438 cryptophycin 1 Proteins 0.000 description 1
- PSNOPSMXOBPNNV-VVCTWANISA-N cryptophycin 1 Chemical compound C1=C(Cl)C(OC)=CC=C1C[C@@H]1C(=O)NC[C@@H](C)C(=O)O[C@@H](CC(C)C)C(=O)O[C@H]([C@H](C)[C@@H]2[C@H](O2)C=2C=CC=CC=2)C/C=C/C(=O)N1 PSNOPSMXOBPNNV-VVCTWANISA-N 0.000 description 1
- 108010090203 cryptophycin 8 Proteins 0.000 description 1
- PSNOPSMXOBPNNV-UHFFFAOYSA-N cryptophycin-327 Natural products C1=C(Cl)C(OC)=CC=C1CC1C(=O)NCC(C)C(=O)OC(CC(C)C)C(=O)OC(C(C)C2C(O2)C=2C=CC=CC=2)CC=CC(=O)N1 PSNOPSMXOBPNNV-UHFFFAOYSA-N 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 239000004148 curcumin Substances 0.000 description 1
- 229940109262 curcumin Drugs 0.000 description 1
- 229960002104 cyanocobalamin Drugs 0.000 description 1
- 235000000639 cyanocobalamin Nutrition 0.000 description 1
- 239000011666 cyanocobalamin Substances 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000003678 cyclohexadienyl group Chemical group C1(=CC=CCC1)* 0.000 description 1
- 125000006547 cyclononyl group Chemical group [H]C1([H])C([H])([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
- 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
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000131 cyclopropyloxy group Chemical group C1(CC1)O* 0.000 description 1
- UWFYSQMTEOIJJG-FDTZYFLXSA-N cyproterone acetate Chemical compound C1=C(Cl)C2=CC(=O)[C@@H]3C[C@@H]3[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(C)=O)(OC(=O)C)[C@@]1(C)CC2 UWFYSQMTEOIJJG-FDTZYFLXSA-N 0.000 description 1
- 229960000978 cyproterone acetate Drugs 0.000 description 1
- 208000002445 cystadenocarcinoma Diseases 0.000 description 1
- 229940104302 cytosine Drugs 0.000 description 1
- 229960003901 dacarbazine Drugs 0.000 description 1
- 229960002806 daclizumab Drugs 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- PCCPERGCFKIYIS-AWEZNQCLSA-N daxalipram Chemical compound C1=C(OC)C(OCCC)=CC([C@@]2(C)OC(=O)NC2)=C1 PCCPERGCFKIYIS-AWEZNQCLSA-N 0.000 description 1
- 230000001934 delay Effects 0.000 description 1
- 229960005052 demecolcine Drugs 0.000 description 1
- 229960003662 desonide Drugs 0.000 description 1
- WBGKWQHBNHJJPZ-LECWWXJVSA-N desonide Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]1(C)C[C@@H]2O WBGKWQHBNHJJPZ-LECWWXJVSA-N 0.000 description 1
- 229950003913 detorubicin Drugs 0.000 description 1
- 229910052805 deuterium Inorganic materials 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 229960002344 dexamethasone sodium phosphate Drugs 0.000 description 1
- PLCQGRYPOISRTQ-FCJDYXGNSA-L dexamethasone sodium phosphate Chemical compound [Na+].[Na+].C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)COP([O-])([O-])=O)(O)[C@@]1(C)C[C@@H]2O PLCQGRYPOISRTQ-FCJDYXGNSA-L 0.000 description 1
- 229960004193 dextropropoxyphene Drugs 0.000 description 1
- XLMALTXPSGQGBX-GCJKJVERSA-N dextropropoxyphene Chemical compound C([C@](OC(=O)CC)([C@H](C)CN(C)C)C=1C=CC=CC=1)C1=CC=CC=C1 XLMALTXPSGQGBX-GCJKJVERSA-N 0.000 description 1
- NIJJYAXOARWZEE-UHFFFAOYSA-N di-n-propyl-acetic acid Natural products CCCC(C(O)=O)CCC NIJJYAXOARWZEE-UHFFFAOYSA-N 0.000 description 1
- 208000033679 diabetic kidney disease Diseases 0.000 description 1
- 125000005959 diazepanyl group Chemical group 0.000 description 1
- 125000002576 diazepinyl group Chemical group N1N=C(C=CC=C1)* 0.000 description 1
- WVYXNIXAMZOZFK-UHFFFAOYSA-N diaziquone Chemical compound O=C1C(NC(=O)OCC)=C(N2CC2)C(=O)C(NC(=O)OCC)=C1N1CC1 WVYXNIXAMZOZFK-UHFFFAOYSA-N 0.000 description 1
- 229950002389 diaziquone Drugs 0.000 description 1
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 1
- 229940038472 dicalcium phosphate Drugs 0.000 description 1
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- RGLYKWWBQGJZGM-ISLYRVAYSA-N diethylstilbestrol Chemical compound C=1C=C(O)C=CC=1C(/CC)=C(\CC)C1=CC=C(O)C=C1 RGLYKWWBQGJZGM-ISLYRVAYSA-N 0.000 description 1
- 229960000452 diethylstilbestrol Drugs 0.000 description 1
- 206010012818 diffuse large B-cell lymphoma Diseases 0.000 description 1
- FOCAHLGSDWHSAH-UHFFFAOYSA-N difluoromethanethione Chemical compound FC(F)=S FOCAHLGSDWHSAH-UHFFFAOYSA-N 0.000 description 1
- 125000004852 dihydrofuranyl group Chemical group O1C(CC=C1)* 0.000 description 1
- 125000005043 dihydropyranyl group Chemical group O1C(CCC=C1)* 0.000 description 1
- 125000005057 dihydrothienyl group Chemical group S1C(CC=C1)* 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- GXGAKHNRMVGRPK-UHFFFAOYSA-N dimagnesium;dioxido-bis[[oxido(oxo)silyl]oxy]silane Chemical compound [Mg+2].[Mg+2].[O-][Si](=O)O[Si]([O-])([O-])O[Si]([O-])=O GXGAKHNRMVGRPK-UHFFFAOYSA-N 0.000 description 1
- 125000000532 dioxanyl group Chemical group 0.000 description 1
- HYPPXZBJBPSRLK-UHFFFAOYSA-N diphenoxylate Chemical compound C1CC(C(=O)OCC)(C=2C=CC=CC=2)CCN1CCC(C#N)(C=1C=CC=CC=1)C1=CC=CC=C1 HYPPXZBJBPSRLK-UHFFFAOYSA-N 0.000 description 1
- 229960004192 diphenoxylate Drugs 0.000 description 1
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 1
- 229910000396 dipotassium phosphate Inorganic materials 0.000 description 1
- 235000019797 dipotassium phosphate Nutrition 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 229960002563 disulfiram Drugs 0.000 description 1
- 125000005883 dithianyl group Chemical group 0.000 description 1
- 125000005411 dithiolanyl group Chemical group S1SC(CC1)* 0.000 description 1
- 239000002934 diuretic Substances 0.000 description 1
- 229940030606 diuretics Drugs 0.000 description 1
- 239000003534 dna topoisomerase inhibitor Substances 0.000 description 1
- 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- AMRJKAQTDDKMCE-UHFFFAOYSA-N dolastatin Chemical compound CC(C)C(N(C)C)C(=O)NC(C(C)C)C(=O)N(C)C(C(C)C)C(OC)CC(=O)N1CCCC1C(OC)C(C)C(=O)NC(C=1SC=CN=1)CC1=CC=CC=C1 AMRJKAQTDDKMCE-UHFFFAOYSA-N 0.000 description 1
- 229930188854 dolastatin Natural products 0.000 description 1
- OFDNQWIFNXBECV-VFSYNPLYSA-N dolastatin 10 Chemical compound CC(C)[C@H](N(C)C)C(=O)N[C@@H](C(C)C)C(=O)N(C)[C@@H]([C@@H](C)CC)[C@H](OC)CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](C=1SC=CN=1)CC1=CC=CC=C1 OFDNQWIFNXBECV-VFSYNPLYSA-N 0.000 description 1
- 108010045524 dolastatin 10 Proteins 0.000 description 1
- XWAIAVWHZJNZQQ-UHFFFAOYSA-N donepezil hydrochloride Chemical compound [H+].[Cl-].O=C1C=2C=C(OC)C(OC)=CC=2CC1CC(CC1)CCN1CC1=CC=CC=C1 XWAIAVWHZJNZQQ-UHFFFAOYSA-N 0.000 description 1
- 229960003135 donepezil hydrochloride Drugs 0.000 description 1
- MVCOAUNKQVWQHZ-UHFFFAOYSA-N doramapimod Chemical compound C1=CC(C)=CC=C1N1C(NC(=O)NC=2C3=CC=CC=C3C(OCCN3CCOCC3)=CC=2)=CC(C(C)(C)C)=N1 MVCOAUNKQVWQHZ-UHFFFAOYSA-N 0.000 description 1
- ZWAOHEXOSAUJHY-ZIYNGMLESA-N doxifluridine Chemical compound O[C@@H]1[C@H](O)[C@@H](C)O[C@H]1N1C(=O)NC(=O)C(F)=C1 ZWAOHEXOSAUJHY-ZIYNGMLESA-N 0.000 description 1
- 229950005454 doxifluridine Drugs 0.000 description 1
- 229960002918 doxorubicin hydrochloride Drugs 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 229950004203 droloxifene Drugs 0.000 description 1
- 229960004242 dronabinol Drugs 0.000 description 1
- OEHFRZLKGRKFAS-UHFFFAOYSA-N droxicam Chemical compound C12=CC=CC=C2S(=O)(=O)N(C)C(C2=O)=C1OC(=O)N2C1=CC=CC=N1 OEHFRZLKGRKFAS-UHFFFAOYSA-N 0.000 description 1
- 229960001850 droxicam Drugs 0.000 description 1
- 229940000406 drug candidate Drugs 0.000 description 1
- 239000000890 drug combination Substances 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 229960005501 duocarmycin Drugs 0.000 description 1
- VQNATVDKACXKTF-XELLLNAOSA-N duocarmycin Chemical compound COC1=C(OC)C(OC)=C2NC(C(=O)N3C4=CC(=O)C5=C([C@@]64C[C@@H]6C3)C=C(N5)C(=O)OC)=CC2=C1 VQNATVDKACXKTF-XELLLNAOSA-N 0.000 description 1
- 229930184221 duocarmycin Natural products 0.000 description 1
- 229950009791 durvalumab Drugs 0.000 description 1
- JWJOTENAMICLJG-QWBYCMEYSA-N dutasteride Chemical compound O=C([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)N[C@@H]4CC3)C)CC[C@@]21C)NC1=CC(C(F)(F)F)=CC=C1C(F)(F)F JWJOTENAMICLJG-QWBYCMEYSA-N 0.000 description 1
- 229960004199 dutasteride Drugs 0.000 description 1
- AFMYMMXSQGUCBK-AKMKHHNQSA-N dynemicin a Chemical compound C1#C\C=C/C#C[C@@H]2NC(C=3C(=O)C4=C(O)C=CC(O)=C4C(=O)C=3C(O)=C3)=C3[C@@]34O[C@]32[C@@H](C)C(C(O)=O)=C(OC)[C@H]41 AFMYMMXSQGUCBK-AKMKHHNQSA-N 0.000 description 1
- 239000003221 ear drop Substances 0.000 description 1
- 229940047652 ear drops Drugs 0.000 description 1
- 229960002224 eculizumab Drugs 0.000 description 1
- FSIRXIHZBIXHKT-MHTVFEQDSA-N edatrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CC(CC)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FSIRXIHZBIXHKT-MHTVFEQDSA-N 0.000 description 1
- 229950006700 edatrexate Drugs 0.000 description 1
- 229960000284 efalizumab Drugs 0.000 description 1
- 210000003162 effector t lymphocyte Anatomy 0.000 description 1
- VLCYCQAOQCDTCN-UHFFFAOYSA-N eflornithine Chemical compound NCCCC(N)(C(F)F)C(O)=O VLCYCQAOQCDTCN-UHFFFAOYSA-N 0.000 description 1
- 239000003602 elastase inhibitor Substances 0.000 description 1
- 239000003792 electrolyte Substances 0.000 description 1
- XOPYFXBZMVTEJF-PDACKIITSA-N eleutherobin Chemical compound C(/[C@H]1[C@H](C(=CC[C@@H]1C(C)C)C)C[C@@H]([C@@]1(C)O[C@@]2(C=C1)OC)OC(=O)\C=C\C=1N=CN(C)C=1)=C2\CO[C@@H]1OC[C@@H](O)[C@@H](O)[C@@H]1OC(C)=O XOPYFXBZMVTEJF-PDACKIITSA-N 0.000 description 1
- XOPYFXBZMVTEJF-UHFFFAOYSA-N eleutherobin Natural products C1=CC2(OC)OC1(C)C(OC(=O)C=CC=1N=CN(C)C=1)CC(C(=CCC1C(C)C)C)C1C=C2COC1OCC(O)C(O)C1OC(C)=O XOPYFXBZMVTEJF-UHFFFAOYSA-N 0.000 description 1
- 229950000549 elliptinium acetate Drugs 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 229940073621 enbrel Drugs 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- JOZGNYDSEBIJDH-UHFFFAOYSA-N eniluracil Chemical compound O=C1NC=C(C#C)C(=O)N1 JOZGNYDSEBIJDH-UHFFFAOYSA-N 0.000 description 1
- 229950010213 eniluracil Drugs 0.000 description 1
- 229950011487 enocitabine Drugs 0.000 description 1
- JRURYQJSLYLRLN-BJMVGYQFSA-N entacapone Chemical compound CCN(CC)C(=O)C(\C#N)=C\C1=CC(O)=C(O)C([N+]([O-])=O)=C1 JRURYQJSLYLRLN-BJMVGYQFSA-N 0.000 description 1
- 229960003337 entacapone Drugs 0.000 description 1
- 239000002702 enteric coating Substances 0.000 description 1
- 238000009505 enteric coating Methods 0.000 description 1
- 229940116977 epidermal growth factor Drugs 0.000 description 1
- 229940030275 epigallocatechin gallate Drugs 0.000 description 1
- YJGVMLPVUAXIQN-UHFFFAOYSA-N epipodophyllotoxin Natural products COC1=C(OC)C(OC)=CC(C2C3=CC=4OCOC=4C=C3C(O)C3C2C(OC3)=O)=C1 YJGVMLPVUAXIQN-UHFFFAOYSA-N 0.000 description 1
- 208000037828 epithelial carcinoma Diseases 0.000 description 1
- 229950002973 epitiostanol Drugs 0.000 description 1
- 229930013356 epothilone Natural products 0.000 description 1
- 150000003883 epothilone derivatives Chemical class 0.000 description 1
- 229950009760 epratuzumab Drugs 0.000 description 1
- 229940082789 erbitux Drugs 0.000 description 1
- 229950004292 erlizumab Drugs 0.000 description 1
- 201000004101 esophageal cancer Diseases 0.000 description 1
- ITSGNOIFAJAQHJ-BMFNZSJVSA-N esorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)C[C@H](C)O1 ITSGNOIFAJAQHJ-BMFNZSJVSA-N 0.000 description 1
- 229950002017 esorubicin Drugs 0.000 description 1
- LJQQFQHBKUKHIS-WJHRIEJJSA-N esperamicin Chemical compound O1CC(NC(C)C)C(OC)CC1OC1C(O)C(NOC2OC(C)C(SC)C(O)C2)C(C)OC1OC1C(\C2=C/CSSSC)=C(NC(=O)OC)C(=O)C(OC3OC(C)C(O)C(OC(=O)C=4C(=CC(OC)=C(OC)C=4)NC(=O)C(=C)OC)C3)C2(O)C#C\C=C/C#C1 LJQQFQHBKUKHIS-WJHRIEJJSA-N 0.000 description 1
- 229940011871 estrogen Drugs 0.000 description 1
- 239000000262 estrogen Substances 0.000 description 1
- 239000000328 estrogen antagonist Substances 0.000 description 1
- 201000007281 estrogen-receptor positive breast cancer Diseases 0.000 description 1
- JKKFKPJIXZFSSB-CBZIJGRNSA-N estrone 3-sulfate Chemical compound OS(=O)(=O)OC1=CC=C2[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CCC2=C1 JKKFKPJIXZFSSB-CBZIJGRNSA-N 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- QSRLNKCNOLVZIR-KRWDZBQOSA-N ethyl (2s)-2-[[2-[4-[bis(2-chloroethyl)amino]phenyl]acetyl]amino]-4-methylsulfanylbutanoate Chemical compound CCOC(=O)[C@H](CCSC)NC(=O)CC1=CC=C(N(CCCl)CCCl)C=C1 QSRLNKCNOLVZIR-KRWDZBQOSA-N 0.000 description 1
- 229940093499 ethyl acetate Drugs 0.000 description 1
- 229940012017 ethylenediamine Drugs 0.000 description 1
- 125000000219 ethylidene group Chemical group [H]C(=[*])C([H])([H])[H] 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 229940009626 etidronate Drugs 0.000 description 1
- 229960005237 etoglucid Drugs 0.000 description 1
- LIQODXNTTZAGID-OCBXBXKTSA-N etoposide phosphate Chemical compound COC1=C(OP(O)(O)=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 LIQODXNTTZAGID-OCBXBXKTSA-N 0.000 description 1
- 229960000752 etoposide phosphate Drugs 0.000 description 1
- 210000000632 euchromatin Anatomy 0.000 description 1
- 210000003527 eukaryotic cell Anatomy 0.000 description 1
- 230000017188 evasion or tolerance of host immune response Effects 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 239000003889 eye drop Substances 0.000 description 1
- 229940012356 eye drops Drugs 0.000 description 1
- 229950011548 fadrozole Drugs 0.000 description 1
- 229940043168 fareston Drugs 0.000 description 1
- 229940087861 faslodex Drugs 0.000 description 1
- 235000019197 fats Nutrition 0.000 description 1
- 229950001563 felvizumab Drugs 0.000 description 1
- ZWJINEZUASEZBH-UHFFFAOYSA-N fenamic acid Chemical class OC(=O)C1=CC=CC=C1NC1=CC=CC=C1 ZWJINEZUASEZBH-UHFFFAOYSA-N 0.000 description 1
- 229960001419 fenoprofen Drugs 0.000 description 1
- 229950003662 fenretinide Drugs 0.000 description 1
- PJMPHNIQZUBGLI-UHFFFAOYSA-N fentanyl Chemical compound C=1C=CC=CC=1N(C(=O)CC)C(CC1)CCN1CCC1=CC=CC=C1 PJMPHNIQZUBGLI-UHFFFAOYSA-N 0.000 description 1
- 229960002428 fentanyl Drugs 0.000 description 1
- 230000027950 fever generation Effects 0.000 description 1
- 230000004761 fibrosis Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- DBEPLOCGEIEOCV-WSBQPABSSA-N finasteride Chemical compound N([C@@H]1CC2)C(=O)C=C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H](C(=O)NC(C)(C)C)[C@@]2(C)CC1 DBEPLOCGEIEOCV-WSBQPABSSA-N 0.000 description 1
- 229960004039 finasteride Drugs 0.000 description 1
- 229960000556 fingolimod Drugs 0.000 description 1
- KKGQTZUTZRNORY-UHFFFAOYSA-N fingolimod Chemical compound CCCCCCCCC1=CC=C(CCC(N)(CO)CO)C=C1 KKGQTZUTZRNORY-UHFFFAOYSA-N 0.000 description 1
- 150000002206 flavan-3-ols Chemical class 0.000 description 1
- 235000011987 flavanols Nutrition 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 229960004369 flufenamic acid Drugs 0.000 description 1
- LPEPZBJOKDYZAD-UHFFFAOYSA-N flufenamic acid Chemical compound OC(=O)C1=CC=CC=C1NC1=CC=CC(C(F)(F)F)=C1 LPEPZBJOKDYZAD-UHFFFAOYSA-N 0.000 description 1
- FEBLZLNTKCEFIT-VSXGLTOVSA-N fluocinolone acetonide Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]2(C)C[C@@H]1O FEBLZLNTKCEFIT-VSXGLTOVSA-N 0.000 description 1
- 229960001347 fluocinolone acetonide Drugs 0.000 description 1
- 229960003973 fluocortolone Drugs 0.000 description 1
- GAKMQHDJQHZUTJ-ULHLPKEOSA-N fluocortolone Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2C[C@@H](C)[C@H](C(=O)CO)[C@@]2(C)C[C@@H]1O GAKMQHDJQHZUTJ-ULHLPKEOSA-N 0.000 description 1
- 229960004437 fluocortolone caproate Drugs 0.000 description 1
- 229960005283 fluocortolone pivalate Drugs 0.000 description 1
- XZBJVIQXJHGUBE-HZMVJJPJSA-N fluocortolone pivalate Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2C[C@@H](C)[C@H](C(=O)COC(=O)C(C)(C)C)[C@@]2(C)C[C@@H]1O XZBJVIQXJHGUBE-HZMVJJPJSA-N 0.000 description 1
- 238000002376 fluorescence recovery after photobleaching Methods 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- YLRFCQOZQXIBAB-RBZZARIASA-N fluoxymesterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1CC[C@](C)(O)[C@@]1(C)C[C@@H]2O YLRFCQOZQXIBAB-RBZZARIASA-N 0.000 description 1
- 229960001751 fluoxymesterone Drugs 0.000 description 1
- 229960002650 fluprednidene acetate Drugs 0.000 description 1
- DEFOZIFYUBUHHU-IYQKUMFPSA-N fluprednidene acetate Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1CC(=C)[C@@](C(=O)COC(=O)C)(O)[C@@]1(C)C[C@@H]2O DEFOZIFYUBUHHU-IYQKUMFPSA-N 0.000 description 1
- 229960002390 flurbiprofen Drugs 0.000 description 1
- SYTBZMRGLBWNTM-UHFFFAOYSA-N flurbiprofen Chemical compound FC1=CC(C(C(O)=O)C)=CC=C1C1=CC=CC=C1 SYTBZMRGLBWNTM-UHFFFAOYSA-N 0.000 description 1
- 229960002074 flutamide Drugs 0.000 description 1
- MKXKFYHWDHIYRV-UHFFFAOYSA-N flutamide Chemical compound CC(C)C(=O)NC1=CC=C([N+]([O-])=O)C(C(F)(F)F)=C1 MKXKFYHWDHIYRV-UHFFFAOYSA-N 0.000 description 1
- 230000004907 flux Effects 0.000 description 1
- 201000005206 focal segmental glomerulosclerosis Diseases 0.000 description 1
- 231100000854 focal segmental glomerulosclerosis Toxicity 0.000 description 1
- 150000002224 folic acids Chemical class 0.000 description 1
- 201000003444 follicular lymphoma Diseases 0.000 description 1
- 229950004923 fontolizumab Drugs 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 229940001490 fosamax Drugs 0.000 description 1
- 229960004783 fotemustine Drugs 0.000 description 1
- YAKWPXVTIGTRJH-UHFFFAOYSA-N fotemustine Chemical compound CCOP(=O)(OCC)C(C)NC(=O)N(CCCl)N=O YAKWPXVTIGTRJH-UHFFFAOYSA-N 0.000 description 1
- 238000005194 fractionation Methods 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 230000002538 fungal effect Effects 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- LNTHITQWFMADLM-UHFFFAOYSA-M gallate Chemical compound OC1=CC(C([O-])=O)=CC(O)=C1O LNTHITQWFMADLM-UHFFFAOYSA-M 0.000 description 1
- 229940044658 gallium nitrate Drugs 0.000 description 1
- 108010074605 gamma-Globulins Proteins 0.000 description 1
- 206010017758 gastric cancer Diseases 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- QTQAWLPCGQOSGP-GBTDJJJQSA-N geldanamycin Chemical compound N1C(=O)\C(C)=C/C=C\[C@@H](OC)[C@H](OC(N)=O)\C(C)=C/[C@@H](C)[C@@H](O)[C@H](OC)C[C@@H](C)CC2=C(OC)C(=O)C=C1C2=O QTQAWLPCGQOSGP-GBTDJJJQSA-N 0.000 description 1
- 229960000578 gemtuzumab Drugs 0.000 description 1
- 229940020967 gemzar Drugs 0.000 description 1
- 238000001415 gene therapy Methods 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 210000004602 germ cell Anatomy 0.000 description 1
- 229960003776 glatiramer acetate Drugs 0.000 description 1
- 208000005017 glioblastoma Diseases 0.000 description 1
- 208000002409 gliosarcoma Diseases 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 229960002442 glucosamine Drugs 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 235000001727 glucose Nutrition 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 125000005456 glyceride group Chemical group 0.000 description 1
- YQEMORVAKMFKLG-UHFFFAOYSA-N glycerine monostearate Natural products CCCCCCCCCCCCCCCCCC(=O)OC(CO)CO YQEMORVAKMFKLG-UHFFFAOYSA-N 0.000 description 1
- SVUQHVRAGMNPLW-UHFFFAOYSA-N glycerol monostearate Natural products CCCCCCCCCCCCCCCCC(=O)OCC(O)CO SVUQHVRAGMNPLW-UHFFFAOYSA-N 0.000 description 1
- 229960002449 glycine Drugs 0.000 description 1
- 229930182470 glycoside Natural products 0.000 description 1
- 150000002343 gold Chemical class 0.000 description 1
- 229940015045 gold sodium thiomalate Drugs 0.000 description 1
- 229960001743 golimumab Drugs 0.000 description 1
- 229960002913 goserelin Drugs 0.000 description 1
- 229960003690 goserelin acetate Drugs 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 125000001188 haloalkyl group Chemical group 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 229960003878 haloperidol Drugs 0.000 description 1
- 231100000869 headache Toxicity 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 208000025750 heavy chain disease Diseases 0.000 description 1
- 201000002222 hemangioblastoma Diseases 0.000 description 1
- 208000014951 hematologic disease Diseases 0.000 description 1
- 208000018706 hematopoietic system disease Diseases 0.000 description 1
- 208000006454 hepatitis Diseases 0.000 description 1
- 231100000283 hepatitis 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
- 229940022353 herceptin Drugs 0.000 description 1
- 125000005114 heteroarylalkoxy group Chemical group 0.000 description 1
- 125000004446 heteroarylalkyl group Chemical group 0.000 description 1
- 210000004458 heterochromatin Anatomy 0.000 description 1
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 229960002885 histidine Drugs 0.000 description 1
- 230000013632 homeostatic process Effects 0.000 description 1
- 102000045108 human EGFR Human genes 0.000 description 1
- 102000048362 human PDCD1 Human genes 0.000 description 1
- 239000003906 humectant Substances 0.000 description 1
- 229940048921 humira Drugs 0.000 description 1
- XGIHQYAWBCFNPY-AZOCGYLKSA-N hydrabamine Chemical compound C([C@@H]12)CC3=CC(C(C)C)=CC=C3[C@@]2(C)CCC[C@@]1(C)CNCCNC[C@@]1(C)[C@@H]2CCC3=CC(C(C)C)=CC=C3[C@@]2(C)CCC1 XGIHQYAWBCFNPY-AZOCGYLKSA-N 0.000 description 1
- 229960000890 hydrocortisone Drugs 0.000 description 1
- 229960001067 hydrocortisone acetate Drugs 0.000 description 1
- 229960001524 hydrocortisone butyrate Drugs 0.000 description 1
- 229960001330 hydroxycarbamide Drugs 0.000 description 1
- 229960004171 hydroxychloroquine Drugs 0.000 description 1
- XXSMGPRMXLTPCZ-UHFFFAOYSA-N hydroxychloroquine Chemical compound ClC1=CC=C2C(NC(C)CCCN(CCO)CC)=CC=NC2=C1 XXSMGPRMXLTPCZ-UHFFFAOYSA-N 0.000 description 1
- 229960002927 hydroxychloroquine sulfate Drugs 0.000 description 1
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 description 1
- KNOSIOWNDGUGFJ-UHFFFAOYSA-N hydroxysesamone Natural products C1=CC(O)=C2C(=O)C(CC=C(C)C)=C(O)C(=O)C2=C1O KNOSIOWNDGUGFJ-UHFFFAOYSA-N 0.000 description 1
- 229960001550 hyoscyamine sulfate Drugs 0.000 description 1
- 230000003463 hyperproliferative effect Effects 0.000 description 1
- 229940015872 ibandronate Drugs 0.000 description 1
- 208000008384 ileus Diseases 0.000 description 1
- 238000005417 image-selected in vivo spectroscopy Methods 0.000 description 1
- 125000003037 imidazol-2-yl group Chemical group [H]N1C([*])=NC([H])=C1[H] 0.000 description 1
- 125000002632 imidazolidinyl group Chemical group 0.000 description 1
- 125000002636 imidazolinyl group Chemical group 0.000 description 1
- 230000002519 immonomodulatory effect Effects 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 229940127121 immunoconjugate Drugs 0.000 description 1
- 230000005847 immunogenicity Effects 0.000 description 1
- 102000018358 immunoglobulin Human genes 0.000 description 1
- 239000003018 immunosuppressive agent Substances 0.000 description 1
- 229940125721 immunosuppressive agent Drugs 0.000 description 1
- DBIGHPPNXATHOF-UHFFFAOYSA-N improsulfan Chemical compound CS(=O)(=O)OCCCNCCCOS(C)(=O)=O DBIGHPPNXATHOF-UHFFFAOYSA-N 0.000 description 1
- 229950008097 improsulfan Drugs 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 1
- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000008595 infiltration Effects 0.000 description 1
- 238000001764 infiltration Methods 0.000 description 1
- 230000004968 inflammatory condition Effects 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 229940102223 injectable solution Drugs 0.000 description 1
- 229940102213 injectable suspension Drugs 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 229950004101 inotuzumab ozogamicin Drugs 0.000 description 1
- 238000012739 integrated shape imaging system Methods 0.000 description 1
- 108010021315 integrin beta7 Proteins 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 201000006334 interstitial nephritis Diseases 0.000 description 1
- 238000007917 intracranial administration Methods 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000007919 intrasynovial administration Methods 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 229960005386 ipilimumab Drugs 0.000 description 1
- 229960001888 ipratropium Drugs 0.000 description 1
- OEXHQOGQTVQTAT-JRNQLAHRSA-N ipratropium Chemical compound O([C@H]1C[C@H]2CC[C@@H](C1)[N@@+]2(C)C(C)C)C(=O)C(CO)C1=CC=CC=C1 OEXHQOGQTVQTAT-JRNQLAHRSA-N 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 208000028867 ischemia Diseases 0.000 description 1
- OMEUGRCNAZNQLN-UHFFFAOYSA-N isis 5132 Chemical compound O=C1NC(=O)C(C)=CN1C1OC(COP(O)(=S)OC2C(OC(C2)N2C(NC(=O)C(C)=C2)=O)COP(O)(=S)OC2C(OC(C2)N2C3=NC=NC(N)=C3N=C2)COP(O)(=S)OC2C(OC(C2)N2C(N=C(N)C=C2)=O)COP(O)(=S)OC2C(OC(C2)N2C3=C(C(NC(N)=N3)=O)N=C2)COP(O)(=S)OC2C(OC(C2)N2C(NC(=O)C(C)=C2)=O)COP(O)(=S)OC2C(OC(C2)N2C3=NC=NC(N)=C3N=C2)COP(O)(=S)OC2C(OC(C2)N2C(N=C(N)C=C2)=O)COP(O)(=S)OC2C(OC(C2)N2C3=NC=NC(N)=C3N=C2)COP(O)(=S)OC2C(OC(C2)N2C3=C(C(NC(N)=N3)=O)N=C2)COP(S)(=O)OC2C(OC(C2)N2C(NC(=O)C(C)=C2)=O)COP(O)(=S)OC2C(OC(C2)N2C3=C(C(NC(N)=N3)=O)N=C2)COP(O)(=S)OC2C(OC(C2)N2C(NC(=O)C(C)=C2)=O)COP(O)(=S)OC2C(OC(C2)N2C(N=C(N)C=C2)=O)COP(O)(=S)OC2C(OC(C2)N2C(N=C(N)C=C2)=O)COP(O)(=S)OC2C(OC(C2)N2C3=C(C(NC(N)=N3)=O)N=C2)COP(O)(=S)OC2C(OC(C2)N2C(N=C(N)C=C2)=O)COP(O)(=S)OC2C(OC(C2)N2C(N=C(N)C=C2)=O)COP(O)(=S)OC2C(OC(C2)N2C(N=C(N)C=C2)=O)COP(O)(=S)OC2C(OC(C2)N2C(NC(=O)C(C)=C2)=O)CO)C(O)C1 OMEUGRCNAZNQLN-UHFFFAOYSA-N 0.000 description 1
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 description 1
- 238000006317 isomerization reaction Methods 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000005956 isoquinolyl group Chemical group 0.000 description 1
- 125000004628 isothiazolidinyl group Chemical group S1N(CCC1)* 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 229950002252 isoxicam Drugs 0.000 description 1
- YYUAYBYLJSNDCX-UHFFFAOYSA-N isoxicam Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC=1C=C(C)ON=1 YYUAYBYLJSNDCX-UHFFFAOYSA-N 0.000 description 1
- MWDZOUNAPSSOEL-UHFFFAOYSA-N kaempferol Natural products OC1=C(C(=O)c2cc(O)cc(O)c2O1)c3ccc(O)cc3 MWDZOUNAPSSOEL-UHFFFAOYSA-N 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- DKYWVDODHFEZIM-UHFFFAOYSA-N ketoprofen Chemical compound OC(=O)C(C)C1=CC=CC(C(=O)C=2C=CC=CC=2)=C1 DKYWVDODHFEZIM-UHFFFAOYSA-N 0.000 description 1
- 229960000991 ketoprofen Drugs 0.000 description 1
- 229960004958 ketotifen Drugs 0.000 description 1
- 229940054136 kineret Drugs 0.000 description 1
- TYQCGQRIZGCHNB-JLAZNSOCSA-N l-ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(O)=C(O)C1=O TYQCGQRIZGCHNB-JLAZNSOCSA-N 0.000 description 1
- 229950000518 labetuzumab Drugs 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- CWPGNVFCJOPXFB-UHFFFAOYSA-N lapachol Chemical compound C1=CC=C2C(=O)C(=O)C(CC=C(C)C)=C(O)C2=C1 CWPGNVFCJOPXFB-UHFFFAOYSA-N 0.000 description 1
- SIUGQQMOYSVTAT-UHFFFAOYSA-N lapachol Natural products CC(=CCC1C(O)C(=O)c2ccccc2C1=O)C SIUGQQMOYSVTAT-UHFFFAOYSA-N 0.000 description 1
- 229950002183 lebrikizumab Drugs 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 229950007278 lenercept Drugs 0.000 description 1
- 229940115286 lentinan Drugs 0.000 description 1
- 230000021633 leukocyte mediated immunity Effects 0.000 description 1
- 229960004393 lidocaine hydrochloride Drugs 0.000 description 1
- YECIFGHRMFEPJK-UHFFFAOYSA-N lidocaine hydrochloride monohydrate Chemical compound O.[Cl-].CC[NH+](CC)CC(=O)NC1=C(C)C=CC=C1C YECIFGHRMFEPJK-UHFFFAOYSA-N 0.000 description 1
- 229950002950 lintuzumab Drugs 0.000 description 1
- 208000012987 lip and oral cavity carcinoma Diseases 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 206010024627 liposarcoma Diseases 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 239000008297 liquid dosage form Substances 0.000 description 1
- 239000006194 liquid suspension Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 208000019423 liver disease Diseases 0.000 description 1
- 229950001750 lonafarnib Drugs 0.000 description 1
- PGYPOBZJRVSMDS-UHFFFAOYSA-N loperamide hydrochloride Chemical compound Cl.C=1C=CC=CC=1C(C=1C=CC=CC=1)(C(=O)N(C)C)CCN(CC1)CCC1(O)C1=CC=C(Cl)C=C1 PGYPOBZJRVSMDS-UHFFFAOYSA-N 0.000 description 1
- 229960002983 loperamide hydrochloride Drugs 0.000 description 1
- OXROWJKCGCOJDO-JLHYYAGUSA-N lornoxicam Chemical compound O=C1C=2SC(Cl)=CC=2S(=O)(=O)N(C)\C1=C(\O)NC1=CC=CC=N1 OXROWJKCGCOJDO-JLHYYAGUSA-N 0.000 description 1
- 229960002202 lornoxicam Drugs 0.000 description 1
- YROQEQPFUCPDCP-UHFFFAOYSA-N losoxantrone Chemical compound OCCNCCN1N=C2C3=CC=CC(O)=C3C(=O)C3=C2C1=CC=C3NCCNCCO YROQEQPFUCPDCP-UHFFFAOYSA-N 0.000 description 1
- 229950008745 losoxantrone Drugs 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 229960000994 lumiracoxib Drugs 0.000 description 1
- KHPKQFYUPIUARC-UHFFFAOYSA-N lumiracoxib Chemical compound OC(=O)CC1=CC(C)=CC=C1NC1=C(F)C=CC=C1Cl KHPKQFYUPIUARC-UHFFFAOYSA-N 0.000 description 1
- RVFGKBWWUQOIOU-NDEPHWFRSA-N lurtotecan Chemical compound O=C([C@]1(O)CC)OCC(C(N2CC3=4)=O)=C1C=C2C3=NC1=CC=2OCCOC=2C=C1C=4CN1CCN(C)CC1 RVFGKBWWUQOIOU-NDEPHWFRSA-N 0.000 description 1
- 229950002654 lurtotecan Drugs 0.000 description 1
- 208000012804 lymphangiosarcoma Diseases 0.000 description 1
- 208000003747 lymphoid leukemia Diseases 0.000 description 1
- 229960003646 lysine Drugs 0.000 description 1
- 125000003588 lysine group Chemical group [H]N([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- 150000002669 lysines Chemical class 0.000 description 1
- 229940124302 mTOR inhibitor Drugs 0.000 description 1
- 201000000564 macroglobulinemia Diseases 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 239000000391 magnesium silicate Substances 0.000 description 1
- 229910000386 magnesium trisilicate Inorganic materials 0.000 description 1
- 229940099273 magnesium trisilicate Drugs 0.000 description 1
- 235000019793 magnesium trisilicate Nutrition 0.000 description 1
- 201000004792 malaria Diseases 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
- 239000003628 mammalian target of rapamycin inhibitor Substances 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- MQXVYODZCMMZEM-ZYUZMQFOSA-N mannomustine Chemical compound ClCCNC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CNCCCl MQXVYODZCMMZEM-ZYUZMQFOSA-N 0.000 description 1
- 229950008612 mannomustine Drugs 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229940099262 marinol Drugs 0.000 description 1
- 229950002736 marizomib Drugs 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- WKPWGQKGSOKKOO-RSFHAFMBSA-N maytansine Chemical compound CO[C@@H]([C@@]1(O)C[C@](OC(=O)N1)([C@H]([C@@H]1O[C@@]1(C)[C@@H](OC(=O)[C@H](C)N(C)C(C)=O)CC(=O)N1C)C)[H])\C=C\C=C(C)\CC2=CC(OC)=C(Cl)C1=C2 WKPWGQKGSOKKOO-RSFHAFMBSA-N 0.000 description 1
- 229960004961 mechlorethamine Drugs 0.000 description 1
- HAWPXGHAZFHHAD-UHFFFAOYSA-N mechlorethamine Chemical compound ClCCN(C)CCCl HAWPXGHAZFHHAD-UHFFFAOYSA-N 0.000 description 1
- 229960003803 meclofenamic acid Drugs 0.000 description 1
- 238000013160 medical therapy Methods 0.000 description 1
- PSGAAPLEWMOORI-PEINSRQWSA-N medroxyprogesterone acetate Chemical compound C([C@@]12C)CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2CC[C@]2(C)[C@@](OC(C)=O)(C(C)=O)CC[C@H]21 PSGAAPLEWMOORI-PEINSRQWSA-N 0.000 description 1
- 229960002985 medroxyprogesterone acetate Drugs 0.000 description 1
- 208000023356 medullary thyroid gland carcinoma Diseases 0.000 description 1
- 229960003464 mefenamic acid Drugs 0.000 description 1
- HYYBABOKPJLUIN-UHFFFAOYSA-N mefenamic acid Chemical compound CC1=CC=CC(NC=2C(=CC=CC=2)C(O)=O)=C1C HYYBABOKPJLUIN-UHFFFAOYSA-N 0.000 description 1
- 230000021121 meiosis Effects 0.000 description 1
- 108010000525 member 1 small inducible cytokine subfamily E Proteins 0.000 description 1
- 201000008350 membranous glomerulonephritis Diseases 0.000 description 1
- 206010027191 meningioma Diseases 0.000 description 1
- 229950009246 mepitiostane Drugs 0.000 description 1
- 229960005108 mepolizumab Drugs 0.000 description 1
- 208000030159 metabolic disease Diseases 0.000 description 1
- 230000015689 metaplastic ossification Effects 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- VJRAUFKOOPNFIQ-TVEKBUMESA-N methyl (1r,2r,4s)-4-[(2r,4s,5s,6s)-5-[(2s,4s,5s,6s)-5-[(2s,4s,5s,6s)-4,5-dihydroxy-6-methyloxan-2-yl]oxy-4-hydroxy-6-methyloxan-2-yl]oxy-4-(dimethylamino)-6-methyloxan-2-yl]oxy-2-ethyl-2,5,7,10-tetrahydroxy-6,11-dioxo-3,4-dihydro-1h-tetracene-1-carboxylat Chemical compound O([C@H]1[C@@H](O)C[C@@H](O[C@H]1C)O[C@H]1[C@H](C[C@@H](O[C@H]1C)O[C@H]1C[C@]([C@@H](C2=CC=3C(=O)C4=C(O)C=CC(O)=C4C(=O)C=3C(O)=C21)C(=O)OC)(O)CC)N(C)C)[C@H]1C[C@H](O)[C@H](O)[C@H](C)O1 VJRAUFKOOPNFIQ-TVEKBUMESA-N 0.000 description 1
- QRMNENFZDDYDEF-GOSISDBHSA-N methyl (8s)-8-(bromomethyl)-2-methyl-4-(4-methylpiperazine-1-carbonyl)oxy-6-(5,6,7-trimethoxy-1h-indole-2-carbonyl)-7,8-dihydro-3h-pyrrolo[3,2-e]indole-1-carboxylate Chemical compound C1([C@H](CBr)CN(C1=C1)C(=O)C=2NC3=C(OC)C(OC)=C(OC)C=C3C=2)=C2C(C(=O)OC)=C(C)NC2=C1OC(=O)N1CCN(C)CC1 QRMNENFZDDYDEF-GOSISDBHSA-N 0.000 description 1
- WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 1
- 230000011987 methylation Effects 0.000 description 1
- 238000007069 methylation reaction Methods 0.000 description 1
- HRHKSTOGXBBQCB-VFWICMBZSA-N methylmitomycin Chemical compound O=C1C(N)=C(C)C(=O)C2=C1[C@@H](COC(N)=O)[C@@]1(OC)[C@H]3N(C)[C@H]3CN12 HRHKSTOGXBBQCB-VFWICMBZSA-N 0.000 description 1
- 229960004584 methylprednisolone Drugs 0.000 description 1
- 229960001293 methylprednisolone acetate Drugs 0.000 description 1
- PLBHSZGDDKCEHR-LFYFAGGJSA-N methylprednisolone acetate Chemical compound 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(C)=O)CC[C@H]21 PLBHSZGDDKCEHR-LFYFAGGJSA-N 0.000 description 1
- 229960000334 methylprednisolone sodium succinate Drugs 0.000 description 1
- HPNSFSBZBAHARI-UHFFFAOYSA-N micophenolic acid Natural products OC1=C(CC=C(C)CCC(O)=O)C(OC)=C(C)C2=C1C(=O)OC2 HPNSFSBZBAHARI-UHFFFAOYSA-N 0.000 description 1
- 206010027599 migraine Diseases 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 229960005485 mitobronitol Drugs 0.000 description 1
- 229960003539 mitoguazone Drugs 0.000 description 1
- MXWHMTNPTTVWDM-NXOFHUPFSA-N mitoguazone Chemical compound NC(N)=N\N=C(/C)\C=N\N=C(N)N MXWHMTNPTTVWDM-NXOFHUPFSA-N 0.000 description 1
- VFKZTMPDYBFSTM-GUCUJZIJSA-N mitolactol Chemical compound BrC[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CBr VFKZTMPDYBFSTM-GUCUJZIJSA-N 0.000 description 1
- 229950010913 mitolactol Drugs 0.000 description 1
- 230000011278 mitosis Effects 0.000 description 1
- 229950007812 mocetinostat Drugs 0.000 description 1
- 229960001664 mometasone Drugs 0.000 description 1
- QLIIKPVHVRXHRI-CXSFZGCWSA-N mometasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(Cl)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CCl)(O)[C@@]1(C)C[C@@H]2O QLIIKPVHVRXHRI-CXSFZGCWSA-N 0.000 description 1
- 239000002899 monoamine oxidase inhibitor Substances 0.000 description 1
- CQDGTJPVBWZJAZ-UHFFFAOYSA-N monoethyl carbonate Chemical compound CCOC(O)=O CQDGTJPVBWZJAZ-UHFFFAOYSA-N 0.000 description 1
- VYGYNVZNSSTDLJ-HKCOAVLJSA-N monorden Natural products CC1CC2OC2C=C/C=C/C(=O)CC3C(C(=CC(=C3Cl)O)O)C(=O)O1 VYGYNVZNSSTDLJ-HKCOAVLJSA-N 0.000 description 1
- LBFBRXGCXUHRJY-HKHDRNBDSA-M montelukast sodium Chemical compound [Na+].CC(C)(O)C1=CC=CC=C1CC[C@H](C=1C=C(\C=C\C=2N=C3C=C(Cl)C=CC3=CC=2)C=CC=1)SCC1(CC([O-])=O)CC1 LBFBRXGCXUHRJY-HKHDRNBDSA-M 0.000 description 1
- 229960001951 montelukast sodium Drugs 0.000 description 1
- 229960004715 morphine sulfate Drugs 0.000 description 1
- GRVOTVYEFDAHCL-RTSZDRIGSA-N morphine sulfate pentahydrate Chemical compound O.O.O.O.O.OS(O)(=O)=O.O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O.O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O GRVOTVYEFDAHCL-RTSZDRIGSA-N 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 229960001521 motavizumab Drugs 0.000 description 1
- ZTFBIUXIQYRUNT-MDWZMJQESA-N mubritinib Chemical compound C1=CC(C(F)(F)F)=CC=C1\C=C\C1=NC(COC=2C=CC(CCCCN3N=NC=C3)=CC=2)=CO1 ZTFBIUXIQYRUNT-MDWZMJQESA-N 0.000 description 1
- 208000001725 mucocutaneous lymph node syndrome Diseases 0.000 description 1
- 208000027531 mycobacterial infectious disease Diseases 0.000 description 1
- 229960000951 mycophenolic acid Drugs 0.000 description 1
- HPNSFSBZBAHARI-RUDMXATFSA-N mycophenolic acid Chemical compound OC1=C(C\C=C(/C)CCC(O)=O)C(OC)=C(C)C2=C1C(=O)OC2 HPNSFSBZBAHARI-RUDMXATFSA-N 0.000 description 1
- 208000025113 myeloid leukemia Diseases 0.000 description 1
- 201000000050 myeloid neoplasm Diseases 0.000 description 1
- 208000001611 myxosarcoma Diseases 0.000 description 1
- ZKKVUIPXPPDIRD-UHFFFAOYSA-N n-(3-chlorophenyl)quinazolin-4-amine Chemical compound ClC1=CC=CC(NC=2C3=CC=CC=C3N=CN=2)=C1 ZKKVUIPXPPDIRD-UHFFFAOYSA-N 0.000 description 1
- NJSMWLQOCQIOPE-OCHFTUDZSA-N n-[(e)-[10-[(e)-(4,5-dihydro-1h-imidazol-2-ylhydrazinylidene)methyl]anthracen-9-yl]methylideneamino]-4,5-dihydro-1h-imidazol-2-amine Chemical compound N1CCN=C1N\N=C\C(C1=CC=CC=C11)=C(C=CC=C2)C2=C1\C=N\NC1=NCCN1 NJSMWLQOCQIOPE-OCHFTUDZSA-N 0.000 description 1
- BLCLNMBMMGCOAS-UHFFFAOYSA-N n-[1-[[1-[[1-[[1-[[1-[[1-[[1-[2-[(carbamoylamino)carbamoyl]pyrrolidin-1-yl]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-[(2-methylpropan-2-yl)oxy]-1-oxopropan-2-yl]amino]-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]amin Chemical compound C1CCC(C(=O)NNC(N)=O)N1C(=O)C(CCCN=C(N)N)NC(=O)C(CC(C)C)NC(=O)C(COC(C)(C)C)NC(=O)C(NC(=O)C(CO)NC(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)C(CC=1NC=NC=1)NC(=O)C1NC(=O)CC1)CC1=CC=C(O)C=C1 BLCLNMBMMGCOAS-UHFFFAOYSA-N 0.000 description 1
- YCKACRNXVWJWBX-UHFFFAOYSA-N n-phenyl-7h-pyrrolo[2,3-d]pyrimidin-4-amine Chemical class N=1C=NC=2NC=CC=2C=1NC1=CC=CC=C1 YCKACRNXVWJWBX-UHFFFAOYSA-N 0.000 description 1
- 229960004270 nabumetone Drugs 0.000 description 1
- 239000002105 nanoparticle Substances 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 229960003940 naproxen sodium Drugs 0.000 description 1
- CDBRNDSHEYLDJV-FVGYRXGTSA-M naproxen sodium Chemical compound [Na+].C1=C([C@H](C)C([O-])=O)C=CC2=CC(OC)=CC=C21 CDBRNDSHEYLDJV-FVGYRXGTSA-M 0.000 description 1
- 239000007922 nasal spray Substances 0.000 description 1
- 229960005027 natalizumab Drugs 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 229940086322 navelbine Drugs 0.000 description 1
- 229960004398 nedocromil Drugs 0.000 description 1
- RQTOOFIXOKYGAN-UHFFFAOYSA-N nedocromil Chemical compound CCN1C(C(O)=O)=CC(=O)C2=C1C(CCC)=C1OC(C(O)=O)=CC(=O)C1=C2 RQTOOFIXOKYGAN-UHFFFAOYSA-N 0.000 description 1
- 201000008383 nephritis Diseases 0.000 description 1
- 230000009251 neurologic dysfunction Effects 0.000 description 1
- 239000003900 neurotrophic factor Substances 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 229940080607 nexavar Drugs 0.000 description 1
- 229960002653 nilutamide Drugs 0.000 description 1
- XWXYUMMDTVBTOU-UHFFFAOYSA-N nilutamide Chemical compound O=C1C(C)(C)NC(=O)N1C1=CC=C([N+]([O-])=O)C(C(F)(F)F)=C1 XWXYUMMDTVBTOU-UHFFFAOYSA-N 0.000 description 1
- 229950010203 nimotuzumab Drugs 0.000 description 1
- 229960001420 nimustine Drugs 0.000 description 1
- VFEDRRNHLBGPNN-UHFFFAOYSA-N nimustine Chemical compound CC1=NC=C(CNC(=O)N(CCCl)N=O)C(N)=N1 VFEDRRNHLBGPNN-UHFFFAOYSA-N 0.000 description 1
- 150000002823 nitrates Chemical class 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- KGTDRFCXGRULNK-JYOBTZKQSA-N nogalamycin Chemical compound CO[C@@H]1[C@@](OC)(C)[C@@H](OC)[C@H](C)O[C@H]1O[C@@H]1C2=C(O)C(C(=O)C3=C(O)C=C4[C@@]5(C)O[C@H]([C@H]([C@@H]([C@H]5O)N(C)C)O)OC4=C3C3=O)=C3C=C2[C@@H](C(=O)OC)[C@@](C)(O)C1 KGTDRFCXGRULNK-JYOBTZKQSA-N 0.000 description 1
- 229950009266 nogalamycin Drugs 0.000 description 1
- 229940085033 nolvadex Drugs 0.000 description 1
- 231100000344 non-irritating Toxicity 0.000 description 1
- 239000012740 non-selective inhibitor Substances 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
- UMRZSTCPUPJPOJ-KNVOCYPGSA-N norbornane Chemical compound C1C[C@H]2CC[C@@H]1C2 UMRZSTCPUPJPOJ-KNVOCYPGSA-N 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 230000001293 nucleolytic effect Effects 0.000 description 1
- 239000002777 nucleoside Substances 0.000 description 1
- 210000001623 nucleosome Anatomy 0.000 description 1
- 210000004940 nucleus Anatomy 0.000 description 1
- 235000020824 obesity Nutrition 0.000 description 1
- 229960000435 oblimersen Drugs 0.000 description 1
- 229950005751 ocrelizumab Drugs 0.000 description 1
- 125000005060 octahydroindolyl group Chemical group N1(CCC2CCCCC12)* 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- KVWDHTXUZHCGIO-UHFFFAOYSA-N olanzapine Chemical compound C1CN(C)CCN1C1=NC2=CC=CC=C2NC2=C1C=C(C)S2 KVWDHTXUZHCGIO-UHFFFAOYSA-N 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- CZDBNBLGZNWKMC-MWQNXGTOSA-N olivomycin Chemical class O([C@@H]1C[C@@H](O[C@H](C)[C@@H]1O)OC=1C=C2C=C3C[C@H]([C@@H](C(=O)C3=C(O)C2=C(O)C=1)O[C@H]1O[C@@H](C)[C@H](O)[C@@H](OC2O[C@@H](C)[C@H](O)[C@@H](O)C2)C1)[C@H](OC)C(=O)[C@@H](O)[C@@H](C)O)[C@H]1C[C@H](O)[C@H](OC)[C@H](C)O1 CZDBNBLGZNWKMC-MWQNXGTOSA-N 0.000 description 1
- 229960000470 omalizumab Drugs 0.000 description 1
- 229950011093 onapristone Drugs 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 229940035567 orencia Drugs 0.000 description 1
- 201000008968 osteosarcoma Diseases 0.000 description 1
- 230000002611 ovarian Effects 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 125000005961 oxazepanyl group Chemical group 0.000 description 1
- 125000004287 oxazol-2-yl group Chemical group [H]C1=C([H])N=C(*)O1 0.000 description 1
- 125000000160 oxazolidinyl group Chemical group 0.000 description 1
- 125000000466 oxiranyl group Chemical group 0.000 description 1
- 229960000797 oxitropium Drugs 0.000 description 1
- NVOYVOBDTVTBDX-PMEUIYRNSA-N oxitropium Chemical compound CC[N+]1(C)[C@H]2C[C@@H](C[C@@H]1[C@H]1O[C@@H]21)OC(=O)[C@H](CO)C1=CC=CC=C1 NVOYVOBDTVTBDX-PMEUIYRNSA-N 0.000 description 1
- 229960002085 oxycodone Drugs 0.000 description 1
- MUZQPDBAOYKNLO-RKXJKUSZSA-N oxycodone hydrochloride Chemical compound [H+].[Cl-].O=C([C@@H]1O2)CC[C@@]3(O)[C@H]4CC5=CC=C(OC)C2=C5[C@@]13CCN4C MUZQPDBAOYKNLO-RKXJKUSZSA-N 0.000 description 1
- 101800000857 p40 protein Proteins 0.000 description 1
- 230000036407 pain Effects 0.000 description 1
- 229960000402 palivizumab Drugs 0.000 description 1
- WLJNZVDCPSBLRP-UHFFFAOYSA-N pamoic acid Chemical compound C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1 WLJNZVDCPSBLRP-UHFFFAOYSA-N 0.000 description 1
- VREZDOWOLGNDPW-UHFFFAOYSA-N pancratistatine Natural products C1=C2C3C(O)C(O)C(O)C(O)C3NC(=O)C2=C(O)C2=C1OCO2 VREZDOWOLGNDPW-UHFFFAOYSA-N 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 229960005184 panobinostat Drugs 0.000 description 1
- FWZRWHZDXBDTFK-ZHACJKMWSA-N panobinostat Chemical compound CC1=NC2=CC=C[CH]C2=C1CCNCC1=CC=C(\C=C\C(=O)NO)C=C1 FWZRWHZDXBDTFK-ZHACJKMWSA-N 0.000 description 1
- 208000004019 papillary adenocarcinoma Diseases 0.000 description 1
- 201000010198 papillary carcinoma Diseases 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 229960004662 parecoxib Drugs 0.000 description 1
- TZRHLKRLEZJVIJ-UHFFFAOYSA-N parecoxib Chemical compound C1=CC(S(=O)(=O)NC(=O)CC)=CC=C1C1=C(C)ON=C1C1=CC=CC=C1 TZRHLKRLEZJVIJ-UHFFFAOYSA-N 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 229950011485 pascolizumab Drugs 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- QIMGFXOHTOXMQP-GFAGFCTOSA-N peplomycin Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCCN[C@@H](C)C=1C=CC=CC=1)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1NC=NC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C QIMGFXOHTOXMQP-GFAGFCTOSA-N 0.000 description 1
- 229950003180 peplomycin Drugs 0.000 description 1
- 238000013146 percutaneous coronary intervention Methods 0.000 description 1
- 239000002304 perfume Substances 0.000 description 1
- YEHCICAEULNIGD-MZMPZRCHSA-N pergolide Chemical compound C1=CC([C@H]2C[C@@H](CSC)CN([C@@H]2C2)CCC)=C3C2=CNC3=C1 YEHCICAEULNIGD-MZMPZRCHSA-N 0.000 description 1
- 229960004851 pergolide Drugs 0.000 description 1
- 208000008494 pericarditis Diseases 0.000 description 1
- 229950010632 perifosine Drugs 0.000 description 1
- SZFPYBIJACMNJV-UHFFFAOYSA-N perifosine Chemical compound CCCCCCCCCCCCCCCCCCOP([O-])(=O)OC1CC[N+](C)(C)CC1 SZFPYBIJACMNJV-UHFFFAOYSA-N 0.000 description 1
- 230000000737 periodic effect Effects 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 229950003203 pexelizumab Drugs 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000001792 phenanthrenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3C=CC12)* 0.000 description 1
- 125000001791 phenazinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3N=C12)* 0.000 description 1
- 125000001484 phenothiazinyl group Chemical group C1(=CC=CC=2SC3=CC=CC=C3NC12)* 0.000 description 1
- 125000001644 phenoxazinyl group Chemical group C1(=CC=CC=2OC3=CC=CC=C3NC12)* 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- 229950009215 phenylbutanoic acid Drugs 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 239000002587 phosphodiesterase IV inhibitor Substances 0.000 description 1
- 229940043441 phosphoinositide 3-kinase inhibitor Drugs 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 1
- 208000024724 pineal body neoplasm Diseases 0.000 description 1
- 201000004123 pineal gland cancer Diseases 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- NUKCGLDCWQXYOQ-UHFFFAOYSA-N piposulfan Chemical compound CS(=O)(=O)OCCC(=O)N1CCN(C(=O)CCOS(C)(=O)=O)CC1 NUKCGLDCWQXYOQ-UHFFFAOYSA-N 0.000 description 1
- 229950001100 piposulfan Drugs 0.000 description 1
- 229960001221 pirarubicin Drugs 0.000 description 1
- PEZPMAYDXJQYRV-UHFFFAOYSA-N pixantrone Chemical compound O=C1C2=CN=CC=C2C(=O)C2=C1C(NCCN)=CC=C2NCCN PEZPMAYDXJQYRV-UHFFFAOYSA-N 0.000 description 1
- 229960004403 pixantrone Drugs 0.000 description 1
- 229960001237 podophyllotoxin Drugs 0.000 description 1
- YJGVMLPVUAXIQN-XVVDYKMHSA-N podophyllotoxin Chemical compound COC1=C(OC)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@H](O)[C@@H]3[C@@H]2C(OC3)=O)=C1 YJGVMLPVUAXIQN-XVVDYKMHSA-N 0.000 description 1
- YVCVYCSAAZQOJI-UHFFFAOYSA-N podophyllotoxin Natural products COC1=C(O)C(OC)=CC(C2C3=CC=4OCOC=4C=C3C(O)C3C2C(OC3)=O)=C1 YVCVYCSAAZQOJI-UHFFFAOYSA-N 0.000 description 1
- 229920000058 polyacrylate Polymers 0.000 description 1
- 229920000768 polyamine Polymers 0.000 description 1
- 201000006292 polyarteritis nodosa Diseases 0.000 description 1
- 208000030761 polycystic kidney disease Diseases 0.000 description 1
- 208000037244 polycythemia vera Diseases 0.000 description 1
- 150000008442 polyphenolic compounds Chemical class 0.000 description 1
- 235000013824 polyphenols Nutrition 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 150000004804 polysaccharides Chemical class 0.000 description 1
- 229950004406 porfiromycin Drugs 0.000 description 1
- 239000004302 potassium sorbate Substances 0.000 description 1
- 235000010241 potassium sorbate Nutrition 0.000 description 1
- 229940069338 potassium sorbate Drugs 0.000 description 1
- FASDKYOPVNHBLU-ZETCQYMHSA-N pramipexole Chemical compound C1[C@@H](NCCC)CCC2=C1SC(N)=N2 FASDKYOPVNHBLU-ZETCQYMHSA-N 0.000 description 1
- 229960003089 pramipexole Drugs 0.000 description 1
- 229960002794 prednicarbate Drugs 0.000 description 1
- FNPXMHRZILFCKX-KAJVQRHHSA-N prednicarbate Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)COC(=O)CC)(OC(=O)OCC)[C@@]1(C)C[C@@H]2O FNPXMHRZILFCKX-KAJVQRHHSA-N 0.000 description 1
- 229960004694 prednimustine Drugs 0.000 description 1
- 229940063238 premarin Drugs 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000037452 priming Effects 0.000 description 1
- 230000002206 pro-fibrotic effect Effects 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 229920002414 procyanidin Polymers 0.000 description 1
- 229940087463 proleukin Drugs 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 150000005599 propionic acid derivatives Chemical class 0.000 description 1
- 229960004063 propylene glycol Drugs 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 229950008679 protamine sulfate Drugs 0.000 description 1
- 238000000159 protein binding assay Methods 0.000 description 1
- 235000004252 protein component Nutrition 0.000 description 1
- 239000003909 protein kinase inhibitor Substances 0.000 description 1
- 230000004850 protein–protein interaction Effects 0.000 description 1
- WOLQREOUPKZMEX-UHFFFAOYSA-N pteroyltriglutamic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)NC(CCC(=O)NC(CCC(=O)NC(CCC(O)=O)C(O)=O)C(O)=O)C(O)=O)C=C1 WOLQREOUPKZMEX-UHFFFAOYSA-N 0.000 description 1
- 239000003379 purinergic P1 receptor agonist Substances 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 229950010131 puromycin Drugs 0.000 description 1
- PMXCMJLOPOFPBT-HNNXBMFYSA-N purvalanol A Chemical compound C=12N=CN(C(C)C)C2=NC(N[C@@H](CO)C(C)C)=NC=1NC1=CC=CC(Cl)=C1 PMXCMJLOPOFPBT-HNNXBMFYSA-N 0.000 description 1
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 1
- 125000002755 pyrazolinyl group Chemical group 0.000 description 1
- 125000002206 pyridazin-3-yl group Chemical group [H]C1=C([H])C([H])=C(*)N=N1 0.000 description 1
- ILVXOBCQQYKLDS-UHFFFAOYSA-N pyridine N-oxide Chemical class [O-][N+]1=CC=CC=C1 ILVXOBCQQYKLDS-UHFFFAOYSA-N 0.000 description 1
- HAMAGKWXRRTWCJ-UHFFFAOYSA-N pyrido[2,3-b][1,4]oxazin-3-one Chemical compound C1=CN=C2OC(=O)C=NC2=C1 HAMAGKWXRRTWCJ-UHFFFAOYSA-N 0.000 description 1
- 150000008518 pyridopyrimidines Chemical class 0.000 description 1
- 235000008160 pyridoxine Nutrition 0.000 description 1
- 239000011677 pyridoxine Substances 0.000 description 1
- 150000003230 pyrimidines Chemical class 0.000 description 1
- JOZPEVMCAKXSEY-UHFFFAOYSA-N pyrimido[5,4-d]pyrimidine Chemical class N1=CN=CC2=NC=NC=C21 JOZPEVMCAKXSEY-UHFFFAOYSA-N 0.000 description 1
- 150000004944 pyrrolopyrimidines Chemical class 0.000 description 1
- 229940107700 pyruvic acid Drugs 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 229960001285 quercetin Drugs 0.000 description 1
- 235000005875 quercetin Nutrition 0.000 description 1
- ZTHJULTYCAQOIJ-WXXKFALUSA-N quetiapine fumarate Chemical compound [H+].[H+].[O-]C(=O)\C=C\C([O-])=O.C1CN(CCOCCO)CCN1C1=NC2=CC=CC=C2SC2=CC=CC=C12.C1CN(CCOCCO)CCN1C1=NC2=CC=CC=C2SC2=CC=CC=C12 ZTHJULTYCAQOIJ-WXXKFALUSA-N 0.000 description 1
- 150000003246 quinazolines Chemical class 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- UOWVMDUEMSNCAV-WYENRQIDSA-N rachelmycin Chemical compound C1([C@]23C[C@@H]2CN1C(=O)C=1NC=2C(OC)=C(O)C4=C(C=2C=1)CCN4C(=O)C1=CC=2C=4CCN(C=4C(O)=C(C=2N1)OC)C(N)=O)=CC(=O)C1=C3C(C)=CN1 UOWVMDUEMSNCAV-WYENRQIDSA-N 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- AECPBJMOGBFQDN-YMYQVXQQSA-N radicicol Chemical compound C1CCCC(=O)C[C@H]2[C@H](Cl)C(=O)CC(=O)[C@H]2C(=O)O[C@H](C)C[C@H]2O[C@@H]21 AECPBJMOGBFQDN-YMYQVXQQSA-N 0.000 description 1
- 229930192524 radicicol Natural products 0.000 description 1
- 229960003876 ranibizumab Drugs 0.000 description 1
- BMKDZUISNHGIBY-UHFFFAOYSA-N razoxane Chemical compound C1C(=O)NC(=O)CN1C(C)CN1CC(=O)NC(=O)C1 BMKDZUISNHGIBY-UHFFFAOYSA-N 0.000 description 1
- 229960000460 razoxane Drugs 0.000 description 1
- 208000002574 reactive arthritis Diseases 0.000 description 1
- 229940038850 rebif Drugs 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 206010038038 rectal cancer Diseases 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 201000001275 rectum cancer Diseases 0.000 description 1
- 229940116176 remicade Drugs 0.000 description 1
- 230000008521 reorganization Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 229960003254 reslizumab Drugs 0.000 description 1
- 229940016667 resveratrol Drugs 0.000 description 1
- 235000021283 resveratrol Nutrition 0.000 description 1
- 239000003340 retarding agent Substances 0.000 description 1
- 229930002330 retinoic acid Natural products 0.000 description 1
- 201000009410 rhabdomyosarcoma Diseases 0.000 description 1
- OWPCHSCAPHNHAV-LMONGJCWSA-N rhizoxin Chemical compound C/C([C@H](OC)[C@@H](C)[C@@H]1C[C@H](O)[C@]2(C)O[C@@H]2/C=C/[C@@H](C)[C@]2([H])OC(=O)C[C@@](C2)(C[C@@H]2O[C@H]2C(=O)O1)[H])=C\C=C\C(\C)=C\C1=COC(C)=N1 OWPCHSCAPHNHAV-LMONGJCWSA-N 0.000 description 1
- 108091092562 ribozyme Proteins 0.000 description 1
- 229960004181 riluzole Drugs 0.000 description 1
- 229940089617 risedronate Drugs 0.000 description 1
- 229940106887 risperdal Drugs 0.000 description 1
- RAPZEAPATHNIPO-UHFFFAOYSA-N risperidone Chemical compound FC1=CC=C2C(C3CCN(CC3)CCC=3C(=O)N4CCCCC4=NC=3C)=NOC2=C1 RAPZEAPATHNIPO-UHFFFAOYSA-N 0.000 description 1
- 229960004136 rivastigmine Drugs 0.000 description 1
- 229950004892 rodorubicin Drugs 0.000 description 1
- 229960002586 roflumilast Drugs 0.000 description 1
- MNDBXUUTURYVHR-UHFFFAOYSA-N roflumilast Chemical compound FC(F)OC1=CC=C(C(=O)NC=2C(=CN=CC=2Cl)Cl)C=C1OCC1CC1 MNDBXUUTURYVHR-UHFFFAOYSA-N 0.000 description 1
- MBABCNBNDNGODA-WPZDJQSSSA-N rolliniastatin 1 Natural products O1[C@@H]([C@@H](O)CCCCCCCCCC)CC[C@H]1[C@H]1O[C@@H]([C@H](O)CCCCCCCCCC[C@@H](O)CC=2C(O[C@@H](C)C=2)=O)CC1 MBABCNBNDNGODA-WPZDJQSSSA-N 0.000 description 1
- 229960003452 romidepsin Drugs 0.000 description 1
- 108010091666 romidepsin Proteins 0.000 description 1
- OHRURASPPZQGQM-GCCNXGTGSA-N romidepsin Chemical compound O1C(=O)[C@H](C(C)C)NC(=O)C(=C/C)/NC(=O)[C@H]2CSSCC\C=C\[C@@H]1CC(=O)N[C@H](C(C)C)C(=O)N2 OHRURASPPZQGQM-GCCNXGTGSA-N 0.000 description 1
- OHRURASPPZQGQM-UHFFFAOYSA-N romidepsin Natural products O1C(=O)C(C(C)C)NC(=O)C(=CC)NC(=O)C2CSSCCC=CC1CC(=O)NC(C(C)C)C(=O)N2 OHRURASPPZQGQM-UHFFFAOYSA-N 0.000 description 1
- 229950010316 rontalizumab Drugs 0.000 description 1
- IMUQLZLGWJSVMV-UOBFQKKOSA-N roridin A Natural products CC(O)C1OCCC(C)C(O)C(=O)OCC2CC(=CC3OC4CC(OC(=O)C=C/C=C/1)C(C)(C23)C45CO5)C IMUQLZLGWJSVMV-UOBFQKKOSA-N 0.000 description 1
- 229950009092 rovelizumab Drugs 0.000 description 1
- VHXNKPBCCMUMSW-FQEVSTJZSA-N rubitecan Chemical compound C1=CC([N+]([O-])=O)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VHXNKPBCCMUMSW-FQEVSTJZSA-N 0.000 description 1
- ZCBUQCWBWNUWSU-SFHVURJKSA-N ruboxistaurin Chemical compound O=C1NC(=O)C2=C1C(C1=CC=CC=C11)=CN1CCO[C@H](CN(C)C)CCN1C3=CC=CC=C3C2=C1 ZCBUQCWBWNUWSU-SFHVURJKSA-N 0.000 description 1
- 229950000261 ruboxistaurin Drugs 0.000 description 1
- 229950005374 ruplizumab Drugs 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 1
- NGWSFRIPKNWYAO-SHTIJGAHSA-N salinosporamide A Chemical compound C([C@@H]1[C@H](O)[C@]23C(=O)O[C@]2([C@H](C(=O)N3)CCCl)C)CCC=C1 NGWSFRIPKNWYAO-SHTIJGAHSA-N 0.000 description 1
- NGWSFRIPKNWYAO-UHFFFAOYSA-N salinosporamide A Natural products N1C(=O)C(CCCl)C2(C)OC(=O)C21C(O)C1CCCC=C1 NGWSFRIPKNWYAO-UHFFFAOYSA-N 0.000 description 1
- 229960000953 salsalate Drugs 0.000 description 1
- 229930182947 sarcodictyin Natural products 0.000 description 1
- 201000000980 schizophrenia Diseases 0.000 description 1
- 201000008407 sebaceous adenocarcinoma Diseases 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- WUWDLXZGHZSWQZ-WQLSENKSSA-N semaxanib Chemical compound N1C(C)=CC(C)=C1\C=C/1C2=CC=CC=C2NC\1=O WUWDLXZGHZSWQZ-WQLSENKSSA-N 0.000 description 1
- 229940035004 seroquel Drugs 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 229950008684 sibrotuzumab Drugs 0.000 description 1
- 230000007781 signaling event Effects 0.000 description 1
- 150000004760 silicates Chemical class 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 229940068638 simponi Drugs 0.000 description 1
- 229950003804 siplizumab Drugs 0.000 description 1
- 229940112726 skelid Drugs 0.000 description 1
- 201000000849 skin cancer Diseases 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- AGHLUVOCTHWMJV-UHFFFAOYSA-J sodium;gold(3+);2-sulfanylbutanedioate Chemical compound [Na+].[Au+3].[O-]C(=O)CC(S)C([O-])=O.[O-]C(=O)CC(S)C([O-])=O AGHLUVOCTHWMJV-UHFFFAOYSA-J 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 230000003381 solubilizing effect Effects 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 229950006551 sontuzumab Drugs 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- OAVGBZOFDPFGPJ-UHFFFAOYSA-N sotrastaurin Chemical compound C1CN(C)CCN1C1=NC(C=2C(NC(=O)C=2C=2C3=CC=CC=C3NC=2)=O)=C(C=CC=C2)C2=N1 OAVGBZOFDPFGPJ-UHFFFAOYSA-N 0.000 description 1
- 125000003003 spiro group Chemical group 0.000 description 1
- OGNAOIGAPPSUMG-UHFFFAOYSA-N spiro[2.2]pentane Chemical compound C1CC11CC1 OGNAOIGAPPSUMG-UHFFFAOYSA-N 0.000 description 1
- FYGUBWKMMCWIKB-UHFFFAOYSA-N spiro[2.3]hexane Chemical compound C1CC11CCC1 FYGUBWKMMCWIKB-UHFFFAOYSA-N 0.000 description 1
- HEMCGZPSGYRIOL-UHFFFAOYSA-N spiro[2.4]heptane Chemical compound C1CC11CCCC1 HEMCGZPSGYRIOL-UHFFFAOYSA-N 0.000 description 1
- FOEYMRPOKBCNCR-UHFFFAOYSA-N spiro[2.5]octane Chemical compound C1CC11CCCCC1 FOEYMRPOKBCNCR-UHFFFAOYSA-N 0.000 description 1
- CTDQAGUNKPRERK-UHFFFAOYSA-N spirodecane Chemical compound C1CCCC21CCCCC2 CTDQAGUNKPRERK-UHFFFAOYSA-N 0.000 description 1
- 229950006315 spirogermanium Drugs 0.000 description 1
- ICXJVZHDZFXYQC-UHFFFAOYSA-N spongistatin 1 Natural products OC1C(O2)(O)CC(O)C(C)C2CCCC=CC(O2)CC(O)CC2(O2)CC(OC)CC2CC(=O)C(C)C(OC(C)=O)C(C)C(=C)CC(O2)CC(C)(O)CC2(O2)CC(OC(C)=O)CC2CC(=O)OC2C(O)C(CC(=C)CC(O)C=CC(Cl)=C)OC1C2C ICXJVZHDZFXYQC-UHFFFAOYSA-N 0.000 description 1
- 206010041823 squamous cell carcinoma Diseases 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 239000003206 sterilizing agent Substances 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- SEEPANYCNGTZFQ-UHFFFAOYSA-N sulfadiazine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)NC1=NC=CC=N1 SEEPANYCNGTZFQ-UHFFFAOYSA-N 0.000 description 1
- 229960004306 sulfadiazine Drugs 0.000 description 1
- 230000010741 sumoylation Effects 0.000 description 1
- WINHZLLDWRZWRT-ATVHPVEESA-N sunitinib Chemical compound CCN(CC)CCNC(=O)C1=C(C)NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C1C WINHZLLDWRZWRT-ATVHPVEESA-N 0.000 description 1
- 229960001796 sunitinib Drugs 0.000 description 1
- 238000004808 supercritical fluid chromatography Methods 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 208000034223 susceptibility to 2 systemic lupus erythematosus Diseases 0.000 description 1
- 201000010965 sweat gland carcinoma Diseases 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 206010042863 synovial sarcoma Diseases 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 201000000596 systemic lupus erythematosus Diseases 0.000 description 1
- 229960001967 tacrolimus Drugs 0.000 description 1
- 229950001072 tadocizumab Drugs 0.000 description 1
- 229950004218 talizumab Drugs 0.000 description 1
- 229960003454 tamoxifen citrate Drugs 0.000 description 1
- 229950007866 tanespimycin Drugs 0.000 description 1
- AYUNIORJHRXIBJ-TXHRRWQRSA-N tanespimycin Chemical compound N1C(=O)\C(C)=C\C=C/[C@H](OC)[C@@H](OC(N)=O)\C(C)=C\[C@H](C)[C@@H](O)[C@@H](OC)C[C@H](C)CC2=C(NCC=C)C(=O)C=C1C2=O AYUNIORJHRXIBJ-TXHRRWQRSA-N 0.000 description 1
- 229940099419 targretin Drugs 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 229940063683 taxotere Drugs 0.000 description 1
- 229950001788 tefibazumab Drugs 0.000 description 1
- 229960001674 tegafur Drugs 0.000 description 1
- WFWLQNSHRPWKFK-ZCFIWIBFSA-N tegafur Chemical compound O=C1NC(=O)C(F)=CN1[C@@H]1OCCC1 WFWLQNSHRPWKFK-ZCFIWIBFSA-N 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- 206010043207 temporal arteritis Diseases 0.000 description 1
- 229960000235 temsirolimus Drugs 0.000 description 1
- WZWYJBNHTWCXIM-UHFFFAOYSA-N tenoxicam Chemical compound O=C1C=2SC=CC=2S(=O)(=O)N(C)C1=C(O)NC1=CC=CC=N1 WZWYJBNHTWCXIM-UHFFFAOYSA-N 0.000 description 1
- 229960002871 tenoxicam Drugs 0.000 description 1
- 229960000195 terbutaline Drugs 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 201000003120 testicular cancer Diseases 0.000 description 1
- 125000001935 tetracenyl group Chemical group C1(=CC=CC2=CC3=CC4=CC=CC=C4C=C3C=C12)* 0.000 description 1
- 229960004989 tetracycline hydrochloride Drugs 0.000 description 1
- BSYVTEYKTMYBMK-UHFFFAOYSA-N tetrahydrofurfuryl alcohol Chemical compound OCC1CCCO1 BSYVTEYKTMYBMK-UHFFFAOYSA-N 0.000 description 1
- 125000005888 tetrahydroindolyl group Chemical group 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000005958 tetrahydrothienyl group Chemical group 0.000 description 1
- 125000004632 tetrahydrothiopyranyl group Chemical group S1C(CCCC1)* 0.000 description 1
- 125000005247 tetrazinyl group Chemical group N1=NN=NC(=C1)* 0.000 description 1
- 235000014620 theaflavin Nutrition 0.000 description 1
- 229960004559 theobromine Drugs 0.000 description 1
- 229960000278 theophylline Drugs 0.000 description 1
- 125000004525 thiadiazinyl group Chemical group S1NN=C(C=C1)* 0.000 description 1
- 125000005307 thiatriazolyl group Chemical group S1N=NN=C1* 0.000 description 1
- 125000005308 thiazepinyl group Chemical group S1N=C(C=CC=C1)* 0.000 description 1
- 125000006407 thiazinanyl group Chemical group 0.000 description 1
- 125000004305 thiazinyl group Chemical group S1NC(=CC=C1)* 0.000 description 1
- 125000000437 thiazol-2-yl group Chemical group [H]C1=C([H])N=C(*)S1 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000001583 thiepanyl group Chemical group 0.000 description 1
- 125000002053 thietanyl group Chemical group 0.000 description 1
- 125000001730 thiiranyl group Chemical group 0.000 description 1
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
- 229940033663 thimerosal Drugs 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 125000005503 thioxanyl group Chemical group 0.000 description 1
- RZWIIPASKMUIAC-VQTJNVASSA-N thromboxane Chemical compound CCCCCCCC[C@H]1OCCC[C@@H]1CCCCCCC RZWIIPASKMUIAC-VQTJNVASSA-N 0.000 description 1
- 201000002510 thyroid cancer Diseases 0.000 description 1
- 206010043778 thyroiditis Diseases 0.000 description 1
- YFTWHEBLORWGNI-UHFFFAOYSA-N tiamiprine Chemical compound CN1C=NC([N+]([O-])=O)=C1SC1=NC(N)=NC2=C1NC=N2 YFTWHEBLORWGNI-UHFFFAOYSA-N 0.000 description 1
- 229950011457 tiamiprine Drugs 0.000 description 1
- 229940019375 tiludronate Drugs 0.000 description 1
- 229950009158 tipifarnib Drugs 0.000 description 1
- 208000037816 tissue injury Diseases 0.000 description 1
- 229960003114 tixocortol pivalate Drugs 0.000 description 1
- BISFDZNIUZIKJD-XDANTLIUSA-N tixocortol pivalate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)CSC(=O)C(C)(C)C)(O)[C@@]1(C)C[C@@H]2O BISFDZNIUZIKJD-XDANTLIUSA-N 0.000 description 1
- UJLAWZDWDVHWOW-YPMHNXCESA-N tofacitinib Chemical compound C[C@@H]1CCN(C(=O)CC#N)C[C@@H]1N(C)C1=NC=NC2=C1C=CN2 UJLAWZDWDVHWOW-YPMHNXCESA-N 0.000 description 1
- 229960001350 tofacitinib Drugs 0.000 description 1
- 229960002905 tolfenamic acid Drugs 0.000 description 1
- YEZNLOUZAIOMLT-UHFFFAOYSA-N tolfenamic acid Chemical compound CC1=C(Cl)C=CC=C1NC1=CC=CC=C1C(O)=O YEZNLOUZAIOMLT-UHFFFAOYSA-N 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 229940044693 topoisomerase inhibitor Drugs 0.000 description 1
- 229950001802 toralizumab Drugs 0.000 description 1
- 229960004380 tramadol Drugs 0.000 description 1
- 239000006211 transdermal dosage form Substances 0.000 description 1
- IUCJMVBFZDHPDX-UHFFFAOYSA-N tretamine Chemical compound C1CN1C1=NC(N2CC2)=NC(N2CC2)=N1 IUCJMVBFZDHPDX-UHFFFAOYSA-N 0.000 description 1
- 229950001353 tretamine Drugs 0.000 description 1
- 229960005294 triamcinolone Drugs 0.000 description 1
- GFNANZIMVAIWHM-OBYCQNJPSA-N triamcinolone Chemical compound O=C1C=C[C@]2(C)[C@@]3(F)[C@@H](O)C[C@](C)([C@@]([C@H](O)C4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 GFNANZIMVAIWHM-OBYCQNJPSA-N 0.000 description 1
- PXSOHRWMIRDKMP-UHFFFAOYSA-N triaziquone Chemical compound O=C1C(N2CC2)=C(N2CC2)C(=O)C=C1N1CC1 PXSOHRWMIRDKMP-UHFFFAOYSA-N 0.000 description 1
- 229960004560 triaziquone Drugs 0.000 description 1
- 229930013292 trichothecene Natural products 0.000 description 1
- 150000003327 trichothecene derivatives Chemical class 0.000 description 1
- 229960001670 trilostane Drugs 0.000 description 1
- KVJXBPDAXMEYOA-CXANFOAXSA-N trilostane Chemical compound OC1=C(C#N)C[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CC[C@@]32O[C@@H]31 KVJXBPDAXMEYOA-CXANFOAXSA-N 0.000 description 1
- 229950000212 trioxifene Drugs 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 229960000875 trofosfamide Drugs 0.000 description 1
- UMKFEPPTGMDVMI-UHFFFAOYSA-N trofosfamide Chemical compound ClCCN(CCCl)P1(=O)OCCCN1CCCl UMKFEPPTGMDVMI-UHFFFAOYSA-N 0.000 description 1
- 229950010147 troxacitabine Drugs 0.000 description 1
- RXRGZNYSEHTMHC-BQBZGAKWSA-N troxacitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1O[C@@H](CO)OC1 RXRGZNYSEHTMHC-BQBZGAKWSA-N 0.000 description 1
- HDZZVAMISRMYHH-LITAXDCLSA-N tubercidin Chemical compound C1=CC=2C(N)=NC=NC=2N1[C@@H]1O[C@@H](CO)[C@H](O)[C@H]1O HDZZVAMISRMYHH-LITAXDCLSA-N 0.000 description 1
- 201000008827 tuberculosis Diseases 0.000 description 1
- 229950003364 tucotuzumab celmoleukin Drugs 0.000 description 1
- 108700008509 tucotuzumab celmoleukin Proteins 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 230000005851 tumor immunogenicity Effects 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
- 229950009811 ubenimex Drugs 0.000 description 1
- 238000010798 ubiquitination Methods 0.000 description 1
- 125000002948 undecyl 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])C([H])([H])C([H])([H])[H] 0.000 description 1
- 210000003932 urinary bladder Anatomy 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- VBEQCZHXXJYVRD-GACYYNSASA-N uroanthelone Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CS)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C(C)C)[C@@H](C)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCSC)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)CNC(=O)CNC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CS)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CS)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O)C(C)C)[C@@H](C)CC)C1=CC=C(O)C=C1 VBEQCZHXXJYVRD-GACYYNSASA-N 0.000 description 1
- 229950004362 urtoxazumab Drugs 0.000 description 1
- 229960003824 ustekinumab Drugs 0.000 description 1
- 206010046766 uterine cancer Diseases 0.000 description 1
- 210000004291 uterus Anatomy 0.000 description 1
- MSRILKIQRXUYCT-UHFFFAOYSA-M valproate semisodium Chemical compound [Na+].CCCC(C(O)=O)CCC.CCCC(C([O-])=O)CCC MSRILKIQRXUYCT-UHFFFAOYSA-M 0.000 description 1
- 229960000604 valproic acid Drugs 0.000 description 1
- LLDWLPRYLVPDTG-UHFFFAOYSA-N vatalanib succinate Chemical compound OC(=O)CCC(O)=O.C1=CC(Cl)=CC=C1NC(C1=CC=CC=C11)=NN=C1CC1=CC=NC=C1 LLDWLPRYLVPDTG-UHFFFAOYSA-N 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 229940099039 velcade Drugs 0.000 description 1
- 229960003862 vemurafenib Drugs 0.000 description 1
- GPXBXXGIAQBQNI-UHFFFAOYSA-N vemurafenib Chemical group CCCS(=O)(=O)NC1=CC=C(F)C(C(=O)C=2C3=CC(=CN=C3NC=2)C=2C=CC(Cl)=CC=2)=C1F GPXBXXGIAQBQNI-UHFFFAOYSA-N 0.000 description 1
- UGGWPQSBPIFKDZ-KOTLKJBCSA-N vindesine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(N)=O)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1N=C1[C]2C=CC=C1 UGGWPQSBPIFKDZ-KOTLKJBCSA-N 0.000 description 1
- 229960004355 vindesine Drugs 0.000 description 1
- CILBMBUYJCWATM-PYGJLNRPSA-N vinorelbine ditartrate Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O.OC(=O)[C@H](O)[C@@H](O)C(O)=O.C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC CILBMBUYJCWATM-PYGJLNRPSA-N 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 230000029812 viral genome replication Effects 0.000 description 1
- 229950004393 visilizumab Drugs 0.000 description 1
- 229940011671 vitamin b6 Drugs 0.000 description 1
- WAEXFXRVDQXREF-UHFFFAOYSA-N vorinostat Chemical compound ONC(=O)CCCCCCC(=O)NC1=CC=CC=C1 WAEXFXRVDQXREF-UHFFFAOYSA-N 0.000 description 1
- 229960000237 vorinostat Drugs 0.000 description 1
- 229960001771 vorozole Drugs 0.000 description 1
- XLMPPFTZALNBFS-INIZCTEOSA-N vorozole Chemical compound C1([C@@H](C2=CC=C3N=NN(C3=C2)C)N2N=CN=C2)=CC=C(Cl)C=C1 XLMPPFTZALNBFS-INIZCTEOSA-N 0.000 description 1
- 210000002268 wool Anatomy 0.000 description 1
- 229940075420 xanthine Drugs 0.000 description 1
- 229940053867 xeloda Drugs 0.000 description 1
- 229950008250 zalutumumab Drugs 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 229950009268 zinostatin Drugs 0.000 description 1
- 229940002005 zometa Drugs 0.000 description 1
- 229960000641 zorubicin Drugs 0.000 description 1
- FBTUMDXHSRTGRV-ALTNURHMSA-N zorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(\C)=N\NC(=O)C=1C=CC=CC=1)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 FBTUMDXHSRTGRV-ALTNURHMSA-N 0.000 description 1
- 229940039925 zyprexa Drugs 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
-
- 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
- A61K31/4709—Non-condensed quinolines 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
- A61K31/435—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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/538—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with carbocyclic ring 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
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/5415—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
-
- 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
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
Definitions
- the present invention relates to compounds useful as inhibitors of CBP/EP300 and methods of treating cancer using such inhibitors.
- Chromatin is a complex combination of DNA and protein that makes up chromosomes. It is found inside the nuclei of eukaryotic cells and is divided between heterochromatin (condensed) and euchromatin (extended) forms. The major components of chromatin are DNA and proteins. Histones are the chief protein components of chromatin, acting as spools around which DNA winds. The functions of chromatin are to package DNA into a smaller volume to fit in the cell, to strengthen the DNA to allow mitosis and meiosis, and to serve as a mechanism to control expression and DNA replication.
- the chromatin structure is controlled by a series of post-translational modifications to histone proteins, notably histones H3 and H4, and most commonly within the “histone tails” which extend beyond the core nucleosome structure.
- Histone tails tend to be free for protein-protein interaction and are also the portion of the histone most prone to post-translational modification. These modifications include acetylation, methylation, phosphorylation, ubiquitinylation, and SUMOylation.
- These epigenetic marks are written and erased by specific enzymes that place the tags on specific residues within the histone tail, thereby forming an epigenetic code, which is then interpreted by the cell to allow gene specific regulation of chromatin structure and thereby transcription.
- histones are amongst the most susceptible to post-translational modification. Histone modifications are dynamic, as they can be added or removed in response to specific stimuli, and these modifications direct both structural changes to chromatin and alterations in gene transcription. Distinct classes of enzymes, namely histone acetyltransferases (HATs) and histone deacetylases (HDACs), acetylate or de-acetylate specific histone lysine residues (Struhl K., Genes Dev., 1989, 12, 5, 599-606).
- HATs histone acetyltransferases
- HDACs histone deacetylases
- Bromodomains which are approximately 110 amino acids long, are found in a large number of chromatin-associated proteins and have been identified in approximately 70 human proteins, often adjacent to other protein motifs (Jeanmougin F., et al., Trends Biochem. Sci., 1997, 22, 5, 151-153; and Tamkun J. W., et al., Cell, 1992, 7, 3, 561-572). Interactions between bromodomains and modified histones may be an important mechanism underlying chromatin structural changes and gene regulation. Bromodomain-containing proteins have been implicated in disease processes including cancer, inflammation and viral replication. See, e.g., Prinjha et al., Trends Pharm. Sci., 33(3):146-153 (2012) and Muller et al., Expert Rev., 13(29): 1-20 (September 2011).
- Bromodomains reside within key chromatin modifying complexes that serve to control distinctive disease-associated transcriptional pathways. This is highlighted by the observation that mutations in bromodomain-containing proteins are linked to cancer, as well as immune and neurologic dysfunction. Hence, the selective inhibition of bromodomains across a specific family, such as the selective inhibition of a bromodomain of CBP/EP300, creates varied opportunities as novel therapeutic agents in human dysfunction.
- One aspect is a compound of formula (I) or formula (II):
- R 1 of Formula (I) is C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, 3-12 membered carbocycle, and 3-12 membered heterocycle, wherein each C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, 3-12 membered carbocycle, and 3-12 membered heterocycle of R 1 is optionally substituted with one or more groups R b ;
- R 2 of Formula (I) is selected from C 6 -C 20 aryl, C 1 -C 20 heteroaryl, —(C 6 -C 20 aryl)-(C 1 -C 20 heteroaryl), —(C 1 -C 20 heteroaryl)-(C 6 -C 20 aryl), and —(C 1 -C 20 heteroaryl)-(C 1 -C 20 heteroaryl), wherein each C 6 -C 20 aryl, C 1 -C 20 heteroaryl, —(C 6 -C 20 aryl)-(C 1 -C 20 heteroaryl) and —(C 1 -C 20 heteroaryl)-(C 1 -C 20 heteroaryl) is independently optionally substituted with one or more substituent groups independently selected from R c , oxo, —F, —Cl, —Br, —I, —NO 2 , —N(R a ) 2 , —CN, —C(O)—N
- R 3 of Formula (I) is C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, 3-12 membered carbocycle, and 3-12 membered heterocycle, wherein each C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, 3-12 membered carbocycle, and 3-12 membered heterocycle of R 3 is optionally substituted with one or more groups R e ; or
- R 2 and R 3 of Formula (I) taken together with the nitrogen to which they are attached form a 3-12 membered heterocycle that is optionally substituted with one or more groups R e ;
- R 4 of Formula (I) is C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, 3-5 membered carbocycle, 3-5 membered heterocycle, —C(O)—N(R h ) 2 , —S(O)—N(R h ) 2 , —S(O) 2 —N(R h ) 2 , —C(O)—R h , —C(O)—O—R h , —S(O)—R h , or —S(O) 2 —R h , wherein any C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, 3-5 membered carbocycle, and 3-5 membered heterocycle is optionally substituted with one or more substituent groups independently selected from —F, —Cl, —Br, —I, 3-5 membered carbocycle, —C(O)—N(R h
- each R a of Formula (I) is independently selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, and heterocyclyl, wherein each C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C 1-6 alkoxy, carbocyclyl, heterocyclyl, and C 1 -C 6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; or two R a are taken together with the nitrogen to which they are attached to form a heterocyclyl that is optionally substituted with one or more groups independently selected from oxo, halo and C 1-3 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo;
- each R b of Formula (I) is independently selected from oxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, —F, —Cl, —Br, —I, —NO 2 , —N(R c ) 2 , —CN, —C(O)—N(R c ) 2 , —S(O)—N(R c ) 2 , —S(O) 2 —N(R c ) 2 , —O—R c , —S—R c , —O—C(O)—R c , —O—C(O)—O—R c , —C(O)—O—R c , —C(O)—O—R c , —C(O)—O—R c , —S(O)—R c
- each R c of Formula (I) is independently selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, and heterocyclyl, wherein any C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, carbocyclyl, heterocyclyl, halo, —NO 2 , —N(R d ) 2 , —CN, —C(O)—N(R d ) 2 , —S(O)—N(R d ) 2 , —S(O) 2 —N(R d ) 2 , —O—R d , —S—R d , —O—C(O)—R d , —C(O)—R d , —C(O)—O—R d
- each R d of Formula (I) is independently selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, carbocyclyl, and heterocyclyl, wherein each C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C 1-6 alkoxy, carbocyclyl, heterocyclyl, and C 1 -C 6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; or two R d are taken together with the nitrogen to which they are attached to form a heterocyclyl that is optionally substituted with one or more groups independently selected from oxo, halo and C 1-3 alkyl that is optionally substituted with one or more groups independently selected from oxo and
- each R e of Formula (I) is independently selected from oxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, —F, —Cl, —Br, —I, —NO 2 , —N(R f ) 2 , —CN, —C(O)—N(R f ) 2 , —S(O)—N(R f ) 2 , —S(O) 2 —N(R f ) 2 , —O—R f , —S—R f , —O—C(O)—R f , —O—C(O)—O—R f , —C(O)—O—R f , —C(O)—O—R f , —C(O)—O—R f , —S(O)—R f
- each R f of Formula (I) is independently selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, and heterocyclyl, wherein any C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, carbocyclyl, heterocyclyl, halo, —NO 2 , —N(R g ) 2 , —CN, —C(O)—N(R g ) 2 , —S(O)—N(R g ) 2 , —S(O) 2 —N(R g ) 2 , —O—R g , —S—R g , —O—C(O)—R g , —C(O)—R g , —C(O)—O—R g
- each R g of Formula (I) is independently selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, carbocyclyl, and heterocyclyl, wherein each C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C 1-6 alkoxy, carbocyclyl, heterocyclyl, and C 1 -C 6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; or two R g are taken together with the nitrogen to which they are attached to form a heterocyclyl that is optionally substituted with one or more groups independently selected from oxo, halo and C 1-3 alkyl that is optionally substituted with one or more groups independently selected from oxo and
- each R h of Formula (I) is independently selected from hydrogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, and C 2-5 cycloalkyl, wherein each C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, and C 2-5 cycloalkyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C 1-3 alkoxy, and C 1 -C 3 alkyl that is optionally substituted with one or more groups independently selected from halo; and
- R 1 of Formula (II) is selected from C 6 -C 20 aryl, C 1 -C 20 heteroaryl, —(C 6 -C 20 aryl)-(C 1 -C 20 heteroaryl), and —(C 1 -C 20 heteroaryl)-(C 1 -C 20 heteroaryl), wherein each C 6 -C 20 aryl, C 1 -C 20 heteroaryl, —(C 6 -C 20 aryl)-(C 1 -C 20 heteroaryl) and —(C 1 -C 20 heteroaryl)-(C 1 -C 20 heteroaryl) is independently optionally substituted with one or more substituent groups independently selected from R c , oxo, —F, —Cl, —Br, —I, —NO 2 , —N(R a ) 2 , —CN, —C(O)—N(R a ) 2 , —S(O)—N(R a ) 2
- R 2 of Formula (II) is C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, 3-12 membered carbocycle, and 3-12 membered heterocycle, wherein each C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, 3-12 membered carbocycle, and 3-12 membered heterocycle of R 2 is optionally substituted with one or more groups R b ;
- R 3 of Formula (II) is C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, 3-5 membered carbocycle, 3-5 membered heterocycle, —C(O)—N(R e ) 2 , —S(O)—N(R e ) 2 , —S(O) 2 —N(R e ) 2 , —C(O)—R e , —C(O)—O—R e , —S(O)—R e , or —S(O) 2 —R e , wherein any C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, 3-5 membered carbocycle, and 3-5 membered heterocycle is optionally substituted with one or more substituent groups independently selected from —F, —Cl, —Br, —I, 3-5 membered carbocycle, —C(O)—N(R e
- each R a of Formula (II) is independently selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, and heterocyclyl, wherein each C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C 1-6 alkoxy, carbocyclyl, heterocyclyl, and C 1 -C 6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; or two R a are taken together with the nitrogen to which they are attached to form a heterocyclyl that is optionally substituted with one or more groups independently selected from oxo, halo and C 1-3 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo;
- each R b of Formula (II) is independently selected from oxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, —F, —Cl, —Br, —I, —NO 2 , —N(R c ) 2 , —CN, —C(O)—N(R c ) 2 , —S(O)—N(R c ) 2 , —S(O) 2 —N(R c ) 2 , —O—R c , —S—R c , —O—C(O)—R c , —O—C(O)—O—R c , —C(O)—O—R c , —C(O)—O—R c , —C(O)—O—R c , —S(O)—R
- each R c of Formula (II) is independently selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, and heterocyclyl, wherein any C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, carbocyclyl, heterocyclyl, halo, —NO 2 , —N(R d ) 2 , —CN, —C(O)—N(R d ) 2 , —S(O)—N(R d ) 2 , —S(O) 2 —N(R d ) 2 , —O—R d , —S—R d , —O—C(O)—R d , —C(O)—R d , —C(O)—O—R d
- each R d of Formula (II) is independently selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, carbocyclyl, and heterocyclyl, wherein each C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C 1-6 alkoxy, carbocyclyl, heterocyclyl, and C 1 -C 6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; or two R d are taken together with the nitrogen to which they are attached to form a heterocyclyl that is optionally substituted with one or more groups independently selected from oxo, halo and C 1-3 alkyl that is optionally substituted with one or more groups independently selected from oxo
- each R e of Formula (II) is independently selected from hydrogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, and C 2-5 cycloalkyl, wherein each C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, and C 2-5 cycloalkyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C 1-3 alkoxy, and C 1 -C 3 alkyl that is optionally substituted with one or more groups independently selected from halo; provided that R 1 is not unsubstituted phenyl, when R 2 is carboxymethyl or 2-carboxyethyl.
- Another aspect includes a compound of formula (I):
- R 1 is C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, 3-12 membered carbocycle, and 3-12 membered heterocycle, wherein each C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, 3-12 membered carbocycle, and 3-12 membered heterocycle of R 1 is optionally substituted with one or more groups R b ;
- R 2 is selected from C 6 -C 20 aryl, C 1 -C 20 heteroaryl, —(C 6 -C 20 aryl)-(C 1 -C 20 heteroaryl), —(C 1 -C 20 heteroaryl)-(C 6 -C 20 aryl), and —(C 1 -C 20 heteroaryl)-(C 1 -C 20 heteroaryl), wherein each C 6 -C 20 aryl, C 1 -C 20 heteroaryl, —(C 6 -C 20 aryl)-(C 1 -C 20 heteroaryl) and —(C 1 -C 20 heteroaryl)-(C 1 -C 20 heteroaryl) is independently optionally substituted with one or more substituent groups independently selected from R c , oxo, —F, —Cl, —Br, —I, —NO 2 , —N(R a ) 2 , —CN, —C(O)—N(R a
- R 3 is C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, 3-12 membered carbocycle, and 3-12 membered heterocycle, wherein each C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, 3-12 membered carbocycle, and 3-12 membered heterocycle of R 3 is optionally substituted with one or more groups R e ; or
- R 2 and R 3 taken together with the nitrogen to which they are attached form a 3-12 membered heterocycle that is optionally substituted with one or more groups R e ;
- R 4 is C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, 3-5 membered carbocycle, 3-5 membered heterocycle, —C(O)—N(R h ) 2 , —S(O)—N(R h ) 2 , —S(O) 2 —N(R h ) 2 , —C(O)—R h , —C(O)—O—R h , —S(O)—R h , or —S(O) 2 —R h , wherein any C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, 3-5 membered carbocycle, and 3-5 membered heterocycle is optionally substituted with one or more substituent groups independently selected from —
- each R a is independently selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, and heterocyclyl, wherein each C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C 1-6 alkoxy, carbocyclyl, heterocyclyl, and C 1 -C 6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; or two R a are taken together with the nitrogen to which they are attached to form a heterocyclyl that is optionally substituted with one or more groups independently selected from oxo, halo and C 1-3 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo;
- each R b is independently selected from oxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, —F, —Cl, —Br, —I, —NO 2 , —N(R c ) 2 , —CN, —C(O)—N(R c ) 2 , —S(O)—N(R c ) 2 , —S(O) 2 —N(R c ) 2 , —O—R c , —S—R c , —O—C(O)—R c , —O—C(O)—O—R c , —C(O)—O—R c , —C(O)—O—R c , —C(O)—O—R c , —S(O)—R c , —S
- each R c is independently selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, and heterocyclyl, wherein any C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, carbocyclyl, heterocyclyl, halo, —NO 2 , —N(R d ) 2 , —CN, —C(O)—N(R d ) 2 , —S(O)—N(R d ) 2 , —S(O) 2 —N(R d ) 2 , —O—R d , —S—R d , —O—C(O)—R d , —C(O)—R d , —C(O)—O—R d , —S(
- each R d is independently selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, carbocyclyl, and heterocyclyl, wherein each C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C 1-6 alkoxy, carbocyclyl, heterocyclyl, and C 1 -C 6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; or two R d are taken together with the nitrogen to which they are attached to form a heterocyclyl that is optionally substituted with one or more groups independently selected from oxo, halo and C 1-3 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo;
- each R e is independently selected from oxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, —F, —Cl, —Br, —I, —NO 2 , —N(R f ) 2 , —CN, —C(O)—N(R f ) 2 , —S(O)—N(R f ) 2 , —S(O) 2 —N(R f ) 2 , —O—R f , —S—R f , —O—C(O)—R f —O—C(O)—O—R f , —C(O)—R f , —C(O)—R f , —C(O)—O—R f , —S(O)—R f , —S(O) 2 —
- each R f is independently selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, and heterocyclyl, wherein any C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, carbocyclyl, heterocyclyl, halo, —NO 2 , —N(R g ) 2 , —CN, —C(O)—N(R g ) 2 , —S(O)—N(R g ) 2 , —S(O) 2 —N(R g ) 2 , —O—R g , —S—R g , —O—C(O)—R g , —C(O)—R g , —C(O)—O—R g , —S(
- each R g is independently selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, carbocyclyl, and heterocyclyl, wherein each C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C 1-6 alkoxy, carbocyclyl, heterocyclyl, and C 1 -C 6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; or two R g are taken together with the nitrogen to which they are attached to form a heterocyclyl that is optionally substituted with one or more groups independently selected from oxo, halo and C 1-3 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; and
- each R h is independently selected from hydrogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, and C 2-5 cycloalkyl, wherein each C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, and C 2-5 cycloalkyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C 1-3 alkoxy, and C 1 -C 3 alkyl that is optionally substituted with one or more groups independently selected from halo.
- Another aspect includes a compound of formula (II):
- R 1 is selected from C 6 -C 20 aryl, C 1 -C 20 heteroaryl, —(C 6 -C 20 aryl)-(C 1 -C 20 heteroaryl), and —(C 1 -C 20 heteroaryl)-(C 1 -C 20 heteroaryl), wherein each C 6 -C 20 aryl, C 1 -C 20 heteroaryl, —(C 6 -C 20 aryl)-(C 1 -C 20 heteroaryl) and —(C 1 -C 20 heteroaryl)-(C 1 -C 20 heteroaryl) is optionally substituted with one or more substituent groups independently selected from R c , oxo, —F, —Cl, —Br, —I, —NO 2 , —N(R a ) 2 , —CN, —C(O)—N(R a ) 2 , —S(O)—N(R a ) 2 , —S(O
- R 2 is C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, 3-12 membered carbocycle, and 3-12 membered heterocycle, wherein each C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, 3-12 membered carbocycle, and 3-12 membered heterocycle of R 2 is optionally substituted with one or more groups R b ;
- R 3 is C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, 3-5 membered carbocycle, 3-5 membered heterocycle, —C(O)—N(R e ) 2 , —S(O)—N(R e ) 2 , —S(O) 2 —N(R e ) 2 , —C(O)—R e , —C(O)—O—R e , —S(O)—R e , or —S(O) 2 —R e , wherein any C 1-4 -alkyl, C 2-4 alkenyl, C 2-4 alkynyl, 3-5 membered carbocycle, and 3-5 membered heterocycle is optionally substituted with one or more substituent groups independently selected from —F, —Cl, —Br, —I, 3-5 membered carbocycle, —C(O)—N(R e ) 2
- each R a is independently selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, and heterocyclyl, wherein each C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C 1-6 alkoxy, carbocyclyl, heterocyclyl, and C 1 -C 6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; or two R a are taken together with the nitrogen to which they are attached to form a heterocyclyl that is optionally substituted with one or more groups independently selected from oxo, halo and C 1-3 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo;
- each R b is independently selected from oxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, —F, —Cl, —Br, —I, —NO 2 , —N(R c ) 2 , —CN, —C(O)—N(R c ) 2 , —S(O)—N(R c ) 2 , —S(O) 2 —N(R c ) 2 , —O—R c , —S—R c , —O—C(O)—R c , —O—C(O)—O—R c , —C(O)—O—R c , —C(O)—O—R c , —C(O)—O—R c , —S(O)—R c , —S
- each R c is independently selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, and heterocyclyl, wherein any C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, carbocyclyl, heterocyclyl, halo, —NO 2 , —N(R d ) 2 , —CN, —C(O)—N(R d ) 2 , —S(O)—N(R d ) 2 , —S(O) 2 —N(R d ) 2 , —O—R d , —S—R d , —O—C(O)—R d , —C(O)—R d , —C(O)—O—R d , —S(
- each R d is independently selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, carbocyclyl, and heterocyclyl, wherein each C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C 1-6 alkoxy, carbocyclyl, heterocyclyl, and C 1 -C 6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; or two R d are taken together with the nitrogen to which they are attached to form a heterocyclyl that is optionally substituted with one or more groups independently selected from oxo, halo and C 1-3 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; and
- each R e is independently selected from hydrogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, and C 2-5 cycloalkyl, wherein each C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, and C 2-5 cycloalkyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C 1-3 alkoxy, and C 1 -C 3 alkyl that is optionally substituted with one or more groups independently selected from halo.
- compositions comprising a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant, carrier, or vehicle.
- Another aspect includes a method for treating a CBP and/or EP300-mediated disorder in an animal comprising administering a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof to the animal.
- Another aspect includes a method for treating a CBP and/or EP300-mediated disorder in an animal, wherein the disorder is cancer, comprising administering a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof to the animal.
- Another aspect includes a method for treating a CBP and/or EP300-mediated disorder in an animal, wherein the disorder is a fibrotic disease, comprising administering a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof to the animal.
- Another aspect includes a method for treating a CBP and/or EP300-mediated disorder in an animal, wherein the disorder is a fibrotic lung disease, comprising administering a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof to the animal.
- Another aspect includes a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof for use in medical therapy.
- Another aspect includes a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof for the prophylactic or therapeutic treatment of a CBP and/or EP300-mediated disorder.
- Another aspect includes the use of a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof to prepare a medicament for treating a CBP and/or EP300-mediated disorder in an animal (e.g. a mammal such as a human).
- an animal e.g. a mammal such as a human.
- Another aspect includes compounds for the study of CBP and/or EP300.
- Another aspect includes synthetic intermediates and synthetic processes disclosed herein that are useful for preparing a compound of formula (I) or formula (II) or a salt thereof.
- FIG. 1 Outline of protocol for assaying CBP/p300 SMIs for inhibition of profibrotic gene induction by TGF ⁇ .
- FIGS. 2A-E Gene expression as measured by qPCR in primary human fibroblasts treated with TGF ⁇ and ( FIG. 2A ) an inhibitor of TGF ⁇ receptor kinase activity or ( FIGS. 2B-E ) CBP/p300 inhibitors of Formula (I).
- Heat maps show TGF ⁇ induction of each gene in the presence of CBP/p300 inhibitor after normalization to induction in the absence of inhibitor. Duplicate treatments are represented as two rows for each inhibitor concentration.
- CBP/p300 inhibitors reduce TGF ⁇ -driven gene expression in a dose-dependent manner. Expression of Serpine1 is unchanged, indicating that TGF ⁇ signaling is intact.
- FIGS. 3A-B Expression as measured by qPCR of ( FIG. 3A ) ACTA2 or ( FIG. 3B ) COL3A1 in primary human fibroblasts treated with TGF ⁇ and CBP/p300 inhibitors of Formula (I).
- CBP/p300 inhibitors reduce TGF ⁇ -driven ACTA2 and COL3A1 expression in a dose-dependent manner.
- FIGS. 4A-E Gene expression as measured by qPCR in primary human fibroblasts treated with TGF ⁇ and ( FIG. 4A ) an inhibitor of TGF ⁇ receptor kinase activity or ( FIGS. 4B-E ) CBP/p300 inhibitors of Formula (II).
- Heat maps show TGF ⁇ induction of each gene in the presence of CBP/p300 inhibitor after normalization to induction in the absence of inhibitor. Duplicate treatments are represented as two rows for each inhibitor concentration.
- CBP/p300 inhibitors reduce TGF ⁇ -driven gene expression in a dose-dependent manner. Expression of Serpine1 is unchanged, indicating that TGF ⁇ signaling is intact.
- FIGS. 5A-B Expression as measured by qPCR of ( FIG. 5A ) ACTA2 or ( FIG. 5B ) COL3A1 in primary human fibroblasts treated with TGF ⁇ and CBP/p300 inhibitors of Formula (II).
- CBP/p300 inhibitors reduce TGF ⁇ -driven ACTA2 and COL3A1 expression in a dose-dependent manner.
- FIGS. 6A-E Gene expression as measured by qPCR in primary human fibroblasts treated with TGF ⁇ and ( FIG. 6A ) an inhibitor of TGF ⁇ receptor kinase activity or ( FIGS. 6B-E ) benzodiazepinone (“BZD”) series CBP/p300 inhibitors.
- Heat maps show TGF ⁇ induction of each gene in the presence of CBP/p300 inhibitor after normalization to induction in the absence of inhibitor. Duplicate treatments are represented as two rows for each inhibitor concentration.
- CBP/p300 inhibitors reduce TGF ⁇ -driven gene expression in a dose-dependent manner. Expression of Serpine1 is unchanged, indicating that TGF ⁇ signaling is intact.
- FIGS. 7A-B Expression as measured by qPCR of ( FIG. 7A ) ACTA2 or ( FIG. 7B ) COL3A1 in primary human fibroblasts treated with TGF ⁇ and BZD series CBP/p300 inhibitors.
- CBP/p300 inhibitors reduce TGF ⁇ -driven ACTA2 and COL3A1 expression in a dose-dependent manner.
- FIGS. 8A-D Gene expression as measured by qPCR in primary human fibroblasts treated with TGF ⁇ and ( FIG. 8A ) an inhibitor of TGF ⁇ receptor kinase activity or ( FIGS. 8B-D ) heterocyclic CBP/p300 inhibitors.
- Heat maps show TGF ⁇ induction of each gene in the presence of CBP/p300 inhibitor after normalization to induction in the absence of inhibitor. Duplicate treatments are represented as two rows for each inhibitor concentration.
- CBP/p300 inhibitors reduce TGF ⁇ -driven gene expression in a dose-dependent manner. Expression of Serpine1 is unchanged, indicating that TGF ⁇ signaling is intact.
- FIGS. 9A-B Expression as measured by qPCR of ( FIG. 9A ) ACTA2 or ( FIG. 9B ) COL3A1 in primary human fibroblasts treated with TGF ⁇ and heterocyclic CBP/p300 inhibitors.
- CBP/p300 inhibitors reduce TGF ⁇ -driven ACTA2 and COL3A1 expression in a dose-dependent manner.
- FIGS. 10A-C Gene expression as measured by qPCR in primary human fibroblasts treated with TGF ⁇ and ( FIG. 10A ) an inhibitor of TGF ⁇ receptor kinase activity or ( FIGS. 10B-C ) modified CBP/p300 inhibitors with decreased activity.
- Heat maps show TGF ⁇ induction of each gene in the presence of CBP/p300 inhibitor after normalization to induction in the absence of inhibitor. Duplicate treatments are represented as two rows for each inhibitor concentration. After modification of CBP/p300 inhibitors, the effect on TGF ⁇ -driven gene expression is either (B) eliminated or (C) reduced.
- FIGS. 11A-B Expression as measured by qPCR of ( FIG. 11A ) ACTA2 or ( FIG. 11B ) COL3A1 in primary human fibroblasts treated with TGF ⁇ and modified CBP/p300 inhibitors with decreased activity. The effect on TGF ⁇ -driven gene expression is reduced or eliminated.
- FIGS. 12A-B ( FIG. 12A ) Gene expression as measured by qPCR in the lung of mice treated with bleomycin to induce pulmonary fibrosis. Mice were treated with bleomycin plus vehicle or bleomycin plus the indicated dose of CBP/p300 inhibitor G0272 (compound of Formula II). Heat maps show expression of genes assayed, after normalization to GAPDH endogenous control, with each column representing one mouse. G0272 decreased the expression of fibrotic genes in the lung of mice treated with bleomycin to induce pulmonary fibrosis.
- FIG. 12 B Collagen synthesis as measured by mass spectrometry of deuterated hydroxyproline in the lung of mice treated with bleomycin to induce pulmonary fibrosis. Mice were treated with bleomycin plus vehicle or indicated dose of CBP/p300 inhibitor G0272. G0272 decreased collagen synthesis in the lung of mice treated with bleomycin to induce pulmonary fibrosis.
- FIGS. 13A-B Gene expression as measured by qPCR in the lung of mice treated with bleomycin to induce pulmonary fibrosis. Mice were treated with bleomycin plus vehicle or indicated dose of CBP/p300 inhibitor G5049 (compound of Formula (I)). Heat maps show expression of genes assayed, after normalization to GAPDH endogenous control, with each column representing one mouse. G5049 decreased the expression of fibrotic genes in mice treated with bleomycin to induce pulmonary fibrosis.
- FIG. 13B Collagen synthesis as measured by mass spectrometry of deuterated hydroxyproline in the lung of mice treated with bleomycin to induce pulmonary fibrosis. Mice were treated with bleomycin plus vehicle or indicated dose of CBP/p300 inhibitor G5049. G5049 decreased collagen synthesis in the lung of mice treated with bleomycin to induce pulmonary fibrosis.
- FIGS. 14A-B Gene expression as measured by qPCR in the lung of mice in decreased collagen synthesis in the lung of mice treated with bleomycin to induce pulmonary fibrosis. Mice were treated with bleomycin plus vehicle or indicated dose of CBP/p300 inhibitor G3486. Heat maps show expression of genes assayed, after normalization to GAPDH endogenous control, with each column representing one mouse. G3486 decreased the expression of fibrotic genes in the lung of mice treated with bleomycin to induce pulmonary fibrosis.
- FIG. 14B Collagen synthesis as measured by mass spectrometry of deuterated hydroxyproline in the lung of mice treated with bleomycin to induce pulmonary fibrosis. Mice were treated with bleomycin plus vehicle or indicated dose of CBP/p300 inhibitor G3486. G3486 decreased collagen synthesis in the lung of mice treated with bleomycin to induce pulmonary fibrosis.
- compounds of formula I or formula II include enantiomeric, diastereomeric and geometric (or conformational) isomeric forms of a given structure.
- R and S configurations for each asymmetric center, Z and E double bond isomers, Z and E conformational isomers, single stereochemical isomers, as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures are included.
- all tautomeric forms of structures depicted herein are included.
- structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms.
- compounds of formula I or formula II wherein the independent replacement or enrichment of one or more hydrogen by deuterium or tritium, carbon by 13 C— or 14 C carbon, nitrogen by a 15 N nitrogen, sulfur by a 33 S, 34 S or 36 S sulfur, oxygen by a 17 O or 18 O oxygen, or fluorine by a 18 F are included.
- Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents.
- Optically-enriched means that the mixture of enantiomers is made up of a significantly greater proportion of one enantiomer, and may be described by enantiomeric excess (ee %). In certain embodiments, the mixture of enantiomers is made up of at least about 90% by weight of a given enantiomer (about 90% ee).
- the mixture of enantiomers is made up of at least about 95%, 98% or 99% by weight of a given enantiomer (about 95%, 98% or 99% ee).
- Enantiomers and diastereomers may be isolated from racemic mixtures by any method known to those skilled in the art, including recrystallization from solvents in which one stereoisomer is more soluble than the other, chiral high pressure liquid chromatography (HPLC), supercritical fluid chromatography (SFC), the formation and crystallization of chiral salts, which are then separated by any of the above methods, or prepared by asymmetric syntheses and optionally further enriched.
- HPLC high pressure liquid chromatography
- SFC supercritical fluid chromatography
- heteroatom means any atom independently selected from an atom other than carbon or hydrogen, for example, one or more of oxygen, sulfur, nitrogen, phosphorus or silicon (including any oxidized form of nitrogen, sulfur, phosphorus or silicon; and the quaternized form of any nitrogen).
- halo and “halogen” as used herein refer to an atom selected from fluorine (fluoro, —F), chlorine (chloro, —Cl), bromine (bromo, —Br) and iodine (iodo, —I).
- unsaturated means that a moiety has one or more units of unsaturation.
- carbocyclyl used alone or as part of a larger moiety, refers to a saturated, partially unsaturated, or aromatic ring system having 3 to 20 carbon atoms.
- carbocyclyl includes 3 to 12 carbon atoms (C 3 -C 12 ).
- carbocyclyl includes C 3 -C 8 , C 3 -C 10 or C 5 -C 10 .
- carbocyclyl, as a monocycle includes C 3 -C 8 , C 3 -C 6 or C 5 -C 6 .
- carbocyclyl, as a bicycle includes C 7 -C 12 .
- carbocyclyl as a spiro system, includes C 5 -C 12 .
- monocyclic carbocyclyls include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, perdeuteriocyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, phenyl, and cyclododecyl; bicyclic carbocyclyls having 7 to 12 ring atoms include [4,3], [4,4], [4,5], [5,5], [5,6] or [6,6]
- carbocyclyl includes aryl ring systems as defined herein.
- carbocycyl also includes cycloalkyl rings (e.g. saturated or partially unsaturated mono-, bi-, or spiro-carbocycles).
- alkyl refers to a saturated linear or branched-chain hydrocarbon radical.
- the alkyl radical is one to eighteen carbon atoms (C 1 -C 18 ).
- the alkyl radical is C 0 -C 6 , C 0 -C 5 , C 0 -C 3 , C 1 -C 12 , C 1 -C 10 , C 1 -C 8 , C 1 -C 6 , C 1 -C 5 , C 1 -C 4 or C 1 -C 3 .
- C 0 alkyl refers to a bond.
- alkyl groups include methyl (Me, —CH 3 ), ethyl (Et, —CH 2 CH 3 ), 1-propyl (n-Pr, n-propyl, —CH 2 CH 2 CH 3 ), 2-propyl (i-Pr, i-propyl, —CH(CH 3 ) 2 ), 1-butyl (n-Bu, n-butyl, —CH 2 CH 2 CH 2 CH 3 ), 2-methyl-1-propyl (i-Bu, i-butyl, —CH 2 CH(CH 3 ) 2 ), 2-butyl (s-Bu, s-butyl, —CH(CH 3 )CH 2 CH 3 ), 2-methyl-2-propyl (t-Bu, t-butyl, —C(CH 3 ) 3 ), 1-pentyl (n-pentyl, —CH 2 CH 2 CH 2 CH 3 ), 2-pentyl (—CH(CH 3 )CH 2 CH 2 CH 2 CH
- alkenyl denotes a linear or branched-chain hydrocarbon radical with at least one carbon-carbon double bond.
- An alkenyl includes radicals having “cis” and “trans” orientations, or alternatively, “E” and “Z” orientations.
- the alkenyl radical is two to eighteen carbon atoms (C 2 -C 18 ).
- the alkenyl radical is C 2 -C 12 , C 2 -C 10 , C 2 -C 8 , C 2 -C 6 or C 2 -C 3 .
- Examples include, but are not limited to, ethenyl or vinyl (—CH ⁇ CH 2 ), prop-1-enyl (—CH ⁇ CHCH 3 ), prop-2-enyl (—CH 2 CH ⁇ CH 2 ), 2-methylprop-1-enyl, but-1-enyl, but-2-enyl, but-3-enyl, buta-1,3-dienyl, 2-methylbuta-1,3-diene, hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl and hexa-1,3-dienyl.
- alkynyl refers to a linear or branched hydrocarbon radical with at least one carbon-carbon triple bond.
- the alkynyl radical is two to eighteen carbon atoms (C 2 -C 18 ).
- the alkynyl radical is C 2 -C 12 , C 2 -C 10 , C 2 -C 8 , C 2 -C 6 or C 2 -C 3 .
- Examples include, but are not limited to, ethynyl (—C ⁇ CH), prop-1-ynyl (—C ⁇ CCH 3 ), prop-2-ynyl (propargyl, —CH 2 C ⁇ CH), but-1-ynyl, but-2-ynyl and but-3-ynyl.
- alkoxy refers to a linear or branched radical represented by the formula —OR in which R is alkyl, alkenyl, alkynyl or carbocycyl. Alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, and cyclopropoxy.
- haloalkyl refers to an alkyl as defined herein that is substituted with one or more (e.g. 1, 2, 3, or 4) halo groups.
- aryl used alone or as part of a larger moiety as in “arylalkyl”, “arylalkoxy”, or “aryloxyalkyl”, refers to a monocyclic, bicyclic or tricyclic, carbon ring system, that includes fused rings, wherein at least one ring in the system is aromatic.
- aryl may be used interchangeably with the term “aryl ring”.
- aryl includes groups having 6-20 carbon atoms (C 6 -C 20 aryl).
- aryl includes groups having 6-10 carbon atoms (C 6 -C 10 aryl).
- aryl groups include phenyl, naphthyl, anthracyl, biphenyl, phenanthrenyl, naphthacenyl, 1,2,3,4-tetrahydronaphthalenyl, 1H-indenyl, 2,3-dihydro-1H-indenyl, and the like, which may be substituted or independently substituted by one or more substituents described herein.
- a particular aryl is phenyl.
- aryl includes an aryl ring fused to one or more carbocyclic rings, such as indanyl, dihydrophenanthryl, or tetrahydronaphthyl, and the like, where the radical or point of attachment is on an aromatic ring.
- heteroaryl used alone or as part of a larger moiety, e.g., “heteroarylalkyl”, or “heteroarylalkoxy”, refers to a monocyclic, bicyclic or tricyclic ring system having 5 to 14 ring atoms, wherein at least one ring is aromatic and contains at least one heteroatom.
- heteroaryl includes 4-6 membered monocyclic aromatic groups where one or more ring atoms is nitrogen, sulfur or oxygen that is independently optionally substituted.
- heteroaryl includes 5-6 membered monocyclic aromatic groups where one or more ring atoms is nitrogen, sulfur or oxygen that is independently optionally substituted.
- the heteroaryl group is a C 1 -C 20 heteroaryl group, where the heteroaryl ring contains 1-20 carbon atoms and the remaining ring atoms include one or more nitrogen, sulfur, or oxygen atoms.
- Example heteroaryl groups include thienyl, furyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, thiatriazolyl, oxatriazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazinyl, tetrazinyl, tetrazolo[1,5-b]pyridazinyl, imidazol[1,2-a]pyrimidinyl, purinyl, benzoxazolyl, benzofuryl
- heteroaryl also includes groups in which a heteroaryl is fused to one or more aryl, carbocyclyl, or heterocyclyl rings, where the radical or point of attachment is on the heteroaryl ring.
- Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H
- heterocyclyl or “heterocycle” refers to a “carbocyclyl” as defined herein, wherein one or more (e.g. 1, 2, 3, or 4) carbon atoms have been replaced with a heteroatom (e.g. O, N, or S).
- a heterocyclyl or heterocycle refers to a saturated ring system, such as a 3 to 12 membered saturated heterocyclyl ring system.
- a heterocyclyl or heterocycle refers to a heteroaryl ring system, such as a 5 to 14 membered heteroaryl ring system.
- a heterocyclyl or heterocycle can optionally be substituted with one or more substituents independently selected from those defined herein.
- heterocyclyl or heterocycle includes 3-12 ring atoms and includes monocycles, bicycles, tricycles and spiro ring systems, wherein the ring atoms are carbon, and one to five ring atoms is a heteroatom selected from nitrogen, sulfur or oxygen, which is independently optionally substituted by one or more groups.
- heterocyclyl or heterocycle includes 1 to 4 heteroatoms.
- heterocyclyl or heterocycle includes 3- to 7-membered monocycles having one or more heteroatoms selected from nitrogen, sulfur or oxygen.
- heterocyclyl or heterocycle includes 4- to 6-membered monocycles having one or more heteroatoms selected from nitrogen, sulfur or oxygen.
- heterocyclyl or heterocycle includes 3-membered monocycles.
- heterocyclyl or heterocycle includes 4-membered monocycles.
- heterocyclyl or heterocycle includes 5-6 membered monocycles.
- the heterocyclyl or heterocycle group includes 0 to 3 double bonds. Any nitrogen or sulfur heteroatom may optionally be oxidized (e.g. NO, SO, SO 2 ), and any nitrogen heteroatom may optionally be quaternized (e.g. [NR 4 ] + Cl ⁇ , [NR 4 ] + OH ⁇ ).
- Example heterocyclyls or heterocycles include oxiranyl, aziridinyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, 1,2-dithietanyl, 1,3-dithietanyl, pyrrolidinyl, dihydro-1H-pyrrolyl, dihydrofuranyl, tetrahydrofuranyl, dihydrothienyl, tetrahydrothienyl, imidazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, dihydropyranyl, tetrahydropyranyl, hexahydrothiopyranyl, hexahydropyrimidinyl, oxazinanyl, thiazinanyl, thioxanyl, homopiperazinyl, homopiperidin
- Examples of 5-membered heterocyclyls or heterocycles containing a sulfur or oxygen atom and one to three nitrogen atoms are thiazolyl, including thiazol-2-yl and thiazol-2-yl N-oxide, thiadiazolyl, including 1,3,4-thiadiazol-5-yl and 1,2,4-thiadiazol-5-yl, oxazolyl, for example oxazol-2-yl, and oxadiazolyl, such as 1,3,4-oxadiazol-5-yl, and 1,2,4-oxadiazol-5-yl.
- Example 5-membered ring heterocyclyls or heterocycles containing 2 to 4 nitrogen atoms include imidazolyl, such as imidazol-2-yl; triazolyl, such as 1,3,4-triazol-5-yl; 1,2,3-triazol-5-yl, 1,2,4-triazol-5-yl, and tetrazolyl, such as 1H-tetrazol-5-yl.
- Example benzo-fused 5-membered heterocyclyls or heterocycles are benzoxazol-2-yl, benzthiazol-2-yl and benzimidazol-2-yl.
- Example 6-membered heterocyclyls or heterocycles contain one to three nitrogen atoms and optionally a sulfur or oxygen atom, for example pyridyl, such as pyrid-2-yl, pyrid-3-yl, and pyrid-4-yl; pyrimidyl, such as pyrimid-2-yl and pyrimid-4-yl; triazinyl, such as 1,3,4-triazin-2-yl and 1,3,5-triazin-4-yl; pyridazinyl, in particular pyridazin-3-yl, and pyrazinyl.
- pyridyl such as pyrid-2-yl, pyrid-3-yl, and pyrid-4-yl
- pyrimidyl such as pyrimid-2-yl and pyrimid-4-yl
- triazinyl such as 1,3,4-triazin-2-yl and 1,3,5-triazin-4
- pyridine N-oxides and pyridazine N-oxides and the pyridyl, pyrimid-2-yl, pyrimid-4-yl, pyridazinyl and the 1,3,4-triazin-2-yl groups are other example heterocyclyl groups.
- heterocyclyl or “heterocycle” also includes groups in which a heterocyclyl is fused to one or more aryl, carbocyclyl, or heterocyclyl rings, where the radical or point of attachment is on the heterocyclyl ring.
- Nonlimiting examples include tetrahydroquinolinyl and tetrahydroisoquinolinyl.
- partially unsaturated refers to a ring moiety that includes at least one double or triple bond between ring atoms but the ring moiety is not aromatic.
- an inhibitor refers to a compound that binds to and inhibits the bromodomain of CBP and/or EP300 with measurable affinity and activity.
- an inhibitor has an IC 50 or binding constant of less about 20 ⁇ M, less than about 1 ⁇ M, less than about 500 nM, less than about 100 nM, or less than about 10 nM.
- measurable affinity and “measurably inhibit,” as used herein, refer to a measurable reduction in activity (e.g., reduction in recognition of lysine acetyl recognition of chromatin) of the bromodomain of CBP and/or EP300 between: (i) a sample comprising a compound of formula I or formula II or composition thereof and such bromodomain, and (ii) an equivalent sample comprising such bromodomain, in the absence of said compound, or composition thereof.
- “Pharmaceutically acceptable salts” include both acid and base addition salts. It is to be understood that when a compound or Example herein is shown as a specific salt, the corresponding free-base, as well as other salts of the corresponding free-base (including pharmaceutically acceptable salts of the corresponding free-base) are contemplated.
- “Pharmaceutically acceptable acid addition salt” refers to those salts which retain the biological effectiveness and properties of the free bases and which are not biologically or otherwise undesirable, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid and the like, and organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic classes of organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid, maloneic acid, succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilic acid, benzoic acid, cinnamic acid, mandelic acid, embonic acid, phenylacetic acid, methanes
- “Pharmaceutically acceptable base addition salts” include those derived from inorganic bases such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Particularly base addition salts are the ammonium, potassium, sodium, calcium and magnesium salts.
- Salts derived from pharmaceutically acceptable organic nontoxic bases includes salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, tromethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperizine, piperidine, N-ethylpiperidine, polyamine resins and the like.
- Particular organic non-toxic bases are isopropylamine, diethylamine, ethanolamine, tromethamine, dicyclohexylamine, choline, and caffeine.
- tautomer or “tautomeric form” refers to structural isomers of different energies which are interconvertible via a low energy barrier.
- proton tautomers also known as prototropic tautomers
- Valence tautomers include interconversions by reorganization of some of the bonding electrons.
- a “solvate” refers to an association or complex of one or more solvent molecules and a compound of the present invention.
- solvents include water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid and ethanolamine.
- hydrate refers to the complex where the solvent molecule is water.
- “Therapeutically effective amount” refers to an amount of a compound of the present invention that (i) treats the particular disease, condition or disorder, (ii) attenuates, ameliorates or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) delays the onset of one or more symptoms of the particular disease, condition or disorder described herein.
- the therapeutically effective amount of the drug may reduce the number of cancer cells; reduce the tumor size; inhibit (i.e., slow to some extent and preferably stop) cancer cell infiltration into peripheral organs; inhibit (i.e., slow to some extent and preferably stop) tumor metastasis; inhibit, to some extent, tumor growth; and/or relieve to some extent one or more of the symptoms associated with the cancer.
- efficacy can, for example, be measured by assessing the time to disease progression (TTP) and/or determining the response rate (RR).
- TTP time to disease progression
- RR response rate
- the therapeutic effective amount is an amount sufficient to decrease or alleviate an allergic disorder, the symptoms of an autoimmune and/or inflammatory disease, or the symptoms of an acute inflammatory reaction (e.g. asthma).
- Treatment refers to clinical intervention in an attempt to alter the natural course of the individual or cell being treated, and can be performed either for prophylaxis or during the course of clinical pathology. Desirable effects of treatment include one or more of preventing recurrence of disease, alleviation of symptoms, diminishment of any direct or indirect pathological consequences of the disease, stabilized (i.e., not worsening) state of disease, preventing metastasis, decreasing the rate of disease progression, amelioration or palliation of the disease state, prolonging survival as compared to expected survival if not receiving treatment and remission or improved prognosis.
- a compound of formula I or formula II is used to delay development of a disease or disorder or to slow the progression of a disease or disorder.
- Those individuals in need of treatment include those already with the condition or disorder as well as those prone to have the condition or disorder, (for example, through a genetic mutation or abberent expression of a gene or protein).
- CBP/EP300 bromodomain inhibitor or “CBP and/or EP300 bromodomain inhibitor” refers to a compound that binds to the CBP bromodomain and/or EP300 bromodomain and inhibits and/or reduces a biological activity of CBP and/or EP300.
- CBP/EP300 bromodomain inhibitor binds to the CBP and/or EP300 primarily (e.g., solely) through contacts and/or interactions with the CBP bromodomain and/or EP300 bromodomain.
- CBP/EP300 bromodomain inhibitor binds to the CBP and/or EP300 through contacts and/or interactions with the CBP bromodomain and/or EP300 bromodomain as well as additional CBP and/or EP300 residues and/or domains.
- CBP/EP300 bromodomain inhibitor substantially or completely inhibits the biological activity of the CBP and/or EP300.
- the biological activity is binding of the bromodomain of CBP and/or EP300 to chromatin (e.g., histones associated with DNA) and/or another acetylated protein.
- the CBP/EP300 bromodomain inhibitor blocks CBP/EP300 activity so as to restore a functional response by T-cells (e.g., proliferation, cytokine production, target cell killing) from a dysfunctional state to antigen stimulation.
- the CBP/EP300 bromodomain inhibitor binds to and inhibits CBP bromodomain.
- the CBP/EP300 bromodomain inhibitor binds to and inhibits EP300 bromodomain.
- a or “an” means one or more, unless clearly indicated otherwise.
- another means at least a second or more.
- R 1 is C 1-12 alkyl or 3-12 membered heterocycle, wherein each C 1-12 alkyl and 3-12 membered heterocycle of R 1 is optionally substituted with one or more groups R b .
- R 1 is methyl or a 4-6 membered heterocycle, wherein each methyl and 4-6 membered heterocycle of R 1 is optionally substituted with one or more groups R b .
- R 1 is methyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dioxothiolanyl, piperidyl, or pyrrolidinyl, wherein each methyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dioxothiolanyl, piperidyl, or pyrrolidinyl of R 1 is optionally substituted with one or more groups R b .
- R 1 is methyl or cyclopropylmethyl.
- R 1 is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dioxothiolanyl, piperidyl, or pyrrolidinyl, and each R b is independently selected from methyl, acetyl, and oxo.
- R 1 is cyclohexyl, aryl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dioxothiolanyl, dioxothianyl, piperidyl, pyrrolidinyl, pyridyl, or oxepanyl, and each R b is independently selected from oxo, C 1-6 alkyl, —OR c , —C(O)—R c , oxetanyl, —S(O) 2 —R c , and —CH 2 CN.
- R 1 is selected from the group consisting of:
- R 1 is:
- R 2 is C 6 -C 20 aryl optionally substituted with one or more substituent groups independently selected from R c
- R 3 is C 1-12 alkyl or 3-12 membered carbocycle, wherein each C 1-12 alkyl and 3-12 membered carbocycle of R 3 is optionally substituted with one or more groups R e .
- R 2 is phenyl optionally substituted with one or more substituent groups independently selected from R c
- R 3 is methyl or phenyl, wherein each methyl and phenyl of R 3 is optionally substituted with one or more groups R e .
- R c is a 5-membered heterocyclyl optionally substituted with methyl; and R 3 is benzyl, methyl, cyanomethyl, or phenyl.
- R c is pyrazolyl optionally substituted with methyl; and R 3 is benzyl, methyl, cyanomethyl, or phenyl.
- R 2 and R 3 taken together with the nitrogen to which they are attached form a 3-12 membered heterocycle that is optionally substituted with one or more groups R e .
- R 2 and R 3 taken together with the nitrogen to which they are attached form a bicyclic heterocycle that is optionally substituted with one or more groups R e .
- R 2 and R 3 taken together with the nitrogen to which they are attached form a 9-12 membered bicyclic heterocycle that is optionally substituted with one or more groups R e .
- R 2 and R 3 taken together with the nitrogen to which they are attached form a 9- or 10-membered bicyclic heterocycle that is optionally substituted with one or more groups R e .
- R 2 and R 3 taken together with the nitrogen to which they are attached form a 9- or 10-membered bicyclic heterocycle that is optionally substituted with one or more groups R e ; and wherein the 9- or 10-membered bicyclic heterocycle comprises at least one aromatic ring.
- the at least one aromatic ring is a benzo ring.
- —NR 2 R 3 taken together is selected from the group consisting of:
- each —NR 2 R 3 is optionally substituted with one or more groups R e .
- —NR 2 R 3 taken together is selected from the group consisting of:
- R 3 is C 1-12 alkyl or 3-12 membered carbocycle, wherein each C 1-12 alkyl and 3-12 membered carbocycle of R 3 is optionally substituted with one or more groups R e .
- R 3 is methyl or phenyl, wherein each methyl and phenyl of R 3 is optionally substituted with one or more groups R e .
- R 3 is benzyl, methyl, cyanomethyl, or phenyl.
- R 4 is 3-5 membered heterocycle, —C(O)—N(R h ) 2 , —C(O)—R h , —C(O)—O—R h , or —S(O) 2 —R h , wherein any 3-5 membered heterocycle is optionally substituted with one or more substituent groups independently selected from —F, —Cl, —Br, —I, 3-5 membered carbocycle, —C(O)—N(R h ) 2 , —S(O)—N(R h ) 2 , —S(O) 2 —N(R h ) 2 , —O—R h , —S—R h , —O—C(O)—R h , —O—C(O)—O—R h , —C(O)—R h , —C(O)—R h , —C(O)—O
- R h is independently selected from hydrogen, C 1-4 alkyl, and C 2-5 cycloalkyl, wherein each C 1-4 alkyl, and C 2-5 cycloalkyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C 1-3 alkoxy, and C 1 -C 3 alkyl that is optionally substituted with one or more groups independently selected from halo.
- R 4 is acetyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, methoxycarbonyl, propanoyl, cyclopropylcarbonyl, methylsulfonyl, butanoyl, difluoroacetyl, thiadiazole or isoxazole.
- R 4 is substituted or unsubstituted acetyl, propionyl, butyryl, cyclopropylcarbonyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, methoxycarbonyl, methylsulfonyl, difluoroacetyl, thiadiazole, methylthiadiazole, oxadiazole, methyloxadiazole, or isoxazole.
- R 4 is selected from the group consisting of:
- R 1 is methyl or a 4-6 membered heterocycle, wherein each methyl and 4-6 membered heterocycle of R 1 is optionally substituted with one or more groups R b ;
- R 2 is phenyl optionally substituted with one or more substituent groups independently selected from R c ;
- R 3 is methyl or phenyl, wherein each methyl and phenyl of R 3 is optionally substituted with one or more groups R e .
- R 1 is methyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dioxothiolanyl, piperidyl, or pyrrolidinyl, wherein each methyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dioxothiolanyl, piperidyl, or pyrrolidinyl of R 1 is optionally substituted with one or more groups R b
- R 2 is phenyl optionally substituted with one or more substituent groups independently selected from R c ;
- R 3 is methyl or phenyl, wherein each methyl and phenyl of R 3 is optionally substituted with one or more groups R e .
- R 1 is methyl or a 4-6 membered heterocycle, wherein each methyl and 4-6 membered heterocycle of R 1 is optionally substituted with one or more groups R b ;
- R 2 and R 3 taken together with the nitrogen to which they are attached form a 9- or 10-membered bicyclic heterocycle that is optionally substituted with one or more groups R e .
- R 1 is tetrahydrofuranyl, tetrahydropyranyl, dioxothiolanyl, piperidyl, or pyrrolidinyl, wherein each tetrahydrofuranyl, tetrahydropyranyl, dioxothiolanyl, piperidyl, or pyrrolidinyl of R 1 is optionally substituted with one or more groups R b ; and
- R 2 and R 3 taken together with the nitrogen to which they are attached form a 9- or 10-membered bicyclic heterocycle that is optionally substituted with one or more groups R e .
- R 1 is methyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dioxothiolanyl, piperidyl, or pyrrolidinyl, wherein each methyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dioxothiolanyl, piperidyl, or pyrrolidinyl of R 1 is optionally substituted with one or more groups R b ; and —NR 2 R 3 taken together is selected from the group consisting of:
- R 1 is methyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dioxothiolanyl, piperidyl, or pyrrolidinyl, wherein each methyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dioxothiolanyl, piperidyl, or pyrrolidinyl of R 1 is optionally substituted with one or more groups R b
- R 2 is phenyl optionally substituted with one or more substituent groups independently selected from R c ;
- R 3 is methyl or phenyl, wherein each methyl and phenyl of R 3 is optionally substituted with one or more groups R e ;
- R 4 is acetyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, methoxycarbonyl, propanoyl, cyclopropylcarbonyl, methylsulfonyl, butanoyl, difluoroacetyl, thiadiazole or isoxazole.
- R 1 is methyl or a 4-6 membered heterocycle, wherein each methyl and 4-6 membered heterocycle of R 1 is optionally substituted with one or more groups R b ;
- R 2 and R 3 taken together with the nitrogen to which they are attached form a 9- or 10-membered bicyclic heterocycle that is optionally substituted with one or more groups R e ;
- R 4 is acetyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, methoxycarbonyl, propanoyl, cyclopropylcarbonyl, methylsulfonyl, butanoyl, difluoroacetyl, thiadiazole or isoxazole.
- R 1 is methyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dioxothiolanyl, piperidyl, or pyrrolidinyl, wherein each methyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dioxothiolanyl, piperidyl, or pyrrolidinyl of R 1 is optionally substituted with one or more groups R b ;
- R 2 and R 3 taken together with the nitrogen to which they are attached form a 9- or 10-membered bicyclic heterocycle that is optionally substituted with one or more groups R e ;
- R 4 is acetyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, methoxycarbonyl, propanoyl, cyclopropylcarbonyl, methylsulfonyl, butanoyl, difluoroacetyl, thiadiazole or isoxazole.
- R 1 is methyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dioxothiolanyl, piperidyl, or pyrrolidinyl, wherein each methyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dioxothiolanyl, piperidyl, or pyrrolidinyl of R 1 is optionally substituted with one or more groups R b ;
- NR 2 R 3 taken together is selected from the group consisting of:
- R 4 is acetyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, methoxycarbonyl, propanoyl, cyclopropylcarbonyl, methylsulfonyl, butanoyl, difluoroacetyl, thiadiazole or isoxazole.
- the compound of Formula (I) is selected from the group consisting of:
- the compound of Formula (I) is a compound as described in the Examples herein, or a freebase or salt thereof.
- any of the embodiments described for the compound of Formula (I) may be combined with any other embodiment described for the compound of Formula (I).
- R 1 is not unsubstituted phenyl, when R 2 is carboxymethyl or 2-carboxyethyl.
- R 1 is selected from C 6 -C 20 aryl, C 1 -C 20 heteroaryl, —(C 6 -C 20 aryl)-(C 1 -C 20 heteroaryl), and —(C 1 -C 20 heteroaryl)-(C 1 -C 20 heteroaryl), wherein each C 6 -C 20 aryl, C 1 -C 20 heteroaryl, —(C 6 -C 20 aryl)-(C 1 -C 20 heteroaryl) and —(C 1 -C 20 heteroaryl)-(C 1 -C 20 heteroaryl) is optionally substituted with one or more substituent groups independently selected from R c , oxo, —F, —Cl, —Br, —N(R a ) 2 , —CN, —C(O)—N(R a ) 2 , —O—R a , —C(O)—R a ,
- R 1 is selected from —(C 6 -C 20 aryl)-(C 1 -C 20 heteroaryl) and —(C 1 -C 20 heteroaryl)-(C 1 -C 20 heteroaryl), wherein each —(C 6 -C 20 aryl)-(C 1 -C 20 heteroaryl) and —(C 1 -C 20 heteroaryl)-(C 1 -C 20 heteroaryl) is optionally substituted with one or more substituent groups independently selected from R c , oxo, —F, —Cl, —Br, —N(R a ) 2 , —CN, —C(O)—N(R a ) 2 , —O—R a , —C(O)—R a , —N(R a )—S(O)—R a , and —S(O) 2 —R a .
- R 1 is selected from C 6 -C 20 aryl and C 1 -C 20 heteroaryl, wherein each C 6 -C 20 aryl and C 1 -C 20 heteroaryl, is optionally substituted with one or more substituent groups independently selected from R c , oxo, —F, —Cl, —Br, —N(R a ) 2 , —CN, —C(O)—N(R a ) 2 , —O—R a , —C(O)—R a , —N(R a )—S(O)—R a , and —S(O) 2 —R a .
- R 1 is selected from —(C 6 -C 20 aryl)-(C 1 -C 20 heteroaryl), and —(C 1 -C 20 heteroaryl)-(C 1 -C 20 heteroaryl), wherein each —(C 6 -C 20 aryl)-(C 1 -C 20 heteroaryl) and —(C 1 -C 20 heteroaryl)-(C 1 -C 20 heteroaryl) is optionally substituted with one or more substituent groups independently selected from R c , oxo, —F, —Cl, —Br, —I, —NO 2 , —N(R a ) 2 , —CN, —C(O)—N(R a ) 2 , —S(O)—N(R a ) 2 , —S(O) 2 —N(R a ) 2 , —O—R a , —S—R a , —S—R a
- R 1 is —(C 6 -C 20 aryl)-(C 1 -C 20 heteroaryl), wherein —(C 6 -C 20 aryl)-(C 1 -C 20 heteroaryl) is optionally substituted with one or more substituent groups independently selected from R c , oxo, —F, —Cl, —Br, —I, —NO 2 , —N(R a ) 2 , —CN, —C(O)—N(R a ) 2 , —S(O)—N(R a ) 2 , —S(O) 2 —N(R a ) 2 , —O—R a , —S—R a , —O—C(O)—R a , —O—C(O)—O—R a , —O—C(O)—O—R a , —C(O)—R a , —C(O
- R 1 is —(C 1 -C 20 heteroaryl)-(C 1 -C 20 heteroaryl), wherein —(C 1 -C 20 heteroaryl)-(C 1 -C 20 heteroaryl) is optionally substituted with one or more substituent groups independently selected from R c , oxo, —F, —Cl, —Br, —I, —NO 2 , —N(R a ) 2 , —CN, —C(O)—N(R a ) 2 , —S(O)—N(R a ) 2 , —S(O) 2 —N(R a ) 2 , —O—R a , —S—R a , —O—C(O)—R a , —O—C(O)—O—R a , —O—C(O)—O—R a , —C(O)—R a , —C(O
- each R b is independently selected from oxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, —F, —Cl, —Br, —I, —NO 2 , —N(R c ) 2 , —CN, —C(O)—N(R c ) 2 , —S(O)—N(R c ) 2 , —S(O) 2 —N(R c ) 2 , —O—R c , —S—R c , —O—C(O)—R c , —O—C(O)—O—R c , —C(O)—R c , —S(O)—R c , —S(O) 2 —R c , —O—C(O) 2 —R c , —S
- each R c is independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, and heterocyclyl.
- each R a is independently selected from hydrogen, C 1-6 alkyl, carbocyclyl, and heterocyclyl, wherein each C 1-6 alkyl, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from halo, C 1-6 alkoxy, and C 1 -C 6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; or two R a are taken together with the nitrogen to which they are attached to form a heterocyclyl that is optionally substituted with one or more groups independently selected from oxo, halo and C 1-3 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo;
- each R b is independently selected from C 1-6 alkyl, carbocyclyl, heterocyclyl, —CN, —C(O)—N(R c ) 2 , —O—R c , —C(O)—O—R c , and —S(O) 2 —R c , wherein any C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, and heterocyclyl, is optionally substituted with one or more groups independently selected from halo and C 1-6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo.
- each R c is independently selected from hydrogen, C 1-6 alkyl, and carbocyclyl, wherein any C 1-6 alkyl and carbocyclyl is optionally substituted with one or more groups independently selected from halo, —N(R d ) 2 , —CN, —C(O)—N(R d ) 2 , —O—R d , —S(O) 2 —R d , —N(R d )—C(O)—R d , —N(R d )—S(O) 2 —R d , and C 1-6 alkyl, which carbocyclyl and C 1-6 alkyl are optionally substituted with one or more groups independently selected from halo and —O—R d .
- each R d is independently selected from hydrogen and C 1-6 alkyl, wherein each C 1-6 alkyl is optionally substituted with one or more groups independently selected from halo and C 1-6 alkoxy; or two R d are taken together with the nitrogen to which they are attached to form a heterocyclyl that is optionally substituted with one or more groups independently selected from oxo, halo and C 1-3 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo.
- R 1 is selected from aryl that is optionally substituted with one or more substituent groups independently selected from R c , —F, —Cl, —Br, —I, —NO 2 , —N(R a ) 2 , —CN, —C(O)—N(R a ) 2 , —S(O)—N(R a ) 2 , —S(O) 2 —N(R a ) 2 , —O—R a , —S—R a , —O—C(O)—R a , —O—C(O)—O—R a , —C(O)—O—R a , —C(O)—O—R a , —S(O)—R a , —S(O) 2 —R a , —O—C(O)—N(R a ) 2 , —O—R c , —
- R 1 is selected from heteroaryl that is optionally substituted with one or more substituent groups independently selected from R c , —F, —Cl, —Br, —I, —NO 2 , —N(R a ) 2 , —CN, —C(O)—N(R a ) 2 , —S(O)—N(R a ) 2 , —S(O) 2 —N(R a ) 2 , —O—R a , —S—R a , —O—C(O)—R a , —O—C(O)—O—R a , —C(O)—R a , —C(O)—O—R a , —S(O)—R a , —S(O) 2 —R a , —O—C(O)—N(R a ) 2 , —O—R c , —F,
- R 1 is phenyl that is optionally substituted with one or more substituent groups independently selected from R c , —F, —Cl, —Br, —I, —NO 2 , —N(R a ) 2 , —CN, —C(O)—N(R a ) 2 , —S(O)—N(R a ) 2 , —S(O) 2 —N(R a ) 2 , —O—R a , —S—R a , —O—C(O)—R a , —O—C(O)—O—R a , —C(O)—R a , —C(O)—O—R a , —S(O)—R a , —S(O) 2 —R a , —O—C(O)—N(R a ) 2 , —N
- R 1 is selected from:
- R 1 is phenyl-pyrazolyl, pyrazolyl, phenyl-triazolyl, indazolyl, phenyl-oxazolyl, phenyl, pyridyl-pyrazolyl, tetralinyl, pyridyl, 3,4-dihydroisoquinolin-1-one, phenyl-phenyl, phenyl-pyridyl, phenyl-isoxazolyl, phenyl-cyclohexenyl, phenyl-cyclohexyl, phenyl-thiazolyl, and phenyl-pyrimidinyl, wherein each phenyl, pyrazolyl, triazolyl, indazolyl, oxazolyl, pyridyl, tetralinyl, 3,4-dihydroisoquinolin-1-one, isoxazolyl,
- R 2 is C 1-12 alkyl, C 2-12 alkenyl, 3-12 membered carbocycle, or 3-12 membered heterocycle, wherein each C 1-12 alkyl, C 2-12 alkenyl, 3-12 membered carbocycle, and 3-12 membered heterocycle of R 2 is optionally substituted with one or more groups R b .
- R 2 is C 1-6 alkyl, C 2-6 alkenyl, 3-6 membered carbocycle, or 3-6 membered heterocycle, wherein each C 1-6 alkyl, C 2-6 alkenyl, 3-6 membered carbocycle, and 3-6 membered heterocycle of R 2 is optionally substituted with one or more groups R b .
- R 2 is methyl, ethyl, isopropyl, cyclopropylmethyl, 2-methoxyethyl, benzyl, N-methylacetamide, 2-pyridylmethyl, 3-pyridylmethyl, N-ethylacetamide, 4-pyridylmethyl, cyclopropyl, 1-phenylethyl, oxazol-5-ylmethyl, (1-methyl-3-piperidyl)methyl, propanamide, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxy-1-methyl-ethyl, butanenitrile, propanenitrile, 2,2-difluorocyclopropylmethyl, (E)-pent-3-enyl, ethyl-2-acetate, 2-(3-piperidyl)ethyl, 2-(1-methyl-3-piperidyl)ethyl, 1-(1-methylpyrazol-3-yl)ethyl, 2,
- R 2 is methyl, cyclopropylmethyl, 2,2,2-trifluoroethyl, 2,2-difluorocyclopropylmethyl, 2-(aminocarbonyl)ethyl, 3,3,3-trifluoropropyl, 2-(methylsulfonyl)ethyl, 2-fluorocyclopropylmethyl, 1-methylcyclopropylmethyl, 2-cyanoethyl, 2-methoxyethyl, oxazol-5-ylmethyl, N-ethylaminocarbonylmethyl, phenethyl, 2-(pyrid-2-yl)ethyl, 2-(pyrid-4-yl)ethyl, tetrahydrofuran-3-yl, oxetan-3-yl, oxetan-3-ylmethyl, or tetrahydropyran-4-yl.
- R 2 is methyl, cyclopropylmethyl, tetrahydrofuran-3-yl, oxetan-3-yl, oxetan-3-ylmethyl, or tetrahydropyran-4-yl.
- R 1 is phenyl-pyrazolyl, pyrazolyl, phenyl-triazolyl, indazolyl, phenyl-oxazolyl, phenyl, pyridyl-pyrazolyl, tetralinyl, pyridyl, 3,4-dihydroisoquinolin-1-one, phenyl-phenyl, phenyl-pyridyl, phenyl-isoxazolyl, phenyl-cyclohexenyl, phenyl-cyclohexyl, phenyl-thiazolyl, and phenyl-pyrimidinyl, wherein each phenyl, pyrazolyl, triazolyl, indazolyl, oxazolyl, pyridyl, tetralinyl, 3,4-dihydroisoquinolin-1-one, isoxazolyl,
- R 1 is phenyl-pyrazolyl, pyrazolyl, phenyl-triazolyl, indazolyl, phenyl-oxazolyl, phenyl, pyridyl-pyrazolyl, tetralinyl, pyridyl, 3,4-dihydroisoquinolin-1-one, phenyl-phenyl, phenyl-pyridyl, phenyl-isoxazolyl, phenyl-cyclohexenyl, phenyl-cyclohexyl, phenyl-thiazolyl, and phenyl-pyrimidinyl, wherein each phenyl, pyrazolyl, triazolyl, indazolyl, oxazolyl, pyridyl, tetralinyl, 3,4-dihydroisoquinolin-1-one, isoxazolyl,
- R 1 is phenyl-pyrazolyl, pyrazolyl, phenyl-triazolyl, indazolyl, phenyl-oxazolyl, phenyl, pyridyl-pyrazolyl, tetralinyl, pyridyl, 3,4-dihydroisoquinolin-1-one, phenyl-phenyl, phenyl-pyridyl, phenyl-isoxazolyl, phenyl-cyclohexenyl, phenyl-cyclohexyl, phenyl-thiazolyl, and phenyl-pyrimidinyl, wherein each phenyl, pyrazolyl, triazolyl, indazolyl, oxazolyl, pyridyl, tetralinyl, 3,4-dihydroisoquinolin-1-one, isoxazolyl,
- R 2 is:
- R 3 is acetyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, methoxycarbonyl, propanoyl, cyclopropylcarbonyl, methylsulfonyl, butanoyl, difluoroacetyl, thiadiazole or isoxazole.
- R 3 is substituted or unsubstituted acetyl, propionyl, butyryl, cyclopropylcarbonyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, methoxycarbonyl, methylsulfonyl, difluoroacetyl, thiadiazole, methylthiadiazole, oxadiazole, methyloxadiazole, or isoxazole.
- R 3 is selected from the group consisting of:
- R 3 is selected from the group consisting of:
- the compound of Formula (II) is selected from the group consisting of:
- the compound of Formula (II) is a compound as described in the Examples herein, or a freebase or salt thereof.
- any of the embodiments described for the compound of Formula (II) may be combined with any other embodiment described for the compound of Formula (II).
- compositions comprising a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof.
- the composition further comprises a pharmaceutically acceptable carrier, adjuvant, or vehicle.
- the composition further comprises an amount of the compound effective to measurably inhibit a bromodomain of CBP and/or EP300.
- the composition is formulated for administration to a patient in need thereof.
- patient refers to an animal, such as a mammal, such as a human. In one embodiment, patient or individual refers to a human.
- compositions of this invention refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated.
- Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block
- compositions comprising a compound of formula I or formula II or salt thereof may be administered orally, parenterally, by inhalation spray, topically, transdermally, rectally, nasally, buccally, sublingually, vaginally, intraperitoneal, intrapulmonary, intradermal, epidural or via an implanted reservoir.
- parenteral as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques.
- the composition comprising a compound of formula I or formula II or salt thereof is formulated as a solid dosage form for oral administration.
- Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
- the solid oral dosage form comprising a compound of formula (I) or formula (II) or a salt thereof further comprises one or more of (i) an inert, pharmaceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate, and (ii) filler or extender such as starches, lactose, sucrose, glucose, mannitol, or silicic acid, (iii) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose or acacia, (iv) humectants such as glycerol, (v) disintegrating agent such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates or
- the solid oral dosage form is formulated as capsules, tablets or pills.
- the solid oral dosage form further comprises buffering agents.
- such compositions for solid oral dosage forms may be formulated as fillers in soft and hard-filled gelatin capsules comprising one or more excipients such as lactose or milk sugar, polyethylene glycols and the like.
- tablets, dragees, capsules, pills and granules of the compositions comprising a compound of formula I or formula II or salt thereof optionally comprise coatings or shells such as enteric coatings. They may optionally comprise opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
- embedding compositions include polymeric substances and waxes, which may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
- a composition comprises micro-encapsulated compound of formula (I) or formula (II) or salt thereof, and optionally, further comprises one or more excipients.
- compositions comprise liquid dosage formulations comprising a compound of formula I or formula II or salt thereof for oral administration, and optionally further comprise one or more of pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
- the liquid dosage form optionally, further comprise one or more of an inert diluent such as water or other solvent, a solubilizing agent, and an emulsifier such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols or fatty acid esters of sorbitan, and mixtures thereof.
- liquid oral compositions optionally further comprise one or more adjuvant, such as a wetting agent, a suspending agent, a sweetening agent, a flavoring agent and a perfuming agent.
- sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
- the sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
- acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution.
- sterile, fixed oils are conventionally employed as a solvent or suspending medium.
- any bland fixed oil can be employed including synthetic mono- or diglycerides.
- fatty acids such as oleic acid are used in the preparation of injectables.
- Injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
- the rate of compound release can be controlled.
- biodegradable polymers include poly(orthoesters) and poly(anhydrides).
- Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.
- the composition for rectal or vaginal administration are formulated as suppositories which can be prepared by mixing a compound of formula (I) or formula (II) or a salt thereof with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax, for example those which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the compound of formula (I) or formula (II).
- suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax, for example those which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the compound of formula (I) or formula (II).
- Example dosage forms for topical or transdermal administration of a compound of formula (I) or formula (II) include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches.
- the compound of formula (I) or formula (II) or a salt thereof is admixed under sterile conditions with a pharmaceutically acceptable carrier, and optionally preservatives or buffers. Additional formulation examples include an ophthalmic formulation, ear drops, eye drops, transdermal patches.
- Transdermal dosage forms can be made by dissolving or dispensing the compound of formula (I) or formula (II) or a salt thereof in medium, for example ethanol or dimethylsulfoxide.
- Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
- Nasal aerosol or inhalation formulations of a compound of formula (I) or formula (II) or a salt thereof may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promotors to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.
- compositions may be administered with or without food. In certain embodiments, pharmaceutically acceptable compositions are administered without food. In certain embodiments, pharmaceutically acceptable compositions of this invention are administered with food.
- Specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, the judgment of the treating physician, and the severity of the particular disease being treated.
- the amount of a provided compound of formula I or formula II or salt thereof in the composition will also depend upon the particular compound in the composition.
- the therapeutically effective amount of the compound of the invention administered parenterally per dose will be in the range of about 0.01-100 mg/kg, alternatively about 0.1 to 20 mg/kg of patient body weight per day, with the typical initial range of compound used being 0.3 to 15 mg/kg/day.
- oral unit dosage forms such as tablets and capsules, contain from about 5 to about 100 mg of the compound of the invention.
- An example tablet oral dosage form comprises about 2 mg, 5 mg, 25 mg, 50 mg, 100 mg, 250 mg or 500 mg of a compound of formula (I) or formula (II) or salt thereof, and further comprises about 5-30 mg anhydrous lactose, about 5-40 mg sodium croscarmellose, about 5-30 mg polyvinylpyrrolidone (PVP) K30 and about 1-10 mg magnesium stearate.
- the process of formulating the tablet comprises mixing the powdered ingredients together and further mixing with a solution of the PVP.
- the resulting composition can be dried, granulated, mixed with the magnesium stearate and compressed to tablet form using conventional equipment.
- An example of an aerosol formulation can be prepared by dissolving about 2-500 mg of a compound of formula I or formula II or salt thereof, in a suitable buffer solution, e.g. a phosphate buffer, and adding a tonicifier, e.g. a salt such sodium chloride, if desired.
- a suitable buffer solution e.g. a phosphate buffer
- a tonicifier e.g. a salt such sodium chloride
- Another aspect includes the use of a compound of formula (I) or formula (II) or a salt thereof for the inhibition of a bromodomain (in vitro or in vivo) (e.g., in vitro or in vivo inhibition of the bromodomain of CBP/EP300).
- Another embodiment includes a method for treating a bromodomain-mediated disorder (e.g., CBP/EP300 bromodomain-mediated disorder) in an animal comprising administering a compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof to the animal.
- CBP/EP300-mediated disorders include, but are not limited to those disorders described herein.
- Another embodiment includes a method of increasing efficacy of a cancer treatment comprising a cytotoxic agent in an animal comprising administering to the animal an effective amount of a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof.
- Another embodiment includes a method of extending the duration of response to a cancer therapy in an animal, comprising administering to an animal undergoing the cancer therapy a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, wherein the duration of response to the cancer therapy when the compound of formula (I) or formula (II) or the pharmaceutically acceptable salt thereof is administered is extended over the duration of response to the cancer therapy in the absence of the administration of the compound of formula (I) or formula (II) or the pharmaceutically acceptable salt thereof.
- Another embodiment includes a method of treating cancer in an individual comprising administering to the individual (a) a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, and (b) a cytotoxic agent.
- the cytotoxic agent is selected from anti-microtubule agents, platinum coordination complexes, alkylating agents, antibiotic agents, topoisomerase II inhibitors, antimetabolites, topoisomerase I inhibitors, hormones and hormonal analogues, signal transduction pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors, immunotherapeutic agents, proapoptotic agents, inhibitors of LDH-A, inhibitors of fatty acid biosynthesis, cell cycle signaling inhibitors, HDAC inhibitors, proteasome inhibitors, and inhibitors of cancer metabolism.
- the cytotoxic agent is a taxane. In one embodiment the taxane is paclitaxel or docetaxel. In one embodiment the cytotoxic agent is a platinum agent. In one embodiment the cytotoxic agent is an antagonist of EGFR. In one embodiment the antagonist of EGFR is N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine or a pharmaceutically acceptable salt thereof (e.g., erlotinib). In one embodiment the cytotoxic agent is a RAF inhibitor. In one embodiment the RAF inhibitor is a BRAF or CRAF inhibitor. In one embodiment the RAF inhibitor is vemurafenib. In one embodiment the cytotoxic agent is a PI3K inhibitor.
- treatment may be administered after one or more symptoms have developed. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example to prevent or delay their recurrence.
- the CBP/EP300 bromodomain inhibitor interferes with the associating of CBP and/or EP300 with histones, in particular acetylated lysines in histones.
- the CBP/EP300 bromodomain inhibitor inhibits binding of CBP and/or EP300 to chromatin (e.g., histone associated DNA).
- the CBP/EP300 bromodomain inhibitor inhibits and/or reduces binding of the CBP bromodomain and/or EP300 bromodomain to chromatin (e.g., histone associated DNA).
- the CBP/EP300 bromodomain inhibitor does not affect association of other domains of CBP and/or EP300 to chromatin.
- CBP/EP300 bromodomain inhibitor binds to the CBP and/or EP300 primarily (e.g., solely) through contacts and/or interactions with the CBP bromodomain and/or EP300 bromodomain. In some embodiments, CBP/EP300 bromodomain inhibitor binds to the CBP and/or EP300 through contacts and/or interactions with the CBP bromodomain and/or EP300 bromodomain as well as additional CBP and/or EP300 residues and/or domains.
- Methods of assaying association with chromatin include, but are not limited to, chromatin fractionation, BRET assay (Promega), FRAP assay, Chromatin Immunoprecipitation (ChIP), biophysical binding assay, and/or Histone Association Assay. See, e.g., Das et al., BioTechniques 37:961-969 (2004).
- the CBP/EP300 bromodomain inhibitor does not affect effector function in CD8 cells (i.e., effector function is substantially the same in the presence and/or absence of the CBP/EP300 bromodomain inhibitor). In some embodiments, the CBP/EP300 bromodomain inhibitor does not affect expression levels of perforin, granzyme, and/or EOMES (i.e., expression levels of one or more perforin, granzyme, and/or EOMES are substantially the same in the presence and/or absence of the CBP/EP300 bromodomain inhibitor).
- the CBP/EP300 bromodomain inhibitor does not affect expression levels of effector cytokines IFN- ⁇ and/or TNF ⁇ (i.e., expression levels of effector cytokines IFN- ⁇ and/or TNF ⁇ are substantially the same in the presence and/or absence of the CBP/EP300 bromodomain inhibitor).
- the CBP/EP300 bromodomain inhibitor enhances na ⁇ ve T cell responsiveness to CD3/CD28 stimulation in the presence of Treg cells.
- the CBP/EP300 bromodomain inhibitor does not substantially bind to (e.g., does not bind to) the HAT domain of CBP and/or EP300. In some embodiments, the CBP/EP300 bromodomain inhibitor does not substantially bind to (e.g., does not bind to) the HAT domain of CBP and/or EP300 as identified in Delvecchio et al., Nat. Struct . & Mol. Biol. 20:1040-1046 (2013), which is incorporated by reference in its entirety.
- the CBP/EP300 bromodomain inhibitor does not substantially bind to one or more residues of the amino acid sequence ENKFSAKRLQTTR LGNHLEDRVNKFLRRQNHPEAGEVFVRVVASSDKTVEVKPGMKSRFVDSGEMSESFPY RTKALFAFEEIDGVDVCFFGMHVQEYGSDCPPPNTRRVYISYLDSIHFFRPRCLRTAVYH EILIGYLEYVKKLGYVTGHIWACPPSEGDDYIFHCHPPDQKIPKPKRLQEWYKKMLDKA FAERIIHDYKDIFKQATEDRLTSAKELPYFEGDFWPNVLEESIKELEQEEEERKKEESTAA SETTEGSQGDSKNAKKKNNKKTNKNKSSISRANKKKPSMPNVSNDLSQKLYATMEKH KEVFFVIHLHAGPVINTLPPIVDPDPLLSCDLMDGRDAFLTLARDKHWEFSSLRRSKWST LCMLVELHTQGQD
- the CBP/EP300 bromodomain inhibitor does not substantially bind to one or more residues of the amino acid sequence ENKFSAKRLPSTRLGTFLENRVNDFLRRQNHPESGEVTVRVVHASDKTVEVKPGMKAR FVDSGEMAESFPYRTKALFAFEEIDGVDLCFFGMHVQEYGSDCPPPNQRRVYISYLDSV HFFRPKCLRTAVYHEILIGYLEYVKKLGYTTGHIWACPPSEGDDYIFHCHPPDQKIPKPK RLQEWYKKMLDKAVSERIVHDYKDIFKQATEDRLTSAKELPYFEGDFWPNVLEESIKEL EQEEEERKREENTSNESTDVTKGDSKNAKKKNNKKTSKNKSSLSRGNKKKPGMPNVSN DLSQKLYATMEKHKEVFFVIRLIAGPAANSLPPIVDPDPLIPCDLMDGRDAFLTLARDKH LEFSSLRRAQWSTM
- CBP/EP300 bromodomain inhibitors are expected to have improved and/or distinct properties over other compounds, such as “HAT” inhibitor compounds.
- HAT inhibition is expected to result in a global reduction in protein acetylation (histone and non-histone), likely affecting cell viability in a significant way.
- CBP/EP300 bromodomain inhibition preserves the HAT activity of these proteins while resulting in the reduction of transcriptional activity of a relatively small subset of target genes.
- provided are methods of enhancing immune function in an individual having cancer comprising administering an effective amount of any CBP/EP300 bromodomain inhibitors disclosed herein.
- the CD8 T cells in the individual have enhanced priming, activation, proliferation, and/or cytolytic activity relative to prior to the administration of the CBP/EP300 bromodomain inhibitor.
- the number of CD8 T cells is elevated relative to prior to administration of the CBP/EP300 bromodomain inhibitors.
- the CD8 T cells have reduced levels of expression of one or more of the following biomarkers: IFNA17, IGF1, FSCN1, SUMO2, CIorf129, EIF2S2, TDGF1, AIDA, CCR4, CD160, MC4R, KRTAP2-2, MTIJP, OR4N2, KRTAP4-5, MTIL//MTIL, ILI3, LCEID, KIR2DL2, LOC158696, LIF, 1L28A, TAS2R13, CTLA4, and/or FOXP3 relative to prior to administration of the CBP/EP300 bromodomain inhibitor.
- the CD8 T cells have reduced levels of expression of CD160 and/or KIR2DL2 relative to prior to administration of the CBP/EP300 bromodomain inhibitor.
- the enhanced immune function is characterized by Treg cells in the individual (e.g., at the tumor site(s)) have reduced levels of expression of one or more of the following markers: 1L28A, GPR87, ANKRD37, CABLES1, RAPGEF2, TRIM69, MT1L//MT1L, FAM1138, FOXP3, CSF2, OCM2, GLIPR1, FGFBP2, CTLA4, CST7, GOLGA6L1, IFIT3, FAM13A, APOD, AK2, CLDN1, HSD11B1, DNAJC12, PHEX, IL2, FOXD4L3, GNA15, ZBTB32, RDH10, OR52E5, CYP2A6, GZMH, CCL20, ADM, LOC100131541, RNF122, FAM36A, AMY2B, GPR183, MYOF, IL29, AIDA, SPRYI, ENOPH1, IL1RN, SLAMF1,
- the Treg cell biomarker is one or more of LAG3, CTLA4, and/or FOXP3.
- the enhanced immune function is characterized by enhanced naive T cell responsiveness to CD3/CD28 stimulation in the presence of Treg cells.
- the CD8 T cell priming is characterized by increased T cell proliferation and/or enhanced cytolytic activity in CD8 T cells.
- the CD8 T cell activation is characterized by an elevated frequency of T-IFN + CD8 T cells.
- the CD8 T cell is an antigen-specific T-cell.
- the immune evasion is inhibited.
- the methods provided herein are useful in treating conditions where enhanced immunogenicity is desired such as increasing tumor immunogenicity for the treatment of cancer.
- CBP/EP300 bromodomain inhibitors for use to enhance T-cell function to upregulate cell-mediated immune responses and for the treatment of T cell dysfunctional disorders, tumor immunity.
- the CBP/EP300 bromodomain inhibitors promote anti-tumor immunity by inhibiting the suppressive function of regulatory T (Treg) cells and/or relieving T cell exhaustion on chronically stimulated CD8 + T cells.
- CBP/EP300 bromodomain inhibitors are further useful in reducing FOXP3 expression during extra-thymic Treg cell differentiation.
- Continual FOXP3 expression is essential to maintain suppressive activity in Treg cells.
- reduced FOXP3 expression through CBP/EP300 bromodomain inhibition impairs Treg cells suppressive activity and promotes tumor antiimmunity.
- Treg cells are highly enriched in tumors derived from multiple cancer indications, including melanoma, NSCLC, renal, overian, colon, pancreatic, hepatocellular, and breast cancer.
- increased intratumoral Treg cell densities are associated with poor patient prognosis. These indications include NSCLC, ovarian, pancreatic, hepatocellular, and breast cancer.
- CBP/EP300 bromodomain inhibitors are predicted to impair intratumoral Treg cell function in these cancer indications to enhance effector T cell activity.
- the CBP/EP300 bromodomain inhibitors may be used to treat infectious diseases, where some pathogens may have evolved to manipulate regulatory T (Treg) cells to immunosuppress the host to ensure survival, such as in retrovial infections (e.g., HIV), mycobacterial infections (e.g., tuberculosis), and parasitic infections (e.g., Leishmania and malaria).
- retrovial infections e.g., HIV
- mycobacterial infections e.g., tuberculosis
- parasitic infections e.g., Leishmania and malaria
- the methods provided herein are useful in treating a CBP and/or EP300-mediated disorder involving fibrosis.
- the CBP and/or EP300-mediated disorder is a fibrotic disease.
- Certain fibrotic diseases may include, for example, pulmonary fibrosis, silicosis, cystic fibrosis, renal fibrosis, liver fibrosis, liver cirrhosis, primary sclerosing cholangitis, primary biliary cirrhosis, endomyocardial fibrosis, mediastinal fibrosis, myelofibrosis, retroperitoneal fibrosis, progressive massive fibrosis, nephrogenic systemic fibrosis, Crohn's disease, keloid, myocardial infarction, systemic sclerosis or arthro fibrosis.
- the CBP and/or EP300-mediated disorder is a fibrotic lung disease.
- Fibrotic lung diseases may include, for example, idiopathic pulmonary fibrosis, fibrotic interstitial lung disease, interstitial pneumonia, fibrotic variant of non-specific interstitial pneumonia, cystic fibrosis, lung fibrosis, chronic obstructive pulmonary lung disease (COPD), or pulmonary arterial hypertension.
- the fibrotic lung disease is idiopathic pulmonary fibrosis.
- any CBP and/or EP300 inhibitor may be used to treat fibrotic disease.
- the CBP and/or EP300 inhibitor is a compound of formula (I) or of formula (II), as described herein.
- the CBP and/or EP300 inhibitor is a compound of formula (III):
- X is NH, O, S, or —C(R a ) 2 —;
- each R a is independently selected from the group consisting of H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 3-6 carbocyclyl;
- ring A is a 6 membered heteroaryl ring or a benzo ring, wherein ring A is optionally substituted with one or more groups R b that are independently selected from the group consisting of R c , —F, —Cl, —Br, —I, —NO 2 , —N(R d ) 2 , —CN, —C(O)—N(R d ) 2 , —S(O)—N(R d ) 2 , —S(O) 2 —N(R d ) 2 , —O—R d , —S—R d , —O—C(O)—R d , —O—C(O)—O—R d , —C(O)—O—R d , —C(O)—R d , —C(O)—O—R d , —S(O)—R d , —S(O
- each R f is independently selected from the group consisting of oxo, 3-20 membered carbocyclyl, 3-20 membered heterocyclyl, halo, —NO 2 , —N(R g ) 2 , —CN, —C(O)—N(R g ) 2 , —S(O)—N(R g ) 2 , —S(O) 2 —N(R g ) 2 , —O—R g , —S—R g , —O—C(O)—R g , —C(O)—R g , —C(O)—O—R g , —S(O)—R g , —S(O) 2 —R g , —C(O)—N(R g ) 2 , —N(R g )—C(O)—R g , —Si(R h ) 3 , —
- each R g is independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3-20 membered carbocyclyl, and 3-20 membered heterocyclyl, wherein each C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, 3-20 membered carbocyclyl, and 3-20 membered heterocyclyl is optionally substituted with one or more groups R j , or two R g are taken together with the nitrogen to which they are attached to form a 3-20 membered heterocyclyl that is optionally substituted with one or more groups independently selected from the group consisting of oxo, halo and C 1-3 alkyl that is optionally substituted with one or more groups independently selected from the group consisting of oxo and halo;
- each R h is independently selected from the group consisting of H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 3-6 carbocyclyl;
- each R j is independently selected from the group consisting of oxo, halo, amino, hydroxyl, —Si(R k ) 3 , 3-20 membered carbocyclyl, 3-20 membered heterocyclyl, and C 1 -C 6 alkyl, wherein any 3-20 membered carbocyclyl, 3-20 membered heterocyclyl, and C 1 -C 6 alkyl is optionally substituted with one or more groups independently selected from the group consisting of oxo, C 1 -C 4 alkyl, and halo;
- each R k is independently selected from the group consisting of H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 3-6 carbocyclyl;
- each R i is independently selected from the group consisting of oxo, halo, C 1-6 alkyl, cyano, —N(R 1 ) 2 , —O—R 1 , —S(O)—R 1 , —S(O) 2 —R 1 , —S(O)—N(R 1 ) 2 , —S(O) 2 —N(R 1 ) 2 , —N(R 1 )—S(O)—R 1 , —N(R 1 )—C(O)—R 1 , —N(R 1 )—C(O)—O—R 1 , —N(R 1 )—S(O) 2 —R 1 , 3-20 membered heterocyclyl, and 3-20 membered carbocyclyl that is optionally substituted with one or more groups independently selected from the group consisting of halo, and C 1-6 alkyl;
- each R l is independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3-20 membered carbocyclyl, and 3-20 membered heterocyclyl, wherein each C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, 3-20 membered carbocyclyl, and 3-20 membered heterocyclyl is optionally substituted with one or more groups R m ; or two R l are taken together with the nitrogen to which they are attached to form a 3-20 membered heterocyclyl that is optionally substituted with one or more groups independently selected from the group consisting of oxo, halo and C 1-3 alkyl that is optionally substituted with one or more groups independently selected from the group consisting of oxo and halo; and
- each R m is independently selected from the group consisting of oxo, halo, amino, hydroxyl, —Si(R n ) 3 , 3-20 membered carbocyclyl, 3-20 membered heterocyclyl, and C 1 -C 6 alkyl, wherein any 3-20 membered carbocyclyl, 3-20 membered heterocyclyl, and C 1 -C 6 alkyl is optionally substituted with one or more groups independently selected from the group consisting of oxo, C 1 -C 4 alkyl, and halo;
- each R n is independently selected from the group consisting of H, C 4-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 3-6 carbocyclyl;
- each R d is independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3-20 membered carbocyclyl, and 3-20 membered heterocyclyl, wherein each C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3-20 membered carbocyclyl, and 3-20 membered heterocyclyl is optionally substituted with one or more groups R o , or two R d are taken together with the nitrogen to which they are attached to form a 3-20 membered heterocyclyl that is optionally substituted with one or more groups independently selected from the group consisting of oxo, halo and C 1-3 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo;
- each R o is independently selected from the group consisting of oxo, halo, amino, hydroxyl, cyano, —O—R p , 3-20 membered carbocyclyl, 3-20 membered heterocyclyl, and C 1 -C 6 alkyl, wherein any C 1 -C 6 alkyl, 3-20 membered carbocyclyl and 3-20 membered heterocyclyl is optionally substituted with one or more groups independently selected from the group consisting of oxo, C 1 -C 4 alkyl, —O—R q , and halo;
- each R p is independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3-20 membered carbocyclyl, and 3-20 membered heterocyclyl, wherein each C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, 3-20 membered carbocyclyl, and 3-20 membered heterocyclyl is optionally substituted with one or more groups R r ,
- each R r is independently selected from the group consisting of oxo, halo, amino, hydroxyl, —Si(R s ) 3 , 3-20 membered carbocyclyl, 3-20 membered heterocyclyl, and C 1 -C 6 alkyl, wherein any 3-20 membered carbocyclyl, 3-20 membered heterocyclyl, and C 1 -C 6 alkyl is optionally substituted with one or more groups independently selected from the group consisting of oxo, C 1 -C 4 alkyl, and halo;
- each R s is independently selected from the group consisting of H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 3-6 carbocyclyl;
- each R q is independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3-20 membered carbocyclyl, and 3-20 membered heterocyclyl, wherein each C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, 3-20 membered carbocyclyl, and 3-20 membered heterocyclyl is optionally substituted with one or more groups R t ,
- each R t is independently selected from the group consisting of oxo, halo, amino, hydroxyl, —Si(R u ) 3 , 3-20 membered carbocyclyl, 3-20 membered heterocyclyl, and C 1 -C 6 alkyl, wherein any 3-20 membered carbocyclyl, 3-20 membered heterocyclyl, and C 1 -C 6 alkyl is optionally substituted with one or more groups independently selected from the group consisting of oxo, C 1 -C 4 alkyl, and halo;
- each R u is independently selected from the group consisting of H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 3-6 carbocyclyl;
- the CBP and/or EP300 inhibitor is:
- a “CBP and/or EP300-mediated disorder” is characterized by the participation of the bromodomains of CBP and/or EP300 in the inception, manifestation of one or more symptoms or disease markers, severity, or progression of a disorder.
- the bromodomain-mediated disorder is a CBP bromodomain-mediated disorder.
- the bromodomain-mediated disorder is an EP300 bromodomain-mediated disorder.
- CBP and/or EP300 bromodomain-mediated disorders include cancers, including, but not limited to acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acute T-cell leukemia, basal cell carcinoma, bile duct carcinoma, bladder cancer, brain cancer, breast cancer, bronchogenic carcinoma, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myelocytic (granulocytic) leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, dysproliferative changes
- the cancer is lung cancer, breast cancer, pancreatic cancer, colorectal cancer, and/or melanoma.
- the cancer is lung.
- the lung cancer is NSCLC.
- the cancer is breast cancer.
- the cancer is melanoma.
- CBP and/or EP300-mediated disorders also include inflammatory diseases, inflammatory conditions, and autoimmune diseases, including, but not limited to: Addison's disease, acute gout, ankylosing spondylitis, asthma, atherosclerosis, Behcet's disease, bullous skin diseases, chronic obstructive pulmonary disease (COPD), Crohn's disease, dermatitis, eczema, giant cell arteritis, glomerulonephritis, hepatitis, hypophysitis, inflammatory bowel disease, Kawasaki disease, lupus nephritis, multiple sclerosis, myocarditis, myositis, nephritis, organ transplant rejection, osteoarthritis, pancreatitis, pericarditis, Polyarteritis nodosa, pneumonitis, primary biliary cirrhosis, psoriasis, psoriatic arthritis, rheumatoid arthritis,
- CBP and/or EP300-mediated disorders also include AIDS; chronic kidney diseases, including, but are not limited to diabetic nephropathy, hypertensive nephropathy, HIV-associated nephropathy, glomerulonephritis, lupus nephritis, IgA nephropathy, focal segmental glomerulosclerosis, membranous glomerulonephritis, minimal change disease, polycystic kidney disease and tubular interstitial nephritis; acute kidney injury or disease or condition including, but are not limited to ischemia-reperfusion induced, cardiac and major surgery induced, percutaneous coronary intervention induced, radio-contrast agent induced, sepsis induced, pneumonia induced, and drug toxicity induced; obesity; dyslipidemia; hypercholesterolemia; Alzheimer's disease; metabolic syndrome; hepatic steatosis; type II diabetes; insulin resistance; and diabetic retinopathy.
- chronic kidney diseases including, but are not limited
- CBP and/or EP300 inhibitors may also be used to provide male contraception.
- CBP and/or EP300-mediated disorders also include fibrotic diseases.
- Certain fibrotic diseases may include, for example, pulmonary fibrosis, silicosis, cystic fibrosis, renal fibrosis, liver fibrosis, liver cirrhosis, primary sclerosing cholangitis, primary biliary cirrhosis, endomyocardial fibrosis, mediastinal fibrosis, myelofibrosis, retroperitoneal fibrosis, progressive massive fibrosis, nephrogenic systemic fibrosis, Crohn's disease, keloid, myocardial infarction, systemic sclerosis or arthro fibrosis.
- Fibrotic lung diseases may include, for example, idiopathic pulmonary fibrosis, fibrotic interstitial lung disease, interstitial pneumonia, fibrotic variant of non-specific interstitial pneumonia, cystic fibrosis, lung fibrosis, chronic obstructive pulmonary lung disease (COPD), or pulmonary arterial hypertension.
- the fibrotic lung disease is idiopathic pulmonary fibrosis.
- the compounds of formula (I) or formula (II) or salts thereof may be employed alone or in combination with other agents for treatment.
- the second agent of the pharmaceutical combination formulation or dosing regimen may have complementary activities to the compound of formula (I) or formula (II) such that they do not adversely affect each other.
- the compounds may be administered together in a unitary pharmaceutical composition or separately.
- a compound or a pharmaceutically acceptable salt can be co-administered with a cytotoxic agent to treat proliferative diseases and cancer.
- co-administering refers to either simultaneous administration, or any manner of separate sequential administration, of a compound of formula (I) or formula (II) or a salt thereof, and a further active pharmaceutical ingredient or ingredients, including cytotoxic agents and radiation treatment. If the administration is not simultaneous, the compounds are administered in a close time proximity to each other. Furthermore, it does not matter if the compounds are administered in the same dosage form, e.g. one compound may be administered topically and another compound may be administered orally.
- Those additional agents may be administered separately from an inventive compound-containing composition, as part of a multiple dosage regimen.
- those agents may be part of a single dosage form, mixed together with a compound of this invention in a single composition. If administered as part of a multiple dosage regime, the two active agents may be submitted simultaneously, sequentially or within a period of time from one another normally within five hours from one another.
- the term “combination,” “combined,” and related terms refers to the simultaneous or sequential administration of therapeutic agents in accordance with this invention.
- a compound of the present invention may be administered with another therapeutic agent simultaneously or sequentially in separate unit dosage forms or together in a single unit dosage form.
- the present invention provides a single unit dosage form comprising a compound of formula I or formula II, an additional therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
- compositions of this invention are formulated such that a dosage of between 0.01-100 mg/kg body weight/day of an inventive can be administered.
- any agent that has activity against a disease or condition being treated may be co-administered.
- agents can be found in Cancer Principles and Practice of Oncology by V. T. Devita and S. Hellman (editors), 6 th edition (Feb. 15, 2001), Lippincott Williams & Wilkins Publishers.
- a person of ordinary skill in the art would be able to discern which combinations of agents would be useful based on the particular characteristics of the drugs and the disease involved.
- the treatment method includes the co-administration of a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof and at least one cytotoxic agent.
- cytotoxic agent refers to a substance that inhibits or prevents a cellular function and/or causes cell death or destruction.
- Cytotoxic agents include, but are not limited to, radioactive isotopes (e.g., At 211 , I 131 , I 125 , Y 90 , Re 186 , Re 188 , Sm 153 , Bi 212 , P 32 , Pb 212 and radioactive isotopes of Lu); chemotherapeutic agents; growth inhibitory agents; enzymes and fragments thereof such as nucleolytic enzymes; and toxins such as small molecule toxins or enzymatically active toxins of bacterial, fungal, plant or animal origin, including fragments and/or variants thereof.
- radioactive isotopes e.g., At 211 , I 131 , I 125 , Y 90 , Re 186 , Re 188 , Sm 153 , Bi 212 , P 32 , Pb 212 and radioactive isotopes of Lu
- chemotherapeutic agents e.g., At 211 , I 131 , I 125
- Exemplary cytotoxic agents can be selected from anti-microtubule agents, platinum coordination complexes, alkylating agents, antibiotic agents, topoisomerase II inhibitors, antimetabolites, topoisomerase I inhibitors, hormones and hormonal analogues, signal transduction pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors, immunotherapeutic agents, proapoptotic agents, inhibitors of LDH-A; inhibitors of fatty acid biosynthesis; cell cycle signaling inhibitors; HDAC inhibitors, proteasome inhibitors; and inhibitors of cancer metabolism.
- “Chemotherapeutic agent” includes chemical compounds useful in the treatment of cancer.
- chemotherapeutic agents include erlotinib (TARCEVA®, Genentech/OSI Pharm.), bortezomib (VELCADE®, Millennium Pharm.), disulfiram, epigallocatechin gallate, salinosporamide A, carfilzomib, 17-AAG(geldanamycin), radicicol, lactate dehydrogenase A (LDH-A), fulvestrant (FASLODEX®, AstraZeneca), sunitib (SUTENT®, Pfizer/Sugen), letrozole (FEMARA®, Novartis), imatinib mesylate (GLEEVEC®., Novartis), finasunate (VATALANIB, Novartis), oxaliplatin (ELOXATIN®, Sanofi), 5-FU (5-fluorouracil), leucovorin, Rapamycin (Sirol
- dynemicin including dynemicin A; bisphosphonates, such as clodronate; an esperamicin; as well as neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromophores), aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, ADRIAMYCIN® (doxorubicin), morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin, es
- Chemotherapeutic agent also includes (i) anti-hormonal agents that act to regulate or inhibit hormone action on tumors such as anti-estrogens and selective estrogen receptor modulators (SERMs), including, for example, tamoxifen (including NOLVADEX®; tamoxifen citrate), raloxifene, droloxifene, iodoxyfene, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, and FARESTON® (toremifine citrate); (ii) aromatase inhibitors that inhibit the enzyme aromatase, which regulates estrogen production in the adrenal glands, such as, for example, 4(5)-imidazoles, aminoglutethimide, MEGASE® (megestrol acetate), AROMASIN® (exemestane; Pfizer), formestanie, fadrozole, RIVISOR® (vorozole), FEMARA®(let
- Chemotherapeutic agent also includes antibodies such as alemtuzumab (Campath), bevacizumab (AVASTIN®, Genentech); cetuximab (ERBITUX®, Imclone); panitumumab (VECTIBIX®, Amgen), rituximab (RITUXAN®, Genentech/Biogen Idec), pertuzumab (OMNITARG®, 2C4, Genentech), trastuzumab (HERCEPTIN®, Genentech), tositumomab (Bexxar, Corixia), and the antibody drug conjugate, gemtuzumab ozogamicin (MYLOTARG®, Wyeth).
- antibodies such as alemtuzumab (Campath), bevacizumab (AVASTIN®, Genentech); cetuximab (ERBITUX®, Imclone); panitumumab (VECTIBIX®, Amgen), rituximab
- Additional humanized monoclonal antibodies with therapeutic potential as agents in combination with the compounds of the invention include: apolizumab, aselizumab, atlizumab, bapineuzumab, bivatuzumab mertansine, cantuzumab mertansine, cedelizumab, certolizumab pegol, cidfusituzumab, cidtuzumab, daclizumab, eculizumab, efalizumab, epratuzumab, erlizumab, felvizumab, fontolizumab, gemtuzumab ozogamicin, inotuzumab ozogamicin, ipilimumab, labetuzumab, lintuzumab, matuzumab, mepolizumab, motavizumab, motovizumab, natalizumab, nimotuzumab, nolovizum
- Chemotherapeutic agent also includes “EGFR inhibitors,” which refers to compounds that bind to or otherwise interact directly with EGFR and prevent or reduce its signaling activity, and is alternatively referred to as an “EGFR antagonist.”
- EGFR inhibitors refers to compounds that bind to or otherwise interact directly with EGFR and prevent or reduce its signaling activity
- Examples of such agents include antibodies and small molecules that bind to EGFR.
- antibodies which bind to EGFR include MAb 579 (ATCC CRL HB 8506), MAb 455 (ATCC CRL HB8507), MAb 225 (ATCC CRL 8508), MAb 528 (ATCC CRL 8509) (see, U.S. Pat. No.
- the anti-EGFR antibody may be conjugated with a cytotoxic agent, thus generating an immunoconjugate (see, e.g., EP659,439A2, Merck Patent GmbH).
- EGFR antagonists include small molecules such as compounds described in U.S. Pat. Nos.
- EGFR antagonists include OSI-774 (CP-358774, erlotinib, TARCEVA® Genentech/OSI Pharmaceuticals); PD 183805 (CI 1033, 2-propenamide, N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(4-morpholinyl)propoxy]-6-quinazolinyl]-, dihydrochloride, Pfizer Inc.); ZD1839, gefitinib (IRESSA®) 4-(3′-Chloro-4′-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline, AstraZeneca); ZM 105180 ((6-amino-4-(3-methylphenyl-amino)-quinazoline, Zeneca); BIBX-1382 (N8-(3-chloro-4-fluoro-phenyl)-N2-(1-methylpiperidin
- Chemotherapeutic agents also include “tyrosine kinase inhibitors” including the EGFR-targeted drugs noted in the preceding paragraph; small molecule HER2 tyrosine kinase inhibitor such as TAK165 available from Takeda; CP-724,714, an oral selective inhibitor of the ErbB2 receptor tyrosine kinase (Pfizer and OSI); dual-HER inhibitors such as EKB-569 (available from Wyeth) which preferentially binds EGFR but inhibits both HER2 and EGFR-overexpressing cells; lapatinib (GSK572016; available from Glaxo-SmithKline), an oral HER2 and EGFR tyrosine kinase inhibitor; PKI-166 (available from Novartis); pan-HER inhibitors such as canertinib (CI-1033; Pharmacia); Raf-1 inhibitors such as antisense agent ISIS-5132 available from ISIS Pharmaceuticals which inhibit Raf-1 signaling; non-HER targeted
- Chemotherapeutic agents also include dexamethasone, interferons, colchicine, metoprine, cyclosporine, amphotericin, metronidazole, alemtuzumab, alitretinoin, allopurinol, amifostine, arsenic trioxide, asparaginase, BCG live, bevacuzimab, bexarotene, cladribine, clofarabine, darbepoetin alfa, denileukin, dexrazoxane, epoetin alfa, elotinib, filgrastim, histrelin acetate, ibritumomab, interferon alfa-2a, interferon alfa-2b, lenalidomide, levamisole, mesna, methoxsalen, nandrolone, nelarabine, nofetumomab, oprelvekin,
- Chemotherapeutic agents also include hydrocortisone, hydrocortisone acetate, cortisone acetate, tixocortol pivalate, triamcinolone acetonide, triamcinolone alcohol, mometasone, amcinonide, budesonide, desonide, fluocinonide, fluocinolone acetonide, betamethasone, betamethasone sodium phosphate, dexamethasone, dexamethasone sodium phosphate, fluocortolone, hydrocortisone-17-butyrate, hydrocortisone-17-valerate, aclometasone dipropionate, betamethasone valerate, betamethasone dipropionate, prednicarbate, clobetasone-17-butyrate, clobetasol-17-propionate, fluocortolone caproate, fluocortolone pivalate and fluprednidene acetate; immune selective
- celecoxib or etoricoxib proteosome inhibitor
- CCI-779 tipifarnib (R11577); orafenib, ABT510
- Bcl-2 inhibitor such as oblimersen sodium (GENASENSE®)
- pixantrone farnesyltransferase inhibitors
- SCH 6636 farnesyltransferase inhibitors
- pharmaceutically acceptable salts, acids or derivatives of any of the above as well as combinations of two or more of the above such as CHOP, an abbreviation for a combined therapy of cyclophosphamide, doxorubicin, vincristine, and prednisolone
- FOLFOX an abbreviation for a treatment regimen with oxaliplatin (ELOXATIN®) combined with 5-FU and leucovorin.
- Chemotherapeutic agents also include non-steroidal anti-inflammatory drugs with analgesic, antipyretic and anti-inflammatory effects.
- NSAIDs include non-selective inhibitors of the enzyme cyclooxygenase.
- Specific examples of NSAIDs include aspirin, propionic acid derivatives such as ibuprofen, fenoprofen, ketoprofen, flurbiprofen, oxaprozin and naproxen, acetic acid derivatives such as indomethacin, sulindac, etodolac, diclofenac, enolic acid derivatives such as piroxicam, meloxicam, tenoxicam, droxicam, lornoxicam and isoxicam, fenamic acid derivatives such as mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid, and COX-2 inhibitors such as celecoxib, etoricoxib, lumirac
- NSAIDs can be indicated for the symptomatic relief of conditions such as rheumatoid arthritis, osteoarthritis, inflammatory arthropathies, ankylosing spondylitis, psoriatic arthritis, Reiter's syndrome, acute gout, dysmenorrhoea, metastatic bone pain, headache and migraine, postoperative pain, mild-to-moderate pain due to inflammation and tissue injury, pyrexia, ileus, and renal colic.
- conditions such as rheumatoid arthritis, osteoarthritis, inflammatory arthropathies, ankylosing spondylitis, psoriatic arthritis, Reiter's syndrome, acute gout, dysmenorrhoea, metastatic bone pain, headache and migraine, postoperative pain, mild-to-moderate pain due to inflammation and tissue injury, pyrexia, ileus, and renal colic.
- chemotherapeutic agents include, but are not limited to, doxorubicin, dexamethasone, vincristine, cyclophosphamide, fluorouracil, topotecan, interferons, platinum derivatives, taxanes (e.g., paclitaxel, docetaxel), vinca alkaloids (e.g., vinblastine), anthracyclines (e.g., doxorubicin), epipodophyllotoxins (e.g., etoposide), cisplatin, an mTOR inhibitor (e.g., a rapamycin), methotrexate, actinomycin D, dolastatin 10, colchicine, trimetrexate, metoprine, cyclosporine, daunorubicin, teniposide, amphotericin, alkylating agents (e.g., chlorambucil), 5-fluorouracil, campthothecin, cisplatin
- compounds of the present invention are administered in combination with an antiproliferative or chemotherapeutic agent selected from any one or more of abarelix, aldesleukin, alemtuzumab, alitretinoin, allopurinol, altretamine, amifostine, anastrozole, arsenic trioxide, asparaginase, azacitidine, BCG live, bevacuzimab, fluorouracil, bexarotene, bleomycin, bortezomib, busulfan, calusterone, capecitabine, camptothecin, carboplatin, carmustine, cetuximab, chlorambucil, cladribine, clofarabine, cyclophosphamide, cytarabine, dactinomycin, darbepoetin alfa, daunorubicin, denileukin, dexrazox
- Chemotherapeutic agents also include treatments for Alzheimer's Disease such as donepezil hydrochloride and rivastigmine; treatments for Parkinson's Disease such as L-DOPA/carbidopa, entacapone, ropinrole, pramipexole, bromocriptine, pergolide, trihexephendyl, and amantadine; agents for treating multiple sclerosis (MS) such as beta interferon (e.g., Avonex® and Rebif®), glatiramer acetate, and mitoxantrone; treatments for asthma such as albuterol and montelukast sodium; agents for treating schizophrenia such as zyprexa, risperdal, seroquel, and haloperidol; anti-inflammatory agents such as corticosteroids, TNF blockers, IL-1 RA, azathioprine, cyclophosphamide, and sulfasalazine; immunomodulatory and immunosuppressive agents such as cycl
- chemotherapeutic agents include pharmaceutically acceptable salts, acids or derivatives of any of chemotherapeutic agents, described herein, as well as combinations of two or more of them.
- a PD-1 axis binding antagonist includes a PD-1 binding antagonist, a PD-L1 binding antagonist and a PD-L2 binding antagonist.
- PD-1 axis binding antagonist is a molecule that inhibits the interaction of a PD-1 axis binding partner with either one or more of its binding partner, so as to remove T-cell dysfunction resulting from signaling on the PD-1 signaling axis—with a result being to restore or enhance T-cell function (e.g., proliferation, cytokine production, target cell killing).
- a PD-1 axis binding antagonist includes a PD-1 binding antagonist, a PD-L1 binding antagonist and a PD-L2 binding antagonist.
- PD-1 binding antagonists is a molecule that decreases, blocks, inhibits, abrogates or interferes with signal transduction resulting from the interaction of PD-1 with one or more of its binding partners, such as PDL1, PDL2.
- the PD-1 binding antagonist is a molecule that inhibits the binding of PD-1 to its binding partners.
- the PD-1 binding antagonist inhibits the binding of PD-1 to PDL1 and/or PDL2.
- PD-1 binding antagonists include anti-PD-1 antibodies, antigen binding fragments thereof, immunoadhesins, fusion proteins, oligopeptides and other molecules that decrease, block, inhibit, abrogate or interfere with signal transduction resulting from the interaction of PD-1 with PDL1 and/or PDL2.
- a PD-1 binding antagonist reduces the negative co-stimulatory signal mediated by or through cell surface proteins expressed on T lymphocytes mediated signaling through PD-1 so as render a dysfunctional T-cell less dysfunctional (e.g., enhancing effector responses to antigen recognition).
- the PD-1 binding antagonist is an anti-PD-1 antibody.
- a PD-1 binding antagonist is nivolumab described herein (also known as MDX-1106-04, MDX-1106, ONO-4538, BMS-936558, and OPDIVO®).
- a PD-1 binding antagonist is pembrolizumab described herein (also known as MK-3475, Merck 3475, KEYTRUDA®, and SCH-900475).
- a PD-1 binding antagonist is CT-011 described herein (also known as hBAT or hBAT-1).
- a PD-1 binding antagonist is AMP-224 (also known as B7-DCIg) described herein.
- PDL1 binding antagonists is a molecule that decreases, blocks, inhibits, abrogates or interferes with signal transduction resulting from the interaction of PDL1 with either one or more of its binding partners, such as PD-1, B7-1.
- a PDL1 binding antagonist is a molecule that inhibits the binding of PDL1 to its binding partners.
- the PDL1 binding antagonist inhibits binding of PDL1 to PD-1 and/or B7-1.
- the PDL1 binding antagonists include anti-PDL1 antibodies, antigen binding fragments thereof, immunoadhesins, fusion proteins, oligopeptides and other molecules that decrease, block, inhibit, abrogate or interfere with signal transduction resulting from the interaction of PDL1 with one or more of its binding partners, such as PD-1, B7-1.
- a PDL1 binding antagonist reduces the negative co-stimulatory signal mediated by or through cell surface proteins expressed on T lymphocytes mediated signaling through PDL1 so as to render a dysfunctional T-cell less dysfunctional (e.g., enhancing effector responses to antigen recognition).
- a PDL1 binding antagonist is an anti-PDL1 antibody.
- an anti-PDL1 antibody is YW243.55.S70 described herein.
- an anti-PDL1 antibody is MDX-1105 described herein (also known as BMS-936559).
- an anti-PDL1 antibody is MPDL3280A described herein.
- an anti-PDL1 antibody is MEDI4736 described herein.
- PDL2 binding antagonists is a molecule that decreases, blocks, inhibits, abrogates or interferes with signal transduction resulting from the interaction of PD-L2 with either one or more of its binding partners, such as PD-1.
- a PD-L2 binding antagonist is a molecule that inhibits the binding of PD-L2 to its binding partners.
- the PD-L2 binding antagonist inhibits binding of PD-L2 to PD-1.
- the PD-L2 antagonists include anti-PD-L2 antibodies, antigen binding fragments thereof, immunoadhesins, fusion proteins, oligopeptides and other molecules that decrease, block, inhibit, abrogate or interfere with signal transduction resulting from the interaction of PD-L2 with either one or more of its binding partners, such as PD-1.
- a PD-L2 binding antagonist reduces the negative co-stimulatory signal mediated by or through cell surface proteins expressed on T lymphocytes mediated signaling through PD-L2 so as render a dysfunctional T-cell less dysfunctional (e.g., enhancing effector responses to antigen recognition).
- a PD-L2 binding antagonist is an immunoadhesin.
- PD-1 include CD279 and SLEB2.
- Alternative names for “PD-L1” include B7-H 1, B7-4, CD274, and B7-H.
- Alternative names for “PD-L2” include B7-DC, Btdc, and CD273.
- PD-1, PD-L1, and PD-L2 are human PD-1, PD-L1 and PD-L2.
- the PD-1 binding antagonist is a molecule that inhibits the binding of PD-1 to its ligand binding partners.
- the PD-1 ligand binding partners are PD-L1 and/or PD-L2.
- a PD-L1 binding antagonist is a molecule that inhibits the binding of PD-L1 to its binding partners.
- PD-L1 binding partners are PD-1 and/or B7-1.
- the PD-L2 binding antagonist is a molecule that inhibits the binding of PD-L2 to its binding partners.
- a PD-L2 binding partner is PD-1.
- the antagonist may be an antibody, an antigen binding fragment thereof, an immunoadhesin, a fusion protein, or oligopeptide.
- the PD-1 binding antagonist is an anti-PD-1 antibody (e.g., a human antibody, a humanized antibody, or a chimeric antibody).
- the anti-PD-1 antibody is selected from the group consisting of MDX-1 106, Merck 3475 (also known as: pembrolizumab, lambrolizumab, or MK-3475), nivolumab (BMS-936558), CT-011, and MPDL3280A.
- the PD-1 binding antagonist is an immunoadhesin (e.g., an immunoadhesin comprising an extracellular or PD-1 binding portion of PD-L1 or PD-L2 fused to a constant region (e.g., an Fc region of an immunoglobulin sequence).
- the PD-1 binding antagonist is AMP-224.
- the PD-L1 binding antagonist is anti-PD-L1 antibody.
- the anti-PD-L1 binding antagonist is selected from the group consisting of YW243.55.S70, MPDL3280A and MDX-1 105.
- MDX-1 105 also known as BMS-936559, is an anti-PD-L1 antibody described in WO2007/005874.
- Antibody YW243.55.S70 (heavy and light chain variable region sequences shown in SEQ ID Nos. 20 and 21, respectively) is an anti-PD-L1 described in WO 2010/077634 A1.
- MDX-1 106 also known as MDX-1 106-04, ONO-4538 or BMS-936558, is an anti-PD-1 antibody described in WO2006/121168.
- Merck 3745 also known as MK-3475 or SCH-900475, is an anti-PD-1 antibody described in WO2009/114335.
- CT-011 also known as hBAT or hBAT-1, is an anti-PD-1 antibody described in WO2009/101611.
- AMP-224 also known as B7-DCIg, is a PD-L2-Fc fusion soluble receptor described in WO2010/027827 and WO201 1/066342.
- the anti-PD-1 antibody is MDX-1 106.
- MDX-1106 includes MDX-1 106-04, ONO-4538, BMS-936558 or Nivolumab.
- the anti-PD-1 antibody is Nivolumab (CAS Registry Number: 946414-94-4).
- the cancer is melanoma, NSCLC, and renal cell carcinoma.
- a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof may be co-administered with methotrexate, tofacitinib, 6-mercaptopurine, azathioprine sulphasalazine, mesalazine, olsalazine chloroquinine/hydroxychloroquinine, penicillamine, aurothiomalate (intramuscular and oral), azathioprine, cochicine, corticosteroids (oral, inhaled, and local injection), a beta-2 adrenoreceptor agonist (salbutamol, terbutaline, salmeteral), a xanthine (theophylline, aminophylline), cromoglycate, nedocromil, ketotifen, ipratropium and oxitropium, cyclosporin, FK506, rapamycin, mycophenolate
- ibuprofen a corticosteroid (e. g. prednisolone), a phosphodiesterase inhibitor, an adensosine agonist, an antithrombotic agent, a complement inhibitor, an adrenergic agent, an agent that interferes with signalling by proinflammatory cytokines such as TNF or IL-1 (e.g., a NIK, IKK, p38 or MAP kinase inhibitor), an IL-1 converting enzyme inhibitor, a T-cell signalling inhibitor (e.g.
- a kinase inhibitor a metalloproteinase inhibitor, sulfasalazine, a 6-mercaptopurine, an angiotensin converting enzyme inhibitor, a soluble cytokine receptor (e.g. soluble p55 or p75 TNF receptors and the derivatives p75TNFRigG (etanercept) and p55TNFRigG (Lenercept), siL-1RI, siL-1RII, siL-6R), an antiinflammatory cytokine (e.g.
- IL-4, IL-1 0, IL-11, IL-13 and TGF celecoxib
- folic acid hydroxychloroquine sulfate
- rofecoxib etanercept
- infliximab adalimumab
- certolizumab tocilizumab
- abatacept naproxen
- valdecoxib sulfasalazine
- methylprednisolone meloxicam
- methylprednisolone acetate gold sodium thiomalate
- aspirin triamcinolone acetonide
- propoxyphene napsylate/apap folate, nabumetone, diclofenac, piroxicam, etodolac, diclofenac sodium, oxaprozin, oxycodone HCl, hydrocodone bitartrate/apap, diclofenac sodium/misoprostol, fentanyl
- a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof may be co-administered with methotrexate or leflunomide.
- a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof may be co-administered with cyclosporine and anti-TNF antibodies as noted above.
- a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof may also be co-administered with: budenoside; epidermal growth factor; a corticosteroid; cyclosporin, sulfasalazine; an aminosalicylate; 6-mercaptopurine; azathioprine; metronidazole; a lipoxygenase inhibitor; mesalamine; olsalazine; balsalazide; an antioxidant; a thromboxane inhibitor; an IL-1 receptor antagonist; an anti-IL-1 monoclonal antibody; an anti-IL-6 monoclonal antibody; a growth factor; an elastase inhibitor; a pyridinyl-imidazole compound; an antibody to or antagonist of other human cytokines or growth factors (e.g.
- prednisolone a phosphodiesterase inhibitor
- an adenosine agonist an antithrombotic agent
- a complement inhibitor an adrenergic agent
- an agent that interferes with signalling by proinflammatory cytokines such as TNF 5 or IL-1 (e.g.
- a NIK, IKK, or MAP kinase inhibitor an IL-1 converting enzyme inhibitor; a TNF converting enzyme inhibitor; a T-cell signalling inhibitor such as kinase inhibitors; a metalloproteinase inhibitor; sulfasalazine; azathioprine; a 6-mercaptopurine; an angiotensin converting enzyme inhibitor; a soluble cytokine receptor (e.g. soluble p55 or p75 TNF receptors, siL-1RI, siL-1RII, siL-6R), and an antiinflammatory cytokine (e.g. IL-4, IL-1 0, IL-11, IL-13 or TGF).
- a cytokine receptor e.g. soluble cytokine receptor (e.g. soluble p55 or p75 TNF receptors, siL-1RI, siL-1RII, siL-6R), and an antiinflammatory cytokine (e.g. IL-4, IL
- a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof may be co-administered with a TNF antagonist (e.g. an anti-TNF antibody), D2E7 (adalimumab), CA2 (infliximab), CDP 571, a TNFR-Ig construct, (p75TNFRigG (etanercept)), a p55TNFRigG (LENERCEPTTM) inhibitor, or a PDE4 inhibitor.
- a TNF antagonist e.g. an anti-TNF antibody
- D2E7 adalimumab
- CA2 infliximab
- CDP 571 e.g. an anti-TNF antibody
- a TNFR-Ig construct e.g. an anti-TNF antibody
- p75TNFRigG etanercept
- LNERCEPTTM p55TNFRigG
- PDE4 inhibitor e.g. an anti
- a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof may be co-administered with a corticosteroid (e.g. budenoside or dexamethasone); sulfasalazine, 5-aminosalicylic acid; olsalazine; an agent that interferes with synthesis or action of proinflammatory cytokines such as IL-1 (e.g. an IL-1 converting enzyme inhibitor or IL-Ira); a T cell signaling inhibitor (e.g.
- a tyrosine kinase inhibitor 6-mercaptopurine; IL-11; mesalamine; prednisone; azathioprine; mercaptopurine; infliximab; methylprednisolone sodium succinate; diphenoxylate/atrop sulfate; loperamide hydrochloride; methotrexate; omeprazole; folate; ciprofloxacin/dextrose-water; hydrocodone bitartrate/apap; tetracycline hydrochloride; fluocinonide; metronidazole; thimerosal/boric acid; cholestyramine/sucrose; ciprofloxacin hydrochloride; hyoscyamine sulfate; meperidine hydrochloride; midazolam hydrochloride; oxycodone HCl/acetaminophen; promethazine hydrochloride; sodium phosphate; sulfame
- a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof may be co-administered with a corticosteroid; prednisolone; methylprednisolone; azathioprine; cyclophosphamide; cyclosporine; methotrexate; 4-aminopyridine; tizanidine; interferon-1a (AVONEX®; Biogen); interferon-1b (BETASERON®; Chiron/Berlex); interferon-n3) (Interferon Sciences/Fujimoto), interferon-(Alfa Wassermann/J&J), interferon 1A-IF (Serono/Inhale Therapeutics), Peginterferon 2b (Enzon/Schering-Plough), Copolymer 1 (Cop-1; COPAXONE®; Teva Pharmaceutical Industries, Inc.); hyperbaric oxygen; intravenous immunoglobulin; cladribine; an antibody
- a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof may be co-administered with antibodies to cell surface molecules such as CD2, CD3, CD4, CD8, CD19, CD20, CD25, CD28, CD30, CD40, CD45, CD69, CD80, CD86, CD90 or their ligands.
- a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof may also be co-administered with methotrexate, cyclosporine, FK506, rapamycin, mycophenolate mofetil, leflunomide, an S1PI agonist, an NSAID (e.g. ibuprofen), a corticosteroid (e.g.
- prednisolone a phosphodiesterase inhibitor, an adensosine agonist, an antithrombotic agent, a complement inhibitor, an adrenergic agent, an agent that interferes with signalling by proinflammatory cytokines such as TNF or IL-1 (e.g., a NIK, IKK, p38 or MAP kinase inhibitor), an IL-1 converting enzyme inhibitor, a TACE inhibitor, a T-cell signaling inhibitor (e. g.
- a kinase inhibitor a metalloproteinase inhibitor, sulfasalazine, azathioprine, a 6-mercaptopurine, an angiotensin converting enzyme inhibitor, a soluble cytokine receptor (e. g. soluble p55 or p75 TNF receptors, siL-1RI, siL-1RII, or siL-6R), or an antiinflammatory cytokine (e.g. IL-4, IL-1 0, IL-13 or TGF).
- a soluble cytokine receptor e. g. soluble p55 or p75 TNF receptors, siL-1RI, siL-1RII, or siL-6R
- an antiinflammatory cytokine e.g. IL-4, IL-1 0, IL-13 or TGF.
- a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof may also be co-administered with agents, such as alemtuzumab, dronabinol, daclizumab, mitoxantrone, xaliproden hydrochloride, fampridine, glatiramer acetate, natalizumab, sinnabidol, immunokine NNS03, ABR-215062, AnergiX.MS, chemokine receptor antagonists, BBR-2778, calagualine, CPI-1189, LEM (liposome encapsulated mitoxantrone), THC.CBD (cannabinoid agonist), MBP-8298, mesopram (PDE4 inhibitor), MNA-715, an anti-IL-6 receptor antibody, neurovax, pirfenidone allotrap 1258 (RDP-1258), sTNF-R1, talampanel, teriflunomide, TGF-be
- a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof may be co-administered with ibuprofen, diclofenac, misoprostol, naproxen, meloxicam, indomethacin, diclofenac, celecoxib, rofecoxib, sulfasalazine, methotrexate, azathioprine, minocyclin, prednisone, an anti-TNF antibody, D2E7 (HUMIRA®), CA2 (infliximab), CDP 571, a TNFR-Ig construct, (p75TNFRigG (ENBREL®), or p55TNFRigG (LENERCEPT®).
- a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof may be co-administered with albuterol, salmeterol/fluticasone, montelukast sodium, fluticasone propionate, budesonide, prednisone, salmeterol xinafoate, levalbuterol HCl, albuterol sulfate/ipratropium, prednisolone sodium phosphate, triamcinolone acetonide, beclomethasone dipropionate, ipratropium bromide, azithromycin, pirbuterol acetate, prednisolone, theophylline anhydrous, methylprednisolone sodium succinate, clarithromycin, zafirlukast, formoterol fumarate, influenza virus vaccine, amoxicillin trihydrate, flunisolide, cromolyn sodium, fexofenadine hydrochloride, flun
- a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof may be co-administered with albuterol sulfate/ipratropium, ipratropium bromide, salmeterol/fluticasone, albuterol, salmeterol xinafoate, fluticasone propionate, prednisone, theophylline anhydrous, methylprednisolone sodium succinate, montelukast sodium, budesonide, formoterol fumarate, triamcinolone acetonide, levofloxacin, guaifenesin, azithromycin, beclomethasone dipropionate, levalbuterol HCl, flunisolide, ceftriaxone sodium, amoxicillin trihydrate, gatifloxacin, zafirlukast, amoxicillin/clavulanate, flunisolide/menthol, chlorpheniramine/hydr
- a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof may be co-administered with calcipotriene, clobetasol propionate, triamcinolone acetonide, halobetasol propionate, tazarotene, methotrexate, fluocinonide, betamethasone diprop augmented, fluocinolone acetonide, acitretin, tar shampoo, betamethasone valerate, mometasone furoate, ketoconazole, pramoxine/fluocinolone, hydrocortisone valerate, flurandrenolide, urea, betamethasone, clobetasol propionate/emoll, fluticasone propionate, azithromycin, hydrocortisone, moisturizing formula, folic acid, desonide, pimecrolimus, coal tar, diflorasone dia
- a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof may be co-administered with methotrexate, etanercept, rofecoxib, celecoxib, folic acid, sulfasalazine, naproxen, leflunomide, methylprednisolone acetate, indomethacin, hydroxychloroquine sulfate, prednisone, sulindac, betamethasone diprop augmented, infliximab, methotrexate, folate, triamcinolone acetonide, diclofenac, dimethylsulfoxide, piroxicam, diclofenac sodium, ketoprofen, meloxicam, methylprednisolone, nabumetone, tolmetin sodium, calcipotriene, cyclosporine, diclofenac sodium/misoprostol
- a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof may be co-administered with an NSAID (e.g. diclofenac, naproxen, ibuprofen, piroxicam, or indomethacin); a COX2 inhibitor (e.g. celecoxib, rofecoxib, or valdecoxib); an anti-malarial (e.g. hydroxychloroquine); a steroid (e.g. prednisone, prednisolone, budenoside, or dexamethasone); a cytotoxic (e.g.
- an NSAID e.g. diclofenac, naproxen, ibuprofen, piroxicam, or indomethacin
- COX2 inhibitor e.g. celecoxib, rofecoxib, or valdecoxib
- an anti-malarial e.g.
- a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof may be co-administered with sulfasalazine, 5-aminosalicylic acid, olsalazine, Imuran®, an agent that interferes with the synthesis, production, or action of a proinflammatory cytokine (e.g. IL-1), or a caspase inhibitor (e.g. a IL-1 converting enzyme inhibitor or IL-Ira).
- a proinflammatory cytokine e.g. IL-1
- a caspase inhibitor e.g. a IL-1 converting enzyme inhibitor or IL-Ira
- a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof may also be co-administered with a T cell signaling inhibitor (e.g. a tyrosine kinase inhibitor), or a molecule that targets T cell activation (e.g. CTLA-4-IgG, an anti-B7 family antibody, or an anti-PD-1 family antibody).
- a T cell signaling inhibitor e.g. a tyrosine kinase inhibitor
- a molecule that targets T cell activation e.g. CTLA-4-IgG, an anti-B7 family antibody, or an anti-PD-1 family antibody.
- a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof can also be co-administered with an IL-11 antibody, an anti-cytokine antibody (e.g. fonotolizumab (anti-IFNg antibody)), or an anti-receptor receptor antibodies (e.g. an anti-IL-6 receptor antibody or an antibody to a B-cell surface molecule).
- an anti-cytokine antibody e.g. fonotolizumab (anti-IFNg antibody)
- an anti-receptor receptor antibodies e.g. an anti-IL-6 receptor antibody or an antibody to a B-cell surface molecule.
- a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof can also be co-administered with LJP 394 (abetimus), an agent that depletes or inactivates B-cells (e.g. Rituximab (anti-CD20 antibody) or lymphostat-B (anti-BlyS antibody)), a TNF antagonist (e.g. an anti-TNF antibody), D2E7 (adalimumab), CA2 (infliximab), CDP 571, a TNFR-Ig construct, (p75TNFRigG (etanercept), or p55TNFRigG (LENERCEPTTM).
- LJP 394 an agent that depletes or inactivates B-cells
- an agent that depletes or inactivates B-cells e.g. Rituximab (anti-CD20 antibody) or lymphostat-B (anti-BlyS antibody)
- a TNF antagonist e.g.
- a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof can also be co-administered with one or more agents used in the prevention or treatment of AIDS: an HIV reverse transcriptase inhibitor, an HIV protease inhibitor, an immunomodulator, or another retroviral drug.
- agents used in the prevention or treatment of AIDS include, but are not limited to, abacavir, adefovir, didanosine, dipivoxil delavirdine, efavirenz, emtricitabine, lamivudine, nevirapine, rilpivirine, stavudine, tenofovir, zalcitabine, and zidovudine.
- protease inhibitors include, but are not limited to, amprenavir, atazanavir, darunavir, indinavir, fosamprenavir, lopinavir, nelfinavir, ritonavir, saquinavir, and tipranavir.
- retroviral drugs include, but are not limited to, elvitegravir, enfuvirtide, maraviroc and raltegravir.
- a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof may be co-administered with insulin or insulins that have been modified to improve the duration of action in the body; agents that stimulate insulin secretion such as acetohexamide, chlorpropamide, glyburide, glimepiride, glipizide, glicazide, glycopyramide, gliquidone, rapaglinide, nataglinide, tolazamide or tolbutamide; agents that are glucagon-like peptide agonists such as exanatide, liraglutide or taspoglutide; agents that inhibit dipeptidyl-peptidase IV such as vildagliptin, sitagliptin, saxagliptin, linagliptin, allogliptin or septagliptin; agents that that
- a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof may be co-administered with dopamine, a diuretic (e.g. furosemide), bumetanide, thiazide, mannitol, calcium gluconate, sodium bicarbonate, albuterol, paricalcitol, doxercalciferol, cinacalcet, or bardoxalone methyl.
- dopamine e.g. furosemide
- bumetanide e.g. furosemide
- thiazide e.g. mannitol
- calcium gluconate sodium bicarbonate
- albuterol paricalcitol
- doxercalciferol cinacalcet
- bardoxalone methyl e.g. bardoxalone
- compositions of this invention are formulated such that a dosage of between 0.01-100 mg/kg body weight/day of an inventive can be administered.
- the additional therapeutic agent and the compound of formula (I) or formula (II) may act synergistically. Therefore, the amount of additional therapeutic agent in such compositions may be less than that required in a monotherapy utilizing only that therapeutic agent, or there may be fewer side effects for the patient given that a lower dose is used. In certain embodiments, in such compositions a dosage of between 0.01-1,000 ⁇ g/kg body weight/day of the additional therapeutic agent can be administered.
- the cytotoxic agent is a targeted therapy.
- the targeted therapy is one or more of an EGFR antagonist, RAF inhibitor, and/or PI3K inhibitor.
- the targeted therapy is an EGFR antagonist.
- the EGFR antagonist is N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine and/or a pharmaceutical acceptable salt thereof.
- the EGFR antagonist is N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine.
- the EGFR antagonist is N-(4-(3-fluorobenzyloxy)-3-chlorophenyl)-6-(5-((2-(methylsulfonyl)ethylamino)methyl)furan-2-yl)quinazolin-4-amine,di4-methylbenzenesulfonate or a pharmaceutically acceptable salt thereof (e.g., lapatinib).
- targeted therapy is a RAF inhibitor.
- the RAF inhibitor is a BRAF inhibitor.
- the RAF inhibitor is a CRAF inhibitor.
- the BRAF inhibitor is vemurafenib.
- the RAF inhibitor is 3-(2-cyanopropan-2-yl)-N-(4-methyl-3-(3-methyl-4-oxo-3,4-dihydroquinazolin-6-ylamino)phenyl)benzamide or a pharmaceutically acceptable salt thereof (e.g., AZ628 (CAS #878739-06-1)).
- the targeted therapy is a PI3K inhibitor.
- the cytotoxic agent is chemotherapy.
- the chemotherapy is a taxane.
- the taxane is paclitaxel.
- the taxane is docetaxel.
- the cytotoxic agent is a platinum agent. In certain embodiments, the platinum agent is carboplatin. In certain embodiments, the platinum agent is cisplatin. In certain embodiments of any of the methods, the cytotoxic agent is a taxane and a platinum agent. In certain embodiments, the taxane is paclitaxel. In certain embodiments, the taxane is docetaxel. In certain embodiments, the platinum agent is carboplatin. In certain embodiments, the platinum agent is cisplatin.
- the cytotoxic agent is a vinca alkyloid. In certain embodiments, the vinca alkyloid is vinorelbine. In certain embodiments of any of the methods, the chemotherapy is a nucleoside analog. In certain embodiments, the nucleoside analog is gemcitabine.
- the cytotoxic agent is radiotherapy.
- the compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof is concomitantly administered with the cytotoxic agent (e.g., targeted therapy, chemotherapy, and/or radiotherapy). In certain embodiments, the compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof is administered prior to and/or concurrently with the cytotoxic agent (e.g., targeted therapy, chemotherapy, and/or radiotherapy).
- the cytotoxic agent e.g., targeted therapy, chemotherapy, and/or radiotherapy.
- compounds of Formula (I) are prepared according to the following general procedures. It will be appreciated that, although the general methods depict the synthesis of certain compounds of the present invention, the following general methods, and other methods known to one of ordinary skill in the art, can be applied to all compounds and subclasses and species of each of these compounds, as described herein.
- the bromo pyrazole (3) can be formed by converting the amino pyrazole (2) using a nitrite such as, but not limited to, isoamylnitrite, sodium nitrite, or tert-butyl nitrite and a copper(II) bromide in organic an solvent such as, but not limited to, acetonitrile at a temperature of about 20° C. to about 60° C. for a time of about 5 hours.
- a nitrite such as, but not limited to, isoamylnitrite, sodium nitrite, or tert-butyl nitrite and a copper(II) bromide
- organic an solvent such as, but not limited to, acetonitrile at a temperature of about 20° C. to about 60° C. for a time of about 5 hours.
- the alkylation of pyraozle N 1 nitrogen of (2) can be carried out using an alkyl iodide/bromide/mesylate/triflate in the presense of an inorganic base such as, but not limited to, sodium hydride or cesium carbonate in a suitable organiv solvent such as, but not limited to, N,N-dimethylformamide (DMF) or tetrahydrofuran (THF) at a temperature ranging from about 0° C. to 120° C. and for a time varying from about 30 minutes to about 16 hours to form compounds of formula (4).
- an inorganic base such as, but not limited to, sodium hydride or cesium carbonate
- a suitable organiv solvent such as, but not limited to, N,N-dimethylformamide (DMF) or tetrahydrofuran (THF) at a temperature ranging from about 0° C. to 120° C. and for a time varying from about 30 minutes to about 16 hours to
- N-tert-butoxycarbonyl (Boc) group using a protic acid such as, but not limited to, trifluoroacetic acid or hydrochloric acid, and subsequent N-acetylation using acetic anhydride in the presence of a base such as, but not limited to, triethylamine (TEA) can readily afford compounds of formula (5).
- a protic acid such as, but not limited to, trifluoroacetic acid or hydrochloric acid
- a base such as, but not limited to, triethylamine (TEA)
- the bromide (5) can cross-couple with aryl/heteroaryl/cycloalkyl amine (6) under a palladium catalyst system such as, but not limited to, Ruphos pre-catalyst in combination with Brettphos/Ruphos ligand or Pd-(ipent-PEPPSI) in the presence of an inorganic base such as, but not limited to, sodium tert-butoxide or cesium carbonate in 1,4-dioxane at elevated temperature to yield compounds of formula (7).
- a palladium catalyst system such as, but not limited to, Ruphos pre-catalyst in combination with Brettphos/Ruphos ligand or Pd-(ipent-PEPPSI) in the presence of an inorganic base such as, but not limited to, sodium tert-butoxide or cesium carbonate in 1,4-dioxane at elevated temperature to yield compounds of formula (7).
- compounds of formula (7) can be prepared from the bromide (5) upon treatment with amine (6) in the presence of an inorganic base under the analogous palladium-catalyzed conditions mentioned above, followed by sequential Boc deprotection and N-acetylation.
- Compounds of formula (9) can be prepared from the bromide (8) upon treatment with aryl, heteroaryl or heterocyclic boronic acids or boronate esters under palladium catalyst conditions such as, but not limited to, [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) in the presence of an inorganic base such as, but not limited to, sodium carbonate in an organic solvent such as, but not limited to, 1,4-dioxane at an elevated temperature.
- palladium catalyst conditions such as, but not limited to, [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) in the presence of an inorganic base such as, but not limited to, sodium carbonate in an organic solvent such as, but not limited to, 1,4-dioxane at an elevated temperature.
- reaction between bromide (8) and 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (10) under a palladium catalyst conditions can produce the corresponding boronate ester (11) that upon treatment with aryl, heteroaryl or heterocyclic halides under the analogous palladium catalyst conditions can also yield compounds of formula (9).
- Compounds of formula (12) can be alkylated using an alkyl iodide/bromide/mesylate/triflate in the presense of an inorganic base such as, but not limited to, sodium hydride or cesium carbonate in a suitable organic solvent such as, but not limited to, DMF or THF at a temperature ranging from about 0° C. to 120° C. to yield compounds of formula (13).
- an inorganic base such as, but not limited to, sodium hydride or cesium carbonate
- a suitable organic solvent such as, but not limited to, DMF or THF at a temperature ranging from about 0° C. to 120° C. to yield compounds of formula (13).
- Piperidine (14) Treatment of piperidine (14) with 4-nitrophenyl chloroformate in the presence of base such as, but not limited to, pyridine followed by addition of methyl amine yields compounds of formula (15).
- Piperidine (14) can also react with aryl, heteroaryl or heterocyclic halides under palladium catalyst conditions to produce compounds of formula (16).
- Example Compound Name NMR m/z Example 2 1-[3-(2,3-dihydro-1,4- 1 H NMR (400 MHz, DMSO-d 6 ) ⁇ 6.81- 355 benzoxazin-4-yl)-1- 6.62 (m, 4H), 5.48-5.45 (m, 1H), 4.93- (oxetan-3-yl)-6,7- 4.84 (m, 4H), 4.28-4.26 (m, 2H), 4.16- dihydro-4H- 4.15 (m, 2H), 3.72-3.68 (m, 4H), 2.77- pyrazolo[4,3-c]pyridin- 2.65 (m, 2H), 2.05-1.95 (m, 3H) 5-yl]ethanone
- Example 3 1-[3-(2,3-dihydro-1,4- 1 H NMR (400 MHz, DMSO-d 6 ) ⁇ 7.09- 371 benzothiazin-4-yl)-1- 7.07 (m, 1
- Example Compound Name NMR m/z Example 29 1-[3-[6-(1,3- 1 H NMR (400 MHz, DMSO-d 6 ) ⁇ 7.69 (s, 447 dimethylpyrazol-4-yl)- 1H), 7.06 (s, 1H), 7.02-6.97 (m, 1H), 6.54- 3,4-dihydro-2H- 6.48 (m, 1H), 5.49-5.41 (m, 1H), 4.96- quinolin-1-yl]-1- 4.81 (m, 4H), 4.11-4.09 (m, 2H), 3.75 (s, (oxetan-3-yl)-6,7- 3H), 3.73-3.59 (m, 4H), 2.87-2.62 (m, dihydro-4H- 4H), 2.23 (s, 3H), 2.05-1.94 (m, 5H) pyrazolo[4,3-c]pyridin- 5-yl]ethanone
- Example 30 1-[1-(oxetan-3-
- Example Compound Name NMR m/z Example Compound Name NMR m/z
- Example 47 1-[3-[6-(1,3- 1 H NMR (400 MHz, DMSO-d 6 ) ⁇ 7.68 (s, 1H), 461 dimethylpyrazol-4-yl)- 7.03 (s, 1H), 6.99-6.94 (m, 1H), 6.49-6.39 3,4-dihydro-2H- (m, 1H), 4.95-4.85 (m, 1H), 4.11-4.09 (m, quinolin-1-yl]-1- 2H), 4.05-3.93 (m, 2H), 3.82-3.68 (m, 7H), tetrahydrofuran-3-yl- 3.60-3.50 (m, 2H), 2.89-2.63 (m, 4H), 2.34- 6,7-dihydro-4H- 2.18 (m, 5H), 2.09-1.90 (m, 5H) pyrazolo[4,3-c]pyridin- 5-yl
- the mixture was irradiated in a microwave at 120° C. for 30 min. After cooling the reaction to room temperature, the mixture was filtered and the filtrate was concentrated in vacuo.
- Example Compound Name NMR m/z Example 66 1-[3-[6-(1- 1 H NMR (400 MHz, DMSO-d 6 ) ⁇ 7.92 447 methylpyrazol-4-yl)-3,4- (s, 1H), 7.68 (s, 1H), 7.20 (s, 1H), 7.15- dihydro-2H-quinolin-1- 7.06 (m, 1H), 6.49-6.37 (m, 1H), 4.93- yl]-1-tetrahydrofuran-3- 4.85 (m, 1H), 4.14-4.06 (m, 2H), 4.05- yl-6,7-dihydro-4H- 3.92 (m, 2H), 3.87-3.65 (m, 7H), 3.62- pyrazolo[4,3-c]pyridin- 3.48 (m, 2H), 2.83-2.78 (m, 4H), 2.37- 5-yl]ethanone 2.18 (m, 2H), 2.06 (s, 2H), 1.95-1
- Racemic 1-[3-[6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-1-tetrahydrofuran-3-yl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (Example 66, 75 mg) was separated using chiral SFC (Chiralcel OJ 250 ⁇ 30 mm I.D., 5 um; Supercritical CO 2 /EtOH (0.1% NH 3 H 2 O) 65:35 at 50 mL/min) to give 1-[3-[6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-1-[(3R)-tetrahydrofuran-3-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (23 mg, first peak) and 1-
- Example 70 1 H NMR (400 MHz, DMSO-d 6 ) ⁇ 7.92 (s, 1H), 7.68 (s, 1H), 7.20 (s, 1H), 7.15-7.06 (m, 1H), 6.49-6.37 (m, 1H), 4.93-4.85 (m, 1H), 4.14-4.06 (m, 2H), 4.05-3.92 (m, 2H), 3.87-3.65 (m, 7H), 3.62-3.48 (m, 2H), 2.83-2.78 (m, 4H), 2.37-2.18 (m, 2H), 2.06-1.94 (m, 5H).
- Example 71 1 H NMR (400 MHz, DMSO-d 6 ) ⁇ 7.92 (s, 1H), 7.68 (s, 1H), 7.20 (s, 1H), 7.15-7.06 (m, 1H), 6.49-6.37 (m, 1H), 4.93-4.85 (m, 1H), 4.14-4.06 (m, 2H), 4.05-3.92 (m, 2H), 3.87-3.65 (m, 7H), 3.62-3.48 (m, 2H), 2.83-2.78 (m, 4H), 2.37-2.18 (m, 2H), 2.06-1.94 (m, 5H).
- Example Compound Name NMR m/z Example 78 1-[3-[6-(1- 1 H NMR (400 MHz, DMSO-d 6 ) ⁇ 7.90 (s, 460 methylpyrazol-4-yl)- 1H), 7.66 (s, 1H), 7.19 (s, 1H), 7.11-7.07 3,4-dihydro-2H- (m, 1H), 6.44-6.38 (m, 1H), 4.30-4.25 quinolin-1-yl]-1-(4- (m, 2H), 4.24-4.10 (m, 2H), 3.87 (s, 3H), piperidyl)-6,7-dihydro- 3.81-3.63 (m, 2H), 3.54-3.51 (m, 2H), 4H-pyrazolo[4,3- 3.24-3.22 (m, 2H), 2.81-2.70 (m, 6H), c]pyridin-5- 2.06-1.93 (m, 9H) yl]ethanone
- Example Compound Name NMR m/z Example 80 1-[1-(1-methyl-4- 1 H NMR (400 MHz, DMSO-d 6 ) ⁇ 8.21 (s, 474 piperidyl)-3-[6-(1- 1H), 7.90 (s, 1H), 7.66 (s, 1H), 7.18 (s, 1H), methylpyrazol-4-yl)- 7.11-7.07 (m, 1H), 6.43-6.38 (m, 1H), 3,4-dihydro-2H- 4.09-4.08 (m, 2H), 4.07-3.99 (m, 1H), quinolin-1-yl]-6,7- 3.81(s, 3H), 3.73-3.66 (m, 4H), 2.93-2.91 dihydro-4H- (m, 2H), 2.80-2.77 (m, 4H), 2.25 (s, 3H), pyrazolo[4,3-c]pyridin- 2.14-2.11 (m, 2H), 2.05-1.95 (m, 3
- Racemic 1-[3-[3-(2,2-difluoroethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-1-tetrahydrofuran-3-yl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (Example 81, 65 mg) was separated using chiral SFC (MG-II; Chiralpak AD 250 ⁇ 30 mm I.D., 5 um; Supercritical CO 2 /EtOH (0.1% NH 3 H 2 O) 70:30 at 60 mL/min) to give (S, S)-1-[3-[3-(2,2-difluoroethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-1-tetrahydrofuran-3-yl-6,7-dihydro-4
- Example 82 1 H NMR (400 MHz, CDCl 3 ) ⁇ 7.68-7.66 (m, 1H), 7.52-7.50 (m, 1H), 7.18-7.12 (m, 2H), 6.54-6.50 (m, 1H), 6.01-5.87 (m, 1H), 4.78-4.74 (m, 1H), 4.21-4.04 (m, 4H), 4.02-3.93 (m, 7H), 3.85-3.76 (m, 2H), 3.45-3.35 (m, 1H), 3.10-3.00 (m, 1H), 2.76-2.70 (m, 2H), 2.42-2.39 (m, 2H), 2.18-1.96 (m, 6H).
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Organic Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Rheumatology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Immunology (AREA)
- Pain & Pain Management (AREA)
- Engineering & Computer Science (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Peptides Or Proteins (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The present invention relates to compounds of formula (I) or formula (II):
and to salts thereof, wherein R1-R4 of formula (I) and R1-R3 of formula (II) have any of the values defined herein, and compositions and uses thereof. The compounds are useful as inhibitors of CBP and/or EP300. Also included are pharmaceutical compositions comprising a compound of formula (I) of formula (II) or a pharmaceutically acceptable salt thereof, and methods of using such compounds and salts in the treatment of various CBP and/or EP300-mediated disorders.
Description
- This application is a continuation of U.S. application Ser. No. 14/952,821, filed Nov. 25, 2015, which claims priority to International Application No. PCT/CN2014/092380, filed Nov. 27, 2014, and International Application No. PCT/CN2015/092965, filed Oct. 27, 2015, which are hereby incorporated by reference.
- The present invention relates to compounds useful as inhibitors of CBP/EP300 and methods of treating cancer using such inhibitors.
- The instant application contains a Sequence Listing which has been submitted in ASCII format via EFS-Web and is hereby incorporated by reference in its entirety. Said ASCII copy, created on Nov. 23, 2015, is named 01076.024US3_SL.txt and is 6,794 bytes in size.
- Chromatin is a complex combination of DNA and protein that makes up chromosomes. It is found inside the nuclei of eukaryotic cells and is divided between heterochromatin (condensed) and euchromatin (extended) forms. The major components of chromatin are DNA and proteins. Histones are the chief protein components of chromatin, acting as spools around which DNA winds. The functions of chromatin are to package DNA into a smaller volume to fit in the cell, to strengthen the DNA to allow mitosis and meiosis, and to serve as a mechanism to control expression and DNA replication. The chromatin structure is controlled by a series of post-translational modifications to histone proteins, notably histones H3 and H4, and most commonly within the “histone tails” which extend beyond the core nucleosome structure. Histone tails tend to be free for protein-protein interaction and are also the portion of the histone most prone to post-translational modification. These modifications include acetylation, methylation, phosphorylation, ubiquitinylation, and SUMOylation. These epigenetic marks are written and erased by specific enzymes that place the tags on specific residues within the histone tail, thereby forming an epigenetic code, which is then interpreted by the cell to allow gene specific regulation of chromatin structure and thereby transcription.
- Of all classes of proteins, histones are amongst the most susceptible to post-translational modification. Histone modifications are dynamic, as they can be added or removed in response to specific stimuli, and these modifications direct both structural changes to chromatin and alterations in gene transcription. Distinct classes of enzymes, namely histone acetyltransferases (HATs) and histone deacetylases (HDACs), acetylate or de-acetylate specific histone lysine residues (Struhl K., Genes Dev., 1989, 12, 5, 599-606).
- Bromodomains, which are approximately 110 amino acids long, are found in a large number of chromatin-associated proteins and have been identified in approximately 70 human proteins, often adjacent to other protein motifs (Jeanmougin F., et al., Trends Biochem. Sci., 1997, 22, 5, 151-153; and Tamkun J. W., et al., Cell, 1992, 7, 3, 561-572). Interactions between bromodomains and modified histones may be an important mechanism underlying chromatin structural changes and gene regulation. Bromodomain-containing proteins have been implicated in disease processes including cancer, inflammation and viral replication. See, e.g., Prinjha et al., Trends Pharm. Sci., 33(3):146-153 (2012) and Muller et al., Expert Rev., 13(29): 1-20 (September 2011).
- Cell-type specificity and proper tissue functionality requires the tight control of distinct transcriptional programs that are intimately influenced by their environment. Alterations to this transcriptional homeostasis are directly associated with numerous disease states, most notably cancer, immuno-inflammation, neurological disorders, and metabolic diseases. Bromodomains reside within key chromatin modifying complexes that serve to control distinctive disease-associated transcriptional pathways. This is highlighted by the observation that mutations in bromodomain-containing proteins are linked to cancer, as well as immune and neurologic dysfunction. Hence, the selective inhibition of bromodomains across a specific family, such as the selective inhibition of a bromodomain of CBP/EP300, creates varied opportunities as novel therapeutic agents in human dysfunction.
- There is a need for treatments for cancer, immunological disorders, and other CBP/EP300 bromodomain related diseases.
- One aspect is a compound of formula (I) or formula (II):
- or a salt thereof, wherein:
- R1 of Formula (I) is C1-12alkyl, C2-12alkenyl, C2-12alkynyl, 3-12 membered carbocycle, and 3-12 membered heterocycle, wherein each C1-12alkyl, C2-12alkenyl, C2-12alkynyl, 3-12 membered carbocycle, and 3-12 membered heterocycle of R1 is optionally substituted with one or more groups Rb;
- R2 of Formula (I) is selected from C6-C20 aryl, C1-C20 heteroaryl, —(C6-C20 aryl)-(C1-C20 heteroaryl), —(C1-C20 heteroaryl)-(C6-C20 aryl), and —(C1-C20 heteroaryl)-(C1-C20 heteroaryl), wherein each C6-C20 aryl, C1-C20 heteroaryl, —(C6-C20 aryl)-(C1-C20 heteroaryl) and —(C1-C20 heteroaryl)-(C1-C20 heteroaryl) is independently optionally substituted with one or more substituent groups independently selected from Rc, oxo, —F, —Cl, —Br, —I, —NO2, —N(Ra)2, —CN, —C(O)—N(Ra)2, —S(O)—N(Ra)2, —S(O)2—N(Ra)2, —O—Ra, —S—Ra, —O—C(O)—Ra, —O—C(O)—O—Ra, —C(O)—Ra, —C(O)—O—Ra, —S(O)—Ra, —S(O)2—Ra, —O—C(O)—N(Ra)2, —N(Ra)—C(O)—ORa, —N(Ra)—C(O)—N(Ra)2, —N(Ra)—C(O)—Ra, —N(Ra)—S(O)—Ra, —N(Ra)—S(O)2—Ra, —N(Ra)—S(O)—N(Ra)2, and —N(Ra)—S(O)2—N(Ra)2;
- R3 of Formula (I) is C1-12alkyl, C2-12alkenyl, C2-12alkynyl, 3-12 membered carbocycle, and 3-12 membered heterocycle, wherein each C1-12alkyl, C2-12alkenyl, C2-12alkynyl, 3-12 membered carbocycle, and 3-12 membered heterocycle of R3 is optionally substituted with one or more groups Re; or
- R2 and R3 of Formula (I) taken together with the nitrogen to which they are attached form a 3-12 membered heterocycle that is optionally substituted with one or more groups Re;
- R4 of Formula (I) is C1-4alkyl, C2-4alkenyl, C2-4alkynyl, 3-5 membered carbocycle, 3-5 membered heterocycle, —C(O)—N(Rh)2, —S(O)—N(Rh)2, —S(O)2—N(Rh)2, —C(O)—Rh, —C(O)—O—Rh, —S(O)—Rh, or —S(O)2—Rh, wherein any C1-4alkyl, C2-4alkenyl, C2-4alkynyl, 3-5 membered carbocycle, and 3-5 membered heterocycle is optionally substituted with one or more substituent groups independently selected from —F, —Cl, —Br, —I, 3-5 membered carbocycle, —C(O)—N(Rh)2, —S(O)—N(Rh)2, —S(O)2—N(Rh)2, —O—Rh, —S—Rh, —O—C(O)—Rh, —O—C(O)—O—Rh, —C(O)—Rh, —C(O)—O—Rh, —S(O)—Rh, —S(O)2—Rh, —O—C(O)—N(Rh)2, —N(Rh)—C(O)—ORh, —N(Rh)—C(O)—N(Rh)2, —N(Rh)—C(O)—Ra, —N(Rh)—S(O)—Rh, —N(Rh)—S(O)2—Rh, —N(Rh)—S(O)—N(Rh)2, and —N(Rh)—S(O)2—N(Rh)2;
- each Ra of Formula (I) is independently selected from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl, wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C1-6alkoxy, carbocyclyl, heterocyclyl, and C1-C6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; or two Ra are taken together with the nitrogen to which they are attached to form a heterocyclyl that is optionally substituted with one or more groups independently selected from oxo, halo and C1-3alkyl that is optionally substituted with one or more groups independently selected from oxo and halo;
- each Rb of Formula (I) is independently selected from oxo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, —F, —Cl, —Br, —I, —NO2, —N(Rc)2, —CN, —C(O)—N(Rc)2, —S(O)—N(Rc)2, —S(O)2—N(Rc)2, —O—Rc, —S—Rc, —O—C(O)—Rc, —O—C(O)—O—Rc, —C(O)—Rc, —C(O)—O—Rc, —S(O)—Rc, —S(O)2—Rc, —O—C(O)—N(Rc)2, —N(Rc)—C(O)—ORc, —N(Rc)—C(O)—N(Rc)2, —N(Rc)—C(O)—Rc, —N(Rc)—S(O)—Rc, —N(Rc)—S(O)2—Rc, —N(Rc)—S(O)—N(Rc)2, and —N(Rc)—S(O)2—N(Rc)2, wherein any C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more groups independently selected from oxo, halo, —NO2, —N(Rc)2, —CN, —C(O)—N(Rc)2, —S(O)—N(Rc)2, —S(O)2—N(Rc)2, —O—Rc, —S—Rc, —O—C(O)—Rc, —C(O)—Rc, —C(O)—O—Rc, —S(O)—Rc, —S(O)2—Rc, —C(O)—N(Rc)2, —N(Rc)—C(O)—Rc, —N(Rc)—S(O)—Rc, —N(Rc)—S(O)2—Rc and C1-6alkyl that is optionally substituted with one or more groups independently selected from oxo and halo;
- each Rc of Formula (I) is independently selected from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl, wherein any C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, carbocyclyl, heterocyclyl, halo, —NO2, —N(Rd)2, —CN, —C(O)—N(Rd)2, —S(O)—N(Rd)2, —S(O)2—N(Rd)2, —O—Rd, —S—Rd, —O—C(O)—Rd, —C(O)—Rd, —C(O)—O—Rd, —S(O)—Rd, —S(O)2—Rd, —C(O)—N(Rd)2, —N(Rd)—C(O)—Rd, —N(Rd)—S(O)—Rd, —N(Rd)—S(O)2—Rd, and C1-6alkyl, which carbocyclyl and C1-6alkyl are optionally substituted with one or more groups independently selected from oxo, halo, C1-6alkyl, cyano, —N(Rd)2, —O—Rd, heterocyclyl, and carbocyclyl that is optionally substituted with one or more groups independently selected from halo, and C1-6alkyl;
- each Rd of Formula (I) is independently selected from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkoxy, carbocyclyl, and heterocyclyl, wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkoxy, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C1-6alkoxy, carbocyclyl, heterocyclyl, and C1-C6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; or two Rd are taken together with the nitrogen to which they are attached to form a heterocyclyl that is optionally substituted with one or more groups independently selected from oxo, halo and C1-3alkyl that is optionally substituted with one or more groups independently selected from oxo and halo;
- each Re of Formula (I) is independently selected from oxo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, —F, —Cl, —Br, —I, —NO2, —N(Rf)2, —CN, —C(O)—N(Rf)2, —S(O)—N(Rf)2, —S(O)2—N(Rf)2, —O—Rf, —S—Rf, —O—C(O)—Rf, —O—C(O)—O—Rf, —C(O)—Rf, —C(O)—O—Rf, —S(O)—Rf, —S(O)2—Rf, —O—C(O)—N(Rf)2, —N(Rf)—C(O)—ORf, —N(Rf)—C(O)—N(Rf)2, —N(Rf)—C(O)—Rf, —N(Rf)—S(O)—Rf, —N(Rf)—S(O)2—Rf, —N(Rf)—S(O)—N(Rf)2, and —N(Rf)—S(O)2—N(Rf)2, wherein any C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more groups independently selected from oxo, halo, —NO2, —N(Rf)2, —CN, —C(O)—N(Rf)2, —S(O)—N(Rf)2, —S(O)2—N(Rf)2, —O—Rf, —S—Rf, —O—C(O)—Rf, —C(O)—Rf, —C(O)—O—Rf, —S(O)—Rf, —S(O)2—Rf, —C(O)—N(Rf)2, —N(Rf)—C(O)—Rf, —N(Rf)—S(O)—Rf, —N(Rf)—S(O)2—Rf, carbocycle, and C1-6alkyl that is optionally substituted with one or more groups independently selected from oxo and halo;
- each Rf of Formula (I) is independently selected from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl, wherein any C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, carbocyclyl, heterocyclyl, halo, —NO2, —N(Rg)2, —CN, —C(O)—N(Rg)2, —S(O)—N(Rg)2, —S(O)2—N(Rg)2, —O—Rg, —S—Rg, —O—C(O)—Rg, —C(O)—Rg, —C(O)—O—Rg, —S(O)—Rg, —S(O)2—Rg, —C(O)—N(Rg)2, —N(Rg)—C(O)—Rg, —N(Rg)—S(O)—Rg, —N(Rg)—S(O)2—Rg, and C1-6alkyl, which carbocyclyl and C1-6alkyl are optionally substituted with one or more groups independently selected from oxo, halo, C1-6alkyl, cyano, —N(Rg)2, —O—Rg, heterocyclyl, and carbocyclyl that is optionally substituted with one or more groups independently selected from halo, and C1-6alkyl;
- each Rg of Formula (I) is independently selected from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkoxy, carbocyclyl, and heterocyclyl, wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkoxy, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C1-6alkoxy, carbocyclyl, heterocyclyl, and C1-C6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; or two Rg are taken together with the nitrogen to which they are attached to form a heterocyclyl that is optionally substituted with one or more groups independently selected from oxo, halo and C1-3alkyl that is optionally substituted with one or more groups independently selected from oxo and halo;
- each Rh of Formula (I) is independently selected from hydrogen, C1-4alkyl, C2-4alkenyl, C2-4alkynyl, and C2-5cycloalkyl, wherein each C1-4alkyl, C2-4alkenyl, C2-4alkynyl, and C2-5cycloalkyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C1-3alkoxy, and C1-C3 alkyl that is optionally substituted with one or more groups independently selected from halo; and
- R1 of Formula (II) is selected from C6-C20 aryl, C1-C20 heteroaryl, —(C6-C20 aryl)-(C1-C20 heteroaryl), and —(C1-C20 heteroaryl)-(C1-C20 heteroaryl), wherein each C6-C20 aryl, C1-C20 heteroaryl, —(C6-C20 aryl)-(C1-C20 heteroaryl) and —(C1-C20 heteroaryl)-(C1-C20 heteroaryl) is independently optionally substituted with one or more substituent groups independently selected from Rc, oxo, —F, —Cl, —Br, —I, —NO2, —N(Ra)2, —CN, —C(O)—N(Ra)2, —S(O)—N(Ra)2, —S(O)2—N(Ra)2, —O—Ra, —S—Ra, —O—C(O)—Ra, —O—C(O)—O—Ra, —C(O)—Ra, —C(O)—O—Ra, —S(O)—Ra, —S(O)2—Ra, —O—C(O)—N(Ra)2, —N(Ra)—C(O)—ORa, —N(Ra)—C(O)—N(Ra)2, —N(Ra)—C(O)—Ra, —N(Ra)—S(O)—Ra, —N(Ra)—S(O)2—Ra, —N(Ra)—S(O)—N(Ra)2, and —N(Ra)—S(O)2—N(Ra)2;
- R2 of Formula (II) is C1-12alkyl, C2-12alkenyl, C2-12alkynyl, 3-12 membered carbocycle, and 3-12 membered heterocycle, wherein each C1-12alkyl, C2-12alkenyl, C2-12alkynyl, 3-12 membered carbocycle, and 3-12 membered heterocycle of R2 is optionally substituted with one or more groups Rb;
- R3 of Formula (II) is C1-4alkyl, C2-4alkenyl, C2-4alkynyl, 3-5 membered carbocycle, 3-5 membered heterocycle, —C(O)—N(Re)2, —S(O)—N(Re)2, —S(O)2—N(Re)2, —C(O)—Re, —C(O)—O—Re, —S(O)—Re, or —S(O)2—Re, wherein any C1-4alkyl, C2-4alkenyl, C2-4alkynyl, 3-5 membered carbocycle, and 3-5 membered heterocycle is optionally substituted with one or more substituent groups independently selected from —F, —Cl, —Br, —I, 3-5 membered carbocycle, —C(O)—N(Re)2, —S(O)—N(Re)2, —S(O)2—N(Re)2, —O—Re, —S—Re, —O—C(O)—Re, —O—C(O)—O—Re, —C(O)—Re, —C(O)—O—Re, —S(O)—Re, —S(O)2—Re, —O—C(O)—N(Re)2, —N(Re)—C(O)—ORe, —N(Re)—C(O)—N(Re)2, —N(Re)—C(O)—Re, —N(Re)—S(O)—Re, —N(Re)—S(O)2—Re, —N(Re)—S(O)—N(Re)2, and —N(Re)—S(O)2—N(Re)2;
- each Ra of Formula (II) is independently selected from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl, wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C1-6alkoxy, carbocyclyl, heterocyclyl, and C1-C6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; or two Ra are taken together with the nitrogen to which they are attached to form a heterocyclyl that is optionally substituted with one or more groups independently selected from oxo, halo and C1-3alkyl that is optionally substituted with one or more groups independently selected from oxo and halo;
- each Rb of Formula (II) is independently selected from oxo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, —F, —Cl, —Br, —I, —NO2, —N(Rc)2, —CN, —C(O)—N(Rc)2, —S(O)—N(Rc)2, —S(O)2—N(Rc)2, —O—Rc, —S—Rc, —O—C(O)—Rc, —O—C(O)—O—Rc, —C(O)—Rc, —C(O)—O—Rc, —S(O)—Rc, —S(O)2—Rc, —O—C(O)—N(Rc)2, —N(Rc)—C(O)—ORc, —N(Rc)—C(O)—N(Rc)2, —N(Rc)—C(O)—Rc, —N(Rc)—S(O)—Rc, —N(Rc)—S(O)2—Rc, —N(Rc)—S(O)—N(Rc)2, and —N(Rc)—S(O)2—N(Rc)2, wherein any C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more groups independently selected from oxo, halo, —NO2, —N(Rc)2, —CN, —C(O)—N(Rc)2, —S(O)—N(Rc)2, —S(O)2—N(Rc)2, —O—Rc, —S—Rc, —O—C(O)—Rc, —C(O)—Rc, —C(O)—O—Rc, —S(O)—Rc, —S(O)2—Rc, —C(O)—N(Rc)2, —N(Rc)—C(O)—Rc, —N(Rc)—S(O)—Rc, —N(Rc)—S(O)2—Rc and C1-6alkyl that is optionally substituted with one or more groups independently selected from oxo and halo;
- each Rc of Formula (II) is independently selected from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl, wherein any C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, carbocyclyl, heterocyclyl, halo, —NO2, —N(Rd)2, —CN, —C(O)—N(Rd)2, —S(O)—N(Rd)2, —S(O)2—N(Rd)2, —O—Rd, —S—Rd, —O—C(O)—Rd, —C(O)—Rd, —C(O)—O—Rd, —S(O)—Rd, —S(O)2—Rd, —C(O)—N(Rd)2, —N(Rd)—C(O)—Rd, —N(Rd)—S(O)—Rd, —N(Rd)—S(O)2—Rd, and C1-6alkyl, which carbocyclyl and C1-6alkyl are optionally substituted with one or more groups independently selected from oxo, halo, C1-6alkyl, cyano, —N(Rd)2, —O—Rd, heterocyclyl, and carbocyclyl that is optionally substituted with one or more groups independently selected from halo, and C1-6alkyl;
- each Rd of Formula (II) is independently selected from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkoxy, carbocyclyl, and heterocyclyl, wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkoxy, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C1-6alkoxy, carbocyclyl, heterocyclyl, and C1-C6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; or two Rd are taken together with the nitrogen to which they are attached to form a heterocyclyl that is optionally substituted with one or more groups independently selected from oxo, halo and C1-3alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; and
- each Re of Formula (II) is independently selected from hydrogen, C1-4alkyl, C2-4alkenyl, C2-4alkynyl, and C2-5cycloalkyl, wherein each C1-4alkyl, C2-4alkenyl, C2-4alkynyl, and C2-5cycloalkyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C1-3alkoxy, and C1-C3 alkyl that is optionally substituted with one or more groups independently selected from halo; provided that R1 is not unsubstituted phenyl, when R2 is carboxymethyl or 2-carboxyethyl.
- Another aspect includes a compound of formula (I):
- or a salt thereof, wherein:
- R1 is C1-12alkyl, C2-12alkenyl, C2-12alkynyl, 3-12 membered carbocycle, and 3-12 membered heterocycle, wherein each C1-12alkyl, C2-12alkenyl, C2-12alkynyl, 3-12 membered carbocycle, and 3-12 membered heterocycle of R1 is optionally substituted with one or more groups Rb;
- R2 is selected from C6-C20 aryl, C1-C20 heteroaryl, —(C6-C20 aryl)-(C1-C20 heteroaryl), —(C1-C20 heteroaryl)-(C6-C20 aryl), and —(C1-C20 heteroaryl)-(C1-C20 heteroaryl), wherein each C6-C20 aryl, C1-C20 heteroaryl, —(C6-C20 aryl)-(C1-C20 heteroaryl) and —(C1-C20 heteroaryl)-(C1-C20 heteroaryl) is independently optionally substituted with one or more substituent groups independently selected from Rc, oxo, —F, —Cl, —Br, —I, —NO2, —N(Ra)2, —CN, —C(O)—N(Ra)2, —S(O)—N(Ra)2, —S(O)2—N(Ra)2, —O—Ra, —S—Ra, —O—C(O)—Ra, —O—C(O)—O—Ra, —C(O)—Ra, —C(O)—O—Ra, —S(O)—Ra, —S(O)2—Ra, —O—C(O)—N(Ra)2, —N(Ra)—C(O)—ORa, —N(Ra)—C(O)—N(Ra)2, —N(Ra)—C(O)—Ra, —N(Ra)—S(O)—Ra, —N(Ra)—S(O)2—Ra, —N(Ra)—S(O)—N(Ra)2, and —N(Ra)—S(O)2—N(Ra)2;
- R3 is C1-12alkyl, C2-12alkenyl, C2-12alkynyl, 3-12 membered carbocycle, and 3-12 membered heterocycle, wherein each C1-12alkyl, C2-12alkenyl, C2-12alkynyl, 3-12 membered carbocycle, and 3-12 membered heterocycle of R3 is optionally substituted with one or more groups Re; or
- R2 and R3 taken together with the nitrogen to which they are attached form a 3-12 membered heterocycle that is optionally substituted with one or more groups Re; R4 is C1-4alkyl, C2-4alkenyl, C2-4alkynyl, 3-5 membered carbocycle, 3-5 membered heterocycle, —C(O)—N(Rh)2, —S(O)—N(Rh)2, —S(O)2—N(Rh)2, —C(O)—Rh, —C(O)—O—Rh, —S(O)—Rh, or —S(O)2—Rh, wherein any C1-4alkyl, C2-4alkenyl, C2-4alkynyl, 3-5 membered carbocycle, and 3-5 membered heterocycle is optionally substituted with one or more substituent groups independently selected from —F, —Cl, —Br, —I, 3-5 membered carbocycle, —C(O)—N(Rh)2, —S(O)—N(Rh)2, —S(O)2—N(Rh)2, —O—Rh, —S—Rh, —O—C(O)—Rh, —O—C(O)—O—Rh, —C(O)—Rh, —C(O)—O—Rh, —S(O)—Rh, —S(O)2—Rh, —O—C(O)—N(Rh)2, —N(Rh)—C(O)—ORh, —N(Rh)—C(O)—N(Rh)2, —N(Rh)—C(O)—Ra, —N(Rh)—S(O)—Rh, —N(Rh)—S(O)2—Rh, —N(Rh)—S(O)—N(Rh)2, and —N(Rh)—S(O)2—N(Rh)2;
- each Ra is independently selected from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl, wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C1-6alkoxy, carbocyclyl, heterocyclyl, and C1-C6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; or two Ra are taken together with the nitrogen to which they are attached to form a heterocyclyl that is optionally substituted with one or more groups independently selected from oxo, halo and C1-3alkyl that is optionally substituted with one or more groups independently selected from oxo and halo;
- each Rb is independently selected from oxo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, —F, —Cl, —Br, —I, —NO2, —N(Rc)2, —CN, —C(O)—N(Rc)2, —S(O)—N(Rc)2, —S(O)2—N(Rc)2, —O—Rc, —S—Rc, —O—C(O)—Rc, —O—C(O)—O—Rc, —C(O)—Rc, —C(O)—O—Rc, —S(O)—Rc, —S(O)2—Rc, —O—C(O)—N(Rc)2, —N(Rc)—C(O)—ORc, —N(Rc)—C(O)—N(Rc)2, —N(Rc)—C(O)—Rc, —N(Rc)—S(O)—Rc, —N(Rc)—S(O)2—Rc, —N(Rc)—S(O)—N(Rc)2, and —N(Rc)—S(O)2—N(Rc)2, wherein any C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more groups independently selected from oxo, halo, —NO2, —N(Rc)2, —CN, —C(O)—N(Rc)2, —S(O)—N(Rc)2, —S(O)2—N(Rc)2, —O—Rc, —S—Rc, —O—C(O)—Rc, —C(O)—Rc, —C(O)—O—Rc, —S(O)—Rc, —S(O)2—Rc, —C(O)—N(Rc)2, —N(Rc)—C(O)—Rc, —N(Rc)—S(O)—Rc, —N(Rc)—S(O)2—R and C1-6alkyl that is optionally substituted with one or more groups independently selected from oxo and halo;
- each Rc is independently selected from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl, wherein any C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, carbocyclyl, heterocyclyl, halo, —NO2, —N(Rd)2, —CN, —C(O)—N(Rd)2, —S(O)—N(Rd)2, —S(O)2—N(Rd)2, —O—Rd, —S—Rd, —O—C(O)—Rd, —C(O)—Rd, —C(O)—O—Rd, —S(O)—Rd, —S(O)2—Rd, —C(O)—N(Rd)2, —N(Rd)—C(O)—Rd, —N(Rd)—S(O)—Rd, —N(Rd)—S(O)2—Rd, and C1-6alkyl, which carbocyclyl and C1-6alkyl are optionally substituted with one or more groups independently selected from oxo, halo, C1-6alkyl, cyano, —N(Rd)2, —O—Rd, heterocyclyl, and carbocyclyl that is optionally substituted with one or more groups independently selected from halo, and C1-6alkyl;
- each Rd is independently selected from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkoxy, carbocyclyl, and heterocyclyl, wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkoxy, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C1-6alkoxy, carbocyclyl, heterocyclyl, and C1-C6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; or two Rd are taken together with the nitrogen to which they are attached to form a heterocyclyl that is optionally substituted with one or more groups independently selected from oxo, halo and C1-3alkyl that is optionally substituted with one or more groups independently selected from oxo and halo;
- each Re is independently selected from oxo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, —F, —Cl, —Br, —I, —NO2, —N(Rf)2, —CN, —C(O)—N(Rf)2, —S(O)—N(Rf)2, —S(O)2—N(Rf)2, —O—Rf, —S—Rf, —O—C(O)—Rf—O—C(O)—O—Rf, —C(O)—Rf, —C(O)—O—Rf, —S(O)—Rf, —S(O)2—Rf, —O—C(O)—N(Rf)2, —N(Rf)—C(O)—ORf, —N(Rf)—C(O)—N(Rf)2, —N(Rf)—C(O)—Rf, —N(Rf)—S(O)—Rf, —N(Rf)—S(O)2—Rf, —N(Rf)—S(O)—N(Rf)2, and —N(Rf)—S(O)2—N(Rf)2, wherein any C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more groups independently selected from oxo, halo, —NO2, —N(Rf)2, —CN, —C(O)—N(Rf)2, —S(O)—N(Rf)2, —S(O)2—N(Rf)2, —O—Rf, —S—Rf, —O—C(O)—Rf, —C(O)—Rf, —C(O)—O—Rf, —S(O)—Rf, —S(O)2—Rf, —C(O)—N(Rf)2, —N(Rf)—C(O)—Rf, —N(Rf)—S(O)—Rf, —N(Rf)—S(O)2—Rf, carbocycle, and C1-6alkyl that is optionally substituted with one or more groups independently selected from oxo and halo;
- each Rf is independently selected from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl, wherein any C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, carbocyclyl, heterocyclyl, halo, —NO2, —N(Rg)2, —CN, —C(O)—N(Rg)2, —S(O)—N(Rg)2, —S(O)2—N(Rg)2, —O—Rg, —S—Rg, —O—C(O)—Rg, —C(O)—Rg, —C(O)—O—Rg, —S(O)—Rg, —S(O)2—Rg, —C(O)—N(Rg)2, —N(Rg)—C(O)—Rg, —N(Rg)—S(O)—Rg, —N(Rg)—S(O)2—Rg, and C1-6alkyl, which carbocyclyl and C1-6alkyl are optionally substituted with one or more groups independently selected from oxo, halo, C1-6alkyl, cyano, —N(Rg)2, —O—Rg, heterocyclyl, and carbocyclyl that is optionally substituted with one or more groups independently selected from halo, and C1-6alkyl;
- each Rg is independently selected from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkoxy, carbocyclyl, and heterocyclyl, wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkoxy, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C1-6alkoxy, carbocyclyl, heterocyclyl, and C1-C6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; or two Rg are taken together with the nitrogen to which they are attached to form a heterocyclyl that is optionally substituted with one or more groups independently selected from oxo, halo and C1-3alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; and
- each Rh is independently selected from hydrogen, C1-4alkyl, C2-4alkenyl, C2-4alkynyl, and C2-5cycloalkyl, wherein each C1-4alkyl, C2-4alkenyl, C2-4alkynyl, and C2-5cycloalkyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C1-3alkoxy, and C1-C3 alkyl that is optionally substituted with one or more groups independently selected from halo.
- Another aspect includes a compound of formula (II):
- or a salt thereof, wherein:
- R1 is selected from C6-C20 aryl, C1-C20 heteroaryl, —(C6-C20 aryl)-(C1-C20 heteroaryl), and —(C1-C20 heteroaryl)-(C1-C20 heteroaryl), wherein each C6-C20 aryl, C1-C20 heteroaryl, —(C6-C20 aryl)-(C1-C20 heteroaryl) and —(C1-C20 heteroaryl)-(C1-C20 heteroaryl) is optionally substituted with one or more substituent groups independently selected from Rc, oxo, —F, —Cl, —Br, —I, —NO2, —N(Ra)2, —CN, —C(O)—N(Ra)2, —S(O)—N(Ra)2, —S(O)2—N(Ra)2, —O—Ra, —S—Ra, —O—C(O)—Ra, —O—C(O)—O—Ra, —C(O)—Ra, —C(O)—O—Ra, —S(O)—Ra, —S(O)2—Ra, —O—C(O)—N(Ra)2, —N(Ra)—C(O)—ORa, —N(Ra)—C(O)—N(Ra)2, —N(Ra)—C(O)—Ra, —N(Ra)—S(O)—Ra, —N(Ra)—S(O)2—Ra, —N(Ra)—S(O)—N(Ra)2, and —N(Ra)—S(O)2—N(Ra)2;
- R2 is C1-12alkyl, C2-12alkenyl, C2-12alkynyl, 3-12 membered carbocycle, and 3-12 membered heterocycle, wherein each C1-12alkyl, C2-12alkenyl, C2-12alkynyl, 3-12 membered carbocycle, and 3-12 membered heterocycle of R2 is optionally substituted with one or more groups Rb;
- R3 is C1-4alkyl, C2-4alkenyl, C2-4alkynyl, 3-5 membered carbocycle, 3-5 membered heterocycle, —C(O)—N(Re)2, —S(O)—N(Re)2, —S(O)2—N(Re)2, —C(O)—Re, —C(O)—O—Re, —S(O)—Re, or —S(O)2—Re, wherein any C1-4-alkyl, C2-4alkenyl, C2-4alkynyl, 3-5 membered carbocycle, and 3-5 membered heterocycle is optionally substituted with one or more substituent groups independently selected from —F, —Cl, —Br, —I, 3-5 membered carbocycle, —C(O)—N(Re)2, —S(O)—N(Re)2, —S(O)2—N(Re)2, —O—Re, —S—Re, —O—C(O)—Re, —O—C(O)—O—Re, —C(O)—Re, —C(O)—O—Re, —S(O)—Re, —S(O)2—Re, —O—C(O)—N(Re)2, —N(Re)—C(O)−ORe, —N(Re)—C(O)—N(Re)2, —N(Re)—C(O)—Re, —N(Re)—S(O)—Re, —N(Re)—S(O)2—Re, —N(Re)—S(O)—N(Re)2, and —N(Re)—S(O)2—N(Re)2;
- each Ra is independently selected from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl, wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C1-6alkoxy, carbocyclyl, heterocyclyl, and C1-C6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; or two Ra are taken together with the nitrogen to which they are attached to form a heterocyclyl that is optionally substituted with one or more groups independently selected from oxo, halo and C1-3alkyl that is optionally substituted with one or more groups independently selected from oxo and halo;
- each Rb is independently selected from oxo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, —F, —Cl, —Br, —I, —NO2, —N(Rc)2, —CN, —C(O)—N(Rc)2, —S(O)—N(Rc)2, —S(O)2—N(Rc)2, —O—Rc, —S—Rc, —O—C(O)—Rc, —O—C(O)—O—Rc, —C(O)—Rc, —C(O)—O—Rc, —S(O)—Rc, —S(O)2—Rc, —O—C(O)—N(Rc)2, —N(Rc)—C(O)—ORc, —N(Rc)—C(O)—N(Rc)2, —N(Rc)—C(O)—Rc, —N(Rc)—S(O)—Rc, —N(Rc)—S(O)2—Rc, —N(Rc)—S(O)—N(Rc)2, and —N(Rc)—S(O)2—N(Rc)2, wherein any C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more groups independently selected from oxo, halo, —NO2, —N(Rc)2, —CN, —C(O)—N(Rc)2, —S(O)—N(Rc)2, —S(O)2—N(Rc)2, —O—Rc, —S—Rc, —O—C(O)—Rc, —C(O)—Rc, —C(O)—O—Rc, —S(O)—Rc, —S(O)2—Rc, —C(O)—N(Rc)2, —N(Rc)—C(O)—Rc, —N(Rc)—S(O)—Rc, —N(Rc)—S(O)2—Rc and C1-6alkyl that is optionally substituted with one or more groups independently selected from oxo and halo;
- each Rc is independently selected from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl, wherein any C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, carbocyclyl, heterocyclyl, halo, —NO2, —N(Rd)2, —CN, —C(O)—N(Rd)2, —S(O)—N(Rd)2, —S(O)2—N(Rd)2, —O—Rd, —S—Rd, —O—C(O)—Rd, —C(O)—Rd, —C(O)—O—Rd, —S(O)—Rd, —S(O)2—Rd, —C(O)—N(Rd)2, —N(Rd)—C(O)—Rd, —N(Rd)—S(O)—Rd, —N(Rd)—S(O)2—Rd, and C1-6alkyl, which carbocyclyl and C1-6alkyl are optionally substituted with one or more groups independently selected from oxo, halo, C1-6alkyl, cyano, —N(Rd)2, —O—Rd, heterocyclyl, and carbocyclyl that is optionally substituted with one or more groups independently selected from halo, and C1-6alkyl;
- each Rd is independently selected from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkoxy, carbocyclyl, and heterocyclyl, wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkoxy, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C1-6alkoxy, carbocyclyl, heterocyclyl, and C1-C6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; or two Rd are taken together with the nitrogen to which they are attached to form a heterocyclyl that is optionally substituted with one or more groups independently selected from oxo, halo and C1-3alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; and
- each Re is independently selected from hydrogen, C1-4alkyl, C2-4alkenyl, C2-4alkynyl, and C2-5cycloalkyl, wherein each C1-4alkyl, C2-4alkenyl, C2-4alkynyl, and C2-5cycloalkyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C1-3alkoxy, and C1-C3 alkyl that is optionally substituted with one or more groups independently selected from halo.
- Another aspect includes a composition comprising a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant, carrier, or vehicle.
- Another aspect includes a method for treating a CBP and/or EP300-mediated disorder in an animal comprising administering a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof to the animal.
- Another aspect includes a method for treating a CBP and/or EP300-mediated disorder in an animal, wherein the disorder is cancer, comprising administering a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof to the animal.
- Another aspect includes a method for treating a CBP and/or EP300-mediated disorder in an animal, wherein the disorder is a fibrotic disease, comprising administering a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof to the animal.
- Another aspect includes a method for treating a CBP and/or EP300-mediated disorder in an animal, wherein the disorder is a fibrotic lung disease, comprising administering a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof to the animal.
- Another aspect includes a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof for use in medical therapy.
- Another aspect includes a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof for the prophylactic or therapeutic treatment of a CBP and/or EP300-mediated disorder.
- Another aspect includes the use of a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof to prepare a medicament for treating a CBP and/or EP300-mediated disorder in an animal (e.g. a mammal such as a human).
- Another aspect includes compounds for the study of CBP and/or EP300.
- Another aspect includes synthetic intermediates and synthetic processes disclosed herein that are useful for preparing a compound of formula (I) or formula (II) or a salt thereof.
-
FIG. 1 . Outline of protocol for assaying CBP/p300 SMIs for inhibition of profibrotic gene induction by TGFβ. -
FIGS. 2A-E . Gene expression as measured by qPCR in primary human fibroblasts treated with TGFβ and (FIG. 2A ) an inhibitor of TGFβ receptor kinase activity or (FIGS. 2B-E ) CBP/p300 inhibitors of Formula (I). Heat maps show TGFβ induction of each gene in the presence of CBP/p300 inhibitor after normalization to induction in the absence of inhibitor. Duplicate treatments are represented as two rows for each inhibitor concentration. CBP/p300 inhibitors reduce TGFβ-driven gene expression in a dose-dependent manner. Expression of Serpine1 is unchanged, indicating that TGFβ signaling is intact. -
FIGS. 3A-B . Expression as measured by qPCR of (FIG. 3A ) ACTA2 or (FIG. 3B ) COL3A1 in primary human fibroblasts treated with TGFβ and CBP/p300 inhibitors of Formula (I). CBP/p300 inhibitors reduce TGFβ-driven ACTA2 and COL3A1 expression in a dose-dependent manner. -
FIGS. 4A-E . Gene expression as measured by qPCR in primary human fibroblasts treated with TGFβ and (FIG. 4A ) an inhibitor of TGFβ receptor kinase activity or (FIGS. 4B-E ) CBP/p300 inhibitors of Formula (II). Heat maps show TGFβ induction of each gene in the presence of CBP/p300 inhibitor after normalization to induction in the absence of inhibitor. Duplicate treatments are represented as two rows for each inhibitor concentration. CBP/p300 inhibitors reduce TGFβ-driven gene expression in a dose-dependent manner. Expression of Serpine1 is unchanged, indicating that TGFβ signaling is intact. -
FIGS. 5A-B . Expression as measured by qPCR of (FIG. 5A ) ACTA2 or (FIG. 5B ) COL3A1 in primary human fibroblasts treated with TGFβ and CBP/p300 inhibitors of Formula (II). CBP/p300 inhibitors reduce TGFβ-driven ACTA2 and COL3A1 expression in a dose-dependent manner. -
FIGS. 6A-E . Gene expression as measured by qPCR in primary human fibroblasts treated with TGFβ and (FIG. 6A ) an inhibitor of TGFβ receptor kinase activity or (FIGS. 6B-E ) benzodiazepinone (“BZD”) series CBP/p300 inhibitors. Heat maps show TGFβ induction of each gene in the presence of CBP/p300 inhibitor after normalization to induction in the absence of inhibitor. Duplicate treatments are represented as two rows for each inhibitor concentration. CBP/p300 inhibitors reduce TGFβ-driven gene expression in a dose-dependent manner. Expression of Serpine1 is unchanged, indicating that TGFβ signaling is intact. -
FIGS. 7A-B . Expression as measured by qPCR of (FIG. 7A ) ACTA2 or (FIG. 7B ) COL3A1 in primary human fibroblasts treated with TGFβ and BZD series CBP/p300 inhibitors. CBP/p300 inhibitors reduce TGFβ-driven ACTA2 and COL3A1 expression in a dose-dependent manner. -
FIGS. 8A-D . Gene expression as measured by qPCR in primary human fibroblasts treated with TGFβ and (FIG. 8A ) an inhibitor of TGFβ receptor kinase activity or (FIGS. 8B-D ) heterocyclic CBP/p300 inhibitors. Heat maps show TGFβ induction of each gene in the presence of CBP/p300 inhibitor after normalization to induction in the absence of inhibitor. Duplicate treatments are represented as two rows for each inhibitor concentration. CBP/p300 inhibitors reduce TGFβ-driven gene expression in a dose-dependent manner. Expression of Serpine1 is unchanged, indicating that TGFβ signaling is intact. -
FIGS. 9A-B . Expression as measured by qPCR of (FIG. 9A ) ACTA2 or (FIG. 9B ) COL3A1 in primary human fibroblasts treated with TGFβ and heterocyclic CBP/p300 inhibitors. CBP/p300 inhibitors reduce TGFβ-driven ACTA2 and COL3A1 expression in a dose-dependent manner. -
FIGS. 10A-C . Gene expression as measured by qPCR in primary human fibroblasts treated with TGFβ and (FIG. 10A ) an inhibitor of TGFβ receptor kinase activity or (FIGS. 10B-C ) modified CBP/p300 inhibitors with decreased activity. Heat maps show TGFβ induction of each gene in the presence of CBP/p300 inhibitor after normalization to induction in the absence of inhibitor. Duplicate treatments are represented as two rows for each inhibitor concentration. After modification of CBP/p300 inhibitors, the effect on TGFβ-driven gene expression is either (B) eliminated or (C) reduced. -
FIGS. 11A-B . Expression as measured by qPCR of (FIG. 11A ) ACTA2 or (FIG. 11B ) COL3A1 in primary human fibroblasts treated with TGFβ and modified CBP/p300 inhibitors with decreased activity. The effect on TGFβ-driven gene expression is reduced or eliminated. -
FIGS. 12A-B . (FIG. 12A ) Gene expression as measured by qPCR in the lung of mice treated with bleomycin to induce pulmonary fibrosis. Mice were treated with bleomycin plus vehicle or bleomycin plus the indicated dose of CBP/p300 inhibitor G0272 (compound of Formula II). Heat maps show expression of genes assayed, after normalization to GAPDH endogenous control, with each column representing one mouse. G0272 decreased the expression of fibrotic genes in the lung of mice treated with bleomycin to induce pulmonary fibrosis. (FIG. 12B) Collagen synthesis as measured by mass spectrometry of deuterated hydroxyproline in the lung of mice treated with bleomycin to induce pulmonary fibrosis. Mice were treated with bleomycin plus vehicle or indicated dose of CBP/p300 inhibitor G0272. G0272 decreased collagen synthesis in the lung of mice treated with bleomycin to induce pulmonary fibrosis. -
FIGS. 13A-B . (FIG. 13A ) Gene expression as measured by qPCR in the lung of mice treated with bleomycin to induce pulmonary fibrosis. Mice were treated with bleomycin plus vehicle or indicated dose of CBP/p300 inhibitor G5049 (compound of Formula (I)). Heat maps show expression of genes assayed, after normalization to GAPDH endogenous control, with each column representing one mouse. G5049 decreased the expression of fibrotic genes in mice treated with bleomycin to induce pulmonary fibrosis. (FIG. 13B ) Collagen synthesis as measured by mass spectrometry of deuterated hydroxyproline in the lung of mice treated with bleomycin to induce pulmonary fibrosis. Mice were treated with bleomycin plus vehicle or indicated dose of CBP/p300 inhibitor G5049. G5049 decreased collagen synthesis in the lung of mice treated with bleomycin to induce pulmonary fibrosis. -
FIGS. 14A-B . (FIG. 14A ) Gene expression as measured by qPCR in the lung of mice in decreased collagen synthesis in the lung of mice treated with bleomycin to induce pulmonary fibrosis. Mice were treated with bleomycin plus vehicle or indicated dose of CBP/p300 inhibitor G3486. Heat maps show expression of genes assayed, after normalization to GAPDH endogenous control, with each column representing one mouse. G3486 decreased the expression of fibrotic genes in the lung of mice treated with bleomycin to induce pulmonary fibrosis. (FIG. 14B ) Collagen synthesis as measured by mass spectrometry of deuterated hydroxyproline in the lung of mice treated with bleomycin to induce pulmonary fibrosis. Mice were treated with bleomycin plus vehicle or indicated dose of CBP/p300 inhibitor G3486. G3486 decreased collagen synthesis in the lung of mice treated with bleomycin to induce pulmonary fibrosis. - Definitions and terms are described in more detail below. Chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed.
- Unless otherwise stated, compounds of formula I or formula II include enantiomeric, diastereomeric and geometric (or conformational) isomeric forms of a given structure. For example, the R and S configurations for each asymmetric center, Z and E double bond isomers, Z and E conformational isomers, single stereochemical isomers, as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures are included. Unless otherwise stated, all tautomeric forms of structures depicted herein are included. Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds of formula I or formula II, wherein the independent replacement or enrichment of one or more hydrogen by deuterium or tritium, carbon by 13C— or 14C carbon, nitrogen by a 15N nitrogen, sulfur by a 33S, 34S or 36S sulfur, oxygen by a 17O or 18O oxygen, or fluorine by a 18F are included. Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents.
- Where a particular enantiomer is described, it may, in certain embodiments be provided substantially free of the corresponding enantiomer, and may also be referred to as “optically enriched.” “Optically-enriched,” as used herein, means that the mixture of enantiomers is made up of a significantly greater proportion of one enantiomer, and may be described by enantiomeric excess (ee %). In certain embodiments, the mixture of enantiomers is made up of at least about 90% by weight of a given enantiomer (about 90% ee). In other embodiments, the mixture of enantiomers is made up of at least about 95%, 98% or 99% by weight of a given enantiomer (about 95%, 98% or 99% ee). Enantiomers and diastereomers may be isolated from racemic mixtures by any method known to those skilled in the art, including recrystallization from solvents in which one stereoisomer is more soluble than the other, chiral high pressure liquid chromatography (HPLC), supercritical fluid chromatography (SFC), the formation and crystallization of chiral salts, which are then separated by any of the above methods, or prepared by asymmetric syntheses and optionally further enriched. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen, et al., Tetrahedron 33:2725 (1977); Eliel, E. L. Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, S. H. Tables of Resolving Agents and Optical Resolutions p. 268 (E. L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, Ind. 1972).
- The term “heteroatom” means any atom independently selected from an atom other than carbon or hydrogen, for example, one or more of oxygen, sulfur, nitrogen, phosphorus or silicon (including any oxidized form of nitrogen, sulfur, phosphorus or silicon; and the quaternized form of any nitrogen).
- The terms “halo” and “halogen” as used herein refer to an atom selected from fluorine (fluoro, —F), chlorine (chloro, —Cl), bromine (bromo, —Br) and iodine (iodo, —I).
- The term “oxo” refers to ═O.
- The term “unsaturated”, as used herein, means that a moiety has one or more units of unsaturation.
- The term “carbocyclyl” used alone or as part of a larger moiety, refers to a saturated, partially unsaturated, or aromatic ring system having 3 to 20 carbon atoms. In one embodiment, carbocyclyl includes 3 to 12 carbon atoms (C3-C12). In another embodiment, carbocyclyl includes C3-C8, C3-C10 or C5-C10. In other embodiment, carbocyclyl, as a monocycle, includes C3-C8, C3-C6 or C5-C6. In another embodiment, carbocyclyl, as a bicycle, includes C7-C12. In another embodiment, carbocyclyl, as a spiro system, includes C5-C12. Examples of monocyclic carbocyclyls include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, perdeuteriocyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, phenyl, and cyclododecyl; bicyclic carbocyclyls having 7 to 12 ring atoms include [4,3], [4,4], [4,5], [5,5], [5,6] or [6,6] ring systems, for example bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, naphthalene, and bicyclo[3.2.2]nonane; and spiro carbocyclyls include spiro[2.2]pentane, spiro[2.3]hexane, spiro[2.4]heptane, spiro[2.5]octane and spiro[4.5]decane. The term carbocyclyl includes aryl ring systems as defined herein. The term carbocycyl also includes cycloalkyl rings (e.g. saturated or partially unsaturated mono-, bi-, or spiro-carbocycles).
- The term “alkyl,” as used herein, refers to a saturated linear or branched-chain hydrocarbon radical. In one embodiment, the alkyl radical is one to eighteen carbon atoms (C1-C18). In other embodiments, the alkyl radical is C0-C6, C0-C5, C0-C3, C1-C12, C1-C10, C1-C8, C1-C6, C1-C5, C1-C4 or C1-C3. C0 alkyl refers to a bond. Examples of alkyl groups include methyl (Me, —CH3), ethyl (Et, —CH2CH3), 1-propyl (n-Pr, n-propyl, —CH2CH2CH3), 2-propyl (i-Pr, i-propyl, —CH(CH3)2), 1-butyl (n-Bu, n-butyl, —CH2CH2CH2CH3), 2-methyl-1-propyl (i-Bu, i-butyl, —CH2CH(CH3)2), 2-butyl (s-Bu, s-butyl, —CH(CH3)CH2CH3), 2-methyl-2-propyl (t-Bu, t-butyl, —C(CH3)3), 1-pentyl (n-pentyl, —CH2CH2CH2CH2CH3), 2-pentyl (—CH(CH3)CH2CH2CH3), 3-pentyl (—CH(CH2CH3)2), 2-methyl-2-butyl (—C(CH3)2CH2CH3), 3-methyl-2-butyl (—CH(CH3)CH(CH3)2), 3-methyl-1-butyl (—CH2CH2CH(CH3)2), 2-methyl-1-butyl (—CH2CH(CH3)CH2CH3), 1-hexyl (—CH2CH2CH2CH2CH2CH3), 2-hexyl (—CH(CH3)CH2CH2CH2CH3), 3-hexyl (—CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (—C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (—CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (—CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (—C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (—CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (—C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (—CH(CH3)C(CH3)3, heptyl, octyl, nonyl, decyl, undecyl and dodecyl.
- The term “alkenyl,” as used herein, denotes a linear or branched-chain hydrocarbon radical with at least one carbon-carbon double bond. An alkenyl includes radicals having “cis” and “trans” orientations, or alternatively, “E” and “Z” orientations. In one example, the alkenyl radical is two to eighteen carbon atoms (C2-C18). In other examples, the alkenyl radical is C2-C12, C2-C10, C2-C8, C2-C6 or C2-C3. Examples include, but are not limited to, ethenyl or vinyl (—CH═CH2), prop-1-enyl (—CH═CHCH3), prop-2-enyl (—CH2CH═CH2), 2-methylprop-1-enyl, but-1-enyl, but-2-enyl, but-3-enyl, buta-1,3-dienyl, 2-methylbuta-1,3-diene, hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl and hexa-1,3-dienyl.
- The term “alkynyl,” as used herein, refers to a linear or branched hydrocarbon radical with at least one carbon-carbon triple bond. In one example, the alkynyl radical is two to eighteen carbon atoms (C2-C18). In other examples, the alkynyl radical is C2-C12, C2-C10, C2-C8, C2-C6 or C2-C3. Examples include, but are not limited to, ethynyl (—C≡CH), prop-1-ynyl (—C≡CCH3), prop-2-ynyl (propargyl, —CH2C≡CH), but-1-ynyl, but-2-ynyl and but-3-ynyl.
- The term “alkoxy” refers to a linear or branched radical represented by the formula —OR in which R is alkyl, alkenyl, alkynyl or carbocycyl. Alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, and cyclopropoxy.
- The term “haloalkyl,” as used herein, refers to an alkyl as defined herein that is substituted with one or more (e.g. 1, 2, 3, or 4) halo groups.
- The term “aryl” used alone or as part of a larger moiety as in “arylalkyl”, “arylalkoxy”, or “aryloxyalkyl”, refers to a monocyclic, bicyclic or tricyclic, carbon ring system, that includes fused rings, wherein at least one ring in the system is aromatic. The term “aryl” may be used interchangeably with the term “aryl ring”. In one embodiment, aryl includes groups having 6-20 carbon atoms (C6-C20 aryl). In another embodiment, aryl includes groups having 6-10 carbon atoms (C6-C10 aryl). Examples of aryl groups include phenyl, naphthyl, anthracyl, biphenyl, phenanthrenyl, naphthacenyl, 1,2,3,4-tetrahydronaphthalenyl, 1H-indenyl, 2,3-dihydro-1H-indenyl, and the like, which may be substituted or independently substituted by one or more substituents described herein. A particular aryl is phenyl. In another embodiment aryl includes an aryl ring fused to one or more carbocyclic rings, such as indanyl, dihydrophenanthryl, or tetrahydronaphthyl, and the like, where the radical or point of attachment is on an aromatic ring.
- The term “heteroaryl” used alone or as part of a larger moiety, e.g., “heteroarylalkyl”, or “heteroarylalkoxy”, refers to a monocyclic, bicyclic or tricyclic ring system having 5 to 14 ring atoms, wherein at least one ring is aromatic and contains at least one heteroatom. In one embodiment, heteroaryl includes 4-6 membered monocyclic aromatic groups where one or more ring atoms is nitrogen, sulfur or oxygen that is independently optionally substituted. In another embodiment, heteroaryl includes 5-6 membered monocyclic aromatic groups where one or more ring atoms is nitrogen, sulfur or oxygen that is independently optionally substituted. In some embodiments, the heteroaryl group is a C1-C20 heteroaryl group, where the heteroaryl ring contains 1-20 carbon atoms and the remaining ring atoms include one or more nitrogen, sulfur, or oxygen atoms. Example heteroaryl groups include thienyl, furyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, thiatriazolyl, oxatriazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazinyl, tetrazinyl, tetrazolo[1,5-b]pyridazinyl, imidazol[1,2-a]pyrimidinyl, purinyl, benzoxazolyl, benzofuryl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, benzoimidazolyl, indolyl, 1,3-thiazol-2-yl, 1,3,4-triazol-5-yl, 1,3-oxazol-2-yl, 1,3,4-oxadiazol-5-yl, 1,2,4-oxadiazol-5-yl, 1,3,4-thiadiazol-5-yl, 1H-tetrazol-5-yl, 1,2,3-triazol-5-yl, pyrid-2-yl N-oxide, and pyrazolo[4,3-c]pyridinyl. The terms “heteroaryl” also includes groups in which a heteroaryl is fused to one or more aryl, carbocyclyl, or heterocyclyl rings, where the radical or point of attachment is on the heteroaryl ring. Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. A heteroaryl group may be mono-, bi- or tri-cyclic.
- As used herein, the term “heterocyclyl” or “heterocycle” refers to a “carbocyclyl” as defined herein, wherein one or more (e.g. 1, 2, 3, or 4) carbon atoms have been replaced with a heteroatom (e.g. O, N, or S). In some embodiments, a heterocyclyl or heterocycle refers to a saturated ring system, such as a 3 to 12 membered saturated heterocyclyl ring system. In some embodiments, a heterocyclyl or heterocycle refers to a heteroaryl ring system, such as a 5 to 14 membered heteroaryl ring system. A heterocyclyl or heterocycle can optionally be substituted with one or more substituents independently selected from those defined herein.
- In one example, heterocyclyl or heterocycle includes 3-12 ring atoms and includes monocycles, bicycles, tricycles and spiro ring systems, wherein the ring atoms are carbon, and one to five ring atoms is a heteroatom selected from nitrogen, sulfur or oxygen, which is independently optionally substituted by one or more groups. In one example, heterocyclyl or heterocycle includes 1 to 4 heteroatoms. In another example, heterocyclyl or heterocycle includes 3- to 7-membered monocycles having one or more heteroatoms selected from nitrogen, sulfur or oxygen. In another example, heterocyclyl or heterocycle includes 4- to 6-membered monocycles having one or more heteroatoms selected from nitrogen, sulfur or oxygen. In another example, heterocyclyl or heterocycle includes 3-membered monocycles. In another example, heterocyclyl or heterocycle includes 4-membered monocycles. In another example, heterocyclyl or heterocycle includes 5-6 membered monocycles. In one example, the heterocyclyl or heterocycle group includes 0 to 3 double bonds. Any nitrogen or sulfur heteroatom may optionally be oxidized (e.g. NO, SO, SO2), and any nitrogen heteroatom may optionally be quaternized (e.g. [NR4]+Cl−, [NR4]+OH−). Example heterocyclyls or heterocycles include oxiranyl, aziridinyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, 1,2-dithietanyl, 1,3-dithietanyl, pyrrolidinyl, dihydro-1H-pyrrolyl, dihydrofuranyl, tetrahydrofuranyl, dihydrothienyl, tetrahydrothienyl, imidazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, dihydropyranyl, tetrahydropyranyl, hexahydrothiopyranyl, hexahydropyrimidinyl, oxazinanyl, thiazinanyl, thioxanyl, homopiperazinyl, homopiperidinyl, azepanyl, oxepanyl, thiepanyl, oxazepinyl, oxazepanyl, diazepanyl, 1,4-diazepanyl, diazepinyl, thiazepinyl, thiazepanyl, tetrahydrothiopyranyl, oxazolidinyl, thiazolidinyl, isothiazolidinyl, 1,1-dioxoisothiazolidinonyl, oxazolidinonyl, imidazolidinonyl, 4,5,6,7-tetrahydro[2H]indazolyl, tetrahydrobenzoimidazolyl, 4,5,6,7-tetrahydrobenzo[d]imidazolyl, 1,6-dihydroimidazol[4,5-d]pyrrolo[2,3-b]pyridinyl, thiazinyl, oxazinyl, thiadiazinyl, oxadiazinyl, dithiazinyl, dioxazinyl, oxathiazinyl, thiatriazinyl, oxatriazinyl, dithiadiazinyl, imidazolinyl, dihydropyrimidyl, tetrahydropyrimidyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, thiapyranyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, pyrazolidinyl, dithianyl, dithiolanyl, pyrimidinonyl, pyrimidindionyl, pyrimidin-2,4-dionyl, piperazinonyl, piperazindionyl, pyrazolidinylimidazolinyl, 3-azabicyclo[3.1.0]hexanyl, 3,6-diazabicyclo[3.1.1]heptanyl, 6-azabicyclo[3.1.1]heptanyl, 3-azabicyclo[3.1.1]heptanyl, 3-azabicyclo[4.1.0]heptanyl, azabicyclo[2.2.2]hexanyl, 2-azabicyclo[3.2.1]octanyl, 8-azabicyclo[3.2.1]octanyl, 2-azabicyclo[2.2.2]octanyl, 8-azabicyclo[2.2.2]octanyl, 7-oxabicyclo[2.2.1]heptane, azaspiro[3.5]nonanyl, azaspiro[2.5]octanyl, azaspiro[4.5]decanyl, 1-azaspiro[4.5]decan-2-only, azaspiro[5.5]undecanyl, tetrahydroindolyl, octahydroindolyl, tetrahydroisoindolyl, tetrahydroindazolyl, 1,1-dioxohexahydrothiopyranyl. Examples of 5-membered heterocyclyls or heterocycles containing a sulfur or oxygen atom and one to three nitrogen atoms are thiazolyl, including thiazol-2-yl and thiazol-2-yl N-oxide, thiadiazolyl, including 1,3,4-thiadiazol-5-yl and 1,2,4-thiadiazol-5-yl, oxazolyl, for example oxazol-2-yl, and oxadiazolyl, such as 1,3,4-oxadiazol-5-yl, and 1,2,4-oxadiazol-5-yl. Example 5-membered ring heterocyclyls or heterocycles containing 2 to 4 nitrogen atoms include imidazolyl, such as imidazol-2-yl; triazolyl, such as 1,3,4-triazol-5-yl; 1,2,3-triazol-5-yl, 1,2,4-triazol-5-yl, and tetrazolyl, such as 1H-tetrazol-5-yl. Example benzo-fused 5-membered heterocyclyls or heterocycles are benzoxazol-2-yl, benzthiazol-2-yl and benzimidazol-2-yl. Example 6-membered heterocyclyls or heterocycles contain one to three nitrogen atoms and optionally a sulfur or oxygen atom, for example pyridyl, such as pyrid-2-yl, pyrid-3-yl, and pyrid-4-yl; pyrimidyl, such as pyrimid-2-yl and pyrimid-4-yl; triazinyl, such as 1,3,4-triazin-2-yl and 1,3,5-triazin-4-yl; pyridazinyl, in particular pyridazin-3-yl, and pyrazinyl. The pyridine N-oxides and pyridazine N-oxides and the pyridyl, pyrimid-2-yl, pyrimid-4-yl, pyridazinyl and the 1,3,4-triazin-2-yl groups, are other example heterocyclyl groups.
- The term “heterocyclyl” or “heterocycle” also includes groups in which a heterocyclyl is fused to one or more aryl, carbocyclyl, or heterocyclyl rings, where the radical or point of attachment is on the heterocyclyl ring. Nonlimiting examples include tetrahydroquinolinyl and tetrahydroisoquinolinyl.
- As used herein, the term “partially unsaturated” refers to a ring moiety that includes at least one double or triple bond between ring atoms but the ring moiety is not aromatic.
- As used herein, the term “inhibitor” refers to a compound that binds to and inhibits the bromodomain of CBP and/or EP300 with measurable affinity and activity. In certain embodiments, an inhibitor has an IC50 or binding constant of less about 20 μM, less than about 1 μM, less than about 500 nM, less than about 100 nM, or less than about 10 nM.
- The terms “measurable affinity” and “measurably inhibit,” as used herein, refer to a measurable reduction in activity (e.g., reduction in recognition of lysine acetyl recognition of chromatin) of the bromodomain of CBP and/or EP300 between: (i) a sample comprising a compound of formula I or formula II or composition thereof and such bromodomain, and (ii) an equivalent sample comprising such bromodomain, in the absence of said compound, or composition thereof.
- “Pharmaceutically acceptable salts” include both acid and base addition salts. It is to be understood that when a compound or Example herein is shown as a specific salt, the corresponding free-base, as well as other salts of the corresponding free-base (including pharmaceutically acceptable salts of the corresponding free-base) are contemplated.
- “Pharmaceutically acceptable acid addition salt” refers to those salts which retain the biological effectiveness and properties of the free bases and which are not biologically or otherwise undesirable, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid and the like, and organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic classes of organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid, maloneic acid, succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilic acid, benzoic acid, cinnamic acid, mandelic acid, embonic acid, phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, salicyclic acid and the like.
- “Pharmaceutically acceptable base addition salts” include those derived from inorganic bases such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Particularly base addition salts are the ammonium, potassium, sodium, calcium and magnesium salts. Salts derived from pharmaceutically acceptable organic nontoxic bases includes salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, tromethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperizine, piperidine, N-ethylpiperidine, polyamine resins and the like. Particular organic non-toxic bases are isopropylamine, diethylamine, ethanolamine, tromethamine, dicyclohexylamine, choline, and caffeine.
- The term “tautomer” or “tautomeric form” refers to structural isomers of different energies which are interconvertible via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via migration of a proton, such as keto-enol and imine-enamine isomerizations. Valence tautomers include interconversions by reorganization of some of the bonding electrons.
- A “solvate” refers to an association or complex of one or more solvent molecules and a compound of the present invention. Examples of solvents include water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid and ethanolamine. The term “hydrate” refers to the complex where the solvent molecule is water.
- “Therapeutically effective amount” refers to an amount of a compound of the present invention that (i) treats the particular disease, condition or disorder, (ii) attenuates, ameliorates or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) delays the onset of one or more symptoms of the particular disease, condition or disorder described herein. In the case of cancer, the therapeutically effective amount of the drug may reduce the number of cancer cells; reduce the tumor size; inhibit (i.e., slow to some extent and preferably stop) cancer cell infiltration into peripheral organs; inhibit (i.e., slow to some extent and preferably stop) tumor metastasis; inhibit, to some extent, tumor growth; and/or relieve to some extent one or more of the symptoms associated with the cancer. For cancer therapy, efficacy can, for example, be measured by assessing the time to disease progression (TTP) and/or determining the response rate (RR). In the case of immunological disorders, the therapeutic effective amount is an amount sufficient to decrease or alleviate an allergic disorder, the symptoms of an autoimmune and/or inflammatory disease, or the symptoms of an acute inflammatory reaction (e.g. asthma).
- “Treatment” (and variations such as “treat” or “treating”) refers to clinical intervention in an attempt to alter the natural course of the individual or cell being treated, and can be performed either for prophylaxis or during the course of clinical pathology. Desirable effects of treatment include one or more of preventing recurrence of disease, alleviation of symptoms, diminishment of any direct or indirect pathological consequences of the disease, stabilized (i.e., not worsening) state of disease, preventing metastasis, decreasing the rate of disease progression, amelioration or palliation of the disease state, prolonging survival as compared to expected survival if not receiving treatment and remission or improved prognosis. In certain embodiments, a compound of formula I or formula II is used to delay development of a disease or disorder or to slow the progression of a disease or disorder. Those individuals in need of treatment include those already with the condition or disorder as well as those prone to have the condition or disorder, (for example, through a genetic mutation or abberent expression of a gene or protein).
- “CBP/EP300 bromodomain inhibitor” or “CBP and/or EP300 bromodomain inhibitor” refers to a compound that binds to the CBP bromodomain and/or EP300 bromodomain and inhibits and/or reduces a biological activity of CBP and/or EP300. In some embodiments, CBP/EP300 bromodomain inhibitor binds to the CBP and/or EP300 primarily (e.g., solely) through contacts and/or interactions with the CBP bromodomain and/or EP300 bromodomain. In some embodiments, CBP/EP300 bromodomain inhibitor binds to the CBP and/or EP300 through contacts and/or interactions with the CBP bromodomain and/or EP300 bromodomain as well as additional CBP and/or EP300 residues and/or domains. In some embodiments, CBP/EP300 bromodomain inhibitor substantially or completely inhibits the biological activity of the CBP and/or EP300. In some embodiments, the biological activity is binding of the bromodomain of CBP and/or EP300 to chromatin (e.g., histones associated with DNA) and/or another acetylated protein. In certain embodiments, the CBP/EP300 bromodomain inhibitor blocks CBP/EP300 activity so as to restore a functional response by T-cells (e.g., proliferation, cytokine production, target cell killing) from a dysfunctional state to antigen stimulation. In some embodiments, the CBP/EP300 bromodomain inhibitor binds to and inhibits CBP bromodomain. In some embodiments, the CBP/EP300 bromodomain inhibitor binds to and inhibits EP300 bromodomain.
- As used herein, “a” or “an” means one or more, unless clearly indicated otherwise. As used herein, “another” means at least a second or more.
- In certain embodiments of compounds of Formula (I), R1 is C1-12alkyl or 3-12 membered heterocycle, wherein each C1-12alkyl and 3-12 membered heterocycle of R1 is optionally substituted with one or more groups Rb.
- In certain embodiments of compounds of Formula (I), R1 is methyl or a 4-6 membered heterocycle, wherein each methyl and 4-6 membered heterocycle of R1 is optionally substituted with one or more groups Rb.
- In certain embodiments of compounds of Formula (I), R1 is methyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dioxothiolanyl, piperidyl, or pyrrolidinyl, wherein each methyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dioxothiolanyl, piperidyl, or pyrrolidinyl of R1 is optionally substituted with one or more groups Rb.
- In certain embodiments of compounds of Formula (I), R1 is methyl or cyclopropylmethyl.
- In certain embodiments of compounds of Formula (I), R1 is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dioxothiolanyl, piperidyl, or pyrrolidinyl, and each Rb is independently selected from methyl, acetyl, and oxo.
- In certain embodiments of compounds of Formula (I), R1 is cyclohexyl, aryl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dioxothiolanyl, dioxothianyl, piperidyl, pyrrolidinyl, pyridyl, or oxepanyl, and each Rb is independently selected from oxo, C1-6alkyl, —ORc, —C(O)—Rc, oxetanyl, —S(O)2—Rc, and —CH2CN.
- In certain embodiments of compounds of Formula (I), R1 is selected from the group consisting of:
- In certain embodiments of compounds of Formula (I), R1 is:
- In certain embodiments of compounds of Formula (I), R2 is C6-C20 aryl optionally substituted with one or more substituent groups independently selected from Rc, and R3 is C1-12alkyl or 3-12 membered carbocycle, wherein each C1-12alkyl and 3-12 membered carbocycle of R3 is optionally substituted with one or more groups Re.
- In certain embodiments of compounds of Formula (I), R2 is phenyl optionally substituted with one or more substituent groups independently selected from Rc, and R3 is methyl or phenyl, wherein each methyl and phenyl of R3 is optionally substituted with one or more groups Re.
- In certain embodiments of compounds of Formula (I), Rc is a 5-membered heterocyclyl optionally substituted with methyl; and R3 is benzyl, methyl, cyanomethyl, or phenyl.
- In certain embodiments of compounds of Formula (I), Rc is pyrazolyl optionally substituted with methyl; and R3 is benzyl, methyl, cyanomethyl, or phenyl.
- In certain embodiments of compounds of Formula (I), R2 and R3 taken together with the nitrogen to which they are attached form a 3-12 membered heterocycle that is optionally substituted with one or more groups Re.
- In certain embodiments of compounds of Formula (I), R2 and R3 taken together with the nitrogen to which they are attached form a bicyclic heterocycle that is optionally substituted with one or more groups Re.
- In certain embodiments of compounds of Formula (I), R2 and R3 taken together with the nitrogen to which they are attached form a 9-12 membered bicyclic heterocycle that is optionally substituted with one or more groups Re.
- In certain embodiments of compounds of Formula (I), R2 and R3 taken together with the nitrogen to which they are attached form a 9- or 10-membered bicyclic heterocycle that is optionally substituted with one or more groups Re.
- In certain embodiments of compounds of Formula (I), R2 and R3 taken together with the nitrogen to which they are attached form a 9- or 10-membered bicyclic heterocycle that is optionally substituted with one or more groups Re; and wherein the 9- or 10-membered bicyclic heterocycle comprises at least one aromatic ring. In certain embodiments the at least one aromatic ring is a benzo ring.
- In certain embodiments of compounds of Formula (I), —NR2R3 taken together is selected from the group consisting of:
- and wherein each —NR2R3 is optionally substituted with one or more groups Re.
- In certain embodiments of compounds of Formula (I), —NR2R3 taken together is selected from the group consisting of:
- In certain embodiments of compounds of Formula (I), R3 is C1-12alkyl or 3-12 membered carbocycle, wherein each C1-12alkyl and 3-12 membered carbocycle of R3 is optionally substituted with one or more groups Re.
- In certain embodiments of compounds of Formula (I), R3 is methyl or phenyl, wherein each methyl and phenyl of R3 is optionally substituted with one or more groups Re.
- In certain embodiments of compounds of Formula (I), R3 is benzyl, methyl, cyanomethyl, or phenyl.
- In certain embodiments of compounds of Formula (I), R4 is 3-5 membered heterocycle, —C(O)—N(Rh)2, —C(O)—Rh, —C(O)—O—Rh, or —S(O)2—Rh, wherein any 3-5 membered heterocycle is optionally substituted with one or more substituent groups independently selected from —F, —Cl, —Br, —I, 3-5 membered carbocycle, —C(O)—N(Rh)2, —S(O)—N(Rh)2, —S(O)2—N(Rh)2, —O—Rh, —S—Rh, —O—C(O)—Rh, —O—C(O)—O—Rh, —C(O)—Rh, —C(O)—O—Rh, —S(O)—Rh, —S(O)2—Rh, —O—C(O)—N(Rh)2, —N(Rh)—C(O)—ORh, —N(Rh)—C(O)—N(Rh)2, —N(Rh)—C(O)—Ra, —N(Rh)—S(O)—Rh, —N(Rh)—S(O)2—Rh, —N(Rh)—S(O)—N(Rh)2, and —N(Rh)—S(O)2—N(Rh)2.
- In certain embodiments of compounds of Formula (I), Rh is independently selected from hydrogen, C1-4alkyl, and C2-5cycloalkyl, wherein each C1-4alkyl, and C2-5cycloalkyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C1-3alkoxy, and C1-C3 alkyl that is optionally substituted with one or more groups independently selected from halo.
- In certain embodiments of compounds of Formula (I), R4 is acetyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, methoxycarbonyl, propanoyl, cyclopropylcarbonyl, methylsulfonyl, butanoyl, difluoroacetyl, thiadiazole or isoxazole.
- In certain embodiments of compounds of Formula (I), R4 is substituted or unsubstituted acetyl, propionyl, butyryl, cyclopropylcarbonyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, methoxycarbonyl, methylsulfonyl, difluoroacetyl, thiadiazole, methylthiadiazole, oxadiazole, methyloxadiazole, or isoxazole.
- In certain embodiments of compounds of Formula (I), R4 is selected from the group consisting of:
- In certain embodiments of compounds of Formula (I):
- R1 is methyl or a 4-6 membered heterocycle, wherein each methyl and 4-6 membered heterocycle of R1 is optionally substituted with one or more groups Rb;
- R2 is phenyl optionally substituted with one or more substituent groups independently selected from Rc; and
- R3 is methyl or phenyl, wherein each methyl and phenyl of R3 is optionally substituted with one or more groups Re.
- In certain embodiments of compounds of Formula (I):
- R1 is methyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dioxothiolanyl, piperidyl, or pyrrolidinyl, wherein each methyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dioxothiolanyl, piperidyl, or pyrrolidinyl of R1 is optionally substituted with one or more groups Rb
- R2 is phenyl optionally substituted with one or more substituent groups independently selected from Rc; and
- R3 is methyl or phenyl, wherein each methyl and phenyl of R3 is optionally substituted with one or more groups Re.
- In certain embodiments of compounds of Formula (I):
- R1 is methyl or a 4-6 membered heterocycle, wherein each methyl and 4-6 membered heterocycle of R1 is optionally substituted with one or more groups Rb; and
- R2 and R3 taken together with the nitrogen to which they are attached form a 9- or 10-membered bicyclic heterocycle that is optionally substituted with one or more groups Re.
- In certain embodiments of compounds of Formula (I):
- R1 is tetrahydrofuranyl, tetrahydropyranyl, dioxothiolanyl, piperidyl, or pyrrolidinyl, wherein each tetrahydrofuranyl, tetrahydropyranyl, dioxothiolanyl, piperidyl, or pyrrolidinyl of R1 is optionally substituted with one or more groups Rb; and
- R2 and R3 taken together with the nitrogen to which they are attached form a 9- or 10-membered bicyclic heterocycle that is optionally substituted with one or more groups Re.
- In certain embodiments of compounds of Formula (I), R1 is methyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dioxothiolanyl, piperidyl, or pyrrolidinyl, wherein each methyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dioxothiolanyl, piperidyl, or pyrrolidinyl of R1 is optionally substituted with one or more groups Rb; and —NR2R3 taken together is selected from the group consisting of:
- In certain embodiments of compounds of Formula (I):
- R1 is methyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dioxothiolanyl, piperidyl, or pyrrolidinyl, wherein each methyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dioxothiolanyl, piperidyl, or pyrrolidinyl of R1 is optionally substituted with one or more groups Rb
- R2 is phenyl optionally substituted with one or more substituent groups independently selected from Rc;
- R3 is methyl or phenyl, wherein each methyl and phenyl of R3 is optionally substituted with one or more groups Re; and
- R4 is acetyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, methoxycarbonyl, propanoyl, cyclopropylcarbonyl, methylsulfonyl, butanoyl, difluoroacetyl, thiadiazole or isoxazole.
- In certain embodiments of compounds of Formula (I):
- R1 is methyl or a 4-6 membered heterocycle, wherein each methyl and 4-6 membered heterocycle of R1 is optionally substituted with one or more groups Rb;
- R2 and R3 taken together with the nitrogen to which they are attached form a 9- or 10-membered bicyclic heterocycle that is optionally substituted with one or more groups Re; and
- R4 is acetyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, methoxycarbonyl, propanoyl, cyclopropylcarbonyl, methylsulfonyl, butanoyl, difluoroacetyl, thiadiazole or isoxazole.
- In certain embodiments of compounds of Formula (I):
- R1 is methyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dioxothiolanyl, piperidyl, or pyrrolidinyl, wherein each methyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dioxothiolanyl, piperidyl, or pyrrolidinyl of R1 is optionally substituted with one or more groups Rb;
- R2 and R3 taken together with the nitrogen to which they are attached form a 9- or 10-membered bicyclic heterocycle that is optionally substituted with one or more groups Re; and
- R4 is acetyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, methoxycarbonyl, propanoyl, cyclopropylcarbonyl, methylsulfonyl, butanoyl, difluoroacetyl, thiadiazole or isoxazole.
- In certain embodiments of compounds of Formula (I):
- R1 is methyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dioxothiolanyl, piperidyl, or pyrrolidinyl, wherein each methyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dioxothiolanyl, piperidyl, or pyrrolidinyl of R1 is optionally substituted with one or more groups Rb;
- NR2R3 taken together is selected from the group consisting of:
- and R4 is acetyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, methoxycarbonyl, propanoyl, cyclopropylcarbonyl, methylsulfonyl, butanoyl, difluoroacetyl, thiadiazole or isoxazole.
- In certain embodiments the compound of Formula (I) is selected from the group consisting of:
- and salts thereof.
- In certain embodiments the compound of Formula (I) is a compound as described in the Examples herein, or a freebase or salt thereof.
- In certain embodiments any of the embodiments described for the compound of Formula (I) may be combined with any other embodiment described for the compound of Formula (I).
- In certain embodiments of compounds of Formula (II), R1 is not unsubstituted phenyl, when R2 is carboxymethyl or 2-carboxyethyl.
- In certain embodiments of compounds of Formula (II), R1 is selected from C6-C20 aryl, C1-C20 heteroaryl, —(C6-C20 aryl)-(C1-C20 heteroaryl), and —(C1-C20 heteroaryl)-(C1-C20 heteroaryl), wherein each C6-C20 aryl, C1-C20 heteroaryl, —(C6-C20 aryl)-(C1-C20 heteroaryl) and —(C1-C20 heteroaryl)-(C1-C20 heteroaryl) is optionally substituted with one or more substituent groups independently selected from Rc, oxo, —F, —Cl, —Br, —N(Ra)2, —CN, —C(O)—N(Ra)2, —O—Ra, —C(O)—Ra, —N(Ra)—S(O)—Ra, and —S(O)2—Ra.
- In certain embodiments of compounds of Formula (II), R1 is selected from —(C6-C20 aryl)-(C1-C20 heteroaryl) and —(C1-C20 heteroaryl)-(C1-C20 heteroaryl), wherein each —(C6-C20 aryl)-(C1-C20 heteroaryl) and —(C1-C20 heteroaryl)-(C1-C20 heteroaryl) is optionally substituted with one or more substituent groups independently selected from Rc, oxo, —F, —Cl, —Br, —N(Ra)2, —CN, —C(O)—N(Ra)2, —O—Ra, —C(O)—Ra, —N(Ra)—S(O)—Ra, and —S(O)2—Ra.
- In certain embodiments of Compounds of Formula (II), R1 is selected from C6-C20 aryl and C1-C20 heteroaryl, wherein each C6-C20 aryl and C1-C20 heteroaryl, is optionally substituted with one or more substituent groups independently selected from Rc, oxo, —F, —Cl, —Br, —N(Ra)2, —CN, —C(O)—N(Ra)2, —O—Ra, —C(O)—Ra, —N(Ra)—S(O)—Ra, and —S(O)2—Ra.
- In certain embodiments of compounds of Formula (II), R1 is selected from —(C6-C20 aryl)-(C1-C20 heteroaryl), and —(C1-C20 heteroaryl)-(C1-C20 heteroaryl), wherein each —(C6-C20 aryl)-(C1-C20 heteroaryl) and —(C1-C20 heteroaryl)-(C1-C20 heteroaryl) is optionally substituted with one or more substituent groups independently selected from Rc, oxo, —F, —Cl, —Br, —I, —NO2, —N(Ra)2, —CN, —C(O)—N(Ra)2, —S(O)—N(Ra)2, —S(O)2—N(Ra)2, —O—Ra, —S—Ra, —O—C(O)—Ra, —O—C(O)—O—Ra, —C(O)—Ra, —C(O)—O—Ra, —S(O)—Ra, —S(O)2—Ra, —O—C(O)—N(Ra)2, —N(Ra)—C(O)—ORa, —N(Ra)—C(O)—N(Ra)2, —N(Ra)—C(O)—Ra, —N(Ra)—S(O)—Ra, —N(Ra)—S(O)2—Ra, —N(Ra)—S(O)—N(Ra)2, and —N(Ra)—S(O)2—N(Ra)2.
- In certain embodiments of compounds of Formula (II), R1 is —(C6-C20 aryl)-(C1-C20 heteroaryl), wherein —(C6-C20 aryl)-(C1-C20 heteroaryl) is optionally substituted with one or more substituent groups independently selected from Rc, oxo, —F, —Cl, —Br, —I, —NO2, —N(Ra)2, —CN, —C(O)—N(Ra)2, —S(O)—N(Ra)2, —S(O)2—N(Ra)2, —O—Ra, —S—Ra, —O—C(O)—Ra, —O—C(O)—O—Ra, —C(O)—Ra, —C(O)—O—Ra, —S(O)—Ra, —S(O)2—Ra, —O—C(O)—N(Ra)2, —N(Ra)—C(O)—ORa, —N(Ra)—C(O)—N(Ra)2, —N(Ra)—C(O)—Ra, —N(Ra)—S(O)—Ra, —N(Ra)—S(O)2—Ra, —N(Ra)—S(O)—N(Ra)2, and —N(Ra)—S(O)2—N(Ra)2.
- In certain embodiments of compounds of Formula (II), R1 is —(C1-C20 heteroaryl)-(C1-C20 heteroaryl), wherein —(C1-C20 heteroaryl)-(C1-C20 heteroaryl) is optionally substituted with one or more substituent groups independently selected from Rc, oxo, —F, —Cl, —Br, —I, —NO2, —N(Ra)2, —CN, —C(O)—N(Ra)2, —S(O)—N(Ra)2, —S(O)2—N(Ra)2, —O—Ra, —S—Ra, —O—C(O)—Ra, —O—C(O)—O—Ra, —C(O)—Ra, —C(O)—O—Ra, —S(O)—Ra, —S(O)2—Ra, —O—C(O)—N(Ra)2, —N(Ra)—C(O)—ORa, —N(Ra)—C(O)—N(Ra)2, —N(Ra)—C(O)—Ra, —N(Ra)—S(O)—Ra, —N(Ra)—S(O)2—Ra, —N(Ra)—S(O)—N(Ra)2, and —N(Ra)—S(O)2—N(Ra)2.
- In certain embodiments of compounds of Formula (II), each Rb is independently selected from oxo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, —F, —Cl, —Br, —I, —NO2, —N(Rc)2, —CN, —C(O)—N(Rc)2, —S(O)—N(Rc)2, —S(O)2—N(Rc)2, —O—Rc, —S—Rc, —O—C(O)—Rc, —O—C(O)—O—Rc, —C(O)—Rc, —S(O)—Rc, —S(O)2—Rc, —O—C(O)—N(Rc)2, —N(Rc)—C(O)—ORc, —N(Rc)—C(O)—N(Rc)2, —N(Rc)—C(O)—Rc, —N(Rc)—S(O)—Rc, —N(Rc)—S(O)2—Rc, —N(Rc)—S(O)—N(Rc)2, and —N(Rc)—S(O)2—N(Rc)2.
- In certain embodiments of compounds of Formula (II), each Rc is independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl.
- In certain embodiments of compounds of Formula (II), each Ra is independently selected from hydrogen, C1-6alkyl, carbocyclyl, and heterocyclyl, wherein each C1-6alkyl, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from halo, C1-6alkoxy, and C1-C6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; or two Ra are taken together with the nitrogen to which they are attached to form a heterocyclyl that is optionally substituted with one or more groups independently selected from oxo, halo and C1-3alkyl that is optionally substituted with one or more groups independently selected from oxo and halo;
- In certain embodiments of compounds of Formula (II), each Rb is independently selected from C1-6alkyl, carbocyclyl, heterocyclyl, —CN, —C(O)—N(Rc)2, —O—Rc, —C(O)—O—Rc, and —S(O)2—Rc, wherein any C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl, is optionally substituted with one or more groups independently selected from halo and C1-6alkyl that is optionally substituted with one or more groups independently selected from oxo and halo.
- In certain embodiments of compounds of Formula (II), each Rc is independently selected from hydrogen, C1-6alkyl, and carbocyclyl, wherein any C1-6alkyl and carbocyclyl is optionally substituted with one or more groups independently selected from halo, —N(Rd)2, —CN, —C(O)—N(Rd)2, —O—Rd, —S(O)2—Rd, —N(Rd)—C(O)—Rd, —N(Rd)—S(O)2—Rd, and C1-6alkyl, which carbocyclyl and C1-6alkyl are optionally substituted with one or more groups independently selected from halo and —O—Rd.
- In certain embodiments of compounds of Formula (II), each Rd is independently selected from hydrogen and C1-6alkyl, wherein each C1-6alkyl is optionally substituted with one or more groups independently selected from halo and C1-6alkoxy; or two Rd are taken together with the nitrogen to which they are attached to form a heterocyclyl that is optionally substituted with one or more groups independently selected from oxo, halo and C1-3alkyl that is optionally substituted with one or more groups independently selected from oxo and halo.
- In certain embodiments of compounds of Formula (II), R1 is selected from aryl that is optionally substituted with one or more substituent groups independently selected from Rc, —F, —Cl, —Br, —I, —NO2, —N(Ra)2, —CN, —C(O)—N(Ra)2, —S(O)—N(Ra)2, —S(O)2—N(Ra)2, —O—Ra, —S—Ra, —O—C(O)—Ra, —O—C(O)—O—Ra, —C(O)—Ra, —C(O)—O—Ra, —S(O)—Ra, —S(O)2—Ra, —O—C(O)—N(Ra)2, —N(Ra)—C(O)—ORa, —N(Ra)—C(O)—N(Ra)2, —N(Ra)—C(O)—Ra, —N(Ra)—S(O)—Ra, —N(Ra)—S(O)2—Ra, —N(Ra)—S(O)—N(Ra)2, and —N(Ra)—S(O)2—N(Ra)2.
- In certain embodiments of compounds of Formula (II), R1 is selected from heteroaryl that is optionally substituted with one or more substituent groups independently selected from Rc, —F, —Cl, —Br, —I, —NO2, —N(Ra)2, —CN, —C(O)—N(Ra)2, —S(O)—N(Ra)2, —S(O)2—N(Ra)2, —O—Ra, —S—Ra, —O—C(O)—Ra, —O—C(O)—O—Ra, —C(O)—Ra, —C(O)—O—Ra, —S(O)—Ra, —S(O)2—Ra, —O—C(O)—N(Ra)2, —N(Ra)—C(O)—ORa, —N(Ra)—C(O)—N(Ra)2, —N(Ra)—C(O)—Ra, —N(Ra)—S(O)—Ra, —N(Ra)—S(O)2—Ra, —N(Ra)—S(O)—N(Ra)2, and —N(Ra)—S(O)2—N(Ra)2.
- In certain embodiments of compounds of Formula (II), R1 is phenyl that is optionally substituted with one or more substituent groups independently selected from Rc, —F, —Cl, —Br, —I, —NO2, —N(Ra)2, —CN, —C(O)—N(Ra)2, —S(O)—N(Ra)2, —S(O)2—N(Ra)2, —O—Ra, —S—Ra, —O—C(O)—Ra, —O—C(O)—O—Ra, —C(O)—Ra, —C(O)—O—Ra, —S(O)—Ra, —S(O)2—Ra, —O—C(O)—N(Ra)2, —N(Ra)—C(O)—ORa, —N(Ra)—C(O)—N(Ra)2, —N(Ra)—C(O)—Ra, —N(Ra)—S(O)—Ra, —N(Ra)—S(O)2—Ra, —N(Ra)—S(O)—N(Ra)2, and —N(Ra)—S(O)2—N(Ra)2.
- In certain embodiments of compounds of Formula (II), R1 is selected from:
- In certain embodiments of compounds of Formula (II), R1 is phenyl-pyrazolyl, pyrazolyl, phenyl-triazolyl, indazolyl, phenyl-oxazolyl, phenyl, pyridyl-pyrazolyl, tetralinyl, pyridyl, 3,4-dihydroisoquinolin-1-one, phenyl-phenyl, phenyl-pyridyl, phenyl-isoxazolyl, phenyl-cyclohexenyl, phenyl-cyclohexyl, phenyl-thiazolyl, and phenyl-pyrimidinyl, wherein each phenyl, pyrazolyl, triazolyl, indazolyl, oxazolyl, pyridyl, tetralinyl, 3,4-dihydroisoquinolin-1-one, isoxazolyl, cyclohexenyl, cyclohexyl, thiazolyl, and pyrimidinyl is optionally substituted with one or more substituent groups independently selected from Rc, oxo, —F, —Cl, —Br, —N(Ra)2, —CN, —C(O)—N(Ra)2, —O—Ra, —C(O)—Ra and —S(O)2—Ra.
- In certain embodiments of compounds of Formula (II), R2 is C1-12alkyl, C2-12alkenyl, 3-12 membered carbocycle, or 3-12 membered heterocycle, wherein each C1-12alkyl, C2-12alkenyl, 3-12 membered carbocycle, and 3-12 membered heterocycle of R2 is optionally substituted with one or more groups Rb.
- In certain embodiments of compounds of Formula (II), R2 is C1-6alkyl, C2-6alkenyl, 3-6 membered carbocycle, or 3-6 membered heterocycle, wherein each C1-6alkyl, C2-6alkenyl, 3-6 membered carbocycle, and 3-6 membered heterocycle of R2 is optionally substituted with one or more groups Rb.
- In certain embodiments of compounds of Formula (II), R2 is methyl, ethyl, isopropyl, cyclopropylmethyl, 2-methoxyethyl, benzyl, N-methylacetamide, 2-pyridylmethyl, 3-pyridylmethyl, N-ethylacetamide, 4-pyridylmethyl, cyclopropyl, 1-phenylethyl, oxazol-5-ylmethyl, (1-methyl-3-piperidyl)methyl, propanamide, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxy-1-methyl-ethyl, butanenitrile, propanenitrile, 2,2-difluorocyclopropylmethyl, (E)-pent-3-enyl, ethyl-2-acetate, 2-(3-piperidyl)ethyl, 2-(1-methyl-3-piperidyl)ethyl, 1-(1-methylpyrazol-3-yl)ethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, 2-(methyl sulfonyl)ethyl, 2-fluorocyclopropylmethyl, 1-methylcyclopropylmethyl, 2-phenylethyl, 3-propanamide, 2-propenyl, 2-(aminocarbonyl)ethyl, 2-cyanoethyl, N-ethylaminocarbonylmethyl, 2-(pyrid-2-yl)ethyl, 2-(pyrid-4-yl)ethyl, 3-methylphenyl, tetrahydrofuran-3-yl, oxetan-3-yl, oxetan-3-ylmethyl, or tetrahydropyran-4-yl.
- In certain embodiments of compounds of Formula (II), R2 is methyl, cyclopropylmethyl, 2,2,2-trifluoroethyl, 2,2-difluorocyclopropylmethyl, 2-(aminocarbonyl)ethyl, 3,3,3-trifluoropropyl, 2-(methylsulfonyl)ethyl, 2-fluorocyclopropylmethyl, 1-methylcyclopropylmethyl, 2-cyanoethyl, 2-methoxyethyl, oxazol-5-ylmethyl, N-ethylaminocarbonylmethyl, phenethyl, 2-(pyrid-2-yl)ethyl, 2-(pyrid-4-yl)ethyl, tetrahydrofuran-3-yl, oxetan-3-yl, oxetan-3-ylmethyl, or tetrahydropyran-4-yl.
- In certain embodiments of compounds of Formula (II), R2 is methyl, cyclopropylmethyl, tetrahydrofuran-3-yl, oxetan-3-yl, oxetan-3-ylmethyl, or tetrahydropyran-4-yl.
- In certain embodiments of compounds of Formula (II), R1 is phenyl-pyrazolyl, pyrazolyl, phenyl-triazolyl, indazolyl, phenyl-oxazolyl, phenyl, pyridyl-pyrazolyl, tetralinyl, pyridyl, 3,4-dihydroisoquinolin-1-one, phenyl-phenyl, phenyl-pyridyl, phenyl-isoxazolyl, phenyl-cyclohexenyl, phenyl-cyclohexyl, phenyl-thiazolyl, and phenyl-pyrimidinyl, wherein each phenyl, pyrazolyl, triazolyl, indazolyl, oxazolyl, pyridyl, tetralinyl, 3,4-dihydroisoquinolin-1-one, isoxazolyl, cyclohexenyl, cyclohexyl, thiazolyl, and pyrimidinyl is optionally substituted with one or more substituent groups independently selected from Rc, oxo, —F, —Cl, —Br, —N(Ra)2, —CN, —C(O)—N(Ra)2, —O—Ra, —C(O)—Ra and —S(O)2—Ra and R2 is methyl, ethyl, isopropyl, cyclopropylmethyl, 2-methoxyethyl, benzyl, N-methylacetamide, 2-pyridylmethyl, 3-pyridylmethyl, N-ethylacetamide, 4-pyridylmethyl, cyclopropyl, 1-phenylethyl, oxazol-5-ylmethyl, (1-methyl-3-piperidyl)methyl, propanamide, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxy-1-methyl-ethyl, butanenitrile, propanenitrile, 2,2-difluorocyclopropylmethyl, (E)-pent-3-enyl, ethyl-2-acetate, 2-(3-piperidyl)ethyl, 2-(1-methyl-3-piperidyl)ethyl, 1-(1-methylpyrazol-3-yl)ethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, 2-(methyl sulfonyl)ethyl, 2-fluorocyclopropylmethyl, 1-methylcyclopropylmethyl, 2-phenylethyl, 3-propanamide, 2-propenyl, 2-(aminocarbonyl)ethyl, 2-cyanoethyl, N-ethylaminocarbonylmethyl, 2-(pyrid-2-yl)ethyl, 2-(pyrid-4-yl)ethyl, 3-methylphenyl, tetrahydrofuran-3-yl, oxetan-3-yl, oxetan-3-ylmethyl, or tetrahydropyran-4-yl.
- In certain embodiments of compounds of Formula (II), R1 is phenyl-pyrazolyl, pyrazolyl, phenyl-triazolyl, indazolyl, phenyl-oxazolyl, phenyl, pyridyl-pyrazolyl, tetralinyl, pyridyl, 3,4-dihydroisoquinolin-1-one, phenyl-phenyl, phenyl-pyridyl, phenyl-isoxazolyl, phenyl-cyclohexenyl, phenyl-cyclohexyl, phenyl-thiazolyl, and phenyl-pyrimidinyl, wherein each phenyl, pyrazolyl, triazolyl, indazolyl, oxazolyl, pyridyl, tetralinyl, 3,4-dihydroisoquinolin-1-one, isoxazolyl, cyclohexenyl, cyclohexyl, thiazolyl, and pyrimidinyl is optionally substituted with one or more substituent groups independently selected from Rc, oxo, —F, —Cl, —Br, —N(Ra)2, —CN, —C(O)—N(Ra)2, —O—Ra, —C(O)—Ra and —S(O)2—Ra and R2 is methyl, cyclopropylmethyl, 2,2,2-trifluoroethyl, 2,2-difluorocyclopropylmethyl, 2-(aminocarbonyl)ethyl, 3,3,3-trifluoropropyl, 2-(methyl sulfonyl)ethyl, 2-fluorocyclopropylmethyl, 1-methylcyclopropylmethyl, 2-cyanoethyl, 2-methoxyethyl, oxazol-5-ylmethyl, N-ethylaminocarbonylmethyl, phenethyl, 2-(pyrid-2-yl)ethyl, 2-(pyrid-4-yl)ethyl, tetrahydrofuran-3-yl, oxetan-3-yl, oxetan-3-ylmethyl, or tetrahydropyran-4-yl.
- In certain embodiments of compounds of Formula (II), R1 is phenyl-pyrazolyl, pyrazolyl, phenyl-triazolyl, indazolyl, phenyl-oxazolyl, phenyl, pyridyl-pyrazolyl, tetralinyl, pyridyl, 3,4-dihydroisoquinolin-1-one, phenyl-phenyl, phenyl-pyridyl, phenyl-isoxazolyl, phenyl-cyclohexenyl, phenyl-cyclohexyl, phenyl-thiazolyl, and phenyl-pyrimidinyl, wherein each phenyl, pyrazolyl, triazolyl, indazolyl, oxazolyl, pyridyl, tetralinyl, 3,4-dihydroisoquinolin-1-one, isoxazolyl, cyclohexenyl, cyclohexyl, thiazolyl, and pyrimidinyl is optionally substituted with one or more substituent groups independently selected from Rc, oxo, —F, —Cl, —Br, —N(Ra)2, —CN, —C(O)—N(Ra)2, —O—Ra, —C(O)—Ra and —S(O)2—Ra and R2 is methyl, cyclopropylmethyl, tetrahydrofuran-3-yl, oxetan-3-yl, oxetan-3-ylmethyl, or tetrahydropyran-4-yl.
- In certain embodiments of compounds of Formula (II), R2 is:
- In certain embodiments of compounds of Formula (II), R3 is acetyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, methoxycarbonyl, propanoyl, cyclopropylcarbonyl, methylsulfonyl, butanoyl, difluoroacetyl, thiadiazole or isoxazole.
- In certain embodiments of compounds of Formula (II), R3 is substituted or unsubstituted acetyl, propionyl, butyryl, cyclopropylcarbonyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, methoxycarbonyl, methylsulfonyl, difluoroacetyl, thiadiazole, methylthiadiazole, oxadiazole, methyloxadiazole, or isoxazole.
- In certain embodiments of compounds of Formula (II), R3 is selected from the group consisting of:
- In certain embodiments of compounds of Formula (II), R3 is selected from the group consisting of:
- In certain embodiments the compound of Formula (II) is selected from the group consisting of:
- and salts thereof
- In certain embodiments the compound of Formula (II) is a compound as described in the Examples herein, or a freebase or salt thereof.
- In certain embodiments any of the embodiments described for the compound of Formula (II) may be combined with any other embodiment described for the compound of Formula (II).
- Another aspect includes a pharmaceutical composition comprising a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof. In one embodiment, the composition further comprises a pharmaceutically acceptable carrier, adjuvant, or vehicle. In another embodiment, the composition further comprises an amount of the compound effective to measurably inhibit a bromodomain of CBP and/or EP300. In certain embodiments, the composition is formulated for administration to a patient in need thereof.
- The term “patient” or “individual” as used herein, refers to an animal, such as a mammal, such as a human. In one embodiment, patient or individual refers to a human.
- The term “pharmaceutically acceptable carrier, adjuvant, or vehicle” refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.
- Compositions comprising a compound of formula I or formula II or salt thereof may be administered orally, parenterally, by inhalation spray, topically, transdermally, rectally, nasally, buccally, sublingually, vaginally, intraperitoneal, intrapulmonary, intradermal, epidural or via an implanted reservoir. The term “parenteral” as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques.
- In one embodiment, the composition comprising a compound of formula I or formula II or salt thereof is formulated as a solid dosage form for oral administration. Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In certain embodiments, the solid oral dosage form comprising a compound of formula (I) or formula (II) or a salt thereof further comprises one or more of (i) an inert, pharmaceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate, and (ii) filler or extender such as starches, lactose, sucrose, glucose, mannitol, or silicic acid, (iii) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose or acacia, (iv) humectants such as glycerol, (v) disintegrating agent such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates or sodium carbonate, (vi) solution retarding agents such as paraffin, (vii) absorption accelerators such as quaternary ammonium salts, (viii) a wetting agent such as cetyl alcohol or glycerol monostearate, (ix) absorbent such as kaolin or bentonite clay, and (x) lubricant such as talc, calcium stearate, magnesium stearate, polyethylene glycols or sodium lauryl sulfate. In certain embodiments, the solid oral dosage form is formulated as capsules, tablets or pills. In certain embodiments, the solid oral dosage form further comprises buffering agents. In certain embodiments, such compositions for solid oral dosage forms may be formulated as fillers in soft and hard-filled gelatin capsules comprising one or more excipients such as lactose or milk sugar, polyethylene glycols and the like.
- In certain embodiments, tablets, dragees, capsules, pills and granules of the compositions comprising a compound of formula I or formula II or salt thereof optionally comprise coatings or shells such as enteric coatings. They may optionally comprise opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions include polymeric substances and waxes, which may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
- In another embodiment, a composition comprises micro-encapsulated compound of formula (I) or formula (II) or salt thereof, and optionally, further comprises one or more excipients.
- In another embodiment, compositions comprise liquid dosage formulations comprising a compound of formula I or formula II or salt thereof for oral administration, and optionally further comprise one or more of pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In certain embodiments, the liquid dosage form optionally, further comprise one or more of an inert diluent such as water or other solvent, a solubilizing agent, and an emulsifier such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols or fatty acid esters of sorbitan, and mixtures thereof. In certain embodiments, liquid oral compositions optionally further comprise one or more adjuvant, such as a wetting agent, a suspending agent, a sweetening agent, a flavoring agent and a perfuming agent.
- Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.
- Injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
- In order to prolong the effect of a compound of formula (I) or formula (II), it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of compound to polymer and the nature of the particular polymer employed, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.
- In certain embodiments, the composition for rectal or vaginal administration are formulated as suppositories which can be prepared by mixing a compound of formula (I) or formula (II) or a salt thereof with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax, for example those which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the compound of formula (I) or formula (II).
- Example dosage forms for topical or transdermal administration of a compound of formula (I) or formula (II) include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The compound of formula (I) or formula (II) or a salt thereof is admixed under sterile conditions with a pharmaceutically acceptable carrier, and optionally preservatives or buffers. Additional formulation examples include an ophthalmic formulation, ear drops, eye drops, transdermal patches. Transdermal dosage forms can be made by dissolving or dispensing the compound of formula (I) or formula (II) or a salt thereof in medium, for example ethanol or dimethylsulfoxide. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
- Nasal aerosol or inhalation formulations of a compound of formula (I) or formula (II) or a salt thereof may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promotors to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.
- In certain embodiments, pharmaceutical compositions may be administered with or without food. In certain embodiments, pharmaceutically acceptable compositions are administered without food. In certain embodiments, pharmaceutically acceptable compositions of this invention are administered with food.
- Specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, the judgment of the treating physician, and the severity of the particular disease being treated. The amount of a provided compound of formula I or formula II or salt thereof in the composition will also depend upon the particular compound in the composition.
- In one embodiment, the therapeutically effective amount of the compound of the invention administered parenterally per dose will be in the range of about 0.01-100 mg/kg, alternatively about 0.1 to 20 mg/kg of patient body weight per day, with the typical initial range of compound used being 0.3 to 15 mg/kg/day. In another embodiment, oral unit dosage forms, such as tablets and capsules, contain from about 5 to about 100 mg of the compound of the invention.
- An example tablet oral dosage form comprises about 2 mg, 5 mg, 25 mg, 50 mg, 100 mg, 250 mg or 500 mg of a compound of formula (I) or formula (II) or salt thereof, and further comprises about 5-30 mg anhydrous lactose, about 5-40 mg sodium croscarmellose, about 5-30 mg polyvinylpyrrolidone (PVP) K30 and about 1-10 mg magnesium stearate. The process of formulating the tablet comprises mixing the powdered ingredients together and further mixing with a solution of the PVP. The resulting composition can be dried, granulated, mixed with the magnesium stearate and compressed to tablet form using conventional equipment. An example of an aerosol formulation can be prepared by dissolving about 2-500 mg of a compound of formula I or formula II or salt thereof, in a suitable buffer solution, e.g. a phosphate buffer, and adding a tonicifier, e.g. a salt such sodium chloride, if desired. The solution may be filtered, e.g. using a 0.2 micron filter, to remove impurities and contaminants.
- Another aspect includes the use of a compound of formula (I) or formula (II) or a salt thereof for the inhibition of a bromodomain (in vitro or in vivo) (e.g., in vitro or in vivo inhibition of the bromodomain of CBP/EP300).
- Another embodiment includes a method for treating a bromodomain-mediated disorder (e.g., CBP/EP300 bromodomain-mediated disorder) in an animal comprising administering a compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof to the animal. CBP/EP300-mediated disorders include, but are not limited to those disorders described herein.
- Another embodiment includes a method of increasing efficacy of a cancer treatment comprising a cytotoxic agent in an animal comprising administering to the animal an effective amount of a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof.
- Another embodiment includes a method of extending the duration of response to a cancer therapy in an animal, comprising administering to an animal undergoing the cancer therapy a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, wherein the duration of response to the cancer therapy when the compound of formula (I) or formula (II) or the pharmaceutically acceptable salt thereof is administered is extended over the duration of response to the cancer therapy in the absence of the administration of the compound of formula (I) or formula (II) or the pharmaceutically acceptable salt thereof.
- Another embodiment includes a method of treating cancer in an individual comprising administering to the individual (a) a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, and (b) a cytotoxic agent. In one embodiment the cytotoxic agent is selected from anti-microtubule agents, platinum coordination complexes, alkylating agents, antibiotic agents, topoisomerase II inhibitors, antimetabolites, topoisomerase I inhibitors, hormones and hormonal analogues, signal transduction pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors, immunotherapeutic agents, proapoptotic agents, inhibitors of LDH-A, inhibitors of fatty acid biosynthesis, cell cycle signaling inhibitors, HDAC inhibitors, proteasome inhibitors, and inhibitors of cancer metabolism. In one embodiment the cytotoxic agent is a taxane. In one embodiment the taxane is paclitaxel or docetaxel. In one embodiment the cytotoxic agent is a platinum agent. In one embodiment the cytotoxic agent is an antagonist of EGFR. In one embodiment the antagonist of EGFR is N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine or a pharmaceutically acceptable salt thereof (e.g., erlotinib). In one embodiment the cytotoxic agent is a RAF inhibitor. In one embodiment the RAF inhibitor is a BRAF or CRAF inhibitor. In one embodiment the RAF inhibitor is vemurafenib. In one embodiment the cytotoxic agent is a PI3K inhibitor.
- In certain embodiments, treatment may be administered after one or more symptoms have developed. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example to prevent or delay their recurrence.
- In some embodiments, the CBP/EP300 bromodomain inhibitor interferes with the associating of CBP and/or EP300 with histones, in particular acetylated lysines in histones. In some embodiments, the CBP/EP300 bromodomain inhibitor inhibits binding of CBP and/or EP300 to chromatin (e.g., histone associated DNA). In some embodiments, the CBP/EP300 bromodomain inhibitor inhibits and/or reduces binding of the CBP bromodomain and/or EP300 bromodomain to chromatin (e.g., histone associated DNA). In some embodiments, the CBP/EP300 bromodomain inhibitor does not affect association of other domains of CBP and/or EP300 to chromatin. In some embodiments, CBP/EP300 bromodomain inhibitor binds to the CBP and/or EP300 primarily (e.g., solely) through contacts and/or interactions with the CBP bromodomain and/or EP300 bromodomain. In some embodiments, CBP/EP300 bromodomain inhibitor binds to the CBP and/or EP300 through contacts and/or interactions with the CBP bromodomain and/or EP300 bromodomain as well as additional CBP and/or EP300 residues and/or domains. Methods of assaying association with chromatin are known in the art and include, but are not limited to, chromatin fractionation, BRET assay (Promega), FRAP assay, Chromatin Immunoprecipitation (ChIP), biophysical binding assay, and/or Histone Association Assay. See, e.g., Das et al., BioTechniques 37:961-969 (2004).
- In some embodiments, the CBP/EP300 bromodomain inhibitor does not affect effector function in CD8 cells (i.e., effector function is substantially the same in the presence and/or absence of the CBP/EP300 bromodomain inhibitor). In some embodiments, the CBP/EP300 bromodomain inhibitor does not affect expression levels of perforin, granzyme, and/or EOMES (i.e., expression levels of one or more perforin, granzyme, and/or EOMES are substantially the same in the presence and/or absence of the CBP/EP300 bromodomain inhibitor). In some embodiments, the CBP/EP300 bromodomain inhibitor does not affect expression levels of effector cytokines IFN-γ and/or TNFα (i.e., expression levels of effector cytokines IFN-γ and/or TNFα are substantially the same in the presence and/or absence of the CBP/EP300 bromodomain inhibitor). In some embodiments, the CBP/EP300 bromodomain inhibitor enhances naïve T cell responsiveness to CD3/CD28 stimulation in the presence of Treg cells.
- In some embodiments, the CBP/EP300 bromodomain inhibitor does not substantially bind to (e.g., does not bind to) the HAT domain of CBP and/or EP300. In some embodiments, the CBP/EP300 bromodomain inhibitor does not substantially bind to (e.g., does not bind to) the HAT domain of CBP and/or EP300 as identified in Delvecchio et al., Nat. Struct. & Mol. Biol. 20:1040-1046 (2013), which is incorporated by reference in its entirety. In some embodiments, the CBP/EP300 bromodomain inhibitor does not substantially bind to one or more residues of the amino acid sequence ENKFSAKRLQTTR LGNHLEDRVNKFLRRQNHPEAGEVFVRVVASSDKTVEVKPGMKSRFVDSGEMSESFPY RTKALFAFEEIDGVDVCFFGMHVQEYGSDCPPPNTRRVYISYLDSIHFFRPRCLRTAVYH EILIGYLEYVKKLGYVTGHIWACPPSEGDDYIFHCHPPDQKIPKPKRLQEWYKKMLDKA FAERIIHDYKDIFKQATEDRLTSAKELPYFEGDFWPNVLEESIKELEQEEEERKKEESTAA SETTEGSQGDSKNAKKKNNKKTNKNKSSISRANKKKPSMPNVSNDLSQKLYATMEKH KEVFFVIHLHAGPVINTLPPIVDPDPLLSCDLMDGRDAFLTLARDKHWEFSSLRRSKWST LCMLVELHTQGQD (amino acid residues 1321-1701 of UniProt No. Q92793 (SEQ ID NO: 1)). In some embodiments, the CBP/EP300 bromodomain inhibitor does not substantially bind to one or more residues of the amino acid sequence ENKFSAKRLPSTRLGTFLENRVNDFLRRQNHPESGEVTVRVVHASDKTVEVKPGMKAR FVDSGEMAESFPYRTKALFAFEEIDGVDLCFFGMHVQEYGSDCPPPNQRRVYISYLDSV HFFRPKCLRTAVYHEILIGYLEYVKKLGYTTGHIWACPPSEGDDYIFHCHPPDQKIPKPK RLQEWYKKMLDKAVSERIVHDYKDIFKQATEDRLTSAKELPYFEGDFWPNVLEESIKEL EQEEEERKREENTSNESTDVTKGDSKNAKKKNNKKTSKNKSSLSRGNKKKPGMPNVSN DLSQKLYATMEKHKEVFFVIRLIAGPAANSLPPIVDPDPLIPCDLMDGRDAFLTLARDKH LEFSSLRRAQWSTMCMLVELHTQSQD (amino acid residues 1285-1664 of UniProt No. Q09472 (SEQ ID NO:2)). In some embodiments, the CBP/EP300 bromodomain inhibitor does not inhibit the histone acetyltransferase (HAT) catalytic activity of CBP and/or EP300.
- Compounds that are CBP/EP300 bromodomain inhibitors are expected to have improved and/or distinct properties over other compounds, such as “HAT” inhibitor compounds. HAT inhibition is expected to result in a global reduction in protein acetylation (histone and non-histone), likely affecting cell viability in a significant way. In some embodiments, CBP/EP300 bromodomain inhibition preserves the HAT activity of these proteins while resulting in the reduction of transcriptional activity of a relatively small subset of target genes.
- In some embodiments, provided are methods of enhancing immune function in an individual having cancer comprising administering an effective amount of any CBP/EP300 bromodomain inhibitors disclosed herein. In some embodiments of any of the methods, the CD8 T cells in the individual have enhanced priming, activation, proliferation, and/or cytolytic activity relative to prior to the administration of the CBP/EP300 bromodomain inhibitor. In some embodiments, the number of CD8 T cells is elevated relative to prior to administration of the CBP/EP300 bromodomain inhibitors. In some embodiments, the CD8 T cells have reduced levels of expression of one or more of the following biomarkers: IFNA17, IGF1, FSCN1, SUMO2, CIorf129, EIF2S2, TDGF1, AIDA, CCR4, CD160, MC4R, KRTAP2-2, MTIJP, OR4N2, KRTAP4-5, MTIL//MTIL, ILI3, LCEID, KIR2DL2, LOC158696, LIF, 1L28A, TAS2R13, CTLA4, and/or FOXP3 relative to prior to administration of the CBP/EP300 bromodomain inhibitor. In some embodiments, the CD8 T cells have reduced levels of expression of CD160 and/or KIR2DL2 relative to prior to administration of the CBP/EP300 bromodomain inhibitor.
- In some embodiments of the methods of enhancing immune function, the enhanced immune function is characterized by Treg cells in the individual (e.g., at the tumor site(s)) have reduced levels of expression of one or more of the following markers: 1L28A, GPR87, ANKRD37, CABLES1, RAPGEF2, TRIM69, MT1L//MT1L, FAM1138, FOXP3, CSF2, OCM2, GLIPR1, FGFBP2, CTLA4, CST7, GOLGA6L1, IFIT3, FAM13A, APOD, AK2, CLDN1, HSD11B1, DNAJC12, PHEX, IL2, FOXD4L3, GNA15, ZBTB32, RDH10, OR52E5, CYP2A6, GZMH, CCL20, ADM, LOC100131541, RNF122, FAM36A, AMY2B, GPR183, MYOF, IL29, AIDA, SPRYI, ENOPH1, IL1RN, SLAMF1, PGM2L1, SSBP3, MMP23B, HIST1H3J, MYO1B, BEND5, S1PR1, CDK6, GPR56, ZC3HIZA, DOK5, DUSPI, CYB5R2, KCNAB2, LAG3, KLF10, GK, SHC4, IL12RB2, CD109, HAVCR2 (TIM-3), LTA, FAM40B, HMGCSI, HSPA1A, ZNF705A, CMAH, KIF3A, CHN1, KBTBD8, TNF, MOP-1, RASGRP4, INSIG1, SLAMF7, OR10H4, LPL, HIST1H2BJ, LIF, IGF1, IL18RAP, OR52N4, OR1D2, CCR4, CXCR5, IL1R1, MICAL2, NRN1, PICALM, B3GNT5, IFI44L, CXCR3, ICOS, IFIT2, NCR3, HSPA1B, CD80, GNG2, C7orf68, GPR171, RPS10OP7, IL23A, LOC283174, PLK2, EMP1, FNBP1L, CD226, RBMS3, IL23R, PTGER4, GZMB, F5, and/or HIST1H2BK relative to prior to administration of CBP/EP300 bromodomain inhibitor. In some embodiments, the Treg cell biomarker is one or more of LAG3, CTLA4, and/or FOXP3. In some embodiments of the methods of enhancing immune function, the enhanced immune function is characterized by enhanced naive T cell responsiveness to CD3/CD28 stimulation in the presence of Treg cells. In some embodiments, the CD8 T cell priming is characterized by increased T cell proliferation and/or enhanced cytolytic activity in CD8 T cells. In some embodiments, the CD8 T cell activation is characterized by an elevated frequency of T-IFN+ CD8 T cells. In some embodiments, the CD8 T cell is an antigen-specific T-cell. In some embodiments, the immune evasion is inhibited.
- In some embodiments, the methods provided herein are useful in treating conditions where enhanced immunogenicity is desired such as increasing tumor immunogenicity for the treatment of cancer. For example, provided herein are CBP/EP300 bromodomain inhibitors for use to enhance T-cell function to upregulate cell-mediated immune responses and for the treatment of T cell dysfunctional disorders, tumor immunity. In some embodiments, the CBP/EP300 bromodomain inhibitors promote anti-tumor immunity by inhibiting the suppressive function of regulatory T (Treg) cells and/or relieving T cell exhaustion on chronically stimulated CD8+ T cells. CBP/EP300 bromodomain inhibitors are further useful in reducing FOXP3 expression during extra-thymic Treg cell differentiation. Continual FOXP3 expression is essential to maintain suppressive activity in Treg cells. In some embodiments, reduced FOXP3 expression through CBP/EP300 bromodomain inhibition impairs Treg cells suppressive activity and promotes tumor antiimmunity. Treg cells are highly enriched in tumors derived from multiple cancer indications, including melanoma, NSCLC, renal, overian, colon, pancreatic, hepatocellular, and breast cancer. In a subset of these indications, increased intratumoral Treg cell densities are associated with poor patient prognosis. These indications include NSCLC, ovarian, pancreatic, hepatocellular, and breast cancer. CBP/EP300 bromodomain inhibitors are predicted to impair intratumoral Treg cell function in these cancer indications to enhance effector T cell activity. In other embodiments, the CBP/EP300 bromodomain inhibitors may be used to treat infectious diseases, where some pathogens may have evolved to manipulate regulatory T (Treg) cells to immunosuppress the host to ensure survival, such as in retrovial infections (e.g., HIV), mycobacterial infections (e.g., tuberculosis), and parasitic infections (e.g., Leishmania and malaria).
- In some embodiments, the methods provided herein are useful in treating a CBP and/or EP300-mediated disorder involving fibrosis. In some embodiments, the CBP and/or EP300-mediated disorder is a fibrotic disease. Certain fibrotic diseases may include, for example, pulmonary fibrosis, silicosis, cystic fibrosis, renal fibrosis, liver fibrosis, liver cirrhosis, primary sclerosing cholangitis, primary biliary cirrhosis, endomyocardial fibrosis, mediastinal fibrosis, myelofibrosis, retroperitoneal fibrosis, progressive massive fibrosis, nephrogenic systemic fibrosis, Crohn's disease, keloid, myocardial infarction, systemic sclerosis or arthro fibrosis.
- In other embodiments, the CBP and/or EP300-mediated disorder is a fibrotic lung disease. Fibrotic lung diseases may include, for example, idiopathic pulmonary fibrosis, fibrotic interstitial lung disease, interstitial pneumonia, fibrotic variant of non-specific interstitial pneumonia, cystic fibrosis, lung fibrosis, chronic obstructive pulmonary lung disease (COPD), or pulmonary arterial hypertension. In certain embodiments, the fibrotic lung disease is idiopathic pulmonary fibrosis.
- In some embodiments, any CBP and/or EP300 inhibitor may be used to treat fibrotic disease. In some embodiments, the CBP and/or EP300 inhibitor is a compound of formula (I) or of formula (II), as described herein. In some embodiments, the CBP and/or EP300 inhibitor is a compound of formula (III):
- or a salt thereof, wherein:
- X is NH, O, S, or —C(Ra)2—;
- each Ra is independently selected from the group consisting of H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, and C3-6carbocyclyl;
- ring A is a 6 membered heteroaryl ring or a benzo ring, wherein ring A is optionally substituted with one or more groups Rb that are independently selected from the group consisting of Rc, —F, —Cl, —Br, —I, —NO2, —N(Rd)2, —CN, —C(O)—N(Rd)2, —S(O)—N(Rd)2, —S(O)2—N(Rd)2, —O—Rd, —S—Rd, —O—C(O)—Rd, —O—C(O)—O—Rd, —C(O)—Rd, —C(O)—O—Rd, —S(O)—Rd, —S(O)2—Rd, —O—C(O)—N(Rd)2, —N(Rd)—C(O)—ORd, —N(Rd)—C(O)—N(Rd)2, —N(Rd)—C(O)—Rd, —N(Rd)—S(O)—Rd, —N(Rd)—S(O)2—Rd, —N(Rd)—S(O)—N(Rd)2, —CH═C(Re)2, and —N(Rd)—S(O)2—N(Rd)2; each Rc is independently selected from the group consisting of hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 3-20 membered carbocyclyl, 3-20 membered heterocyclyl, wherein any C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 3-20 membered carbocyclyl, and 3-20 membered heterocyclyl is optionally substituted with one or more groups Rf;
- each Rf is independently selected from the group consisting of oxo, 3-20 membered carbocyclyl, 3-20 membered heterocyclyl, halo, —NO2, —N(Rg)2, —CN, —C(O)—N(Rg)2, —S(O)—N(Rg)2, —S(O)2—N(Rg)2, —O—Rg, —S—Rg, —O—C(O)—Rg, —C(O)—Rg, —C(O)—O—Rg, —S(O)—Rg, —S(O)2—Rg, —C(O)—N(Rg)2, —N(Rg)—C(O)—Rg, —Si(Rh)3, —N(Rg)—C(O)—O—Rg, —N(Rg)—S(O)—Rg, N(Rg)—S(O)2—Rg, and C1-6alkyl, which 3-20 membered carbocyclyl, 3-20 membered heterocyclyl, and C1-6alkyl are optionally substituted with one or more groups Ri,
- each Rg is independently selected from the group consisting of hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 3-20 membered carbocyclyl, and 3-20 membered heterocyclyl, wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkoxy, 3-20 membered carbocyclyl, and 3-20 membered heterocyclyl is optionally substituted with one or more groups Rj, or two Rg are taken together with the nitrogen to which they are attached to form a 3-20 membered heterocyclyl that is optionally substituted with one or more groups independently selected from the group consisting of oxo, halo and C1-3alkyl that is optionally substituted with one or more groups independently selected from the group consisting of oxo and halo;
- each Rh is independently selected from the group consisting of H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, and C3-6carbocyclyl;
- each Rj is independently selected from the group consisting of oxo, halo, amino, hydroxyl, —Si(Rk)3, 3-20 membered carbocyclyl, 3-20 membered heterocyclyl, and C1-C6 alkyl, wherein any 3-20 membered carbocyclyl, 3-20 membered heterocyclyl, and C1-C6 alkyl is optionally substituted with one or more groups independently selected from the group consisting of oxo, C1-C4alkyl, and halo;
- each Rk is independently selected from the group consisting of H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, and C3-6carbocyclyl;
- each Ri is independently selected from the group consisting of oxo, halo, C1-6alkyl, cyano, —N(R1)2, —O—R1, —S(O)—R1, —S(O)2—R1, —S(O)—N(R1)2, —S(O)2—N(R1)2, —N(R1)—S(O)—R1, —N(R1)—C(O)—R1, —N(R1)—C(O)—O—R1, —N(R1)—S(O)2—R1, 3-20 membered heterocyclyl, and 3-20 membered carbocyclyl that is optionally substituted with one or more groups independently selected from the group consisting of halo, and C1-6alkyl;
- each Rl is independently selected from the group consisting of hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 3-20 membered carbocyclyl, and 3-20 membered heterocyclyl, wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkoxy, 3-20 membered carbocyclyl, and 3-20 membered heterocyclyl is optionally substituted with one or more groups Rm; or two Rl are taken together with the nitrogen to which they are attached to form a 3-20 membered heterocyclyl that is optionally substituted with one or more groups independently selected from the group consisting of oxo, halo and C1-3alkyl that is optionally substituted with one or more groups independently selected from the group consisting of oxo and halo; and
- each Rm is independently selected from the group consisting of oxo, halo, amino, hydroxyl, —Si(Rn)3, 3-20 membered carbocyclyl, 3-20 membered heterocyclyl, and C1-C6 alkyl, wherein any 3-20 membered carbocyclyl, 3-20 membered heterocyclyl, and C1-C6 alkyl is optionally substituted with one or more groups independently selected from the group consisting of oxo, C1-C4alkyl, and halo;
- each Rn is independently selected from the group consisting of H, C4-6alkyl, C2-6alkenyl, C2-6alkynyl, and C3-6carbocyclyl;
- each Rd is independently selected from the group consisting of hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 3-20 membered carbocyclyl, and 3-20 membered heterocyclyl, wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 3-20 membered carbocyclyl, and 3-20 membered heterocyclyl is optionally substituted with one or more groups Ro, or two Rd are taken together with the nitrogen to which they are attached to form a 3-20 membered heterocyclyl that is optionally substituted with one or more groups independently selected from the group consisting of oxo, halo and C1-3alkyl that is optionally substituted with one or more groups independently selected from oxo and halo;
- each Ro is independently selected from the group consisting of oxo, halo, amino, hydroxyl, cyano, —O—Rp, 3-20 membered carbocyclyl, 3-20 membered heterocyclyl, and C1-C6 alkyl, wherein any C1-C6 alkyl, 3-20 membered carbocyclyl and 3-20 membered heterocyclyl is optionally substituted with one or more groups independently selected from the group consisting of oxo, C1-C4 alkyl, —O—Rq, and halo;
- each Rp is independently selected from the group consisting of hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 3-20 membered carbocyclyl, and 3-20 membered heterocyclyl, wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkoxy, 3-20 membered carbocyclyl, and 3-20 membered heterocyclyl is optionally substituted with one or more groups Rr,
- each Rr is independently selected from the group consisting of oxo, halo, amino, hydroxyl, —Si(Rs)3, 3-20 membered carbocyclyl, 3-20 membered heterocyclyl, and C1-C6 alkyl, wherein any 3-20 membered carbocyclyl, 3-20 membered heterocyclyl, and C1-C6 alkyl is optionally substituted with one or more groups independently selected from the group consisting of oxo, C1-C4alkyl, and halo;
- each Rs is independently selected from the group consisting of H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, and C3-6carbocyclyl;
- each Rq is independently selected from the group consisting of hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 3-20 membered carbocyclyl, and 3-20 membered heterocyclyl, wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkoxy, 3-20 membered carbocyclyl, and 3-20 membered heterocyclyl is optionally substituted with one or more groups Rt,
- each Rt is independently selected from the group consisting of oxo, halo, amino, hydroxyl, —Si(Ru)3, 3-20 membered carbocyclyl, 3-20 membered heterocyclyl, and C1-C6 alkyl, wherein any 3-20 membered carbocyclyl, 3-20 membered heterocyclyl, and C1-C6 alkyl is optionally substituted with one or more groups independently selected from the group consisting of oxo, C1-C4alkyl, and halo;
- each Ru is independently selected from the group consisting of H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, and C3-6carbocyclyl; and
- two Re groups taken together with the carbon to which they are attached form a 3-20 membered carbocyclyl;
- or a salt thereof.
- In some embodiments, the CBP and/or EP300 inhibitor is:
- CBP and/or EP300-Mediated Disorders
- A “CBP and/or EP300-mediated disorder” is characterized by the participation of the bromodomains of CBP and/or EP300 in the inception, manifestation of one or more symptoms or disease markers, severity, or progression of a disorder. In one embodiment the bromodomain-mediated disorder is a CBP bromodomain-mediated disorder. In one embodiment the bromodomain-mediated disorder is an EP300 bromodomain-mediated disorder.
- CBP and/or EP300 bromodomain-mediated disorders include cancers, including, but not limited to acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acute T-cell leukemia, basal cell carcinoma, bile duct carcinoma, bladder cancer, brain cancer, breast cancer, bronchogenic carcinoma, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myelocytic (granulocytic) leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, dysproliferative changes (dysplasias and metaplasias), embryonal carcinoma, endometrial cancer, endotheliosarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen-receptor positive breast cancer, essential thrombocythemia, Ewing's tumor, fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma, glioblastoma, gliosarcoma, heavy chain disease, hemangioblastoma, hepatoma, hepatocellular cancer, hormone insensitive prostate cancer, leiomyosarcoma, leukemia, liposarcoma, lung cancer, lymphagioendotheliosarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma (Hodgkin's and non-Hodgkin's), malignancies and hyperproliferative disorders of the bladder, breast, colon, lung, ovaries, pancreas, prostate, skin and uterus, lymphoid malignancies of T-cell or B-cell origin, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myelogenous leukemia, myeloma, myxosarcoma, neuroblastoma, NUT midline carcinoma (NMC), non-small cell lung cancer, oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinomas, papillary carcinoma, pinealoma, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small cell lung carcinoma, solid tumors (carcinomas and sarcomas), small cell lung cancer, stomach cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma, thyroid cancer, Waldenstr6m's macroglobulinemia, testicular tumors, uterine cancer and Wilms' tumor.
- In certain embodiments, the cancer is lung cancer, breast cancer, pancreatic cancer, colorectal cancer, and/or melanoma. In certain embodiments, the cancer is lung. In certain embodiments, the lung cancer is NSCLC. In certain embodiments, the cancer is breast cancer.
- In certain embodiments, the cancer is melanoma.
- CBP and/or EP300-mediated disorders also include inflammatory diseases, inflammatory conditions, and autoimmune diseases, including, but not limited to: Addison's disease, acute gout, ankylosing spondylitis, asthma, atherosclerosis, Behcet's disease, bullous skin diseases, chronic obstructive pulmonary disease (COPD), Crohn's disease, dermatitis, eczema, giant cell arteritis, glomerulonephritis, hepatitis, hypophysitis, inflammatory bowel disease, Kawasaki disease, lupus nephritis, multiple sclerosis, myocarditis, myositis, nephritis, organ transplant rejection, osteoarthritis, pancreatitis, pericarditis, Polyarteritis nodosa, pneumonitis, primary biliary cirrhosis, psoriasis, psoriatic arthritis, rheumatoid arthritis, scleritis, sclerosing cholangitis, sepsis, systemic lupus erythematosus, Takayasu's Arteritis, toxic shock, thyroiditis, type I diabetes, ulcerative colitis, uveitis, vitiligo, vasculitis, and Wegener's granulomatosis.
- CBP and/or EP300-mediated disorders also include AIDS; chronic kidney diseases, including, but are not limited to diabetic nephropathy, hypertensive nephropathy, HIV-associated nephropathy, glomerulonephritis, lupus nephritis, IgA nephropathy, focal segmental glomerulosclerosis, membranous glomerulonephritis, minimal change disease, polycystic kidney disease and tubular interstitial nephritis; acute kidney injury or disease or condition including, but are not limited to ischemia-reperfusion induced, cardiac and major surgery induced, percutaneous coronary intervention induced, radio-contrast agent induced, sepsis induced, pneumonia induced, and drug toxicity induced; obesity; dyslipidemia; hypercholesterolemia; Alzheimer's disease; metabolic syndrome; hepatic steatosis; type II diabetes; insulin resistance; and diabetic retinopathy.
- CBP and/or EP300 inhibitors may also be used to provide male contraception.
- CBP and/or EP300-mediated disorders also include fibrotic diseases. Certain fibrotic diseases may include, for example, pulmonary fibrosis, silicosis, cystic fibrosis, renal fibrosis, liver fibrosis, liver cirrhosis, primary sclerosing cholangitis, primary biliary cirrhosis, endomyocardial fibrosis, mediastinal fibrosis, myelofibrosis, retroperitoneal fibrosis, progressive massive fibrosis, nephrogenic systemic fibrosis, Crohn's disease, keloid, myocardial infarction, systemic sclerosis or arthro fibrosis.
- CBP and/or EP300-mediated disorders also include fibrotic lung diseases. Fibrotic lung diseases may include, for example, idiopathic pulmonary fibrosis, fibrotic interstitial lung disease, interstitial pneumonia, fibrotic variant of non-specific interstitial pneumonia, cystic fibrosis, lung fibrosis, chronic obstructive pulmonary lung disease (COPD), or pulmonary arterial hypertension. In certain embodiments, the fibrotic lung disease is idiopathic pulmonary fibrosis.
- The compounds of formula (I) or formula (II) or salts thereof may be employed alone or in combination with other agents for treatment. For example, the second agent of the pharmaceutical combination formulation or dosing regimen may have complementary activities to the compound of formula (I) or formula (II) such that they do not adversely affect each other. The compounds may be administered together in a unitary pharmaceutical composition or separately. In one embodiment a compound or a pharmaceutically acceptable salt can be co-administered with a cytotoxic agent to treat proliferative diseases and cancer. The term “co-administering” refers to either simultaneous administration, or any manner of separate sequential administration, of a compound of formula (I) or formula (II) or a salt thereof, and a further active pharmaceutical ingredient or ingredients, including cytotoxic agents and radiation treatment. If the administration is not simultaneous, the compounds are administered in a close time proximity to each other. Furthermore, it does not matter if the compounds are administered in the same dosage form, e.g. one compound may be administered topically and another compound may be administered orally.
- Those additional agents may be administered separately from an inventive compound-containing composition, as part of a multiple dosage regimen. Alternatively, those agents may be part of a single dosage form, mixed together with a compound of this invention in a single composition. If administered as part of a multiple dosage regime, the two active agents may be submitted simultaneously, sequentially or within a period of time from one another normally within five hours from one another.
- As used herein, the term “combination,” “combined,” and related terms refers to the simultaneous or sequential administration of therapeutic agents in accordance with this invention. For example, a compound of the present invention may be administered with another therapeutic agent simultaneously or sequentially in separate unit dosage forms or together in a single unit dosage form. Accordingly, the present invention provides a single unit dosage form comprising a compound of formula I or formula II, an additional therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
- The amount of both an inventive compound and additional therapeutic agent (in those compositions which comprise an additional therapeutic agent as described above) that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. In certain embodiments, compositions of this invention are formulated such that a dosage of between 0.01-100 mg/kg body weight/day of an inventive can be administered.
- Typically, any agent that has activity against a disease or condition being treated may be co-administered. Examples of such agents can be found in Cancer Principles and Practice of Oncology by V. T. Devita and S. Hellman (editors), 6th edition (Feb. 15, 2001), Lippincott Williams & Wilkins Publishers. A person of ordinary skill in the art would be able to discern which combinations of agents would be useful based on the particular characteristics of the drugs and the disease involved.
- In one embodiment, the treatment method includes the co-administration of a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof and at least one cytotoxic agent. The term “cytotoxic agent” as used herein refers to a substance that inhibits or prevents a cellular function and/or causes cell death or destruction. Cytotoxic agents include, but are not limited to, radioactive isotopes (e.g., At211, I131, I125, Y90, Re186, Re188, Sm153, Bi212, P32, Pb212 and radioactive isotopes of Lu); chemotherapeutic agents; growth inhibitory agents; enzymes and fragments thereof such as nucleolytic enzymes; and toxins such as small molecule toxins or enzymatically active toxins of bacterial, fungal, plant or animal origin, including fragments and/or variants thereof.
- Exemplary cytotoxic agents can be selected from anti-microtubule agents, platinum coordination complexes, alkylating agents, antibiotic agents, topoisomerase II inhibitors, antimetabolites, topoisomerase I inhibitors, hormones and hormonal analogues, signal transduction pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors, immunotherapeutic agents, proapoptotic agents, inhibitors of LDH-A; inhibitors of fatty acid biosynthesis; cell cycle signaling inhibitors; HDAC inhibitors, proteasome inhibitors; and inhibitors of cancer metabolism.
- “Chemotherapeutic agent” includes chemical compounds useful in the treatment of cancer. Examples of chemotherapeutic agents include erlotinib (TARCEVA®, Genentech/OSI Pharm.), bortezomib (VELCADE®, Millennium Pharm.), disulfiram, epigallocatechin gallate, salinosporamide A, carfilzomib, 17-AAG(geldanamycin), radicicol, lactate dehydrogenase A (LDH-A), fulvestrant (FASLODEX®, AstraZeneca), sunitib (SUTENT®, Pfizer/Sugen), letrozole (FEMARA®, Novartis), imatinib mesylate (GLEEVEC®., Novartis), finasunate (VATALANIB, Novartis), oxaliplatin (ELOXATIN®, Sanofi), 5-FU (5-fluorouracil), leucovorin, Rapamycin (Sirolimus, RAPAMUNE®, Wyeth), Lapatinib (TYKERB®, GSK572016, Glaxo Smith Kline), Lonafamib (SCH 66336), sorafenib (NEXAVAR®, Bayer Labs), gefitinib (IRESSA®, AstraZeneca), AG1478, alkylating agents such as thiotepa and CYTOXAN® cyclosphosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and trimethylomelamine; acetogenins (especially bullatacin and bullatacinone); a camptothecin (including topotecan and irinotecan); bryostatin; callystatin; CC-1065 (including its adozelesin, carzelesin and bizelesin synthetic analogs); cryptophycins (particularly cryptophycin 1 and cryptophycin 8); adrenocorticosteroids (including prednisone and prednisolone); cyproterone acetate; 5α-reductases including finasteride and dutasteride); vorinostat, romidepsin, panobinostat, valproic acid, mocetinostat dolastatin; aldesleukin, talc duocarmycin (including the synthetic analogs, KW-2189 and CB1-TM1); eleutherobin; pancratistatin; a sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, chlomaphazine, chlorophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimnustine; antibiotics such as the enediyne antibiotics (e.g., calicheamicin, especially calicheamicin γ1I and calicheamicin ω1I (Angew Chem. Intl. Ed. Engl. 1994 33:183-186); dynemicin, including dynemicin A; bisphosphonates, such as clodronate; an esperamicin; as well as neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromophores), aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, ADRIAMYCIN® (doxorubicin), morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin, porfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti-adrenals such as aminoglutethimide, mitotane, trilostane; folic acid replenisher such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elfomithine; elliptinium acetate; an epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidamnol; nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK® polysaccharide complex (JHS Natural Products, Eugene, Oreg.); razoxane; rhizoxin; sizofuran; spirogermanium; tenuazonic acid; triaziquone; 2,2′,2″-trichlorotriethylamine; trichothecenes (especially T-2 toxin, verracurin A, roridin A and anguidine); urethan; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside (“Ara-C”); cyclophosphamide; thiotepa; taxoids, e.g., TAXOL (paclitaxel; Bristol-Myers Squibb Oncology, Princeton, N.J.), ABRAXANE® (Cremophor-free), albumin-engineered nanoparticle formulations of paclitaxel (American Pharmaceutical Partners, Schaumberg, Ill.), and TAXOTERE® (docetaxel, doxetaxel; Sanofi-Aventis); chloranmbucil; GEMZAR®(gemcitabine); 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; NAVELBINE® (vinorelbine); novantrone; teniposide; edatrexate; daunomycin; aminopterin; capecitabine (XELODA®); ibandronate; CPT-11; topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids such as retinoic acid; and pharmaceutically acceptable salts, acids and derivatives of any of the above.
- Chemotherapeutic agent also includes (i) anti-hormonal agents that act to regulate or inhibit hormone action on tumors such as anti-estrogens and selective estrogen receptor modulators (SERMs), including, for example, tamoxifen (including NOLVADEX®; tamoxifen citrate), raloxifene, droloxifene, iodoxyfene, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, and FARESTON® (toremifine citrate); (ii) aromatase inhibitors that inhibit the enzyme aromatase, which regulates estrogen production in the adrenal glands, such as, for example, 4(5)-imidazoles, aminoglutethimide, MEGASE® (megestrol acetate), AROMASIN® (exemestane; Pfizer), formestanie, fadrozole, RIVISOR® (vorozole), FEMARA®(letrozole; Novartis), and ARIMIDEX® (anastrozole; AstraZeneca); (iii) anti-androgens such as flutamide, nilutamide, bicalutamide, leuprolide and goserelin; buserelin, tripterelin, medroxyprogesterone acetate, diethylstilbestrol, premarin, fluoxymesterone, all transretionic acid, fenretinide, as well as troxacitabine (a 1,3-dioxolane nucleoside cytosine analog); (iv) protein kinase inhibitors; (v) lipid kinase inhibitors; (vi) antisense oligonucleotides, particularly those which inhibit expression of genes in signaling pathways implicated in aberrant cell proliferation, such as, for example, PKC-alpha, Ralf and H-Ras; (vii) ribozymes such as VEGF expression inhibitors (e.g., ANGIOZYME®) and HER2 expression inhibitors; (viii) vaccines such as gene therapy vaccines, for example, ALLOVECTIN®, LEUVECTIN®, and VAXID®; PROLEUKIN®, rIL-2; a topoisomerase 1 inhibitor such as LURTOTECAN®; ABARELIX®rmRH; and (ix) pharmaceutically acceptable salts, acids and derivatives of any of the above.
- Chemotherapeutic agent also includes antibodies such as alemtuzumab (Campath), bevacizumab (AVASTIN®, Genentech); cetuximab (ERBITUX®, Imclone); panitumumab (VECTIBIX®, Amgen), rituximab (RITUXAN®, Genentech/Biogen Idec), pertuzumab (OMNITARG®, 2C4, Genentech), trastuzumab (HERCEPTIN®, Genentech), tositumomab (Bexxar, Corixia), and the antibody drug conjugate, gemtuzumab ozogamicin (MYLOTARG®, Wyeth). Additional humanized monoclonal antibodies with therapeutic potential as agents in combination with the compounds of the invention include: apolizumab, aselizumab, atlizumab, bapineuzumab, bivatuzumab mertansine, cantuzumab mertansine, cedelizumab, certolizumab pegol, cidfusituzumab, cidtuzumab, daclizumab, eculizumab, efalizumab, epratuzumab, erlizumab, felvizumab, fontolizumab, gemtuzumab ozogamicin, inotuzumab ozogamicin, ipilimumab, labetuzumab, lintuzumab, matuzumab, mepolizumab, motavizumab, motovizumab, natalizumab, nimotuzumab, nolovizumab, numavizumab, ocrelizumab, omalizumab, palivizumab, pascolizumab, pecfusituzumab, pectuzumab, pexelizumab, ralivizumab, ranibizumab, reslivizumab, reslizumab, resyvizumab, rovelizumab, ruplizumab, sibrotuzumab, siplizumab, sontuzumab, tacatuzumab tetraxetan, tadocizumab, talizumab, tefibazumab, tocilizumab, toralizumab, tucotuzumab celmoleukin, tucusituzumab, umavizumab, urtoxazumab, ustekinumab, visilizumab, and the anti-interleukin-12 (ABT-874/J695, Wyeth Research and Abbott Laboratories) which is a recombinant exclusively human-sequence, full-length IgG1λ antibody genetically modified to recognize interleukin-12 p40 protein.
- Chemotherapeutic agent also includes “EGFR inhibitors,” which refers to compounds that bind to or otherwise interact directly with EGFR and prevent or reduce its signaling activity, and is alternatively referred to as an “EGFR antagonist.” Examples of such agents include antibodies and small molecules that bind to EGFR. Examples of antibodies which bind to EGFR include MAb 579 (ATCC CRL HB 8506), MAb 455 (ATCC CRL HB8507), MAb 225 (ATCC CRL 8508), MAb 528 (ATCC CRL 8509) (see, U.S. Pat. No. 4,943,533, Mendelsohn et al.) and variants thereof, such as chimerized 225 (C225 or Cetuximab; ERBUTIX®) and reshaped human 225 (H225) (see, WO 96/40210, Imclone Systems Inc.); IMC-11F8, a fully human, EGFR-targeted antibody (Imclone); antibodies that bind type II mutant EGFR (U.S. Pat. No. 5,212,290); humanized and chimeric antibodies that bind EGFR as described in U.S. Pat. No. 5,891,996; and human antibodies that bind EGFR, such as ABX-EGF or Panitumumab (see WO98/50433, Abgenix/Amgen); EMD 55900 (Stragliotto et al. Eur. J. Cancer 32A:636-640 (1996)); EMD7200 (matuzumab) a humanized EGFR antibody directed against EGFR that competes with both EGF and TGF-alpha for EGFR binding (EMD/Merck); human EGFR antibody, HuMax-EGFR (GenMab); fully human antibodies known as E1.1, E2.4, E2.5, E6.2, E6.4, E2.11, E6. 3 and E7.6. 3 and described in U.S. Pat. No. 6,235,883; MDX-447 (Medarex Inc); and mAb 806 or humanized mAb 806 (Johns et al., J. Biol. Chem. 279(29):30375-30384 (2004)). The anti-EGFR antibody may be conjugated with a cytotoxic agent, thus generating an immunoconjugate (see, e.g., EP659,439A2, Merck Patent GmbH). EGFR antagonists include small molecules such as compounds described in U.S. Pat. Nos. 5,616,582, 5,457,105, 5,475,001, 5,654,307, 5,679,683, 6,084,095, 6,265,410, 6,455,534, 6,521,620, 6,596,726, 6,713,484, 5,770,599, 6,140,332, 5,866,572, 6,399,602, 6,344,459, 6,602,863, 6,391,874, 6,344,455, 5,760,041, 6,002,008, and 5,747,498, as well as the following PCT publications: WO98/14451, WO98/50038, WO99/09016, and WO99/24037. Particular small molecule EGFR antagonists include OSI-774 (CP-358774, erlotinib, TARCEVA® Genentech/OSI Pharmaceuticals); PD 183805 (CI 1033, 2-propenamide, N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(4-morpholinyl)propoxy]-6-quinazolinyl]-, dihydrochloride, Pfizer Inc.); ZD1839, gefitinib (IRESSA®) 4-(3′-Chloro-4′-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline, AstraZeneca); ZM 105180 ((6-amino-4-(3-methylphenyl-amino)-quinazoline, Zeneca); BIBX-1382 (N8-(3-chloro-4-fluoro-phenyl)-N2-(1-methylpiperidin-4-yl)-pyrimido[5,4-d]pyrimidine-2,8-diamine, Boehringer Ingelheim); PKI-166 ((R)-4-[4-[(1-phenylethyl)amino]-1H-pyrrolo[2,3-d]pyrimidin-6-yl]-phenol); (R)-6-(4-hydroxyphenyl)-4-[(1-phenylethyl)amino]-7H-pyrrolo[2,3-d]pyrimidine); CL-387785 (N-[4-[(3-bromophenyl)amino]-6-quinazolinyl]-2-butynamide); EKB-569 (N-[4-[(3-chloro-4-fluorophenyl)amino]-3-cyano-7-ethoxy-6-quinolinyl]-4-(dimethylamino)-2-butenamide) (Wyeth); AG1478 (Pfizer); AG1571 (SU 5271; Pfizer); dual EGFR/HER2 tyrosine kinase inhibitors such as lapatinib (TYKERB®, GSK572016 or N-[3-chloro-4-[(3 fluorophenyl)methoxy]phenyl]-6 [5[[[2methylsulfonyl)ethyl]amino]methyl]-2-furanyl]-4-quinazolinamine).
- Chemotherapeutic agents also include “tyrosine kinase inhibitors” including the EGFR-targeted drugs noted in the preceding paragraph; small molecule HER2 tyrosine kinase inhibitor such as TAK165 available from Takeda; CP-724,714, an oral selective inhibitor of the ErbB2 receptor tyrosine kinase (Pfizer and OSI); dual-HER inhibitors such as EKB-569 (available from Wyeth) which preferentially binds EGFR but inhibits both HER2 and EGFR-overexpressing cells; lapatinib (GSK572016; available from Glaxo-SmithKline), an oral HER2 and EGFR tyrosine kinase inhibitor; PKI-166 (available from Novartis); pan-HER inhibitors such as canertinib (CI-1033; Pharmacia); Raf-1 inhibitors such as antisense agent ISIS-5132 available from ISIS Pharmaceuticals which inhibit Raf-1 signaling; non-HER targeted TK inhibitors such as imatinib mesylate (GLEEVEC®, available from Glaxo SmithKline); multi-targeted tyrosine kinase inhibitors such as sunitinib (SUTENT®, available from Pfizer); VEGF receptor tyrosine kinase inhibitors such as vatalanib (PTK787/ZK222584, available from Novartis/Schering AG); MAPK extracellular regulated kinase I inhibitor CI-1040 (available from Pharmacia); quinazolines, such as PD 153035,4-(3-chloroanilino) quinazoline; pyridopyrimidines; pyrimidopyrimidines; pyrrolopyrimidines, such as CGP 59326, CGP 60261 and CGP 62706; pyrazolopyrimidines, 4-(phenylamino)-7H-pyrrolo[2,3-d] pyrimidines; curcumin (diferuloyl methane, 4,5-bis (4-fluoroanilino)phthalimide); tyrphostines containing nitrothiophene moieties; PD-0183805 (Warner-Lamber); antisense molecules (e.g. those that bind to HER-encoding nucleic acid); quinoxalines (U.S. Pat. No. 5,804,396); tryphostins (U.S. Pat. No. 5,804,396); ZD6474 (Astra Zeneca); PTK-787 (Novartis/Schering AG); pan-HER inhibitors such as CI-1033 (Pfizer); Affinitac (ISIS 3521; Isis/Lilly); imatinib mesylate (GLEEVEC®); PKI 166 (Novartis); GW2016 (Glaxo SmithKline); CI-1033 (Pfizer); EKB-569 (Wyeth); Semaxinib (Pfizer); ZD6474 (AstraZeneca); PTK-787 (Novartis/Schering AG); INC-1C11 (Imclone), rapamycin (sirolimus, RAPAMUNE®); or as described in any of the following patent publications: U.S. Pat. No. 5,804,396; WO 1999/09016 (American Cyanamid); WO 1998/43960 (American Cyanamid); WO 1997/38983 (Warner Lambert); WO 1999/06378 (Warner Lambert); WO 1999/06396 (Warner Lambert); WO 1996/30347 (Pfizer, Inc); WO 1996/33978 (Zeneca); WO 1996/3397 (Zeneca) and WO 1996/33980 (Zeneca).
- Chemotherapeutic agents also include dexamethasone, interferons, colchicine, metoprine, cyclosporine, amphotericin, metronidazole, alemtuzumab, alitretinoin, allopurinol, amifostine, arsenic trioxide, asparaginase, BCG live, bevacuzimab, bexarotene, cladribine, clofarabine, darbepoetin alfa, denileukin, dexrazoxane, epoetin alfa, elotinib, filgrastim, histrelin acetate, ibritumomab, interferon alfa-2a, interferon alfa-2b, lenalidomide, levamisole, mesna, methoxsalen, nandrolone, nelarabine, nofetumomab, oprelvekin, palifermin, pamidronate, pegademase, pegaspargase, pegfilgrastim, pemetrexed disodium, plicamycin, porfimer sodium, quinacrine, rasburicase, sargramostim, temozolomide, VM-26, 6-TG, toremifene, tretinoin, ATRA, valrubicin, zoledronate, and zoledronic acid, and pharmaceutically acceptable salts thereof.
- Chemotherapeutic agents also include hydrocortisone, hydrocortisone acetate, cortisone acetate, tixocortol pivalate, triamcinolone acetonide, triamcinolone alcohol, mometasone, amcinonide, budesonide, desonide, fluocinonide, fluocinolone acetonide, betamethasone, betamethasone sodium phosphate, dexamethasone, dexamethasone sodium phosphate, fluocortolone, hydrocortisone-17-butyrate, hydrocortisone-17-valerate, aclometasone dipropionate, betamethasone valerate, betamethasone dipropionate, prednicarbate, clobetasone-17-butyrate, clobetasol-17-propionate, fluocortolone caproate, fluocortolone pivalate and fluprednidene acetate; immune selective anti-inflammatory peptides (ImSAIDs) such as phenylalanine-glutamine-glycine (FEG) and its D-isomeric form (feG) (IMULAN BioTherapeutics, LLC); anti-rheumatic drugs such as azathioprine, ciclosporin (cyclosporine A), D-penicillamine, gold salts, hydroxychloroquine, leflunomideminocycline, sulfasalazine, tumor necrosis factor alpha (TNFα) blockers such as etanercept (Enbrel), infliximab (Remicade), adalimumab (Humira), certolizumab pegol (Cimzia), golimumab (Simponi), Interleukin 1 (IL-1) blockers such as anakinra (Kineret), T cell costimulation blockers such as abatacept (Orencia), Interleukin 6 (IL-6) blockers such as tocilizumab (ACTEMERA®); Interleukin 13 (IL-13) blockers such as lebrikizumab; Interferon alpha (IFN) blockers such as Rontalizumab; Beta 7 integrin blockers such as rhuMAb Beta7; IgE pathway blockers such as Anti-M1 prime; Secreted homotrimeric LTa3 and membrane bound heterotrimer LTa1/β2 blockers such as Anti-lymphotoxin alpha (LTa); radioactive isotopes (e.g., At211, I131, I125, Y90, Re186, Re188, Sm153, Bi212, P32, Pb212 and radioactive isotopes of Lu); miscellaneous investigational agents such as thioplatin, PS-341, phenylbutyrate, ET-18-OCH3, or farnesyl transferase inhibitors (L-739749, L-744832); polyphenols such as quercetin, resveratrol, piceatannol, epigallocatechine gallate, theaflavins, flavanols, procyanidins, betulinic acid and derivatives thereof; autophagy inhibitors such as chloroquine; delta-9-tetrahydrocannabinol (dronabinol, MARINOL®); beta-lapachone; lapachol; colchicines; betulinic acid; acetylcamptothecin, scopolectin, and 9-aminocamptothecin); podophyllotoxin; tegafur (UFTORAL®); bexarotene (TARGRETIN®); bisphosphonates such as clodronate (for example, BONEFOS® or OSTAC®), etidronate (DIDROCAL®), NE-58095, zoledronic acid/zoledronate (ZOMETA®), alendronate (FOSAMAX®), pamidronate (AREDIA®), tiludronate (SKELID®), or risedronate (ACTONEL®); and epidermal growth factor receptor (EGF-R); vaccines such as THERATOPE® vaccine; perifosine, COX-2 inhibitor (e.g. celecoxib or etoricoxib), proteosome inhibitor (e.g. PS341); CCI-779; tipifarnib (R11577); orafenib, ABT510; Bcl-2 inhibitor such as oblimersen sodium (GENASENSE®); pixantrone; farnesyltransferase inhibitors such as lonafarnib (SCH 6636, SARASAR™); and pharmaceutically acceptable salts, acids or derivatives of any of the above; as well as combinations of two or more of the above such as CHOP, an abbreviation for a combined therapy of cyclophosphamide, doxorubicin, vincristine, and prednisolone; and FOLFOX, an abbreviation for a treatment regimen with oxaliplatin (ELOXATIN®) combined with 5-FU and leucovorin.
- Chemotherapeutic agents also include non-steroidal anti-inflammatory drugs with analgesic, antipyretic and anti-inflammatory effects. NSAIDs include non-selective inhibitors of the enzyme cyclooxygenase. Specific examples of NSAIDs include aspirin, propionic acid derivatives such as ibuprofen, fenoprofen, ketoprofen, flurbiprofen, oxaprozin and naproxen, acetic acid derivatives such as indomethacin, sulindac, etodolac, diclofenac, enolic acid derivatives such as piroxicam, meloxicam, tenoxicam, droxicam, lornoxicam and isoxicam, fenamic acid derivatives such as mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid, and COX-2 inhibitors such as celecoxib, etoricoxib, lumiracoxib, parecoxib, rofecoxib, rofecoxib, and valdecoxib. NSAIDs can be indicated for the symptomatic relief of conditions such as rheumatoid arthritis, osteoarthritis, inflammatory arthropathies, ankylosing spondylitis, psoriatic arthritis, Reiter's syndrome, acute gout, dysmenorrhoea, metastatic bone pain, headache and migraine, postoperative pain, mild-to-moderate pain due to inflammation and tissue injury, pyrexia, ileus, and renal colic.
- In certain embodiments, chemotherapeutic agents include, but are not limited to, doxorubicin, dexamethasone, vincristine, cyclophosphamide, fluorouracil, topotecan, interferons, platinum derivatives, taxanes (e.g., paclitaxel, docetaxel), vinca alkaloids (e.g., vinblastine), anthracyclines (e.g., doxorubicin), epipodophyllotoxins (e.g., etoposide), cisplatin, an mTOR inhibitor (e.g., a rapamycin), methotrexate, actinomycin D,
dolastatin 10, colchicine, trimetrexate, metoprine, cyclosporine, daunorubicin, teniposide, amphotericin, alkylating agents (e.g., chlorambucil), 5-fluorouracil, campthothecin, cisplatin, metronidazole, and imatinib mesylate, among others. In other embodiments, a compound of the present invention is administered in combination with a biologic agent, such as bevacizumab or panitumumab. - In certain embodiments, compounds of the present invention, or a pharmaceutically acceptable composition thereof, are administered in combination with an antiproliferative or chemotherapeutic agent selected from any one or more of abarelix, aldesleukin, alemtuzumab, alitretinoin, allopurinol, altretamine, amifostine, anastrozole, arsenic trioxide, asparaginase, azacitidine, BCG live, bevacuzimab, fluorouracil, bexarotene, bleomycin, bortezomib, busulfan, calusterone, capecitabine, camptothecin, carboplatin, carmustine, cetuximab, chlorambucil, cladribine, clofarabine, cyclophosphamide, cytarabine, dactinomycin, darbepoetin alfa, daunorubicin, denileukin, dexrazoxane, docetaxel, doxorubicin (neutral), doxorubicin hydrochloride, dromostanolone propionate, epirubicin, epoetin alfa, elotinib, estramustine, etoposide phosphate, etoposide, exemestane, filgrastim, floxuridine, fludarabine, fulvestrant, gefitinib, gemcitabine, gemtuzumab, goserelin acetate, histrelin acetate, hydroxyurea, ibritumomab, idarubicin, ifosfamide, imatinib mesylate, interferon alfa-2a, interferon alfa-2b, irinotecan, lenalidomide, letrozole, leucovorin, leuprolide acetate, levamisole, lomustine, megestrol acetate, melphalan, mercaptopurine, 6-MP, mesna, methotrexate, methoxsalen, mitomycin C, mitotane, mitoxantrone, nandrolone, nelarabine, nofetumomab, oprelvekin, oxaliplatin, paclitaxel, palifermin, pamidronate, pegademase, pegaspargase, pegfilgrastim, pemetrexed disodium, pentostatin, pipobroman, plicamycin, porfimer sodium, procarbazine, quinacrine, rasburicase, rituximab, sargramostim, sorafenib, streptozocin, sunitinib maleate, talc, tamoxifen, temozolomide, teniposide, VM-26, testolactone, thioguanine, 6-TG, thiotepa, topotecan, toremifene, tositumomab, trastuzumab, tretinoin, ATRA, uracil mustard, valrubicin, vinblastine, vincristine, vinorelbine, zoledronate, or zoledronic acid.
- Chemotherapeutic agents also include treatments for Alzheimer's Disease such as donepezil hydrochloride and rivastigmine; treatments for Parkinson's Disease such as L-DOPA/carbidopa, entacapone, ropinrole, pramipexole, bromocriptine, pergolide, trihexephendyl, and amantadine; agents for treating multiple sclerosis (MS) such as beta interferon (e.g., Avonex® and Rebif®), glatiramer acetate, and mitoxantrone; treatments for asthma such as albuterol and montelukast sodium; agents for treating schizophrenia such as zyprexa, risperdal, seroquel, and haloperidol; anti-inflammatory agents such as corticosteroids, TNF blockers, IL-1 RA, azathioprine, cyclophosphamide, and sulfasalazine; immunomodulatory and immunosuppressive agents such as cyclosporin, tacrolimus, rapamycin, mycophenolate mofetil, interferons, corticosteroids, cyclophophamide, azathioprine, and sulfasalazine; neurotrophic factors such as acetylcholinesterase inhibitors, MAO inhibitors, interferons, anti-convulsants, ion channel blockers, riluzole, and anti-Parkinsonian agents; agents for treating cardiovascular disease such as beta-blockers, ACE inhibitors, diuretics, nitrates, calcium channel blockers, and statins; agents for treating liver disease such as corticosteroids, cholestyramine, interferons, and anti-viral agents; agents for treating blood disorders such as corticosteroids, anti-leukemic agents, and growth factors; and agents for treating immunodeficiency disorders such as gamma globulin.
- Additionally, chemotherapeutic agents include pharmaceutically acceptable salts, acids or derivatives of any of chemotherapeutic agents, described herein, as well as combinations of two or more of them.
- In another embodiment, provided are methods of using CBP/EP300 bromodomain inhibitors to treat and/or delay progression of cancer in combination with a PD-1 axis binding antagonist. Further provided herein are methods of enhancing immune function in an individual having cancer comprising administering to the individual an effective amount of a CBP/EP300 bromodomain inhibitor and an effective amount of a PD-1 axis binding antagonist. A PD-1 axis binding antagonist includes a PD-1 binding antagonist, a PD-L1 binding antagonist and a PD-L2 binding antagonist.
- The term “PD-1 axis binding antagonist” is a molecule that inhibits the interaction of a PD-1 axis binding partner with either one or more of its binding partner, so as to remove T-cell dysfunction resulting from signaling on the PD-1 signaling axis—with a result being to restore or enhance T-cell function (e.g., proliferation, cytokine production, target cell killing). As used herein, a PD-1 axis binding antagonist includes a PD-1 binding antagonist, a PD-L1 binding antagonist and a PD-L2 binding antagonist.
- The term “PD-1 binding antagonists” is a molecule that decreases, blocks, inhibits, abrogates or interferes with signal transduction resulting from the interaction of PD-1 with one or more of its binding partners, such as PDL1, PDL2. In some embodiments, the PD-1 binding antagonist is a molecule that inhibits the binding of PD-1 to its binding partners. In a specific aspect, the PD-1 binding antagonist inhibits the binding of PD-1 to PDL1 and/or PDL2. For example, PD-1 binding antagonists include anti-PD-1 antibodies, antigen binding fragments thereof, immunoadhesins, fusion proteins, oligopeptides and other molecules that decrease, block, inhibit, abrogate or interfere with signal transduction resulting from the interaction of PD-1 with PDL1 and/or PDL2. In one embodiment, a PD-1 binding antagonist reduces the negative co-stimulatory signal mediated by or through cell surface proteins expressed on T lymphocytes mediated signaling through PD-1 so as render a dysfunctional T-cell less dysfunctional (e.g., enhancing effector responses to antigen recognition). In some embodiments, the PD-1 binding antagonist is an anti-PD-1 antibody. In a specific aspect, a PD-1 binding antagonist is nivolumab described herein (also known as MDX-1106-04, MDX-1106, ONO-4538, BMS-936558, and OPDIVO®). In another specific aspect, a PD-1 binding antagonist is pembrolizumab described herein (also known as MK-3475, Merck 3475, KEYTRUDA®, and SCH-900475). In another specific aspect, a PD-1 binding antagonist is CT-011 described herein (also known as hBAT or hBAT-1). In yet another specific aspect, a PD-1 binding antagonist is AMP-224 (also known as B7-DCIg) described herein.
- The term “PDL1 binding antagonists” is a molecule that decreases, blocks, inhibits, abrogates or interferes with signal transduction resulting from the interaction of PDL1 with either one or more of its binding partners, such as PD-1, B7-1. In some embodiments, a PDL1 binding antagonist is a molecule that inhibits the binding of PDL1 to its binding partners. In a specific aspect, the PDL1 binding antagonist inhibits binding of PDL1 to PD-1 and/or B7-1. In some embodiments, the PDL1 binding antagonists include anti-PDL1 antibodies, antigen binding fragments thereof, immunoadhesins, fusion proteins, oligopeptides and other molecules that decrease, block, inhibit, abrogate or interfere with signal transduction resulting from the interaction of PDL1 with one or more of its binding partners, such as PD-1, B7-1. In one embodiment, a PDL1 binding antagonist reduces the negative co-stimulatory signal mediated by or through cell surface proteins expressed on T lymphocytes mediated signaling through PDL1 so as to render a dysfunctional T-cell less dysfunctional (e.g., enhancing effector responses to antigen recognition). In some embodiments, a PDL1 binding antagonist is an anti-PDL1 antibody. In a specific aspect, an anti-PDL1 antibody is YW243.55.S70 described herein. In another specific aspect, an anti-PDL1 antibody is MDX-1105 described herein (also known as BMS-936559). In still another specific aspect, an anti-PDL1 antibody is MPDL3280A described herein. In still another specific aspect, an anti-PDL1 antibody is MEDI4736 described herein.
- The term “PDL2 binding antagonists” is a molecule that decreases, blocks, inhibits, abrogates or interferes with signal transduction resulting from the interaction of PD-L2 with either one or more of its binding partners, such as PD-1. In some embodiments, a PD-L2 binding antagonist is a molecule that inhibits the binding of PD-L2 to its binding partners. In a specific aspect, the PD-L2 binding antagonist inhibits binding of PD-L2 to PD-1. In some embodiments, the PD-L2 antagonists include anti-PD-L2 antibodies, antigen binding fragments thereof, immunoadhesins, fusion proteins, oligopeptides and other molecules that decrease, block, inhibit, abrogate or interfere with signal transduction resulting from the interaction of PD-L2 with either one or more of its binding partners, such as PD-1. In one embodiment, a PD-L2 binding antagonist reduces the negative co-stimulatory signal mediated by or through cell surface proteins expressed on T lymphocytes mediated signaling through PD-L2 so as render a dysfunctional T-cell less dysfunctional (e.g., enhancing effector responses to antigen recognition). In some embodiments, a PD-L2 binding antagonist is an immunoadhesin.
- Alternative names for “PD-1” include CD279 and SLEB2. Alternative names for “PD-L1” include B7-
H 1, B7-4, CD274, and B7-H. Alternative names for “PD-L2” include B7-DC, Btdc, and CD273. In some embodiments, PD-1, PD-L1, and PD-L2 are human PD-1, PD-L1 and PD-L2. In some embodiments, the PD-1 binding antagonist is a molecule that inhibits the binding of PD-1 to its ligand binding partners. In a specific aspect the PD-1 ligand binding partners are PD-L1 and/or PD-L2. In another embodiment, a PD-L1 binding antagonist is a molecule that inhibits the binding of PD-L1 to its binding partners. In a specific aspect, PD-L1 binding partners are PD-1 and/or B7-1. In another embodiment, the PD-L2 binding antagonist is a molecule that inhibits the binding of PD-L2 to its binding partners. In a specific aspect, a PD-L2 binding partner is PD-1. The antagonist may be an antibody, an antigen binding fragment thereof, an immunoadhesin, a fusion protein, or oligopeptide. In some embodiment, the PD-1 binding antagonist is an anti-PD-1 antibody (e.g., a human antibody, a humanized antibody, or a chimeric antibody). In some embodiments, the anti-PD-1 antibody is selected from the group consisting of MDX-1 106, Merck 3475 (also known as: pembrolizumab, lambrolizumab, or MK-3475), nivolumab (BMS-936558), CT-011, and MPDL3280A. In some embodiments, the PD-1 binding antagonist is an immunoadhesin (e.g., an immunoadhesin comprising an extracellular or PD-1 binding portion of PD-L1 or PD-L2 fused to a constant region (e.g., an Fc region of an immunoglobulin sequence). In some embodiments, the PD-1 binding antagonist is AMP-224. In some embodiments, the PD-L1 binding antagonist is anti-PD-L1 antibody. In some embodiments, the anti-PD-L1 binding antagonist is selected from the group consisting of YW243.55.S70, MPDL3280A and MDX-1 105. MDX-1 105, also known as BMS-936559, is an anti-PD-L1 antibody described in WO2007/005874. Antibody YW243.55.S70 (heavy and light chain variable region sequences shown in SEQ ID Nos. 20 and 21, respectively) is an anti-PD-L1 described in WO 2010/077634 A1. MDX-1 106, also known as MDX-1 106-04, ONO-4538 or BMS-936558, is an anti-PD-1 antibody described in WO2006/121168. Merck 3745, also known as MK-3475 or SCH-900475, is an anti-PD-1 antibody described in WO2009/114335. CT-011, also known as hBAT or hBAT-1, is an anti-PD-1 antibody described in WO2009/101611. AMP-224, also known as B7-DCIg, is a PD-L2-Fc fusion soluble receptor described in WO2010/027827 andWO201 1/066342. In some embodiments, the anti-PD-1 antibody is MDX-1 106. Alternative names for “MDX-1106” include MDX-1 106-04, ONO-4538, BMS-936558 or Nivolumab. In some embodiments, the anti-PD-1 antibody is Nivolumab (CAS Registry Number: 946414-94-4). In some embodiments, the cancer is melanoma, NSCLC, and renal cell carcinoma. - For treating an inflammatory disease or an autoimmune disease, a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof may be co-administered with methotrexate, tofacitinib, 6-mercaptopurine, azathioprine sulphasalazine, mesalazine, olsalazine chloroquinine/hydroxychloroquinine, penicillamine, aurothiomalate (intramuscular and oral), azathioprine, cochicine, corticosteroids (oral, inhaled, and local injection), a beta-2 adrenoreceptor agonist (salbutamol, terbutaline, salmeteral), a xanthine (theophylline, aminophylline), cromoglycate, nedocromil, ketotifen, ipratropium and oxitropium, cyclosporin, FK506, rapamycin, mycophenolate mofetil, leflunomide, an NSAID (e.g. ibuprofen), a corticosteroid (e. g. prednisolone), a phosphodiesterase inhibitor, an adensosine agonist, an antithrombotic agent, a complement inhibitor, an adrenergic agent, an agent that interferes with signalling by proinflammatory cytokines such as TNF or IL-1 (e.g., a NIK, IKK, p38 or MAP kinase inhibitor), an IL-1 converting enzyme inhibitor, a T-cell signalling inhibitor (e.g. a kinase inhibitor), a metalloproteinase inhibitor, sulfasalazine, a 6-mercaptopurine, an angiotensin converting enzyme inhibitor, a soluble cytokine receptor (e.g. soluble p55 or p75 TNF receptors and the derivatives p75TNFRigG (etanercept) and p55TNFRigG (Lenercept), siL-1RI, siL-1RII, siL-6R), an antiinflammatory cytokine (e.g. IL-4, IL-1 0, IL-11, IL-13 and TGF), celecoxib, folic acid, hydroxychloroquine sulfate, rofecoxib, etanercept, infliximab, adalimumab, certolizumab, tocilizumab, abatacept, naproxen, valdecoxib, sulfasalazine, methylprednisolone, meloxicam, methylprednisolone acetate, gold sodium thiomalate, aspirin, triamcinolone acetonide, propoxyphene napsylate/apap, folate, nabumetone, diclofenac, piroxicam, etodolac, diclofenac sodium, oxaprozin, oxycodone HCl, hydrocodone bitartrate/apap, diclofenac sodium/misoprostol, fentanyl, anakinra, tramadol HCl, salsalate, sulindac, cyanocobalamin/fa/pyridoxine, acetaminophen, alendronate sodium, prednisolone, cortisone, betamethasone, morphine sulfate, lidocaine hydrochloride, indomethacin, glucosamine sulf/chondroitin, amitriptyline HCl, sulfadiazine, oxycodone HCV acetaminophen, olopatadine HCl misoprostol, naproxen sodium, omeprazole, cyclophosphamide, rituximab, IL-1 TRAP, MRA, CTLA4-IG, IL-18 BP, anti-IL-12, Anti-IL1S, BIRB-796, SCI0-469, VX-702, AMG-548, VX-740, Roflumilast, IC-485, CDC-801, S1PI agonists (such as FTY720), a PKC family inhibitor (e.g. Ruboxistaurin or AEB-071) or Mesopram. In certain embodiments, a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof may be co-administered with methotrexate or leflunomide. In moderate or severe Rheumatoid arthritis cases, a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof may be co-administered with cyclosporine and anti-TNF antibodies as noted above. A compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof may also be co-administered with: budenoside; epidermal growth factor; a corticosteroid; cyclosporin, sulfasalazine; an aminosalicylate; 6-mercaptopurine; azathioprine; metronidazole; a lipoxygenase inhibitor; mesalamine; olsalazine; balsalazide; an antioxidant; a thromboxane inhibitor; an IL-1 receptor antagonist; an anti-IL-1 monoclonal antibody; an anti-IL-6 monoclonal antibody; a growth factor; an elastase inhibitor; a pyridinyl-imidazole compound; an antibody to or antagonist of other human cytokines or growth factors (e.g. TNF, LT, IL-1, IL-2, IL-6, IL-7, IL-8, IL-12, IL-15, IL-16, IL-23, EMAP-II, GM-CSF, FGF, and PDGF); a cell surface molecule (e.g. CD2, CD3, CD4, CD8, CD25, CD28, CD30, CD40, CD45, CD69, or CD90 or their ligands); methotrexate; cyclosporine; FK506; rapamycin; mycophenolate mofetil; leflunomide; an NSAID (e.g. ibuprofen); a corticosteroid (e.g. prednisolone); a phosphodiesterase inhibitor; an adenosine agonist; an antithrombotic agent; a complement inhibitor; an adrenergic agent; an agent that interferes with signalling by proinflammatory cytokines such as TNF 5 or IL-1 (e.g. a NIK, IKK, or MAP kinase inhibitor); an IL-1 converting enzyme inhibitor; a TNF converting enzyme inhibitor; a T-cell signalling inhibitor such as kinase inhibitors; a metalloproteinase inhibitor; sulfasalazine; azathioprine; a 6-mercaptopurine; an angiotensin converting enzyme inhibitor; a soluble cytokine receptor (e.g. soluble p55 or p75 TNF receptors, siL-1RI, siL-1RII, siL-6R), and an antiinflammatory cytokine (e.g. IL-4, IL-1 0, IL-11, IL-13 or TGF).
- For treating Crohn's disease, a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof may be co-administered with a TNF antagonist (e.g. an anti-TNF antibody), D2E7 (adalimumab), CA2 (infliximab), CDP 571, a TNFR-Ig construct, (p75TNFRigG (etanercept)), a p55TNFRigG (LENERCEPT™) inhibitor, or a PDE4 inhibitor.
- For treating inflammatory bowel disease, a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof may be co-administered with a corticosteroid (e.g. budenoside or dexamethasone); sulfasalazine, 5-aminosalicylic acid; olsalazine; an agent that interferes with synthesis or action of proinflammatory cytokines such as IL-1 (e.g. an IL-1 converting enzyme inhibitor or IL-Ira); a T cell signaling inhibitor (e.g. a tyrosine kinase inhibitor); 6-mercaptopurine; IL-11; mesalamine; prednisone; azathioprine; mercaptopurine; infliximab; methylprednisolone sodium succinate; diphenoxylate/atrop sulfate; loperamide hydrochloride; methotrexate; omeprazole; folate; ciprofloxacin/dextrose-water; hydrocodone bitartrate/apap; tetracycline hydrochloride; fluocinonide; metronidazole; thimerosal/boric acid; cholestyramine/sucrose; ciprofloxacin hydrochloride; hyoscyamine sulfate; meperidine hydrochloride; midazolam hydrochloride; oxycodone HCl/acetaminophen; promethazine hydrochloride; sodium phosphate; sulfamethoxazole/trimethoprim; celecoxib; polycarbophil; propoxyphene napsylate; hydrocortisone; multivitamins; balsalazide disodium; codeine phosphate/apap; colesevelam HCl; cyanocobalamin; folic acid; levofloxacin; methylprednisolone; natalizumab or interferon-gamma.
- For treating multiple sclerosis, a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof may be co-administered with a corticosteroid; prednisolone; methylprednisolone; azathioprine; cyclophosphamide; cyclosporine; methotrexate; 4-aminopyridine; tizanidine; interferon-1a (AVONEX®; Biogen); interferon-1b (BETASERON®; Chiron/Berlex); interferon-n3) (Interferon Sciences/Fujimoto), interferon-(Alfa Wassermann/J&J), interferon 1A-IF (Serono/Inhale Therapeutics), Peginterferon 2b (Enzon/Schering-Plough), Copolymer 1 (Cop-1; COPAXONE®; Teva Pharmaceutical Industries, Inc.); hyperbaric oxygen; intravenous immunoglobulin; cladribine; an antibody to or antagonist of other human cytokines or growth factors and their receptors (e.g. TNF, LT, IL-1, IL-2, IL-6, IL-7, IL-8, IL-12, IL-23, IL-15, IL-16, EMAP-II, GM-CSF, FGF, or PDGF).
- For treating AIDS a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof may be co-administered with antibodies to cell surface molecules such as CD2, CD3, CD4, CD8, CD19, CD20, CD25, CD28, CD30, CD40, CD45, CD69, CD80, CD86, CD90 or their ligands. A compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof may also be co-administered with methotrexate, cyclosporine, FK506, rapamycin, mycophenolate mofetil, leflunomide, an S1PI agonist, an NSAID (e.g. ibuprofen), a corticosteroid (e.g. prednisolone), a phosphodiesterase inhibitor, an adensosine agonist, an antithrombotic agent, a complement inhibitor, an adrenergic agent, an agent that interferes with signalling by proinflammatory cytokines such as TNF or IL-1 (e.g., a NIK, IKK, p38 or MAP kinase inhibitor), an IL-1 converting enzyme inhibitor, a TACE inhibitor, a T-cell signaling inhibitor (e. g. a kinase inhibitor), a metalloproteinase inhibitor, sulfasalazine, azathioprine, a 6-mercaptopurine, an angiotensin converting enzyme inhibitor, a soluble cytokine receptor (e. g. soluble p55 or p75 TNF receptors, siL-1RI, siL-1RII, or siL-6R), or an antiinflammatory cytokine (e.g. IL-4, IL-1 0, IL-13 or TGF).
- A compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof may also be co-administered with agents, such as alemtuzumab, dronabinol, daclizumab, mitoxantrone, xaliproden hydrochloride, fampridine, glatiramer acetate, natalizumab, sinnabidol, immunokine NNS03, ABR-215062, AnergiX.MS, chemokine receptor antagonists, BBR-2778, calagualine, CPI-1189, LEM (liposome encapsulated mitoxantrone), THC.CBD (cannabinoid agonist), MBP-8298, mesopram (PDE4 inhibitor), MNA-715, an anti-IL-6 receptor antibody, neurovax, pirfenidone allotrap 1258 (RDP-1258), sTNF-R1, talampanel, teriflunomide, TGF-beta2, tiplimotide, a VLA-4 antagonist (e.g. TR-14035, VLA4 Ultrahaler, or Antegran-ELAN/Biogen), an interferon gamma antagonist, or an IL-4 agonist.
- For treating ankylosing spondylitis a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof may be co-administered with ibuprofen, diclofenac, misoprostol, naproxen, meloxicam, indomethacin, diclofenac, celecoxib, rofecoxib, sulfasalazine, methotrexate, azathioprine, minocyclin, prednisone, an anti-TNF antibody, D2E7 (HUMIRA®), CA2 (infliximab), CDP 571, a TNFR-Ig construct, (p75TNFRigG (ENBREL®), or p55TNFRigG (LENERCEPT®).
- For treating asthma a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof may be co-administered with albuterol, salmeterol/fluticasone, montelukast sodium, fluticasone propionate, budesonide, prednisone, salmeterol xinafoate, levalbuterol HCl, albuterol sulfate/ipratropium, prednisolone sodium phosphate, triamcinolone acetonide, beclomethasone dipropionate, ipratropium bromide, azithromycin, pirbuterol acetate, prednisolone, theophylline anhydrous, methylprednisolone sodium succinate, clarithromycin, zafirlukast, formoterol fumarate, influenza virus vaccine, amoxicillin trihydrate, flunisolide, cromolyn sodium, fexofenadine hydrochloride, flunisolide/menthol, amoxicillin/clavulanate, levofloxacin, guaifenesin, dexamethasone sodium phosphate, moxifloxacin HCl, doxycycline hyclate, guaifenesin/d-methorphan, p-ephedrine/cod/-chlorphenir, gatifloxacin, cetirizine hydrochloride, mometasone furoate, salmeterol xinafoate, benzonatate, cephalexin, pe/hydrocodone/chlorphenir, cetirizine HCl/pseudoephed, phenylephrine/cod/promethazine, codeine/promethazine, cefprozil, dexamethasone, guaifenesin/pseudoephedrine, chlorpheniramine/hydrocodone, nedocromil sodium, terbutaline sulfate, epinephrine, methylprednisolone, an anti-IL-13 antibody, or metaproterenol sulfate.
- For treating COPD a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof may be co-administered with albuterol sulfate/ipratropium, ipratropium bromide, salmeterol/fluticasone, albuterol, salmeterol xinafoate, fluticasone propionate, prednisone, theophylline anhydrous, methylprednisolone sodium succinate, montelukast sodium, budesonide, formoterol fumarate, triamcinolone acetonide, levofloxacin, guaifenesin, azithromycin, beclomethasone dipropionate, levalbuterol HCl, flunisolide, ceftriaxone sodium, amoxicillin trihydrate, gatifloxacin, zafirlukast, amoxicillin/clavulanate, flunisolide/menthol, chlorpheniramine/hydrocodone, metaproterenol sulfate, methylprednisolone, mometasone furoate, p-ephedrine/cod/chlorphenir, pirbuterol acetate, p-ephedrine/loratadine, terbutaline sulfate, tiotropium bromide, (R,R)-formoterol, TgAAT, cilomilast, or roflumilast.
- For treating psoriasis, a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof may be co-administered with calcipotriene, clobetasol propionate, triamcinolone acetonide, halobetasol propionate, tazarotene, methotrexate, fluocinonide, betamethasone diprop augmented, fluocinolone acetonide, acitretin, tar shampoo, betamethasone valerate, mometasone furoate, ketoconazole, pramoxine/fluocinolone, hydrocortisone valerate, flurandrenolide, urea, betamethasone, clobetasol propionate/emoll, fluticasone propionate, azithromycin, hydrocortisone, moisturizing formula, folic acid, desonide, pimecrolimus, coal tar, diflorasone diacetate, etanercept folate, lactic acid, methoxsalen, he/bismuth subgal/znox/resor, methylprednisolone acetate, prednisone, sunscreen, halcinonide, salicylic acid, anthralin, clocortolone pivalate, coal extract, coal tar/salicylic acid, coal tar/salicylic acid/sulfur, desoximetasone, diazepam, emollient, fluocinonide/emollient, mineral oil/castor oil/na lact, mineral oil/peanut oil, petroleum/isopropyl myristate, psoralen, salicylic acid, soap/tribromsalan, thimerosal/boric acid, celecoxib, infliximab, cyclosporine, alefacept, efalizumab, tacrolimus, pimecrolimus, PUVA, UVB, sulfasalazine, ABT-874 or ustekinamab.
- For treating psoriatic arthritis, a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof may be co-administered with methotrexate, etanercept, rofecoxib, celecoxib, folic acid, sulfasalazine, naproxen, leflunomide, methylprednisolone acetate, indomethacin, hydroxychloroquine sulfate, prednisone, sulindac, betamethasone diprop augmented, infliximab, methotrexate, folate, triamcinolone acetonide, diclofenac, dimethylsulfoxide, piroxicam, diclofenac sodium, ketoprofen, meloxicam, methylprednisolone, nabumetone, tolmetin sodium, calcipotriene, cyclosporine, diclofenac sodium/misoprostol, fluocinonide, glucosamine sulfate, gold sodium thiomalate, hydrocodone bitartrate/apap, ibuprofen, risedronate sodium, sulfadiazine, thioguanine, valdecoxib, alefacept, D2E7 (adalimumab), or efalizumab.
- For treating lupus, a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof may be co-administered with an NSAID (e.g. diclofenac, naproxen, ibuprofen, piroxicam, or indomethacin); a COX2 inhibitor (e.g. celecoxib, rofecoxib, or valdecoxib); an anti-malarial (e.g. hydroxychloroquine); a steroid (e.g. prednisone, prednisolone, budenoside, or dexamethasone); a cytotoxic (e.g. azathioprine, cyclophosphamide, mycophenolate mofetil, or methotrexate); an inhibitor of PDE4, or a purine synthesis inhibitor (e.g. Cellcept®). For example, a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof may be co-administered with sulfasalazine, 5-aminosalicylic acid, olsalazine, Imuran®, an agent that interferes with the synthesis, production, or action of a proinflammatory cytokine (e.g. IL-1), or a caspase inhibitor (e.g. a IL-1 converting enzyme inhibitor or IL-Ira).
- A compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof may also be co-administered with a T cell signaling inhibitor (e.g. a tyrosine kinase inhibitor), or a molecule that targets T cell activation (e.g. CTLA-4-IgG, an anti-B7 family antibody, or an anti-PD-1 family antibody).
- A compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof can also be co-administered with an IL-11 antibody, an anti-cytokine antibody (e.g. fonotolizumab (anti-IFNg antibody)), or an anti-receptor receptor antibodies (e.g. an anti-IL-6 receptor antibody or an antibody to a B-cell surface molecule).
- A compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof can also be co-administered with LJP 394 (abetimus), an agent that depletes or inactivates B-cells (e.g. Rituximab (anti-CD20 antibody) or lymphostat-B (anti-BlyS antibody)), a TNF antagonist (e.g. an anti-TNF antibody), D2E7 (adalimumab), CA2 (infliximab), CDP 571, a TNFR-Ig construct, (p75TNFRigG (etanercept), or p55TNFRigG (LENERCEPT™).
- A compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof can also be co-administered with one or more agents used in the prevention or treatment of AIDS: an HIV reverse transcriptase inhibitor, an HIV protease inhibitor, an immunomodulator, or another retroviral drug. Examples of reverse transcriptase inhibitors include, but are not limited to, abacavir, adefovir, didanosine, dipivoxil delavirdine, efavirenz, emtricitabine, lamivudine, nevirapine, rilpivirine, stavudine, tenofovir, zalcitabine, and zidovudine. Examples of protease inhibitors include, but are not limited to, amprenavir, atazanavir, darunavir, indinavir, fosamprenavir, lopinavir, nelfinavir, ritonavir, saquinavir, and tipranavir. Examples of other retroviral drugs include, but are not limited to, elvitegravir, enfuvirtide, maraviroc and raltegravir.
- For treating type II diabetes, hepatic steatosis, insulin resistance, metabolic syndrome or a related disorder, a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof may be co-administered with insulin or insulins that have been modified to improve the duration of action in the body; agents that stimulate insulin secretion such as acetohexamide, chlorpropamide, glyburide, glimepiride, glipizide, glicazide, glycopyramide, gliquidone, rapaglinide, nataglinide, tolazamide or tolbutamide; agents that are glucagon-like peptide agonists such as exanatide, liraglutide or taspoglutide; agents that inhibit dipeptidyl-peptidase IV such as vildagliptin, sitagliptin, saxagliptin, linagliptin, allogliptin or septagliptin; agents that bind to the peroxisome proliferator-activated receptor gamma such as rosiglitazone or pioglitazone; agents that decrease insulin resistance such as metformin; or agents that reduce glucose absorbance in the small intestine such as acarbose, miglitol or voglibose.
- For treating acute kidney disorders or a chronic kidney disease, a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof may be co-administered with dopamine, a diuretic (e.g. furosemide), bumetanide, thiazide, mannitol, calcium gluconate, sodium bicarbonate, albuterol, paricalcitol, doxercalciferol, cinacalcet, or bardoxalone methyl.
- The amount of both the compound of formula (I) or formula (II) or salt thereof and additional agent (in those compositions which comprise an additional therapeutic agent as described above) that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. In certain embodiments, compositions of this invention are formulated such that a dosage of between 0.01-100 mg/kg body weight/day of an inventive can be administered.
- The additional therapeutic agent and the compound of formula (I) or formula (II) may act synergistically. Therefore, the amount of additional therapeutic agent in such compositions may be less than that required in a monotherapy utilizing only that therapeutic agent, or there may be fewer side effects for the patient given that a lower dose is used. In certain embodiments, in such compositions a dosage of between 0.01-1,000 μg/kg body weight/day of the additional therapeutic agent can be administered.
- Provided herein are methods of extending the duration of response to a cytotoxic agent in an individual with cancer comprising administering to the individual (a) an effective amount of a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof and (b) an effective amount of the cytotoxic agent.
- In certain embodiments of any of the methods, the cytotoxic agent is a targeted therapy. In certain embodiments, the targeted therapy is one or more of an EGFR antagonist, RAF inhibitor, and/or PI3K inhibitor.
- In certain embodiments of any of the methods, the targeted therapy is an EGFR antagonist. In certain embodiments of any of the methods, the EGFR antagonist is N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine and/or a pharmaceutical acceptable salt thereof. In certain embodiments, the EGFR antagonist is N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine. In certain embodiments, the EGFR antagonist is N-(4-(3-fluorobenzyloxy)-3-chlorophenyl)-6-(5-((2-(methylsulfonyl)ethylamino)methyl)furan-2-yl)quinazolin-4-amine,di4-methylbenzenesulfonate or a pharmaceutically acceptable salt thereof (e.g., lapatinib).
- In certain embodiments of any of the methods, targeted therapy is a RAF inhibitor. In certain embodiments, the RAF inhibitor is a BRAF inhibitor. In certain embodiments, the RAF inhibitor is a CRAF inhibitor.
- In certain embodiments, the BRAF inhibitor is vemurafenib. In certain embodiments, the RAF inhibitor is 3-(2-cyanopropan-2-yl)-N-(4-methyl-3-(3-methyl-4-oxo-3,4-dihydroquinazolin-6-ylamino)phenyl)benzamide or a pharmaceutically acceptable salt thereof (e.g., AZ628 (CAS #878739-06-1)).
- In certain embodiments of any of the methods, the targeted therapy is a PI3K inhibitor.
- In certain embodiments of any of the methods, the cytotoxic agent is chemotherapy. In certain embodiments of any of the methods, the chemotherapy is a taxane. In certain embodiments, the taxane is paclitaxel. In certain embodiments, the taxane is docetaxel.
- In certain embodiments of any of the methods, the cytotoxic agent is a platinum agent. In certain embodiments, the platinum agent is carboplatin. In certain embodiments, the platinum agent is cisplatin. In certain embodiments of any of the methods, the cytotoxic agent is a taxane and a platinum agent. In certain embodiments, the taxane is paclitaxel. In certain embodiments, the taxane is docetaxel. In certain embodiments, the platinum agent is carboplatin. In certain embodiments, the platinum agent is cisplatin.
- In certain embodiments of any of the methods, the cytotoxic agent is a vinca alkyloid. In certain embodiments, the vinca alkyloid is vinorelbine. In certain embodiments of any of the methods, the chemotherapy is a nucleoside analog. In certain embodiments, the nucleoside analog is gemcitabine.
- In certain embodiments of any of the methods, the cytotoxic agent is radiotherapy.
- In certain embodiments of any of the methods, the compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof is concomitantly administered with the cytotoxic agent (e.g., targeted therapy, chemotherapy, and/or radiotherapy). In certain embodiments, the compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof is administered prior to and/or concurrently with the cytotoxic agent (e.g., targeted therapy, chemotherapy, and/or radiotherapy).
- As depicted in the Examples of Compounds of Formula (I), below, in certain exemplary embodiments, compounds of Formula (I) are prepared according to the following general procedures. It will be appreciated that, although the general methods depict the synthesis of certain compounds of the present invention, the following general methods, and other methods known to one of ordinary skill in the art, can be applied to all compounds and subclasses and species of each of these compounds, as described herein.
- Compounds of formula (7) may be prepared by general synthetic methods as shown in
Scheme 1. - Reaction between cyano-ketone (1) and hydrazine in a suitable solvent such as ethanol at a temperature ranging from about room temperature to reflux and for a time varying from about 30 minutes to about 2 hours, can readily produce bicycle-pyrazole (2). The bromo pyrazole (3) can be formed by converting the amino pyrazole (2) using a nitrite such as, but not limited to, isoamylnitrite, sodium nitrite, or tert-butyl nitrite and a copper(II) bromide in organic an solvent such as, but not limited to, acetonitrile at a temperature of about 20° C. to about 60° C. for a time of about 5 hours. The alkylation of pyraozle N1 nitrogen of (2) can be carried out using an alkyl iodide/bromide/mesylate/triflate in the presense of an inorganic base such as, but not limited to, sodium hydride or cesium carbonate in a suitable organiv solvent such as, but not limited to, N,N-dimethylformamide (DMF) or tetrahydrofuran (THF) at a temperature ranging from about 0° C. to 120° C. and for a time varying from about 30 minutes to about 16 hours to form compounds of formula (4). Deprotection of N-tert-butoxycarbonyl (Boc) group using a protic acid such as, but not limited to, trifluoroacetic acid or hydrochloric acid, and subsequent N-acetylation using acetic anhydride in the presence of a base such as, but not limited to, triethylamine (TEA) can readily afford compounds of formula (5). The bromide (5) can cross-couple with aryl/heteroaryl/cycloalkyl amine (6) under a palladium catalyst system such as, but not limited to, Ruphos pre-catalyst in combination with Brettphos/Ruphos ligand or Pd-(ipent-PEPPSI) in the presence of an inorganic base such as, but not limited to, sodium tert-butoxide or cesium carbonate in 1,4-dioxane at elevated temperature to yield compounds of formula (7). Alternatively, compounds of formula (7) can be prepared from the bromide (5) upon treatment with amine (6) in the presence of an inorganic base under the analogous palladium-catalyzed conditions mentioned above, followed by sequential Boc deprotection and N-acetylation.
- Compounds of formula (9) may be prepared by general synthetic methods as shown in
Scheme 2. - Compounds of formula (9) can be prepared from the bromide (8) upon treatment with aryl, heteroaryl or heterocyclic boronic acids or boronate esters under palladium catalyst conditions such as, but not limited to, [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) in the presence of an inorganic base such as, but not limited to, sodium carbonate in an organic solvent such as, but not limited to, 1,4-dioxane at an elevated temperature. Alternatively, reaction between bromide (8) and 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (10) under a palladium catalyst conditions can produce the corresponding boronate ester (11) that upon treatment with aryl, heteroaryl or heterocyclic halides under the analogous palladium catalyst conditions can also yield compounds of formula (9).
- Compounds of formula (13) may be prepared by general synthetic methods as shown in Scheme 3.
- Compounds of formula (12) can be alkylated using an alkyl iodide/bromide/mesylate/triflate in the presense of an inorganic base such as, but not limited to, sodium hydride or cesium carbonate in a suitable organic solvent such as, but not limited to, DMF or THF at a temperature ranging from about 0° C. to 120° C. to yield compounds of formula (13).
- Compounds of formula (14) and (15) may be prepared by general synthetic methods as shown in Scheme 4.
- Treatment of piperidine (14) with 4-nitrophenyl chloroformate in the presence of base such as, but not limited to, pyridine followed by addition of methyl amine yields compounds of formula (15). Piperidine (14) can also react with aryl, heteroaryl or heterocyclic halides under palladium catalyst conditions to produce compounds of formula (16).
-
-
- To a solution of ethyl 3-aminopropanoate hydrochloride (366.5 g, 2.39 mol) in MeOH (1.2 L) at room temperature was added NaOH (95.6 g, 2.39 mol) in portions. The mixture was heated to 70° C., acrylonitrile (158 g, 2.98 mol) was added dropwise and the reaction mixture stirred for 6 h. The solution was cooled to 0° C. before (Boc)2O (521 g, 2.39 mol) was added. The reaction was stirred at room temperature for 6 h, filtered, and washed with MeOH (200 mL). The filtrate was concentrated in vacuo to give a yellow oil residue that was re-dissolved in EtOAc and water (500 mL). The aqueous layer was extracted with EtOAc (800 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (638 g) as light yellow oil that required no further purification. 1H NMR (400 MHz, CDCl3) δ 4.17 (q, J=7.2 Hz, 2H), 3.68-3.62 (m, 4H), 2.57-2.53 (m, 4H), 1.49 (s, 9H), 1.29 (t, J=7.2 Hz, 3H).
-
- To toluene (2.7 L) at 25° C. was added NaH (80 g, 2.0 mol) portion-wise and the suspension was heated to 80° C. Ethyl 3-((tert-butoxycarbonyl)(2-cyanoethyl)amino)propanoate (270 g, crude) in anhydrous toluene (270 mL) was added dropwise. The mixture was heated to 100° C. and stirred for 5 hours. The mixture was cooled to room temperature, quenched with sat. aq. ammonium chloride (800 mL) and washed with hexanes (800 mL). The aqueous phase was acidified with HCl (2 N) to
pH 6 and then extracted with EtOAc (1 L×2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (310 g) as yellow oil that required no further purification. - 1H NMR (400 MHz, CDCl3) δ 4.17-4.14 (m, 1H), 3.59-3.56 (m, 2H), 3.43-3.41 (m, 2H), 2.70-2.66 (m, 2H), 1.51 (s, 9H).
-
- A mixture of tert-butyl 3-cyano-4-oxopiperidine-1-carboxylate (310 g, 1.38 mol) and hydrazine mono-hydrate (140 mL, 2.08 mol) in EtOH (1.5 L) was heated to 60° C. for 2 h. The mixture was concentrated in vacuo to give the crude product that was dissolved in EtOAc (1 L) and washed with water (1 L×2). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo to afford the title compound (230 g, 70%) as a colorless solid. 1H NMR (400 MHz, CD3OD) δ 4.28 (s, 2H), 3.66-3.63 (m, 2H), 2.62-2.59 (m, 2H), 1.49 (s, 9H).
-
- To a stirred mixture of tert-butyl 3-amino-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (120 g, 503.6 mmol), CuBr2 (112.5 g, 503.6 mmol) and MeCN (1.2 L) at 0° C. was added isopentyl nitrite (76.7 g, 654.7 mmol) and the reaction mixture stirred for 20 min. The temperature was raised to 60° C. and the reaction mixture was stirred for an additional 5 h. After cooling the reaction to room temperature, the reaction mixture was quenched with water (1 L) and the mixture was extracted with EtOAc (1 L×2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc=4:1) to afford the title compound (Intermediate A, 52 g, 34%) as light yellow solid. LCMS M/Z (M+H) 302.
-
- To a stirred solution of tert-butyl 3-bromo-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (Intermediate A, 32 g, 105.9 mmol) in THF at 0° C. (350 mL) was added NaH (5.08 g, 127.1 mmol) and the mixture was stirred for 30 min. Methyliodide (18.05 g, 127.1 mmol) was added dropwise and the mixture stirred for an additional 2 h. The mixture was quenched with water and extracted with EtOAc (300 mL×2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc=8:1) to afford the title compound (16 g, 48%) as a colorless oil. 1H NMR (400 MHz, CD3OD) δ 4.24 (s, 2H), 3.70 (s, 3H), 3.69-3.67 (m, 2H), 2.70-2.67 (m, 2H), 1.47 (s, 9H).
-
- A mixture of tert-butyl 3-bromo-1-methyl-6,7-dihydro-1H-pyrazolo[4,3-c] pyridine-5 (4H)-carboxylate (12 g, 38.0 mmol) and trifluoroacetic acid (40 mL) in DCM (80 mL) was stirred at room temperature for 2 h. The mixture was concentrated in vacuo and the residue was re-dissolved in DCM (120 mL). The mixture was cooled to 0° C. before TEA (12.1 g, 120 mmol) and acetic anhydride (5.3 g, 52 mmol) were added dropwise. The mixture stirred at room temperature for an additional 2 h before water (100 mL) was added. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (DCM/MeOH=20:1) to afford the title compound (Intermediate B, 8.5 g, 87%) as white solid. 1H NMR (400 MHz, CD3OD) δ 4.40-4.39 (m, 2H), 3.88-3.78 (m, 2H), 3.72 (s, 3H), 2.83-2.70 (m, 2H), 2.20-2.17 (m, 3H).
-
-
- To a stirred solution of tert-butyl 3-bromo-6,7-dihydro-1H-pyrazolo[4,3-c] pyridine-5(4H)-carboxylate (Intermediate A, 6.0 g, 19.8 mmol) in DMF (40 mL) was added Cs2CO3 (9.70 g, 29.8 mmol) and (bromomethyl)cyclopropane (4.0 g, 29.8 mmole). The reaction mixture was heated to 80° C. for 12 h. The mixture was diluted with EtOAc (200 mL), washed with brine (100 mL×3), dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (eluent gradient from petroleum ether to petroleum ether/tert-butyl methyl ether/THF=10:1:1) to give the title compound (3.0 g, 42%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 4.29 (s, 2H), 3.85 (d, J=3.4 Hz, 2H), 3.71 (t, J=5.2 Hz, 2H), 2.67 (t, J=5.2 Hz, 2H), 1.49 (s, 9H), 1.25-1.18 (m, 1H), 0.61-0.55 (m, 2H), 0.35-0.31 (m, 2H).
-
- A mixture of tert-butyl 3-bromo-1-(cyclopropylmethyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (3.0 g, 8.4 mmol) and trifluoroacetic acid (30 mL) in DCM (30 mL) was stirred at room temperature for 2 h. The solvent was concentrated in vacuo and the crude product was re-dissolved in DCM (120 mL). The solution was cooled to 0° C. before TEA (2.49 g, 24.6 mmol) and acetic anhydride (1.26 g, 12.3 mmol) were added dropwise. The reaction mixture was stirred at room temperature for additional 2 h before it was quenched with water. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (DCM/MeOH=20:1) to afford the title compound (2.40 g, 96%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 4.49-4.33 (m, 3H), 3.90-3.70 (m, 4H), 2.77-2.67 (m, 2H), 2.23-2.19 (m, 3H), 1.28-1.18 (m, 1H), 0.63-0.58 (m, 2H), 0.36-0.32 (m, 2H).
-
-
- To a solution of tert-butyl 3-bromo-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5 (4H)-carboxylate (Intermediate A, 40.0 g, 132 mmol) in DMF (500 mL) was added Cs2CO3 (87 g, 264 mmol) and 3-iodooxetane (27 g, 146 mmol). The mixture was heated to 60° C. for 12 h before 3-iodooxetane (5 g, 27.0 mmol) was added and the mixture was stirred at 60° C. for an additional 6 h. After cooling the reaction to room temperature, the mixture was filtered, washed with EtOAc (500 mL) and concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether:tert-butyl methyl ether:THF=from 100:1:1 to 5:1:1) to give the title compound (Intermediate D, 30 g, 64%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 5.30-5.25 (m 1H), 5.18-5.14 (m, 2H), 4.95-4.91 (m, 2H), 4.28 (s, 2H), 3.73-3.66 (m, 2H), 2.64 (t, J=5.6 Hz, 2H), 1.48 (s, 9H).
-
- To a solution of tert-butyl 3-bromo-1-(oxetan-3-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (Intermediate D, 25.0 g, 70.0 mmol) in DCM (50 mL) was added trifluoroacetic acid (50 mL) dropwise at 0° C. The mixture was stirred at room temperature for 2 h. The mixture was concentrated in vacuo and the residue was re-dissolved in DCM (500 mL). The mixture was cooled to 0° C. before triethylamine (36.0 g, 350 mmol) and acetic anhydride (7.2 g, 70.0 mmol) were added dropwise. The mixture was stirred at room temperature for additional 2 h. The reaction was quenched with water. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (DCM/MeOH=80:1) to give the title compound (Intermediate E, 17.0 g, 81%) as a light yellow solid. 1H NMR (400 MHz, CDCl3) δ 5.32-5.27 (m 1H), 5.16-5.13 (m, 2H), 4.95-4.91 (m, 2H), 4.47-4.31 (m, 2H), 3.88-3.70 (m, 2H), 2.75-2.63 (m, 2H), 2.17 (s, 3H).
-
-
- To a solution of (R)-tetrahydrofuran-3-ol (25 g, 253.7 mmol) in DCM (250 mL) at 0° C. was added triethylamine (86 g, 851.2 mmol) and mesyl chloride (39 g, 340.48 mmol) dropwise. The mixture was stirred at room temperature for 12 h. The reaction was quenched with water (100 mL) and extracted with DCM (100 mL×2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (47 g, 99%) as a brown oil. 1H NMR (400 MHz, CDCl3) δ 5.35-5.27 (m, 1H), 4.05-3.83 (m, 4H), 3.04 (s, 3H), 2.28-2.20 (m, 2H).
-
- To a solution of tert-butyl 3-bromo-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5 (4H)-carboxylate (Intermediate A, 24.8 g, 82 mmol) in DMF (200 mL) was added Cs2CO3 (79 g, 246 mmol) and (R)-tetrahydrofuran-3-yl methanesulfonate (17.4 g, 98 mmol). The mixture was heated to 80° C. for 12 h. After cooling the reaction to room temperature, the mixture was concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc=from 10:1 to 3:1) to give the title compound (Intermediate F, 50 g, 71%) as a yellow oil. 1H NMR (400 MHz, DMSO-d6) δ 4.97-4.78 (m, 1H), 4.13 (s, 2H), 3.98-3.86 (m, 2H), 3.81-3.67 (m, 2H), 3.56 (t, J=5.6 Hz, 2H), 2.68 (t, J=5.6 Hz, 2H), 2.33-2.08 (m, 2H), 1.38 (s, 9H).
-
- To a solution of (S)-tert-butyl 3-bromo-1-(tetrahydrofuran-3-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (29 g, 78 mmol) in DCM (300 mL) was added trifluroacetic acid (70 mL) dropwise. The mixture was stirred at room temperature for 2 h. The solvent was concentrated in vacuo and the crude residue was re-dissolved in DMF (100 mL). The mixture was cooled to 0° C. before triethylamine (30 g, 156 mmol) and acetic anhydride (8.7 g, 86 mmol) were added dropwise. The mixture was stirred at room temperature for an additional 2 h. The reaction was quenched with water (200 mL) at 0° C. and extracted with EtOAc (150 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (DCM/MeOH=30:1) to give the title compound (Intermediate G, 21.3 g, 87%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 4.78-4.67 (m, 1H), 4.45-4.29 (m, 2H), 4.15-4.06 (m, 2H), 3.96-3.92 (m, 2H), 3.88-3.70 (m, 2H), 2.71-2.67 (m, 2H), 2.38-2.34 (m, 2H), 2.16 (s, 3H).
-
-
- To a solution of tetrahydro-2H-pyran-4-ol (5 g, 49.0 mmol) and triethylamine (5.94 g, 58.7 mmol) in DCM (100 mL) was added mesyl chloride (16.8 g, 146.9 mmol) dropwise at 0° C. under a nitrogen atmosphere. The mixture was stirred at room temperature for 5 h. Water (100 mL) was added and extracted with DCM (100 mL×2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (4 g, 45%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 4.85-4.81 (m 1H), 3.90-3.87 (m, 2H), 3.52-3.46 (m, 2H), 2.99 (s, 3H), 2.01-1.97 (m, 2H), 1.83-1.80 (m, 2H).
-
- To a solution of tert-butyl 3-bromo-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5 (4H)-carboxylate (Intermediate A, 6 g, 19.8 mmol) in DMF (40 mL) was added Cs2CO3 (19.5 g, 59.6 mmol) and tetrahydro-2H-pyran-4-yl methanesulfonate (3.9 g, 21.8 mmol). The mixture was heated to 80° C. for 12 h under a nitrogen atmosphere. After cooling the reaction to room temperature, the mixture was filtered. The mixture was diluted with EtOAc (100 mL) and washed with brine (100 mL×2). The organic layer was concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether:tert-butyl methyl ether:THF=from 10:1:1 to 2:1:1) to give the title compound (Intermediate H, 3.2 g, 47%) as a clear oil. 1H NMR (400 MHz, DMSO-d6) δ 4.35-4.25 (m, 1H), 4.17 (s, 2H), 3.95-3.93 (m, 2H), 3.62-3.57 (m, 2H), 3.42 (t, J=11.2 Hz, 2H), 2.74-2.73 (m, 2H), 1.98-1.89 (m, 2H), 1.80-1.77 (m, 2H), 1.41 (s, 9H).
-
- To a solution of tert-butyl 3-bromo-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (Intermediate H, 3.2 g, 8.3 mmol) in DCM (20 mL) was added trifluoroacetic acid (20 mL) dropwise at 0° C. The mixture was stirred at room temperature for 2 h. The mixture was concentrated in vacuo and the residue was re-dissolved in DCM (30 mL). The mixture was cooled to 0° C. before triethylamine (2.1 g, 21 mmol) and acetic anhydride (0.93 g, 9.1 mmol) were added dropwise. The mixture was stirred at room temperature for an additional 0.5 h. The reaction was quenched with water (60 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (DCM/MeOH=50:1) to give the title compound (Intermediate I, 2.1 g, 77%) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 4.33-4.29 (m, 1H), 4.28 (s 2H), 3.95-3.92 (m, 2H), 3.70-3.67 (m, 2H), 3.43-3.36 (m, 2H), 2.84-2.69 (m, 2H), 2.09-2.08 (m, 3H), 1.96-1.91 (m, 2H), 1.80-1.76 (m, 2H).
-
-
- To a vial was added 6-(1-methylpyrazol-4-yl)-1,2,3,4-tetrahydroquinoline (see
step 1 of Example 65, 0.300 g, 1.41 mmol), tert-butyl 3-bromo-1-tetrahydropyran-4-yl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate (Intermediate H, 0.625 g, 1.62 mmol), dichloro[1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II) (176 mg, 0.221 mmol), t-BuONa (0.270 g, 2.81 mmol) and 1,4-dioxane (4.7 mL). The mixture was sparged with an argon ballon, and then heated to 120° C. for 16 h under an argon atmosphere. After cooling the reaction to room temperature, DCM (5 mL) was added and the reaction was filtered through celite and concentrated in vacuo. The crude residue was purified by silica gel chromatography (100% heptanes to 100% EtOAc gradient) to give the title compound (0.311 g, 43%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.90 (s, 1H), 7.66 (s, 1H), 7.19 (d, J=2.1 Hz, 1H), 7.10 (dd, J=8.5, 2.1 Hz, 1H), 6.41 (d, J=8.4 Hz, 1H), 4.31-4.20 (m, 1H), 4.02-3.91 (m, 4H), 3.82 (s, 3H), 3.61 (t, J=5.8 Hz, 2H), 3.57-3.50 (m, 2H), 3.44 (dd, J=12.7, 10.6 Hz, 2H), 2.79 (t, J=6.4 Hz, 2H), 2.74 (t, J=5.9 Hz, 2H), 2.01-1.89 (m, 4H), 1.80 (d, J=13.0 Hz, 2H), 1.36 (s, 9H). LCMS M/Z (M+H) 520. -
- To a solution of tert-butyl 3-[6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-1-tetrahydropyran-4-yl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate (311 mg, 0.600 mmol) in DCM (4 mL) was added trifluoroacetic acid (2 mL). The mixture was stirred at room temperature for 3 h and then quenched via the dropwise addition of saturated NaHCO3 and extracted with EtOAc (100 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give crude product that was purified by silica gel chromatography (100% DCM to 15% MeOH in DCM gradient) to give the title compound (158 mg, 63%) as a tan solid. 1H NMR (400 MHz, CD3OD) δ 7.78 (s, 1H), 7.66 (s, 1H), 7.23 (d, J=2.1 Hz, 1H), 7.16 (dd, J=8.5, 2.1 Hz, 1H), 6.48 (d, J=8.4 Hz, 1H), 4.39-4.28 (m, 1H), 4.07 (dd, J=11.7, 4.3 Hz, 2H), 3.89 (s, 3H), 3.83 (s, 2H), 3.66 (t, J=5.8 Hz, 2H), 3.57 (dt, J=12.5, 8.3 Hz, 4H), 3.12 (t, J=6.2 Hz, 2H), 2.86 (t, J=6.4 Hz, 2H), 2.21 (qd, J=12.4, 4.6 Hz, 2H), 2.04 (p, J=6.2 Hz, 2H), 1.87 (dd, J=13.7, 4.0 Hz, 2H). LCMS M/Z (M+H) 419.
-
-
- To a solution of tetrahydro-2H-thiopyran-4-ol (10 g, 84.6 mmol) and triethylamine (35.4 mL, 253.8 mmol) in DCM (150 mL) at 0° C. was added methanesulfonyl chloride (10.7 mL, 138.8 mmol) dropwise under a nitrogen atmosphere. The mixture was stirred at 25° C. for 16 h. Water (100 mL) was added and extracted with DCM (100 mL×2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (17 g, crude) as yellow oil that required no further purification. 1H NMR (400 MHz, DMSO-d6) δ 4.73-4.69 (m, 1H), 3.19 (s, 3H), 2.76-2.63 (m, 4H), 2.17-2.16 (m, 2H), 1.87-1.84 (m, 2H).
-
- To a solution of tert-butyl 3-bromo-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5 (4H)-carboxylate (Intermediate A, 10 g, 33.1 mmol) in DMF (50 mL) was added Cs2CO3 (27 g, 82.7 mmol) and tetrahydro-2H-thiopyran-4-yl methanesulfonate (8.4 g, 43.0 mmol). The mixture was heated to 80° C. for 16 h under a nitrogen atmosphere. After cooling the reaction to room temperature, the mixture was filtered. The mixture was diluted with EtOAc (100 mL) and washed with brine (100 mL×2). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether:tert-butyl methyl ether:THF=from 10:1:1 to 3:1:1) to give the title compound (5.9 g, 44%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 4.17 (s, 2H), 4.09-4.04 (m, 1H), 3.62-3.59 (m, 2H), 2.83-2.77 (m, 2H), 2.71-2.68 (m, 4H), 2.13-2.10 (m, 2H), 2.03-1.93 (m, 2H), 1.44 (s, 9H).
-
- To a solution of tert-butyl 3-bromo-1-(tetrahydro-2H-thiopyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (2.0 g, 5.0 mmol) in THF (10 mL) and water (2 mL) at 0° C. was added Oxone (3.1 g, 5 mmol) portionwise. The mixture was stirred at 25° C. for 2 h. The reaction was quenched by sat. aq. Na2SO3 and extracted with DCM (20 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (Intermediate K, 2.1 g, 98%) as a white solid. LCMS M/Z (M+H) 436.
-
-
- To a solution of tert-butyl 3-bromo-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5 (4H)-carboxylate (Intermediate A, 5 g, 16.6 mmol) in DMF (40 mL) was added Cs2CO3 (19.5 g, 59.6 mmol) and 1-acetylpiperidin-4-yl methanesulfonate (see
step 1 of Example 75, 5.5 g, 24.8 mmol). The mixture was heated to 90° C. for 12 h under a nitrogen atmosphere. After cooling the reaction to room temperature, the mixture was filtered and concentrated in vacuo. The mixture was diluted with DCM (100 mL) and washed with brine (80 mL×2). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether:tert-butyl methyl ether:THF=from 10:1:1 to 2:1:1) to give the title compound (Intermediate L, 2 g, 28%) as clear oil. 1H NMR (400 MHz, DMSO-d6) δ 4.50-4.41 (m, 1H), 4.38-4.29 (m, 1H), 4.16 (s, 2H), 3.94-3.85 (m, 1H), 3.64-3.57 (m, 2H), 3.21-3.09 (m, 1H), 2.75-2.58 (m, 3H), 2.03 (s, 3H), 1.91-1.80 (m, 3H), 1.73-1.61 (m, 1H), 1.41 (s, 9H). -
-
- To a solution of 7-bromo-1,2,3,4-tetrahydroquinoline (8 g, 37 mmol) in 1,4-dioxane (50 mL) and water (50 mL) was added potassium hexacyanoferrate(II) trihydrate (14 g, 37 mmol), KOAc (15 g, 151 mmol), methanesulfonato(2-di-t-butylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (3 g, 3.7 mmol) and 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (1.6 g, 3.7 mmol). The mixture was heated to 110° C. for 12 h under a nitrogen atmosphere. After cooling the reaction to room temperature, the mixture was filtered and concentrated in vacuo. The crude residue was diluted with EtOAc (100 mL), washed with water (50 mL×2) and brine (50 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc=1:1) to give the title compound (5 g, 84%) as a yellow solid. LCMS M/Z (M+H) 158.
-
- To a solution of 1-(3-bromo-1-tetrahydropyran-4-yl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl)ethanone (Intermediates I, 1.0 g, 3.0 mmol) in 1,4-dioxane (10 mL) was added chloro(2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (240 mg, 0.3 mmol), 2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl (142 mg, 0.3 mmol), 1,2,3,4-tetrahydroquinoline-7-carbonitrile (482 mg, 3 mmol) and t-BuONa (0.88 g, 9.1 mmol). The mixture was heated to 120° C. for 12 h under a nitrogen atmosphere. After cooling the reaction to room temperature, the mixture was filtered and concentrated in vacuo. The crude residue was diluted with DCM (100 mL), washed with water (50 mL×3) and brine (50 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (DCM/MeOH=50:1) to give the title compound (900 mg, 73%) as a yellow solid. LCMS M/Z (M+H) 406.
-
- To a solution of 1-(5-acetyl-1-tetrahydropyran-4-yl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-3-yl)-3,4-dihydro-2H-quinoline-7-carbonitrile (900 mg, 2.2 mmol) in DCM (5 mL) at 0° C. was added N-bromosuccinimide (395 mg, 2.2 mmol) by portionwise. The mixture was stirred at room temperature for 1 h. DCM (50 mL) was added, washed with water (30 mL×3) and brine (30 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (Intermediate M, 1 g, 93%) as a yellow solid. LCMS M/Z (M+H) 484.
-
-
- To a solution of tert-butyl 3-bromo-1-tetrahydropyran-4-yl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate (Intermediate H, 10 g, 26 mmol) in 1,4-dioxane (80 mL) was added dichloro[1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloidyl)palladium(II) (2 g, 2.6 mmol), 1,2,3,4-tetrahydroquinoline-7-carbonitrile (4 g, 26 mmol) and t-BuONa (7.3 g, 76 mmol). The mixture was heated to 120° C. for 12 h under a nitrogen atmosphere. After cooling the reaction to room temperature, the mixture was filtered and concentrated in vacuo. The crude residue was diluted with DCM (100 mL), washed with water (50 mL×2) and brine (50 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (DCM/MeOH=100:1) to give the title compound (8 g, 67%) as a yellow solid. LCMS M/Z (M+H) 464.
-
- To a solution of tert-butyl 3-(7-cyano-3,4-dihydro-2H-quinolin-1-yl)-1-tetrahydropyran-4-yl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate (8 g, 17 mmol) in DCM (50 mL) at 0° C. was added N-bromosuccinimide (3 g, 17 mmol) by portionwise. The mixture was stirred at 26° C. for 1 h. DCM (80 mL) was added, washed with water (30 mL×3) and brine (30 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (9 g, 96%) as a yellow solid. LCMS M/Z (M+H) 542.
-
- To a solution of tert-butyl 3-(6-bromo-7-cyano-3,4-dihydro-2H-quinolin-1-yl)-1-tetrahydropyran-4-yl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate (8 g, 14 mmol) in DCM (20 mL) was added trifluoroacetic acid (10 mL, 174 mmol). The reaction was stirred at 26° C. for 1 h and concentrated in vacuo. The crude residue was diluted with DCM (100 mL), washed with sat. aq. NaHCO3 (50 mL×3) and brine (50 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (6.3 g, 96%) as a yellow solid that required no further purification. LCMS M/Z (M+H) 442.
-
- To a solution of 6-bromo-1-(1-tetrahydropyran-4-yl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl)-3,4-dihydro-2H-quinoline-7-carbonitrile (3.3 g, 7.5 mmol) in DCM (20 mL) was added triethylamine (6 mL, 44 mmol) and N-methyl-1H-imidazole-1-carboxamide (1.8 g, 15 mmol). The reaction was stirred at room temperature for 12 h and concentrated in vacuo. The crude residue was diluted with DCM (100 mL), washed with water (50 mL×3) and brine (50 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (DCM/MeOH=50:1) to give the title compound (Intermediate N, 1.9 g, 51%) as a yellow solid. LCMS M/Z (M+H) 500.
-
- To a solution of 3-(6-bromo-7-cyano-3,4-dihydro-2H-quinolin-1-yl)-N-methyl-1-tetrahydropyran-4-yl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxamide (Intermediate N, 1.0 g, 2 mmol) in 1,4-dioxane (10 mL) was added chloro(2-dicyclohexylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl) palladium(II) (157 mg, 0.2 mmol), 2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (95 mg, 0.2 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (762 mg, 3 mmol) and KOAc (393 mg, 4 mmol). The mixture was heated to 80° C. for 16 h under a nitrogen atmosphere. After cooling the reaction to room temperature, the mixture was concentrated in vacuo. The crude residue was diluted with DCM (100 mL), washed with water (50 mL×3) and brine (50 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (DCM/MeOH=50:1) to give the title compound (Intermediate O, 1.2 g, 80%) as a yellow solid. LCMS M/Z (M+H) 547.
-
-
- To a solution of 1-(3-bromo-1-tetrahydropyran-4-yl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl)ethanone (Intermediate I, 8.0 g, 24.4 mmol) in dioxane (60 mL) was added 7-(difluoromethyl)-1,2,3,4-tetrahydroquinoline (4.5 g, 24.4 mmol), chloro(2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (1.89 g, 2.4 mmol), 2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl (1.1 g, 2.4 mmol) and t-BuONa (7.0 g, 73.1 mmol). The mixture was heated to 120° C. for 16 h under a nitrogen atmosphere. After cooling the reaction to room temperature, the mixture was filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (DCM/MeOH=100:1) to give the title compound (6 g, 57%) as a light yellow solid. LCMS M/Z (M+H) 431.
-
- To a solution of 1-(3-(7-(difluoromethyl)-3,4-dihydroquinolin-1(2H)-yl)-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone (6.0 g, 13.9 mmol) in DCM (50 mL) at 0° C. was added N-bromosuccinimide (1.7 g, 9.8 mmol) portionwise. The mixture was stirred at room temperature for 1 h. The mixture was poured into water (30 mL) and extracted with DCM (30 mL×2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (DCM/MeOH=50:1) to give the title compound (Intermediate P, 7.2 g, crude) as a yellow solid that required no further purification. LCMS M/Z (M+H) 509.
-
- To a solution of 1-(3-(6-bromo-7-(difluoromethyl)-3,4-dihydroquinolin-1(2H)-yl)-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone (Intermediate P, 1.0 g, 1.96 mmol) in 1,4-dioxane (10 mL) was added chloro(2-dicyclohexylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl) palladium(II) (154 mg, 0.20 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (748 mg, 2.94 mmol), 2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (94 mg, 0.20 mmol) and potassium acetate (385 mg, 3.93 mmol). The mixture was heated to 80° C. for 16 h under a nitrogen atmosphere. After cooling the reaction to room temperature, the mixture was concentrated in vacuo. DCM (100 mL) was added, the mixture was washed with water (100 mL) and brine (100 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (DCM/MeOH=10:1) to give the title compound (Intermediate Q, 1.2 g, crude) as black oil that required no further purification.
-
-
- To a solution of tert-butyl 3-bromo-1-tetrahydropyran-4-yl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate (Intermediate H, 1.0 g, 2.6 mmol) in 1,4-dioxane (8 mL) was added chloro(2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (201 mg, 0.26 mmol), 2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl (121 mg, 0.26 mmol), 7-(difluoromethyl)-1,2,3,4-tetrahydroquinoline (527 mg, 2.6 mmol) and t-BuONa (746 mg, 7.8 mmol). The mixture was heated to 120° C. for 16 h under a nitrogen atmosphere. After cooling the reaction to room temperature, the mixture was concentrated in vacuo. DCM (100 mL) was added, the mixture was washed with water (50 mL×2) and brine (50 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc=1:1) to give the title compound (720 mg, 55%) as a yellow solid. LCMS M/Z (M+H) 489.
-
- To a solution of tert-butyl 3-(7-(difluoromethyl)-3,4-dihydroquinolin-1(2H)-yl)-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (720 mg, 1.4 mmol) in DCM (10 mL) was added N-bromosuccinimide (250 mg, 1.4 mmol) portionwise. The mixture was stirred at room temperature for 2 h. DCM (30 mL) was added and washed with water (10 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (850 mg, 92%) as a yellow solid that required no further purification. LCMS M/Z (M+H) 567.
-
- To a solution of tert-butyl 3-(6-bromo-7-(difluoromethyl)-3,4-dihydroquinolin-1(2H)-yl)-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (0.78 g, 1.4 mmol) in DCM (2 mL) was added trifluoroacetic acid (1 mL, 13 mmol) dropwise. The mixture was stirred at room temperature for 1 h and concentrated in vacuo. DCM (30 mL) was added, washed with sat. aq. NaHCO3 (10 mL) and brine (10 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (0.7 g, crude) as yellow oil that required no further purification. LCMS M/Z (M+H) 467.
-
- To a solution of 6-bromo-7-(difluoromethyl)-1-(1-tetrahydropyran-4-yl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl)-3,4-dihydro-2H-quinoline (0.7 g, 1.3 mmol) in DCM (10 mL) was added triethylamine (0.9 mL, 6.6 mmol) and N-methyl-1H-imidazole-1-carboxamide (330 mg, 2.6 mmol). The mixture was stirred at room temperature for 12 h. DCM (50 mL) was added, washed with water (30 mL×3) and brine (30 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (DCM/MeOH=50:1) to give the title compound (Intermediate R, 720 mg, 88%) as light yellow oil. LCMS M/Z (M+H) 524.
-
- To a solution of 3-(6-bromo-7-(difluoromethyl)-3,4-dihydroquinolin-1(2H)-yl)-N-methyl-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxamide (Intermediate R, 150 mg, 0.3 mmol) in 1,4-dioxane (5 mL) was added chloro(2-dicyclohexylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl) palladium(II) (23 mg, 0.03 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (109 mg, 0.4 mmol), 2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (14 mg, 0.03 mmol), potassium acetate (57 mg, 0.6 mmol). The mixture was heated to 80° C. for 16 h under a nitrogen atmosphere. After cooling the reaction to room temperature, the mixture was concentrated in vacuo. DCM (50 mL) was added, the mixture was washed with water (30 mL) and brine (30 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (DCM/MeOH=10:1) to give the title compound (Intermediate S, 0.2 g, crude) as a yellow solid. LCMS M/Z (M+H) 572.
-
-
- To a solution of tert-butyl 3-bromo-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (Intermediate A, 80.0 g, 264.8 mmol) in THF (1.5 L) at 0° C. was added sodium hydride (60%, 12.71 g, 317.7 mmol) by portionwise. The mixture was stirred at room temperature for 0.5 h. 2-(Trimethylsilyl)ethoxymethyl chloride (52.97 g, 317.7 mmol) was added dropwise and the mixture stirred at room temperature for an additional 16 h. The mixture was quenched with water (1 L) and extracted with EtOAc (500 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc=5:1) to give the mixture of title compounds (95 g, 83%) as yellow oil. LCMS M/Z (M+H) 434.
-
- To a solution of tert-butyl 3-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate and tert-butyl 3-bromo-2-((2-(trimethyl silyl)ethoxy)methyl)-6,7-dihydro-2H-pyrazolo[4,3-c]pyridine-5 (4H)-carboxylate (65.7 g, 151.9 mmol) in 1,4-dioxane (200 mL) was added chloro(2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (5.9 g, 7.6 mmol), 2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl (3.54 g, 7.6 mmol), 7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinoline (20 g, 75.96 mmol) and t-BuONa (21.9 g, 227.89 mmol). The mixture was heated to 120° C. for 16 h under an argon atmosphere. After cooling the reaction to room temperature, water (800 mL) was added and extracted with EtOAc (500 mL×3). The combined organic layers were washed with brine (500 mL×3), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (DCM/MeOH=50:1) to give the title compound (Intermediate T, 9.1 g, 20%) as yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.54 (s, 1H), 7.41 (s, 1H), 7.03 (s, 1H), 6.88 (s, 1H), 6.52 (t, J=55.6 Hz, 1H), 5.33 (s, 2H), 4.10 (s, 2H), 3.96 (s, 3H), 3.73-3.70 (m, 4H), 3.64 (t, J=8.0 Hz, 1H), 2.87-2.80 (m. 4H), 2.09-2.07 (m, 2H), 1.45 (s, 9H), 0.93 (t, J=8.0 Hz, 1H), 0.00 (s, 9H). LCMS M/Z (M+H) 615.
-
- To a solution of tert-butyl 3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (8.5 g, 13.83 mmol) in THF (50 mL) was added tetrabutylammonium fluoride (1.0 M in THF, 40 mL, 40 mmol). The mixture was heated to 60° C. for 16 h under a nitrogen atmosphere. After cooling the reaction to room temperature, EtOAc (200 mL) was added and washed with brine (100 mL×3). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (DCM/MeOH=20:1) to give the title compound (Intermediate U, 4.4 g, 66%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.54 (s, 1H), 7.42 (s, 1H), 7.03 (s, 1H), 6.87 (s, 1H), 6.52 (t, J=55.6 Hz, 1H), 4.12 (s, 2H), 3.96 (s, 3H), 3.72-3.69 (m, 4H), 2.86-2.76 (m. 4H), 2.08-2.05 (m, 2H), 1.45 (s, 9H). LCMS M/Z (M+H) 485.
-
-
- To a solution of 4-piperidinol (10.0 g, 98.86 mmol) and 3-oxetanone (7.12 g, 98.86 mmol) in 1,2-dichloroethane (150 mL) was added acetic acid (0.59 mL, 9.89 mmol). After stirring at room temperature for 2 h, sodium triacetoxyborohydride (41.91 g, 197.73 mmol) was added portionwise. The resulting mixture was stirred at room temperature for additional 16 h. MeOH (5 mL) was added and the reaction was quenched with conc. NH4OH (5 mL), dried over anhydrou Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (DCM/MeOH=from 30/1 to 10/1) to give the title compound (2.2 g, 14%) as a pale yellow solid. 1H NMR (400 MHz, CDCl3) δ 4.65-4.57 (m, 4H), 3.75-3.69 (m, 1H), 3.48-3.41 (m, 1H), 2.60-2.55 (m, 2H), 2.02-1.96 (m, 2H), 1.92-1.82 (m, 2H), 1.65-1.57 (m, 2H).
-
- To a solution of 1-(oxetan-3-yl)piperidin-4-ol (2.2 g, 14.0 mmol) and triethylamine (3.9 mL, 28.0 mmol) in anhydrous DCM (25 mL) at 0° C. was added methanesulfonyl chloride (1.34 mL, 16.79 mmol). The mixture was stirred at room temperature for 2 h. Water (20 mL) was added and extracted with DCM (20 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (2.6 g, crude) as a white solid that required no further purification. 1H NMR (400 MHz, CDCl3) δ 4.84-4.75 (m, 1H), 4.68-4.59 (m, 4H), 3.56-3.49 (m, 1H), 3.03 (s, 3H), 2.60-2.53 (m, 2H), 2.25-2.20 (m, 2H), 2.16-2.04 (m, 2H), 1.98-1.90 (m, 2H).
-
- To a solution of tert-butyl 3-bromo-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5 (4H)-carboxylate (Intermediate A, 2.0 g, 6.62 mmol) and 1-(oxetan-3-yl)piperidin-4-yl methanesulfonate (2.6 g, 11.05 mmol) in DMF (30 mL) was added Cs2CO3 (6.47 g, 19.86 mmol). The mixture was heated to 90° C. for 8 h. After cooling the reaction to room temperature, the mixture was filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether:tert-butyl methyl ether:THF=from 5:1:1 to 2:1:1) to give the title compound (Intermediate V, 950 mg, 33%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 4.67-4.58 (m, 4H), 4.27 (s, 2H), 3.94-3.90 (m, 1H), 3.75-3.70 (m, 2H), 3.54-3.50 (m, 1H), 2.89-2.84 (m, 2H), 2.70-2.66 (m, 2H), 2.27-2.23 (m, 2H), 1.98-1.87 (m, 4H), 1.49 (s, 9H).
-
- To a solution of 1-[3-bromo-1-(oxetan-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (Intermediate E, 8.2 g, 27.32 mmol), 1,2,3,4-tetrahydroquinoline (4.12 mL, 32.78 mmol) and t-BuONa (5.25 g, 54.64 mmol) in toluene (80 mL) was added 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (1.57 g, 2.73 mmol) and tris(dibenzylideneacetone)dipalladium (1.25 g, 1.37 mmol). The mixture was heated to 110° C. for 16 h under a nitrogen atmosphere. After cooling the reaction to room temperature, water (100 mL) was added and the mixture was extracted with EtOAc (100 mL×3). The combined organic layers were washed with brine (100 mL×3), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give crude product that was purified by silica gel chromatography (petroleum ether/EtOAc=1:1) to give the tittle compound (5.0 g, 44%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.01-6.92 (m, 2H), 6.65-6.61 (m, 1H), 6.49-6.44 (m, 1H), 5.47-5.44 (m, 1H), 4.93-4.90 (m, 2H), 4.86-4.83 (m, 2H), 4.06-4.04 (m, 2H), 3.70-3.58 (m, 4H), 2.80-2.74 (m, 4H), 2.04-1.91 (m, 5H). LCMS M/Z (M+H) 353.
- The following compounds were prepared in a similar fashion to Example 1:
-
-
Example Compound Name NMR m/z Example 2 1-[3-(2,3-dihydro-1,4- 1H NMR (400 MHz, DMSO-d6) δ 6.81- 355 benzoxazin-4-yl)-1- 6.62 (m, 4H), 5.48-5.45 (m, 1H), 4.93- (oxetan-3-yl)-6,7- 4.84 (m, 4H), 4.28-4.26 (m, 2H), 4.16- dihydro-4H- 4.15 (m, 2H), 3.72-3.68 (m, 4H), 2.77- pyrazolo[4,3-c]pyridin- 2.65 (m, 2H), 2.05-1.95 (m, 3H) 5-yl]ethanone Example 3 1-[3-(2,3-dihydro-1,4- 1H NMR (400 MHz, DMSO-d6) δ 7.09- 371 benzothiazin-4-yl)-1- 7.07 (m, 1H), 6.93-6.90 (m, 1H), 6.76- (oxetan-3-yl)-6,7- 6.73 (m, 1H), 6.60-6.54 (m, 1H), 5.46- dihydro-4H- 5.43 (m, 1H), 4.95-4.83 (m, 4H), 3.98- pyrazolo[4,3-c]pyridin- 3.93 (m, 4H), 3.69-3.64 (m, 2H), 3.16- 5-yl]ethanone 3.14 (m, 2H), 2.77-2.64 (m, 2H), 2.04- 1.89 (m, 3H) Example 4 1-[3-(3,4-dihydro-2H- 1H NMR (400 MHz, DMSO-d6) δ 6.98- 311 quinolin-1-yl)-1- 6.89 (m, 2H), 6.65-6.62 (m, 1H), 6.44- methyl-6,7-dihydro- 6.39 (m, 1H), 4.15-4.10 (m, 2H), 3.84- 4H-pyrazolo[4,3- 3.76 (m, 2H), 3.68 (s, 3H), 3.59-3.56 (m, c]pyridin-5- 2H), 2.81-2.71 (m, 4H), 2.01-1.97 (m, yl]ethanone 5H) Example 5 1-[3-(4-methyl-2,3- 1H NMR (400 MHz, DMSO-d6) δ 6.70- 368 dihydroquinoxalin-1- 6.65 (m, 1H), 6.61-6.59 (m, 1H), 6.53- yl)-1-(oxetan-3-yl)-6,7- 6.47 (m, 1H), 6.43-6.37 (m, 1H), 5.46- dihydro-4H- 5.39 (m, 1H), 4.94-4.82 (m, 4H), 4.03- pyrazolo[4,3-c]pyridin- 4.01 (m, 2H), 3.74-3.65 (m, 4H), 3.34- 5-yl]ethanone 3.30 (m, 2H), 2.86 (s, 3H), 2.76-2.61 (m, 2H), 2.03-1.90 (m, 3H) -
-
- To a solution of 1-[3-(3,4-dihydro-2H-quinolin-1-yl)-1-(oxetan-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (4.2 g, 11.9 mmol) in DMF (40 mL) was added N-bromosuccinimide (2.55 g, 14.3 mmol). The mixture was stirred at 20° C. for 12 h under a nitrogen atmosphere. The mixture was concentrated in vacuo. The crude residue was purified by silica gel chromatography (DCM/MeOH=20:1) to give the title compound (5.0 g, 78%) as a white solid. LCMS M/Z (M+H) 431.
-
- To a solution of 1-[3-(6-bromo-3,4-dihydro-2H-quinolin-1-yl)-1-(oxetan-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (100 mg, 0.23 mmol), 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (60.95 mg, 0.28 mmol) and Na2CO3 (49.15 mg, 0.46 mmol) in 1,4-dioxane (2 mL) and water (0.5 mL) was added [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (16.95 mg, 0.02 mmol). The mixture was stirred at 20° C. for 12 h under a nitrogen atmosphere and then concentrated in vacuo. The crude residue was purified by reverse phase chromatography (acetonitrile 18-48%/0.2% formic acid in water) to give the title compound (38 mg, 36%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 8.66 (s, 1H), 7.86-7.84 (m, 1H), 7.38 (s, 1H), 7.29-7.24 (m, 1H), 6.60-6.54 (m, 1H), 5.49-5.42 (m, 1H), 4.94-4.84 (m, 4H), 4.12-4.10 (m, 2H), 3.69-3.62 (m, 4H), 2.93-2.82 (m, 2H), 2.78-2.62 (m, 2H), 2.46 (s, 3H), 2.05-1.94 (m, 5H). LCMS M/Z (M+H) 444.
- The following compounds were prepared in a similar fashion to Step 2 of Example 6:
-
-
Example Compound Name NMR m/z Example 7 1-[3-[6-(1-ethylpyrazol- 1H NMR (400 MHz, DMSO-d6) δ 7.95 447 4-yl)-3,4-dihydro-2H- (s, 1H), 7.66 (s, 1H), 7.20 (s, 1H), 7.10- quinolin-1-yl]-1-(oxetan- 7.08 (m, 1H), 6.48-6.42 (m, 1H), 5.43- 3-yl)-6,7-dihydro-4H- 5.39 (m, 1H), 4.89-4.81 (m, 4H), 4.08- pyrazolo[4,3-c]pyridin- 4.03 (m, 4H), 3.63-3.58 (m, 4H), 2.80- 5-yl]ethanone 2.73 (m, 4H), 2.01-1.89 (m, 5H), 1.34 (t, J = 7.2 Hz, 3H) Example 8 1-[1-(oxetan-3-yl)-3-[6- 1H NMR (400 MHz, DMSO-d6) δ 8.50 430 (4-pyridyl)-3,4-dihydro- (d, J = 4.4 Hz, 2H), 7.63-7.42 (m, 4H), 2H-quinolin-1-yl]-6,7- 6.61-6.55 (m, 1H), 5.50-5.43 (m, 1H), dihydro-4H- 4.94-4.91 (m, 2H), 4.89-4.86 (m, 2H), pyrazolo[4,3-c]pyridin- 4.13-4.11 (m, 2H), 3.72-3.65 (m, 4H), 5-yl]ethanone 2.91-2.88 (m, 2H), 2.79-2.67 (m, 2H), 2.05-1.94 (m, 5H) Example 9 1-[1-(oxetan-3-yl)-3-[6- 1H NMR (400 MHz, DMSO-d6) δ 7.83 419 (1H-pyrazol-4-yl)-3,4- (s, 2H), 7.23 (s, 1H), 7.16-7.12 (m, dihydro-2H-quinolin-1- 1H), 6.48-6.43 (m, 1H), 5.42-5.37 (m, yl]-6,7-dihydro-4H- 1H), 4.89-4.80 (m, 4H), 4.05-4.03 (m, pyrazolo[4,3-c]pyridin- 2H), 3.63-3.57 (m, 4H), 2.80-2.73 (m, 5-yl]ethanone 4H), 2.01-1.93 (m, 5H) Example 10 1-[3-[6-(1- 1H NMR (400 MHz, DMSO-d6) δ 7.83 459 cyclopropylpyrazol-4- (s, 1H), 7.75 (s, 1H), 7.23 (s, 1H), 7.16- yl)-3,4-dihydro-2H- 7.12 (m, 1H), 7.48-7.43 (m, 1H), 5.42- quinolin-1-yl]-1-(oxetan- 5.37 (m, 1H), 4.89-4.80 (m, 4H), 4.05- 3-yl)-6,7-dihydro-4H- 4.03 (m, 2H), 3.63-3.57 (m, 4H), 2.80- pyrazolo[4,3-c]pyridin- 2.73 (m, 4H), 2.01-1.89(m, 3H), 1.01- 5-yl]ethanone 1.91 (m, 4H) Example 11 1-[3-[6-(2,5- 1H NMR (400 MHz, DMSO-d6) δ 7.12 447 dimethylpyrazol-3-yl)- (s, 1H), 7.04-7.02 (m, 1H), 6.57-6.51 3,4-dihydro-2H- (m, 1H), 6.02 (s, 1H), 5.49-5.46 (m, quinolin-1-yl]-1-(oxetan- 1H), 4.91-4.85 (m, 4H), 4.14-4.12 (m, 3-yl)-6,7-dihydro-4H- 2H), 3.71 (s, 3H), 3.68-3.63 (m, 4H), pyrazolo[4,3-c]pyridin- 2.86-2.77 (m, 4H), 2.12 (s, 3H), 2.05- 5-yl]ethanone 1.98 (m, 5H) Example 12 1-[3-[6-(6-hydroxy-3- 1H NMR (400 MHz, DMSO-d6) δ 11.68 446 pyridyl)-3,4-dihydro- (s, 1H), 7.75-7.72 (m, 1H), 7.51 (s, 2H-quinolin-1-yl]-1- 1H), 7.21 (s, 1H), 7.12-7.10 (m, 1H), (oxetan-3-yl)-6,7- 6.51-6.47 (m, 1H), 6.37 (d, J = 9.6 Hz, dihydro-4H- 1H), 5.48-5.42 (m, 1H), 4.91-4.84 (m, pyrazolo[4,3-c]pyridin- 4H), 4.09-4.07 (m, 2H), 3.66-3.59 (m, 5-yl]ethanone 4H), 2.84-2.76 (m, 4H), 2.04-1.93 (m, 5H) Example 13 1-[1-(oxetan-3-yl)-3-[6- 1H NMR (400 MHz, DMSO-d6) δ 7.55 473 (4,5,6,7- (s, 1H), 7.09 (s, 1H), 7.03-7.00 (m, tetrahydropyrazolo[1,5- 1H), 6.54-6.48 (m, 1H), 5.46-5.43 (m, a]pyridin-3-yl)-3,4- 1H), 4.94-4.91 (m, 2H), 4.87-4.83 (m, dihydro-2H-quinolin-1- 2H), 4.10-4.05 (m, 4H), 3.69-3.60 (m, yl]-6,7-dihydro-4H- 4H), 2.85-2.67 (m, 6H), 2.04-1.93 (m, pyrazolo[4,3-c]pyridin- 7H), 1.80-1.71 (m, 2H) 5-yl]ethanone Example 14 1-[3-[6-(2- 1H NMR (400 MHz, DMSO-d6) δ 7.39 433 methylpyrazol-3-yl)-3,4- (s, 1H), 7.17 (s, 1H), 7.11-7.06 (m, dihydro-2H-quinolin-1- 1H), 6.59-6.53 (m, 1H), 6.25 (s, 1H), yl]-1-(oxetan-3-yl)-6,7- 5.50-5.43 (m, 1H), 4.94-4.91 (m, 2H), dihydro-4H- 4.87-4.84 (m, 2H), 4.15-4.13 (m, 2H), pyrazolo[4,3-c]pyridin- 3.81 (s, 1H), 3.70-3.63 (m, 4H), 2.88- 5-yl]ethanone 2.50 (m, 4H), 2.05-1.96 (m, 5H) Example 15 5-[1-[5-acetyl-1-(oxetan- 1H NMR (400 MHz, DMSO-d6) δ 8.45 487 3-yl)-6,7-dihydro-4H- (s, 1H), 8.72 (d, J = 4.8 Hz, 1H), 8.15 pyrazolo[4,3-c]pyridin- (d, J = 8.0 Hz, 1H), 8.01 (d, J = 8.0 Hz, 3-yl]-3,4-dihydro-2H- 1H), 7.26 (s, 1H), 7.44-7.40 (m, 1H), quinolin-6-yl]-N-methyl- 6.64-6.58 (m, 1H), 5.49-5.46 (m, 1H), pyridine-2-carboxamide 4.94-4.91 (m, 2H), 4.87-4.84 (m, 2H), 4.15-4.12 (m, 2H), 3.73-3.65 (m, 4H), 2.92-2.79 (m, 7H), 2.06-1.95 (m, 5H) Example 16 1-[3-[6-(2-methyl-3- 1H NMR (400 MHz, DMSO-d6) δ 8.37 444 pyridyl)-3,4-dihydro- (s, 1H), 7.56-7.53 (m, 1H), 7.25-7.22 2H-quinolin-1-yl]-1- (m, 1H), 7.05 (s, 1H), 7.01-6.96 (m, (oxetan-3-yl)-6,7- 1H), 6.59-6.53 (m, 1H), 5.49-5.44 (m, dihydro-4H- 1H), 4.94-4.91 (m, 2H), 4.87-4.84 (m, pyrazolo[4,3-c]pyridin- 2H), 4.15-4.12 (m, 2H), 3.70-3.63 (m, 5-yl]ethanone 4H), 2.88-2.70 (m, 4H), 2.45 (s, 3H), 2.06-1.95 (m, 5H) Example 17 1-[3-[6-(2-methoxy-4- 1H NMR (400 MHz, DMSO-d6) δ 8.12 460 pyridyl)-3,4-dihydro- (d, J = 5.2 Hz, 1H), 7.51 (s, 1H), 7.43- 2H-quinolin-1-yl]-1- 7.39 (m, 1H), 7.22 (d, J = 5.2 Hz, 1H), (oxetan-3-yl)-6,7- 6.98 (s, 1H), 6.58-6.52 (m, 1H), 5.48- dihydro-4H- 5.45 (m, 1H), 4.94-4.91 (m, 2H), 4.87- pyrazolo[4,3-c]pyridin- 4.84 (m, 2H), 4.13-4.11 (m, 2H), 3.86 5-yl]ethanone (s, 3H), 3.70-3.65 (m, 4H), 2.90-2.66 (m, 4H), 2.05-1.95 (m, 5H) Example 18 1-[1-(oxetan-3-yl)-3-[6- 1H NMR (400 MHz, DMSO-d6) δ 8.81 430 (3-pyridyl)-3,4-dihydro- (s, 1H), 8.45-8.44 (m, 1H), 7.97-7.95 2H-quinolin-1-yl]-6,7- (m, 1H), 7.43-7.31 (m, 3H), 6.61-6.55 dihydro-4H- (m, 1H), 5.50-5.43 (m, 1H), 4.95-4.85 pyrazolo[4,3-c]pyridin- (m, 4H), 4.14-4.11 (m, 2H), 3.74-3.64 5-yl]ethanone (m, 4H), 2.89 (t, J = 6.4 Hz, 2H), 2.79- 2.67 (m, 2H), 2.05-1.95 (m, 5H) Example 19 1-[3-[6-(6-methoxy-3- 1H NMR (400 MHz, DMSO-d6) δ 8.37 460 pyridyl)-3,4-dihydro- (s, 1H), 7.90 (d, J = 8.4 Hz, 1H), 7.33 2H-quinolin-1-yl]-1- (s, 1H), 7.26-7.22 (m, 1H), 6.83 (d, J = (oxetan-3-yl)-6,7- 8.0 Hz, 1H), 6.57-6.53 (m, 1H), 5.48- dihydro-4H- 5.44 (m, 1H), 4.93-4.86 (m, 4H), 4.12- pyrazolo[4,3-c]pyridin- 4.10 (m, 2H), 3.86 (s, 3H), 3.72-3.64 5-yl]ethanone (m, 4H), 2.87-2.66 (m, 4H), 2.05-1.94 (m, 5H) Example 20 1-[3-[6-(2,4- 1H NMR (400 MHz, DMSO-d6) δ 7.23 447 dimethylpyrazol-3-yl)- (s, 1H), 7.01 (s, 1H), 6.95-6.89 (m, 3,4-dihydro-2H- 1H), 6.59-6.53 (m, 1H), 5.47-5.40 (s, quinolin-1-yl]-1-(oxetan- 1H), 4.91-4.82 (m, 4H), 4.14-4.12 (m, 3-yl)-6,7-dihydro-4H- 2H), 3.70-3.60 (m, 7H), 2.85-2.64 (m, pyrazolo[4,3-c]pyridin- 4H), 2.03-1.91 (m, 8H) 5-yl]ethanone Example 21 5-[1-[5-acetyl-1-(oxetan- 1H NMR (400 MHz, DMSO-d6) δ 9.08 455 3-yl)-6,7-dihydro-4H- (s, 1 H), 8.83 (s, 1H), 8.49 (s, 1H), 7.53 pyrazolo[4,3-c]pyridin- (s, 1H), 7.46-7.37 (m, 1H), 6.61-6.50 3-yl]-3,4-dihydro-2H- (m, 1H), 5.45-5.42 (m, 1H), 4.94-4.79 quinolin-6-yl]pyridine- (m, 4H), 4.15-4.05 (m, 2H), 3.73- 3-carbonitrile 3.58 (m, 4H), 2.86 (t, J = 6.0 Hz, 2H), 2.76-2.60 (m, 2H), 2.06-1.90 (m, 5H) Example 22 1-[3-[6-[2-methyl-5- 1H NMR (400 MHz, DMSO-d6) δ 7.25 501 (trifluoromethyl)pyrazol- (s, 1 H), 7.20-7.10 (m, 1H), 6.74 (s, 3-yl]-3,4-dihydro-2H- 1H), 6.64-6.52 (m, 1H), 5.47 (m, 1H), quinolin-1-yl]-1-(oxetan- 4.96-4.82 (m, 4H), 4.19-4.10 (m, 2H), 3-yl)-6,7-dihydro-4H- 3.89 (s, 3H), 3.76-3.60 (m, 4H), 2.87 pyrazolo[4,3-c]pyridin- (t, J = 5.6 Hz, 2H), 2.81-2.64 (m, 2H), 5-yl]ethanone 2.06-1.96 (m, 5H) Example 23 5-[1-[5-acetyl-1-(oxetan- 1H NMR (400 MHz, DMSO-d6) δ 7.93 460 3-yl)-6,7-dihydro-4H- (s, 1H), 7.71-7.68 (m, 1H), 7.21 (s, pyrazolo[4,3-c]pyridin- 1H), 7.12-7.96 (m, 1H), 6.55-6.45 (m, 3-yl]-3,4-dihydro-2H- 1H), 6.40 (d, J = 9.2 Hz, 1H), 5.42 (m, quinolin-6-yl]-1-methyl- 1H), 4.94-4.78 (m, 4H), 4.12-3.99 (m, pyridin-2-one 2H), 3.72-3.56 (m, 4H), 3.45 (s, 3H), 2.81 (t, J = 6.0 Hz, 2H), 2.81-2.63 (m, 2H), 2.10-1.83 (m, 5H) Example 24 1-[1-(oxetan-3-yl)-3-[6- 1H NMR (400 MHz, DMSO-d6) δ 12.75 419 (1H-pyrazol-3-yl)-3,4- (s, 1H), 7.58 (s, 1H), 7.45-7.34 (m, dihydro-2H-quinolin-1- 2H), 6.54-6.48 (m, 2H), 5.47-5.43 (m, yl]-6,7-dihydro-4H- 1H), 4.92-4.83 (m, 4H), 4.10-4.08 (m, pyrazolo[4,3-c]pyridin- 2H), 3.67-3.62 (m, 4H), 2.82-2.77 (m, 5-yl]ethanone 4H), 2.04-1.93 (m, 5H) Example 25 1-[1-(oxetan-3-yl)-3-(6- 1H NMR (400 MHz, DMSO-d6) δ 9.03- 431 pyrimidin-5-yl-3,4- 9.02 (m, 3H), 7.48-7.47 (m, 1H), 7.41- dihydro-2H-quinolin-1- 7.36 (m, 1H), 6.67-6.62 (m, 1H), 5.55- yl)-6,7-dihydro-4H- 5.53 (m, 1H), 5.15-5.12 (m, 2H), 5.04- pyrazolo[4,3-c]pyridin- 5.01 (m, 2H), 4.26-4.24 (m, 2H), 3.89- 5-yl]ethanone 3.76 (m, 4H), 3.00-2.77 (m, 4H), 2.19- 2.05 (m, 5H) Example 26 5-[1-[5-acetyl-1-(oxetan- 1H NMR (400 MHz, DMSO-d6) δ 9.03 455 3-yl)-6,7-dihydro-4H- (s, 1H), 8.22 (d, J = 8.4 Hz, 1H), 8.01 pyrazolo[4,3-c]pyridin- (d, J = 8.0 Hz, 1H), 7.59 (s, 1H), 7.49- 3-yl]-3,4-dihydro-2H- 7.45 (m, 1H), 6.63-6.57 (m, 1H), 5.50- quinolin-6-yl]pyridine- 5.46 (m, 1H), 4.95-4.88 (m, 4H), 4.15- 2-carbonitrile 4.13 (m, 2H), 3.73-3.68 (m, 4H), 2.92- 2.67 (m, 4H), 2.06-1.96 (m, 5H) -
- To a solution of 1-[3-(6-bromo-3,4-dihydro-2H-quinolin-1-yl)-1-(oxetan-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (100 mg, 0.2 mmol) and tributyl(2-pyridyl)stannane (85 mg, 0.2 mmol) in toluene (5 mL) was added tetrakis(triphenylphosphine)palladium(0) (27 mg, 0.02 mmol) under a nitrogen atmosphere. The mixture was heated to 120° C. for 12 h. After cooling the reaction to room temperature, the mixture was concentrated in vacuo. The resultant residue was dissolved in EtOAc (200 mL) and washed with water (200 mL×2) and brine solution (100 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by reverse phase chromatography (
acetonitrile 10%-40%/0.2% formic acid in water) to give the title compound (9 mg, 8%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 8.55 (d, J=4.4 Hz, 1H), 7.82-7.68 (m, 4H), 7.21-7.18 (m, 1H), 6.59-6.53 (m, 1H), 5.50-5.43 (m, 1H), 4.95-4.85 (m, 4H), 4.13-4.11 (m, 2H), 3.74-3.65 (m, 4H), 2.90 (t, J=6.0 Hz, 2H), 2.80-2.76 (m, 2H), 2.05-1.94 (m, 5H). LCMS M/Z (M+H) 430. -
-
- To a mixture of 1-[3-(6-bromo-3,4-dihydro-2H-quinolin-1-yl)-1-(oxetan-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (5 g, 11.6 mmol), Na2CO3 (2.46 g, 23.2 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (8.83 g, 34.8 mmol) in DMF (50 mL) was added [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (847 mg, 1.16 mmol). The mixture was heated to 70° C. for 12 h under a nitrogen atmosphere. After cooling the reaction to room temperature, the mixture was filtered and the filtrate was concentrated in vacuo. The crude residue was purified by silica gel chromatography (DCM/MeOH=50:1) to give the title compound (3.0 g, 27%) as red oil. LCMS M/Z (M+H) 352.
-
- To a mixture of 3-bromo-1-methyl-pyrazole (40 mg, 0.25 mmol), 1-[1-(oxetan-3-yl)-3-[6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-quinolin-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (100 mg, 0.21 mmol) and Na2CO3 (44 mg, 0.42 mmol) in 1,4-dioxane (1 mL) and water (0.25 mL) was added [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (15 mg, 0.02 mmol). The mixture was heated to 100° C. for 12 h under a nitrogen atmosphere. After cooling the reaction to room temperature, the mixture was filtered and the filtrate was concentrated in vacuo. The crude residue was purified by reverse phase chromatography (acetonitrile 22-52%/0.2% formic acid in water) to give the title compound (16 mg, 17%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.60 (s, 1H), 7.41 (s, 1H), 7.35-7.30 (m, 1H), 6.49-6.43 (m, 2H), 5.45-5.40 (m, 1H), 4.91-4.88 (m, 2H), 4.84-4.80 (m, 2H), 4.07-4.04 (m, 2H), 3.79 (s, 3H), 3.64-3.58 (m, 4H), 2.82-2.80 (m, 2H), 2.76-2.61 (m, 2H), 2.01-1.89 (m, 5H). LCMS M/Z (M+H) 433.
- The following compounds were prepared in a similar fashion to
Step 2 of Example 28: -
-
Example Compound Name NMR m/z Example 29 1-[3-[6-(1,3- 1H NMR (400 MHz, DMSO-d6) δ 7.69 (s, 447 dimethylpyrazol-4-yl)- 1H), 7.06 (s, 1H), 7.02-6.97 (m, 1H), 6.54- 3,4-dihydro-2H- 6.48 (m, 1H), 5.49-5.41 (m, 1H), 4.96- quinolin-1-yl]-1- 4.81 (m, 4H), 4.11-4.09 (m, 2H), 3.75 (s, (oxetan-3-yl)-6,7- 3H), 3.73-3.59 (m, 4H), 2.87-2.62 (m, dihydro-4H- 4H), 2.23 (s, 3H), 2.05-1.94 (m, 5H) pyrazolo[4,3-c]pyridin- 5-yl]ethanone Example 30 1-[1-(oxetan-3-yl)-3-(6- 1H NMR (400 MHz, DMSO-d6) δ 7.74 (d, 436 thiazol-2-yl-3,4- J = 3.6 Hz, 1H), 7.58-7.49 (m, 3H), 6.55- dihydro-2H-quinolin-1- 6.49 (m, 1H), 5.46-5.43 (m, 1H), 4.92- yl)-6,7-dihydro-4H- 4.83 (m, 4H), 4.11-4.08 (m, 2H), 3.66- pyrazolo[4,3-c]pyridin- 3.62 (m, 4H), 2.87-2.76 (m, 4H), 2.03- 5-yl]ethanone 1.97 (m, 5H) Example 31 1-[1-(oxetan-3-yl)-3-(6- 1H NMR (400 MHz, DMSO-d6) δ 8.92 (s, 436 thiazol-5-yl-3,4- 1H), 8.08 (s, 1H), 7.35 (s, 1H), 7.27-7.25 dihydro-2H-quinolin-1- (m, 1H), 6.56-6.50 (m, 1H), 5.47-5.46 yl)-6,7-dihydro-4H- (m, 1H), 4.92-4.84 (m, 4H), 4.12-4.09 pyrazolo[4,3-c]pyridin- (m, 2H), 3.69-3.62 (m, 4H), 2.86-2.77 5-yl]ethanone (m, 4H), 2.04-1.94 (m, 5H) Example 32 1-[3-[6-(5-methyl-1H- 1H NMR (400 MHz, DMSO-d6) δ 7.39 (s, 433 pyrazol-3-yl)-3,4- 1H), 7.30-7.28 (m, 1H), 6.51-6.45 (m, dihydro-2H-quinolin-1- 1H), 6.24 (s, 1H), 5.46-5.43 (m, 1H), 4.92- yl]-1-(oxetan-3-yl)-6,7- 4.83 (m, 4H), 4.09-4.07 (m, 2H), 3.67- dihydro-4H- 3.61 (m, 4H), 2.84-2.76 (m, 4H), 2.19 (s, pyrazolo[4,3-c]pyridin- 3H), 2.04-1.92 (m, 5H) 5-yl]ethanone Example 33 N-[5-[1-[5-acetyl-1- 1H NMR (400 MHz, DMSO-d6) δ 10.45 (s, 487 (oxetan-3-yl)-6,7- 1H), 8.50 (s, 1H), 8.06-8.03 (m, 1H), 7.94- dihydro-4H- 7.91 (m, 1H), 7.36 (s, 1H), 7.28-7.26 (m, pyrazolo[4,3-c]pyridin- 1H), 6.56-6.51 (m, 1H), 5.44-5.41 (m, 3-yl]-3,4-dihydro-2H- 1H), 4.91-4.81 (m, 4H), 4.09-4.07 (m, quinolin-6-yl]-2- 2H), 3.65-3.60 (m, 4H), 2.86-2.75 (m, pyridyl]acetamide 4H), 2.06 (s, 3H), 2.02-1.95 (m, 5H) Example 34 4-[1-[5-acetyl-1- 1H NMR (400 MHz, DMSO-d6) δ 8.21 (s, 458 (oxetan-3-yl)-6,7- 1H), 7.30 (s, 1H), 7.24-7.21 (m, 1H), 6.59- dihydro-4H- 6.53 (m, 1H), 5.47-5.44 (m, 1H), 4.92- pyrazolo[4,3-c]pyridin- 4.85 (m, 4H), 4.12-4.10 (m, 2H), 3.93 (s, 3-yl]-3,4-dihydro-2H- 3H), 3.70-3.62 (m, 4H), 2.85-2.77 (m, quinolin-6-yl]-1-methyl- 4H), 2.05-1.94 (m, 5H) pyrazole-3-carbonitrile Example 35 1-[3-[6-(1,5- 1H NMR (400 MHz, DMSO-d6) δ 7.39 (s, 447 dimethylpyrazol-3-yl)- 1H), 7.34-7.26 (m, 1H), 6.54-6.41 (m, 3,4-dihydro-2H- 1H), 6.28 (s, 1H), 5.47-5.42 (m, 1H), 5.02- quinolin-1-yl]-1- 4.76 (m, 4H), 4.16-4.00 (m, 2H), 3.7 (s, (oxetan-3-yl)-6,7- 3H), 3.68-3.61 (m, 4H), 2.88-2.66 (m, dihydro-4H- 4H), 2.24 (s, 3H), 2.05-1.87 (m, 5H) pyrazolo[4,3-c]pyridin- 5-yl]ethanone Example 36 1-[3-[6-(1,5- 1H NMR (400 MHz, DMSO-d6) δ 7.42 (s, 447 dimethylpyrazol-4-yl)- 1H), 7.03 (s, 1H), 6.98-6.94 (m, 1H), 6.55- 3,4-dihydro-2H- 6.49 (m, 1H), 5.48-5.43 (m, 1H), 4.94- quinolin-1-yl]-1- 4.83 (m, 4H), 4.11-4.09 (m, 2H), 3.74 (s, (oxetan-3-yl)-6,7- 3H), 3.71-3.61 (m, 4H), 2.84-2.65 (m, dihydro-4H- 4H), 2.31 (s, 3H), 2.05-1.94 (m, 5H) pyrazolo[4,3-c]pyridin- 5-yl]ethanone Example 37 1-[3-[6-[1- 1H NMR (400 MHz, DMSO-d6) δ 8.49 (s, 469 (difluoromethyl)pyrazol- 1H), 8.12 (s, 1H), 7.78 (t, J = 59.6 Hz, 1H), 4-yl]-3,4-dihydro-2H- 7.37 (s, 1H), 7.28-7.24 (m, 1H), 6.54- quinolin-1-yl]-1- 6.48 (m, 1H), 5.49-5.42 (m, 1H), 4.94- (oxetan-3-yl)-6,7- 4.84 (m, 4H), 4.10-4.08 (m, 2H), 3.73- dihydro-4H- 3.61 (m, 4H), 2.85-2.65 (m, 4H), 2.05- pyrazolo[4,3-c]pyridin- 1.93 (m, 5H) 5-yl]ethanone Example 38 1-[3-[6-[3- 1H NMR (400 MHz, DMSO-d6) δ 7.95 (s, 483 (difluoromethyl)-1- 1H), 7.13 (s, 1H), 7.08-7.04 (m, 1H), 7.00 methyl-pyrazol-4-yl]- (t, J = 53.6 Hz, 1H), 6.54-6.48 (m, 1H), 3,4-dihydro-2H- 5.49-5.42 (m, 1H), 4.94-4.84 (m, 4H), quinolin-1-yl]-1- 4.12-4.10 (m, 2H), 3.87 (s, 3H), 3.72- (oxetan-3-yl)-6,7- 3.61 (m, 4H), 2.84-2.65 (m, 4H), 2.05- dihydro-4H- 1.94 (m, 5H) pyrazolo[4,3-c]pyridin- 5-yl]ethanone Example 39 1-[3-[6-(1,2- 1H NMR (400 MHz, DMSO-d6) δ 7.35 (s, 447 dimethylimidazol-4-yl)- 1H), 7.28-7.26 (m, 2H), 6.48-6.42 (m, 3,4-dihydro-2H- 1H), 5.45-5.42 (m, 1H), 4.92-4.83 (m, quinolin-1-yl]-1- 4H), 4.08-4.06 (m, 2H), 3.68-4.61 (m, (oxetan-3-yl)-6,7- 2H), 3.53 (s, 3H), 2.82-2.67 (m, 4H), 2.28 dihydro-4H- (s, 3H), 2.04-1.92 (m, 5H) pyrazolo[4,3-c]pyridin- 5-yl]ethanone Example 40 1-[3-[6-(4-methyl-1H- 1H NMR (400 MHz, DMSO-d6) δ 7.55 (s, 433 imidazol-2-yl)-3,4- 1H), 7.46-7.44 (m, 1H), 6.53-6.47 (m, dihydro-2H-quinolin-1- 1H), 5.47-5.42 (m, 1H), 4.94-4.84 (m, yl]-1-(oxetan-3-yl)-6,7- 4H), 4.10-4.08 (m, 2H), 3.68-4.62 (m, dihydro-4H- 2H), 2.86-2.67 (m, 4H), 2.28 (s, 3H), 2.10- pyrazolo[4,3-c]pyridin- 1.93 (m, 8H) 5-yl]ethanone Example 41 1-[3-[6-(1-methyl-1,2,4- 1H NMR (400 MHz, DMSO-d6) δ 8.40 (s, 434 triazol-3-yl)-3,4- 1H), 7.65 (s, 1H), 7.60-7.56 (m, 1H), 6.55- dihydro-2H-quinolin-1- 6.49 (m, 1H), 5.47-5.44 (m, 1H), 4.95- yl]-1-(oxetan-3-yl)-6,7- 4.85 (m, 4H), 4.12-4.10 (m, 2H), 3.86 (s, dihydro-4H- 3H), 3.68-4.63 (m, 4H), 2.88-2.79 (m, pyrazolo[4,3-c]pyridin- 4H), 2.05-1.94 (m, 5H) 5-yl]ethanone Example 42 1-[1-(oxetan-3-yl)-3-(6- 1H NMR (400 MHz, DMSO-d6) δ 9.10 (s, 436 thiazol-4-yl-3,4- 1H), 7.83 (s, 1H), 7.67 (s, 1H), 7.60-7.56 dihydro-2H-quinolin-1- (m, 1H), 6.57-6.51 (m, 1H), 5.48-5.42 yl)-6,7-dihydro-4H- (m, 1H), 4.95-4.85 (m, 4H), 4.12-4.10 pyrazolo[4,3-c]pyridin- (m, 2H), 3.72-4.64 (m, 4H), 2.86-2.79 5-yl]ethanone (m, 4H), 2.05-1.94 (m, 5H) Example 43 1-[3-[6-(5- 1H NMR (400 MHz, DMSO-d6) δ 9.16 (s, 508 methylsulfonyl-3- 1H), 8.90 (s, 1H), 8.42 (s, 1H), 7.59 (s, pyridyl)-3,4-dihydro- 1H), 7.49-7.45 (m, 1H), 6.66-6.60 (m, 2H-quinolin-1-yl]-1- 1H), 5.49-5.46 (m, 1H), 4.95-4.85 (m, (oxetan-3-yl)-6,7- 4H), 4.15-4.12 (m, 2H), 3.69-4.66 (m, dihydro-4H- 4H), 3.38 (s, 3H), 2.93-2.79 (m, 4H), 2.05- pyrazolo[4,3-c]pyridin- 1.94 (m, 5H) 5-yl]ethanone -
-
- To a solution of 1-[1-(oxetan-3-yl)-3-[6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-quinolin-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (300 mg, 0.44 mmol), 2,4-dichloropyrimidine (78 mg, 0.53 mmol) and Na2CO3 (93 mg, 0.88 mmol) in 1,4-dioxane (3.0 mL) and water (1.0 mL) was added [1,1′ bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (32 mg, 0.04 mmol). The mixture was heated to 100° C. for 2 h under a nitrogen atmosphere. After cooling the reaction to room temperature, the mixture was filtered and the filtrate was concentrated in vacuo. The crude residue was purified by silica gel chromatography (DCM/MeOH=50:1) to give the title compound (150 mg, 62%) as a yellow solid. LCMS M/Z (M+H) 465.
-
- To a solution of 1-[3-[6-(2-chloropyrimidin-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-1-(oxetan-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (50 mg, 0.09 mmol) in MeOH (2.0 mL) was added 10% Pd/C (10 mg, 0.1 mmol). The mixture was stirred at 25° C. for 12 h under a hydrogen atmosphere (15 Psi). The mixture was filtered and the filtrate was concentrated in vacuo. The crude residue was purified by reverse phase chromatography (acetonitrile 20-16%/0.2% formic acid in water) to give the title compound (8 mg, 19%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 9.06 (s, 1H), 8.67 (d, J=5.6 Hz, 1H), 7.94 (s, 1H), 7.90-7.84 (m, 2H), 6.60-6.54 (m, 1H), 5.50-5.45 (m, 1H), 4.92-4.85 (m, 4H), 4.14-4.12 (m, 2H), 3.69-3.66 (m, 4H), 2.92-2.79 (m, 4H), 2.05-1.94 (m, 5H). LCMS M/Z (M+H) 431.
-
- To a solution of (S)-1-(3-bromo-1-(tetrahydrofuran-3-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone (Intermediate G, 200 mg, 0.64 mmol), 1,2,3,4-tetrahydroquinoline (85 mg, 0.64 mmol) and t-BuONa (123 mg, 1.28 mmol) in 1,4-dioxane (2.0 mL) was added chloro(2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl)[2-(2-aminoethylphenyl)]palladium(ii), methyl-tert-butylether adduct (52 mg, 0.064 mmol) and 2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl (30 mg, 0.064 mmol). The mixture was heated to 120° C. for 12 h under a nitrogen atmosphere. After cooling the reaction to room temperature, the mixture was filtered and the filtrate was concentrated in vacuo. The crude residue was purified by reverse phase chromatography (acetonitrile 38-68%/0.2% formic acid in water) to give the title compound (37 mg, 16%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 6.99 (d, J=7.2 Hz, 1H), 6.95-6.88 (m, 1H), 6.63-6.60 (m, 1H), 6.44-6.39 (m, 1H), 4.98-4.81 (m, 1H), 4.07-3.94 (m, 4H), 3.82-3.68 (m, 4H), 3.57-3.52 (m, 2H), 2.84-2.70 (m, 4H), 2.33-2.19 (m, 2H), 2.06-1.93 (m, 5H). LCMS M/Z (M+H) 367.
-
-
- To a solution of (S)-1-(3-(3,4-dihydroquinolin-1(2H)-yl)-1-(tetrahydrofuran-3-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone (1.3 g, 3.55 mmol) in DMF (13 mL) was added N-bromosuccinimide (695 mg, 3.9 mmol). The mixture was stirred at 20° C. for 12 h under a nitrogen atmosphere. Water (100 mL) was added and the mixture was extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine (30 mL×3), dried over anhydrous Na2SO4 and concentrated in vacuo. The crude residue was purified by silica gel chromatography (DCM/MeOH=50:1) to give the title compound (1.7 g, 86%) as a yellow oil. LCMS M/Z (M+H) 445.
-
- To a solution of N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-carboxamide (141 mg, 0.54 mmol) and 1-[3-(6-bromo-3,4-dihydro-2H-quinolin-1-yl)-1-[(3S)-tetrahydrofuran-3-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (200 mg, 0.45 mmol) in 1,4-dioxane (2 mL) and water (0.5 mL) was added [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (33 mg, 0.04 mmol). The mixture was heated to 100° C. for 12 h under a nitrogen atmosphere. After cooling the reaction to room temperature, the mixture was filtered and filtrate was concentrated in vacuo. The crude residue was purified by reverse phase chromatography (acetonitrile 22-16%/0.2% formic acid in water) to give the title compound (27 mg, 12%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 8.83 (s, 1H), 8.71-8.69 (m, 1H), 8.14 (d, J=8.0 Hz, 1H), 8.01 (d, J=8.8 Hz, 1H), 7.50 (s, 1H), 7.42-7.38 (m, 1H), 6.57-6.51 (m, 1H), 4.95-4.92 (m, 1H), 4.14-4.12 (m, 2H), 4.02-3.90 (m, 2H), 3.83-3.80 (m, 4H), 3.60-3.59 (m, 2H), 2.90-2.82 (m, 4H), 2.88 (s, 3H), 2.35-2.15 (m, 2H), 2.07-1.96 (m, 5H). LCMS M/Z (M+H) 501.
- The following compounds were prepared in a similar fashion to Step 2 of Example 46:
-
-
Example Compound Name NMR m/z Example 47 1-[3-[6-(1,3- 1H NMR (400 MHz, DMSO-d6) δ 7.68 (s, 1H), 461 dimethylpyrazol-4-yl)- 7.03 (s, 1H), 6.99-6.94 (m, 1H), 6.49-6.39 3,4-dihydro-2H- (m, 1H), 4.95-4.85 (m, 1H), 4.11-4.09 (m, quinolin-1-yl]-1- 2H), 4.05-3.93 (m, 2H), 3.82-3.68 (m, 7H), tetrahydrofuran-3-yl- 3.60-3.50 (m, 2H), 2.89-2.63 (m, 4H), 2.34- 6,7-dihydro-4H- 2.18 (m, 5H), 2.09-1.90 (m, 5H) pyrazolo[4,3-c]pyridin- 5-yl]ethanone Example 48 1-[3-[6-(2-methoxy-4- 1H NMR (400 MHz, DMSO-d6) δ 8.10 (d, J = 474 pyridyl)-3,4-dihydro- 5.6 Hz, 1H), 7.48 (s, 1H), 7.39-7.36 (m, 1H), 2H-quinolin-1-yl]-1- 7.21 (d, J = 5.6 Hz, 1H), 6.97 (s, 1H), 6.51- [(3S)-tetrahydrofuran- 6.45 (m, 1H), 4.94-4.88 (m, 1H), 4.13-4.11 3-yl]-6,7-dihydro-4H- (m, 2H), 3.91-3.97 (m, 2H), 3.85 (s, 3H), pyrazolo[4,3-c]pyridin- 3.81-3.70 (m, 4H), 3.58-3.57 (m, 2H), 2.87- 5-yl]ethanone 2.84 (m, 4H), 2.29-2.18 (m, 2H), 2.06-1.95 (m, 5H) Example 49 1-[3-[6-(1- 1H NMR (400 MHz, DMSO-d6) δ 8.00 (s, 1H), 473 cyclopropylpyrazol-4- 7.67 (s, 1H), 7.21 (s, 1H), 7.14-7.09 (m, 1H), yl)-3,4-dihydro-2H- 6.45-6.39 (m, 1H), 4.91-4.88 (m, 1H), 4.09- quinolin-1-yl]-1-[(3S)- 4.07 (m, 4H), 3.81-3.67 (m,, 5H), 3.55-3.53 tetrahydrofuran-3-yl]- (m, 2H), 2.82-2.77 (m, 4H), 2.29-2.15 (m, 6,7-dihydro-4H- 2H), 2.07-1.93 (m, 5H), 1.03-0.93 (m, 4H) pyrazolo[4,3-c]pyridin- 5-yl]ethanone Example 50 1-[3-[7-(1- 1H NMR (400 MHz, DMSO-d6) δ 8.06-8.05 461 methylpyrazol-4-yl)- (m, 1H), 8.00-7.79 (m, 1H), 7.44-7.42 (m, 2,3,4,5-tetrahydro-1- 1H), 7.31-7.26 (m, 1H), 6.90-6.77 (m, 1H), benzazepin-1-yl]-1- 4.81-4.78 (m, 1H), 4.03-3.98 (m, 2H), 3.84- [(3S)-tetrahydrofuran- 3.78 (m, 5H), 3.55-3.43 (m, 6H), 2.77-2.55 3-yl]-6,7-dihydro-4H- (m, 4H), 2.25-2.22 (m, 2H), 1.97-1.62 (m, pyrazolo[4,3-c]pyridin- 7H) 5-yl]ethanone -
-
- To a solution of (S)-1-(3-(6-bromo-3,4-dihydroquinolin-1(2H)-yl)-1-(tetrahydrofuran-3-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone (762 mg, 1.70 mmol), 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (382 mg, 1.70 mmol) and Na2CO3 (363 mg, 3.40 mmol) in 1,4-dioxane (4.0 mL) and water (1 mL) was added [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (125 mg, 0.17 mmol). The mixture was heated to 120° C. for 12 h under a nitrogen atmosphere. After cooling the reaction to room temperature, the mixture was concentrated in vacuo. The crude residue was purified by silica gel chromatography (DCM/MeOH=100:1 to 20:1) to give the title compound (0.58 g, 73%) as a yellow oil. LCMS M/Z (M+H) 462.
-
- To a solution of (S)-1-(3-(6-(6-fluoropyridin-3-yl)-3,4-dihydroquinolin-1(2H)-yl)-1-(tetrahydrofuran-3-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone (170 mg, 0.37 mmol) in EtOH (3.0 mL) was added EtONa (1.0 M in EtOH, 0.55 mL, 0.55 mmol). The mixture was heated to 80° C. for 12 h under a nitrogen atmosphere. After cooling the reaction to room temperature, the mixture was filtered and the filtrate concentrated in vacuo. The crude residue was purified by reverse phase chromatography (acetonitrile 30-60%/0.2% formic acid in water) to give the title compound (11 mg, 6%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.34 (s, 1H), 7.87 (d, J=8.0 Hz, 1H), 7.30 (s, 1H), 7.26-7.19 (m, 1H), 6.80 (d, J=8.0 Hz, 1H), 6.52-6.40 (m, 1H), 4.91-4.88 (m, 1H), 4.33-4.28 (m, 2H), 4.17-4.07 (m, 2H), 4.06-3.91 (m, 2H), 3.86-3.65 (m, 4H), 3.63-3.56 (m, 2H), 2.90-2.68 (m, 4H), 2.30-2.25 (m, 2H), 2.09-1.93 (m, 5H), 1.32 (t, J=7.2 Hz, 3H). LCMS M/Z (M+H) 488.
-
-
- To a mixture of 1-[3-(6-bromo-3,4-dihydro-2H-quinolin-1-yl)-1-[(3S)-tetrahydrofuran-3-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (1.7 g, 3.82 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (2.91 g, 11.45 mmol), AcOK (748 mg, 7.63 mmol) in DMF (17 mL) was added [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (279 mg, 0.38 mmol). The mixture was heated to 100° C. for 2 h under a nitrogen atmosphere. After cooling the reaction to room temperature, the mixture was filtered and the filtrate concentrated in vacuo. The crude residue was purified by silica gel chromatography (DCM/MeOH=100:1) to give the title compound (0.9 g, 40%) as a yellow solid. LCMS M/Z (M+H) 493.
-
- To a suspension of 4-bromo-1-methyl-pyrazole-3-carbonitrile (91 mg, 0.49 mmol), 1-[1-[(3S)-tetrahydrofuran-3-yl]-3-[6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-quinolin-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (200 mg, 0.41 mmol) and Na2CO3 (86 mg, 0.81 mmol) in 1,4-dioxane (2 mL) and water (0.5 mL) was added [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (30 mg, 0.04 mmol). The mixture was heated to 100° C. for 2 h under a nitrogen atmosphere. After cooling the reaction to room temperature, the mixture was filtered and the filtrate was concentrated in vacuo. The crude residue was purified by reverse phase chromatography (acetonitrile 36-16%/0.2% formic acid in water) to give the title compound (22 mg, 11%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.21 (s, 1H), 7.28 (s, 1H), 7.19 (d, J=6.4 Hz, 1H), 6.53-6.46 (m, 1H), 4.96-4.85 (m, 1H), 4.12-4.11 (m, 2H), 4.00-3.95 (m, 2H), 3.93 (s, 3H), 3.81-3.70 (m, 4H), 3.57-3.56 (m, 2H), 2.83-2.80 (m, 4H), 2.28-2.24 (m, 2H), 2.06-1.95 (m, 5H). LCMS M/Z (M+H) 472.
- The following compounds were prepared in a similar fashion to Step 2 of Example 52:
-
-
Example Compound Name NMR m/z Example 53 1-[3-[6-(1,5- 1H NMR (400 MHz, DMSO-d6) δ 7.41 (s, 461 dimethylpyrazol-4-yl)- 1H), 7.01 (s, 1H), 6.96-6.91 (m, 1H), 6.49- 3,4-dihydro-2H- 6.43 (m, 1H), 4.92-4.89 (m, 1H), 4.18- quinolin-1-yl]-1-[(3S)- 4.11 (m, 2H), 4.01-3.85 (m, 2H), 3.82- tetrahydrofuran-3-yl]- 3.68 (m, 4H), 3.74 (s, 3H), 3.56-3.54 (m, 6,7-dihydro-4H- 2H), 2.82-2.79 (m, 4H), 2.30-2.29 (m, pyrazolo[4,3-c]pyridin- 5H), 2.06-1.93 (m, 5H) 5-yl]ethanone Example 54 1-[3-[6-(6-methoxy-3- 1H NMR (400 MHz, DMSO-d6) δ 8.32 (s, 474 pyridyl)-3,4-dihydro- 1H), 7.87-7.84 (m, 1H), 7.28 (s, 1H), 7.18- 2H-quinolin-1-yl]-1- 7.16 (m, 1H), 6.80 (d, J = 8.4 Hz, 1H), 6.49- [(3S)-tetrahydrofuran- 6.43 (m, 1H), 4.90-4.85 (m, 1H), 4.09- 3-yl]-6,7-dihydro-4H- 4.07 (m, 2H), 3.98-3.82 (m, 2H), 3.78 (s, pyrazolo[4,3-c]pyridin- 3H), 3.77-3.67 (m, 4H), 3.63-3.54 (m, 5-yl]ethanone 2H), 2.83-2.80 (m, 4H), 2.47-2.27 (m, 2H), 2.03-1.91 (m, 5H) Example 55 1-[3-[6-(1,3- 1H NMR (400 MHz, DMSO-d6) δ 7.68 (s, 461 dimethylpyrazol-4-yl)- 1H), 7.03 (s, 1H), 6.99-6.94 (m, 1H), 6.47- 3,4-dihydro-2H- 6.41 (m, 1H), 4.92-4.86 (m, 1H), 4.11- quinolin-1-yl]-1-[(3S)- 4.09 (m, 2H), 4.00-3.85 (m, 2H), 3.80- tetrahydrofuran-3-yl]- 3.69 (m, 4H), 3.73 (s, 3H), 3.55-3.54 (m, 6,7-dihydro-4H- 2H), 2.82-2.78 (m, 4H), 2.35-2.29 (m, pyrazolo[4,3-c]pyridin- 2H), 2.22 (s, 3H), 2.21-1.94 (m, 5H) 5-yl]ethanone Example 56 1-[3-[6-(1,5- 1H NMR (400 MHz, DMSO-d6) δ 7.41 (s, 461 dimethylpyrazol-4-yl)- 1H), 7.01 (s, 1H), 6.96-6.91 (m, 1H), 6.49- 3,4-dihydro-2H- 6.43 (m, 1H), 4.93-4.86 (m, 1H), 4.11- quinolin-1-yl]-1- 4.10 (m, 2H), 4.03-3.94 (m, 2H), 3.84- tetrahydrofuran-3-yl- 3.78 (m, 2H), 3.74 (s, 3H), 3.71-3.68 (m, 6,7-dihydro-4H- 2H), 3.58-3.53 (m, 2H), 2.83-2.71 (m, pyrazolo[4,3-c]pyridin- 4H), 2.30-2.19 (m, 3H), 2.06-1.93 (m, 5-yl]ethanone 5H) Example 57 N-[5-[1-[5-acetyl-1- 1H NMR (400 MHz, DMSO-d6) δ 10.50 (s., 501 [(3S)-tetrahydrofuran- 1H), 8.53 (s., 1H), 8.08 (d, J = 8.4 Hz, 1H), 3-yl]-6,7-dihydro-4H- 7.95 (d, J = 8.8 Hz, 1H), 7.38 (s, 1H), 7.33- pyrazolo[4,3-c]pyridin- 7.24 (m, 1H), 6.58-6.46 (m, 1H), 4.93- 3-yl]-3,4-dihydro-2H- 4.88 (m, 1H), 4.17-4.08 (m, 2H), 4.06- quinolin-6-yl]-2- 3.93 (m, 2H), 3.86-3.66 (m, 4H), 3.64- pyridyl]acetamide 3.53 (m, 2H), 2.91-2.69 (m, 4H), 2.36- 2.20 (m, 2H), 2.10-2.07 (m, 5H), 2.02- 1.91 (m, 3H) Example 58 1-[3-[6-(5-methyl-1H- 1H NMR (400 MHz, DMSO-d6) δ 12.61- 447 pyrazol-3-yl)-3,4- 12.17 (m, 1H), 7.44-7.19 (m, 2H), 6.49- dihydro-2H-quinolin- 6.38 (m, 1H), 6.23 (s, 1H), 4.92-4.88 (m., 1-yl]-1-[(3S)- 1H), 4.09 (s., 2H), 4.05-3.92 (m, 2H), 3.86- tetrahydrofuran-3-yl]- 3.64 (m, 4H), 3.61-3.51 (m, 2H), 2.89- 6,7-dihydro-4H- 2.66 (m, 4H), 2.35-2.12 (m, 5H), 2.07- pyrazolo[4,3-c]pyridin- 1.94 (m, 2H), 1.94 (s, 3H) 5-yl]ethanone -
-
- To a solution of 1-(3-bromo-1-tetrahydropyran-4-yl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl)ethanone (Intermediate I, 1.8 g, 5.48 mmol) in 1,4-dioxane (16 mL) was added 1,2,3,4 tetrahydroquinoline (0.7 mL, 5.48 mmol), chloro(2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (426 mg, 0.55 mmol), 2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl (256 mg, 0.55 mmol) and t-BuONa (2.1 g, 21.94 mmol). The mixture was heated to 120° C. for 16 h under a nitrogen atmosphere. After cooling the reaction to room temperature, the mixture was concentrated in vacuo. The crude residue was purified by chromatography column (DCM/MeOH=20:1) to give the title compound (1.7 g, 73%) as a yellow solid.
-
- To a solution of 1-(3-(6-bromo-3,4-dihydroquinolin-1(2H)-yl)-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone (1.7 g, 4.02 mmol) in DCM (20 mL) was added N-bromosuccinimide (787 mg, 4.42 mmol) at room temperature portionwise. The mixture was stirred at room temperature for 1 h. The mixture was concentrated in vacuo. The crude residue was purified by silica gel chromatography (DCM/MeOH=20:1) to give the title compound (2 g, 90%) as a yellow solid.
-
- To a solution of 1-(3-(6-bromo-3,4-dihydroquinolin-1(2H)-yl)-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone (200 mg, 0.36 mmol) in dioxane (10 mL) and water (2 mL) was added N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinamide (96 mg, 0.36 mmol), K2CO3 (152 mg, 1.10 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (26 mg, 0.036 mmol). The mixture was heated to 110° C. for 12 h under a nitrogen atmosphere. After cooling the reaction to room temperature, the mixture was concentrated in vacuo. The residue was purified by Prep-TLC (DCM/MeOH=15:1) to give the title compound (59 mg, 26%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.71 (s, 1H), 8.20-8.17 (m, 1H), 8.00-7.94 (m, 2H), 7.33 (s, 1H), 7.24-7.21 (m, 1H), 6.60 (d, J=8.0 Hz, 1H), 4.31-4.12 (m, 5H), 3.92 (t, J=6.0 Hz, 1H), 3.76-3.70 (m, 3H), 3.53 (t, J=12 Hz, 1H), 3.06 (t, J=4.8 Hz, 1H), 2.96-2.92 (m, 2H), 2.83-2.75 (m, 2H), 2.33-2.30 (m, 2H), 2.18-2.06 (m, 5H), 1.89-1.85 (m, 2H). LCMS M/Z (M+H) 515.
- The following compounds were prepared in a similar fashion to Step 3 of Example 59:
-
-
Example Compound Name NMR m/z Example 60 1-[3-[6-(2-methoxy-4- 1H NMR (400 MHz, DMSO-d6) δ 8.10 (d, J = 488 pyridyl)-3,4-dihydro- 4.0 Hz, 1H), 7.48 (s, 1H), 7.41-7.36 (m, 1H), 2H-quinolin-1-yl]-1- 7.20 (d, J = 4.0 Hz, 1H), 6.97 (s, 1H), 6.51- tetrahydropyran-4-yl- 6.45 (m, 1H), 4.68-4.44 (m, 1H), 4.14-4.12 6,7-dihydro-4H- (m, 2H), 3.96-3.94 (m, 2H), 3.85 (s, 3H), pyrazolo[4,3-c]pyridin- 3.75-3.70 (m, 2H), 3.61-3.58 (m, 2H), 3.45 5-yl]ethanone (t, J = 11.6 Hz, 2H), 2.86-2.67 (m, 4H), 2.06- 1.96 (m, 7H), 1.83-1.80 (m, 2H) Example 61 N-[5-[1-(5-acetyl-1- 1H NMR (400 MHz, DMSO-d6) δ 10.5 (s, 1H), 515 tetrahydropyran-4-yl- 8.52 (s, 1H), 8.08-8.06 (m, 1H), 7.96-7.93 6,7-dihydro-4H- (m, 1H), 7.37 (s, 1H), 7.29-7.25 (m, 1H), pyrazolo[4,3-c]pyridin- 6.53-6.47 (m, 1H), 4.30-4.24 (m, 1H), 4.13- 3-yl)-3,4-dihydro-2H- 4.11 (m, 2H), 3.96-3.93 (m, 2H), 3.75-3.68 quinolin-6-yl]-2- (m, 2H), 3.60-3.55 (m, 2H), 3.44 (t, J = 12.0 pyridyl]acetamide Hz, 2H), 2.85-2.66 (m, 4H), 2.08 (s, 3H), 2.06-1.95 (m, 7H), 1.82-1.79 (m, 2H) Example 62 1-[3-[6-(5-methyl-1H- 1H NMR (400 MHz, DMSO-d6) δ 12.32 (s, 461 pyrazol-3-yl)-3,4- 1H), 7.33 (s, 1H), 7.27-7.22 (m, 1H), 6.42- dihydro-2H-quinolin-1- 6.36 (m, 1H), 6.19 (s, 1H), 4.29-4.23 (m, yl]-1-tetrahydropyran- 1H), 4.11-4.09 (m, 2H), 3.95-3.93 (m, 2H), 4-yl-6,7-dihydro-4H- 3.76-3.68 (m, 2H), 3.58-3.53 (m, 2H), 3.47- pyrazolo[4,3-c]pyridin- 3.41 (m, 2H), 2.83-2.66 (m, 4H), 2.18 (s, 5-yl]ethanone 3H), 2.05-1.93 (m, 7H), 1.82-1.78 (m, 1H) Example 63 1-[3-[6-(1,5- 1H NMR (400 MHz, DMSO-d6) δ 7.41 (s, 1H), 475 dimethylpyrazol-4-yl)- 7.01 (s, 1H), 6.96-6.91 (m, 1H), 6.49-6.43 3,4-dihydro-2H- (m, 1H), 4.29-4.24 (m, 1H), 4.13-4.11 (m, quinolin-1-yl]-1- 2H), 4.00-3.94 (m, 2H), 3.76-3.69 (m, 5H), tetrahydropyran-4-yl- 3.58-3.42 (m, 4H), 2.86-2.71 (m, 4H), 2.30 6,7-dihydro-4H- (s, 3H), 2.07-1.94 (m, 7H), 1.82-1.79 (m, pyrazolo[4,3-c]pyridin- 2H) 5-yl]ethanone Example 64 1-[3-[6-(1- 1H NMR (400 MHz, DMSO-d6) δ 7.91 (s, 1H), 461 methylpyrazol-4-yl)- 7.67 (s, 1H), 7.19 (s, 1H), 7.14-7.03 (m, 1H), 3,4-dihydro-2H- 6.49-6.36 (m, 1H), 4.35-4.19 (m, 1H), 4.16- quinolin-1-yl]-1- 4.02 (m, 2H), 3.96-3.94 (m, 2H), 3.82 (s, tetrahydropyran-4-yl- 3H), 3.77-3.64 (m, 2H), 3.55-3.33 (m, 4H), 6,7-dihydro-4H- 2.90-2.69 (m, 4H), 2.06-1.90 (m, 7H), 1.82- pyrazolo[4,3-c]pyridin- 1.79 (m, 2H) 5-yl]ethanone -
-
- To a solution of 6-bromo-1,2,3,4-tetrahydroquinoline (17.0 g, 80.16 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (25.0 g, 120.23 mmol) and K2CO3 (33.2 g, 240.47 mmol) in dioxane/H2O (5:1, 150 mL) was added [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (5.8 g, 8.02 mmol). The mixture was heated to 120° C. for 16 h under a nitrogen atmosphere. After cooling the reaction to room temperature, the mixture was filtered and the filtrate was concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc=1:1) to give the title compound (8.0 g, 47%) as a yellow solid. 1H NMR (400 MHz, CD3OD) δ 7.71 (s, 1H), 7.62 (s, 1H), 7.07 (d, J=6.0 Hz, 2H), 6.50 (d, J=8.4 Hz, 1H), 3.87 (s, 3H), 3.23 (t, J=5.2 Hz, 2H), 2.75 (t, J=6.4 Hz, 2H), 1.94-1.88 (m, 2H).
-
- To a solution of 6-(1-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinoline (300 mg, 0.98 mmol), 1-(3-bromo-1-methyl-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5 (4H)-yl)ethanone (Intermediate B, 280 mg, 1.08 mmol), chloro(2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl)[2-(2-aminoethylphenyl)]palladium(II), methyl-tert-butylether adduct (84 mg, 0.10 mmol) and 2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl (47 mg, 0.10 mmol) in dioxane (3 mL), was added t-BuONa (284 mg, 2.95 mmol). The mixture was irradiated in a microwave at 120° C. for 30 min. After cooling the reaction to room temperature, the mixture was filtered and the filtrate was concentrated in vacuo. The crude residue was purified by silica gel chromatography (DCM/MeOH=30:1) to give the crude product that was further purified by reverse phase chromatography (acetonitrile 30-60%/0.1% NH4HCO3 in water) to give the title compound (30 mg, 8%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.89 (s, 1H), 7.66 (s, 1H), 7.18 (s, 1H), 7.10-7.07 (m, 1H), 6.42-6.37 (m, 1H), 4.06 (s, 2H), 3.80 (s, 3H), 3.72-3.63 (m, 5H), 3.53-3.50 (m, 2H), 2.77 (s, 3H), 2.64-2.49 (m, 1H), 2.04-1.91 (m, 5H). LCMS M/Z (M+H) 391.
- The following compounds were prepared in a similar fashion to Example 65:
-
-
Example Compound Name NMR m/z Example 66 1-[3-[6-(1- 1H NMR (400 MHz, DMSO-d6) δ 7.92 447 methylpyrazol-4-yl)-3,4- (s, 1H), 7.68 (s, 1H), 7.20 (s, 1H), 7.15- dihydro-2H-quinolin-1- 7.06 (m, 1H), 6.49-6.37 (m, 1H), 4.93- yl]-1-tetrahydrofuran-3- 4.85 (m, 1H), 4.14-4.06 (m, 2H), 4.05- yl-6,7-dihydro-4H- 3.92 (m, 2H), 3.87-3.65 (m, 7H), 3.62- pyrazolo[4,3-c]pyridin- 3.48 (m, 2H), 2.83-2.78 (m, 4H), 2.37- 5-yl]ethanone 2.18 (m, 2H), 2.06 (s, 2H), 1.95-1.94 (m, 3H) Example 67 1-[3-[6-(1- 1H NMR (400 MHz, DMSO-d6) δ 7.93 433 methylpyrazol-4-yl)-3,4- (s, 1H), 7.69 (s, 1H), 7.22 (s, 1H), 7.18- dihydro-2H-quinolin-1- 7.08 (m, 1H), 6.54-6.44 (m, 1H), 5.47- yl]-1-(oxetan-3-yl)-6,7- 5.41 (m, 1H), 4.96-4.82 (m, 4H), 4.11- dihydro-4H- 4.04 (m, 2H), 3.83 (s, 3H), 3.75-3.58 pyrazolo[4,3-c]pyridin- (m, 4H), 2.86-2.61 (m, 4H), 2.05-1.93 5-yl]ethanone (m, 5H) Example 68 1-[3-[7-(1- 1H NMR (400 MHz, DMSO-d6) δ 7.88 447 methylpyrazol-4-yl)-3,4- (s, 1H), 7.57 (s, 1H), 6.97 (d, J = 7.6 Hz, dihydro-2H-quinolin-1- 1H), 6.81 (d, J = 7.6 Hz, 1H), 6.68- yl]-1-tetrahydrofuran-3- 6.63 (m, 1H), 4.91-4.88 (m, 1H), 4.09- yl-6,7-dihydro-4H- 4.07 (m, 4H), 3.84-3.80 (m, 7H), 3.58- pyrazolo[4,3-c]pyridin- 3.57 (m, 2H), 2.84-2.73 (m, 4H), 2.29- 5-yl]ethanone 2.27 (m, 2H), 2.06-1.85 (m, 5H) Example 69 1-[3-[6-[1-methyl-3- 1H NMR (400 MHz, DMSO-d6) δ 8.01 501 (trifluoromethyl)pyrazol- (s, 1H), 7.05 (s, 1H), 7.00-6.96 (m, 4-yl]-3,4-dihydro-2H- 1H), 6.56-6.49 (m, 1H), 5.47-5.43 (m, quinolin-1-yl]-1-(oxetan- 1H), 4.92-4.85 (m, 4H), 4.10 (s, 2H), 3-yl)-6,7-dihydro-4H- 3.92 (s, 3H), 3.72-3.63 (m, 4H), 2.82- pyrazolo[4,3-c]pyridin- 2.65 (m, 4H), 2.09-1.94 (m, 5H) 5-yl]ethanone -
- Racemic 1-[3-[6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-1-tetrahydrofuran-3-yl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (Example 66, 75 mg) was separated using chiral SFC (Chiralcel OJ 250×30 mm I.D., 5 um; Supercritical CO2/EtOH (0.1% NH3H2O)=65:35 at 50 mL/min) to give 1-[3-[6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-1-[(3R)-tetrahydrofuran-3-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (23 mg, first peak) and 1-[3-[6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-1-[(3S)-tetrahydrofuran-3-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (30 mg, second peak). Absolute configuration was arbitrarily assigned to each enantiomer. Example 70: 1H NMR (400 MHz, DMSO-d6) δ 7.92 (s, 1H), 7.68 (s, 1H), 7.20 (s, 1H), 7.15-7.06 (m, 1H), 6.49-6.37 (m, 1H), 4.93-4.85 (m, 1H), 4.14-4.06 (m, 2H), 4.05-3.92 (m, 2H), 3.87-3.65 (m, 7H), 3.62-3.48 (m, 2H), 2.83-2.78 (m, 4H), 2.37-2.18 (m, 2H), 2.06-1.94 (m, 5H). LCMS M/Z (M+H) 447. Example 71: 1H NMR (400 MHz, DMSO-d6) δ 7.92 (s, 1H), 7.68 (s, 1H), 7.20 (s, 1H), 7.15-7.06 (m, 1H), 6.49-6.37 (m, 1H), 4.93-4.85 (m, 1H), 4.14-4.06 (m, 2H), 4.05-3.92 (m, 2H), 3.87-3.65 (m, 7H), 3.62-3.48 (m, 2H), 2.83-2.78 (m, 4H), 2.37-2.18 (m, 2H), 2.06-1.94 (m, 5H). LCMS M/Z (M+H) 447.
-
-
- To a solution of tert-butyl 3-bromo-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate (10.0 g, 33.1 mmol) in DCM (80 mL) at 0° C. was added trifluoacetic acid (40 mL, 538.6 mmol) dropwise. The mixture was stirred at room temperature for 2 h. The mixture was concentrated in vacuo to give 3-bromo-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine (5.9 g, 70.6%) that was dissolved in DCM (100 mL). To the mixture at 0° C. was added triethylamine (18.4 mL, 132.4 mmol) and acetic anhydride (2.7 g, 26.5 mmol) dropwise. The mixture was stirred at 0° C. for an additional 1 h. The reaction was quenched with water (100 mL) and extracted with DCM (200 mL×2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (7.0 g, 87%) as a light green solid.
-
- To a solution of 1-(3-bromo-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-yl)ethanone (6.0 g, 20.2 mmol) and p-toluenesulfonic acid (1.7 g, 10.1 mmol) in THF (40 mL) at 25° C. was added 3,4-dihydro-2H-pyran (3.4 g, 40.3 mmol) dropwise. The mixture was heated to 100° C. for 16 h. After cooling the reaction to room temperature, the mixture was filtered and the filtrate was concentrated in vacuo to give the title compound (7.0 g, 64%) as a brown solid. LCMS M/Z (M+H) 328.
-
- To a solution of 1-(3-bromo-1-tetrahydropyran-2-yl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl)ethanone (7.0 g, 12.6 mmol) in 1,4-dioxane (30 mL) was added t-BuONa (3.6 g, 37.8 mmol), 6-(1-methylpyrazol-4-yl)-1,2,3,4-tetrahydroquinoline (3.2 g, 15.1 mmol), chloro(2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (0.98 g, 1.3 mmol) and 2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl (0.59 g, 1.3 mmol). The mixture was heated to 120° C. for 16 h under a nitrogen atmosphere. After cooling the reaction to room temperature, the reaction was filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (DCM/MeOH=10:1) to give the title compound (5.8 g, 85%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 7.92 (s, 1H), 7.68 (s, 1H), 7.21 (s, 1H), 7.14-7.10 (m, 1H), 6.45-6.39 (m, 1H), 5.30-5.28 (m, 1H), 4.13-4.09 (m, 1H), 4.01-3.87 (m, 2H), 3.82 (s, 3H), 3.62-3.61 (m, 1H), 3.58-3.53 (m, 3H), 2.87-2.76 (m, 4H), 2.25-2.13 (m, 1H), 2.06 (s, 2H), 1.97-1.93 (m, 3H), 1.86-1.80 (m, 1H), 1.64-1.45 (m, 4H). LCMS M/Z (M+H) 461.
-
-
- To a solution of 1-[3-[6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-1-tetrahydropyran-2-yl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (5.8 g, 12.6 mmol) in MeOH (30 mL) at 0° C. was added HCl in MeOH (4M, 10 mL, 40 mmol) dropwise and stirred for 2 h. The mixture was concentrated in vacuo. The crude residue was dissolved in H2O (30 mL) and the pH was adjusted to around 7 with sat. aq. Na2CO3. The mixture was extracted with EtOAc (30 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (3.7 g, 62%) as a yellow solid. LCMS M/Z (M+H) 377.
-
- To a solution of 1-[3-[6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-yl]ethanone (200 mg, 0.53 mmol) and p-toluenesulfonic acid (46 mg, 0.27 mmol) in THF (2 mL) at room temperature was added 2,3-dihydrofuran (74 mg, 1.06 mmol) dropwise. The mixture was heated to 60° C. for 16 h. After cooling the reaction to room temperature, water (10 mL) was added and the mixture was extracted with EtOAc (10 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by reverse phase chromatography (acetonitrile 32-62%/0.1% NH4OH in water) to give the title compound (22 mg, 9%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.92 (s, 1H), 7.68 (s, 1H), 7.20 (s, 1H), 7.14-7.10 (m, 1H), 6.48-6.42 (m, 1H), 5.95-5.92 (m, 1H), 4.15-4.09 (m, 1H), 4.02-3.95 (m, 1H), 3.88-3.82 (m, 5H), 3.72-3.61 (m, 2H), 3.57-3.54 (m, 2H), 2.81-2.78 (m, 4H), 2.58-2.50 (m, 2H), 2.21-2.18 (m, 2H), 2.06-1.93 (m, 5H). LCMS M/Z (M+H) 447.
-
- To a solution of 1-[3-[6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-yl]ethanone (
Step 1, Example 73, 200 mg, 0.53 mmol) and 1,8-diazabicycloundec-7-ene (149 mg, 1.0 mmol) in MeCN (5 mL) was added 2,3-dihydrothiophene 1,1-dioxide (69 mg, 0.6 mmol). The mixture was heated to 80° C. for 2 h under a nitrogen atmosphere. After cooling the reaction to room temperature, water (20 mL) was added and the mixture was extracted with EtOAc (20 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by reverse phase chromatography (acetonitrile 16-46%/0.1% NH4OH in water) to give the title compound (60 mg, 25%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.90 (s, 1H), 7.65 (s, 1H), 7.18 (s, 1H), 7.12-7.07 (m, 1H), 6.48-6.42 (m, 1H), 5.14-5.06 (m, 1H), 4.06-4.04 (m, 2H), 3.79 (s, 3H), 3.76-3.68 (m, 3H), 3.60-3.45 (m, 3H), 3.38-3.36 (m, 1H), 2.84-2.73 (m, 4H), 2.58-2.52 (m, 2H), 2.06-1.93 (m, 5H). LCMS M/Z (M+H) 495. -
-
- To a solution of 1-(4-hydroxy-1-piperidyl)ethanone (200 mg, 1.4 mmol) in DCM (5 mL) at 0° C. was added triethylamine (212 mg, 2.1 mmol) and methanesulfonyl chloride (480 mg, 4.19 mmol). The mixture was stirred at 25° C. for 2 h. Water (50 mL) was added and the mixture was extracted with DCM (50 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (300 mg, crude) as yellow oil that required no further purification. 1H NMR (400 MHz, CDCl3) δ 4.98-4.92 (m, 1H), 3.83-3.81 (m, 1H), 3.67-3.65 (m, 1H), 3.58-3.56 (m, 1H), 3.43-3.41 (m, 1H), 3.06 (s, 3H), 2.01 (s, 3H), 2.00-1.88 (m, 4H).
-
- To a solution of 1-[3-[6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-yl]ethanone (
Step 1, Example 73, 200 mg, 0.53 mmol) in DMF (3 mL) was added (1-acetyl-4-piperidyl) methanesulfonate (309 mg, 1.4 mmol) and Cs2CO3 (346 mg, 1.06 mmol). The mixture was heated to 60° C. for 16 h. After cooling the reaction to room temperature, the mixture was filtered and the filtrate was concentrated in vacuo. The crude residue was purified by reverse phase chromatography (acetonitrile 30-60%/0.1% NH4OH in water) to give the title compound (26 mg, 9%) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 7.91 (s, 1H), 7.67 (s, 1H), 7.19 (s, 1H), 7.12-7.08 (m, 1H), 6.44-6.38 (m, 1H), 4.47-4.44 (m, 1H), 4.30-4.28 (m, 1H), 4.11-4.09 (m, 2H), 3.89-3.70 (m, 5H), 3.54-3.51 (m, 2H), 3.32-3.10 (m, 2H), 2.84-2.67 (m, 4H), 2.06-1.73 (m, 7H), 2.03 (s, 3H). LCMS M/Z (M+H) 502. -
-
- To a solution of 1-[3-[6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-yl]ethanone (
Step 1, Example 73, 300 mg, 0.80 mmol) in MeCN (5 mL) was added 1-benzyl-2,3-dihydropyridin-6-one (298 mg, 1.59 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (243 mg, 1.59 mmol). The mixture was heated to 70° C. for 16 h. After cooling the reaction to room temperature, the mixture was concentrated in vacuo. The crude residue was purified by Prep-TLC (DCM/MeOH=20:1) to give the title compound (200 mg, 45%) as light yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.60-7.58 (m, 1H), 7.43-7.41 (m, 1H), 7.22-7.21 (m, 5H), 7.10-7.00 (m, 2H), 6.42-6.38 (m, 1H), 6.11-6.04 (m, 1H), 5.86-5.83 (m, 1H), 4.80-4.76 (m, 1H), 4.44-4.37 (m, 2H), 4.25-4.00 (m, 2H), 3.86-3.85 (m, 3H), 3.58-3.56 m, 1H), 3.60-3.55 (m, 3H), 3.42 (s, 3H), 3.35-3.15 (m, 3H), 2.81-2.62 (m, 4H), 2.27-2.06 (m, 9H). LCMS M/Z (M+H) 564. -
- To a solution of sat. NH3 in THF (10 mL) at 78° C. was added sodium (26 mg, 1.06 mmol). The mixture was stirred at the same temperature for 10 min before a solution of 4-[5-acetyl-3-[6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-1-yl]-1-benzyl-piperidin-2-one (60 mg, 0.11 mmol) in THF (3 mL) was added dropwise. The mixture was stirred at 78° C. for an additional 2 h. The reaction was quenched with solid NH4Cl (200 mg) and warmed to room temperature. Water (100 mL) was added and the mixture was extracted with DCM (50 mL×2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (80 mg, crude) as a white solid that required no further purification. LCMS M/Z (M+H) 432.
-
- To a solution of 4-[3-[6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]piperidin-2-one (80 mg, 0.19 mmol) in DCM (10 mL) at 0° C. was added triethylamine (0.026 mL, 0.19 mmol) and acetic anhydride (0.018 mL, 0.19 mmol). The mixture stirred for 1 hr before being concentrated in vacuo. The crude residue was purified by reverse phase chromatography (acetonitrile 6-36%/0.2% formic acid in water) to give the title compound (5 mg, 6%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.67-7.65 (m, 1H), 7.50-7.48 (m, 1H), 7.17-7.05 (m, 2H), 6.53-6.50 (m, 1H), 6.04 (s, 1H), 4.44-4.41 (m, 1H), 4.30-4.15 (m, 1H), 4.10-4.09 (m, 1H), 3.93-3.64 (m, 1H), 3.51-3.30 (m, 2H), 3.03-3.01 (m, 1H), 2.88-2.71 (m. 5H), 2.45-2.25 (m, 1H), 2.17-2.03 (m, 6H). LCMS M/Z (M+H) 474.
-
-
- To a solution of tert-butyl 3-hydroxypyrrolidine-1-carboxylate (2 g, 10.68 mmol) and triethylamine (3.24 g, 32.05 mmol) in DCM (10 mL) at 0° C. was added mesyl chloride (1.47 g, 12.82 mmol) dropwise. The mixture was stirred at room temperature for 3 h. The mixture was diluted with DCM (20 mL) and the mixture was washed with brine (10 mL×2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (2.1 g, crude) as colorless oil that required no further purification.
-
- To a solution of 1-(3-bromo-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone (1.3 g, 5.33 mmol) in DMF (10 mL) was added Cs2CO3 (19.5 g, 59.6 mmol) and tert-butyl 3-((methylsulfonyl)oxy)pyrrolidine-1-carboxylate (2.1 g, 7.99 mmol). The mixture was heated to 80° C. for 12 h. After cooling the reaction to room temperature, the reaction was filtered and concentrated in vacuo. The residue was dissolved in EtOAc (40 mL) and the mixture was washed with brine (20 mL×2). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/tert-butyl methyl ether/THF=from 10:1:1 to 1:10:10) to give the title compound (680 mg, 31%) as colorless oil. 1H NMR (400 MHz, CD3OD) δ 4.41-4.39 (m, 2H), 3.92-3.87 (m, 1H), 3.82-3.70 (m, 2H), 3.66-3.43 (m, 4H), 2.88-2.76 (m, 4H), 2.33-2.31 (m, 2H), 2.20-2.17 (m, 3H), 1.48 (s, 9H).
-
- To a solution of tert-butyl 3-(5-acetyl-3-bromo-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidine-1-carboxylate (530 mg, 1.28 mmol) in dioxane (8 mL) was added 6-(1-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinoline (328 mg, 1.54 mmol), chloro(2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl)[2-(2-aminoethylphenyl)]palladium(II), methyl-tert-butylether adduct (104 mg, 0.13 mmol), 2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl (60 mg, 0.13 mmol) and t-BuONa (370 mg, 3.85 mmol). The mixture was heated to 120° C. for 12 h under a nitrogen atmosphere. After cooling the reaction to room temperature, the mixture was concentrated in vacuo. The crude residue was purified by silica gel chromatography (DCM/MeOH=20:1) to give the title compound (420 mg, 60%) as colorless oil. LCMS M/Z (M+H) 546.
-
- To a solution of tert-butyl 3-(5-acetyl-3-(6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4, 5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidine-1-carboxylate (420 mg, 0.77 mmol) in DCM (10 mL) at 0° C. was added trifluoroacetic acid (2 mL) dropwise. The mixture was stirred at room temperature for 1 h and concentrated in vacuo. Water (20 mL) was added and the mixture was made basic with solid NaHCO3 to pH 8 and then the mixture was extracted with EtOAc (20 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the crude product (220 mg) as a yellow solid. Part of the crude product (100 mg) was purified by reverse phase chromatography (acetonitrile 20-50%/0.1% NH4HCO3 in water) to give the title compound (68 mg) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.91 (s, 1H), 7.66 (s, 1H), 7.18 (s, 1H), 7.12-7.07 (m, 1H), 6.43-6.38 (m, 1H), 4.85-4.55 (m, 1H), 4.09-4.06 (m, 2H), 3.81 (s, 3H), 3.75-3.50 (m, 2H), 3.07-3.05 (m, 2H), 2.85-2.75 (m, 5H), 2.70-2.65 (m, 1H), 2.21-2.05 (m, 1H), 1.96-1.91 (m, 6H). LCMS M/Z (M+H) 446.
- The following compound was prepared in a similar fashion to Example 77:
-
-
Example Compound Name NMR m/z Example 78 1-[3-[6-(1- 1H NMR (400 MHz, DMSO-d6) δ 7.90 (s, 460 methylpyrazol-4-yl)- 1H), 7.66 (s, 1H), 7.19 (s, 1H), 7.11-7.07 3,4-dihydro-2H- (m, 1H), 6.44-6.38 (m, 1H), 4.30-4.25 quinolin-1-yl]-1-(4- (m, 2H), 4.24-4.10 (m, 2H), 3.87 (s, 3H), piperidyl)-6,7-dihydro- 3.81-3.63 (m, 2H), 3.54-3.51 (m, 2H), 4H-pyrazolo[4,3- 3.24-3.22 (m, 2H), 2.81-2.70 (m, 6H), c]pyridin-5- 2.06-1.93 (m, 9H) yl]ethanone -
- To a solution of 1-[3-[6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-1-pyrrolidin-3-yl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (120 mg, 0.25 mmol) in MeOH (5 mL), was added aqueous formaldehyde (30%, 54 mg, 0.54 mmol), NaBH3CN (34 mg, 0.54 mmol) and AcOH (0.2 mL). The mixture was stirred at room temperature for 1 h. Water (10 mL) was added and the mixture was extracted with EtOAc (20 mL×2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by reverse phase chromatography (acetonitrile 20-50%/0.1% NH4HCO3 in water) to give the title compound (18 mg, 17%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.90 (s, 1H), 7.66 (s, 1H), 7.19 (s, 1H), 7.12-7.08 (m, 1H), 6.43-6.37 (m, 1H), 4.77-4.73 (m, 1H), 4.11-4.10 (m, 2H), 3.81 (s, 3H), 3.75-3.60 (m, 2H), 3.55-3.50 (m, 2H), 3.01-2.90 (m, 1H), 2.81-2.78 (m, 3H), 2.65-2.60 (m, 2H), 2.55-2.50 (m, 2H), 2.30-2.05 (m, 7H), 1.75-1.65 (m, 3H). LCMS M/Z (M+H) 460.
- The following compound was prepared in a similar fashion to Example 79:
-
-
Example Compound Name NMR m/z Example 80 1-[1-(1-methyl-4- 1H NMR (400 MHz, DMSO-d6) δ 8.21 (s, 474 piperidyl)-3-[6-(1- 1H), 7.90 (s, 1H), 7.66 (s, 1H), 7.18 (s, 1H), methylpyrazol-4-yl)- 7.11-7.07 (m, 1H), 6.43-6.38 (m, 1H), 3,4-dihydro-2H- 4.09-4.08 (m, 2H), 4.07-3.99 (m, 1H), quinolin-1-yl]-6,7- 3.81(s, 3H), 3.73-3.66 (m, 4H), 2.93-2.91 dihydro-4H- (m, 2H), 2.80-2.77 (m, 4H), 2.25 (s, 3H), pyrazolo[4,3-c]pyridin- 2.14-2.11 (m, 2H), 2.05-1.95 (m, 3H), 5-yl]ethanone 2.03-2.00 (m, 4H), 1.93-1.84 (m, 2H) -
-
- To a solution of (methoxymethyl)triphenylphosphonium chloride (22.9 g, 66.81 mmol) in THF (100 mL) at 0° C. was added n-BuLi (2.5 M in hexanes, 31 mL, 76.35 mmol). The resulting deep-red solution was stirred at 0° C. for 5 min before being quickly added to a solution of quinoline-3-carbaldehyde (10 g, 63.63 mmol) in THF (50 mL) at 0° C. The temperature was slowly raised to 25° C. and stirred for an additional 1 h. The solvent was concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc=3:1) to give the title compound (5.5 g, 51%) as yellow oil.
-
- A mixture of (E)-3-(2-methoxyvinyl)quinoline (5.5 g, 29.69 mmol) in aqueous HCl solution (5.5 M, 115 mL) was heated to 80° C. for 1 h under a nitrogen atmosphere. After cooling the reaction to room temperature, sat. aq. NaHCO3 (100 mL×2) was added dropwise and the mixture was extracted with EtOAc (200 mL×2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (5 g, crude) that required no further purification. 1H NMR (400 MHz, CDCl3) δ 9.89 (s, 1H), 8.76 (s, 1H), 8.13-8.10 (m, 1H), 8.03 (s, 1H), 7.83-7.81 (m, 1H), 7.75-7.71 (m, 1H), 7.60-7.58 (m, 1H), 7.24 (s, 1H), 3.94 (s, 2H).
-
- To a solution of 2-(quinolin-3-yl)acetaldehyde (5 g, 29.21 mmol) in DCM (100 mL) at 0° C. was added diethylaminosulfurtrifluoride (18.83 mg, 116.83 mmol). The mixture was stirred at room temperature for 12 h. The mixture was then added to a sat. aq. NaHCO3 (600 mL) dropwise at 0° C. and extracted with DCM (1 L×2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc=5:1) to give the title compound (900 mg, 16%) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.82 (s, 1H), 8.13-8.08 (m, 2H), 7.83-7.81 (m, 1H), 7.73-7.71 (m, 1H), 7.60-7.58 (m, 1H), 6.05 (t, J=60.4 Hz, 1H), 3.40-3.30 (m, 2H).
-
- To a solution of 3-(2,2-difluoroethyl)quinoline (900 mg, 4.66 mmol) and NaBH3CN (1.5 g, 23.29 mmol) in MeOH (10 mL) at 0° C. was added boron trifluoride diethyl etherate (1.18 mL, 9.32 mmol) dropwise. The mixture was heated to 70° C. for 12 h under a nitrogen atmosphere. After cooling the reaction to room temperature, water (10 mL) was added and the mixture was extracted with EtOAc (50 mL×2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc=5:1) to give the title compound (230 mg, 25%) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.02-6.95 (m, 2H), 6.66-6.62 (m, 1H), 6.51-6.49 (m, 1H), 5.98 (t, J=56.8 Hz, 1H), 3.42-3.39 (m, 1H), 3.08-3.04 (m, 1H), 2.95-2.91 (m, 1H), 2.60-2.54 (m, 1H), 2.33-2.19 (m, 1H), 1.96-1.90 (m, 2H).
-
- To a solution of 3-(2,2-difluoroethyl)-1,2,3,4-tetrahydroquinoline (260 mg, 1.32 mmol) in 1,4-dioxane (10 mL) was added (S)-1-(3-bromo-1-(tetrahydrofuran-3-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone (Intermediate G, 414 mg, 1.32 mmol), 2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl (62 mg, 0.13 mmol), chloro(2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl)[2-(2-aminoethylphenyl)]palladium(II), methyl-tert-butylether adduct (96 mg, 0.13 mmol) and t-BuONa (507 mg, 5.27 mmol). The mixture was heated to 120° C. for 16 h under a nitrogen atmosphere. After cooling the reaction to room temperature, the mixture was concentrated in vacuo. The crude residue was purified by silica gel chromatography (DCM/MeOH=20:1) to give the title compound (460 mg, 62%) as a yellow oil. LCMS M/Z (M+H) 431.
-
- To a solution of 1-(3-(3-(2,2-difluoroethyl)-3,4-dihydroquinolin-1(2H)-yl)-1-((S)-tetrahydrofuran-3-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone (460 mg, 0.82 mmol) in DCM (6 mL) was added N-bromosuccinimide (146 mg, 0.82 mmol) at dropwise and the mixture stirred for 1 h. The solvent was concentrated in vacuo and the crude residue was purified by silica gel chromatography (DCM/MeOH=20:1) to give the title compound (400 mg, 76%) as a yellow oil. LCMS M/Z (M+H) 509.
-
- To a solution of 1-(3-(6-bromo-3-(2,2-difluoroethyl)-3,4-dihydroquinolin-1-(2H)-yl)-1-((S)-tetrahydrofuran-3-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone (400 mg, 0.76 mmol) in 1,4-dioxane (12 mL) and water (3 mL) was added 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (163 mg, 0.76 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (56 mg, 0.076 mmol) and K2CO3 (326 mg, 2.36 mmol). The mixture was heated to 110° C. for 12 h under a nitrogen atmosphere. After cooling the reaction to room temperature, water (50 mL) was added and the mixture was extracted with EtOAc (50 mL×2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (DCM/MeOH=50:1) to give the crude compound that was further purified by reverse phase chromatography (acetonitrile 20-50%/0.1% NH4HCO3 in water) to give the title compound (80 mg, 27%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.66-7.64 (m, 1H), 7.50-7.48 (m, 1H), 7.16-7.05 (m, 2H), 6.52-6.49 (m, 1H), 6.15-5.55 (m, 1H), 4.77-4.73 (m, 1H), 4.18-4.10 (m, 4H), 3.97-3.90 (m, 7H), 3.85-3.75 (m, 2H), 3.40-3.35 (m, 1H), 3.10-3.00 (m, 1H), 2.85-2.60 (m, 2H), 2.41-2.39 (m, 2H), 2.16-1.96 (m, 6H). LCMS M/Z (M+H) 511.
-
- Racemic 1-[3-[3-(2,2-difluoroethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-1-tetrahydrofuran-3-yl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (Example 81, 65 mg) was separated using chiral SFC (MG-II; Chiralpak AD 250×30 mm I.D., 5 um; Supercritical CO2/EtOH (0.1% NH3H2O)=70:30 at 60 mL/min) to give (S, S)-1-[3-[3-(2,2-difluoroethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-1-tetrahydrofuran-3-yl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (19 mg, first peak) and (S,R)-1-[3-[3-(2,2-difluoroethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-1-tetrahydrofuran-3-yl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (21 mg, second peak). Absolute configuration was arbitrarily assigned to each diastereomer. Example 82: 1H NMR (400 MHz, CDCl3) δ 7.68-7.66 (m, 1H), 7.52-7.50 (m, 1H), 7.18-7.12 (m, 2H), 6.54-6.50 (m, 1H), 6.01-5.87 (m, 1H), 4.78-4.74 (m, 1H), 4.21-4.04 (m, 4H), 4.02-3.93 (m, 7H), 3.85-3.76 (m, 2H), 3.45-3.35 (m, 1H), 3.10-3.00 (m, 1H), 2.76-2.70 (m, 2H), 2.42-2.39 (m, 2H), 2.18-1.96 (m, 6H). LCMS M/Z (M+H) 511. Example 83: 1H NMR (400 MHz, CDCl3) δ 7.65-7.63 (m, 1H), 7.49-7.47 (m, 1H), 7.18-7.06 (m, 2H), 6.51-6.48 (m, 1H), 5.99-5.96 (m, 1H), 4.78-4.74 (m, 1H), 4.27-4.10 (m, 4H), 4.00-3.90 (m, 7H), 3.85-3.75 (m, 2H), 3.45-3.35 (m, 1H), 3.10-3.00 (m, 1H), 2.74-2.66 (m, 2H), 2.40-2.39 (m, 2H), 2.16-1.95 (m, 6H). LCMS M/Z (M+H) 511.
-
-
- To a solution of 4-bromo-2-nitrobenzaldehyde (10 g, 43.47 mmol) in EtOH (50 mL) and acetic acid (50 mL) was added Fe powder (7.28 g, 130.42 mmol). The mixture was stirred at 0° C. for 40 min under a nitrogen atmosphere. Insoluble solid was filtered off and the filtrate was adjusted to pH=8 by progressively adding solid NaHCO3. The resulting solution was extracted with EtOAc (300 mL×2), washed with saturated NaHCO3 (100 mL) and brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc=10:1) to give the title compound (6 g, 64%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 9.79 (s, 1H), 7.48 (d, J=8.4 Hz, 1H), 7.27 (s, 2H), 6.99 (s, 1H), 6.78 (d, J=8.0 Hz, 1H).
-
- To a solution of 2-amino-4-bromobenzaldehyde (6 g, 28.2 mmol) in toluene (50 mL) was added (E)-1-ethoxyprop-1-ene (6.07 g, 70.49 mmol) and 4-methylbenzenesulfonic acid (0.49 g, 2.82 mmol). The mixture was heated to reflux for 18 h under a nitrogen atmosphere. After cooling the reaction to room temperature, the mixture was concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc=5:1) to give the title compound (4 g, 57%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 8.80 (s, 1H), 8.19-8.17 (m, 2H), 7.88 (d, J=8.8 Hz, 1H), 7.73-7.70 (m, 1H), 2.47 (s, 3H).
-
- To a solution of 7-bromo-3-methyl-quinoline (2.5 g, 11.26 mmol) in toluene (10 mL) was added diphenyl hydrogen phosphate (28.16 mg, 0.11 mmol) and
diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (6.84 g, 27 mmol). The mixture was heated to 60° C. for 12 h under a nitrogen atmosphere. After cooling the reaction to room temperature, the reaction was filtered and the filtrate was concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc=10:1) to give the title compound (2.1 g, 83%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 6.74 (d, J=8.0 Hz, 1H), 6.58 (s, 1H), 6.51-6.48 (m, 1H), 6.00 (s, 1H), 3.18-3.16 (m, 1H), 2.76-2.71 (m, 1H), 2.65-2.61 (m, 1H), 2.27-2.21 (m, 1H), 1.85-1.83 (m, 1H), 0.95 (d, J=6.8 Hz, 1H). -
- To a solution of 7-bromo-3-methyl-1,2,3,4-tetrahydroquinoline (1.2 g, 5.31 mmol) in 1,4-dioxane (6 mL) and water (6 mL) was added potassium hexacyanoferrate(II) trihydrate (1.57 g, 2.65 mmol), methanesulfonato(2-di-tert-butylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (422 mg, 0.53 mmol), 2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (225 mg, 0.53 mmol) and KOAc (65 mg, 0.66 mmol). The mixture was heated to 100° C. for 1 h under a nitrogen atmosphere. After cooling the reaction to room temperature, the reaction was filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc=5:1) to give the title compound (780 mg, 85%) as a yellow solid. LCMS M/Z (M+H) 173.
-
- To a solution of 3-methyl-1,2,3,4-tetrahydroquinoline-7-carbonitrile (430 mg, 2.5 mmol) in 1,4-dioxane (10 mL) was added (S)-1-(3-bromo-1-(tetrahydrofuran-3-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone (Intermediate G, 784 mg, 2.50 mmol), chloro(2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl)[2-(2-aminoethylphenyl)]palladium(II), methyl-tert-butylether adduct (182 mg, 0.25 mmol), t-BuONa (720 mg, 7.49 mmol) and 2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl (117 mg, 0.25 mmol). The mixture was heated to 120° C. for 12 h under a nitrogen atmosphere. After cooling the reaction to room temperature, the mixture was concentrated in vacuo. The crude residue was purified by silica gel chromatography (DCM/MeOH=20:1) to give the title compound (800 mg, 42%) as a yellow oil. LCMS M/Z (M+H) 406.
-
- To a solution of 1-(5-acetyl-1-((S)-tetrahydrofuran-3-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-3-methyl-1,2,3,4-tetrahydroquinoline-7-carbonitrile (800 mg, 1.05 mmol) in MeCN (6 mL) at 0° C. was N-bromosuccinimide (186 mg, 1.05 mmol). The mixture was stirred at 0° C. for 2 h under a nitrogen atmosphere. The mixture was concentrated in vacuo. The crude residue was purified by silica gel chromatography (DCM/MeOH=16:1) to give the title compound (600 mg, 56%) as yellow oil. LCMS M/Z (M+H) 486.
-
- To a solution of 1-(5-acetyl-1-((S)-tetrahydrofuran-3-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-6-bromo-3-methyl-1,2,3,4-tetrahydroquinoline-7-carbonitrile (600 mg, 0.74 mmol) in THF (5 mL) and water (1 mL) was added 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (309.27 mg, 1.49 mmol), chloro(2-dicyclohexylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl) palladium(II) (58 mg, 0.07 mmol), Na2CO3 (236 mg, 2.23 mmol) and 2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (35 mg, 0.07 mmol). The mixture was heated to 60° C. for 12 h under a nitrogen atmosphere. After cooling the reaction to room temperature, the reaction was filtered and concentrated in vacuo. The crude residue was purified by reverse phase chromatography (acetonitrile 15-45%/0.1% NH4HCO3 in water) to give the title compound (150 mg, 37%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.88-7.83 (m, 1H), 7.76-7.75 (m, 1H), 7.21-7.16 (m, 1H), 6.73-6.70 (m, 1H), 4.80-4.78 (m, 1H), 4.26-4.11 (m, 4H), 4.05-3.90 (m, 6H), 3.79-3.78 (m, 1H), 3.75-3.60 (m, 1H), 3.30-3.25 (m, 1H), 2.91-2.78 (m, 3H), 2.60-2.50 (m, 1H), 2.42-2.39 (m, 1H), 2.18-2.08 (m, 4H), 1.12-1.08 (m, 3H). LCMS M/Z (M+H) 486.
- The following compound was prepared in a similar fashion to Example 84:
-
-
Example Compound Name NMR m/z Example 85 1-(5-acetyl-1- 1H NMR (400 MHz, DMSO-d6) δ 8.05 (s, 500 (tetrahydro-2H-pyran- 1H), 7.79 (s, 1H), 7.34 (s, 1H), 6.72-6.68 4-yl)-4,5,6,7- (m, 1H), 4.34-4.26 (m, 1H), 4.18-4.16 tetrahydro-1H- (m, 2H), 3.96-3.93 (m, 2H), 3.87 (s, 3H), pyrazolo[4,3-c]pyridin- 3.73-3.71 (m, 2H), 3.58-3.48 (m, 2H), 3-yl)-3-methyl-6-(1- 3.35-3.15 (m, 2H), 2.88-2.74 (m, 2H), methyl-1H-pyrazol-4- 2.56-2.54 (m, 2H), 2.08-1.95 (m, 6H), yl)-1,2,3,4- 1.84-1.81 (m, 2H), 1.04-1.02 (m, 3H) tetrahydroquinoline-7- carbonitrile -
-
- To a solution of 3-quinolinecarbaldehyde (6.0 g, 38.2 mmol) in MeOH (60 mL) at 0° C. was added NaBH4 (1.73 g, 45.8 mmol) portionwise. The mixture was stirred at room temperature for 4 h. The reaction was quenched with water (100 mL), concentrated in vacuo and extracted with EtOAc (100 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (5.6 g, crude) as yellow oil that required no further purification. 1H NMR (400 MHz, DMSO-d6) δ 8.88 (s, 1H), 8.23 (s, 1H), 8.03-7.95 (m, 2H), 7.74-7.70 (m, 1H), 7.60-7.57 (m, 1H), 5.53 (s, 1H), 4.73 (d, J=2.8 Hz, 2H).
-
- To a solution of 3-quinolylmethanol (5.6 g, 35.2 mmol) and NaBH3CN (11.1 g, 175.9 mmol) in MeOH (60 mL) at 0° C. was added boron trifluoride diethyl etherate (28.5 mL, 105.5 mmol) dropwise. The mixture was heated to 70° C. for 12 h under a nitrogen atmosphere. After cooling the reaction to room temperature, the reaction was quenched with sat. aq. NaHCO3 (100 mL), the organic layer was removed and the aqueous layer was extracted with EtOAc (100 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc=20:1 to 4:1) to give (1,2-dihydroquinolin-3-yl)methanol (2.6 g, 46%). The resulting compound was dissolved in MeOH (25 mL) and 10% Pd/C (1.7 g, 1.61 mmol) was added. The mixture was stirred at 25° C. for 12 h under a hydrogen atmosphere (15 psi). The reaction was filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc=9:1 to 2:1) to give the title compound (840 mg, 32%) as a light yellow oil. 1H NMR (400 MHz, DMSO-d6) δ 6.83-6.80 (m 2H), 6.42-6.37 (m, 2H), 5.59 (s, 1H), 4.62-4.59 (m, 1H), 3.41-3.40 (m, 1H), 3.33-3.29 (m, 2H), 2.86-2.84 (m, 1H), 2.63-2.62 (m, 1H), 2.39-2.33 (m, 1H), 1.89-1.85 (m, 1H).
-
- To a solution of 1,2,3,4-tetrahydroquinolin-3-ylmethanol (840 mg, 5.15 mmol) and imidazole (1.75 g, 25.7 mmol) in THF (40 mL) was added tert-butyl-dimethylsilyl chloride (1.71 g, 11.3 mmol) dropwise. The mixture was stirred at room temperature for 16 h. Brine (40 mL) was added and the mixture was extracted with EtOAc (40 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc=40:1 to 9:1) to give the title compound (1.2 g, 84%) as yellow oil. LCMS M/Z (M+H) 365.
-
- To a solution of 1-[3-bromo-1-[(3S)-tetrahydrofuran-3-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (Intermediate G, 1.2 g, 3.82 mmol) in 1,4-dioxane (12 mL) was added tert-butoxysodium (532 mg, 5.54 mmol), tert-butyl-dimethyl-(1,2,3,4-tetrahydroquinolin-3-ylmethoxy)silane (615 mg, 2.22 mmol), chloro(2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl)[2-(2-aminoethylphenyl)]palladium(II), methyl-tert-butylether adduct (375 mg, 0.46 mmol) and 2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl (214 mg, 0.46 mmol). The mixture was heated to 120° C. for 16 h under a nitrogen atmosphere. After cooling the reaction to room temperature, the reaction was filtered and the filtrate was concentrated in vacuo. The crude residue was purified by silica gel chromatography (DCM/MeOH=100:1) to give the title compound (1.2 g, 61%) as yellow oil. LCMS M/Z (M+H) 511.
-
- To a solution of 1-[3-[3-[[tert-butyl(dimethyl)silyl]oxymethyl]-3,4-dihydro-2H-quinolin-1-yl]-1-[(3S)-tetrahydrofuran-3-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (1.2 g, 2.35 mmol) in DCM (90 mL) at 0° C. was added N-bromosuccinimide (376 mg, 2.11 mmol) dropwise. The mixture was stirred at 0° C. for 0.5 h, quenched with water (100 mL), and extracted with DCM (100 mL×2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (DCM/MeOH=50:1 to 20:1) to give the title compound (1.16 g, 84%) as light yellow oil. LCMS M/Z (M+H) 591.
-
- To a solution of 1-[3-[6-bromo-3-[[tert-butyl(dimethyl)silyl]oxymethyl]-3,4-dihydro-2H-quinolin-1-yl]-1-[(3S)-tetrahydrofuran-3-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (0.6 g, 1.02 mmol) in 1,4-dioxane (4 mL) and water (1 mL) was added Na2CO3 (324 mg, 3.05 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (254 mg, 1.22 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (85 mg, 0.10 mmol). The mixture was heated to 120° C. for 16 h under a nitrogen atmosphere. After cooling the reaction to room temperature, the mixture was filtered and the filtrate was concentrated in vacuo. The crude residue was purified by silica gel chromatography (DCM/MeOH=50:1 to 20:1) to give the title compound (340 mg, 57%) as a yellow oil. LCMS M/Z (M+H) 591.
-
- To a solution of 1-[3-[3-[[tert-butyl(dimethyl)silyl]oxymethyl]-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-1-[(3S)-tetrahydrofuran-3-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (340 mg, 0.58 mmol) in THF (2 mL) was added tetrabutylammonium fluoride (1.0 M in THF, 0.69 mL, 0.69 mmol). The mixture was heated to 80° C. for 16 h under a nitrogen atmosphere. After cooling the reaction to room temperature, water (10 mL) was added and the mixture was extracted with EtOAc (5 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by reverse phase chromatography (acetonitrile 23-53%/0.1% NH4OH in water) to give the title compound (102 mg, 37%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.92 (s, 1H), 7.68 (s, 1H), 7.21 (s, 1H), 7.13-7.10 (m, 1H), 6.45-6.39 (m, 1H), 4.95-4.70 (m, 1H), 4.68 (br s, 1H), 4.08-3.96 (m, 4H), 3.82-3.67 (m, 7H), 3.45-3.50 (m, 2H), 3.27-3.25 (m, 2H), 2.83-2.62 (m, 3H), 2.54-2.52 (m, 1H), 2.33-2.25 (m, 2H), 2.06-1.93 (m, 4H). LCMS M/Z (M+H) 477.
- The following compound was prepared in a similar fashion to Example 86:
-
-
Example Compound Name NMR m/z Example 87 1-[3-[4- 1H NMR (400 MHz, DMSO-d6) δ 7.92 (s, 477 (hydroxymethyl)-6-(1- 1H), 7.68 (s, 1H), 7.29 (s, 1H), 7.14-7.10 methylpyrazol-4-yl)- (m, 1H), 6.46-6.39 (m, 1H), 4.90-4.83 3,4-dihydro-2H- (m, 2H), 4.07-3.80 (m, 4H), 3.69-3.60 quinolin-1-yl]-1- (m, 7H), 3.55-3.48 (m, 2H), 3.31-3.25 tetrahydrofuran-3-yl- (m, 2H), 2.89-2.83 (m, 2H), 2.73-2.65 6,7-dihydro-4H- (m, 1H), 2.28-2.23 (m, 2H), 2.06-1.93 pyrazolo[4,3-c]pyridin- (m, 5H). 5-yl]ethanone -
- Racemic 1-[3-[3-(hydroxymethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-1-tetrahydrofuran-3-yl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (Example 86, 76 mg) was separated using chiral SFC (SFC80; Chiralpak AD 250×30 mm I.D., 5 um; Supercritical CO2/MeOH+NH3.H2O=55/45; 50 mL/min) to give (S,R)-1-[3-[3-(hydroxymethyl)-6-(1-methylpyrazol-4-yl)-3, 4-dihydro-2H-quinolin-1-yl]-1-tetrahydrofuran-3-yl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (24 mg, first peak) and (S,S)-1-[3-[3-(hydroxymethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-1-tetrahydrofuran-3-yl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (24 mg, second peak). Absolute configuration was arbitrarily assigned to each diastereomer. Example 88: 1H NMR (400 MHz, DMSO-d6) δ 7.91 (s, 1H), 7.67 (s, 1H), 7.21 (s, 1H), 7.13-7.09 (m, 1H), 6.45-6.39 (m, 1H), 4.92-4.88 (m, 1H), 4.68-4.67 (m, 1H), 4.08-3.98 (m, 4H), 3.82-3.69 (m, 7H), 3.67-3.45 (m, 1H), 3.42-3.39 (m, 2H), 3.25-3.20 (m, 1H), 2.83-2.60 (m, 3H), 2.55-2.53 (m, 1H), 2.28-2.25 (m, 2H), 2.06-1.93 (m, 4H). LCMS M/Z (M+H) 477. Example 89: 1H NMR (400 MHz, DMSO-d6) δ 7.91 (s, 1H), 7.67 (s, 1H), 7.21 (s, 1H), 7.13-7.09 (m, 1H), 6.45-6.39 (m, 1H), 4.92-4.88 (m, 1H), 4.68-4.67 (m, 1H), 4.08-3.98 (m, 4H), 3.82-3.69 (m, 7H), 3.67-3.45 (m, 1H), 3.42-3.39 (m, 2H), 3.25-3.20 (m, 1H), 2.83-2.60 (m, 3H), 2.55-2.53 (m, 1H), 2.28-2.24 (m, 2H), 2.06-1.93 (m, 4H). LCMS M/Z (M+H) 477.
-
- Racemic 1-[3-[4-(hydroxymethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-1-tetrahydrofuran-3-yl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (Example 87, 100 mg) was separated using chiral SFC (Chiralpak AD 250×30 mm I.D., 5 um; Supercritical CO2/MeOH+NH3.H2O=55/45; 25 mL/min) to give (S,S)-1-[3-[4-(hydroxymethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-1-tetrahydrofuran-3-yl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (30 mg, first peak) and (S,R)-1-[3-[4-(hydroxymethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-1-tetrahydrofuran-3-yl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (34 mg, second peak). Absolute configuration was arbitrarily assigned to each diastereomer. Example 90: 1H NMR (400 MHz, DMSO-d6) δ 7.92 (s, 1H), 7.68 (s, 1H), 7.29 (s, 1H), 7.14-7.10 (m, 1H), 6.45-6.39 (m, 1H), 4.90-4.83 (m, 2H), 4.07-3.80 (m, 4H), 3.69 (s, 3H), 3.68-3.60 (m, 8H), 2.89-2.83 (m, 2H), 2.73-2.65 (m, 1H), 2.28-2.24 (m, 2H), 2.06-1.92 (m, 5H). LCMS M/Z (M+H) 477. Example 91: 1H NMR (400 MHz, DMSO-d6) δ 7.91 (s, 1H), 7.67 (s, 1H), 7.28 (s, 1H), 7.13-7.09 (m, 1H), 6.42-6.38 (m, 1H), 4.92-4.87 (m, 2H), 3.69 (s, 3H), 3.68-3.60 (m, 8H), 2.89-2.83 (m, 2H), 2.73-2.60 (m, 1H), 2.26-2.21 (m, 2H), 2.05-1.84 (m, 5H). LCMS M/Z (M+H) 477.
-
- To a solution of 1-[3-[3-(hydroxymethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2-quinolin-1-yl]-1-[(3S)-tetrahydrofuran-3-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (190 mg, 0.40 mmol) in DMF (1 mL) at 0° C. was added NaH (60%, 19 mg, 0.48 mmol). The mixture was stirred at 0° C. for 1 h under a nitrogen atmosphere. MeI (68 mg, 0.48 mmol) was added dropwise at 0° C. The mixture was stirred at 25° C. for an additional 2 h. The reaction mixture was quenched with water (2 mL) and extracted with EtOAc (2 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by reverse phase chromatography (acetonitrile 27-57%/0.1% NH4OH in water) to give the title compound (24 mg, 14%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.92 (s, 1H), 7.68 (s, 1H), 7.22 (s, 1H), 7.14-7.10 (m, 1H), 6.45-6.39 (m, 1H), 4.93-4.87 (m, 1H), 4.09-4.08 (m, 2H), 4.01-3.96 (m, 2H), 3.82-3.80 (m, 5H), 3.74-3.62 (m, 2H), 3.37-3.25 (m, 7H), 2.85-2.84 (m, 2H), 2.70-2.55 (m, 2H), 2.29-2.25 (m, 3H), 2.06-1.94 (m, 3H). LCMS M/Z (M+H) 491.
-
-
- To a solution of 1,2,3,4-tetrahydroquinoxaline (50 g, 372.6 mmol) in THF (200 mL) and water (50 mL) was added sodium hydroxide (29.8 g, 745.3 mmol) and di-tert-butyl dicarbonate (89.5 g, 409.9 mmol). The mixture was stirred at the room temperature for 16 h. After completion of the reaction, water (20 mL) was added and the mixture was extracted with DCM (200 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc=20:1 to 4:1) to give the title compound (17.0 g, 20%) as a yellow solid.
-
- To a solution of tert-butyl 3,4-dihydro-2H-quinoxaline-1-carboxylate (17 g, 72.6 mmol) in MeCN (150 mL) was added N-bromosuccinimide (12.3 g, 68.9 mmol) by portionwise at 0° C. The mixture was stirred at 0° C. for 1 h. The reaction was quenched with water (200 mL), extracted with EtOAc (200 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc=20:1 to 4:1) to give the title compound (14.0 g, 62%) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 7.50 (s, 1H), 6.95-6.92 (m, 1H), 6.52-6.50 (m, 1H), 6.29 (s, 1H), 3.58-3.56 (m, 2H), 3.24-3.23 (m, 2H), 1.45 (s, 9H).
-
- To a solution of tert-butyl 7-bromo-3,4-dihydro-2H-quinoxaline-1-carboxylate (14 g, 44.7 mmol) in THF (75 mL) and water (15 mL) was added [2-(2-aminophenyl)phenyl]-chloro-palladium-dicyclohexyl-[3-(2,4,6-triisopropylphenyl)phenyl]phosphane (3.5 g, 4.47 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (11.2 g, 53.6 mmol), Na2CO3 (14.2 g, 134.1 mmol) and dicyclohexyl-[3-(2,4,6-triisopropylphenyl)phenyl]phosphane (2.2 g, 4.5 mmol). The mixture was heated to 60° C. for 16 h. Water (20 mL) was added and the mixture was extracted with DCM (60 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc=20:1 to 3:1) to give the title compound (7.7 g, 55%) as a yellow solid. LCMS M/Z (M+H) 315.
-
- To a solution of 1-[3-bromo-1-[(3S)-tetrahydrofuran-3-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (Intermediate G, 6.5 g, 20.7 mmol) in 1,4-dioxane (40 mL) was added [2-(2-aminoethyl)phenyl]-chloro-palladium, dicyclohexyl-[2-(2,6-diisopropoxyphenyl)phenyl]phosphane (1.5 g, 2.1 mmol), tert-butoxysodium (5.96 g, 62.1 mmol), dicyclohexyl-[2-(2,6-diisopropoxyphenyl)phenyl]phosphane (965 mg, 2.1 mmol) and tert-butyl 7-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinoxaline-1-carboxylate (7.2 g, 22.8 mmol). The mixture was heated to 110° C. for 16 h under a nitrogen atmosphere. After cooling the reaction to room temperature, the reaction was filtered and concentrated. The crude residue was purified by silica gel chromatography (DCM/MeOH=20:1) to give the title compound (7 g, 53%) as a yellow solid. LCMS M/Z (M+H) 548.
-
- To a solution of tert-butyl 4-[5-acetyl-1-[(3S)-tetrahydrofuran-3-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-3-yl]-7-(1-methylpyrazol-4-yl)-2,3-dihydroquinoxaline-1-carboxylate (7 g, 12.8 mmol) in MeOH (25 mL) at 0° C. was added HCl in MeOH (4 M, 6.4 mL, 25.6 mmol) dropwise. The mixture was stirred at 0° C. for 2 h and then concentrated in vacuo. Water (30 mL) was added and the mixture was made basic with sat. aq. NaHCO3 to pH 7 and then extracted with EtOAc (30 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give crude product (3.9 g) as a brown solid. The crude product (200 mg) was purified by reverse phase chromatography (acetonitrile 18-48%/0.1% NH4HCO3 in water) to give the title compound (103 mg) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.82 (s, 1H), 7.58 (s, 1H), 6.66 (s, 1H), 6.58-6.55 (m, 1H), 6.40-6.34 (m, 1H), 5.75 (s, 1H), 4.89-4.84 (m, 1H), 4.08-4.07 (m, 2H), 3.99-3.97 (m, 2H), 3.81-3.79 (m, 5H), 3.70-3.55 (m, 2H), 3.55-3.53 (m, 2H), 3.33-3.31 (m, 2H), 2.81-2.62 (m, 2H), 2.26-2.23 (m, 2H), 2.05-1.92 (m, 3H). LCMS M/Z (M+H) 448.
- The following compound was prepared in a similar fashion to Example 93:
-
-
Example Compound Name NMR m/z Example 94 1-[3-(3,4-dihydro-2H- 1H NMR (400 MHz, DMSO-d6) δ 6.73- 354 quinoxalin-1-yl)-1- 6.53 (m, 4H), 5.28-5.19 (m, 3H), 4.95- (oxetan-3-yl)-6,7- 4.92 (m, 2H), 4.23-4.05 (m, 2H), 4.02- dihydro-4H- 3.90 (m, 1H), 3.87-3.78 (m, 4H), 3.51- pyrazolo[4,3-c]pyridin- 3.49 (m, 2H), 2.74-2.63 (m, 2H), 2.13- 5-yl]ethanone 1.99 (m, 3H) -
- To a solution of 1-[3-[6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinoxalin-1-yl]-1-[(3S)-tetrahydrofuran-3-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (Example 93, 220 mg, 0.49 mmol) in DMF (2 mL) at 0° C. was added NaH (60%, 24 mg, 0.59 mmol). The mixture was stirred at 0° C. for 1 h, then MeI (0.04 mL, 0.59 mmol) was added. The mixture was stirred at room temperature for 4 h. The reaction was quenched with water (5 mL) and extracted with EtOAc (5 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by reverse phase chromatography (
acetonitrile 50%/0.1% NH4OH in water) to give the title compound (30 mg, 13%) as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ 7.94 (s, 1H), 7.68 (s, 1H), 6.74 (s, 1H), 6.70-6.66 (m, 1H), 6.38-6.32 (m, 1H), 4.90-4.85 (m, 1H), 4.06-4.05 (m, 2H), 3.99-3.98 (m, 2H), 3.82-3.79 (m, 5H), 3.68-3.65 (m, 4H), 3.30-3.29 (m, 2H), 2.91 (s, 3H), 2.81-2.65 (m, 2H), 2.29-2.23 (m, 2H), 2.05-1.92 (m, 3H). LCMS M/Z (M+H) 462. -
-
- To a solution of 5-quinolinamine (9 g, 62.4 mmol) in water (80 mL) at 0° C. was added concentrated HCl (5.2 mL, 62.4 mmol) and NaNO2 (6.5 g, 93.6 mmol) portionwise. The mixture was stirred at 0° C. for 1 h, then a solution of CuCl (9.2 g, 93.7 mmol) in concentrated HCl (5.2 mL, 62.4 mmol) was added dropwise at 0° C. After stirring at 0° C. for 2 h, the mixture was made basic with sat. aq. NaHCO3 to pH 7 and then extracted with EtOAc (100 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc=9:1 to 5:1) to give the title compound (9.2 g, 90%) as clear oil. 1H NMR (400 MHz, DMSO-d6) δ 8.99-8.98 (m, 1H), 8.51 (d, J=8.0 Hz, 1H), 8.01 (d, J=8.0 Hz, 1H), 7.77-7.73 (m, 2H), 7.68-7.65 (m, 1H).
-
- To a solution of 5-chloroquinoline (5.0 g, 30.7 mmol), NaBH3CN (7.7 g, 122.3 mmol) in EtOH (200 mL) at 0° C. was added conc. HCl (10.2 mL, 122.3 mmol) dropwise. The reaction was allowed to stir at room temperature for 15 min, and then heated to 60° C. for 2 h. After cooling the reaction to room temperature, the mixture was basified with NaOH (2 N) to pH 9 and then extracted with EtOAc (200 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc=9:1) to give the title compound (4.88 g, 95%) as a light yellow oil. 1H NMR (400 MHz, DMSO-d6) δ 6.85-6.81 (m, 1H), 6.49 (d, J=8.0 Hz, 1H), 6.41 (d, J=8.0 Hz, 1H), 5.98 (s, 1H), 3.15-3.12 (m, 2H), 2.65 (t, J=6.4 Hz, 2H), 1.83-1.79 (m, 2H).
-
- To a solution of 1-[3-bromo-1-[(3S)-tetrahydrofuran-3-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (Intermediate G, 1.0 g, 3.2 mmol) in 1,4-dioxane (10 mL) was added 5-chloro-1,2,3,4-tetrahydroquinoline (0.64 g, 3.8 mmol), t-BuONa (0.92 g, 9.6 mmol), tris(dibenzylideneacetone)dipalladium (0.29 g, 0.32 mmol) and (5-diphenylphosphanyl-9,9-dimethyl-xanthen-4-yl)-diphenyl-phosphane (0.37 g, 0.64 mmol). The mixture was heated to 110° C. for 16 h under a nitrogen atmosphere. After cooling the reaction to room temperature, the reaction was filtered and concentrated in vacuo. The crude residue was purified by reverse phase chromatography (acetonitrile 70%-40%/0.1% NH4OH in water) to give the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 6.96-6.90 (m, 1H), 6.75 (d, J=8.0 Hz, 1H), 6.41-6.35 (m, 1H), 4.93-4.87 (m, 1H), 4.09-4.08 (m, 2H), 4.02-3.93 (m, 2H), 3.81-3.68 (m, 4H), 3.55-3.50 (m, 2H), 2.83-2.71 (m, 4H), 2.33-2.20 (m, 2H), 2.06-1.94 (m, 5H). LCMS M/Z (M+H) 401.
-
-
- To a solution of 1-[3-(5-chloro-3,4-dihydro-2H-quinolin-1-yl)-1-[(3S)-tetrahydrofuran-3-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (880 mg, 1.67 mmol) in DCM (6 mL) at 0° C. was added N-bromosuccinimide (281 mg, 1.6 mmol) portionwise. The mixture was stirred at 25° C. for 0.5 h and then concentrated in vacuo. The crude residue was purified by silica gel chromatography (DCM/MeOH=50:1 to 20:1) to give the title compound (1 g, 95%) as a yellow solid. LCMS M/Z (M+H) 481.
-
- To a solution of 1-[3-(6-bromo-5-chloro-3,4-dihydro-2H-quinolin-1-yl)-1-[(3S)-tetrahydrofuran-3-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (1.0 g, 2.1 mmol) in 1,4-dioxane (8 mL) and water (2 mL) was added Na2CO3 (663 mg, 6.3 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (477 mg, 2.3 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (152 mg, 0.21 mmol). The mixture was heated to 100° C. for 16 h under a nitrogen atmosphere. After cooling the reaction to room temperature, the mixture was filtered and the filtrate was concentrated in vacuo. The crude residue was purified by reverse phase chromatography (acetonitrile 40-70%/0.1% NH4OH in water) to give the title compound (430 mg, 32%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.94 (s, 1H), 7.63 (s, 1H), 7.13-7.08 (m, 1H), 6.47-6.41 (m, 1H), 4.95-4.85 (m, 1H), 4.12-4.10 (m, 2H), 4.01-3.99 (m, 2H), 3.86-3.69 (m, 7H), 3.58-3.48 (m, 2H), 2.87-2.68 (m, 4H), 2.32-2.15 (m, 2H), 2.07-1.96 (m, 5H). LCMS M/Z (M+H) 481.
- The following compound was prepared in a similar fashion to Example 97:
-
-
Example Compound Name NMR m/z Example 98 1-[3-[5-fluoro-6-(1- 1H NMR (400 MHz, DMSO-d6) δ 7.94 (s, 465 methylpyrazol-4-yl)- 1H), 7.71 (s, 1H), 7.25-7.19 (m, 1H), 6.35- 3,4-dihydro-2H- 6.24 (m, 1H), 4.96-4.85 (m, 1H), 4.16- quinolin-1-yl]-1-[(3S)- 4.08 (m, 2H), 4.06-3.91 (m, 2H), 3.89- tetrahydrofuran-3-yl]- 3.65 (m, 7H), 3.58-3.48 (m, 2H), 2.88- 6,7-dihydro-4H- 2.66 (m, 4H), 2.35-2.17 (m, 2H), 1.96 (s, pyrazolo[4,3-c]pyridin- 2H), 2.07 (s, 3H) 5-yl]ethanone -
-
- To a solution of 3-bromoquinoline (10.0 g, 48.06 mmol) was added diethyl zinc (1M in THF, 192 mL, 192 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.8 g, 4.81 mmol) in THF (100 mL). The mixture was heated to 70° C. for 16 h under a nitrogen atmosphere. After cooling the reaction to room temperature, saturated aqueous NH4Cl (50 mL) was added and the mixture was extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc=9:1) to give the title compound (5.2 g, 68%) as brown oil. 1H NMR (400 MHz, DMSO-d6) δ 8.79 (s, 1H), 8.08 (d, J=8.8 Hz, 1H), 7.91 (s, 1H), 7.75 (d, J=8.0 Hz, 1H), 7.64 (t, J=8.0 Hz, 1H), 7.50 (t, J=7.6 Hz, 1H), 1.36-1.32 (m, 2H), 1.34 (t, J=7.6 Hz, 3H).
-
- To a solution of 3-ethylquinoline (5.2 g, 32.68 mmol) in MeOH (50 mL) was added NaBH3CN (6.2 g, 98.04 mmol) and boron trifluoride diethyl etherate (9.3 g, 65.36 mmol). The mixture was heated to 80° C. for 16 h. After cooling the reaction to room temperature, sat. aq. NaHCO3 (100 mL) was added and the mixture was extracted with EtOAc (100 mL×2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give 3-ethyl-1,2-dihydroquinoline (5.0 g, crude) as a brown oil. To a solution of 3-ethyl-1,2-dihydroquinoline (5.0 g, 30.83 mmol) in MeOH (50 mL) was added 10% Pd/C (1.0 g). The mixture was stirred at 30° C. under a hydrogen atmosphere (15 psi) for 16 h. The mixture was filtered and the filtrate was concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc=100:1) to give the title compound (1.8 g, 33%) as a brown oil.
-
- To a solution of 3-ethyl-1,2,3,4-tetrahydroquinoline (2.0 g, 12.30 mmol) in DCM (20 mL), N-bromosuccinimide (2.0 g, 11.10 mmol) was added. The mixture was stirred at 30° C. for 2 h and concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc=100:1) to give the title compound (2.0 g, 66%) as a brown solid.
-
- To a solution of 6-bromo-3-ethyl-1,2,3,4-tetrahydroquinoline (2.0 g, 5.50 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.4 g, 6.60 mmol) and K2CO3 (2.3 g, 16.49 mmol) in dioxane/H2O (25 mL, 4:1) was added [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (403 mg, 0.55 mmol). The mixture was heated to 110° C. for 16 h under a nitrogen atmosphere. After cooling the reaction to room temperature, the mixture was filtered and the filtrate was concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc=5:1) to give the title compound (600 mg, 46%) as a brown solid.
-
- To a solution of 3-ethyl-6-(1-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinoline (600 mg, 2.49 mmol) and (S)-1-(3-bromo-1-(tetrahydrofuran-3-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone (Intermediate G, 859 mg, 2.74 mmol) in dioxane (10 mL) was added chloro(2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl)[2-(2-aminoethylphenyl)]palladium(II), methyl-tert-butylether adduct (203 mg, 0.25 mmol), 2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl (116 mg, 0.25 mmol) and t-BuONa (716 mg, 7.46 mmol). The mixture was stirred at 120° C. for 16 h under a nitrogen atmosphere. After cooling the reaction to room temperature, the mixture was filtered and the filtrate was concentrated in vacuo. The crude residue was purified by reverse phase chromatography (acetonitrile 34-64%/0.1% NH4OH in water) to give the title compound (130 mg, 11%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.91 (s, 1H), 7.68 (s, 1H), 7.21 (s, 1H), 7.14-7.07 (m, 1H), 6.47-6.36 (m, 1H), 4.94-4.85 (m, 1H), 4.09 (s, 2H), 4.04-3.93 (m, 2H), 3.86-3.64 (m, 7H), 3.60 (d, J=11.6 Hz, 1H), 3.27-3.16 (m, 1H), 2.95-2.80 (m, 2H), 2.75-2.65 (m, 1H), 2.46 (s, 1H), 2.35-2.19 (m, 2H), 2.06 (s, 2H), 1.94 (s, 1H), 1.85 (s, 1H), 1.46-1.28 (m, 2H), 1.00-0.87 (m, 3H). LCMS M/Z (M+H) 475.
-
- Racemic 1-[3-[3-ethyl-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-1-tetrahydrofuran-3-yl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (Example 99, 104 mg) was separated using chiral SFC (SFC80; Chiralpak AD 250×30 mm I.D., 5 um; Supercritical CO2/MeOH+NH3.H2O=55/45; 50 mL/min) to give (S, R)-1-[3-[3-ethyl-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-1-tetrahydrofuran-3-yl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (26 mg, first peak) and (S, S)-1-[3-[3-ethyl-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-1-tetrahydrofuran-3-yl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (26 mg, second peak). Absolute configuration was arbitrarily assigned to each diastereomer. Example 100: 1H NMR (400 MHz, DMSO-d6) δ 7.91 (s, 1H), 7.68 (s, 1H), 7.21 (s, 1H), 7.14-7.07 (m, 1H), 6.47-6.36 (m, 1H), 4.94-4.85 (m, 1H), 4.09 (s, 2H), 4.04-3.93 (m, 2H), 3.86-3.64 (m, 7H), 3.60 (d, J=11.6 Hz, 1H), 3.27-3.16 (m, 1H), 2.95-2.80 (m, 2H), 2.75-2.65 (m, 1H), 2.46 (s, 1H), 2.35-2.19 (m, 2H), 2.06 (s, 2H), 1.94 (s, 1H), 1.85 (s, 1H), 1.46-1.28 (m, 2H), 1.00-0.87 (m, 3H). LCMS M/Z (M+H) 475. Example 101: 1H NMR (400 MHz, DMSO-d6) δ 7.91 (s, 1H), 7.68 (s, 1H), 7.21 (s, 1H), 7.14-7.07 (m, 1H), 6.47-6.36 (m, 1H), 4.94-4.85 (m, 1H), 4.09 (s, 2H), 4.04-3.93 (m, 2H), 3.86-3.64 (m, 7H), 3.60 (d, J=11.6 Hz, 1H), 3.27-3.16 (m, 1H), 2.95-2.80 (m, 2H), 2.75-2.65 (m, 1H), 2.46 (s, 1H), 2.35-2.19 (m, 2H), 2.06 (s, 2H), 1.94 (s, 1H), 1.85 (s, 1H), 1.46-1.28 (m, 2H), 1.00-0.87 (m, 3H). LCMS M/Z (M+H) 475.
-
-
- To a solution of 7-chloro-4-methyl-quinoline (5 g, 28.15 mmol) and sodium cyanoborohydride (5.31 g, 84.45 mmol) in MeOH (60 mL) was added boron trifluoride diethyl etherate (3.41 mL, 56.3 mmol) dropwise. The mixture was heated to 70° C. for 16 h under a nitrogen atmosphere. After cooling the reaction to room temperature, the mixture was concentrated in vacuo. EtOAc (100 mL) was added and the mixture was washed with water (100 mL×2) and brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc=20:1) to give the title compound (3 g, 53%) as brown solid.
-
- To a solution of 1-[3-bromo-1-[(3S)-tetrahydrofuran-3-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (Intermediate G, 5.19 g, 16.51 mmol) in 1,4-dioxane (40 mL) was added 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (1.91 g, 3.3 mmol), cesium carbonate (16.14 g, 49.54 mmol), 7-chloro-4-methyl-1,2,3,4-tetrahydroquinoline (3.33 g, 16.51 mmol) and tris(dibenzylideneacetone) dipalladium(0) (1.51 g, 1.65 mmol). The mixture was heated to 120° C. for 16 h under a nitrogen atmosphere. After cooling the reaction to room temperature, the mixture was filtered and the filtrate was concentrated in vacuo. The crude residue was purified by silica gel chromatography (DCM/MeOH=50:1) to give the title compound (3.1 g, 27%) as a brown solid.
-
- To a solution of 1-[3-(7-chloro-4-methyl-3,4-dihydro-2H-quinolin-1-yl)-1-[(3S)-tetrahydrofuran-3-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (3.4 g, 4.92 mmol) in DCM (30 mL) at 0° C. was added N-bromosuccinimide (788 mg, 4.42 mmol). The mixture was stirred at 26° C. for 16 h and then stirred at 30° C. for 0.5 h. The mixture was concentrated in vacuo. The crude residue was purified by silica gel chromatography (DCM/MeOH=20:1) to give the title compound (2.7 g, 89%) as a brown solid.
-
- To a solution of 1-[3-(6-bromo-7-chloro-4-methyl-3,4-dihydro-2H-quinolin-1-yl)-1-[(3S)-tetrahydrofuran-3-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (1.5 g, 3.04 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (758 mg, 3.65 mmol) in 1,4-dioxane (15 mL) and water (3 mL) was added potassium carbonate (1.26 g, 9.11 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (222 mg, 0.300 mmol). The mixture was heated to 120° C. for 16 h under a nitrogen atmosphere. After cooling the reaction to room temperature, the mixture was concentrated in vacuo. The crude residue was purified by silica gel chromatography (DCM/MeOH=20:1) to give the crude product (900 mg) as a brown solid. The crude product (50 mg) was purified by Prep-TLC (DCM/MeOH=20:1) to give the title compound (18 mg) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.97 (s, 1H), 7.70 (s, 1H), 7.26 (s, 1H), 6.56-6.45 (m, 1H), 4.92 (s, 1H), 4.21-4.10 (m, 2H), 4.07-3.96 (m, 2H), 3.89-3.66 (m, 7H), 3.62-3.50 (m, 2H), 3.00-2.70 (m, 3H), 2.30-2.17 (m, 2H), 2.12-1.93 (m, 4H), 1.70 (d, J=6.0 Hz, 1H), 1.34-1.20 (m, 3H). LCMS M/Z (M+H) 495.
-
- To a solution of 1-[3-[7-chloro-4-methyl-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-1-[(3S)-tetrahydrofuran-3-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (200 mg, 0.36 mmol) in 1,4-dioxane (2 mL) and water (2 mL) was added KOAc (4.46 mg, 0.05 mmol), potassium hexacyanoferrate(II) trihydrate (72 mg, 0.22 mmol), methanesulfonato(2-di-tert-butylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (32 mg, 0.04 mmol) and 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (28 mg, 0.04 mmol). The mixture was heated to 110° C. for 1 h under a nitrogen atmosphere. After cooling the reaction to room temperature, the mixture was concentrated in vacuo. The crude residue was purified by Prep-TLC (DCM/MeOH=20:1) to give the title compound (110 mg, 62%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.09 (s, 1H), 7.82 (s, 1H), 7.42 (s, 1H), 6.80-6.71 (m, 1H), 4.94 (s, 1H), 4.16 (d, J=11.6 Hz, 2H), 4.05-3.93 (m, 2H), 3.89 (s, 3H), 3.85-3.70 (m, 4H), 3.64-3.53 (m, 2H), 3.07-2.98 (m, 1H), 2.89-2.72 (m, 2H), 2.34-2.22 (m, 2H), 2.11-1.97 (m, 4H), 1.80-1.70 (m, 1H), 1.37-1.28 (m, 3H). LCMS M/Z (M+H) 486.
-
- Racemic 1-(5-acetyl-1-tetrahydrofuran-3-yl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-3-yl)-4-methyl-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinoline-7-carbonitrile (Example 103, 150 mg) was separated using chiral SFC (Chiralpak AD 250 mm×30 mm I.D., 5 um; Supercritical CO2/MEOH+NH4OH=75/25; 60 mL/min) to give (S, S)-1-(5-acetyl-1-tetrahydrofuran-3-yl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-3-yl)-4-methyl-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinoline-7-carbonitrile (32 mg, first peak) and (S, R)-1-(5-acetyl-1-tetrahydrofuran-3-yl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-3-yl)-4-methyl-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinoline-7-carbonitrile (27 mg, second peak). Absolute configuration was arbitrarily assigned to each diastereomer. Example 104: 1H NMR (400 MHz, DMSO-d6) δ 8.09 (s, 1H), 7.82 (s, 1H), 7.42 (s, 1H), 6.80-6.71 (m, 1H), 4.94 (s, 1H), 4.16 (d, J=11.6 Hz, 2H), 4.05-3.93 (m, 2H), 3.89 (s, 3H), 3.85-3.70 (m, 4H), 3.64-3.53 (m, 2H), 3.07-2.98 (m, 1H), 2.89-2.72 (m, 2H), 2.34-2.22 (m, 2H), 2.11-1.97 (m, 4H), 1.80-1.70 (m, 1H), 1.37-1.28 (m, 3H). LCMS M/Z (M+H) 486. Example 105: 1H NMR (400 MHz, DMSO-d6) δ 8.09 (s, 1H), 7.82 (s, 1H), 7.42 (s, 1H), 6.80-6.71 (m, 1H), 4.94 (s., 1H), 4.16 (d, J=11.6 Hz, 2H), 4.05-3.93 (m, 2H), 3.89 (s, 3H), 3.85-3.70 (m, 4H), 3.64-3.53 (m, 2H), 3.07-2.98 (m, 1H), 2.89-2.72 (m, 2H), 2.34-2.22 (m, 2H), 2.11-1.97 (m, 4H), 1.80-1.70 (m, 1H), 1.37-1.28 (m, 3H). LCMS M/Z (M+H) 486.
-
-
- To a solution of 4-methylquinoline (5.0 g, 34.9 mmol) and NaBH3CN (8.78 g, 139.7 mmol) in MeOH (30 mL) was added boron trifluoride diethyl etherate (37 mL, 70 mmol) dropwise. The mixture was heated to 70° C. for 16 h under a nitrogen atmosphere. After cooling the reaction to room temperature, the reaction was quenched with sat. aq. NaHCO3 (10 mL) and the mixture was extracted with EtOAc (10 mL×3). The combined organic layers were washed with sat. aq. NaHCO3 (10 mL×3), dried over anhydrous Na2SO4 and concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc=10:1) to give the title compound (4.0 g, 78%) as colorless oil. LCMS M/Z (M+H) 148.
-
- To a solution of 4-methyl-1,2,3,4-tetrahydroquinoline (2.0 g, 13.6 mmol) in DCM (20.0 mL) was added N-bromosuccinimide (2.42 g, 13.6 mmol) in portionwise. The mixture was stirred at 30° C. for 3 h under a nitrogen atmosphere. After cooling the reaction to room temperature, the reaction was quenched with sat. aq. NaHCO3 (10 mL) and extracted with EtOAc (10 mL×3). The combined organic layers were washed with sat. aq. NaHCO3 (10 mL×3), dried over anhydrous Na2SO4 and concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc=20:1) to give the title compound (1.0 g, 33%) as a brown oil.
-
- To a stirred solution of 6-bromo-4-methyl-1,2,3,4-tetrahydroquinoline (750 mg, 3.32 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (830 mg, 3.98 mmol), K2CO3 (1.38 g, 10 mmol) in dioxane/H2O (8 mL, 3:1) was added [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (121 mg, 0.166 mmol). The mixture was heated to 120° C. for 12 h under a nitrogen atmosphere. After cooling the reaction to room temperature, water (10 mL) was added and the mixture was extracted with EtOAc (10 mL×3). The combined organic layers were washed with sat. aq. NaHCO3 (10 mL×3), dried over anhydrous Na2SO4 and concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc=5:1) to give the title compound (700 mg, 93%) as a light yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.63 (s, 1H), 7.46 (s, 1H), 7.14 (s, 1H), 7.08-7.05 (m, 1H), 6.48 (d, J=8.4 Hz, 1H), 3.90 (s, 3H), 3.33-3.26 (m, 2H), 3.93-3.90 (m, 1H), 2.00-1.97 (m, 1H), 1.70-1.66 (m, 1H), 1.31 (d, J=7.2 Hz, 3H).
-
- To a solution of 4-methyl-6-(1-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinoline (400 mg, 1.76 mmol), (S)-1-(3-bromo-1-(tetrahydrofuran-3-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone (634 mg, 2.11 mmol) and t-BuONa (507 mg, 5.28 mmol) in dioxane (5 mL) was added chloro(2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl)[2-(2-aminoethylphenyl)]palladium(II), methyl-tert-butylether adduct (72 mg, 0.088 mmol) and 2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl (39 mg, 0.088 mmol). The mixture was heated to 120° C. for 12 h under a nitrogen atmosphere. After cooling the reaction to room temperature, water (10 mL) was added and the mixture was extracted with EtOAc (10 mL×3). The combined organic layers were washed with sat. aq. NaHCO3 (10 mL×3), dried over anhydrous Na2SO4 and concentrated in vacuo. The crude residue was purified by reverse phase chromatography (acetonitrile 25-55%/0.1% NH4HCO3 in water) to give the title compound (200 mg, 25%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.68-7.65 (m, 1H), 7.51-7.49 (m, 1H), 7.23-7.19 (m, 1H), 7.10-7.05 (m, 1H), 6.54-6.50 (m, 1H), 4.78-4.74 (m, 1H), 4.27-3.89 (m, 10H), 3.71-3.55 (m, 2H), 2.30-2.72 (m, 3H), 2.45-2.35 (m, 2H), 2.15-1.77 (m, 4H), 1.79-1.77 (m, 1H), 1.38-1.36 (m, 3H). LCMS M/Z (M+H) 461.
- The following compounds were prepared in a similar fashion to Example 106:
-
-
Example Compound Name NMR m/z Example 107 1-[3-[4-methyl-6-(1- 1H NMR (400 MHz, DMSO-d6) δ 7.93 (s, 447 methylpyrazol-4-yl)- 1H), 7.68 (s, 1H), 7.28 (s, 1H), 7.13-7.09 3,4-dihydro-2H- (m, 1H), 6.49-6.42 (m, 1H), 5.46-5.40 quinolin-1-yl]-1- (m, 1 H), 4.92-4.87 (m, 2H), 4.85-4.81 (oxetan-3-yl)-6,7- (m, 2H), 4.01-3.80 (m, 2H), 3.80 (s, 3H), dihydro-4H- 3.39-3.57 (m, 4H), 2.96-2.91 (m, 1H), pyrazolo[4,3- 2.75-2.62 (m, 2H), 2.02-1.89 (m, 4H), c]pyridin-5- 1.71-1.66 (m, 1H), 1.31 (d, J = 6.8 Hz, yl]ethanone 3H) Example 108 1-[3-[4-ethyl-6-(1- 1H NMR (400 MHz, CDCl3) δ 7.66-7.64 475 methylpyrazol-4-yl)- (m, 1H), 7.50-7.47 (m, 1H), 7.18-7.04 3,4-dihydro-2H- (m, 2H), 6.54-6.49 (m, 1H), 4.75-4.73 quinolin-1-yl]-1- (m, 1H), 4.17-4.10 (m, 3H), 4.00-3.90 tetrahydrofuran-3-yl- (m, 7H), 3.71-3.64 (m, 3H), 2.72-2.70 6,7-dihydro-4H- (m, 3H), 2.43-2.34 (m, 2H), 2.14-1.94 pyrazolo[4,3- (m, 5H), 1.81-1.78 (m, 1H), 1.61-1.59 c]pyridin-5- (m, 1H), 1.03 (t, J = 7.2 Hz, 3H) yl]ethanone Example 109 1-[3-[3-methyl-6-(1- 1H NMR (400 MHz, DMSO-d6) δ 7.93 (s, 447 methylpyrazol-4-yl)- 1H), 7.69 (s, 1H), 7.22 (s, 1H), 7.15-7.11 3,4-dihydro-2H- (m, 1H), 6.51-6.45 (m, 1H), 5.48-5.43 quinolin-1-yl]-1- (m, 1H), 4.94-4.84 (m, 4H), 4.08-4.07 (oxetan-3-yl)-6,7- (m, 2H), 3.83 (s, 3H), 3.73-3.64 (m, 4H), dihydro-4H- 3.26-3.20 (m, 1H), 2.91-2.67 (m, 4H), pyrazolo[4,3- 2.05-1.92 (m, 3H), 1.07-1.04 (m, 3H) c]pyridin-5- yl]ethanone Example 110 1-[3-[3-methyl-6-(1- 1H NMR (400 MHz, DMSO-d6) δ 7.91 (s, 461 methylpyrazol-4-yl)- 1H), 7.67 (s, 1H), 7.19 (s, 1H), 7.13-7.08 3,4-dihydro-2H- (m, 1H), 6.44-6.39 (m, 1H), 4.92-4.86 quinolin-1-yl]-1- (m, 1H), 4.08 (s, 2H), 4.00-3.95 (m, 2H), tetrahydrofuran-3-yl- 3.82 (s, 3H), 3.75-3.54 (m, 4H), 3.42- 6,7-dihydro-4H- 3.38 (m, 2H), 3.18-3.13 (m, 1H), 2.87- pyrazolo[4,3- 2.67 (m, 4H), 2.33-2.22 (m, 2H), 2.06- c]pyridin-5- 1.93 (m, 3H), 1.06-1.01 (m, 3H) yl]ethanone -
- Racemic 1-[3-[4-methyl-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-1-tetrahydrofuran-3-yl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (Example 106, 190 mg) was separated using chiral SFC (Chiralpak AD-3 50*4.6 mm I.D., 3 um; Mobile phase: ethanol (0.05% diethyl amine) in CO2 from 5% to 40%; Flow rate: 60 mL/min) to give (S, S)-1-[3-[4-methyl-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-1-tetrahydrofuran-3-yl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (92 mg, first peak) and (S, R)-1-[3-[4-methyl-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-1-tetrahydrofuran-3-yl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (76 mg, second peak). Absolute configuration was arbitrarily assigned to each diastereomer. Example 111: 1H NMR (400 MHz, CDCl3) δ 7.68-7.65 (m, 1H), 7.51-7.49 (m, 1H), 7.23-7.19 (m, 1H), 7.10-7.05 (m, 1H), 6.54-6.50 (m, 1H), 4.78-4.74 (m, 1H), 4.27-3.89 (m, 10H), 3.71-3.55 (m, 2H), 3.00-2.72 (m, 3H), 2.45-2.35 (m, 2H), 2.15-1.77 (m, 4H), 1.79-1.77 (m, 1H), 1.38-1.36 (m, 3H). LCMS M/Z (M+H) 461. Example 112: 1H NMR (400 MHz, CDCl3) δ 7.68-7.65 (m, 1H), 7.51-7.49 (m, 1H), 7.23-7.19 (m, 1H), 7.10-7.05 (m, 1H), 6.54-6.50 (m, 1H), 4.78-4.74 (m, 1H), 4.27-3.89 (m, 10H), 3.71-3.55 (m, 2H), 3.00-2.72 (m, 3H), 2.45-2.35 (m, 2H), 2.15-1.77 (m, 4H), 1.79-1.77 (m, 1H), 1.38-1.36 (m, 3H). LCMS M/Z (M+H) 461.
-
- Racemic 1-[3-[3-methyl-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-1-tetrahydrofuran-3-yl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (Example 110, 85 mg) was separated using chiral SFC (Chiralpak AD 250×30 mm I.D., 5 um; Supercritical CO2/EtOH+NH3.H2O=45/55; 45 ml/min) to give (S,R)-1-[3-[3-methyl-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-1-tetrahydrofuran-3-yl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (18 mg, first peak) and (S,S)-1-[3-[3-methyl-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-1-tetrahydrofuran-3-yl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (21 mg, second peak). Absolute configuration was arbitrarily assigned to each diastereomer. Example 113: 1H NMR (400 MHz, DMSO-d6) δ 7.89 (s, 1H), 7.65 (s, 1H), 7.16 (s, 1H), 7.11-7.06 (m, 1H), 6.42-6.37 (m, 1H), 4.87-4.84 (m, 1H), 4.06 (s, 2H), 4.00-3.93 (m, 2H), 3.79 (s, 3H), 3.76-3.52 (m, 4H), 3.28-3.26 (m, 2H), 3.16-3.11 (m, 1H), 2.85-2.65 (m, 4H), 2.30-2.20 (m, 2H), 2.04-1.91 (m, 3H), 1.02-0.99 (m, 3H). LCMS M/Z (M+H) 461. Example 114: 1H NMR (400 MHz, DMSO-d6) δ 7.89 (s, 1H), 7.65 (s, 1H), 7.16 (s, 1H), 7.11-7.06 (m, 1H), 6.43-6.37 (m, 1H), 4.88-4.84 (m, 1H), 4.06 (s, 2H), 4.01-3.92 (m, 2H), 3.79 (s, 3H), 3.77-3.52 (m, 4H), 3.28-3.26 (m, 2H), 3.19-3.11 (m, 1H), 2.85-2.65 (m, 4H), 2.30-2.19 (m, 2H), 2.04-1.91 (m, 3H), 1.01-0.99 (m, 3H). LCMS M/Z (M+H) 461.
-
- Racemic 1-[3-[4-ethyl-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-1-tetrahydrofuran-3-yl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (Example 108, 100 mg) was separated using chiral SFC (Chiralpak AD-H 250×4.6 mm I.D., 5 um Mobile phase: 40% ethanol (0.05% diethylamine) in CO2 Flow rate: 60 mL/min) to give (S,S)-1-[3-[4-ethyl-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-1-tetrahydrofuran-3-yl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (33 mg, first peak) and (S,R)-1-[3-[4-ethyl-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-1-tetrahydrofuran-3-yl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (22 mg, second peak). Absolute configuration was arbitrarily assigned to each diastereomer. Example 115: 1H NMR (400 MHz, CDCl3) δ 7.66-7.64 (m, 1H), 7.50-7.47 (m, 1H), 7.18-7.04 (m, 2H), 6.54-6.49 (m, 1H), 4.75-4.73 (m, 1H), 4.17-4.10 (m, 3H), 4.00-3.90 (m, 7H), 3.71-3.64 (m, 3H), 2.72-2.70 (m, 3H), 2.43-2.34 (m, 2H), 2.14-1.94 (m, 5H), 1.81-1.78 (m, 1H), 1.61-1.59 (m, 1H), 1.03 (t, J=7.2 Hz, 3H). LCMS M/Z (M+H) 475. Example 116: 1H NMR (400 MHz, CDCl3) δ 7.66-7.64 (m, 1H), 7.50-7.47 (m, 1H), 7.18-7.04 (m, 2H), 6.54-6.49 (m, 1H), 4.75-4.73 (m, 1H), 4.17-4.10 (m, 3H), 4.00-3.90 (m, 7H), 3.71-3.64 (m, 3H), 2.72-2.70 (m, 3H), 2.43-2.34 (m, 2H), 2.14-1.94 (m, 5H), 1.81-1.78 (m, 1H), 1.61-1.59 (m, 1H), 1.03 (t, J=7.2 Hz, 3H). LCMS M/Z (M+H) 475.
-
-
- To a solution of 3-bromoquinoline (3.0 g, 14.4 mmol) in toluene/H2O (22 mL, 10:1) was added cyclopropylboronic acid (6.2 g, 7.21 mmol), palladium(II) acetate (162 mg, 0.72 mmol), tricyclohexylphosphine (404 mg, 1.44 mmol) and K3PO4 (10.7 g, 50.5 mmol). The mixture was heated to 100° C. for 16 h under a nitrogen atmosphere. After cooling the reaction to room temperature, EtOAc (40 mL) was added and washed with H2O (50 mL×2). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc=3:1) to give the title compound (2.4 g, 98%) as yellow oil. 1H NMR (400 MHz, DMSO-d6) δ 8.75 (d, J=2.0 Hz, 1H), 7.97 (s, 1H), 7.95-7.93 (m, 1H), 7.87-7.85 (m, 1H), 7.65-7.63 (m, 1H), 7.56-7.54 (m, 1H), 2.16-2.11 (m, 1H), 1.08-1.06 (m, 2H), 0.89-0.86 (m, 2H).
-
- To a solution of 3-cyclopropylquinoline (2.3 g, 13.6 mmol) in dry toluene (45 mL) was added
diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (8.3 g, 32.6 mmol) and diphenyl hydrogen phosphate (34 mg, 0.14 mmol). The mixture was heated to 60° C. for 12 h under a nitrogen atmosphere. After cooling the reaction to room temperature, the mixture was concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc=30:1) to give the title compound (2.3 g, 98%) as a white solid; 1H NMR (400 MHz, DMSO-d6) δ 6.83-6.79 (m, 2H), 6.41-6.36 (m, 2H), 5.63 (s, 1H), 3.25-3.22 (m, 1H), 2.97-2.92 (m, 1H), 2.75-2.70 (m, 1H), 2.53-2.48 (m, 1H), 1.08-0.98 (m, 1H), 0.64-0.55 (m, 1H), 0.46-0.38 (m, 2H), 0.22-0.15 (m, 2H). -
- To a solution of (S)-1-(3-bromo-1-(tetrahydrofuran-3-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone (Intermediate G, 200 mg, 0.64 mmol) in dioxane (8 mL) was added 3-cyclopropyl-1,2,3,4-tetrahydroquinoline (132 mg, 0.76 mmol), 2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl (30 mg, 0.06 mmol), chloro(2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl)[2-(2-aminoethylphenyl)]palladium(II), methyl-tert-butylether adduct (52 mg, 0.06 mmol) and t-BuONa (214 mg, 2.23 mmol). The mixture was heated to 120° C. for 16 h under a nitrogen atmosphere. After cooling the reaction to room temperature, EtOAc (30 mL) was added the mixture was washed with H2O (30 mL×2). The organic layer was dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo. The crude residue was purified by silica gel chromatography (DCM/MeOH=3:1) to give the title compound (150 mg, crude) as yellow oil that required no further purification. LCMS M/Z (M+H) 407.
-
- To a solution of 1-(1-cyclopentyl-3-(3-cyclopropyl-3,4-dihydroquinolin-1(2H)-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone (150 mg, crude) in DCM (4 mL) at 0° C. was added N-bromosuccinimide (41 mg, 0.23 mmol). The mixture was stirred at 0° C. and gradually raised to room temperature for 1 h under a nitrogen atmosphere. DCM (30 mL) was added and the mixture was washed with H2O (30 mL) and sat. aq. NaHCO3 (30 mL×2). The organic layer was dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo to give the title compound (130 mg, crude) as brown oil that required no further purification.
-
- To a solution of 1-(3-(6-bromo-3-cyclopropyl-3,4-dihydroquinolin-1(2H)-yl)-1-((S)-tetrahydrofuran-3-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5 (4H)-yl)ethanone (630 mg, 1.3 mmol) in THF/H2O (6 mL, 5:1) was added 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (405 mg, 2.0 mmol), 2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (62 mg, 0.13 mmol), chloro(2-dicyclohexylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl) palladium(II) (102 mg, 0.13 mmol) and K2CO3 (448 mg, 3.24 mmol). The mixture was heated to 60° C. for 16 h under a nitrogen atmosphere. After cooling the reaction to room temperature, EtOAc (100 mL) was added and the mixture was washed with H2O (60 mL×2). The organic layer was dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo. The crude residue was purified by reverse phase chromatography (acetonitrile 32-62%/0.225% formic acid in water) to give the title compound (240 mg, 27%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.91 (s, 1H), 7.67 (s, 1H), 7.22 (s, 1H), 7.12-7.08 (m, 1H), 6.45-6.39 (m, 1H), 4.93-4.85 (m, 1H), 4.08 (s, 2H), 4.03-3.95 (m, 2H), 3.82 (s, 3H), 3.77-3.63 (m, 4H), 3.41-3.33 (m, 2H), 2.93-2.83 (m, 2H), 2.72-2.63 (m, 2H), 2.32-2.25 (m, 2H), 2.06, 1.96 (2s, 3H), 1.30-1.19 (m, 1H), 0.74-0.63 (m, 1H), 0.50-0.40 (m, 2H), 0.29-0.17 (m, 2H). LCMS M/Z (M+H) 487.
- The following compound was prepared in a similar fashion to Example 117:
-
-
Example Compound Name NMR m/z Example 118 1-[3-[6-(1- 1H NMR (400 MHz, DMSO-d6) δ 7.93 (s, 523 methylpyrazol-4-yl)-3- 1H), 7.70 (s, 1H), 7.40-7.27 (m, 5H), 7.27- phenyl-3,4-dihydro- 7.21 (m, 1H), 7.20-7.13 (m, 1H), 6.53- 2H-quinolin-1-yl]-1- 6.47 (m, 1H), 4.88 (br s, 1H), 4.18-3.91 tetrahydrofuran-3-yl- (m, 4H), 3.84-3.59 (m, 9H), 3.28-3.16 6,7-dihydro-4H- (m, 1H), 3.14-2.96 (m, 2H), 2.86-2.65 pyrazolo[4,3-c]pyridin- (m, 2H), 2.31-2.16 (m, 2H), 2.10-1.88 5-yl]ethanone (m, 3H) -
- Racemic 1-[3-[6-(1-methylpyrazol-4-yl)-3-phenyl-3,4-dihydro-2H-quinolin-1-yl]-1-tetrahydrofuran-3-yl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (Example 118, 150 mg) was separated using chiral SFC (Chiralpak AD 250 mm×30 mm I.D., 5 um; Supercritical CO2/MeOH+NH4OH=55/45; 50 mL/min) to give (S,S)-1-[3-[6-(1-methylpyrazol-4-yl)-3-phenyl-3,4-dihydro-2H-quinolin-1-yl]-1-tetrahydrofuran-3-yl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (52 mg, first peak) and (S,R)-1-[3-[6-(1-methylpyrazol-4-yl)-3-phenyl-3,4-dihydro-2H-quinolin-1-yl]-1-tetrahydrofuran-3-yl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (64 mg, second peak). Absolute configuration was arbitrarily assigned to each diastereomer. Example 119: 1H NMR (400 MHz, DMSO-d6) δ 7.93 (s, 1H), 7.70 (s, 1H), 7.40-7.27 (m, 5H), 7.27-7.21 (m, 1H), 7.20-7.13 (m, 1H), 6.53-6.47 (m, 1H), 4.90-4.87 (m, 1H), 4.18-3.91 (m, 4H), 3.84-3.59 (m, 9H), 3.28-3.16 (m, 1H), 3.14-2.96 (m, 2H), 2.86-2.65 (m, 2H), 2.31-2.16 (m, 2H), 2.10-1.88 (m, 3H). LCMS M/Z (M+H) 523. Example 120: 1H NMR (400 MHz, DMSO-d6) δ 7.93 (s, 1H), 7.70 (s, 1H), 7.40-7.27 (m, 5H), 7.27-7.21 (m, 1H), 7.20-7.13 (m, 1H), 6.53-6.47 (m, 1H), 4.90-4.87 (m, 1H), 4.18-3.91 (m, 4H), 3.84-3.59 (m, 9H), 3.28-3.16 (m, 1H), 3.14-2.96 (m, 2H), 2.86-2.65 (m, 2H), 2.31-2.16 (m, 2), 2.10-1.88 (m, 3H). LCMS M/Z (M+H) 523.
-
-
- To a solution of 7-methylquinoline (27.0 g, 189 mmol) at 160° C. was added SeO2 (21.0 g, 189 mmol) portionwise over 5 min. The mixture was stirred at 160° C. for 8 h. After cooling the reaction to room temperature, DCM (400 mL) was added and the mixture was filtered though celite. The organic layer was concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc=10:1) to give the title compound (14.0 g, 47%) as yellow oil. 1H NMR (400 MHz, CDCl3) δ 10.23 (s, 1H), 9.03 (d, J=2.8 Hz, 1H), 8.56 (s, 1H), 8.22 (d, J=8.4 Hz, 1H), 8.04 (d, J=8.4 Hz, 1H), 7.93 (d, J=8.4 Hz, 1H), 7.55-7.52 (m, 1H).
-
- To a solution of 7-(difluoromethyl)quinoline (14.0 g, 89.2 mmol) in DCM (150 mL) 0° C. was added diethylaminosulfurtrifluoride (65.0 g, 446 mmol) dropwise over 20 min. The mixture was stirred at room temperature for 16 h. The mixture was poured into sat. aq. NaHCO3 (1 L) at 0° C. and extracted with DCM (200 mL×2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc=5:1) to give the title compound (13.0 g, 81%) as yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.92 (d, J=2.8 Hz, 1H), 8.15 (d, J=8.4 Hz, 2H), 7.86 (d, J=8.4 Hz, 1H), 7.63 (d, J=8.8 Hz, 1H), 7.44-7.41 (m, 1H), 6.78 (t, J=56.0 Hz, 1H).
-
- To a solution of 7-(difluoromethyl)quinoline (13.0 g, 72.6 mmol) and NaBH3CN (23.0 g, 363 mmol) in MeOH (150 mL) at 0° C. was added boron trifluoride diethyl etherate (17.9 mL, 145 mmol) dropwise over 20 min. The mixture was heated to 90° C. for 24 h. After cooling the reaction to room temperature, the mixture was poured into sat. aq. NaHCO3 (1 L) at 0° C. and extracted with DCM (200 mL×2). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc=20:1) to give the title compound (8.0 g, 56%) as brown oil. 1H NMR (400 MHz, CDCl3) δ 7.00 (d, J=7.2 Hz, 1H), 6.71 (d, J=8.0 Hz, 1H), 6.59 (s, 1H), 6.50 (t, J=56.8 Hz, 1H), 3.33 (t, J=5.6 Hz, 2H), 2.79 (t, J=6.4 Hz, 2H), 1.98-1.92 (m, 2H).
-
- To a solution of 7-(difluoromethyl)-1,2,3,4-tetrahydroquinoline (7.0 g, 38.3 mmol) in DCM (100 mL) at 0° C. was added N-bromosuccinimide (6.9 g, 38.3 mmol) portionwise over 20 min. The mixture was stirred at room temperature for 16 h. The mixture was poured into water (100 mL) and extracted with DCM (200 mL×2). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc=300:1) to give the title compound (6.0 g, 60%) as light yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.13 (s, 1H), 6.78 (t, J=55.2 Hz, 1H), 6.72 (s, 1H), 3.31 (t, J=5.2 Hz, 2H), 2.74 (t, J=6.0 Hz, 2H), 1.95-1.87 (m, 2H).
-
- To a solution of 6-bromo-7-(difluoromethyl)-1,2,3,4-tetrahydroquinoline (600 mg, 2.3 mmol) in dioxane (8 mL) and H2O (2 mL) was added K2CO3 (635 mg, 4.6 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (169 mg, 0.23 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (478 mg, 2.3 mmol). The mixture was heated to 110° C. for 18 h under a nitrogen atmosphere. After cooling the reaction to room temperature, the mixture was concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc=40:1) to give the title compound (520 mg, 86%) as yellow oil. LCMS M/Z (M+H) 264.
-
- To a solution of 7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinoline (263 mg, 1.0 mmol) in dioxane (10 mL) was added 1-(3-bromo-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone (Intermediate I, 327 mg, 1.0 mmol), chloro(2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl)[2-(2-aminoethylphenyl)]palladium(II), methyl-tert-butylether adduct (82 mg, 0.10 mmol), 2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl (47 mg, 0.10 mmol) and t-BuONa (288 mg, 3.0 mmol). The mixture was heated to 120° C. for 16 h under a nitrogen atmosphere. After cooling the reaction to room temperature, the mixture was concentrated in vacuo. The crude residue was purified by prep-TLC (DCM/MeOH=20:1) to give the title compound (26 mg, 6%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.75 (s, 1H), 7.50 (s, 1H), 7.10 (s, 1H), 6.96-6.63 (m, 2H), 4.33-4.25 (m, 1H), 4.20-4.09 (m, 2H), 3.99-3.90 (m, 2H), 3.86 (s, 3H), 3.78-3.66 (m, 2H), 3.63-3.55 (m, 2H), 3.49-3.41 (m, 2H), 2.89-2.66 (m, 4H), 2.11-1.90 (m, 7H), 1.85-1.80 (m, 2H). LCMS M/Z (M+H) 511.
- The following compounds were prepared in a similar fashion to Example 121:
-
-
Example Compound Name NMR m/z Example 122 1-[3-[7- 1H NMR (400 MHz, DMSO-d6) δ 7.77 (s, 483 (difluoromethyl)-6-(1- 1H), 7.51 (s, 1H), 7.14 (s, 1H), 6.96-6.67 methylpyrazol-4-yl)- (m, 2H), 5.48-5.45 (m, 1H), 4.93-4.84 (m, 3,4-dihydro-2H- 4H), 4.15-4.10 (m, 2H), 3.87 (s, 3H), 3.71- quinolin-1-yl]-1- 3.66 (m, 4H), 2.86-2.68 (m, 4H), 2.06- (oxetan-3-yl)-6,7- 1.95 (m, 5H) dihydro-4H- pyrazolo[4,3- c]pyridin-5- yl]ethanone Example 123 1-[3-[7- 1H NMR (400 MHz, DMSO-d6) δ 7.76 (s, 497 (difluoromethyl)-6-(1- 1H), 7.50 (s, 1H), 7.11 (s, 1H), 6.94-6.65 methylpyrazol-4-yl)- (m, 2H), 4.94-4.88 (m, 1H), 4.16-4.12 (m, 3,4-dihydro-2H- 2H), 4.03-3.90 (m, 2H), 3.86 (s, 3H), 3.82- quinolin-1-yl]-1- 3.79 (m, 4H), 3.70-3.56 (m, 2H), 2.86- tetrahydrofuran-3-yl- 2.74 (m, 4H), 2.29-2.22 (m, 2H), 2.07- 6,7-dihydro-4H- 1.96 (m, 5H) pyrazolo[4,3- c]pyridin-5- yl]ethanone Example 124 5-(1-(5-acetyl-1- 1H NMR (400 MHz, DMSO-d6) δ 8.84- 565 (tetrahydro-2H-pyran- 8.82 (m, 1H), 8.55 (d, J = 4.0 Hz, 1H), 8.06 4-yl)-4,5,6,7- (d, J = 8.0 Hz, 1H), 7.92-7.90 (m, 1H), tetrahydro-1H- 7.14 (s, 1H), 6.89 (s, 1H), 6.74 (t, J = 54.8 pyrazolo[4,3- Hz, 1H), 4.37-4.26 (m, 1H), 4.22-4.18 (m, c]pyridin-3-yl)-7- 2H), 3.98-3.94 (m, 2H), 3.80-3.68 (m, (difluoromethyl)- 2H), 3.67-3.58 (m, 2H), 3.46 (t, J = 12.0 1,2,3,4- Hz, 2H), 2.93-2.74 (m, 7H), 2.09-1.91 (m, tetrahydroquinolin-6- 7H), 1.87-1.80 (m, 2H) yl)-N- methylpicolinamide -
-
- To a solution of 7-chloro-1,2,3,4-tetrahydroquinoline (14 g, 80 mmol) in DCM (100 mL) at 0° C. was added N-bromosuccinimide (14.8 g, 80 mmol). The mixture was stirred at room temperature for 1 h. Water (100 mL) was added and the mixture was extracted with DCM (100 mL×2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc=100:1) to give the title compound (7.1 g, 36%) as a light yellow solid. LCMS M/Z (M+H) 246.
-
- To a solution of 6-bromo-7-chloro-1,2,3,4-tetrahydroquinoline (2.1 g, 8.5 mmol) in dioxane/H2O (60 mL, 5:1) was added 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.9 g, 9.4 mmol), Na2CO3 (1.8 g, 17 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (622 mg, 0.9 mmol). The mixture was heated to 100° C. for 12 h under a nitrogen atmosphere. After cooling the reaction to room temperature, the mixture was concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc=4:1) to give the title compound (2.0 g, 95%) as yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 7.88-7.85 (m, 1H), 7.61 (s, 1H), 7.01 (s, 1H), 6.53 (s, 1H), 5.95 (s, 1H), 3.86-3.84 (m, 3H), 3.38-3.16 (m, 2H), 2.65-2.62 (m, 2H), 1.80-1.74 (m, 2H).
-
- To a solution of 7-chloro-6-(1-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinoline (247 mg, 1.0 mmol) in dioxane (3 mL) and toluene (3 mL) was added t-BuONa (288 mg, 3.0 mmol), tris(dibenzylideneacetone)dipalladium (46 mg, 0.05 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (59 mg, 0.1 mmol) and (5)-1-(3-bromo-1-(tetrahydrofuran-3-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone (Intermediate G, 313 mg, 1.0 mmol). The mixture was heated to 90° C. for 16 h under a nitrogen atmosphere. After cooling the reaction to room temperature, the mixture was concentrated in vacuo. The crude residue was purified by Prep-TLC (DCM/MeOH=20:1) to give the title compound (240 mg, 50%) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 7.97 (s, 1H), 7.68 (s, 1H), 7.21-7.20 (m, 1H), 6.54-6.50 (m, 1H), 4.95-4.89 (m, 1H), 4.18-4.15 (m, 2H), 4.03-3.98 (m, 2H), 3.85-3.71 (m, 7H), 3.54-3.50 (m, 2H), 2.86-2.77 (m, 4H), 2.33-2.27 (m, 2H), 2.08-1.94 (m, 5H). LCMS M/Z (M+H) 481.
-
- To a solution of 1-(3-(7-chloro-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1-(oxetan-3-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone (200 mg, 0.429 mmol) in dioxane (5 mL) and H2O (3 mL) was added KOAc (170 mg, 1.72 mmol), tris(dibenzylideneacetone)dipalladium (40 mg, 0.0429 mmol), 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (69 mg, 0.0858 mmol) and potassium hexacyanoferrate(II) trihydrate (1.0 g, 2.57 mmol). The mixture was heated to 120° C. for 36 h under a nitrogen atmosphere. After cooling the reaction to room temperature, the mixture was concentrated in vacuo. The crude residue was purified by reverse phase chromatography (acetonitrile 37-67%/0.1% NH4OH in water) to give the title compound (50 mg, 25%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.07 (s, 1H), 7.80 (s, 1H), 7.36 (s, 1H), 6.79-6.74 (m, 1H), 4.94-4.91 (m, 1H), 4.19-4.17 (m, 2H), 4.03-3.96 (m, 2H), 3.83-3.72 (m, 7H), 3.58-3.54 (m, 2H), 2.89-2.75 (m, 4H), 2.32-2.25 (m, 2H), 2.09-1.95 (m, 5H). LCMS M/Z (M+H) 472.
- The following compounds were prepared in a similar fashion to Example 126:
-
-
Example Compound Name NMR m/z Example 127 1-[5-acetyl-1-(oxetan-3- 1H NMR (400 MHz, DMSO-d6) δ 8.07 (s, 458 yl)-6,7-dihydro-4H- 1H), 7.80 (s, 1H), 7.38 (s, 1H), 6.83-6.77 pyrazolo[4,3-c]pyridin- (m, 1H), 5.51-5.44 (m, 1H), 4.93-4.87 (m, 3-yl]-6-(1- 4H), 4.18-4.15 (m, 2H), 3.88 (s, 3H), 3.73- methylpyrazol-4-yl)- 3.61 (m, 4H), 2.91-2.67 (m, 4H), 2.07-1.98 3,4-dihydro-2H- (m, 5H) quinoline-7-carbonitrile Example 128 1-(5-acetyl-1- 1H NMR (400 MHz, DMSO-d6) δ 8.06 (s, 486 tetrahydropyran-4-yl- 1H), 7.80 (s, 1H), 7.35 (s, 1H), 6.75-6.70 6,7-dihydro-4H- (m, 1H), 4.36-4.31 (m, 1H), 4.20-4.17 (m, pyrazolo[4,3-c]pyridin- 2H), 3.97-3.94 (m, 2H), 3.88 (s, 3H), 3.77- 3-yl)-6-(1- 3.72 (m, 2H), 3.59-3.51 (m, 4H), 2.89-2.67 methylpyrazol-4-yl)- (m, 4H), 2.08-1.99 (m, 3H), 1.96-1.81 (m, 3,4-dihydro-2H- 6H) quinoline-7-carbonitrile Example 129 1-(5-acetyl-1- 1H NMR (400 MHz, DMSO-d6) δ 7.44 (s, 500 tetrahydropyran-4-yl- 1H), 7.08 (s, 1H), 6.79-6.74 (m, 1H), 4.33- 6,7-dihydro-4H- 4.28 (m, 1H), 4.21-4.18 (m, 2H), 3.96-3.94 pyrazolo[4,3-c]pyridin- (m, 2H), 3.78 (s, 3H), 3.73-3.71 (m, 2H), 3-yl)-6-(1,5- 3.60-3.55 (m, 2H), 3.48-3.42 (m, 2H), 2.89- dimethylpyrazol-4-yl)- 2.75 (m, 4H), 2.23 (s, 3H), 2.08-2.00 (m, 3,4-dihydro-2H- 3H), 2.06-1.96 (m, 4H), 1.85-1.82 (m, 2H) quinoline-7-carbonitrile Example 130 1-[5-acetyl-1-(oxetan-3- 1H NMR (400 MHz, DMSO-d6) δ 7.45 (s, 472 yl)-6,7-dihydro-4H- 1H), 7.11 (s, 1H), 6.91-6.72 (m, 1H), 5.51- pyrazolo[4,3-c]pyridin- 5.45 (m, 1H), 5.08-4.73 (m, 4H), 4.30-4.08 3-yl]-6-(1,5- (m, 2H), 3.78 (s, 3H), 3.76-3.68 (m, 2H), dimethylpyrazol-4-yl)- 3.67-3.61 (m, 2H), 2.90-2.68 (m, 4H), 2.24 3,4-dihydro-2H- (s, 3H), 2.07-1.99 (m, 5H) quinoline-7-carbonitrile Example 131 5-[1-[5-acetyl-1-[(3S)- 1H NMR (400 MHz, DMSO-d6) δ 8.86 (d, J = 526 tetrahydrofuran-3-yl]- 4.4 Hz, 1H), 8.77 (s, 1H), 8.13-8.08 (m, 6,7-dihydro-4H- 2H), 7.43 (s, 1H), 6.90-6.87 (m, 1H), 5.05- pyrazolo[4,3-c]pyridin- 4.85 (m, 1H), 4.23-4.20 (m, 2H), 4.02-4.00 3-yl]-7-cyano-3,4- (m, 2H), 3.84-3.80 (m, 4 H), 3.61-3.59 (m, dihydro-2H-quinolin-6- 2H), 2.93-2.84 (m, 5H), 2.66-2.50 (m, 2H), yl]-N-methyl-pyridine- 2.35-2.20 (m, 2H), 2.09-1.99 (m, 5H) 2-carboxamide Example 132 1-[5-acetyl-1-[(3S)- 1H NMR (400 MHz, DMSO-d6) δ 8.05 (s, 472 tetrahydrofuran-3-yl]- 1H), 7.77 (s, 1H), 7.24-7.20 (m, 1H), 6.78- 6,7-dihydro-4H- 6.71 (m, 1H), 4.93-4.90 (m, 1H), 4.14-4.12 pyrazolo[4,3-c]pyridin- (m, 2H), 4.01-3.94 (m, 4H), 3.88 (s, 3H), 3-yl]-6-(1- 3.83-3.79 (m, 2H), 2.99-2.96 (m, 2H), 2.84- methylpyrazol-4-yl)- 2.60 (m, 2H), 2.30-2.20 (m, 2H), 2.07- 3,4-dihydro-2H- 1.96 (m, 5H) quinoline-5-carbonitrile Example 133 5-(1-(5-acetyl-1- 1H NMR (400 MHz, DMSO-d6) δ 8.86-8.85 540 (tetrahydro-2H-pyran-4- (m, 1H), 8.78 (s, 1H), 8.14-8.09 (m, 2H), yl)-4,5,6,7-tetrahydro- 7.43 (s, 1 H), 6.91-6.84 (m, 1H), 4.35-4.27 1H-pyrazolo[4,3- (m, 1H), 4.25-4.22 (m, 2H), 3.98-3.95 (m, c]pyridin-3-yl)-7- 2H), 3.76-3.74 (m, 2H), 3.63-3.61(m, 2H), cyano-1,2,3,4- 3.50-3.44 (m, 2H), 2.96-2.83 (m, 7H), 2.10- tetrahydroquinolin-6- 1.97 (m, 7H), 1.87-1.82 (m, 2H) yl)-N- methylpicolinamide -
- To a solution of 1-[3-[7-chloro-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-1-[(3S)-tetrahydrofuran-3-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (150 mg, 0.313 mmol) in toluene (3 mL) and H2O (1 mL), was added MeBF3K (116 mg, 0.939 mmol), palladium(II) acetate (7 mg, 0.0313 mmol), Cs2CO3 (612 mg, 0.626 mmol) and di(adamantan-1-yl)(butyl)phosphine (23 mg, 0.0616 mmol). The mixture was heated to 100° C. for 18 h under a nitrogen atmosphere. After cooling the reaction to room temperature, the mixture was concentrated in vacuo. The crude residue was purified by Prep-TLC (DCM/MeOH=20:1) to give the title compound (21 mg, 15%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.76 (s, 1H), 7.52 (s, 1H), 6.99-6.98 (m, 1H), 6.36-6.34 (m, 1H), 4.90-4.85 (m, 1H), 4.14-4.05 (m, 2H), 4.04-3.93 (m, 2H), 3.87-3.66 (m, 7H), 3.58-3.52 (m, 2H), 2.84-2.67 (m, 4H), 2.34-2.21 (m, 2H), 2.15 (s, 3H), 2.09-1.81 (m, 5H). LCMS M/Z (M+H) 461.
-
-
- To a solution of sodium (41.2 g, 1.8 mol) in EtOH (1200 mL) was added quinolin-3-ol (20 g, 137.8 mmol) at 80° C. The mixture was heated to 80° C. for 2 h. After cooling the reaction to room temperature, ice water (100 mL) was added and the mixture was extracted with EtOAc (300 mL×3). The combined organic layers were concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc=10:1) to give the title compound (10 g, 48%) as a yellow oil, LCMS M/Z (M+H) 150.
-
- To a solution of 1,2,3,4-tetrahydroquinolin-3-ol (5.0 g, 33.5 mmol) and imidazole (11.4 g, 167.6 mmol) in THF (50 mL) was added tert-butyl-dimethylsilyl chloride (12.6 g, 83.8 mmol). The mixture was heated to 80° C. for 12 h. After cooling the reaction to room temperature, the mixture was concentrated in vacuo. EtOAc (100 mL) was added and the mixture was washed with water (100 mL×3) and brine (100 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc=10:1) to give the title compound (3.5 g, 38%) as yellow oil, 1H NMR (400 MHz, DMSO-d6) δ 6.86-6.82 (m, 2H), 6.47-6.40 (m, 2H), 5.64 (s, 1H), 4.09-4.05 (m, 1H), 3.22-3.19 (m, 1H), 2.93-2.80 (m, 2H), 2.63-2.57 (m, 1H), 0.87 (s, 9H), 0.09-0.01 (m, 6H).
-
- To a solution of tert-butyl-dimethyl-(1,2,3,4-tetrahydroquinolin-3-yloxy)silane (260.79 mg, 0.99 mmol) in 1,4-dioxane (3 mL) was added 1-[3-bromo-1-[(3S)-tetrahydrofuran-3-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (Intermediate G, 313 mg, 0.99 mmol), dicyclohexyl-[2-(2,6-diisopropoxyphenyl)phenyl]phosphane (46.19 mg, 0.10 mmol) and dichloro[1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II) (76.89 mg, 0.10 mmol). The mixture was heated to 120° C. for 16 h under a nitrogen atmosphere. After cooling the reaction to room temperature, the mixture was concentrated in vacuo. The crude residue was purified by silica gel chromatography (DCM/MeOH=80:1) to give the title compound (200 mg, 41%) as a light yellow solid. LCMS M/Z (M+H) 497.
-
- To a solution of 1-[3-[3-[tert-butyl(dimethyl)silyl]oxy-3,4-dihydro-2H-quinolin-1-yl]-1-[(3S)-tetrahydrofuran-3-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (200 mg, 0.40 mmol) in DCM (2 mL) was added N-bromosuccinimide (71.66 mg, 0.40 mmol) portionwise. The mixture was stirred at room temperature for 2 h. Water (20 mL) was added and the mixture was extracted with DCM (20 mL×2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (280 mg, crude) as yellow oil that required no further purification. LCMS M/Z (M+H) 575.
-
- A solution of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (97.17 mg, 0.47 mmol), 1-[3-[6-bromo-3-[tert-butyl(dimethyl)silyl]oxy-3,4-dihydro-2H-quinolin-1-yl]-1-[(3S)-tetrahydrofuran-3-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (Intermediate G, 280 mg, 0.39 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (28.47 mg, 0.04 mmol) and Na2CO3 (82.49 mg, 0.78 mmol) in 1,4-dioxane (2 mL) and water (0.5 mL) was heated to 110° C. for 12 h under a nitrogen atmosphere. After cooling the reaction to room temperature, the mixture was concentrated in vacuo. The crude residue was purified by Prep-TLC (DCM/MeOH=20:1) to give the title compound (200 mg, 62%) as a light yellow solid. LCMS M/Z (M+H) 577.
-
- To a solution of 1-[3-[3-[tert-butyl(dimethyl)silyl]oxy-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-1-[(3S)-tetrahydrofuran-3-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (200 mg, 0.24 mmol) in THF (2 mL) was added tetrabutylammonium fluoride (253.8 mg, 0.97 mmol). The mixture was heated to 80° C. for 16 h under a nitrogen atmosphere. After cooling the reaction to room temperature, water (20 mL) was added and the mixture was extracted with DCM (20 mL×2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by reverse phase chromatography (acetonitrile 8-28%/0.1% NH4HCO3 in water) to give the title compound (8 mg, 7%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.67-7.65 (m, 1H), 7.51-7.49 (m, 1H), 7.20-7.09 (m, 2H), 6.57-6.53 (m, 1H), 4.78-4.73 (m, 1H), 4.29-4.25 (m, 2H), 4.17-4.12 (m, 3H), 3.99-3.64 (m, 9H), 3.17-3.14 (m, 1H), 2.92-2.73 (m, 3H), 2.42-2.31 (m, 2H), 2.17-2.03 (m, 3H). LCMS M/Z (M+H) 463.
-
- To a solution of (S)-1-[3-[3-hydroxy-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-1-tetrahydrofuran-3-yl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (Example 135, 150 mg, 0.32 mmol) in THF (3 mL) at 0° C. was added NaH (60%, 38.92 mg, 0.97 mmol). The mixture was stirred at 0° C. for 30 min. Iodomethane (0.1 mL, 1.6 mmol) was added at 0° C. The mixture was stirred at 25° C. for an additional 16 h, quenched with MeOH (1 mL) and concentrated in vacuo. The crude residue was purified by reverse phase chromatography (acetonitrile 36-66%/0.1% NH4HCO3 in water) to give the title compound (62 mg, 40%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.92 (s, 1H), 7.68 (s, 1H), 7.22 (s, 1H), 7.15-7.11 (m, 1H), 6.45-6.38 (m, 1H), 4.90-4.86 (m, 1H), 4.06-3.96 (m, 4H), 3.83-3.80 (m, 6H), 3.69-3.64 (m, 3H), 3.54-3.45 (m, 1H), 3.41 (s, 3H), 3.05-3.00 (m, 1H), 2.82-2.67 (m, 3H), 2.28-2.24 (m, 2H), 2.05-1.90 (m, 3H). LCMS M/Z (M+H) 477.
- The following compounds were prepared in a similar fashion to Example 136:
-
-
Example Compound Name NMR m/z Example 137 (S)-1-[3-[3-ethoxy-6- 1H NMR (400 MHz, DMSO-d6) δ 7.92 (s, 491 (1-methylpyrazol-4- 1H), 7.68 (s, 1H), 7.22 (s, 1H), 7.15-7.11 yl)-3,4-dihydro-2H- (m, 1H), 6.46-6.39 (m, 1H), 4.90-4.86 (m, quinolin-1-yl]-1- 1H), 4.12-3.98 (m, 4H), 3.85-3.80 (m, tetrahydrofuran-3-yl- 6H), 3.70-3.65 (m, 2H), 3.50-3.41 (m, 6,7-dihydro-4H- 4H), 3.04-3.00 (m, 1H), 2.82-2.67 (m, pyrazolo[4,3- 3H), 2.28-2.23 (m, 2H), 2.05-1.90 (m, c]pyridin-5- 3H), 1.07 (t, J = 6.8 Hz, 3H) yl]ethanone Example 138 (S)-1-[3-[3- 1H NMR (400 MHz, DMSO-d6) δ 7.92 (s, 505 isopropoxy-6-(1- 1H), 7.68 (s, 1H), 7.22 (s, 1H), 7.15-7.10 methylpyrazol-4-yl)- (m, 1H), 6.47-6.40 (m, 1H), 4.92-4.87 (m, 3,4-dihydro-2H- 1H), 4.06-3.95 (m, 5H), 3.83-3.63 (m, quinolin-1-yl]-1- 9H), 3.44-3.35 (m, 1H), 3.03-3.00 (m, tetrahydrofuran-3-yl- 1H), 2.83-2.71 (m, 3H), 2.28-2.24 (m, 6,7-dihydro-4H- 2H), 2.05-1.91 (m, 3H), 1.09-1.03 (m, pyrazolo[4,3- 6H) c]pyridin-5- yl]ethanone -
-
- To a solution of 1-[3-[3-hydroxy-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-1-[(3S)-tetrahydrofuran-3-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (200 mg, 0.43 mmol) in DCM (2 mL) at 0° C. was added methanesulfonyl chloride (0.07 mL, 0.86 mmol) and triethylamine (0.18 mL, 1.3 mmol). The mixture was stirred at 25° C. for 2 h. Water (10 mL) was added and the mixture was extracted with DCM (10 mL×2). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo to give the title compound (400 mg, crude) as a yellow oil that required no further purification. LCMS M/Z (M+H)=541.
-
- To a solution of potassium cyanide (48 mg, 0.74 mmol) in DMSO (2 mL) was added [1-[5-acetyl-1-[(3S)-tetrahydrofuran-3-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-3-yl]-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-3-yl]methanesulfonate (400 mg, 0.74 mmol). The mixture was stirred at room temperature for 16 h. Water (20 mL) was added and the mixture was extracted with DCM (20 mL×2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by reverse phase chromatography (acetonitrile 15-45%/0.1% NH4HCO3 in water) to give (S)-1-(5-acetyl-1-tetrahydrofuran-3-yl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-3-yl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinoline-3-carbonitrile (17.5 mg, 5%) as a white solid and (S)-2-[1-(5-acetyl-1-tetrahydrofuran-3-yl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-3-yl)-5-(1-methylpyrazol-4-yl)indolin-2-yl]acetonitrile (10 mg, 3%) as a light yellow solid. Example 139: 1H NMR (400 MHz, DMSO-d6) δ 7.95 (s, 1H), 7.71 (s, 1H), 7.30 (s, 1H), 7.22-7.17 (m, 1H), 6.50-6.43 (m, 1H), 4.95-4.90 (m, 1H), 4.15-4.11 (m, 1H), 4.02-3.93 (m, 3H), 3.83-3.75 (m, 6H), 3.74-3.70 (m, 1H), 3.55-3.52 (m, 1H), 3.26-3.22 (m, 1H), 3.12-3.09 (m, 1H), 2.87-2.84 (m, 1H), 2.65-2.60 (m, 2H), 2.33-2.30 (m, 3H), 2.07-1.89 (m, 3H). LCMS M/Z (M+H) 472. Example 140: 1H NMR (400 MHz, DMSO-d6) δ 7.96 (s, 1H), 7.72 (s, 1H), 7.37 (s, 1H), 7.23-7.21 (m, 1H), 6.66-6.60 (m, 1H), 4.93-4.89 (m, 1H), 4.58-4.47 (m, 1H), 4.35-4.33 (m, 2H), 4.01-3.97 (m, 3H), 3.86-3.79 (m, 6H), 3.42-3.34 (m, 2H), 2.98-2.85 (m, 4H), 2.68-2.65 (m, 1H), 2.33-2.25 (m, 2H), 2.09-2.00 (m, 3H). LCMS M/Z (M+H) 472.
-
-
- To a solution of 3-fluoroaniline (5.0 g, 45 mmol) and pyridine (7.2 g, 90 mmol) in acetone (120 mL), was added 3-chloropropanoyl chloride (6.3 g, 49.5 mmol). The mixture was heated to 50° C. for 12 h under nitrogen. After cooling the reaction to room temperature, the mixture was concentrated in vacuo. Water (200 mL) was added and the mixture was acidified with HCl (1 N) to pH 7 and then extracted with EtOAc (200 mL×3). The combined organic layers were washed with brine (100 mL×3), dried over anhydrous Na2SO4 and concentrated in vacuo to give the title compound (9 g, 99%) as a brown solid.
-
- To a solution of 3-chloro-N-(3-fluorophenyl)propanamide (2.0 g, 9.9 mmol) was added AlCl3 (5.0 g, 37.9 mmol). The mixture was heated to 120° C. for 5 h under a nitrogen atmosphere. After cooling the reaction to room temperature, ice (20 g) and conc. HCl (15 mL) were added. The resulting precipitate was filtered, washed with H2O (20 mL) and recrystallized from EtOH. The precipitate was collected and dried to give the title compound (1.0 g, 62%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.42 (s, 1H), 7.13-7.10 (m, 1H), 6.72-6.67 (m, 1H), 6.56-6.53 (m, 1H), 2.95 (t, J=7.2 Hz, 2H), 2.65 (t, J=7.6 Hz, 2H).
-
- To a solution of 7-fluoro-3,4-dihydroquinolin-2(1H)-one (1.0 g, 6.0 mmol) in THF (20 mL) was added BH3-THF (18 mL, 18 mmol). The mixture was heated to 70° C. for 12 h under a nitrogen atmosphere. After cooling the reaction to room temperature, MeOH (10 mL) and conc. HCl (4 mL) were added. The mixture was concentrated in vacuo. The crude residue was dissolved in EtOAc (50 mL), washed with sat. aq. NaHCO3 (20 mL×2) and brine (20 mL×2), dried over anhydrous Na2SO4 and concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc=10:1) to give the title compound (730 mg, 80%) as a colorless oil. LCMS M/Z (M+H) 151.
-
- To a solution of 7-fluoro-1,2,3,4-tetrahydroquinoline (3.0 g, 20 mmol) and triethylamine (6.1 g, 60 mmol) in DCM (100 mL) was added DMAP (cat.) and di-tert-butyl dicarbonate (6.5 g, 30 mmol). The mixture was stirred at 20° C. for 12 h under a nitrogen atmosphere. The mixture was concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc=20:1) to give the title compound (600 mg, 12%) as a brown oil.
-
- To a solution of tert-butyl 7-fluoro-3,4-dihydroquinoline-1(2H)-carboxylate (600 mg, 2.4 mmol) in DCM (20 mL) was added N-bromosuccinimide (420 mg, 2.4 mmol). The mixture was stirred at 15° C. for 2 h under a nitrogen atmosphere. Water (30 mL) was added and the mixture was extracted with DCM (20 mL×2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc=10:1) to give the title compound (500 mg, 63%) as a brown oil.
-
- To a solution of tert-butyl 6-bromo-7-fluoro-3,4-dihydroquinoline-1(2H)-carboxylate (500 mg, 1.5 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (320 mg, 1.5 mmol) and K2CO3 (520 mg, 3.8 mmol) in dioxane (20 mL) and H2O (2 mL) was added [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (70 mg, 0.1 mmol). The mixture was heated to 90° C. for 12 h under a nitrogen atmosphere. After cooling the reaction to room temperature, the mixture was concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc=3:1) to give the title compound (300 mg, 61%) as a brown oil. LCMS M/Z (M+H) 332.
-
- To a solution of tert-butyl 7-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylate (300 mg, 0.9 mmol) in DCM (10 mL) was added trifluoroacetic acid (5 mL). The mixture was stirred at 18° C. for 2 h under a nitrogen atmosphere. The mixture was concentrated in vacuo to give the crude residue that was dissolved in EtOAc (50 mL), washed with sat. aq. NaHCO3 (50 mL×2) and brine (50 mL×2), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc=3:1) to give the title compound (130 mg, 65%) as a brown solid. 1H NMR (400 MHz, CDCl3) δ 7.72 (s, 1H), 7.62 (s, 1H), 7.08 (d, J=8.8 Hz, 1H), 6.23 (d, J=12.4 Hz, 1H), 3.93 (s, 3H), 3.31 (t, J=5.2 Hz, 2H), 2.75 (t, J=6.4 Hz, 2H), 1.97-1.91 (m, 2H).
-
- To a solution of 7-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinoline (200 mg, 0.86 mmol) in dioxane (10 mL) was added 1-(3-bromo-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone (Intermediate I, 312 mg, 0.95 mmol), chloro(2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (67 mg, 0.09 mmol), 2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl (40 mg, 0.09 mmol) and t-BuONa (333 mg, 3.46 mmol). The mixture was heated to 120° C. for 16 h under a nitrogen atmosphere. After cooling the reaction to room temperature, the mixture was concentrated in vacuo. The crude residue was purified by reverse phase chromatography (acetonitrile 30-60%/0.1% NH4HCO3 in water) to give the title compound (75 mg, 18%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.75-7.73 (m, 1H), 7.64-7.60 (m, 1H), 7.19-7.11 (m, 1H), 6.28-6.24 (m, 1H), 4.31-4.11 (m, 5H), 3.92-3.90 (m, 4H), 3.76-3.65 (m, 3H), 3.55-3.55 (m, 2H), 2.85-2.75 (m, 4H), 2.32-2.29 (m, 2H), 2.11-2.05 (m, 5H), 1.88-1.60 (m, 2H). LCMS M/Z (M+H) 479.
- The following compounds were prepared in a similar fashion to Example 141:
-
-
Example Compound Name NMR m/z Example 142 1-[3-[7-fluoro-6-(1- 1H NMR (400 MHz, DMSO-d6) δ 7.91 (s, 465 methylpyrazol-4-yl)- 1H), 7.71 (s. 1H), 7.30 (d, J = 8.8 Hz, 3,4-dihydro-2H- 1H), 6.29-6.20 (m, 1H), 4.94-4.88 (m, quinolin-1-yl]-1- 1H), 4.18-4.15 (m, 2H), 4.03-3.94 (m, tetrahydrofuran-3-yl- 2H), 3.84 (s, 3H), 3.82-3.69 (m, 2H), 6,7-dihydro-4H- 3.53-3.51 (m, 2H), 3.48-3.41 (m, 2H), pyrazolo[4,3- 2.86-2.66 (m, 4H), 2.33-2.21 (m, 2H), c]pyridin-5- 2.07-1.90 (m, 5H) yl]ethanone Example 143 1-[3-[7-fluoro-6-(1- 1H NMR (400 MHz, DMSO-d6) δ 7.91 (s, 465 methylpyrazol-4-yl)- 1H), 7.71 (s, 1H), 7.30 (d, J = 8.8 Hz, 3,4-dihydro-2H- 1H), 6.29-6.20 (m, 1H), 4.94-4.88 (m, quinolin-1-yl]-1-[(3S)- 1H), 4.18-4.15 (m, 2H), 4.03-3.94 (m, tetrahydrofuran-3-yl]- 2H), 3.84 (s, 3H), 3.82-3.69 (m, 2H), 6,7-dihydro-4H- 3.53-3.51 (m, 2H), 3.48-3.41 (m, 2H), pyrazolo[4,3- 2.86-2.66 (m, 4H), 2.33-2.21 (m, 2H), c]pyridin-5- 2.07-1.94 (m, 5H) yl]ethanone Example 144 1-[3-[7-fluoro-6-(1- 1H NMR (400 MHz, DMSO-d6) δ 7.89 (s, 451 methylpyrazol-4-yl)- 1H), 7.70 (s, 1H), 7.31 (d, J = 8.8 Hz, 3,4-dihydro-2H- 1H), 6.31-6.23 (m, 1H), 5.45-5.42 (m, quinolin-1-yl]-1- 1H), 4.89-4.83 (m, 4H), 4.14-4.12 (m, (oxetan-3-yl)-6,7- 2H), 3.82 (s, 3H), 3.70-3.66 (m, 2H), dihydro-4H- 3.58-3.57 (m, 2H), 2.77-2.63 (m, 4H), pyrazolo[4,3- 2.03-1.93 (m, 5H) c]pyridin-5- yl]ethanone -
-
- To a solution of quinolin-7-ol (5 g, 34.44 mmol) and Cs2CO3 (22.46 g, 68.89 mmol) in DMF (50 mL) was added iodomethane (2.1 mL, 34.44 mmol). The mixture was stirred at 20° C. for 12 h under a nitrogen atmosphere. Water (100 mL) was added and the mixture was extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine (100 mL×3), dried over anhydrous Na2SO4 and concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc=10:1) to give the title compound (2.0 g, 25%) as a yellow oil.
-
- To a solution of 7-methoxyquinoline (800 mg, 5.03 mmol) in MeOH (8 mL) was added PtO2 (137 mg, 0.6 mmol). The mixture was heated to 76° C. for 12 h under a hydrogen atmosphere (15 psi). After cooling the reaction to room temperature, the mixture was concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc=10:1) to give the title compound (350 mg, 38%) as a yellow solid.
-
- To a solution of 1-[3-bromo-1-[(3S)-tetrahydrofuran-3-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (Intermediate G, 566 mg, 1.8 mmol), 7-methoxy-1,2,3,4-tetrahydroquinoline (353 mg, 2.16 mmol) and t-BuONa (346 mg, 3.6 mmol) in toluene (5 mL) was added chloro(2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl)[2-(2-aminoethylphenyl)]palladium(II), methyl-tert-butylether adduct (146.91 mg, 0.18 mmol) and 2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl (84 mg, 0.18 mmol). The mixture was heated to 120° C. for 12 h under a nitrogen atmosphere. After cooling the reaction to room temperature, the mixture was concentrated in vacuo. The crude residue was purified by silica gel chromatography (DCM/MeOH=100:1) to give the title compound (240 mg, 26%) as a red oil. LCMS M/Z (M+H) 397.
-
- To a solution of 1-[3-(7-methoxy-3,4-dihydro-2H-quinolin-1-yl)-1-[(3S)-tetrahydrofuran-3-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (442 mg, 1.11 mmol) in DCM (5 mL) was added N-bromosuccinimide (198 mg, 1.11 mmol). The mixture was stirred at 20° C. for 1 h under a nitrogen atmosphere. Water (50 mL) was added and the mixture was extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine (30 mL×3), dried over anhydrous Na2SO4 and concentrated in vacuo to give the title compound (320 mg, crude) as a yellow oil that required no further purification. LCMS M/Z (M+H) 475.
-
- To a solution of 1-[3-(6-bromo-7-methoxy-3,4-dihydro-2H-quinolin-1-yl)-1-[(3S)-tetrahydrofuran-3-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (320 mg, 0.67 mmol) in dioxane (3 mL) and water (1 mL) was added [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (49 mg, 0.07 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (168 mg, 0.81 mmol) and Na2CO3 (143 mg, 1.35 mmol). The mixture was heated to 110° C. for 12 h under a nitrogen atmosphere. After cooling the reaction to room temperature, the mixture was concentrated in vacuo. The crude residue was purified by reverse phase chromatography (acetonitrile 30-16%/0.2% formic acid in water) to give the title compound (85 mg, 24%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.90 (s, 1H), 7.72 (s, 1H), 7.19 (s, 1H), 6.29 (s, 1H), 4.95-4.86 (m, 1H), 4.19-4.22 (m, 2H), 4.00-3.92 (m, 2H), 3.82-3.55 (m, 6H), 3.80 (s, 3H), 3.61 (s, 3H), 2.83-2.72 (m, 4H), 2.38-2.12 (m, 2H), 2.07-1.91 (m, 5H). LCMS M/Z (M+H) 477.
-
-
- To a solution of quinolin-7-ol (1 g, 6.89 mmol) and (2-chloro-2,2-difluoro-acetyl)oxysodium (10.5 g, 68.89 mmol) in DMF (10 mL) and water (10 mL) was added K2CO3 (9.51 g, 68.89 mmol). The mixture was heated to 100° C. for 12 h under a nitrogen atmosphere. After cooling the reaction to room temperature, the mixture was concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc=20:1) to give the title compound (240 mg, 16%) as a yellow solid.
-
- To a solution of 7-(difluoromethoxy)quinoline (230 mg, 1.18 mmol) and NaBH3CN (371 mg, 5.89 mmol) in MeOH (5 mL) was added boron trifluoride diethyl etherate (0.29 mL, 2.36 mmol). The mixture was heated to 80° C. for 12 h under a nitrogen atmosphere. Water (20 mL) was added and the mixture was extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine (30 mL×3), dried over anhydrous Na2SO4 and concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc=100:1) to give the title compound (120 mg, 44%) as a white solid. 1H NMR (CDCl3) δ 6.89 (d, J=8.0 Hz, 1H), 6.43 (t, J=74.8 Hz, 1H), 6.34-6.32 (m, 1H), 6.22 (s, 1H), 3.30 (t, J=5.2 Hz, 2H), 2.72 (t, J=6.8 Hz, 2H), 1.95-1.89 (m, 2H).
-
- To a solution of 1-(3-bromo-1-tetrahydropyran-4-yl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl)ethanone (Intermediate I, 500 mg, 1.4 mmol), t-BuONa (269 mg, 2.8 mmol) and 7-(difluoromethoxy)-1,2,3,4-tetrahydroquinoline (335 mg, 1.68 mmol) in dioxane (5 mL) was added 2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl (65 mg, 0.14 mmol) and chloro(2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (109 mg, 0.14 mmol). The mixture was heated to 120° C. for 12 h under a nitrogen atmosphere. After cooling the reaction to room temperature, the mixture was concentrated in vacuo. The crude residue was purified by silica gel chromatography (DCM/MeOH=100:1) to give the title compound (340 mg, 43%) as a yellow oil. LCMS M/Z (M+H) 447.
-
- To a solution of 1-[3-[7-(difluoromethoxy)-3,4-dihydro-2H-quinolin-1-yl]-1-tetrahydropyran-4-yl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (340 mg, 0.61 mmol) in DCM (3 mL) was added N-bromosuccinimide (0.12 g, 0.67 mmol). The mixture was stirred at 30° C. for 1 h. Water (50 mL) was added and the mixture was extracted with EtOAc (50 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (250 mg, crude) as yellow oil that required no further purification. LCMS M/Z (M+H) 525.
-
- To a solution of 1-[3-[6-bromo-7-(difluoromethoxy)-3,4-dihydro-2H-quinolin-1-yl]-1-tetrahydropyran-4-yl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (300 mg, 0.46 mmol) in dioxane (3 mL) and water (1 mL) was added [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (41 mg, 0.05 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (114 mg, 0.55 mmol) and Na2CO3 (99 mg, 0.91 mmol). The mixture was heated to 100° C. for 12 h under a nitrogen atmosphere. After cooling the reaction to room temperature, the mixture was concentrated in vacuo. The crude residue was purified by reverse phase chromatography (acetonitrile 1-28%/0.2% formic acid in water) to give the title compound (38 mg, 15%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.87 (s, 1H), 7.71 (s, 1H), 7.29 (s, 1H), 6.93 (t, J=74.4 Hz, 1H), 6.46-6.43 (m, 1H), 4.31-4.24 (m, 1H), 4.20-4.18 (m, 2H), 3.95-3.93 (m, 2H), 3.84 (s, 3H), 3.75-3.67 (m, 2H), 3.55-3.53 (m, 2H), 3.47-3.44 (m, 2H), 2.85-2.73 (m, 4H), 2.08-1.94 (m, 7H), 1.87-1.81 (m, 2H). LCMS M/Z (M+H) 527.
- The following compounds were prepared in a similar fashion to Example 146:
-
-
Example Compound Name NMR m/z Example 147 1-[3-[7- 1H NMR (400 MHz, DMSO-d6) δ 7.86 (s, 499 (difluoromethoxy)-6- 1H), 7.69 (s, 1H), 7.30 (s, 1H), 6.94 (t, J = (1-methylpyrazol-4- 74.4 Hz, 1H), 6.47-6.43 (m, 1H), 5.46- yl)-3,4-dihydro-2H- 5.43 (m, 1H), 4.90-4.80 (m, 4H), 4.15- quinolin-1-yl]-1- 4.12 (m, 2H), 3.81 (s, 3H), 3.65-3.57 (m, (oxetan-3-yl)-6,7- 4H), 2.79-2.75 (m, 4H), 2.47-1.91(m, dihydro-4H- 5H) pyrazolo[4,3- c]pyridin-5- yl]ethanone Example 148 1-[3-[7- 1H NMR (400 MHz, DMSO-d6) δ 7.88 (s, 513 (difluoromethoxy)-6- 1H), 7.71 (s, 1H), 7.30 (s, 1H), 6.94 (t, J = (1-methylpyrazol-4- 74.4 Hz, 1H), 6.46-6.43 (m, 1H), 4.85- yl)-3,4-dihydro-2H- 4.94 (m, 1H), 4.19-4.17 (m, 2H), 4.01- quinolin-1-yl]-1-[(3S)- 3.92 (m, 2H), 3.84 (s, 3H), 3.80-3.69 (m, tetrahydrofuran-3-yl]- 4H), 3.56-3.54 (m, 2H), 3.84-3.77 (m, 6,7-dihydro-4H- 4H), 2.15-2.35 (m, 2H), 2.08-1.98 (m, pyrazolo[4,3- 5H) c]pyridin-5- yl]ethanone -
-
- To a solution of 2-bromo-5-(trifluoromethoxy)aniline (7 g, 27.34 mmol), ethyl acrylate (4.4 mL, 40.95 mmol) and triethylamine (7.6 mL, 54.68 mmol) in MeCN (70 mL) was added palladium(II) acetate (614 mg, 2.73 mmol) and tris(2-methylphenyl)phosphine (2.24 g, 8.2 mmol). The mixture was heated to 120° C. for 12 h under a nitrogen atmosphere. After cooling the reaction to room temperature, the mixture was concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc=100:1 to 50:1 to 20:1) to give the title compound (2.8 g, 29%) as a yellow oil.
-
- To a solution of ethyl (E)-3-[2-amino-4-(trifluoromethoxy)phenyl]prop-2-enoate (500 mg, 1.82 mmol) in MeOH (5 mL) was added 10% Pd/C (50 mg, 1.82 mmol). The mixture was stirred at 20° C. for 12 h under a hydrogen atmosphere (15 Psi). The mixture was concentrated in vacuo to give the title compound (410 mg, crude) as yellow oil that required no further purification. LCMS M/Z (M+H) 278.
-
- To a solution of ethyl 3-[2-amino-4-(trifluoromethoxy)phenyl]propanoate (2.7 g, 7.79 mmol) in AcOH (27 mL) was added conc. HCl (0.65 mL, 7.79 mmol). The mixture was heated to 90° C. for 1 h under a nitrogen atmosphere. After cooling the reaction to room temperature, ice water (20 mL) was added and the mixture was made basic with NaOH (2 N) to pH 9 and then extracted with EtOAc (100 mL×3). The combined organic layers were washed with brine (100 mL×3), dried over anhydrous Na2SO4 and concentrated in vacuo to give the title compound (1.8 g, crude) as a yellow solid that required no further purification. LCMS M/Z (M+H) 232.
-
- To a solution of 7-(trifluoromethoxy)-3,4-dihydro-1H-quinolin-2-one (500 mg, 1.73 mmol) in THF (5 mL) was added lithium aluminium hydride (85 mg, 2.25 mmol). The mixture was stirred at 20° C. for 12 h under a nitrogen atmosphere. Water (1 mL) was added and the mixture was filtered and concentrated in vacuo to give the title compound (0.35 g, crude) as yellow oil that required no further purification. LCMS M/Z (M+H) 218.
-
- To a solution of 1-[3-bromo-1-[(3S)-tetrahydrofuran-3-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (Intermediate G, 400 mg, 1.21 mmol), 7-(trifluoromethoxy)-1,2,3,4-tetrahydroquinoline (371 mg, 1.45 mmol) and t-BuONa (256 mg, 2.42 mmol) in dioxane (4 mL), was added chloro(2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl)[2-(2-aminoethylphenyl)]palladium(II), methyl-tert-butylether adduct (99 mg, 0.12 mmol) and 2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl (57 mg, 0.12 mmol). The mixture was heated to 120° C. for 12 h under a nitrogen atmosphere. After cooling the reaction to room temperature, the mixture was concentrated in vacuo. The crude residue was purified by silica gel chromatography (DCM/MeOH=100:1) to give the title compound (200 mg, 29%) as yellow oil. LCMS M/Z (M+H) 451.
-
- To a solution of 1-[1-[(3S)-tetrahydrofuran-3-yl]-3-[7-(trifluoromethoxy)-3,4-dihydro-2H-quinolin-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (300 mg, 0.53 mmol) in DCM (2 mL) was added N-bromosuccinimide (95 mg, 0.53 mmol). The mixture was stirred at 26° C. for 1 h. Water (50 mL) was added and the mixture was extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine (30 mL×3), dried over anhydrous Na2SO4 and concentrated in vacuo to give the title compound (310 mg, crude) as yellow oil that required no further purification. LCMS M/Z (M+H) 531.
-
- To a solution of 1-[3-[6-bromo-7-(trifluoromethoxy)-3,4-dihydro-2H-quinolin-1-yl]-1-[(3S)-tetrahydrofuran-3-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (310 mg, 0.47 mmol) in dioxane (3 mL) and water (1 mL) was added Na2CO3 (99 mg, 0.94 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (117 mg, 0.56 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (34 mg, 0.05 mmol). The mixture was heated to 120° C. for 12 h under a nitrogen atmosphere. After cooling the reaction to room temperature, the mixture was concentrated in vacuo. The crude residue was purified by reverse phase chromatography (acetonitrile 35-16%/0.2% formic acid in water) to give the title compound (13 mg, 5%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.88 (s, 1H), 7.67 (s, 1H), 7.33 (s, 1H), 6.60-6.56 (m, 1H), 4.93-4.89 (m, 1H), 4.21-4.15 (m, 2H), 4.23-4.02 (m, 2H), 3.85 (s, 3H), 3.73-3.68 (m, 4H), 3.55-3.53 (m, 2H), 2.85-2.80 (m, 4H), 2.08-1.96 (m, 5H). LCMS M/Z (M+H) 531.
-
-
- To a solution of 6-(1-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinoline (
Step 1 of Example 65, 3.0 g, 14.1 mmol) in dioxane (30 mL) was added (S)-tert-butyl 3-bromo-1-(tetrahydrofuran-3-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5 (4H)-carboxylate (Intermediate F, 6.3 g, 16.9 mmol), Cs2CO3 (9.2 g, 28.1 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (814 mg, 1.41 mmol) and tris(dibenzylideneacetone)dipalladium (644 mg, 0.70 mmol). The mixture was heated to 110° C. for 16 h under a nitrogen atmosphere. After cooling the reaction to room temperature, the mixture was filtered and the filtrate was concentrated in vacuo. The crude residue was purified by silica gel chromatography (DCM/MeOH=30:1) to give the title compound (4.0 g, 56%) as a brown solid. -
- To a solution of (S)-tert-butyl 3-(6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1-(tetrahydrofuran-3-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (4.0 g, 7.93 mmol) in DCM (40 mL) was added trifluoroacetic acid (10 mL). The mixture was stirred at 30° C. for 3 h, added sat. aq. NaHCO3 (200 mL) and the mixture was extracted with DCM (100 mL×2). The combined organic layers were washed with brine (100 mL×3), dried over anhydrous Na2SO4 and concentrated in vacuo. The crude residue was purified by silica gel chromatography (DCM/MeOH=20:1) to give the title compound (1.9 g, 59%) as a brown solid.
-
- To a solution of (S)-6-(1-methyl-1H-pyrazol-4-yl)-1-(1-(tetrahydrofuran-3-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-1,2,3,4-tetrahydroquinoline (200 mg, 0.49 mmol) in DCM (5 mL) was added trimethylsilyl isocyanate (114 mg, 0.99 mmol). The mixture was stirred at 30° C. for 3 h and concentrated in vacuo. The crude residue was purified by reverse phase chromatography (acetonitrile 27-57%/0.1% NH4OH in water) to give the title compound (125 mg, 57%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.91 (s, 1H), 7.67 (s, 1H), 7.18 (s, 1H), 7.09 (d, J=8.0 Hz, 1H), 6.41 (d, J=8.4 Hz, 1H), 6.05 (s, 2H), 4.93-4.84 (m, 1H), 4.05-3.91 (m, 4H), 3.85-3.74 (m, 5H), 3.56 (m, 4H), 2.80 (t, J=6.0 Hz, 2H), 2.70 (s, 2H), 2.32-2.16 (m, 2H), 2.01-1.89 (m, 2H). LCMS M/Z (M+H) 448.
- The following compounds were prepared in a similar fashion to Example 150:
-
-
Example Compound Name NMR m/z Example 151 3-[6-(1-methylpyrazol- 1H NMR (400 MHz, DMSO-d6) δ 7.89 (s, 434 4-yl)-3,4-dihydro-2H- 1H), 7.65 (s, 1H), 7.18 (s, 1H), 7.09 (d, J = quinolin-1-yl]-1- 8.4 Hz, 1H), 6.46 (d, J = 8.4 Hz, 1H), 6.01 (s, (oxetan-3-yl)-6,7- 2H), 5.45-5.38 (m, 1H), 4.90 (t, J = 8.4 Hz, dihydro-4H- 2H), 4.83 (t, J = 8.4 Hz, 2H), 3.94 (s, 2H), pyrazolo[4,3- 3.88 (s, 3H), 3.59-3.51 (m, 4H), 2.80 (t, J = c]pyridine-5- 6.0 Hz, 2H), 2.62-2.60 (m, 3H), 1.97-1.91 carboxamide (m, 2H) Example 152 3-[7- 1H NMR (400 MHz, DMSO-d6) δ 7.87 (s, 528 (difluoromethoxy)-6- 1H), 7.71 (s, 1H), 7.29 (s, 1H), 6.95 (t, J = (1-methylpyrazol-4-yl)- 74.4 Hz, 1H), 6.45 (s, 1H), 6.10 (s, 2H), 4.31- 3,4-dihydro-2H- 4.24 (m, 1H), 4.08 (s, 2H), 3.94-3.92 (m, quinolin-1-yl]-1- 2H), 3.84 (s, 3H), 3.60-3.53 (m, 4H), 3.48- tetrahydropyran-4-yl- 3.42 (m, 2H), 2.81-2.71(m, 4H), 2.07-1.94 6,7-dihydro-4H- (m, 4H), 1.81-1.78 (m, 2H) pyrazolo[4,3- c]pyridine-5- carboxamide Example 153 3-[7-cyano-6-(1- 1H NMR (400 MHz, DMSO-d6) δ 8.06 (s, 487 methylpyrazol-4-yl)- 1H), 7.79 (s, 1H), 7.34 (s, 1H), 6.72 (s, 1H), 3,4-dihydro-2H- 4.32-4.30 (m, 1H), 4.07 (s, 2H), 3.96-3.93 quinolin-1-yl]-1- (m, 2H), 3.87 (s, 3H), 3.64-3.61 (m, 2H), tetrahydropyran-4-yl- 3.57-3.54 (m, 2H), 3.46-3.42 (m, 2H), 2.88- 6,7-dihydro-4H- 2.85 (m, 2H), 2.76-2.75 (m, 2H), 1.98- pyrazolo[4,3- 1.92 (m, 4H), 1.84-1.81 (m, 2H) c]pyridine-5- carboxamide Example 154 3-[7-(difluoromethyl)- 1H NMR (400 MHz, DMSO-d6) δ 7.75 (s, 498 6-(1-methylpyrazol-4- 1H), 7.49 (s, 1H), 7.09 (s, 1H), 6.84 (s, 1H), yl)-3,4-dihydro-2H- 6.78 (t, J = 55.2 Hz, 1H), 6.07 (s, 2H), 4.94- quinolin-1-yl]-1-[(3S)- 4.89 (m, 1H), 4.03-3.86 (m, 4H), 3.82 (s, tetrahydrofuran-3-yl]- 3H), 3.80-3.78 (m, 2H), 3.59-3.57 (m, 4H), 6,7-dihydro-4H- 2.83-2.74 (m, 4H), 2.29-2.21 (m, 2H), 1.98- pyrazolo[4,3- 1.96 (m, 2H) c]pyridine-5- carboxamide Example 155 3-[7-(difluoromethyl)- 1H NMR (400 MHz, DMSO-d6) δ 7.75 (s, 512 6-(1-methylpyrazol-4- 1H), 7.50 (s, 1H), 7.09 (s, 1H), 6.83 (s, 1H), yl)-3,4-dihydro-2H- 6.78 (t, J = 55.2 Hz, 1H), 6.08 (s, 2H), 4.31- quinolin-1-yl]-1- 4.26 (m, 1H), 4.02 (s, 2H), 3.97-3.94 (m, tetrahydropyran-4-yl- 2H), 3.86 (s, 3H), 3.60-3.55 (m, 4H), 3.48- 6,7-dihydro-4H- 3.42 (m, 2H), 2.84-2.67 (m, 4H), 2.00-1.94 pyrazolo[4,3- (m, 4H), 1.83-1.80 (m, 2H) c]pyridine-5- carboxamide -
- To a solution of (S)-6-(1-methyl-1H-pyrazol-4-yl)-1-(1-(tetrahydrofuran-3-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-1,2,3,4-tetrahydroquinoline (200 mg, 0.49 mmol) in DMF (3 mL) was added 4-nitrophenyl carbonochloridate (150 mg, 0.74 mmol) and pyridine (117 mg, 1.48 mmol). The mixture was stirred at 30° C. for 4 h before a solution of methanamine in THF (1M, 2.5 mL, 2.50 mmol) was added. The mixture was heated to 70° C. for 16 h. After cooling the reaction to room temperature, the mixture was concentrated in vacuo. The crude residue was purified by Prep-TLC (DCM/MeOH=20:1) to give the title compound (26 mg, 23%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 7.90 (s, 1H), 7.67 (s, 1H), 7.18 (s, 1H), 7.09 (d, J=8.4 Hz, 1H), 6.54 (d, J=4.0 Hz, H), 6.40 (d, J=8.0 Hz, H), 4.90-4.86 (m, 1H), 4.06-3.90 (m, 5H), 3.87-3.70 (m, 7H), 3.61-3.52 (m, 4H), 2.81-2.70 (m, 4H), 2.32-2.16 (m, 2H), 1.98-1.93 (m, 2H). LCMS M/Z (M+H) 462.
- The following compounds were prepared in a similar fashion to Example 156:
-
-
Example Compound Name NMR m/z Example 157 3-[7-(difluoromethoxy)-6- 1H NMR (400 MHz, DMSO-d6) δ 7.87 (s, 542 (1-methylpyrazol-4-yl)- 1H), 7.71 (s, 1H), 7.29 (s, 1H), 6.93 (t, J = 3,4-dihydro-2H-quinolin- 74.4 Hz, 1H), 6.55 (d, J = 4.4 Hz, 1H), 1-yl]-N-methyl-1- 6.43 (s, 1H), 4.29-4.26 (m, 1H), 4.07 (s, tetrahydropyran-4-yl-6,7- 2H), 3.95-3.92 (m, 2H), 3.84 (s, 3H), 3.60- dihydro-4H-pyrazolo[4,3- 3.52 (m, 4H), 3.44 (t, J = 11.6 Hz, 2H), c]pyridine-5-carboxamide 2.81-2.70 (m, 4H), 2.54 (d, J = 4.4 Hz, 3H), 2.07-1.93 (m, 4H), 1.80-1.77 (m, 2H) Example 158 3-[7-cyano-6-(1- 1H NMR (400 MHz, DMSO-d6) δ 8.06 (s, 487 methylpyrazol-4-yl)-3,4- 1H), 7.79 (s, 1H), 7.35 (s, 1H), 6.74 (s, dihydro-2H-quinolin-1- 1H), 6.57-6.56 (m, 1H), 4.95-4.89 (m, yl]-N-methyl-1-[(3S)- 1H), 4.04-3.95 (m, 4H), 3.88 (s, 3H), 3.82- tetrahydrofuran-3-yl]-6,7- 3.80 (m, 2H), 3.61-3.55 (m, 4H), 2.89- dihydro-4H-pyrazolo[4,3- 2.85 (m, 2H), 2.73-2.70 (m, 2H), 2.55 (d, c]pyridine-5-carboxamide J = 4.8 Hz, 3H), 2.30-2.20 (m, 2H), 1.99- 1.96 (m, 2H) Example 159 3-[7-cyano-6-(1- 1H NMR (400 MHz, DMSO-d6) δ 8.06 (s, 501 methylpyrazol-4-yl)-3,4- 1H), 7.79 (s, 1H), 7.35 (s, 1H), 6.70, (s, dihydro-2H-quinolin-1- 1H), 6.57-6.56 (m, 1H), 4.33-4.28 (m, yl]-N-methyl-1- 1H), 4.05 (s, 2H), 3.99-3.94 (m, 2H), 3.88 tetrahydropyran-4-yl-6,7- (s, 3H), 3.62-3.56 (m, 4H), 3.48-3.40 dihydro-4H-pyrazolo[4,3- (m, 3H), 2.87-2.74 (m, 4H), 2.55-2.54 c]pyridine-5-carboxamide (m, 3H), 1.98-1.81 (m, 6H) Example 160 3-[6-(1,5-dimethylpyrazol- 1H NMR (400 MHz, DMSO-d6) δ 7.41 (s, 490 4-yl)-3,4-dihydro-2H- 1H), 7.00 (s, 1H), 6.92 (d, J = 8.0 Hz, 1H), quinolin-1-yl]-N-methyl-1- 6.54 (s, 1H), 6.45 (d, J = 8.0 Hz, 1H), 4.18- tetrahydropyran-4-yl-6,7- 4.08 (m, 1H), 4.07-3.88 (m, 4H), 3.74 dihydro-4H-pyrazolo[4,3- (s, 3H), 3.65-3.50 (m, 4H), 3.48-3.41 c]pyridine-5-carboxamide (m, 2H), 2.81-2.70 (m, 4H), 2.52 (s, 3H), 2.03-1.87 (m, 4H), 1.85-1.71 (m, 2H) Example 161 3-[7-(difluoromethyl)-6- 1H NMR (400 MHz, DMSO-d6) δ 7.75 (s, 534 (1-methylpyrazol-4-yl)- 1H), 7.50 (s, 1H), 7.10 (s, 1H), 6.83 (s, 3,4-dihydro-2H-quinolin- 1H), 6.79 (t, J = 55.2 Hz, 1H), 6.56-6.55 1-yl]-N-methyl-1-[(3S)- (m, 1H), 4.93-4.89 (m, 1H), 4.04-3.96 tetrahydrofuran-3-yl]-6,7- (m, 4H), 3.87 (s, 3H), 3.86-3.71 (m, 2H), dihydro-4H-pyrazolo[4,3- 3.60-3.55 (m, 4H), 2.84-2.60 (m, 4H), c]pyridine-5-carboxamide 2.55-2.53 (m, 3H), 2.28-2.22 (m, 2H), 1.98-1.95 (m, 2H) Example 162 3-[7-(difluoromethyl)-6- 1H NMR (400 MHz, DMSO-d6) δ 7.76- 526 (1-methylpyrazol-4-yl)- 7.75 (m, 1H), 7.49 (s, 1H), 7.10 (s, 1H), 3,4-dihydro-2H-quinolin- 6.83 (s, 1H), 6.92-6.78 (t, J = 55.2 Hz, 1-yl]-N-methyl-1- 1H), 6.65-6.53 (m, 1H), 4.31-4.28 (m, tetrahydropyran-4-yl-6,7- 1H), 4.13-3.93 (m, 4H), 3.86 (s, 3H), 3.69- dihydro-4H-pyrazolo[4,3- 3.58 (m, 4H), 3.48-3.42 (m, 2H), 2.84- c]pyridine-5-carboxamide 2.74 (m, 4H), 2.54-2.53 (m, 3H), 1.97- 1.80 (m, 6H) Example 163 3-(7-(difluoromethyl)-6- 1H NMR (400 MHz, DMSO-d6) δ 8.84- 580 (6- 8.82 (m, 1H), 8.55 (s, 1H), 8.07 (d, J = 8.0 (methylcarbamoyl)pyridin- Hz, 1H), 7.92-7.90 (m, 1H), 7.13 (s, 1H), 3-yl)-3,4-dihydroquinolin- 6.89 (s, 1H), 6.75 (t, J = 54.8 Hz, 1H), 6.57 1(2H)-yl)-N-methyl-1- (d, J = 4.0 Hz, 1H), 4.37-4.24 (m, 1H), (tetrahydro-2H-pyran-4- 4.07 (s, 2H), 3.95 (d, J = 8.0 Hz, 2H), 3.64- yl)-6,7-dihydro-1H- 3.60 (m, 4H), 3.46 (t, J = 11.6 Hz, 2H), pyrazolo[4,3-c]pyridine- 2.94-2.70 (m, 7H), 2.55 (d, J = 4.0 Hz, 5(4H)-carboxamide 3H), 2.06-1.91 (m, 4H), 1.82-1.76 (m, 1H) Example 164 3-(6-(difluoromethyl)-5- 1H NMR (400 MHz, DMSO-d6) δ 7.80 (s, 512 (1-methyl-1H-pyrazol-4- 1H), 7.77 (s, 1H), 7.52 (s, 1H), 7.19 (s, yl)indolin-1-yl)-N-methyl- 1H), 6.83 (t, J = 55.6 Hz, 1H), 6.62-6.61 1-(tetrahydro-2H-pyran-4- (m, 1H), 4.41 (s, 2H), 4.27-4.21 (m, 1H), yl)-6,7-dihydro-1H- 4.06 (t, J = 10.0 Hz, 2H), 3.98-3.95 (m, pyrazolo[4,3-c]pyridine- 2H), 3.88 (s, 3H), 3.60 (t, J = 6.0 Hz, 2H), 5(4H)-carboxamide 3.49-3.43 (m, 2H), 3.18 (t, J = 8.0 Hz, 2H), 2.70-2.65 (m, 2H), 2.59 (d, J = 4.0 Hz, 3H), 2.05-1.98 (m, 2H), 1.80-1.77 (m, 2H) Example 165 N-methyl-3-(6-(6- 1H NMR (400 MHz, DMSO-d6) δ 8.83 (d, 530 (methylcarbamoyl)pyridin- J = 1.6 Hz, 1H), 8.71 (d, J = 5.2 Hz, 1H), 3-yl)-3,4-dihydroquinolin- 8.15-8.12 (m, 1H), 8.00 (d, J = 8.8 Hz, 1(2H)-yl)-1-(tetrahydro- 1H), 7.49 (s, 1H), 7.40-7.38 (m, 1H), 6.55- 2H-pyran-4-yl)-6,7- 6.51 (m, 2H), 4.31-4.26 (m, 1H), 4.02 dihydro-1H-pyrazolo[4,3- (s, 2H), 3.96-3.94 (m, 2H), 3.61-3.57 c]pyridine-5(4H)- (m, 4H), 3.48-3.45 (m, 2H), 2.89 (t, J = carboxamide 6.8 Hz, 2H), 2.82 (d, J = 5.2 Hz, 3H), 2.75- 2.70 (m, 2H), 2.53 (d, J = 4.8 Hz, 3H), 2.02-1.93 (m, 4H), 1.82-1.80 (m, 2H) -
- To a solution of (S)-6-(1-methyl-1H-pyrazol-4-yl)-1-(1-(tetrahydrofuran-3-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-1,2,3,4-tetrahydroquinoline (200 mg, 0.49 mmol) in DMF (3 mL) was added dimethylcarbamic chloride (106 mg, 0.99 mmol) and triethylamine (149 mg, 1.47 mmol). The mixture was stirred at 30° C. for 16 h. The mixture was filtered and the filtrate was concentrated in vacuo. The crude residue was purified by reverse phase chromatography (acetonitrile 31-61%/0.1% NH4OH in water) to give the title compound (108 mg, 46%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.91 (s, 1H), 7.68 (s, 1H), 7.19 (s, 1H), 7.12-7.08 (m, 1H), 6.40 (d, J=8.4 Hz, 1H), 4.93-4.84 (m, 1H), 4.06-3.93 (m, 2H), 3.86-3.71 (m, 7H), 3.55-3.50 (m, 2H), 3.40-3.36 (m, 2H), 2.84-2.75 (m, 4H), 2.69 (s, 6H), 2.35-2.17 (m, 2H), 1.98-1.88 (m, 2H). LCMS M/Z (M+H) 476.
- The following compound was prepared in a similar fashion to Example 166:
-
-
Example Compound Name NMR m/z Example 167 methyl 3-[7- 1H NMR (400 MHz, DMSO-d6) δ 7.76 (s, 513 (difluoromethyl)-6-(1- 1H), 7.51 (s, 1H), 7.10 (s, 1H), 6.81 (s, 1H), methylpyrazol-4-yl)- 6.79 (t, J = 55.2 Hz, 1H), 4.93-4.89 (m, 1H), 3,4-dihydro-2H- 4.09 (s, 2H), 4.06-3.81 (m, 2H), 3.80 (s, quinolin-1-yl]-1-[(3S)- 3H), 3.77-3.71 (m, 2H), 3.67-3.57 (m, 7H), tetrahydrofuran-3-yl]- 2.88-2.65 (m, 4H), 2.28-2.22 (m, 2H), 1.97- 6,7-dihydro-4H- 1.94 (m, 2H) pyrazolo[4,3- c]pyridine-5- carboxylate -
-
- To a solution of 6-bromoindoline (5 g, 25.1 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (6.3 g, 30.3 mmol) in dioxane (80 mL) and water (20 mL) was added Na2CO3 (8.03 g, 75.7 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.83 g, 2.51 mmol). The mixture was heated to 100° C. for 12 h under a nitrogen atmosphere. After cooling the reaction to room temperature, water (200 mL) was added and the mixture was extracted with EtOAc (200 mL×2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc=1:1) to give the title compound (1.8 g, 36%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.70 (s, 1H), 7.54 (s, 1H), 7.10 (d, J=8.0 Hz, 1H), 6.83 (d, J=8.0 Hz, 1H), 6.77 (s, 1H), 3.93 (s, 3H), 3.59 (t, J=8.4 Hz, 2H), 3.04 (t, J=8.4 Hz, 2H).
-
- A mixture of 1-(3-bromo-1-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl)ethanone (Intermediated B, 200 mg, 0.77 mol), 6-(1-methylpyrazol-4-yl)indoline (154 mg, 0.77 mmol), 2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl (36 mg, 0.08 mmol), chloro(2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl)[2-(2-aminoethylphenyl)]palladium(II), methyl-tert-butylether adduct (63 mg, 0.08 mmol), t-BuONa (223 mg, 2.32 mmol) in 1,4-dioxane (4 mL) was heated to 120° C. for 12 h. After cooling the reaction to room temperature, the mixture was diluted with water (20 mL), extracted with DCM (20 mL×2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by reverse phase chromatography (acetonitrile 8-38%/0.2% formic acid in water) to give the title compound (39 mg, 13%) as a white solid. 1H NMR (400 MHz, CD3OD) δ 7.86 (d, J=4.8 Hz, 1H), 7.71 (s, 1H), 7.13-7.11 (m, 1H), 7.00-6.90 (m, 2H), 4.53-4.47 (m, 2H), 3.97-3.85 (m, 4H), 3.90 (s, 3H), 3.71 (s, 3H), 3.19-3.11 (m, 2H), 2.86-2.75 (m, 2H), 2.22-2.08 (m, 3H). LCMS M/Z (M+H) 377.
- The following compounds were prepared in a similar fashion to Example 168:
-
-
Example Compound Name NMR m/z Example 169 1-[1-methyl-3-[5-(1- 1H NMR (400 MHz, CD3OD) δ 7.79 (s, 377 methylpyrazol-4- 1H), 7.69 (s, 1H), 7.32 (d, J = 4.8 Hz, yl)indolin-1-yl]-6,7- 1H), 7.24-7.21 (m, 1H), 6.91-6.87 (m, dihydro-4H- 1H), 4.52-4.48 (m, 2H), 3.97-3.83 (m, pyrazolo[4,3-c]pyridin- 4H), 3.89 (s, 3H), 3.68 (s, 3H), 3.17- 5-yl]ethanone 3.13 (m, 2H), 2.84-2.73 (m, 2H), 2.20- 2.12 (m, 3H) Example 170 1-[1- 1H NMR (400 MHz, CD3OD) δ 7.85 (s, 417 (cyclopropylmethyl)-3- 1H), 7.71 (s, 1H), 7.14-7.04 (m, 2H), [6-(1-methylpyrazol-4- 6.94-6.90 (m, 1H), 4.55-4.50 (m, 2H), yl)indolin-1-yl]-6,7- 3.99-3.85 (m, 6H), 3.90 (s, 3H), 3.15- dihydro-4H- 3.13 (m, 2H), 2.90-2.78 (m, 2H), 2.22- pyrazolo[4,3-c]pyridin- 2.10 (m, 3H), 1.26-1.25 (m, 1H), 0.63- 5-yl]ethanone 0.57 (m, 2H), 0.43-0.41 (m, 2H) Example 171 1-[3-[5-(1- 1H NMR (400 MHz, CDCl3) δ 7.69 (s, 433 methylpyrazol-4- 1H), 7.51 (s, 1H), 7.41-7.13 (m, 3H), yl)indolin-1-yl]-1- 4.74-4.71 (m, 1H), 4.68-4.48 (m, 2H), tetrahydrofuran-3-yl- 4.12-4.06 (m, 2H), 4.04-4.01 (m, 4H), 6,7-dihydro-4H- 3.99 (s, 3H), 3.93-3.75 (m, 2H), 3.21- pyrazolo[4,3-c]pyridin- 3.17 (m, 2H), 2.73-2.70 (m, 2H), 2.45- 5-yl]ethanone 2.32 (m, 2H), 2.20-2.15 (m, 3) Example 172 1-[1- 1H NMR (400 MHz, CD3OD) δ 7.16- 337 (cyclopropylmethyl)-3- 7.13 (m, 1H), 7.05-7.04 (m, 1H), 6.90- indolin-1-yl-6,7- 6.87 (m, 1H), 6.73-6.72 (m, 1H), 4.52- dihydro-4H- 4.49 (m, 2H), 3.96-3.86 (m, 6H), 3.16- pyrazolo[4,3-c]pyridin- 3.14 (m, 2H), 2.88-2.78 (m, 2H), 2.22- 5-yl]ethanone 2.15 (m, 3H), 1.29-1.27 (m, 1H), 0.61- 0.58 (m, 2H), 0.42-0.38 (m, 2H) Example 173 1-(3-indolin-1-yl-1- 1H NMR (400 MHz, CD3OD) δ 7.12- 297 methyl-6,7-dihydro- 7.08 (m, 1H), 7.01-6.97 (m, 1H), 6.83- 4H-pyrazolo[4,3- 6.79 (m, 1H), 6.69-6.68 (m, 1H), 4.47- c]pyridin-5- 4.43 (m, 2H), 3.92-3.80 (m, 4H), 3.66 yl)ethanone (s, 3H), 3.11-3.09 (m, 2H), 2.81-2.71 (m, 2H), 2.18-2.09 (m, 3H) Example 174 1-[3-[5-(1- 1H NMR (400 MHz, DMSO-d6) δ 7.94 (s, 446 methylpyrazol-4- 1H), 7.71 (s, 1H), 7.44-7.24 (m, 3H), yl)indolin-1-yl]-1- 4.55-4.53 (m, 2H), 4.27-4.19 (m, 1H), tetrahydropyran-4-yl- 4.04-3.96 (m, 4H), 3.83 (s, 3H), 3.74- 6,7-dihydro-4H- 3.70 (m, 2H), 3.48-3.42 (m, 2H), 3.14- pyrazolo[4,3-c]pyridin- 3.10 (m, 2H), 2.80-2.68 (m, 2H), 2.10- 5-yl]ethanone 1.99 (m, 5H), 1.79-1.77 (m, 2H) Example 175 1-[3-[5-(1- 1H NMR (400 MHz, DMSO-d6) δ 7.95 (s, 419 methylpyrazol-4- 1H), 7.73 (s, 1H), 7.56-7.47 (m, 1H), yl)indolin-1-yl]-1- 5.44-4.41 (m, 1H), 5.50-4.96 (m, 2H), (oxetan-3-yl)-6,7- 4.86-4.84 (m, 2H), 4.55-4.54 (m, 2H), dihydro-4H- 4.08-4.01 (m, 2H), 3.83 (s, 3H), 3.71- pyrazolo[4,3-c]pyridin- 3.68 (m, 2H), 3.17-3.15 (m, 2H), 2.74- 5-yl]ethanone 2.61 (m, 2H), 2.50-2.09 (m, 3) Example 176 1-[1-methyl-3-[5′-(1- 1H NMR (400 MHz, CD3OD) δ 7.76- 403 methylpyrazol-4- 7.77 (m, 1H), 7.66 (s, 1H), 7.17-7.21 yl)spiro[cyclopropane- (m, 1H), 6.91-6.97 (m, 1H), 6.81-6.82 1,3′-indoline]-1′-yl]- (m, 1H), 4.47-4.51 (m, 2H), 3.97 (s, 6,7-dihydro-4H- 2H), 3.79-3.89 (m, 5H), 3.66-3.67 (m, pyrazolo[4,3-c]pyridin- 3H), 2.70-2.82 (m, 2H), 2.11-2.18 (m, 5-yl]ethanone 3H), 1.04-1.11 (m, 4H) -
- Racemic 1-[3-[5-(1-methylpyrazol-4-yl)indolin-1-yl]-1-tetrahydrofuran-3-yl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (Example 71, 50 mg) was separated by using chiral SFC (
Chiralcel OJ 250×30 mm I.D., 10 um; Supercritical CO2/MeOH (0.1% NH3 H2O)=50/50 at 70 mL/min) to give (R)-1-[3-[5-(1-methylpyrazol-4-yl)indolin-1-yl]-1-tetrahydrofuran-3-yl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (5 mg, first peak) and (S)-1-[3-[5-(1-methylpyrazol-4-yl)indolin-1-yl]-1-tetrahydrofuran-3-yl-6, 7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (27 mg, second peak). Absolute configuration was arbitrarily assigned to each enantiomer. Example 177: 1H NMR (400 MHz, DMSO-d6) δ 7.94 (s, 1H), 7.72 (s, 1H), 7.42-7.32 (m, 2H), 7.26-7.23 (m, 1H), 4.89-4.83 (m, 1H), 4.55-4.53 (m, 2H), 4.05-3.97 (m, 4H), 3.86-3.70 (m, 7H), 3.14-3.10 (m, 2H), 2.80-2.67 (m, 2H), 2.26-2.23 (m, 2H), 2.10-2.28 (m, 3H). LCMS M/Z (M+H) 433. Example 178: 1H NMR (400 MHz, DMSO-d6) δ 7.94 (s, 1H), 7.72 (s, 1H), 7.42-7.32 (m, 2H), 7.26-7.23 (m, 1H), 4.88-4.86 (m, 1H), 4.55-4.53 (m, 2H), 4.03-3.96 (m, 4H), 3.86-3.70 (m, 7H), 3.14-3.10 (m, 2H), 2.80-2.67 (m, 2H), 2.26-2.24 (m, 2H), 2.10-2.28 (m, 3H). LCMS M/Z (M+H) 433. -
-
- To a solution of 5-bromoindoline (3.3 g, 16.7 mmol) in DCM (33 mL) at room temperature was added 4-dimethylaminopyridine (0.21 g, 1.7 mmol), di-iso-propylethyl amine (4.3 g, 33.4 mmol) and di-tert-butyldicarbonate (5.8 g, 26.7 mmol). The resulting mixture was stirred at room temperature for 16 h and then concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc=9:1) to give the title compound (3.63 g, 73%) as a white solid.
-
- To a solution of tert-butyl 5-bromoindoline-1-carboxylate (6 g, 20.12 mmol) in dioxane (100 mL) was added [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.5 g, 2.01 mmol), KOAc (6 g, 60.37 mmol) and 4,4,4′,4′,5,5,5′,5′-Octamethyl-2,2′-bi(1,3,2-dioxaborolane) (6.1 g, 24.15 mmol). The mixture was heated to 80° C. for 12 h under a nitrogen atmosphere. After cooling the reaction to room temperature, the mixture was concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc=10:1) to give the title compound (5.5 g, 80%) as a yellow solid.
-
- To a solution of tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indoline-1-carboxylate (2.5 g, 7.24 mmol) in dioxane (20 mL) and H2O (4 mL) was added Na2CO3 (1.5 g, 14.48 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (500 mg, 0.7 mmol) and 4-bromo-1-methyl-3-(trifluoromethyl)-1H-pyrazole (1.7 g, 7.24 mmol). The mixture was heated to 120° C. for 12 h under a nitrogen atmosphere. After cooling the reaction to room temperature, the mixture was concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc=1:1) to give the title compound (2.3 g, 86%) as a yellow solid. LCMS M/Z (M+H) 368.
-
- To a solution of tert-butyl 5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)indoline-1-carboxylate (2.3 g, 6.26 mmol) in EtOAc (10 mL) was added HCl/EtOAc (4 M, 10 mL) at 0° C. The mixture was stirred at room temperature for 1 h and concentrated in vacuo. Water (20 mL) was added and the mixture was made basic with solid NaHCO3 to pH 8 and then the mixture extracted with EtOAc (50 mL×2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (1.6 g, 95%) as a yellow solid. LCMS M/Z (M+H) 268.
-
- To a solution of 5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)indoline (600 mg, 2.25 mmol) in dioxane (10 mL) was added 1-(3-bromo-1-(tetrahydrofuran-3-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone (705 mg, 2.25 mmol), chloro(2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl)[2-(2-aminoethylphenyl)]palladium(II), methyl-tert-butylether adduct (167 mg, 0.23 mmol), 2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl (107 mg, 0.23 mmol) and t-BuONa (863 mg, 8.98 mmol). The mixture was heated to 120° C. for 12 h under a nitrogen atmosphere. After cooling the reaction to room temperature, the mixture was concentrated in vacuo. The crude residue was purified by reverse phase chromatography (acetonitrile 15-45%/0.1% NH4HCO3 in water) to give the title compound (150 mg, 13%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.01 (s, 1H), 7.42-7.33 (m, 1H), 7.13 (s, 1H), 7.07-7.05 (m, 1H), 4.90-4.86 (m, 1H), 4.55-4.54 (m, 2H), 4.05-4.00 (m, 4H), 3.99 (s, 3H), 3.99-3.86 (m, 2H), 3.85-3.70 (m, 2H), 3.14 (t, J=8.0 Hz, 2H), 2.80-2.67 (m, 2H), 2.26-2.24 (m, 2H), 2.10-2.08 (m, 3H). LCMS M/Z (M+H) 501.
- The following compounds were prepared in a similar fashion to Example 179:
-
-
Example Compound Name NMR m/z Example 180 1-[1-methyl-3-[5-[1- 1H NMR (400 MHz, CD3OD) δ 7.74 (s, 1H), 445 methyl-3- 7.17 (s, 1H), 7.11-7.08 (m, 1H), 6.94-6.91 (trifluoromethyl)pyrazol- (m, 1H), 4.53-4.49 (m, 2H), 3.99-3.97 (m, 4-yl]indolin-1-yl]-6,7- 2H), 3.94 (s, 3H), 3.88-3.81 (m, 2H), 3.68 (s, dihydro-4H- 3H), 3.14 (t, J = 8.0 Hz, 2H), 2.82-2.72 (m, pyrazolo[4,3-c]pyridin- 2H), 2.22-2.13 (m, 3H) 5-yl]ethanone Example 181 1-[3-[5-[1-methyl-3- 1H NMR (400 MHz, DMSO-d6) δ 8.02 (s, 487 (trifluoromethyl)pyrazol- 1H), 7.58-7.47 (m, 1H), 7.15 (s, 1H), 7.13- 4-yl]indolin-1-yl]-1- 7.09 (m, 1H), 5.47-5.43 (m, 1H), 4.98-4.95 (oxetan-3-yl)-6,7- (m, 2H), 4.87-4.82 (m, 2H), 4.56-4.54 (m, dihydro-4H- 2H), 4.09-4.00 (m, 2H), 3.93 (s, 3H), 3.71- pyrazolo[4,3-c]pyridin- 3.67 (m, 2H), 3.19-3.15 (m, 2H), 2.74-2.61 5-yl]ethanone (m, 2H), 2.09-2.07 (m, 3H) -
- Racemic 1-[3-[5-[1-methyl-3-(trifluoromethyl)pyrazol-4-yl]indolin-1-yl]-1-tetrahydrofuran-3-yl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (Example 179, 120 mg) was separated by using chiral SFC (Chiralcel OJ 250×30 mm I.D., 5 um; Supercritical CO2/MeOH(0.1% NH3 H2O)=65/35 at 50 mL/min) to give (R)-1-[3-[5-[1-methyl-3-(trifluoromethyl)pyrazol-4-yl]indolin-1-yl]-1-tetrahydrofuran-3-yl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (47 mg, first peak) and (S)-1-[3-[5-[1-methyl-3-(trifluoromethyl)pyrazol-4-yl]indolin-1-yl]-1-tetrahydrofuran-3-yl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (32 mg, second peak). Absolute configuration was arbitrarily assigned to each enantiomer. Example 182: 1H NMR (400 MHz, DMSO-d6) δ 8.01 (s, 1H), 7.42-7.33 (m, 1H), 7.13 (s, 1H), 7.07-7.05 (m, 1H), 4.90-4.89 (m, 1H), 4.55-4.54 (m, 2H), 4.05-4.00 (m, 4H), 3.99 (s, 3H), 3.99-3.86 (m, 2H), 3.85-3.70 (m, 2H), 3.15 (t, J=8.0 Hz, 2H), 2.80-2.67 (m, 2H), 2.26-2.24 (m, 2H), 2.10-2.08 (m, 3H). LCMS M/Z (M+H) 501. Example 183: 1H NMR (400 MHz, DMSO-d6) δ 8.01 (s, 1H), 7.42-7.33 (m, 1H), 7.12 (s, 1H), 7.06-7.04 (m, 1H), 4.89-4.86 (m, 1H), 4.54-4.53 (m, 2H), 4.04-4.00 (m, 4H), 3.99 (s, 3H), 3.98-3.85 (m, 2H), 3.83-3.69 (m, 2H), 3.14 (t, J=8.0 Hz, 2H), 2.80-2.67 (m, 2H), 2.25-2.24 (m, 2H), 2.09-2.07 (m, 3H). LCMS M/Z (M+H) 501.
-
-
- To a solution of tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indoline-1-carboxylate (1.5 g, 4.34 mmol) in dioxane (15 mL) and H2O (3 mL) was added K2CO3 (1.2 g, 8.69 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (290 mg, 0.4 mmol) and 4-bromo-1,5-dimethyl-1H-pyrazole (912 mg, 5.21 mmol). The mixture was heated to 120° C. for 12 h under a nitrogen atmosphere. After cooling the reaction to room temperature, the mixture was concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc=1:1) to give the title compound (1.2 g, 88%) as a yellow solid. LCMS M/Z (M+H) 314.
-
- To a solution of tert-butyl 5-(1,5-dimethyl-1H-pyrazol-4-yl)indoline-1-carboxylate (1.2 g, 3.83 mmol) in EtOAc (10 mL) was added HCl in EtOAc (4 M, 10 mL). The resulting mixture was stirred at room temperature for 1 h and concentrated in vacuo. Water (20 mL) was added and the mixture was mad basic with solid NaHCO3 to pH 8 and then extracted with EtOAc (50 mL×2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (700 mg, 74%) as a yellow solid.
-
- To a solution of 5-(1,5-dimethyl-1H-pyrazol-4-yl)indoline (400 mg, 1.88 mmol) in dioxane (10 mL) was added 1-(3-bromo-1-(tetrahydrofuran-3-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone (590 mg, 1.88 mmol), chloro(2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl)[2-(2-aminoethylphenyl)]palladium(II), methyl-tert-butylether adduct (136 mg, 0.19 mmol), 2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl (88 mg, 0.19 mmol) and tBuONa (721 mg, 7.5 mmol). The mixture was heated to 120° C. for 12 h under a nitrogen atmosphere. After cooling the reaction to room temperature, the mixture was concentrated in vacuo. The crude residue was purified by silica gel chromatography (DCM/MeOH=20:1) to give the title compound (200 mg, 24%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.45-7.35 (m, 2H), 7.14 (s, 1H), 7.06-7.03 (m, 1H), 4.90-4.83 (m, 1H), 4.56-4.54 (m, 2H), 4.05-3.95 (m, 4H), 3.88-3.82 (m, 4H), 3.75 (s, 3H), 3.14 (t, J=8.8 Hz, 2H), 2.80-2.67 (m, 2H), 2.33 (s, 3H), 2.26-2.24 (m, 2H), 2.10-2.08 (m, 3H). LCMS M/Z (M+H) 447.
-
- Racemic 1-[3-[5-(1,5-dimethylpyrazol-4-yl)indolin-1-yl]-1-tetrahydrofuran-3-yl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (Example 184, 167 mg) was separated by using chiral SFC (
Chiralcel OJ 250×30 mm I.D., 5 um; Supercritical CO2/MeOH (0.1% NH3H2O)=65/35 at 50 mL/min) to give (R)-1-[3-[5-(1,5-dimethylpyrazol-4-yl)indolin-1-yl]-1-tetrahydrofuran-3-yl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (76 mg, first peak) and (S)-1-[3-[5-(1,5-dimethylpyrazol-4-yl)indolin-1-yl]-1-tetrahydrofuran-3-yl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (68 mg, second peak). Absolute configuration was arbitrarily assigned to each enantiomer. Example 185: 1H NMR (400 MHz, DMSO-d6) δ 7.45-7.43 (m, 2H), 7.14 (s, 1H), 7.06-7.03 (m, 1H), 4.89-4.83 (m, 1H), 4.55-4.54 (m, 2H), 4.03-3.97 (m, 4H), 3.85-3.70 (m, 4H), 3.75 (s, 3H), 3.14 (t, J=8.8 Hz, 2H), 2.80-2.67 (m, 2H), 2.32 (s, 3H), 2.25-2.24 (m, 2H), 2.10-2.08 (m, 3H). LCMS M/Z (M+H) 447. Example 186: 1H NMR (400 MHz, DMSO-d6) δ 7.45-7.43 (m, 2H), 7.14 (s, 1H), 7.06-7.03 (m, 1H), 4.90-4.83 (m, 1H), 4.56-4.54 (m, 2H), 4.03-3.97 (m, 4H), 3.86-3.70 (m, 4H), 3.83 (s, 3H), 3.14 (t, J=8.8 Hz, 2H), 2.80-2.67 (m, 2H), 2.33 (s, 3H), 2.26-2.24 (m, 2H), 2.10-2.08 (m, 3H). LCMS M/Z (M+H) 447. -
-
- To a solution of tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indoline-1-carboxylate (1.8 g, 5.32 mmol) in dioxane (20 mL) and H2O (4 mL) was added K2CO3 (2 g, 14.52 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (350 mg, 0.5 mmol) and 4-bromo-1-methyl-1H-pyrazole-3-carbonitrile (0.9 g, 4.84 mmol). The mixture was heated to 120° C. for 12 h under a nitrogen atmosphere. After cooling the reaction to room temperature, the mixture was concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc=1:1) to give the title compound (1.13 g, 70%) as yellow solid. LCMS M/Z (M+Ht-Bu) 269.
-
- To a solution of tert-butyl 5-(3-cyano-1-methyl-1H-pyrazol-4-yl)indoline-1-carboxylate (1.13 g, 3.50 mmol) in EtOAc (10 mL) was added HCl/EtOAc (4 M, 4 mL). The mixture was stirred at room temperature for 1 h and concentrated in vacuo. Water (20 mL) was added and the mixture was made basic with solid NaHCO3 to pH 8 and then extracted with EtOAc (50 mL×2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (0.79 g, 90%) as yellow solid.
-
- To a solution of 4-(indolin-5-yl)-1-methyl-1H-pyrazole-3-carbonitrile (500 mg, 2.23 mmol) in dioxane (10 mL) was added 1-(3-bromo-1-(tetrahydrofuran-3-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone (770 mg, 2.45 mmol), chloro(2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl)[2-(2-aminoethylphenyl)]palladium(II), methyl-tert-butylether adduct (160 mg, 0.22 mmol), 2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl (100 mg, 0.22 mmol) and t-BuONa (856 mg, 8.91 mmol). The mixture was heated to 120° C. for 12 h. After cooling the reaction to room temperature, the mixture was concentrated in vacuo. The crude residue was purified by silica gel chromatography (DCM/MeOH=20:1) to give the title compound (250 mg, 24%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.24 (s, 1H), 7.49-7.32 (m, 3H), 4.90-4.84 (m, 1H), 4.56-4.54 (m, 2H), 4.10-3.99 (m, 4H), 3.95 (s, 3H), 3.86-3.70 (m, 4H), 3.17 (t, J=8.0 Hz, 2H), 2.80-2.68 (m, 2H), 2.26-2.25 (m, 2H), 2.10-2.08 (m, 3H). LCMS M/Z (M+H) 458.
-
- Racemic 4-(1-(5-acetyl-1-(tetrahydrofuran-3-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)indolin-5-yl)-1-methyl-1H-pyrazole-3-carbonitrile (Example 187, 200 mg) was separated by using chiral SFC (Chiralcel OJ 250×30 mm I.D., 5 um; Supercritical CO2/MeOH (0.1% NH3H2O)=60/40 at 80 mL/min) to give (R)-4-(1-(5-acetyl-1-(tetrahydrofuran-3-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)indolin-5-yl)-1-methyl-1H-pyrazole-3-carbonitrile (62 mg, first peak) and (S)-4-(1-(5-acetyl-1-(tetrahydrofuran-3-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)indolin-5-yl)-1-methyl-1H-pyrazole-3-carbonitrile (65 mg, second peak). Absolute configuration was arbitrarily assigned to each enantiomer. Example 188: 1H NMR (400 MHz, DMSO-d6) δ 8.25 (s, 1H), 7.49-7.35 (m, 3H), 4.89-4.87 (m, 1H), 4.56-4.54 (m, 2H), 4.07-3.99 (m, 4H), 3.95 (s, 3H), 3.86-3.70 (m, 4H), 3.17 (t, J=8.0 Hz, 2H), 2.81-2.68 (m, 2H), 2.27-2.25 (m, 2H), 2.10-2.08 (m, 3H). LCMS M/Z (M+H) 458. Example 189: 1H NMR (400 MHz, DMSO-d6) δ 8.25 (s, 1H), 7.49-7.33 (m, 3H), 4.89-4.85 (m, 1H), 4.56-4.54 (m, 2H), 4.10-3.99 (m, 4H), 3.95 (s, 3H), 3.86-3.70 (m, 4H), 3.17 (t, J=8.0 Hz, 2H), 2.81-2.68 (m, 2H), 2.27-2.23 (m, 2H), 2.10-2.08 (s, 3H). LCMS M/Z (M+H) 458.
-
-
- To a solution of 6-fluoroindoline (5 g, 36.46 mmol) in DCM (100 mL) was added DMAP (445 mg, 3.65 mmol), triethylamine (15 mL, 109 mmol) and di-tert-butyl dicarbonate (9.5 g, 43.75 mmol). The resulting mixture was stirred at room temperature for 16 h. The mixture was concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc=50:1) to give the title compound (6.8 g, 78%) as a white solid.
-
- To a solution of tert-butyl 6-fluoroindoline-1-carboxylate (3 g, 12.64 mmol) in DCM (50 mL), was added N-bromosuccinimide (2.7 g, 15.17 mmol). The mixture was stirred at room temperature for 2 h. The mixture was concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc=20:1) to give the title compound (3.6 g, 90%) as a yellow solid.
-
- To a solution of tert-butyl 5-bromo-6-fluoroindoline-1-carboxylate (1.5 g, 4.74 mmol) in dioxane/H2O (12 mL, 5/1) was added 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.09 g, 5.22 mmol), K2CO3 (1.3 g, 9.5 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (340 mg, 0.47 mmol). The mixture was irradiated in a microwave at 120° C. for 0.5 h. After cooling the reaction to room temperature, the mixture was concentrated in vacuo. The crude residue was purified by silica gel chromatography (DCM/MeOH=20:1) to give the title compound (900 mg, 60%) as a yellow solid. LCMS M/Z (M+H) 318.
-
- To a solution of tert-butyl 6-fluoro-5-(1-methyl-1H-pyrazol-4-yl)indoline-1-carboxylate (900 mg, 2.84 mmol) in EtOAc (10 mL) was added HCl in EtOAc (4 M, 2 mL). The resulting mixture was stirred at room temperature for 1 h and then concentrated in vacuo. Water (20 mL) was added and the mixture was made basic with solid NaHCO3 to pH 8 and then extracted with EtOAc (50 mL×2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (400 mg, crude) as a light yellow solid that required no further purification.
-
- To a solution of 6-fluoro-5-(1-methyl-1H-pyrazol-4-yl)indoline (200 mg, 0.9 mmol) in dioxane (5 mL) was added 1-(3-bromo-1-(tetrahydrofuran-3-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone (318 mg, 1.01 mmol), chloro(2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl)[2-(2-aminoethylphenyl)]palladium(II), methyl-tert-butylether adduct (70 mg, 0.09 mmol), 2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl (40 mg, 0.09 mmol) and tBuONa (306 mg, 3.18 mmol). The mixture was irradiated in a microwave at 120° C. for 0.5 h. After cooling the reaction to room temperature, the mixture was concentrated in vacuo. The crude residue was purified by silica gel chromatography (DCM/MeOH=10:1) to give the title compound (60 mg, 15%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.94 (s, 1H), 7.75 (s, 1H), 7.40-7.25 (m, 2H), 4.59-4.56 (m, 1H), 4.58-4.57 (m, 2H), 4.13-4.00 (m, 4H), 3.86-3.82 (m, 5H), 3.73-3.69 (m, 2H), 3.17-3.10, (m, 2H), 2.80-2.67 (m, 2H), 2.32-2.24 (m, 2H), 2.10-2.09 (m, 3H). LCMS M/Z (M+H) 451.
- The following compound was prepared in a similar fashion to Example 190:
-
-
Example Compound Name NMR m/z Example 191 1-[3-[6-fluoro-5-(1- 1H NMR (400 MHz, DMSO-d6) δ 7.91 (s, 395 methylpyrazol-4- 1H), 7.71 (s, 1H), 7.37-7.35 (m, 1H), 7.27- yl)indolin-1-yl]-1- 7.16 (m, 1H), 4.53-4.51 (m, 2H), 4.07- methyl-6,7-dihydro- 3.97 (m, 2H), 3.93 (s, 3H), 3.70-3.65 (m, 2 4H-pyrazolo[4,3- H), 3.61 (s, 3H), 3.11-3.06 (m, 2H), 2.74- c]pyridin-5- 2.60 (m, 2H), 2.07-2.05 (m, 3H) yl]ethanone -
-
- To a stirred solution of 5-bromo-3-methyl-1H-indole (1.0 g, 4.76 mmol) in AcOH (10 mL) was added NaBH3CN (898 mg, 14.28 mmol) portionwise. The mixture was stirred at room temperature for 4 h under a nitrogen atmosphere. The mixture was concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc=20:1) to give the title compound (400 mg, 40%) as a colorless oil.
-
- To a stirred solution of 5-bromo-3-methylindoline (200 mg, 0.94 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (216 mg, 1.04 mmol) and K2CO3 (391 mg, 2.83 mmol) in dioxane/H2O (3.0 mL, 3:1) was added [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (70 mg, 0.094 mmol). The mixture was irradiated in a microwave at 120° C. for 0.5 h. After cooling the reaction to room temperature, water (10 mL) was added and the mixture was extracted with EtOAc (10 mL×3). The combined organic layers were washed with sat. aq. NaHCO3 (10 mL×3), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc=3:1) to give the title compound (120 mg, 60%) as a light yellow oil.
-
- To a solution of 3-methyl-5-(1-methyl-1H-pyrazol-4-yl)indoline (110 mg, 0.52 mmol), 1-(3-bromo-1-methyl-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5 (4H)-yl)ethanone (Intermediate B, 160 mg, 0.62 mmol) and t-BuONa (149 mg, 1.53 mmol) in dioxane (2.0 mL) was added chloro(2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl)[2-(2-aminoethylphenyl)]palladium(II), methyl-tert-butylether adduct (42 mg, 0.052 mmol), 2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl (24 mg, 0.052 mmol). The mixture was irradiated in a microwave at 120° C. for 45 min. After cooling the reaction to room temperature, water (10 mL) was added and the mixture was extracted with EtOAc (10 mL×3). The combined organic layers were washed with sat. aq. NaHCO3 (10 mL×3), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by reverse phase chromatography (acetonitrile 25-55%/0.1% NH4HCO3 in water) to give the title compound (50 mg, 25%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.93 (s, 1H), 7.70 (s, 1H), 7.29 (s, 1H), 7.23-7.15 (m, 2H), 4.48-4.46 (m, 2H), 4.14-4.06 (m, 1H), 3.80 (s, 3H), 3.68-3.65 (m, 2H), 3.59 (s, 3H), 3.47-3.41 (m, 2H), 2.74-2.58 (m, 2H), 2.07-2.04 (m, 3H), 1.31 (d, J=4.4 Hz, 3H). LCMS M/Z (M+H) 391.
-
- Racemic 1-[1-methyl-3-[3-methyl-5-(1-methylpyrazol-4-yl)indolin-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (Example 192, 160 mg) was separated by using chiral SFC (Chiralpak AS-
H 150*4.6 mm I.D., 5 um Mobile phase: ethanol (0.05% diethylamine) in CO2 from 5% to 40% Flow rate: 60 mL/min) to give (R)-1-[1-methyl-3-[3-methyl-5-(1-methylpyrazol-4-yl)indolin-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (38 mg, first peak) and (S)-1-[1-methyl-3-[3-methyl-5-(1-methylpyrazol-4-yl)indolin-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (42 mg, second peak). Absolute configuration was arbitrarily assigned to each enantiomer. Example 193: 1H NMR (400 MHz, DMSO-d6) δ 7.93 (s, 1H), 7.70 (s, 1H), 7.29 (s, 1H), 7.23-7.15 (m, 2H), 4.48-4.47 (m, 2H), 4.14-4.06 (m, 1H), 3.80 (s, 3H), 3.68-3.65 (m, 2H), 3.59 (s, 3H), 3.47-3.41 (m, 2H), 2.74-2.58 (m, 2H), 2.07-2.04 (m, 3H), 1.31 (d, J=4.4 Hz, 3H). LCMS M/Z (M+H) 391. Example 194: 1H NMR (400 MHz, DMSO-d6) δ 7.93 (s, 1H), 7.70 (s, 1H), 7.29 (s, 1H), 7.23-7.15 (m, 2H), 4.48-4.47 (m, 2H), 4.14-4.06 (m, 1H), 3.80 (s, 3H), 3.68-3.65 (m, 2H), 3.59 (s, 3H), 3.47-3.41 (m, 2H), 2.74-2.58 (m, 2H), 2.07-2.04 (m 3H), 1.31 (d, J=4.4 Hz, 3H). LCMS M/Z (M+H) 391. -
- To a solution of 3-methyl-5-(1-methyl-1H-pyrazol-4-yl)indoline (185 mg, 0.87 mmol), (R)-1-(3-bromo-1-(tetrahydrofuran-3-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5 (4H)-yl)ethanone (300 mg, 0.95 mmol) and t-BuONa (25 mg, 2.6 mmol) in dioxane (5 mL), was added chloro(2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl)[2-(2-aminoethylphenyl)]palladium(ii), methyl-tert-butylether adduct (74 mg, 0.088 mmol), 2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl (41 mg, 0.088 mmol). The mixture was heated to 120° C. for 12 h under a nitrogen atmosphere. After cooling the reaction to room temperature, water (10 mL) was added and the mixture was extracted with EtOAc (10 mL×3). The combined organic layers were washed with sat. aq. NaHCO3 (10 mL×3), dried over anhydrous Na2SO4 and concentrated in vacuo. The crude residue was purified by reverse phase chromatography (acetonitrile 25-55%/0.1% NH4HCO3 in water) to give racemic (R)-1-[1-methyl-3-[3-methyl-5-(1-methylpyrazol-4-yl)indolin-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (120 mg, 31%) as a white solid which was separated by using chiral SFC (Chiralcel OJ-3 50*4.6 mm I.D., 3 um Mobile phase: ethanol (0.05% diethylamine) in CO2 from 5% to 40% Flow rate: 80 mL/min) to give (R,R)-1-[3-[3-methyl-5-(1-methylpyrazol-4-yl)indolin-1-yl]-1-tetrahydrofuran-3-yl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (32 mg, first peak) and (R,S)-1-[3-[3-methyl-5-(1-methylpyrazol-4-yl)indolin-1-yl]-1-tetrahydrofuran-3-yl-6, 7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (24 mg, second peak). Absolute configuration was arbitrarily assigned to each diastereomer. Example 195: 1H NMR (400 MHz, DMSO-d6) δ 7.95 (s, 1H), 7.72 (s, 1H), 7.40-7.23 (m, 3H), 4.88-4.83 (m, 1H), 4.54-4.53 (m, 2H), 4.16-4.02 (m, 1H), 4.00-3.98 (m, 2H), 3.85-3.77 (m, 7H), 3.68-3.44 (m, 2H), 2.78-2.66 (m, 2H), 2.24-2.21 (m, 2H), 2.09-2.07 (m, 3H), 1.34 (d, J=6.4 Hz, 3H). LCMS M/Z (M+H) 447. Example 196: 1H NMR (400 MHz, DMSO-d6) δ 7.95 (s, 1H), 7.72 (s, 1H), 7.40-7.23 (m, 3H), 4.88-4.83 (m, 1H), 4.54-4.53 (m, 2H), 4.16-4.02 (m, 1H), 4.00-3.98 (m, 2H), 3.85-3.77 (m, 7H), 3.68-3.44 (m, 2H), 2.78-2.66 (m, 2H), 2.24-2.21 (m, 2H), 2.09-2.07 (m, 3H), 1.34 (d, J=6.4 Hz, 3H). LCMS M/Z (M+H) 447.
-
- To a solution of 3-methyl-5-(1-methyl-1H-pyrazol-4-yl)indoline (185 mg, 0.87 mmol), (S) 1-(3-bromo-1-(tetrahydrofuran-3-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5 (4H)-yl)ethanone (Intermediate G, 300 mg, 0.95 mmol) and t-BuONa (25 mg, 2.6 mmol) in dioxane (5 mL), was added chloro(2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl)[2-(2-aminoethylphenyl)]palladium(II), methyl-tert-butylether adduct (74 mg, 0.088 mmol) and 2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl (41 mg, 0.088 mmol). The mixture was heated to 120° C. for 12 h under a nitrogen atmosphere. After cooling the reaction to room temperature, water (10 mL) was added and the mixture was extracted with EtOAc (10 mL×3). The combined organic layers were washed with sat. aq. NaHCO3 (10 mL×3), dried over anhydrous Na2SO4 and concentrated in vacuo. The crude residue was purified by reverse phase chromatography (acetonitrile 25-55%/0.1% NH4HCO3 in water) to give racemic 1-(3-(3-methyl-5-(1-methyl-1H-pyrazol-4-yl)indolin-1-yl)-1-((S)-tetrahydrofuran-3-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone (130 mg, 34%) as a white solid that was separated by chiral SFC (Chiralpak AD-3 150×4.6 mm I.D., 3 um Mobile phase: 40% of ethanol (0.05% diethylamine) in CO2 Flow rate: 50 mL/min) to give (S,S)-1-[3-[3-methyl-5-(1-methylpyrazol-4-yl)indolin-1-yl]-1-tetrahydrofuran-3-yl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (36 mg, first peak) and (R,S)-1-[3-[3-methyl-5-(1-methylpyrazol-4-yl)indolin-1-yl]-1-tetrahydrofuran-3-yl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (43 mg, second peak). Absolute configuration was arbitrarily assigned to each diastereomer. Example 197: 1H NMR (400 MHz, DMSO-d6) δ 7.95 (s, 1H), 7.72 (s, 1H), 7.40-7.23 (m, 3H), 4.88-4.83 (m, 1H), 4.54-4.53 (m, 2H), 4.16-4.02 (m, 1H), 4.00-3.98 (m, 2H), 3.85-3.77 (m, 7H), 3.68-3.44 (m, 2H), 2.78-2.66 (m, 2H), 2.24-2.21 (m, 2H), 2.09-2.07 (m, 3H), 1.34 (d, J=6.4 Hz, 3H). LCMS M/Z (M+H) 447. Example 198: 1H NMR (400 MHz, DMSO-d6) δ 7.95 (s, 1H), 7.72 (s, 1H), 7.40-7.23 (m, 3H), 4.88-4.83 (m, 1H), 4.54-4.53 (m, 2H), 4.16-4.02 (m, 1H), 4.00-3.98 (m, 2H), 3.85-3.77 (m, 7H), 3.68-3.44 (m, 2H), 2.78-2.66 (m, 2H), 2.24-2.21 (m, 2H), 2.09-2.07 (m, 3H), 1.34 (d, J=6.4 Hz, 3H). LCMS M/Z (M+H) 447.
-
-
- To a solution of (4-bromophenyl)hydrazine (6.0 g, 26.8 mmol) in AcOH (60 mL) was added isobutyraldehyde (1.94 g, 26.8 mmol) dropwise. The mixture was heated to 60° C. for 3 h under a nitrogen atmosphere. After cooling the reaction to room temperature, NaBH(OAc)3 (5.69 g, 26.8 mmol) was added in portionwise at 0° C. The mixture was stirred at room temperature for an additional 1 h. The mixture was concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc=10:1) to give the title compound (600 mg, 10%) as a yellow oil.
-
- To a solution of 5-bromo-3,3-dimethylindoline (360 mg, 1.59 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (364 mg, 1.75 mmol), K2CO3 (660 mg, 4.78 mmol) in dioxane/H2O (3.0 mL, 3:1) was added [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (117 mg, 0.160 mmol). The mixture was heated to 120° C. for 0.5 h under microwave conditions. After cooling the reaction to room temperature, water (10 mL) was added and the mixture was extracted with EtOAc (10 mL×3). The combined organic layers were washed with sat. aq. NaHCO3 (10 mL×3), dried over anhydrous Na2SO4 and concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc=3:1) to give the title compound (140 mg, 39%) as a light yellow oil.
-
- To a solution of 3,3-dimethyl-5-(1-methyl-1H-pyrazol-4-yl)indoline (200 mg, 0.88 mmol), 1-(3-bromo-1-methyl-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5 (4H)-yl)ethanone (Intermediate B, 272 mg, 1.06 mmol) and t-BuONa (254 mg, 2.64 mmol) in dioxane (5 mL) was added chloro(2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl)[2-(2-aminoethylphenyl)]palladium(II), methyl-tert-butylether adduct (74 mg, 0.088 mmol) and 2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl (41 mg, 0.088 mmol). The mixture was irradiated in a microwave at 120° C. for 45 min. After cooling the reaction to room temperature, water (10 mL) was added and the mixture was extracted with EtOAc (10 mL×3). The combined organic layers were washed with sat. aq. NaHCO3 (10 mL×3), dried over anhydrous Na2SO4 and concentrated in vacuo. The crude residue was purified by reverse phase chromatography (acetonitrile 25-55%/0.1% NH4HCO3 in water) to give the title compound (65 mg, 18%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.68 (s, 1H), 7.52-7.51 (m, 1H), 7.29 (s, 1H), 7.21-6.88 (m, 3H), 4.62 (s, 1H), 4.40 (s, 1H), 3.92-3.91 (m, 4H), 3.76-3.72 (m, 3H), 3.68 (s, 3H), 2.75-2.67 (m, 2H), 2.19-2.12 (m, 3H), 1.40-1.37 (m, 3H). LCMS M/Z (M+H) 405.
-
-
- To a solution of (4-bromophenyl)hydrazine hydrochloride (5.0 g, 22.4 mmol) in AcOH (20 mL) was added butyraldehyde (1.61 g, 22.4 mmol) dropwise. The mixture was heated to 60° C. for 3 h under a nitrogen atmosphere. After cooling the reaction to room temperature, the mixture was concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc=10:1) to give the title compound (800 mg, 16%) as a yellow oil.
-
- To a solution of 5-bromo-3-ethyl-1H-indole (800 mg, 3.57 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (891 mg, 4.28 mmol) and K2CO3 (1.48 g, 10.7 mmol) in dioxane/H2O (10 mL, 4:1) was added [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (250 mg, 0.36 mmol). The mixture was heated to 120° C. for 12 h under a nitrogen atmosphere. After cooling the reaction to room temperature, water (10 mL) was added and the mixture was extracted with EtOAc (10 mL×3). The combined organic layers were washed with sat. aq. NaHCO3 (10 mL×3), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc=3:1) to give the title compound (500 mg, 62%) as a yellow solid.
-
- To a stirred solution of 3-ethyl-5-(1-methyl-1H-pyrazol-4-yl)-1H-indole (0.5 g, 2.22 mmol) in AcOH (6 mL) was added NaBH3CN (418 mg, 6.66 mmol) portionwise. The mixture was stirred at room temperature for 3 h under a nitrogen atmosphere. The mixture was concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc=3:1) to give the title compound (280 mg, 56%) as a yellow oil.
-
- To a solution of 3-ethyl-5-(1-methyl-1H-pyrazol-4-yl)indoline (150 mg, 0.66 mmol), 1-(3-bromo-1-(tetrahydrofuran-3-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5 (4H)-yl)ethanone (249 mg, 0.79 mmol) and t-BuONa (190 mg, 1.98 mmol) in dioxane (3 mL) was added chloro(2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl)[2-(2-aminoethylphenyl)]palladium(II), methyl-tert-butylether adduct (56 mg, 0.068 mmol) and 2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl (32 mg, 0.068 mmol). The mixture was heated to 120° C. for 12 h under a nitrogen atmosphere. After cooling the reaction to room temperature, water (10 mL) was added and the mixture was extracted with EtOAc (10 mL×3). The combined organic layers were washed with sat. aq. NaHCO3 (10 mL×3), dried over anhydrous Na2SO4 and concentrated in vacuo. The crude residue was purified by reverse phase chromatography (acetonitrile 25-55%/0.1% NH4HCO3 in water) to give the title compound (33 mg, 11%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.95 (s, 1H), 7.71 (s, 1H), 7.38-7.25 (m, 3H), 4.86-4.85 (m, 1H), 4.57-4.52 (m, 2H), 4.09-3.97 (m, 3H), 3.85-3.62 (m, 9H), 2.78-2.66 (m, 2H), 2.24-2.23 (m, 2H), 2.09-2.07 (m, 3H), 1.88-1.83 (m, 1H), 1.60-1.55 (m, 1H), 0.96 (t, J=3.2 Hz, 3H). LCMS M/Z (M+H) 461.
-
- To a solution of 3-ethyl-5-(1-methyl-1H-pyrazol-4-yl)indoline (320 mg, 1.41 mmol), 1-(3-bromo-1-(oxetan-3-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5 (4H)-yl)ethanone (423 mg, 1.41 mmol) and t-BuONa (406 mg, 4.22 mmol) in dioxane (3 mL) was added chloro(2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl)[2-(2-aminoethylphenyl)]palladium(II), methyl-tert-butylether adduct (114 mg, 0.14 mmol) and 2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl (63 mg, 0.14 mmol). The mixture was heated to 120° C. for 12 h under a nitrogen atmosphere. After cooling the reaction to room temperature, water (10 mL) was added and the mixture was extracted with EtOAc (10 mL×3). The combined organic layers were washed with sat. aq. NaHCO3 (10 mL×3), dried over anhydrous Na2SO4 and concentrated in vacuo. The crude residue was purified by reverse phase chromatography (acetonitrile 25-55%/0.1% NH4HCO3 in water) to give racemic 1-[3-[3-ethyl-5-(1-methylpyrazol-4-yl)indolin-1-yl]-1-(oxetan-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (175 mg, 28%) as a white solid that was separated by chiral SFC (Chiralpak AD-3 50*4.6 mm I.D., 3 um; Mobile phase: ethanol (0.05% diethylamine) in CO2 from 5% to 40%; Flow rate: 80 mL/min) to give (S)-1-[3-[3-ethyl-5-(1-methylpyrazol-4-yl)indolin-1-yl]-1-(oxetan-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (30 mg, first peak) and (R)-1-[3-[3-ethyl-5-(1-methylpyrazol-4-yl)indolin-1-yl]-1-(oxetan-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (30 mg, second peak). Absolute configuration was arbitrarily assigned to each enantiomer. Example 201: 1H NMR (400 MHz, DMSO-d6) δ 7.97 (s, 1H), 7.73 (s, 1H), 7.51-7.41 (m, 1H), 7.34-7.28 (m, 2H), 5.43-5.38 (m, 1H), 4.97-4.94 (m, 2H), 4.85-4.81 (m, 2H), 4.55-4.22 (m, 2H), 4.20-4.12 (m, 1H), 3.83 (s, 3H), 3.71-3.63 (m, 3H), 2.74-2.60 (m, 2H), 2.08-2.07 (m, 3H), 1.90-1.84 (m, 1H), 1.61-1.55 (m, 1H), 0.99-0.95 (m, 3H). LCMS M/Z (M+H) 447. Example 202: 1H NMR (400 MHz, DMSO-d6) δ 7.97 (s, 1H), 7.73 (s, 1H), 7.51-7.41 (m, 1H), 7.34-7.28 (m, 2H), 5.43-5.38 (m, 1H), 4.97-4.94 (m, 2H), 4.85-4.81 (m, 2H), 4.55-4.22 (m, 2H), 4.20-4.12 (m, 1H), 3.83 (s, 3H), 3.71-3.63 (m, 3H), 2.74-2.60 (m, 2H), 2.08-2.07 (m, 3H), 1.90-1.84 (m, 1H), 1.61-1.55 (m, 1H), 0.99-0.95 (m, 3H). LCMS M/Z (M+H) 447.
-
-
- To a stirred solution of 1H-indole-6-carbonitrile (3.0 g, 21.1 mmol) in AcOH (10 mL) was added NaBH3CN (3.98 g, 63.3 mmol) portionwise. The mixture was stirred at room temperature for 16 h under a nitrogen atmosphere. The mixture was concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc=5:1) to give the title compound (800 mg, 26%) as a white solid.
-
- To a solution of indoline-6-carbonitrile (120 mg, 0.83 mmol), 1-(3-bromo-1-methyl-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone (Intermediate B, 258 mg, 1.0 mmol) and t-BuONa (200 mg, 2.08 mmol) in dioxane (5 mL) was added chloro(2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl)[2-(2-aminoethylphenyl)]palladium(II), methyl-tert-butylether adduct (68 mg, 0.083 mmol) and 2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl (37 mg, 0.083 mmol). The mixture was heated to 120° C. for 12 h under a nitrogen atmosphere. After cooling the reaction to room temperature, water (10 mL) was added and the mixture was extracted with EtOAc (10 mL×3). The combined organic layers were washed with sat. aq. NaHCO3 (10 mL×3), dried over anhydrous Na2SO4 and concentrated in vacuo. The crude residue was purified by reverse phase chromatography (acetonitrile 25-55%/0.1% NH4HCO3 in water) to give the title compound (150 mg, 56%) as colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.54-7.34 (m, 1H), 7.18-7.13 (m, 1H), 7.05-7.01 (m, 1H), 4.62-4.44 (m, 2H), 4.06-4.02 (m, 2H), 3.92-3.91 (m, 1H), 3.77-3.71 (m, 4H), 3.24-3.18 (m, 2H), 3.78-3.70 (m, 2H), 2.20-2.16 (m, 3H). LCMS M/Z (M+H) 322.
-
- To a stirred solution of 1-(5-acetyl-1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)indoline-6-carbonitrile (Example 203, 190 mg, 0.59 mmol) in DMF (3.0 mL) was added tri-n-butuytin azide (390 mg, 1.18 mmol) in portions. The mixture was heated to 120° C. for 24 h under a nitrogen atmosphere. The mixture was concentrated in vacuo. The crude residue was purified by reverse phase chromatography (acetonitrile 25-55%/0.1% NH4HCO3 in water) to give the title compound (8 mg, 4%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.58-7.57 (m, 1H), 7.22-7.20 (m, 1H), 6.93 (s, 1H), 4.57 (s, 2H), 4.01 (t, J=8.0 Hz, 2H), 3.86-3.83 (m, 2H), 3.63 (s, 3H), 3.12 (m, J=8.0 Hz, 2H), 2.80-2.77 (m, 2H), 2.26 (s, 3H). LCMS M/Z (M+H) 365.
-
-
- To a solution of (4-bromophenyl)hydrazine hydrochloride (5.0 g, 22.4 mmol) in AcOH (20 mL) was added cyclobutanecarbaldehyde (1.61 g, 22.4 mmol) dropwise. The mixture was heated to 60° C. for 3 h under a nitrogen atmosphere. The mixture was concentrated in vacuo. The crude residue was purified by column chromatography (petroleum ether/EtOAc=10:1) to give the title compound (2.5 g, 47%) as a yellow oil.
-
- To a stirred solution of 5′-bromospiro[cyclobutane-1,3′-indole] (1.2 g, 5.08 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.27 g, 6.10 mmol) and K2CO3 (2.11 g, 15.25 mmol) in dioxane/H2O (10 mL, 4:1) was added [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (450 mg, 0.5 mmol). The mixture was heated to 120° C. for 12 h under a nitrogen atmosphere. After cooling the reaction to room temperature, water (10 mL) was added and the mixture was extracted with EtOAc (10 mL×3). The combined organic layers were washed with sat. aq. NaHCO3 (10 mL×3), dried over anhydrous Na2SO4 and concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc=3:1) to give the title compound (0.65 g, 54%) as a yellow solid. LCMS M/Z (M+H) 238.
-
- To a solution of 5′-(1-methyl-1H-pyrazol-4-yl)spiro[cyclobutane-1,3′-indole] (0.65 g, 2.74 mmol) in AcOH (5.0 mL) was added NaBH3CN (0.52 g, 8.22 mmol) portionwise. The mixture was stirred at room temperature for 3 h under a nitrogen atmosphere. The mixture was concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc=3:1) to give the title compound (160 mg, 40%) as a colorless oil.
-
- To a solution of 5′-(1-methyl-1H-pyrazol-4-yl)spiro[cyclobutane-1,3′-indoline] (160 mg, 0.67 mmol), 1-(3-bromo-1-(tetrahydrofuran-3-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone (252 mg, 0.80 mmol) and t-BuONa (193 mg, 2.00 mmol) in dioxane (3 mL) was added chloro(2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl)[2-(2-aminoethylphenyl)]palladium(II), methyl-tert-butylether adduct (56 mg, 0.067 mmol) and 2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl (32 mg, 0.067 mmol). The mixture was heated to 120° C. for 12 h under a nitrogen atmosphere. After cooling the reaction to room temperature, water (10 mL) was added and the mixture was extracted with EtOAc (10 mL×3). The combined organic layers were washed with sat. aq. NaHCO3 (10 mL×3), dried over anhydrous Na2SO4 and concentrated in vacuo. The crude residue was purified by reverse phase chromatography (acetonitrile 25-55%/0.1% NH4HCO3 in water) to give the title compound (20 mg, 6%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.95 (s, 1H), 7.72 (s, 1H), 7.35-7.20 (m, 3H), 4.88-4.71 (m, 2H), 4.54-4.48 (m, 2H), 4.04-4.00 (m, 2H), 3.89-3.69 (m, 8H), 2.82-2.68 (m, 2H), 2.30-2.25 (m, 2H), 2.10-2.08 (m, 3H), 1.85-1.62 (m, 5H), 1.30-1.24 (m, 1H). LCMS M/Z (M+H) 473.
-
-
- To a solution of 6-bromo-5-chloro-1H-indole (500 mg, 2.17 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.54 g, 2.60 mmol) and Na2CO3 (0.69 g, 6.51 mmol) in DME/H2O (10 mL, 4:1) was added bis(triphenylphosphine)palladium(II) dichloride (140 mg, 0.22 mmol). The mixture was heated to 120° C. for 12 h under a nitrogen atmosphere. After cooling the reaction to room temperature, water (10 mL) was added and the mixture was extracted with EtOAc (10 mL×3). The combined organic layers were washed with sat. aq. NaHCO3 (10 mL×3), dried over anhydrous Na2SO4 and concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc=3:1) to give the title compound (0.38 g, 76%) as a light yellow solid.
-
- To a solution of 5-chloro-6-(1-methyl-1H-pyrazol-4-yl)-1H-indole (0.32 g, 1.38 mmol) in AcOH (4.0 mL) was added NaBH3CN (0.26 g, 4.14 mmol) portionwise. The mixture was stirred at room temperature for 3 h under a nitrogen atmosphere. The mixture was concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc=3:1) to give the title compound (150 mg, 46%) as a white solid.
-
- To a solution of 5-chloro-6-(1-methyl-1H-pyrazol-4-yl)indoline (150 mg, 0.64 mmol), 1-(3-bromo-1-(tetrahydrofuran-3-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5 (4H)-yl)ethanone (262 mg, 0.83 mmol) and t-BuONa (185 mg, 1.93 mmol) in dioxane (5 mL) was added chloro(2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl)[2-(2-aminoethylphenyl)]palladium(II), methyl-tert-butylether adduct (52 mg, 0.064 mmol) and 2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl (28 mg, 0.064 mmol). The mixture was heated to 120° C. for 12 h under a nitrogen atmosphere. After cooling the reaction to room temperature, water (10 mL) was added and the mixture was extracted with EtOAc (10 mL×3). The combined organic layers were washed with sat. aq. NaHCO3 (10 mL×3), dried over anhydrous Na2SO4 and concentrated in vacuo. The crude residue was purified by Prep-TLC (DCM/MeOH=20:1) to give the title compound (110 mg, 37%) as a yellow oil. LCMS M/Z (M+H) 467.
-
- To a solution of 1-(3-(5-chloro-6-(1-methyl-1H-pyrazol-4-yl)indolin-1-yl)-1-(tetrahydrofuran-3-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone (100 mg, 0.21 mmol), potassium hexacyanoferrate(II) trihydrate (248 mg, 0.63 mmol), 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (18 mg, 0.021 mmol) and KOAc (84 mg, 0.86 mmol) in dioxane/H2O (5 mL, 4:1) was added tris(dibenzylideneacetone)dipalladium (10 mg, 0.011 mmol). The mixture was heated to 120° C. for 36 h under a nitrogen atmosphere. After cooling the reaction to room temperature, water (10 mL) was added and the mixture was extracted with EtOAc (10 mL×3). The combined organic layers were washed with sat. aq. NaHCO3 (10 mL×3), dried over anhydrous Na2SO4 and concentrated in vacuo. The crude residue was purified by reverse phase chromatography (acetonitrile 25-55%/0.1% NH4HCO3 in water) to give the title compound (10 mg, 11%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.13 (d, J=5.6 Hz, 1H), 7.79-7.57 (m, 2H), 7.46 (s, 1H), 4.92-4.89 (m, 2H), 4.57-4.54 (m, 2H), 4.09-3.98 (m, 4H), 3.89-3.84 (m, 5H), 3.71-3.70 (m, 2H), 3.17 (t, J=8.8 Hz, 2H), 2.83-2.69 (m, 2H), 2.32-2.21 (m, 2H), 2.10-2.07 (m, 3H). LCMS M/Z (M+H) 458.
-
-
- To a solution of 6-bromo-4-chloro-1H-indole (500 mg, 2.17 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.54 g, 2.60 mmol) and Na2CO3 (0.69 g, 6.51 mmol) in DME/H2O (10 mL, 4:1) was added bis(triphenylphosphine)palladium(II) dichloride (140 mg, 0.22 mmol). The mixture was heated to 120° C. for 12 h under a nitrogen atmosphere. After cooling the reaction to room temperature, water (10 mL) was added and the mixture was extracted with EtOAc (10 mL×3). The combined organic layers were washed with sat. aq. NaHCO3 (10 mL×3), dried over anhydrous Na2SO4 and concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc=3:1) to give the title compound (0.38 g, 76%) as a light yellow solid.
-
- To a solution of 4-chloro-6-(1-methyl-1H-pyrazol-4-yl)-1H-indole (0.33 g, 1.53 mmol) in AcOH (3 mL) was added NaBH3CN (0.27 g, 4.27 mmol) in portions. The mixture was stirred at room temperature for 3 h under a nitrogen atmosphere. The mixture was concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc=3:1) to give the title compound (200 mg, 60%) as a light yellow solid. LCMS M/Z (M+H) 234.
-
- To a solution of 4-chloro-6-(1-methyl-1H-pyrazol-4-yl)indoline (180 mg, 0.77 mmol), 1-(3-bromo-1-(tetrahydrofuran-3-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5 (4H)-yl)ethanone (314 mg, 1.00 mmol) and t-BuONa (222 mg, 2.31 mmol) in dioxane (4 mL) was added chloro(2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl)[2-(2-aminoethylphenyl)]palladium(II), methyl-tert-butylether adduct (63 mg, 0.077 mmol) and 2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl (34 mg, 0.077 mmol). The mixture was heated to 120° C. for 12 h under a nitrogen atmosphere. After cooling the reaction to room temperature, water (10 mL) was added and the mixture was extracted with EtOAc (10 mL×3). The combined organic layers were washed with sat. aq. NaHCO3 (10 mL×3), dried over anhydrous Na2SO4 and concentrated in vacuo. The crude residue was purified by Prep-TLC (DCM/MeOH=20:1) to give the title compound (130 mg, 36%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.06-8.05 (m, 1H), 7.76-7.75 (m, 1H), 7.46 (s, 1H), 7.62-7.48 (m, 1H), 6.94 (s, 1H), 4.90 (s, 1H), 4.54-4.53 (m, 2H), 4.10-4.02 (m, 24H), 3.88-3.84 (m, 5H), 3.74-3.71 (m, 2H), 3.13 (t, J=8.4 Hz, 2H), 2.81-2.68 (m, 2H), 2.30-2.22 (m, 2H), 2.10-2.07 (m, 3H). LCMS M/Z (M+H) 467.
-
- To a solution of 1-(3-(4-chloro-6-(1-methyl-1H-pyrazol-4-yl)indolin-1-yl)-1-(tetrahydrofuran-3-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone (130 mg, 0.28 mmol), potassium hexacyanoferrate(II) trihydrate (323 mg, 0.84 mmol) and 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (45 mg, 0.056 mmol), KOAc (109 mg, 1.11 mmol) in dioxane/H2O (5 mL, 4:1) was added tris(dibenzylideneacetone)dipalladium (30 mg, 0.028 mmol). The mixture was heated to 120° C. for 36 h under a nitrogen atmosphere. After cooling the reaction to room temperature, water (10 mL) was added and the mixture was extracted with EtOAc (10 mL×3).
- The combined organic layers were washed with sat. aq. NaHCO3 (10 mL×3), dried over anhydrous Na2SO4 and concentrated in vacuo. The crude residue was purified by reverse phase chromatography (acetonitrile 25-55%/0.1% NH4HCO3 in water) to give the title compound (16 mg, 13%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.11 (d, J=4.4 Hz, 1H), 7.97-7.85 (m, 2H), 7.29 (s, 1H), 4.92-4.89 (m, 1H), 4.57-4.56 (m, 2H), 4.10-4.02 (m, 4H), 3.90-3.85 (m, 5H), 3.73-3.72 (m, 2H), 3.29-3.26 (m, 2H), 2.83-2.70 (m, 2H), 2.34-2.29 (m, 2H), 2.11-2.08 (m, 3H). LCMS M/Z (M+H) 458.
-
-
- To a solution of 6-bromo-4-fluoro-1H-indole (500 mg, 2.34 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.63 g, 3.04 mmol) and K2CO3 (0.97 g, 7.01 mmol) in dioxane/H2O (10.0 mL, 4:1) was added [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (171 mg, 0.24 mmol). The mixture was heated to 120° C. for 12 h under a nitrogen atmosphere. After cooling the reaction to room temperature, water (10 mL) was added and the mixture was extracted with EtOAc (10 mL×3). The combined organic layers were washed with sat. aq. NaHCO3 (10 mL×3), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc=3:1) to give the title compound (0.33 g, 66%) as a light yellow solid.
-
- To a solution of 4-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-1H-indole (0.33 g, 1.53 mmol) in AcOH (3 mL) was added NaBH3CN (0.29 g, 4.6 mmol) in portions. The mixture was stirred at room temperature for 3 h under a nitrogen atmosphere. The crude mixture was concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc=3:1) to give the title compound (210 mg, 63%) as a light yellow solid. LCMS M/Z (M+H) 218.
-
- To a solution of 4-fluoro-6-(1-methyl-1H-pyrazol-4-yl)indoline (150 mg, 0.69 mmol), 1-(3-bromo-1-(tetrahydrofuran-3-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5 (4H)-yl)ethanone (282 mg, 0.90 mmol) and t-BuONa (200 mg, 2.07 mmol) in dioxane (3 mL) was added chloro(2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl)[2-(2-aminoethylphenyl)]palladium(II), methyl-tert-butylether adduct (56 mg, 0.069 mmol) and 2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl (31 mg, 0.069 mmol). The mixture was heated to 120° C. for 12 h under a nitrogen atmosphere. After cooling the reaction to room temperature, water (10 mL) was added and the mixture was extracted with EtOAc (10 mL×3). The combined organic layers were washed with sat. aq. NaHCO3 (10 mL×3), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by reverse phase chromatography (acetonitrile 25-55%/0.1% NH4HCO3 in water) to give the title compound (60 mg, 19%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.04 (s, 1H), 7.75 (s, 1H), 7.33 (s, 1H), 6.76 (s, 1H), 4.92-4.89 (m, 1H), 4.55-4.53 (m, 2H), 4.06-4.02 (m, 4H), 3.88-3.84 (m, 5H), 3.75-3.72 (m, 2H), 3.14 (t, J=8.4 Hz, 2H), 2.84-2.69 (m, 2H), 2.30-2.28 (m, 2H), 2.11-2.07 (m, 3H). LCMS M/Z (M+H) 451.
-
-
- To a solution of 5-fluoroindoline hydrochloride (1.6 g, 9.2 mmol) in H2SO4 (10 mL) at 0° C. was added Ag2SO4 (1.72 g, 5.5 mmol) portionwise. The mixture was stirred at that temperature for 0.5 h before bromine (2.2 g, 13.8 mmol) was added dropwise. The crude mixture was stirred at room temperature for an additional 2 h. Water (20 mL) was added and the mixture was neutralized with sat. aq. NaHCO3 to pH 7 and then extracted with EtOAc (20 mL×3). The combined organic layers were washed with sat. aq. NaHCO3 (20 mL×3), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc=3:1) to give the title compound (560 mg, 28%) as a brown oil. 1H NMR (400 MHz, DMSO-d6) δ 7.03 (d, J=8.8 Hz, 1H), 6.62 (d, J=5.6 Hz, 1H), 5.85 (s, 1H), 3.43 (t, J=8.8 Hz, 2H), 3.43 (t, J=8.8 Hz, 2H).
-
- To a solution of 6-bromo-5-fluoroindoline (560 mg, 2.59 mmol) in DCM (10.0 mL) was added di-tert-butyl dicarbonate (848 mg, 3.89 mmol) and diisopropylethylamine (580 mg, 4.51 mmol). The mixture was stirred at room temperature for 12 h under a nitrogen atmosphere. The mixture was concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc=20:1) to give the title compound (520 mg, 63%) as a brown oil.
-
- To a solution of tert-butyl 6-bromo-5-fluoroindoline-1-carboxylate (520 mg, 1.64 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (410 mg, 1.97 mmol) and K2CO3 (682 mg, 4.93 mmol) in dioxane/H2O (4 mL, 3:1) was added [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (120 mg, 0.165 mmol). The mixture was heated to 120° C. for 12 h under a nitrogen atmosphere. After cooling the reaction to room temperature, water (10 mL) was added and the mixture was extracted with EtOAc (10 mL×3). The combined organic layers were washed with sat. aq. NaHCO3 (10 mL×3), dried over anhydrous Na2SO4 and concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc=5:1) to give the title compound (380 mg, 78%) as a colorless oil.
-
- To a stirred solution of tert-butyl 5-fluoro-6-(1-methyl-1H-pyrazol-4-yl)indoline-1-carboxylate (460 mg, 1.45 mmol) in EtOAc (3 mL) was added HCl in EtOAc (4 M, 10 mL). The mixture was stirred at room temperature for 4 h under a nitrogen atmosphere. The mixture was concentrated in vacuo. Water (20 mL) was added and the mixture was neutralized with sat. aq. NaHCO3 to pH 7 and then extracted with EtOAc (20 mL×3). The combined organic layers were washed with sat. aq. NaHCO3 (20 mL×3), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (260 mg, 83%) as a colorless oil.
-
- To a solution of 5-fluoro-6-(1-methyl-1H-pyrazol-4-yl)indoline (150 mg, 0.69 mmol), 1-(3-bromo-1-(tetrahydrofuran-3-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5 (4H)-yl)ethanone (260 mg, 0.83 mmol) and t-BuONa (299 mg, 2.07 mmol) in dioxane (3 mL) was added chloro(2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl)[2-(2-aminoethylphenyl)]palladium(II), methyl-tert-butylether adduct (56 mg, 0.069 mmol) and 2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl (32 mg, 0.069 mmol). The mixture was heated to 120° C. for 12 h under a nitrogen atmosphere. After cooling the reaction to room temperature, water (10 mL) was added and the mixture was extracted with EtOAc (10 mL×3). The combined organic layers were washed with sat. aq. NaHCO3 (10 mL×3), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by reverse phase chromatography (acetonitrile 25-55%/0.1% NH4HCO3 in water) to give the title compound (49 mg, 16%) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 7.97 (s, 1H), 7.83-7.67 (m, 2H), 7.04 (d, J=10.4 Hz, 1H), 4.89-4.87 (m, 1H), 4.56-4.54 (m, 2H), 4.05-3.98 (m, 4H), 3.88 (s, 3H), 3.88-3.86 (m, 2H), 3.72-3.69 (m, 2H), 3.11-3.07 (m, 2H), 2.81-2.66 (m, 2H), 2.27-2.19 (m, 2H), 2.09-2.06 (m, 3H). LCMS M/Z (M+H) 451.
-
-
- To a solution of methyl 1H-indole-6-carboxylate (5.0 g, 28.54 mmol) in AcOH (30 mL) was added NaBH3CN (5.4 g, 85.62 mmol). The mixture was stirred at 30° C. for 16 h. The reaction was quenched with sat. aq. NaHCO3 (300 mL) and extracted with EtOAc (100 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc=50:1 to 3:1) to give the title compound (1.2 g, 24%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.16 (d, J=7.6 Hz, 1H), 7.14 (d, J=7.6 Hz, 1H), 5.75 (s, 1H), 3.78 (s, 3H), 3.52 (t, J=8.4 Hz, 2H), 2.95 (t, J=8.4 Hz, 2H).
-
- To a solution of methyl indoline-6-carboxylate (600 mg, 3.40 mmol), 1-(3-bromo-1-methyl-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone (Intermediate B, 960 mg, 3.74 mmol), 2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl (158 mg, 0.34 mmol) and chloro(2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl)[2-(2-aminoethylphenyl)]palladium(II), methyl-tert-butylether adduct (277 mg, 0.34 mmol) in dioxane (10 mL) was added t-BuONa (976 mg, 10.20 mmol). The mixture was heated to 120° C. for 16 h under a nitrogen atmosphere. After cooling the reaction to room temperature, water (20 mL) was added and the mixture was extracted with EtOAc (20 mL×2). 1 M HCl (2 mL) was added to aqueous phase and then extracted with EtOAc (20 mL×2). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by reverse phase chromatography (acetonitrile 5-35%/0.1% NH4HCO3 in water) to give the title compound (120 mg, 10%) as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ 7.58 (s, 1H), 7.28 (d, J=7.2 Hz, 1H), 7.10 (d, J=7.6 Hz, 1H), 4.45 (s, 2H), 3.96-3.90 (m, 2H), 3.76-3.69 (m, 5H), 3.16-3.05 (m, 2H), 2.77-2.65 (m, 2H), 2.08-2.06 (m, 3H). LCMS M/Z (M+H) 341.
-
- To a solution of 1-(5-acetyl-1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)indoline-6-carboxylic acid (90 mg, 0.26 mmol) in MeOH (5 mL) was added SOCl2 (60 mg, 0.5 mmol). The mixture was heated to 70° C. for 2 h under a nitrogen atmosphere. After cooling the reaction to room temperature, the mixture was concentrated in vacuo. The crude residue was purified by silica gel chromatography (DCM/MeOH=20:1) to give the title compound (30 mg, 32%) as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ 7.78 (d, J=10.8 Hz, 1H), 7.34 (d, J=7.6 Hz, 1H), 7.23 (d, J=7.6 Hz, 1H), 4.50 (d, J=4.0 Hz, 2H), 4.09-3.95 (m, 2H), 3.80 (s, 3H), 3.76-3.68 (m, 2H), 3.65 (s, 3H), 3.17 (t, J=8.4 Hz, 2H), 2.77-2.66 (m, 2H), 2.10-2.07 (m, 3H). LCMS M/Z (M+H) 355.
-
-
- To a solution of 5-bromo-1H-indole (4.0 g, 20.4 mmol) in MeCN/AcOH (80 mL, 19:1) was added N-methyl-N-methylenemethanaminium iodide (4.5 g, 24.3 mmol). After stirring at 20° C. for 3 h, additional N-methyl-N-methylenemethanaminium iodide (0.4 g, 2.2 mmol) was added. The mixture was stirred at 20° C. for additional 1 h. Water (50 mL) was added and the mixture was made basic with 10% aq. KOH (45 mL) to pH>9 and then extracted with EtOAc (300 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was dissolved in EtOH (40 mL) before MeI (5.7 g, 40 mmol) was added and the mixture stirred at 20° C. for 16 h. The mixture was concentrated in vacuo to give the ammonium salt as a yellow solid (7.9 g, crude). To this crude salt (7.9 g) in DMF (50 mL) was added a solution of NaCN (5.0 g, 0.10 mmol) in water (10 mL). The mixture was heated to 70° C. for 4 h. After cooling the reaction to room temperature, EtOAc (350 mL) was added and the mixture was washed with water (50 mL×5). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc=1:1) to give the title compound (2.6 g, 54%) as a yellow solid.
-
- To a solution of 2-(5-bromo-1H-indol-3-yl)acetonitrile (1.3 g, 5.53 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.4 g, 6.64 mmol) and K2CO3 (2.3 g, 16.59 mmol) in dioxane/H2O (13 mL, 3:1) was added [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (405 mg, 0.55 mmol). The mixture was heated to 120° C. for 16 h under a nitrogen atmosphere. After cooling the reaction to room temperature, the mixture was concentrated in vacuo. The crude residue was purified by silica gel chromatography (DCM/MeOH=30:1) to give the title compound (1.1 g, 83%) as a brown solid.
-
- To a solution of 2-(5-(1-methyl-1H-pyrazol-4-yl)-1H-indol-3-yl)acetonitrile (1.1 g, 4.66 mmol) in trifluoroacetic acid (10 mL) was added triethylsilane (1.6 g, 13.97 mmol) at 0° C. The mixture was stirred at 20° C. for 24 h. Water (20 mL) was added and the mixture was extracted with EtOAc (10 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuo. The crude residue was purified by silica gel chromatography (DCM/MeOH=30:1) to give the title compound (1.0 g, 91%) as brown solid.
-
- To a solution of 2-(5-(1-methyl-1H-pyrazol-4-yl)indolin-3-yl)acetonitrile (230 mg, 1.0 mmol), 1-(3-bromo-1-(tetrahydrofuran-3-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5 (4H)-yl)ethanone (334 mg, 1.1 mmol), chloro(2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl)[2-(2-aminoethylphenyl)]palladium(II), methyl-tert-butylether adduct (81 mg, 0.1 mmol) and 2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl (45 mg, 0.1 mmol) was added t-BuONa (278 mg, 3.0 mmol). The mixture was heated to 120° C. for 12 h under a nitrogen atmosphere. After cooling the reaction to room temperature, the mixture was concentrated in vacuo. The crude residue was purified by reverse phase chromatography (acetonitrile 27-57%/0.1% NH4OH in water) to give the title compound (32 mg, 7%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.02 (s, 1H), 7.74 (s, 1H), 7.60-7.48 (m, 1H), 7.24 (d, J=7.2 Hz, 1H), 6.96 (d, J=7.6 Hz, 1H), 4.97-4.86 (m, 1H), 4.61-4.49 (m, 2H), 4.30-4.13 (m, 1H), 4.11-3.99 (m, 2H), 3.89 (d, J=5.0 Hz, 2H), 3.85 (s, 3H), 3.80-3.62 (m, 4H), 3.06-2.90 (m, 2H), 2.83-2.51 (m, 2H), 2.37-2.19 (m, 2H), 2.12-2.06 (m, 3H). LCMS M/Z (M+H) 472.
-
- To a solution of 2-(5-(1-methyl-1H-pyrazol-4-yl)indolin-3-yl)acetonitrile (600 mg, 2.52 mmol), 1-(3-bromo-1-(oxetan-3-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5 (4H)-yl)ethanone (Intermediate E, 831 mg, 2.77 mmol), chloro(2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl)[2-(2-aminoethylphenyl)]palladium(II), methyl-tert-butylether adduct (211 mg, 0.25 mmol) and 2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl (118 mg, 0.25 mmol) in dioxane (6 mL) was added t-BuONa (726 mg, 7.55 mmol). The mixture was heated to 120° C. for 16 h under a nitrogen atmosphere. After cooling the reaction to room temperature, the mixture was concentrated in vacuo. The crude residue was purified by reverse phase chromatography (acetonitrile 26-56%/0.1% NH4OH in water) to give racemic 2-[1-[5-acetyl-1-(oxetan-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-3-yl]-5-(1-methylpyrazol-4-yl)indolin-3-yl]acetonitrile (150 mg, 13%) as a white solid which was separated by chiral SFC (Chiralpak AD 250×30 mm I.D., 5 um; Supercritical CO2/MeOH+NH3.H2O=55/45; 80 ml/min) to give (S)-2-[1-[5-acetyl-1-(oxetan-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-3-yl]-5-(1-methylpyrazol-4-yl)indolin-3-yl]acetonitrile (65 mg, first peak) and (R)-2-[1-[5-acetyl-1-(oxetan-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-3-yl]-5-(1-methylpyrazol-4-yl)indolin-3-yl]acetonitrile (62 mg, second peak). Absolute configuration was arbitrarily assigned to each enantiomer. Example 214: 1H NMR (400 MHz, DMSO-d6) δ 8.01 (s, 1H), 7.72 (s, 1H), 7.52-7.43 (m, 1H), 7.24 (d, J=7.6 Hz, 1H), 6.95 (d, J=7.6 Hz, 1H), 5.42 (m, 1H), 4.97-4.93 (m, 2H), 4.89-4.80 (m, 2H), 4.53-4.41 (m, 2H), 4.29-4.14 (m, 1H), 3.81 (s, 3H), 3.80-3.59 (m, 4H), 3.02-2.93 (m, 2H), 2.74-2.62 (m, 2H), 2.07-2.00 (m, 3H). LCMS M/Z (M+H) 458. Example 215: 1H NMR (400 MHz, DMSO-d6) δ 8.01 (s, 1H), 7.72 (s, 1H), 7.52-7.43 (m, 1H), 7.24 (d, J=7.6 Hz, 1H), 6.95 (d, J=7.6 Hz, 1H), 5.42 (m, 1H), 4.97-4.93 (m, 2H), 4.89-4.80 (m, 2H), 4.53-4.41 (m, 2H), 4.29-4.14 (m, 1H), 3.81 (s, 3H), 3.80-3.59 (m, 4H), 3.02-2.93 (m, 2H), 2.74-2.62 (m, 2H), 2.07-2.00 (m, 3H). LCMS M/Z (M+H) 458.
-
-
- To a solution of 4-fluoro-1H-indole (5.0 g, 37.0 mmol) in AcOH (50 mL), NaBH3CN (4.7 g, 74.0 mmol) was added. The mixture was stirred at 20° C. for 30 min. Water (50 mL) was added and the mixture was extracted with EtOAc (50 mL×2). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuo to give the title compound (4.5 g, 90%) as a brown oil.
-
- To a solution of 4-fluoroindoline (2.5 g, 18.23 mmol), di-tert-butyl dicarbonate (6.0 g, 27.34 mmol) and di-iso-propyl-ethylamine (5.5 g, 54.68 mmol) in DCM (25 mL) was added DMAP (222 mg, 1.82 mmol). The mixture was stirred at 20° C. for 12 h. The mixture was concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc=50:1) to give the title compound (4 g, 93%) as a brown oil.
-
- To a solution of tert-butyl 4-fluoroindoline-1-carboxylate (3.0 g, 12.64 mmol) in DCM (30 mL) was added N-bromosuccinimide (3.4 g, 12.64 mmol). The mixture was stirred at 20° C. for 2 h. The mixture was concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc=9:1) to give the title compound (3.0 g, 75%) as a brown oil.
-
- To a solution of tert-butyl 5-bromo-4-fluoroindoline-1-carboxylate (2.0 g, 6.33 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.0 g, 9.49 mmol) and Na2CO3 (2.0 g, 18.98 mmol) in dioxane/H2O (27 mL, 3:1) was added [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (461 mg, 0.63 mmol). The mixture was heated to 120° C. for 12 h under a nitrogen atmosphere. After cooling the reaction to room temperature, the mixture was concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc=1:1) to give the title compound (1.5 g, 75%) as a brown solid.
-
- A solution of tert-butyl 4-fluoro-5-(1-methyl-1H-pyrazol-4-yl)indoline-1-carboxylate (1.0 g, 3.15 mmol) in HCl/EtOAc (4 M, 10 mL) was stirred at 20° C. for 12 h. The mixture was concentrated in vacuo to give the title compound (500 mg, 73%) as a brown solid.
-
- To a solution of 4-fluoro-5-(1-methyl-1H-pyrazol-4-yl)indoline (300 mg, 1.38 mmol), 1-(3-bromo-1-methyl-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5 (4H)-yl)ethanone (Intermediate B, 392 mg, 1.52 mmol), chloro(2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl)[2-(2-aminoethylphenyl)]palladium(II), methyl-tert-butylether adduct (117 mg, 0.14 mmol) and 2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl (65 mg, 0.14 mmol) in dioxane (3 mL) was added t-BuONa (398 mg, 4.14 mmol). The mixture was irradiated in a microwave at 120° C. for 45 min. After cooling the reaction to room temperature, the mixture was concentrated in vacuo. The crude residue was purified by reverse phase chromatography (acetonitrile 20-50%/0.1% NH4HCO3 in water) to give the title compound (17 mg, 3%) as a green solid. 1H NMR (400 MHz, DMSO-d6) δ 7.94 (s, 2H), 7.72 (s, 1H), 7.34-7.31 (m, 1H), 7.15-7.03 (m, 1H), 4.50-4.48 (m, 2H), 4.09-3.99 (m, 2H), 3.86 (s, 3H), 3.73-3.62 (m, 2H), 3.41 (s, 3H), 3.17 (t, J=8.4 Hz, 1H), 2.75-2.62 (m, 2H), 2.09-2.06 (m, 3H). LCMS M/Z (M+H) 395.
-
-
- To a solution of 7-fluoro-1H-indole (5.0 g, 37 mmol) in AcOH (30 mL) at 0° C. was added NaCNBH3 (9.3 g, 148 mmol). The mixture was stirred at room temperature for 2 h. Water (50 mL) was added and the mixture was extracted with EtOAc (50 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (4.6 g, 90%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 9.82 (s, 1H), 7.37-7.32 (m, 1H), 7.23-7.15 (m, 2H), 3.75-3.65 (m, 1H), 3.52-3.44 (m, 1H), 3.36-3.27 (m, 1H), 3.15-3.09 (m, 1H).
-
- To a solution of 7-fluoroindoline (4.5 g, 32.8 mmol) in DCM (10 mL) was added N-bromosuccinimide (5.8 g, 32.8 mmol). The mixture was stirred at room temperature for 2 h. The mixture was concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc=20:1) to give the title compound (4.0 g, 56%) as a yellow solid. LCMS M/Z (M+H) 216.
-
- To a solution of 5-bromo-7-fluoroindoline (1.0 g, 4.6 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (963 mg, 4.6 mmol) in dioxane (12 mL) and H2O (3 mL) was added [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (336 mg, 0.46 mmol) and Na2CO3 (980 mg, 9.3 mmol). The mixture was heated to 110° C. for 12 h under a nitrogen atmosphere. After cooling the reaction to room temperature, the mixture was concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc=2:1) to give the title compound (560 mg, 55%) as a yellow solid. LCMS M/Z (M+H) 218.
-
- To a solution of 7-fluoro-5-(1-methyl-1H-pyrazol-4-yl)indoline (200 mg, 0.92 mmol) and 1-(3-bromo-1-methyl-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5 (4H)-yl)ethanone (Intermediate B, 238 mg, 0.92 mmol) in dioxane (5 mL) was added chloro(2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl)[2-(2-aminoethylphenyl)]palladium(II), methyl-tert-butylether adduct (82 mg, 0.10 mmol), dicyclohexyl(2′,6′-diisopropoxy-[1,1′-biphenyl]-2-yl)phosphine (54 mg, 0.10 mmol) and t-BuONa (177 mg, 1.8 mmol). The mixture was heated to 120° C. for 12 h under a nitrogen atmosphere. After cooling the reaction to room temperature, the mixture was concentrated in vacuo. The crude residue was purified by reverse phase chromatography (acetonitrile 20-55%/0.1% NH4HCO3 in water) to give the title compound (25 mg, 7%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.03 (s, 1H), 7.78 (s, 1H), 7.21 (s, 1H), 7.13-7.08 (m, 1H), 4.29-4.27 (m, 2H), 3.83 (s, 3H), 3.80-3.75 (m, 2H), 3.71-3.63 (m, 2H), 3.56 (s, 3H), 3.11 (t, J=8.6 Hz, 2H), 2.73-2.60 (m, 2H), 2.05-1.99 (m, 3H). LCMS M/Z (M+H) 395.
-
-
- To a solution of 1H-indole-6-carbaldehyde (19.0 g, 131 mmol) and triethylamine (40.0 g, 390 mmol) in DCM (100 mL) was added 4-dimethylaminopyridine (catalytic) and di-tert-butyl dicarbonate (42.8 g, 196 mmol). The mixture was stirred at 15° C. for 16 h under a nitrogen atmosphere. The mixture was concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc=20:1) to give the title compound (23.0 g, 72%) as a brown solid. LCMS M/Z (M+H) 246.
-
- To a solution of tert-butyl 6-formyl-1H-indole-1-carboxylate (1.0 g, 4.1 mmol) in DCM (15 mL) was added (diethylamino)sulfur trifluoride (3.0 g, 18.6 mmol) under a nitrogen atmosphere. The mixture was stirred at 20° C. for 16 h. The mixture was quenched with sat. aq. NaHCO3 (30 mL) and then extracted with DCM (50 mL×2). The combined organic layers were washed with brine (50 mL×2), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc=20:1) to give the title compound (450 mg, 45%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.36 (s, 1H), 7.69 (d, J=3.6 Hz, 1H), 7.64 (d, J=8.4 Hz, 1H), 7.40 (d, J=8.4 Hz, 1H), 6.77 (t, J=56.8 Hz, 1H), 6.62 (d, J=3.6 Hz, 1H), 1.70 (s, 9H).
-
- To a solution of tert-butyl 6-(difluoromethyl)-1H-indole-1-carboxylate (450 mg, 1.7 mmol) in MeOH (20 mL) was added Pd/C (70 mg, 10% by weight). The mixture was stirred at room temperature for 12 h under hydrogen atmosphere (15 psi). The mixture was concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc=20:1) to give the title compound (310 mg, 69%) as a white solid.
-
- To a solution of tert-butyl 6-(difluoromethyl)indoline-1-carboxylate (310 mg, 1.2 mmol) in DMF (5 mL) was added N-bromosuccinimide (210 mg, 1.2 mmol). The mixture was stirred at 15° C. for 12 h under a nitrogen atmosphere. EtOAc (30 mL) was added and the mixture was washed with brine (20 mL×2), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc=20:1) to give the title compound (300 mg, 75%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.15-7.79 (m, 1H), 7.34 (s, 1H), 6.87 (t, J=55.2 Hz, 1H), 4.02 (t, J=8.0 Hz, 2H), 3.12 (t, J=8.4 Hz, 2H), 1.58-1.57 (m, 9H).
-
- To a solution of tert-butyl 5-bromo-6-(difluoromethyl)indoline-1-carboxylate (300 mg, 0.86 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (220 mg, 1.0 mmol) and K2CO3 (520 mg, 3.8 mmol) in dioxane (20 mL) and H2O (2 mL) was added [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (70 mg, 0.1 mmol). The mixture was heated to 90° C. for 12 h under a nitrogen atmosphere. After cooling the reaction to room temperature, the mixture was concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc=3:1) to give the title compound (280 mg, 93%) as a brown oil. LCMS M/Z (M+H) 350.
-
- To a solution of tert-butyl 6-(difluoromethyl)-5-(1-methyl-1H-pyrazol-4-yl)indoline-1-carboxylate (280 mg, 0.8 mmol) in DCM (10 mL) was added trifluoroacetic acid (5 mL). The mixture was stirred at 18° C. for 2 h under a nitrogen atmosphere. The mixture was concentrated in vacuo. EtOAc (50 mL) was added and the mixture was washed with sat. aq. NaHCO3 (50 mL) and brine (50 mL×2), filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc=5:1 to 3:1) to give the title compound (190 mg, 95%) as a brown solid. 1H NMR (400 MHz, CDCl3) δ 7.53 (s, 1H), 7.41 (s, 1H), 7.11 (s, 1H), 6.97 (s, 1H), 6.56 (t, J=55.6 Hz, 1H), 3.96 (s, 3H), 3.63 (t, J=8.4 Hz, 2H), 3.08 (t, J=8.4 Hz, 2H).
-
- To a solution of 6-(difluoromethyl)-5-(1-methylpyrazol-4-yl)indoline (90 mg, 0.36 mmol), tert-butoxysodium (69 mg, 0.72 mmol) and 1-[3-bromo-1-(oxetan-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (Intermediate E, 108 mg, 0.36 mmol) in 1,4-dioxane (5 mL) was added chloro(2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl)[2-(2-aminoethylphenyl)]palladium(II), methyl-tert-butylether adduct (30 mg, 0.04 mmol) and 2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl (16 mg, 0.04 mmol). The mixture was heated to 120° C. for 12 h under a nitrogen atmosphere. After cooling the reaction to room temperature, the mixture was concentrated in vacuo. EtOAc (100 ml) was added and the mixture was washed with water (100 mL×2) and brine (50 mL), dried over anhydrous Na2SO4 and concentrated in vacuo. The crude residue was purified by reverse phase chromatography (acetonitrile 6-36%/0.2% formic acid in water) to give the title compound (48 mg, 28%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.88-7.78 (m, 2H), 7.53 (s, 1H), 7.22 (s, 1H), 7.00-6.71 (m, 1H), 5.47-5.41 (m, 1H), 4.98-4.83 (m, 2H), 4.86-4.83 (m, 2H), 4.57-4.55 (m, 2H), 4.15-4.05 (m, 2H), 3.88 (s, 3H), 3.72-3.67 (m, 2H), 3.23-3.19 (m, 2H), 2.76-2.61 (m, 2H), 2.09-2.08 (m, 3H). LCMS M/Z (M+H) 469.
-
-
- To a solution of 5-bromo-6-chloro-1H-indole (10.0 g, 43.4 mmol) in THF (20 mL) and water (4 mL) was added 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (9.0 g, 43.4 mmol), chloro(2-dicyclohexylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl) palladium(II) (1.7 g, 2.2 mmol), 2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (2.1 g, 4.34 mmol) and Na2CO3 (9.2 g, 86.8 mmol). The mixture was heated to 60° C. for 16 h under a nitrogen atmosphere. The solution was concentrated in vacuo. The crude residue was purified by silica gel chromatography (DCM/MeOH=20:1) to give the title compound (9.6 g, 74%) as a yellow solid. LCMS M/Z (M+H) 232.
-
- To a solution of 6-chloro-5-(1-methylpyrazol-4-yl)-1H-indole (2.0 g, 6.7 mmol) in AcOH (10 mL) was added sodium cyanoborohydride (410 mg, 6.7 mmol). The mixture was stirred at 26° C. for 2 h. The mixture was concentrated in vacuo. EtOAc (200 mL) was added and the mixture was washed with water (200 mL×2) and brine (100 mL), dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc=3:1) to give the title compound (1.4 g, 57%) as a yellow solid. LCMS M/Z (M+H) 234.
-
- To a solution of 6-chloro-5-(1-methylpyrazol-4-yl)indoline (0.7 g, 2.6 mmol), potassium acetate (1.0 g, 10.3 mmol) and potassium hexacyanoferrate(II) trihydrate (5.9 g, 15.4 mmol) in 1,4-dioxane (30 mL) and water (30 mL) was added [2-(2-aminophenyl)phenyl]-methylsulfonyloxy-palladium di-tert-butyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane (204 mg, 0.3 mmol) and di-tert-butyl(2′,4′,6′-triisopropyl-[1,1′-biphenyl]-2-yl)phosphine (218 mg, 0.5 mmol). The mixture was heated to 120° C. for 2 h under a nitrogen atmosphere. After cooling the reaction to room temperature, the mixture was concentrated in vacuo. EtOAc (500 mL) was added and the mixture was washed with water (200 mL×2) and brine (100 mL), dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc=3:1) to give the title compound (540 mg, 67%) as a yellow solid. LCMS M/Z (M+H) 225.
-
- To a solution of 1-(3-bromo-1-tetrahydropyran-4-yl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl)ethanone (Intermediate I, 300 mg, 0.9 mmol), 5-(1-methylpyrazol-4-yl)indoline-6-carbonitrile (246 mg, 1.1 mmol) and tert-butoxysodium (176 mg, 1.8 mmol) in 1,4-dioxane (5 mL) was added chloro(2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (71 mg, 0.09 mmol), dicyclohexyl(2′,6′-diisopropoxy-[1,1′-biphenyl]-2-yl)phosphine (43 mg, 0.09 mmol). The mixture was heated to 120° C. for 12 h under a nitrogen atmosphere. After cooling the reaction to room temperature, the mixture was concentrated in vacuo. EtOAc (300 mL) was added and the mixture was washed with water (300 mL×2) and brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was recrystallized from MeOH (5 mL) to give the title compound (155 mg, 36%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.11 (s, 1H), 7.83 (s, 1H), 7.78-7.71 (m, 1H), 7.44 (s, 1H), 4.60-4.58 (m, 2H), 4.29-4.24 (m, 1H), 4.16-4.06 (m, 2H), 4.00-3.98 (m, 2H), 3.90 (s, 3H), 3.75-3.69 (m, 2H), 3.50-3.44 (m, 2H), 3.26-3.21 (m, 2H), 2.84-2.68 (m, 2H), 2.11-2.10 (m, 3H), 2.05-1.98 (m, 2H), 1.82-1.79 (m, 2H). LCMS M/Z (M+H) 472.
-
-
- To a solution of 1H-indole-4-carbaldehyde (10 g, 68.89 mmol) in MeOH (200 mL) at 0° C. was added NaBH4 (3.1 g, 82.67 mmol). The resulting mixture was stirred at 0° C. for 0.5 h. Water (100 mL) was added slowly and the mixture was extracted with EtOAc (300 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated to give the title compound (10 g, crude) as a colorless oil that required no further purification.
-
- To a solution of (1H-indol-4-yl)methanol (10 g, 67.95 mmol) in AcOH (100 mL) was added NaBH3CN (12.8 g, 203.84 mmol) portionwise. The resulting mixture was stirred at room temperature for 2 h. Water (200 mL) was added and the mixture was made basic with solid NaHCO3 to pH 8 and then extracted with EtOAc (600 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc=10:1) to give the title compound (6 g, 60%) as a white solid.
-
- To a solution of indolin-4-ylmethanol (6 g, 40.22 mmol) in THF (200 mL) was added 1H-Imidazole (11 g, 160.87 mmol) and tert-butyl-dimethylsilyl chloride (13.3 g, 88.48 mmol). The mixture was stirred at room temperature for 12 h and the resulting precipitate was removed by filtration. The filtrate was concentrated in vacuo. EtOAc (200 mL) was added and the mixture was washed with water (200 mL×2). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc=10:1) to give the title compound (8 g, 75%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 6.89-6.86 (m, 1H), 6.52 (d, J=7.6 Hz, 1H), 6.40 (d, J=7.6 Hz, 1H), 5.43 (s, 1H), 4.57 (s, 2H), 3.40 (t, J=8.4 Hz, 2H), 2.85 (t, J=8.4 Hz, 2H), 0.89 (s, 9H), 0.06 (s, 6H).
-
- To a solution of 4-(((tert-butyldimethylsilyl)oxy)methyl)indoline (8 g, 30.37 mmol) in DCM (200 mL) was added DMAP (371 mg, 3.04 mmol), triethylamine (9.2 g, 91.1 mmol) and di-tert-butyl dicarbonate (8 g, 36.44 mmol). The resulting mixture was stirred at room temperature for 16 h. The mixture was concentrated in vacuo. Water (100 mL) was added and the mixture was extracted with EtOAc (200 mL×2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc=50:1) to give the title compound (9 g, 81%) as a white solid.
-
- To a solution of tert-butyl 4-(((tert-butyldimethylsilyl)oxy)methyl)indoline-1-carboxylate (9 g, 24.75 mmol) in DCM (200 mL) was added N-bromosuccinimide (4.9 g, 27.23 mmol). The resulting mixture was stirred at room temperature for 2 h. The mixture was concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc=50:1) to give the title compound (9.5 g, 86%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.58-7.50 (m, 1H), 7.37 (d, J=8.4 Hz, 1H), 4.70 (s, 2H), 3.93 (t, J=8.4 Hz, 2H), 3.15 (t, J=8.4 Hz, 2H), 1.49 (s, 9H), 0.87 (s, 9H), 0.08 (s, 6H).
-
- To a solution of tert-butyl 5-bromo-4-(((tert-butyldimethylsilyl)oxy)methyl)indoline-1-carboxylate (9.5 g, 21.47 mmol) in dioxane (100 mL) and H2O (10 mL) was added K2CO3 (6.8 g, 64.41 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1 g, 2.2 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (4.5 g, 21.47 mmol). The mixture was heated to 120° C. for 12 h under a nitrogen atmosphere. After cooling the reaction to room temperature, the mixture was concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc=3:1) to give the title compound (4.9 g, 51%) as a yellow solid.
-
- To a solution of tert-butyl4-(((tert-butyldimethylsilyl)oxy)methyl)-5-(1-methyl-1H-pyrazol-4-yl)indoline-1-carboxylate (1 g, 2.25 mmol) in DCM (60 mL) was added trifluoroacetic acid (10 mL). The mixture was stirred at room temperature for 1 h. Water (60 mL) was added and the mixture was made basic with solid NaHCO3 to pH 8 and then extracted with DCM (60 mL×2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (600 mg, crude) as a yellow solid that required no further purification. 1H NMR (400 MHz, DMSO-d6) δ 7.69 (s, 1H), 7.48 (s, 1H), 6.92 (d, J=8.4 Hz, 1H), 6.49 (d, J=8.4 Hz, 1H), 5.76 (s, 1H), 4.50 (s, 2H), 3.84 (s, 3H), 3.44 (t, J=8.4 Hz, 2H), 2.99 (t, J=8.4 Hz, 2H), 0.88 (s, 9H), 0.06 (s, 6H).
-
- To a solution of 4-(((tert-butyldimethylsilyl)oxy)methyl)-5-(1-methyl-1H-pyrazol-4-yl)indoline (300 mg, 0.87 mmol) in dioxane (10 mL) was added 1-(3-bromo-1-(tetrahydrofuran-3-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone (302 mg, 0.96 mmol), chloro(2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl) [2-(2-aminoethylphenyl)]palladium(II), methyl-tert-butylether adduct (65 mg, 0.08 mmol), 2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl (35 mg, 0.08 mmol) and t-BuONa (336 mg, 3.49 mmol). The mixture was heated to 120° C. for 12 h under a nitrogen atmosphere. After cooling the reaction to room temperature, the mixture was concentrated in vacuo. The crude residue was purified by silica gel chromatography (DCM/MeOH=20:1) to give the title compound (150 mg, 30%) as a yellow solid. LCMS M/Z (M+H) 577.
-
- To a solution of 1-(3-(4-(((tert-butyldimethylsilyl)oxy)methyl)-5-(1-methyl-1H-pyrazol-4-yl)indolin-1-yl)-1-(tetrahydrofuran-3-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone (150 mg, 0.26 mmol) in THF (10 mL) was added tetrabutylammonium fluoride (82 mg, 0.31 mmol). The mixture was stirred at room temperature for 3 h. The resulting mixture was concentrated in vacuo. Water (10 mL) was added and the mixture was extracted with EtOAc (20 mL×2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by reverse phase chromatography (acetonitrile 20-50%/0.1% NH4HCO3 in water) to give the title compound (33 mg, 24%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 7.87 (s, 1H), 7.78 (s, 1H), 7.69-7.65 (m, 1H), 7.56 (s, 1H), 7.48 (s, 1H), 7.24 (d, J=8.0 Hz, 2H), 7.07 (d, J=8.0 Hz, 1H), 6.90-6.89 (m, 1H), 5.01-4.90 (m, 1H), 4.85-4.78 (m, 4H), 4.77 (s, 1H), 4.53 (s, 2H), 4.49 (s, 2H), 4.43-4.42 (m, 2H), 4.07-4.01 (m, 8H), 3.90-3.84 (m, 10H), 3.82 (s, 2H), 3.26 (t, J=8.6 Hz, 2H), 2.95-2.70 (m, 2H), 2.69-2.60 (m, 2H), 2.30-2.27 (m, 2H), 2.25-2.09 (m, 2H), 2.05 (s, 6H). LCMS M/Z (M+H) 463.
-
-
- To a solution of tert-butyl 4-(((tert-butyldimethylsilyl)oxy)methyl)-5-(1-methyl-1H-pyrazol-4-yl)indoline-1-carboxylate (1 g, 2.26 mmol) in DCM (40 mL) was added HCl in EtOAc (10 mL). The mixture was stirred at room temperature for 30 min. Water (20 mL) was added and the mixture was made basic with solid NaHCO3 to pH 8 and then extracted with EtOAc (100 mL×2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (700 mg, crude) as a white solid that required no further purification. LCMS M/Z (M+H) 330.
-
- To a solution of tert-butyl 4-(hydroxymethyl)-5-(1-methyl-1H-pyrazol-4-yl)indoline-1-carboxylate (700 mg, 2.13 mmol) in MeOH (10 mL) was added Pd/C (1 g, 10% wt.). The mixture was stirred at room temperature for 12 h under hydrogen atmosphere (15 psi). The reaction was filtered and the filtrate was concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc=1:1) to give the title compound (120 mg, 18%) as a yellow solid. LCMS M/Z (M+H) 314.
-
- To a solution of tert-butyl 4-methyl-5-(1-methyl-1H-pyrazol-4-yl)indoline-1-carboxylate (120 mg, 0.38 mmol) in EtOAc (2 mL) was added HCl in EtOAc (4M, 2 mL). The mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated in vacuo. Water (10 mL) was added and the mixture was made basic with solid NaHCO3 to pH 8 and then extracted with EtOAc (30 mL×2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (80 mg, crude) as a yellow solid that required no further purification.
-
- To a solution of 4-methyl-5-(1-methyl-1H-pyrazol-4-yl)indoline (80 mg, 0.38 mmol) in dioxane (5 mL) was added 1-(3-bromo-1-(tetrahydrofuran-3-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-yl)ethanone (142 mg, 0.45 mmol), chloro(2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl)[2-(2-aminoethylphenyl)]palladium(II), methyl-tert-butylether adduct (180 mg, 0.04 mmol), 2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl (25 mg, 0.04 mmol) and t-BuONa (144 mg, 1.5 mmol). The mixture was heated to 100° C. for 12 h under a nitrogen atmosphere. After cooling the reaction to room temperature, the mixture was concentrated in vacuo. The crude residue was purified by reverse phase chromatography (acetonitrile 20-50%/0.1% NH4HCO3 in water) to give the title compound (45 mg, 20%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.76 (s, 1H), 7.50 (s, 1H), 7.23-7.17 (m, 1H), 7.03-7.00 (m, 1H), 4.88-4.82 (m, 1H), 4.54-4.52 (m, 2H), 4.03-3.98 (m, 3H), 3.85 (s, 3H), 3.83-3.69 (m, 2H), 3.31 (s, 3H), 3.08 (t, J=8.4 Hz, 2H), 2.79-2.66 (m, 2H), 2.25-2.08 (m, 7H). LCMS M/Z (M+H) 447.
-
-
- To a solution of 4-bromoaniline (3.0 g, 17.4 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (4.4 g, 20.9 mmol) and K2CO3 (4.9 g, 34.9 mmol) in 1,4-dioxane (20 mL) and water (5 mL) was added [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.2 g, 1.7 mmol). The mixture was heated to 120° C. for 12 h. After cooling the reaction to room temperature, the mixture was filtered and the filtrate was concentrated in vacuo. Water (100 mL) was added and the mixture was extracted with EtOAc (300 mL×3). The combined organic layers were washed with brine (100 mL×3), dried over anhydrous Na2SO4 and concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc=1:1) to give the title compound (2.7 g, 72%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 7.85 (s, 1H), 7.63 (s, 1H), 7.19 (d, J=8.8 Hz, 2H), 6.54 (d, J=8.4 Hz, 2H), 5.00 (s, 2H), 3.81 (s, 3H).
-
- To a solution of 1-[3-bromo-1-[(3S)-tetrahydrofuran-3-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (Intermediate G, 1.0 g, 3.2 mmol), t-BuONa (0.6 g, 6.4 mmol) and 4-(1-methylpyrazol-4-yl)aniline (661.6 mg, 3.8 mmol) in 1,4-dioxane (10 mL) was added chloro(2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl) [2-(2-aminoethylphenyl)]palladium(II), methyl-tert-butylether adduct (260.0 mg, 0.3 mmol) and 2-(dicyclohexylphosphino)3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl (170.6 mg, 0.3 mmol). The mixture was heated to 120° C. for 12 h. After cooling the reaction to room temperature, the mixture was filtered and the filtrate was concentrated in vacuo. Water (100 mL) was added and the mixture was extracted with EtOAc (100 mL×3). The combined organic layers were washed with brine (100 mL×3), dried over anhydrous Na2SO4 and concentrated in vacuo. The crude residue was purified by silica gel chromatography (DCM/MeOH=20:1) to give the title compound (920 mg, 59%) as a yellow solid. LCMS M/Z (M+H) 407.
-
- To a solution of 1-[3-[4-(1-methylpyrazol-4-yl)anilino]-1-[(3S)-tetrahydro ran-3-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (100 mg, 0.25 mmol) in DMF (2 mL) was added NaH (60%, 20 mg, 0.49 mmol). The mixture was stirred at 25° C. for 0.5 h before iodoethane (46 mg, 0.3 mmol) was added dropwise. The mixture was stirred at 25° C. for another 2 h. Water (5 mL) was added and the mixture was extracted with EtOAc (5 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The crude residue was purified by reverse phase chromatography (acetonitrile 29-59%/0.1% NH4OH in water) to give the title compound (45 mg, 42%) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 7.97 (s, 1H), 7.72 (s, 1H), 7.40-7.36 (m, 2H), 6.78-6.74 (m, 2H), 4.91-4.84 (m, 1H), 4.01-3.99 (m, 2H), 3.90 (s, 2H), 3.83-3.79 (m, 5H), 3.72-3.65 (m, 4H), 2.82-2.67 (m, 2H), 2.27-2.22 (m, 2H), 2.03-1.85 (m, 3H), 1.16-1.12 (m, 3H). LCMS M/Z (M+H) 435.
- The following compounds were prepared in a similar fashion to Example 222:
-
-
Example Compound Name NMR m/z Example 223 1-[3-[N-benzyl-4-(1- 1H NMR (400 MHz, DMSO-d6) δ 7.94 (s, 495 methylpyrazol-4- 1H), 7.69 (s, 1H), 7.39-7.19 (m, 7H), 6.78- yl)anilino]-1-[(3S)- 6.73 (m, 2H), 4.96 (s, 2H), 4.89-4.85 (m, tetrahydrofuran-3-yl]- 1H), 4.00-3.94 (m, 4H), 3.81 (s, 3H), 3.80- 6,7-dihydro-4H- 3.66 (m, 4H), 2.81-2.67 (m, 2H), 2.28-2.22 pyrazolo[4,3-c]pyridin- (m, 2H), 2.04-1.85 (m, 3H) 5-yl]ethanone Example 224 1-[1-methyl-3-[N- 1H NMR (400 MHz, DMSO-d6) δ 8.05 (d, J = 433 methyl-4-[1-methyl-3- 4.0 Hz, 1H), 7.26-7.23 (m, 2H), 6.88-6.84 (trifluoromethyl)pyrazol- (m, 2H), 3.98-3.92 (m, 5H), 3.72-3.66 (m, 4-yl]anilino]-6,7- 5H), 3.27 (s, 3H), 2.78-2.63 (m, 2H), 2.05- dihydro-4H- 1.88 (m, 5H) pyrazolo[4,3-c]pyridin- 5-yl]ethanone Example 225 1-[1- 1H NMR (400 MHz, DMSO-d6) δ 7.97 (s, 405 (cyclopropylmethyl)-3- 1H), 7.72 (s, 1H), 7.41-7.38 (m, 2H), 6.82- [N-methyl-4-(1- 6.77 (m, 2H), 3.99-3.97 (m, 2H), 3.83-3.81 methylpyrazol-4- (m, 5H), 3.71-3.65 (m, 2H), 3.25 (s, 3H), yl)anilino]-6,7-dihydro- 2.80-2.67 (m, 2H), 2.05-1.89 (m, 3H), 1.19- 4H-pyrazolo[4,3- 1.17 (m, 1H), 0.53-0.49 (m, 2H), 0.34- c]pyridin-5-yl]ethanone 0.33 (m, 2H) Example 226 1-[3-[N-methyl-4-[1- 1H NMR (400 MHz, DMSO-d6) δ 8.04-8.03 489 methyl-3- (m, 1H), 7.25-7.22 (m, 2H), 6.85-6.80 (m, (trifluoromethyl)pyrazol- 2H), 4.93-4.87 (m, 1H), 4.03-3.93 (m, 4H), 4-yl]anilino]-1- 3.82 (s, 3H), 3.80-3.71 (m, 4H), 3.36 (s, 3H), tetrahydrofuran-3-yl- 2.84-2.70 (m, 2H), 2.28-2.24 (m, 2H), 2.07- 6,7-dihydro-4H- 1.90 (m, 3H) pyrazolo[4,3-c]pyridin- 5-yl]ethanone Example 227 2-[N-(5-acetyl-1- Not Determined 390 methyl-6,7-dihydro-4H- pyrazolo[4,3-c]pyridin- 3-yl)-4-(1- methylpyrazol-4- yl)anilino]acetonitrile Example 228 1-[1-methyl-3-[N- 1H NMR (400 MHz, DMSO-d6) δ 8.00-7.67 365 methyl-4-(1- (m, 2H), 7.45-7.33 (m, 2H), 6.86-6.73 (m, methylpyrazol-4- 2H), 3.95 (d, J = 1.7 Hz, 2H), 3.83 (s, 3H), yl)anilino]-6,7-dihydro- 3.74-3.58 (m, 5H), 3.24 (d, J = 1.4 Hz, 3H), 4H-pyrazolo[4,3- 2.81-2.58 (m, 2H), 2.04 (s, 2H), 1.87 (s, 1H) c]pyridin-5-yl]ethanone -
- To a solution of 1-[3-[4-(1-methylpyrazol-4-yl)anilino]-1-[(3S)-tetrahydrofuran-3-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (
Step 2 of Example 222, 100 mg, 0.3 mmol), iodobenzene (0.04 mL, 0.4 mmol) and t-BuOK (55.2 mg, 0.5 mmol) in toluene (5 mL) was added 2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (21 mg, 0.05 mmol) and tris(dibenzylideneacetone)dipalladium (23 mg, 0.02 mmol). The mixture was heated to 130° C. for 12 h under a nitrogen atmosphere. After cooling the reaction to room temperature, the mixture was concentrated in vacuo. Water (50 mL) was added and the mixture was extracted with EtOAc (100 mL×3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4 and concentrated in vacuo. The crude residue was purified by reverse phase chromatography (acetonitrile 15-45%/0.1% NH4HCO3 in water) to give the title compound (13 mg, 10%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.03 (s, 1H), 7.77 (s, 1H), 7.48-7.42 (m, 2H), 7.32-7.18 (m, 2H), 6.98-6.91 (m, 5H), 4.92-4.88 (m, 1H), 4.01-3.97 (m, 1H), 3.84 (s, 3H), 3.81-3.73 (m, 4H), 3.69-3.61 (m, 2H), 2.84-2.69 (m, 2H), 2.29-2.14 (m, 2H), 2.03-1.73 (m, 3H). LCMS M/Z (M+H) 483. -
-
- To a solution of 6-chloro-1,2,3,4-tetrahydro-1,7-naphthyridine (200 mg, 1.19 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (296 mg, 1.42 mmol) and Na2CO3 (377 mg, 3.56 mmol) in 1,4-dioxane (5 mL) and H2O (1 mL) was added chloro(2-dicyclohexylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl) palladium(II) (93 mg, 0.12 mmol) and 2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (57 mg, 0.12 mmol). The resulting mixture was heated to 100° C. for 16 h under a nitrogen atmosphere. After cooling to room temperature, the mixture was filtered and concentrated in vacuo. The crude residue was purified by Prep-TLC (DCM/MeOH=10:1) to give the title compound (200 mg, 79%) as a pale yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.89 (s, 1H), 7.86 (s, 1H), 7.81 (s, 1H), 7.09 (s, 1H), 4.24 (s, 1H), 3.93 (s, 3H), 3.36 (t, J=6.4 Hz, 2H), 2.78 (t, J=6.4 Hz, 2H), 1.99-1.93 (m, 2H).
-
- To a solution of 6-(1-methylpyrazol-4-yl)-1,2,3,4-tetrahydro-1,7-naphthyridine (100 mg, 0.47 mmol) and 1-(3-bromo-1-tetrahydropyran-4-yl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl)ethanone (Intermediate I, 184 mg, 0.56 mmol) in 1,4-dioxane (1.5 mL) was added t-BuONa (90 mg, 0.93 mmol) and dichloro[1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II) (56 mg, 0.07 mmol). The reaction mixture was heated to 120° C. for 16 h under a nitrogen atmosphere. After cooling to room temperature, the mixture was filtered and concentrated in vacuo. The crude residue was purified by reverse phase chromatography (acetonitrile 15-45%/0.05 NH4OH in water) to give the title compound (23 mg, 11%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.03 (s, 1H), 7.80 (s, 1H), 7.76-7.69 (m, 1H), 7.29 (s, 1H), 4.33-4.22 (m, 1H), 4.21-4.12 (m, 2H), 3.99-3.90 (m, 2H), 3.83 (s, 3H), 3.79-3.68 (m, 2H), 3.59-3.48 (m, 4H), 2.88-2.65 (m, 4H), 2.09-1.91 (m, 7H), 1.85-1.75 (m, 2H). LCMS M/Z (M+H) 462.
-
- To a solution of 6-(1-methylpyrazol-4-yl)-1-(1-tetrahydropyran-4-yl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl)-3,4-dihydro-2H-quinoline (Intermediate J, 17.4 mg, 0.0416 mmol) in DCM (0.21 mL) was added TEA (9.3 μL, 0.067 mmol) and propionyl chloride (5.1 μL, 0.058 mmol). The mixture was stirred at room temperature for 1.5 h, water (1 mL) was added and the resulting biphasic mixture was extracted with DCM (1 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the crude product that was purified by reverse phase chromatography (acetonitrile 5-50%/0.1% formic acid in water) to give the title compound (8.7 mg, 42% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.91 (s, 1H), 7.67 (d, J=0.9 Hz, 1H), 7.19 (d, J=2.1 Hz, 1H), 7.09 (d, J=8.5 Hz, 1H), 6.42 (t, J=7.9 Hz, 1H), 4.26 (s, 1H), 4.10 (s, 2H), 3.95 (dd, J=12.1, 3.7 Hz, 2H), 3.82 (s, 3H), 3.79-3.68 (m, 2H), 3.56-3.54 (m, 2H), 3.47-3.42 (m, 2H), 2.88-2.77 (m, 4H), 2.42-2.08 (m, 2H), 2.08-1.89 (m, 4H), 1.81 (d, J=11.8 Hz, 2H), 1.00-0.89 (m, 3H). LCMS M/Z (M+H) 475.
- The following compounds were prepared in a similar fashion to Example 231:
-
-
Example Compound Name NMR m/z Example 232 cyclopropyl(3-(6-(1- 1H NMR (400 MHz, DMSO-d6) δ 7.90 (d, J = 487 methyl-1H-pyrazol-4- 0.8 Hz, 1H), 7.66 (d, J = 0.8 Hz, 1H), yl)-3,4- 7.23-7.14 (m, 1H), 7.09 (d, J = 8.3 Hz, dihydroquinolin-1(2H)- 1H), 6.42 (d, J = 9.2 Hz, 1H), 4.36 (s, 1H), yl)-1-(tetrahydro-2H- 4.32-4.22 (m, 1H), 4.10 (s, 2H), 3.99- pyran-4-yl)-6,7- 3.92 (m, 3H), 3.82 (s, 4H), 3.59-3.51 (m, dihydro-1H- 2H), 3.49-3.41 (m, 2H), 2.91-2.70 (m, pyrazolo[4,3-c]pyridin- 4H), 2.04-1.92 (m, 4H), 1.81 (d, J = 12.6 5(4H)-yl)methanone Hz, 2H), 0.71 (d, J = 5.9 Hz, 4H) Example 233 6-(1-methyl-1H- 1H NMR (400 MHz, DMSO-d6) δ 7.91 (d, J = 497 pyrazol-4-yl)-1-(5- 0.8 Hz, 1H), 7.67 (d, J = 0.8 Hz, 1H), (methylsulfonyl)-1- 7.22-7.16 (m, 1H), 7.10 (dd, J = 8.4, 2.2 (tetrahydro-2H-pyran- Hz, 1H), 6.39 (d, J = 8.4 Hz, 1H), 4.33- 4-yl)-4,5,6,7- 4.22 (m, 1H), 3.96 (dd, J = 11.2, 4.3 Hz, tetrahydro-1H- 2H), 3.89 (s, 2H), 3.82 (s, 3H), 3.57-3.52 pyrazolo[4,3-c]pyridin- (m, 2H), 3.51-3.42 (m, 4H), 2.92-2.87 3-yl)-1,2,3,4- (m, 5H), 2.83-2.77 (m, 2H), 2.04-1.93 tetrahydroquinoline (m, 4H), 1.82 (d, J = 13.3 Hz, 2H) Example 234 1-(3-(6-(1-methyl-1H- 1H NMR (400 MHz, DMSO-d6) δ 7.90 (d, J = 489 pyrazol-4-yl)-3,4- 3.0 Hz, 1H), 7.70-7.64 (m, 1H), 7.19 (s, dihydroquinolin-1(2H)- 1H), 7.14-7.06 (m, 1H), 6.44-6.40 (m, yl)-1-(tetrahydro-2H- 1H), 4.29-4.21 (m, 1H), 4.10 (s, 2H), 3.95 pyran-4-yl)-6,7- (d, J = 11.9 Hz, 2H), 3.82 (s, 3H), 3.77- dihydro-1H- 3.70 (m, 2H), 3.59-3.52 (m, 2H), 3.48- pyrazolo[4,3-c]pyridin- 3.41 (m, 2H), 2.85-2.70 (m, 4H), 2.38- 5(4H)-yl)butan-1-one 2.17 (m, 2H), 2.00-2.17 (m, 4H), 1.80 (d, J = 12.4 Hz, 2H), 1.53-1.40 (m, 2H), 0.90- 0.77 (m, 3H) -
- To a solution of 6-(1-methylpyrazol-4-yl)-1-(1-tetrahydropyran-4-yl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl)-3,4-dihydro-2H-quinoline (Intermediate J, 35.5 mg, 0.0848 mmol) in MeCN (0.4 mL) was added O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate (32.0 mg, 0.0976 mmol), TEA (35.5 μL, 0.254 mmol) and 2,2-difluoroacetic acid (10.7 μL, 0.170 mmol). The mixture was stirred at room temperature for 1.5 h, then concentrated in vacuo to give crude product that was purified by reverse phase chromatography (acetonitrile 5-50%/0.1% formic acid in water) to give the title compound (7.2 mg, 15%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.92-7.91 (m, 1H), 7.68-7.67 (m, 1H), 7.21-7.19 (m, 1H), 7.14-7.07 (m, 1H), 6.82-6.61 (m, 1H), 6.45-6.41 (m, 1H), 4.28 (s, 1H), 4.21-4.17 (m, 2H), 4.00-3.91 (m, 2H), 3.88-3.75 (m, 5H), 3.59-3.52 (m, 2H), 3.51-3.41 (m, 2H), 2.92-2.77 (m, 4H), 2.02-1.89 (m, 4H), 1.81 (d, J=12.8 Hz, 2H). LCMS M/Z (M+H) 497.
-
- To a vial was added 6-(1-methylpyrazol-4-yl)-1-(1-tetrahydropyran-4-yl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl)-3,4-dihydro-2H-quinoline (Intermediate J, 18.8 mg, 0.0449 mmol), 2-bromo-1,3,4-thiadiazole (15.0 mg, 0.0898 mmol), dichloro[1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II) (7.5 mg, 0.0090 mmol), t-BuONa (8.6 mg, 0.090 mmol) and 1,4-dioxane (0.4 mL). The mixture was sparged with an argon ballon, and then heated to 120° C. for 16 h under an argon atmosphere. After cooling the reaction to room temperature, DCM (1 mL) was added and the reaction was filtered through celite and concentrated in vacuo to give the crude product that was purified by reverse phase chromatography (acetonitrile 5-85%/0.1% NH4OH in water) to give the title compound (2.5 mg, 10%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.78 (s, 1H), 7.91 (d, J=0.8 Hz, 1H), 7.68 (d, J=0.8 Hz, 1H), 7.21 (d, J=2.1 Hz, 1H), 7.12 (dd, J=8.4, 2.2 Hz, 1H), 6.45 (d, J=8.4 Hz, 1H), 4.37-4.25 (m, 1H), 4.18 (s, 2H), 4.00-3.90 (m, 2H), 3.85 (t, J=5.8 Hz, 2H), 3.82 (s, 3H), 3.62-3.53 (m, 2H), 3.45 (t, J=11.5 Hz, 2H), 2.94 (t, J=5.7 Hz, 2H), 2.82 (t, J=6.4 Hz, 2H), 2.05-1.92 (m, 4H), 1.81 (d, J=10.9 Hz, 2H). LCMS M/Z (M+H) 503.
-
- To a vial was added 6-(1-methylpyrazol-4-yl)-1-(1-tetrahydropyran-4-yl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl)-3,4-dihydro-2H-quinoline (Intermediate J, 20.0 mg, 0.048 mmol), dichloro[1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II) (8.0 mg, 0.0096 mmol), t-BuONa (9.2 mg, 0.096 mmol), 1,4-dioxane (0.2 mL) and 3-bromoisoxazole (10.8 mg, 0.717 mmol). The mixture was sparged with an argon ballon, and then heated to 120° C. for 16 h under an argon atmosphere. After cooling the reaction to room temperature, DCM (1 mL) was added and the reaction was filtered through celite and concentrated in vacuo to give the crude product that was purified by reverse phase chromatography (acetonitrile 5-50%/0.1% formic acid in water) to give the title compound (4.6 mg, 20%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.91-7.90 (m, 1H), 7.67-7.66 (m, 1H), 7.24-7.16 (m, 1H), 7.12-7.05 (m, 1H), 6.54-6.39 (m, 1H), 4.30-4.24 (m, 1H), 4.12 (s, 2H), 4.06 (d, J=8.2 Hz, 2H), 3.95 (d, J=11.4 Hz, 2H), 3.82 (s, 3H), 3.67-3.51 (m, 4H), 3.50-3.42 (m, 2H), 2.90-2.76 (m, 4H), 2.01-1.90 (m, 4H), 1.79 (d, J=12.9 Hz, 2H). LCMS M/Z (M+H) 486.
-
-
- To a solution of 7-chloro-4-methyl-quinoline (5.0 g, 28.15 mmol) in toluene (100 mL) was added 2,2-difluoro-1-phenyl-ethanone (8.79 g, 56.3 mmol), chloro[(tricyclohexylphosphine)-2-(2′-aminobiphenyl)]palladium(II) (1.66 g, 2.81 mmol) and K3PO4 (23.9 g, 112.59 mmol). The reaction mixture was heated to 120° C. for 16 h under a nitrogen atmosphere. After cooling the reaction to room temperature, water (100 mL) was added and the mixture was extracted with DCM (100 mL×2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (5 g, crude) as brown oil that required no further purification. LCMS M/Z (M+H) 298.
-
- To a solution of 2,2-difluoro-2-(4-methyl-7-quinolyl)-1-phenyl-ethanone (5.0 g, 16.82 mmol) in toluene (100 mL) and water (6 mL) was added KOH (5.66 g, 100.91 mmol). The reaction mixture was heated to 100° C. for 16 h. After cooling the reaction to room temperature, water (100 mL) was added and the mixture was extracted with DCM (100 mL×2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc=10/1) to give the title compound (3.7 g, 80%) as yellow oil. LCMS M/Z (M+H) 194.
-
- To a solution of 7-(difluoromethyl)-4-methyl-quinoline (3.7 g, 19.15 mmol) and sodium cyanoborohydride (6.02 g, 95.76 mmol) in MeOH (200 mL) at 0° C. was added boron trifluoride diethyl etherate (20.67 mL, 38.30 mmol) dropwise. The reaction mixture was heated to 100° C. for 36 h under a nitrogen atmosphere. After cooling the reaction to room temperature, sat. aq. NaHCO3 (100 mL) was added and the mixture was extracted with DCM (100 mL×2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc=50/1) to give the mixture of 7-(difluoromethyl)-4-methyl-1,2,3,4-tetrahydroquinoline and 7-(difluoromethyl)-4-methyl-1,2-dihydroquinoline (2.5 g, ratio=7:2) as a brown oil. The resulting mixture was dissolved in MeOH (50 mL) and 10% Pd/C (403 mg, 0.19 mmol) was added. The mixture was stirred at 25° C. for 1 h under a hydrogen atmosphere (15 psi). The reaction was filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc=100/1) to give the title compound (1.9 g, 50%) as a light yellow oil. LCMS M/Z (M+H) 198.
-
- To a solution of 7-(difluoromethyl)-4-methyl-1,2,3,4-tetrahydroquinoline (899 mg, 4.56 mmol), tert-butyl 3-bromo-1-(tetrahydro-2H-pyran-4-yl)-6, 7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (Intermediate H, 1.6 g, 4.14 mmol) and t-BuONa (1.19 g, 12.43 mmol) in 1,4-dioxane (20 mL) was added chloro(2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (322 mg, 0.41 mmol), 2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl (193 mg, 0.41 mmol). The mixture was heated to 120° C. for 16 h under a nitrogen atmosphere. After cooling the reaction to room temperature, the mixture was filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc=3/1) to give the title compound (1.15 g, 44%) as a yellow oil. LCMS M/Z (M+H) 503.
-
- To a solution of tert-butyl 3-(7-(difluoromethyl)-4-methyl-3,4-dihydroquinolin-1(2H)-yl)-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (1.15 g, 1.81 mmol) in DCM (12 mL) at 0° C. was added N-bromosuccinimide (322 mg, 1.81 mmol) in DCM (8 mL) dropwise. The mixture was stirred at room temperature for 2 h. Water (20 mL) was added and the mixture was extracted with DCM (20 mL×2). The combined organic layers were washed with brine (20 mL×3), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (1 g, crude) as yellow oil that required no further purification. LCMS M/Z (M+H) 581.
-
- To a solution of tert-butyl 3-(6-bromo-7-(difluoromethyl)-4-methyl-3,4-dihydroquinolin-1(2H)-yl)-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (800 mg, 1.38 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (344 mg, 1.65 mmol) and Na2CO3 (292 mg, 2.75 mmol) in THF (15 mL) and water (3 mL) was added chloro(2-dicyclohexylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl) palladium(II) (108 mg, 0.14 mmol) and 2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (66 mg, 0.14 mmol). The mixture was heated to 60° C. for 12 h under a nitrogen atmosphere. After cooling the reaction to room temperature, the mixture was filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc=1/1) to give the title compound (560 mg, 70%) as yellow oil. LCMS M/Z (M+H) 583.
-
- To a solution of tert-butyl 3-(7-(difluoromethyl)-4-methyl-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (200 mg, 0.34 mmol) in DCM (1 mL) at 0° C. was added trifluoroacetic acid (0.2 mL, 0.34 mmol). The mixture was stirred at room temperature for 1 h and concentrated in vacuo to give the title compound (200 mg, crude) as yellow oil that required no further purification. LCMS M/Z (M+H) 483.
-
- To a solution of 7-(difluoromethyl)-4-methyl-6-(1-methyl-1H-pyrazol-4-yl)-1-(1-(tetrahydro-2H-pyran-4-yl)-4, 5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-1,2,3,4-tetrahydroquinoline (166 mg, 0.34 mmol) in DCM (2 mL) at 0° C. was added triethylamine (0.15 mL, 1.03 mmol) and acetic anhydride (0.065 mL, 0.69 mmol). The mixture was stirred at 0° C. for 1 h and concentrated in vacuo. DCM (10 mL) was added, washed with water (10 mL×3) and brine (10 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by Prep-TLC (DCM/MeOH=10/1) to give the title compound (60 mg, 31%) as a white solid that was separated by using chiral SFC (SFC80;
Chiralpak OJ 250×30 mm, 5 um; Supercritical CO2/MeOH+base=75/25, 60 mL/min) to give (S)-1-[3-[7-(difluoromethyl)-4-methyl-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-1-tetrahydropyran-4-yl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (23 mg, first peak) and (R)-1-[3-[7-(difluoromethyl)-4-methyl-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-1-tetrahydropyran-4-yl-6, 7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (14 mg, second peak). Absolute configuration was arbitrarily assigned to each enantiomer. Example 238: 1H NMR (400 MHz, DMSO-d6) δ 7.77 (s, 1H), 7.51 (s, 1H), 7.17 (s, 1H), 6.94-6.65 (m, 2H), 4.29-4.23 (m, 1H), 4.15-4.08 (m, 2H), 3.99-3.93 (m, 2H), 3.87 (s, 3H), 3.74-3.50 (m, 6H), 2.92-2.70 (m, 3H), 2.07-1.92 (m, 6H), 1.84-1.72 (m, 3H), 1.32-1.28 (m, 3H). LCMS M/Z (M+H) 525. Example 239: 1H NMR (400 MHz, DMSO-d6) δ 7.77 (s, 1H), 7.51 (s, 1H), 7.17 (s, 1H), 6.94-6.65 (m, 2H), 4.29-4.23 (m, 1H), 4.15-4.08 (m, 2H), 3.99-3.93 (m, 2H), 3.87 (s, 3H), 3.74-3.50 (m, 6H), 2.92-2.70 (m, 3H), 2.07-1.92 (m, 6H), 1.84-1.72 (m, 3H), 1.32-1.28 (m, 3H). LCMS M/Z (M+H) 525. - The following compounds were prepared in a similar fashion to Example 238:
-
-
Example Compound Name NMR m/z Example (S)-1-[3-[7- 1H NMR (400 MHz, DMSO-d6) δ 7.75 (s, 525 240 (difluoromethyl)-3- 1H), 7.50 (s, 1H), 7.10 (s, 1H), methyl-6-(1- 6.94-6.64 (m, 2H), 4.33-4.24 (m, 1H), methylpyrazol-4-yl)-3,4- 4.16-4.11 (m, 2H), 3.97-3.93 (m, 2H), 3.86 (s, 3H), dihydro-2H-quinolin-1- 3.70-3.57 (m, 2H), 3.48-3.44 (m, 2H), yl]-1-tetrahydropyran-4- 3.26-3.18 (m, 2H), 2.91-2.66 (m, 4H), yl-6,7-dihydro-4H- 2.13-1.89 (m, 6H), 1.84-1.80 (m, 2H), pyrazolo[4,3-c]pyridin- 1.05-1.03 (m, 3H) 5-yl]ethanone Example (R)-1-[3-[7- 1H NMR (400 MHz, DMSO-d6) δ 7.75 (s, 525 241 (difluoromethyl)-3- 1H), 7.50 (s, 1H), 7.10 (s, 1H), methyl-6-(1- 6.94-6.64 (m, 2H), 4.34-4.24 (m, 1H), methylpyrazol-4-yl)-3,4- 4.18-4.09 (m, 2H), 3.96-3.93 (m, 2H), 3.86 (s, 3H), dihydro-2H-quinolin-1- 3.73-3.56 (m, 2H), 3.50-3.43 (m, 2H), yl]-1-tetrahydropyran-4- 3.29-3.17 (m, 2H), 2.98-2.57 (m, 4H), yl-6,7-dihydro-4H- 2.11-1.93 (m, 6H), 1.84-1.80 (m, 2H), pyrazolo[4,3-c]pyridin- 1.07-1.00 (m, 3H) 5-yl]ethanone Example 1-[3-[7- 1H NMR (400 MHz, DMSO-d6) δ 7.75 (s, 525 242 (difluoromethyl)-6-(1- 1H), 7.50 (s, 1H), 7.10 (s, 1H), 6.82 (s, methylpyrazol-4-yl)-3,4- 1H), 6.79 (t, J = 55.2 Hz, 1H), dihydro-2H-quinolin-1- 4.30-4.20 (m, 1H), 4.19-4.10 (m, 2H), yl]-1-tetrahydropyran-4- 3.96-3.93 (m, 2H), 3.86 (s, 3H), 3.79-3.68 (m, 2H), yl-6,7-dihydro-4H- 3.60-3.57 (m, 2H), 3.45 (t, J = 12.0 Hz, pyrazolo[4,3-c]pyridin- 2H), 2.89-2.74 (m, 4H), 2.42-2.26 (m, 5-yl]propan-1-one 2H), 2.00-1.76 (m, 6H), 1.02-0.87 (m, 3H) Example 1-[3-[7- 1H NMR (400 MHz, DMSO-d6) δ 8.18 (d, J = 5.2 Hz, 538 243 (difluoromethyl)-6-(2- 1H), 7.09 (s, 1H), 6.95-6.84 (m, methoxy-4-pyridyl)-3,4- 2H), 6.80-6.59 (m, 2H), 4.30-4.25 (m, dihydro-2H-quinolin-1- 1H), 4.23-4.12 (m, 2H), 3.96-3.93 (m, yl]-1-tetrahydropyran-4- 2H), 3.87 (s, 3H), 3.79-3.67 (m, 2H), yl-6,7-dihydro-4H- 3.63-3.60 (m, 2H), 3.53-3.44 (m, 2H), pyrazolo[4,3-c]pyridin- 2.93-2.72 (m, 4H), 2.10-1.93 (m, 7H), 5-yl]ethanone 1.88-1.79 (m, 2H) Example 1-[3-[6- 1H NMR (400 MHz, DMSO-d6) δ 511 244 (difluoromethyl)-5-(1,5- 7.81-7.73 (m, 1H), 7.26 (s, 1H), 6.99 (s, 1H), dimethylpyrazol-4- 6.59 (t, J = 54.8 Hz, 1H), 4.59-4.55 (m, yl)indolin-1-yl]-1- 2H), 4.30-4.20 (m, 1H), 4.15-3.90 (m, tetrahydropyran-4-yl- 4H), 3.83-3.64 (m, 5H), 3.47 (t, J = 12.0 Hz, 6,7-dihydro-4H- 2H), 3.19 (t, J = 8.0 Hz, 2H), pyrazolo[4,3-c]pyridin- 2.87-2.67 (m, 2H), 2.23-1.93 (m, 8H), 5-yl]ethanone 1.82-1.78 (m, 2H) Example 1-[3-[6-(1- 1H NMR (400 MHz, DMSO-d6) δ 7.72 (s, 529 245 methylpyrazol-4-yl)-7- 1H), 7.42 (s, 1H), 7.10 (s, 1H), (trifluoromethyl)-3,4- 6.99-6.95 (m, 1H), 4.32-4.24 (m, 1H), dihydro-2H-quinolin-1- 4.22-4.17 (m, 2H), 3.95-3.91 (m, 2H), 3.84 (s, 3H), yl]-1-tetrahydropyran-4- 3.70-3.68 (m, 2H), 3.58-3.56 (m, 2H), yl-6,7-dihydro-4H- 3.44 (t, J = 12.0 Hz, 2H), 2.84-2.74 (m, pyrazolo[4,3-c]pyridin- 4H), 2.07-1.94 (m, 7H), 1.82-1.78 (m, 5-yl]ethanone 2H) Example 1-[3-[7-methyl-6-(1- 1H NMR (400 MHz, DMSO-d6) δ 7.76 (s, 475 246 methylpyrazol-4-yl)-3,4- 1H), 7.52 (s, 1H), 7.01-6.93 (m, 1H), dihydro-2H-quinolin-1- 6.36-6.29 (m, 1H), 4.32-4.20 (m, 1H), yl]-1-tetrahydropyran-4- 4.14-4.04 (m, 2H), 3.97-3.92 (m, 2H), 3.84 (s, yl-6,7-dihydro-4H- 3H), 3.78-3.65 (m, 2H), 3.58-3.50 (m, pyrazolo[4,3-c]pyridin- 2H), 3.45 (t, J = 11.6 Hz, 2H), 5-yl]ethanone 2.90-2.69 (m, 4H), 2.16 (s, 3H), 2.09-1.87 (m, 7H), 1.85-1.80 (m 2H) Example 1-[3-[6-(1- 1H NMR (400 MHz, DMSO-d6) δ 7.88 (s, 545 247 methylpyrazol-4-yl)-7- 1H), 7.67 (s, 1H), 7.33 (s, 1H), (trifluoromethoxy)-3,4- 6.65-6.53 (m, 1H), 4.34-4.15 (m, 3H), dihydro-2H-quinolin-1- 3.96-3.93 (m, 2H), 3.86 (s, 3H), 3.78-3.65 (m, 2H), yl]-1-tetrahydropyran-4- 3.57-3.52 (m, 2H), 3.45 (t, J = 11.6 Hz, yl-6,7-dihydro-4H- 2H), 2.89-2.72 (m, 4H), 2.08-1.85 (m, pyrazolo[4,3-c]pyridin- 7H), 1.83-1.78 (m, 2H) 5-yl]ethanone -
- To a solution of 7-(difluoromethyl)-4-methyl-6-(1-methyl-1H-pyrazol-4-yl)-1-(1-(tetrahydro-2H-pyran-4-yl)-4, 5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-1,2,3,4-tetrahydroquinoline (Step 7 of Example 238 & 239, 180 mg, 0.4 mmol) in DMF (2 mL) was added 4-nitrophenyl carbonochloridate (752 mg, 3.7 mmol) and pyridine (3 mL, 3.7 mmol). The mixture was stirred at 26° C. for 12 h before a solution of methanamine in THF (1M, 6 mL, 6 mmol) was added. The mixture was heated to 60° C. for 12 h. After cooling the reaction to room temperature, the mixture was concentrated in vacuo. The crude residue was purified by reverse phase chromatography (acetonitrile 30-60%/0.05% NH4OH in water) to give the title compound (106 mg, 31%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 7.77 (s, 1H), 7.51 (s, 1H), 7.17 (s, 1H), 6.82 (s, 1H), 6.79 (t, J=55.6 Hz, 1H), 6.56-6.53 (m, 1H), 4.34-4.28 (m, 1H), 4.03-3.90 (m, 4H), 3.87 (s, 3H), 3.71-3.51 (m, 4H), 3.48-3.42 (m, 2H), 3.00-2.95 (m, 1H), 2.75-2.72 (m, 2H), 2.53 (d, J=4.0 Hz, 3H), 2.10-1.90 (m, 3H), 1.88-1.68 (m, 3H), 1.32 (d, J=6.8 Hz, 3H). LCMS M/Z (M+H) 540.
- The following compounds were prepared in a similar fashion to Example 248:
-
-
Example Compound Name NMR m/z Example 3-[7-(difluoromethyl)-6- 1H NMR (400 MHz, DMSO-d6) δ 8.18 (d, 553 249 (2-methoxy-4-pyridyl)- J = 5.2 Hz, 1H), 7.09 (s, 1H), 3,4-dihydro-2H- 6.97-6.82 (m, 2H), 6.80-6.60 (m, 2H), 6.57 (d, J = 4.4 Hz, quinolin-1-yl]-N- 1H), 4.32-4.25 (m, 1H), 4.05 (s, methyl-1- 2H), 3.96-3.93 (m, 2H), 3.88 (s, 3H), tetrahydropyran-4-yl- 3.62-3.59 (m, 4H), 3.49-3.42 (m, 2H), 6,7-dihydro-4H- 2.89-2.85 (m, 2H), 2.77-2.74 (m, 2H), 2.54 (d, pyrazolo[4,3-c]pyridine- J = 4.0 Hz, 3H), 2.09-1.92 (m, 4H), 5-carboxamide 1.83-1.78 (m, 2H) Example (R)-3-[7- 1H NMR (400 MHz, DMSO-d6) δ 7.75 (s, 540 250 (difluoromethyl)-3- 1H), 7.50 (s, 1H), 7.09 (s, 1H), 6.80 (s, methyl-6-(1- 1H), 6.79 (t, J = 56.0 Hz, 1H), methylpyrazol-4-yl)-3,4- 6.57-6.56 (m, 1H), 4.32-4.25 (m, 1H), 4.01 (s, 2H), dihydro-2H-quinolin-1- 3.95-3.93 (m, 2H), 3.86 (s, 3H), yl]-N-methyl-1- 3.65-3.53 (m, 4H), 3.48-3.42 (m, 2H), tetrahydropyran-4-yl- 3.25-3.19 (m, 1H), 2.91-2.88 (m, 1H), 6,7-dihydro-4H- 2.75-2.72 (m, 2H), 2.53 (d, J = 4.0 Hz, 3H), pyrazolo[4,3-c]pyridine- 2.11-2.08 (m, 1H), 2.01-1.94 (m, 2H), 5-carboxamide 1.82-1.79 (m, 2H), 1.05 (d, J = 6.8 Hz, 3H) Example (S)-3-[7- 1H NMR (400 MHz, DMSO-d6) δ 7.75 (s, 540 251 (difluoromethyl)-3- 1H), 7.50 (s, 1H), 7.09 (s, 1H), 6.78 (s, methyl-6-(1- 1H), 6.77 (t, J = 55.2 Hz, 1H), methylpyrazol-4-yl)-3,4- 6.53-6.52 (m, 1H), 4.32-4.25 (m, 1H), 4.01 (s, 2H), dihydro-2H-quinolin-1- 3.95-3.93 (m, 2H), 3.86 (s, 3H), yl]-N-methyl-1- 3.65-3.53 (m, 4H), 3.48-3.42 (m, 2H), tetrahydropyran-4-yl- 3.25-3.19 (m, 1H), 2.91-2.88 (m, 1H), 6,7-dihydro-4H- 2.77-2.70 (m, 2H), 2.53 (d, J = 4.0 Hz, 3H), pyrazolo[4,3-c]pyridine- 2.11-2.08 (m, 1H), 2.03-1.93 (m, 2H), 5-carboxamide 1.82-1.79 (m, 2H), 1.05 (d, J = 6.8 Hz, 3H) Example 3-[6-(6-acetamido-3- 1H NMR (400 MHz, CDCl3) δ 580 252 pyridyl)-7- 8.26-8.23 (m, 2H), 8.00 (s, 1H), 7.69-7.67 (m, 1H), (difluoromethyl)-3,4- 6.98 (s, 1H), 6.89 (s, 1H), 6.40 (t, J = 55.2 Hz, dihydro-2H-quinolin-1- 1H), 6.40 (s, 1H), 4.42-4.38 (m, 1H), yl]-N-methyl-1- 4.15-4.12 (m, 2H), 4.01 (s, 2H), tetrahydropyran-4-yl- 3.80-3.74 (m, 4H), 3.55-3.51 (m, 2H), 6,7-dihydro-4H- 2.91-2.88 (m, 2H), 2.81-2.78 (m, 5H), pyrazolo[4,3-c]pyridine- 2.38-2.26 (m, 2H), 2.25 (s, 3H), 2.11-2.08 (m, 5-carboxamide 2H), 1.89-1.86 (m, 2H) Example 3-[6-(difluoromethyl)-5- 1H NMR (400 MHz, DMSO-d6) δ 7.77 (s, 526 253 (1,5-dimethylpyrazol-4- 1H), 7.26 (s, 1H), 6.99 (s, 1H), yl)indolin-1-yl]-N- 6.74-6.42 (m, 2H), 4.41 (s, 2H), 4.30-4.17 (m, 1H), methyl-1- 4.06 (t, J = 8.4 Hz, 2H), 3.99-3.94 (m, tetrahydropyran-4-yl- 2H), 3.78 (s, 3H), 3.62-3.58 (m, 2H), 6,7-dihydro-4H- 3.46 (t, J = 11.6 Hz, 2H), 3.22-3.18 (m, 2H), pyrazolo[4,3-c]pyridine- 2.69-2.66 (m, 2H), 2.59 (d, J = 4.4 Hz, 5-carboxamide 3H), 2.15 (s, 3H), 2.08-1.93 (m, 2H), 1.80-1.77 (m, 2H) Example N-methyl-3-[6-(1- 1H NMR (400 MHz, DMSO-d6) δ 7.71 (s, 544 254 methylpyrazol-4-yl)-7- 1H), 7.42 (s, 1H), 7.09 (s, 1H), 6.96 (s, (trifluoromethyl)-3,4- 1H), 6.55-6.54 (m, 1H), 4.35-4.22 (m, dihydro-2H-quinolin-1- 1H), 4.05 (s, 2H), 3.94-3.92 (m, 2H), yl]-1-tetrahydropyran-4- 3.84 (s, 3H), 3.60-3.55 (s, 4H), yl-6,7-dihydro-4H- 3.46-3.40 (m, 2H), 2.85-2.82 (m, 2H), pyrazolo[4,3-c]pyridine- 2.73-2.71 (m, 2H), 2.53 (d, J = 4.0 Hz, 3H), 5-carboxamide 1.99-1.87 (m, 4H), 1.85-1.75 (m, 2H) Example N-methyl-3-[7-methyl- 1H NMR (400 MHz, DMSO-d6) δ 7.75 (s, 490 255 6-(1-methylpyrazol-4- 1H), 7.51 (s, 1H), 6.97 (s, 1H), yl)-3,4-dihydro-2H- 6.58-6.48 (m, 1H), 6.32 (s, 1H), 4.31-4.19 (m, 1H), quinolin-1-yl]-1- 4.03-3.90 (m, 4H), 3.84 (s, 3H), tetrahydropyran-4-yl- 3.60-3.55 (m, 2H), 3.56-3.50 (m, 2H), 3.45 (t, J = 11.2 Hz, 6,7-dihydro-4H- 2H), 2.79-2.68 (m, 4H), pyrazolo[4,3-c]pyridine- 2.54 (d, J = 4.8 Hz, 3H), 2.15 (s, 3H), 5-carboxamide 2.04-1.89 (m, 4H), 1.82-1.78 (m, 2H) Example N-methyl-3-[6-(1- 1H NMR (400 MHz, DMSO-d6) δ 7.87 (s, 560 256 methylpyrazol-4-yl)-7- 1H), 7.67 (s, 1H), 7.33 (s, 1H), 6.59 (s, (trifluoromethoxy)-3,4- 1H), 6.58-6.50 (m, 1H), 4.35-4.20 (m, dihydro-2H-quinolin-1- 1H), 4.08 (s, 2H), 3.96-3.92 (m, 2H), yl]-1-tetrahydropyran-4- 3.85 (s, 3H), 3.63-3.57 (m, 2H), 3.57-3.51 (m, yl-6,7-dihydro-4H- 2H), 3.45 (t, J = 11.6 Hz, 2H), 2.82 (t, J = 6.0 Hz, pyrazolo[4,3-c]pyridine- 2H), 2.75-2.65 (m, 2H), 2.55 (d, J = 4.0 Hz, 5-carboxamide 3H), 2.04-1.89 (m, 4H), 1.81 1.77 (m, 2H) -
-
- To a solution of tert-butyl 3-bromo-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (Intermediate H, 0.5 g, 1.3 mmol) in 1,4-dioxane (10 mL) was added 7-chloro-6-(1-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinoline (320 mg, 1.3 mmol), chloro(2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (100 mg, 0.13 mmol), 2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl (60 mg, 0.13 mmol) and t-BuONa (373 mg, 3.9 mmol). The mixture was heated to 120° C. for 12 h under a nitrogen atmosphere. After cooling the reaction to room temperature, the mixture was filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (DCM/MeOH=50:1) to give the title compound (1.1 g, 42% purity) as a yellow solid that required no further purification. LCMS M/Z (M+H) 553.
-
- To a solution of tert-butyl 3-(7-chloro-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1-(tetrahydro-2H-pyran-4-yl)-6, 7-dihydro-1H-pyrazolo[4,3-c]pyridine-5 (4H)-carboxylate (1.1 g, 2.0 mmol) in DCM (3 mL) was added trifluoroacetic acid (1.5 mL, 20 mmol). The mixture was stirred at 26° C. for 1 h and concentrated in vacuo. DCM (30 mL) was added, washed with sat. aq. NaHCO3 (10 mL×3) and brine (10 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (450 mg, crude) as a yellow oil that required no further purification. LCMS M/Z (M+H) 453.
-
- To a solution of 7-chloro-6-(1-methyl-1H-pyrazol-4-yl)-1-(1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-1,2,3,4-tetrahydroquinoline (200 mg, 0.36 mmol) in DCM (5 mL) was added triethylamine (2.5 mL, 1.8 mmol) and N-methyl-1H-imidazole-1-carboxamide (135 mg, 1.1 mmol). The mixture was stirred at 20° C. for 1 h and concentrated in vacuo. DCM (50 mL) was added, washed with water (30 mL×3) and brine (30 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by reverse phase chromatography (acetonitrile 30-60%/0.05% NH4OH in water) to give the title compound (23 mg, 12%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.96 (s, 1H), 7.67 (s, 1H), 7.19 (s, 1H), 6.56-6.55 (m, 1H), 6.49 (s, 1H), 4.35-4.24 (m, 1H), 4.04 (s, 2H), 3.96-3.94 (m, 2H), 3.85 (s, 3H), 3.63-3.51 (m, 4H), 3.48-3.42 (m, 2H), 2.82-2.70 (m, 4H), 2.54 (d, J=4.0 Hz, 3H), 1.99-1.90 (m, 4H), 1.83-1.80 (m, 2H). LCMS M/Z (M+H) 510.
-
- To a solution of 3-[7-chloro-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-N-methyl-1-tetrahydropyran-4-yl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxamide (Example 257, 50 mg, 0.1 mmol) in 1,4-dioxane (2 mL) and water (0.5 mL) was added palladium(II) acetate (4 mg, 0.02 mmol), cyclopropylboronic acid (17 mg, 0.2 mmol), tricyclohexylphosphine (6 mg, 0.02 mmol) and Cs2CO3 (96 mg, 0.3 mmol). The mixture was irradiated in a microwave at 80° C. for 0.5 h. After cooling the reaction to room temperature, the mixture was filtered and concentrated in vacuo. The crude residue was purified by reverse phase chromatography (acetonitrile 25-55%/0.05% NH4OH in water) to give the title compound (15 mg, 71% purity) which was further separated by using chiral SFC (SFC80;
Chiralpak AD 250×30 mm I.D., 5 um; Supercritical CO2/IPA+NH3.H2O=65/35; 80 mL/min) to give the title compound (5 mg, 10%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.83 (s, 1H), 7.59 (s, 1H), 6.97 (s, 1H), 6.53-6.52 (m, 1H), 6.21 (s, 1H), 4.29-4.24 (m, 1H), 4.02-3.91 (m, 4H), 3.85 (s, 3H), 3.62-3.49 (m, 4H), 3.48-3.42 (m, 2H), 2.79-2.69 (m, 4H), 2.54 (d, J=4.0 Hz, 3H), 2.05-1.86 (m, 5H), 1.82-1.79 (m, 2H), 0.80-0.78 (m, 2H), 0.35-0.34 (m, 2H). LCMS M/Z (M+H) 516. -
- To a solution of 3-[7-chloro-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-N-methyl-1-tetrahydropyran-4-yl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxamide (Example 257, 50 mg, 0.1 mmol) in 1,4-dioxane (2 mL) and water (0.5 mL) was added palladium(II) acetate (4 mg, 0.02 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (30 mg, 0.2 mmol), K3PO4 (42 mg, 0.2 mmol) and 2-dicyclohexyl phosphino-2′,6′-dimethoxybiphenyl (4 mg, 0.01 mmol). The mixture was irradiated in a microwave at 80° C. for 0.5 h. After cooling the reaction to room temperature, the mixture was filtered and concentrated in vacuo. The crude residue was purified by reverse phase chromatography (acetonitrile 22-52%/0.05% NH4OH in water) to give the title compound (15 mg, 31%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.68 (s, 1H), 7.43 (s, 1H), 6.98 (s, 1H), 6.81-6.74 (m, 1H), 6.70 (s, 1H), 6.56-6.51 (m, 1H), 5.32 (d, J=18.8 Hz, 1H), 5.09 (d, J=12.0 Hz, 1H), 4.32-4.20 (m, 1H), 4.03 (s, 2H), 3.97-3.91 (m, 2H), 3.85 (s, 3H), 3.61-3.54 (m, 4H), 3.48-3.42 (m, 2H), 2.81-2.72 (m, 4H), 2.53 (d, J=4.4 Hz, 3H), 2.01-1.93 (m, 4H), 1.82-1.81 (m, 2H). LCMS M/Z (M+H) 502.
-
- To a solution of N-methyl-3-[6-(1-methylpyrazol-4-yl)-7-vinyl-3,4-dihydro-2H-quinolin-1-yl]-1-tetrahydropyran-4-yl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxamide (Example 259, 80 mg, 0.16 mmol) in MeOH (5 mL) was added 10% Pd/C (13 mg). The mixture was stirred at 25° C. for 12 h under a hydrogen atmosphere (15 psi). The mixture was filtered and concentrated in vacuo. The crude residue was separated by using chiral SFC (SFC80;
Chiralpak AD 250×30 mm I.D., 5 um; Supercritical CO2/MEOH+NH3.H2O=70/30; 80 mL/min) to give the title compound (6 mg, 2%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.70 (s, 1H), 7.44 (s, 1H), 6.90 (s, 1H), 6.54-6.53 (m, 1H), 6.37 (s, 1H), 4.32-4.19 (m, 1H), 4.00 (s, 2H), 3.96-3.94 (m, 2H), 3.85 (s, 3H), 3.62-3.51 (m, 4H), 3.48-3.42 (m, 2H), 2.79-2.69 (m, 4H), 2.53 (d, J=4.4 Hz, 3H), 2.46-2.44 (m, 2H), 2.04-1.90 (m, 4H), 1.81-1.79 (m, 2H), 0.98 (t, J=8.0 Hz, 3H). LCMS M/Z (M+H) 504. -
-
- To a solution of 7-bromoquinoline (2.0 g, 9.6 mmol), N1, N2-dimethylethane-1,2-diamine (339 mg, 3.9 mmol) and copper(I) trifluoromethanesulfonate (409 mg, 1.9 mmol) in DMSO (20 mL) was added sodium methanesulfinate (5 g, 48.1 mmol). The mixture was heated to 120° C. for 2 h under a nitrogen atmosphere. After cooling the reaction to room temperature, the mixture was filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc=1:1) to give the title compound (1.2 g, 60%) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 9.09-9.08 (m, 1H), 8.55-8.53 (m, 2H), 8.27 (d, J=8.0 Hz, 3H), 8.07-8.05 (m, 1H), 7.75-7.72 (m, 1H), 3.34 (s, 1H).
-
- To a solution of 7-(methylsulfonyl)quinoline (1.6 g, 7.9 mmol) in toluene (20 mL) was added diethyl-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate (6.0 g, 23.6 mmol) and diphenylphosphate (98 mg, 0.39 mmol). The mixture was heated to 60° C. for 16 h. After cooling the reaction to room temperature, the mixture was filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc=2:1) to give the title compound (1.2 g, 72%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.03 (d, J=7.2 Hz, 1H), 6.91-6.90 (m, 1H), 6.86-6.84 (m, 1H), 6.25 (s, 1H), 3.21-3.17 (m, 2H), 3.04 (s, 3H), 2.71-2.68 (m, 2H), 1.80-1.74 (m, 2H).
-
- To a solution of tert-butyl 3-bromo-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (Intermediate H, 1.2 g, 3.1 mmol) in 1,4-dioxane (10 mL) was added 7-(methylsulfonyl)-1,2,3,4-tetrahydroquinoline (644 mg, 3.1 mmol), chloro(2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (249 mg, 0.3 mmol), 2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl (142 mg, 0.3 mmol) and t-BuONa (878 mg, 9.1 mmol). The mixture was heated to 110° C. for 16 h under a nitrogen atmosphere. After cooling the reaction to room temperature, the mixture was filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (DCM/MeOH=50:1) to give the title compound (970 mg, 62%) as a light yellow solid. LCMS M/Z (M+H) 517.
-
- To a solution of tert-butyl 3-(7-(methylsulfonyl)-3,4-dihydroquinolin-1(2H)-yl)-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (970 mg, 1.9 mmol) in DCM (8 mL) at 0° C. was added N-bromosuccinimide (318 mg, 1.8 mmol). The mixture was stirred at room temperature for 2 h. Water (20 mL) was added and the mixture was extracted with DCM (20 mL×3). The combined organic layers were washed with brine (20 mL×3), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (1.1 g, crude) as a yellow solid that required no further purification. LCMS M/Z (M+H) 597.
-
- To a solution of tert-butyl 3-(6-bromo-7-(methylsulfonyl)-3,4-dihydroquinolin-1(2H)-yl)-1-(tetrahydro-2H-pyran-4-yl)-6, 7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (300 mg, 0.5 mmol) in THF (5 mL) and water (1 mL) was added 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (126 mg, 0.6 mmol), chloro(2-dicyclohexylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl) palladium(II) (40 mg, 0.05 mmol), 2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (24 mg, 0.05 mmol) and Na2CO3 (160 mg, 1.5 mmol). The mixture was heated to 60° C. for 16 h under a nitrogen atmosphere. After cooling the reaction to room temperature, the mixture was filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (DCM/MeOH=50:1) to give the title compound (200 mg, 67%) as a yellow solid. LCMS M/Z (M+H) 597.
-
- To a solution of tert-butyl 3-(6-(1-methyl-1H-pyrazol-4-yl)-7-(methylsulfonyl)-3,4-dihydroquinolin-1(2H)-yl)-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (100 mg, 0.17 mmol) in DCM (2 mL) at 0° C. was added trifluoroacetic acid (0.12 mL, 1.7 mmol). The mixture was stirred at room temperature for 1 h and concentrated in vacuo to give the title compound (131 mg, crude) as a yellow oil that required no further purification. LCMS M/Z (M+H) 497.
-
- To a solution of 6-(1-methyl-1H-pyrazol-4-yl)-7-(methylsulfonyl)-1-(1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-1,2,3,4-tetrahydroquinoline (131 mg, 0.26 mmol) in DCM (2 mL) was added triethylamine (0.18 mL, 1.3 mmol) and N-methyl-1H-imidazole-1-carboxamide (50 mg, 0.4 mmol). The mixture was stirred at room temperature for 16 h and concentrated in vacuo. DCM (10 mL) was added, washed with water (10 mL×3) and brine (10 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by reverse phase chromatography (acetonitrile 18-48%/0.05% NH4OH in water) to give the title compound (28 mg, 19%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.85 (s, 1H), 7.57 (s, 1H), 7.32 (s, 1H), 7.10 (s, 1H), 6.56-6.47 (m, 1H), 4.28-4.27 (m, 1H), 4.03 (s, 2H), 3.92-3.91 (m, 2H), 3.86 (s, 3H), 3.61-3.56 (m, 4H), 3.47-3.40 (m, 2H), 2.86-2.83 (m, 2H), 2.74-2.72 (m, 5H), 2.52 (d, J=4.4 Hz, 3H), 2.00-1.94 (m, 4H), 1.80-1.79 (m, 2H). LCMS M/Z (M+H) 554.
-
-
- To a solution of 2-(methylamino)ethanol (1.67 g, 22.2 mmol) and 1-bromo-2-(difluoromethyl)-5-fluoro-4-nitro-benzene (5.0 g, 18.5 mmol) in DMF (50 mL) was added N,N-diisopropylethylamine (6.65 mL, 37.0 mmol). The mixture was heated to 80° C. for 16 h. After cooling the reaction to room temperature, water (50 mL) was added and the mixture was extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine (50 mL×3), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc=3:1) to give the title compound (5.5 g, 91%) as a red oil. 1H NMR (400 MHz, CDCl3) 8.03 (s, 1H), 7.41 (s, 1H), 6.80 (t, J=55.2 Hz, 1H), 3.86 (t, J=5.2 Hz, 2H), 3.49 (t, J=5.2 Hz, 2H), 2.91 (s, 3H).
-
- To a solution of 2-((5-bromo-4-(difluoromethyl)-2-nitrophenyl)(methyl)amino)ethanol (2.0 g, 6.15 mmol) and pyridine (0.5 mL, 6.15 mmol) in DCM (20 mL) at 0° C. was added thionylchloride (0.89 mL, 12.3 mmol) dropwise. The mixture was stirred at room temperature for 16 h. DCM (50 mL) was added, washed with sat. aq. NaHCO3 (50 mL×3), brine (50 mL×2), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (2.2 g, crude) as a red oil that required no further purification. LCMS M/Z (M+H) 345.
-
- To a solution of 5-bromo-N-(2-chloroethyl)-4-(difluoromethyl)-N-methyl-2-nitro-aniline (2.0 g, 5.82 mmol) in AcOH (20 mL) was added Fe powder (1.63 g, 29.1 mmol). The mixture was stirred at 20° C. for 1 h. Insoluble solid was filtered off, the filtrate was adjusted to pH 8 by addition of sat. aq. NaHCO3 and the mixture was extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine (50 mL×3), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (2 g, crude) as a red oil that required no further purification. LCMS M/Z (M+H) 315.
-
- To a solution of 5-bromo-N-(2-chloroethyl)-4-(difluoromethyl)-N-methylbenzene-1,2-diamine (2.0 g, 6.38 mmol) in DMF (50 mL) was added potassium iodide (2.12 g, 12.8 mmol) and potassium carbonate (2.64 g, 19.1 mmol). The mixture was heated to 80° C. for 3 h. After cooling the reaction to room temperature, water (100 mL) was added and extracted with EtOAc (100 mL×3). The combined organic layers were washed with brine (100 mL×2), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (1.7 g, crude) as brown oil that required no further purification. LCMS M/Z (M+H) 277.
-
- To a solution of 7-bromo-6-(difluoromethyl)-1-methyl-1,2,3,4-tetrahydroquinoxaline (1.7 g, 6.13 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.53 g, 7.36 mmol) and sodium carbonate (1.95 g, 18.4 mmol) in THF (20 mL) and water (4 mL) was added chloro(2-dicyclohexylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl) palladium(II) (483 mg, 0.61 mmol) and 2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (292 mg, 0.61 mmol). The mixture was heated to 60° C. for 16 h under a nitrogen atmosphere. After cooling the reaction to room temperature, the mixture was filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc=1:3) to give the title compound (500 mg, 32%) as a dark green solid. 1H NMR (400 MHz, CDCl3) δ 9.87 (s, 1H), 7.55 (s, 1H), 7.41 (s, 1H), 7.11 (s, 1H), 6.34 (s, 1H), 3.96 (s, 3H), 3.95-3.91 (m, 1H), 3.47-3.43 (m, 4H), 2.99 (s, 3H).
-
- To a solution of 1-methyl-7-(1-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinoxaline-6-carbaldehyde (500 mg, 1.95 mmol), tert-butyl 3-bromo-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5 (4H)-carboxylate (Intermediate H, 904 mg, 2.34 mmol) and t-BuONa (562 mg, 5.85 mmol) in 1,4-dioxane (15 mL) was added dichloro[1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II) (155 mg, 0.20 mmol). The mixture was heated to 120° C. for 16 h under a nitrogen atmosphere. After cooling the reaction to room temperature, the mixture was filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (DCM/MeOH=50/1) to give the title compound (600 mg, 55%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 9.87 (s, 1H), 7.57 (s, 1H), 7.44 (s, 1H), 7.10 (s, 1H), 6.41 (s, 1H), 4.20-4.01 (m, 5H), 3.98 (s, 3H), 3.85-3.68 (m, 4H), 3.62-3.43 (m, 4H), 3.07 (s., 3H), 2.74-2.70 (m, 2H), 2.33-2.26 (m, 2H), 1.88-1.82 (m, 2H), 1.43 (s, 9H).
-
- To a solution of tert-butyl 3-(7-formyl-4-methyl-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinoxalin-1(2H)-yl)-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (300 mg, 0.53 mmol) in EtOH (2 mL) was added sodium acetate (66 mg, 0.80 mmol) in water (1 mL) and hydroxylamine hydrochloride (56 mg, 0.80 mmol) in water (1 mL). The mixture was stirred at 20° C. for 16 h. DCM (20 mL) was added and the mixture was washed with water (10 mL×3), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (300 mg, crude) as a brown solid that required no further purification. LCMS M/Z (M+H) 519.
-
- To a solution of (E)-tert-butyl 3-(7-((hydroxyimino)methyl)-4-methyl-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinoxalin-1(2H)-yl)-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (150 mg, 0.26 mmol) in THF (3 mL) was added 2,4,6-tripropyl-1,3,5,2,4,6-
trioxatriphosphinane 2,4,6-trioxide (414 mg, 1.3 mmol) and triethylamine (0.55 mL, 3.9 mmol). The mixture was heated to 60° C. for 16 h. After cooling the reaction to room temperature, DCM (20 mL) was added and the mixture was washed with water (10 mL×3), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (150 mg, crude) as a brown solid. LCMS M/Z (M+H) 559. -
- To a solution of tert-butyl 3-(7-cyano-4-methyl-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinoxalin-1(2H)-yl)-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (300 mg, 0.54 mmol) in DCM (3 mL) at 0° C. was added trifluoroacetic acid (1.0 mL, 13.5 mmol). The mixture was stirred at room temperature for 2 h. DCM (20 mL) was added and washed with sat. aq. NaHCO3 (10 mL×3), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (130 mg, crude) as a brown oil that required no further purification. LCMS M/Z (M+H) 459.
-
- To a solution of 1-methyl-7-(1-methyl-1H-pyrazol-4-yl)-4-(1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-1,2,3,4-tetrahydroquinoxaline-6-carbonitrile (130 mg, 0.28 mmol) in DCM (2 mL) was added triethylamine (0.12 mL, 0.85 mmol) and N-methyl-1H-imidazole-1-carboxamide (71 mg, 0.57 mmol). The mixture was stirred at room temperature for 16 h and concentrated in vacuo. DCM (10 mL) was added, washed with water (10 mL×3) and brine (10 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by reverse phase chromatography (acetonitrile 30-60%/0.05% NH4OH in water) to give the title compound (58 mg, 40%) as a white solid. 1H NMR (400 MHz, DMSO-d6) 8.10 (s, 1H), 7.83 (s, 1H), 6.68 (s, 1H), 6.57-6.52 (m, 1H), 6.50 (s, 1H), 4.33-4.28 (m, 1H), 4.02-4.00 (m, 2H), 3.95-3.92 (m, 2H), 3.88 (s, 3H), 3.65-3.60 (m, 4H), 3.52-3.45 (m, 4H), 3.03 (s, 1H), 2.75-2.70 (m, 2H), 2.54 (d, J=4.8 Hz, 3H), 2.01-1.95 (m, 2H), 1.82-1.77 (m, 2H). LCMS M/Z (M+H) 516.
-
- To a solution of 1-methyl-7-(1-methyl-1H-pyrazol-4-yl)-4-(1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-1,2,3,4-tetrahydroquinoxaline-6-carbonitrile (233 mg, 0.51 mmol) in DCM (2 mL) at 0° C. was added triethylamine (0.35 mL, 2.5 mmol) and acetic anhydride (0.05 mL, 0.51 mmol). The mixture was stirred at room temperature for 0.5 h. The reaction solution was diluted with DCM (10 mL), washed with water (10 mL×2), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by reverse phase chromatography (acetonitrile 35-65%/0.05% NH4OH in water) to give the title compound (36 mg, 14%) as a light brown solid. 1H NMR (400 MHz, DMSO-d6) δ 8.08 (s, 1H), 7.82 (s, 1H), 6.67 (s, 1H), 6.54-6.49 (m, 1H), 4.30-4.20 (m, 1H), 4.14-4.08 (m, 2H), 3.95-3.92 (m, 2H), 3.86 (s, 3H), 3.70-3.65 (m, 2H), 3.64-3.62 (m, 2H), 3.48-3.44 (m, 4H), 3.02 (s, 3H), 2.85-2.73 (m, 2H), 2.06-1.95 (m, 5H), 1.82-1.79 (m, 2H). LCMS M/Z (M+H) 501.
-
-
- To a solution of 2-(methylamino)propanoic acid (10.0 g, 96.97 mmol) in THF (200 mL) was added LiAlH4 (5.52 g, 145.46 mmol) portionwise. The mixture was heated to 70° C. for 16 h. After cooling the reaction to room temperature, water (10 mL) was added. The mixture was filtered and concentrated in vacuo. The crude residue was washed with HCl/EtOAc (2 M, 50 mL) to give the title compound (5.3 g, 61%) as a brown oil that required no further purification. 1H NMR (400 MHz, CD3OD) δ3.81-3.78 (m, 1H), 3.56-3.51 (m, 1H), 3.26-3.22 (m, 1H), 2.68 (s, 3H), 1.28 (d, J=7.2 Hz, 3H).
-
- To a solution of 2-bromo-4-fluoro-5-nitro-benzonitrile (0.5 g, 2.04 mmol) in DMF (10 mL) was added N,N-diisopropylethylamine (0.53 g, 4.08 mmol) and 2-(methylamino)propan-1-ol (0.6 g, 6.73 mmol). The mixture was heated to 80° C. for 12 h. After cooling the reaction to room temperature, water (50 mL) was added and extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine (30 mL×3), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc=1:1) to give the title compound (440 mg, 69%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.04 (s, 1H), 7.46 (s, 1H), 3.95-3.92 (m, 1H), 3.76-3.73 (m, 1H), 3.65-3.62 (m, 1H), 2.73 (s, 3H), 1.28 (d, J=7.2 Hz, 3H).
-
- To a solution of 2-bromo-4-((1-hydroxypropan-2-yl)(methyl)amino)-5-nitrobenzonitrile (220 mg, 0.7 mmol) and pyridine (0.056 mL, 0.7 mmol) in DCM (10 mL) at 0° C. was added thionylchloride (0.1 mL, 1.4 mmol) dropwise. The mixture was stirred at 20° C. for 16 h. DCM (70 mL) was added and the mixture was washed with sat. aq. NaHCO3 (40 mL×3), washed with brine (40 mL×2), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (200 mg, crude) as a brown oil that required no further purification.
-
- To a solution of 2-bromo-4-((1-chloropropan-2-yl)(methyl)amino)-5-nitrobenzonitrile (200 mg, 0.6 mmol) in AcOH (20 mL) was added Fe powder (168 mg, 3 mmol). The mixture was stirred at 20° C. for 2 h. Insoluble solid was filtered off, the filtrate was adjusted to pH=8 by adding sat. aq. NaHCO3 and extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine (50 mL×3), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (150 mg, crude) as a red oil that required no further purification. LCMS M/Z (M+H) 302.
-
- To a solution of 5-amino-2-bromo-4-((1-chloropropan-2-yl)(methyl)amino)benzonitrile (2.63 g, 8.69 mmol) in DMF (50 mL) was added potassium iodide (2.89 g, 17.38 mmol) and potassium carbonate (3.6 g, 26.07 mmol). The mixture was heated to 80° C. for 5 h. After cooling the reaction to room temperature, water (150 mL) was added and the mixture was extracted with EtOAc (100 mL×3). The combined organic layers were washed with brine (100 mL×2), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc=3:1) to give the title compound (1.1 g, 48%) as a yellow solid. LCMS M/Z (M+H) 266.
-
- To a solution of 7-bromo-1,2-dimethyl-1,2,3,4-tetrahydroquinoxaline-6-carbonitrile (900 mg, 3.38 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (844 mg, 4.06 mmol) and sodium carbonate (1.1 g, 10.15 mmol) in THF (50 mL) and water (10 mL) was added chloro(2-dicyclohexylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl) palladium(II) (266 mg, 0.34 mmol) and 2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (161 mg, 0.34 mmol). The mixture was heated to 60° C. for 12 h under a nitrogen atmosphere. After cooling the reaction to room temperature, the mixture was filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (DCM/MeOH=20/1) to give the title compound (0.81 g, 90%) as a brown solid. LCMS M/Z (M+H) 268.
-
- To a solution of 1,2-dimethyl-7-(1-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinoxaline-6-carbonitrile (800 mg, 2.99 mmol), tert-butyl 3-bromo-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (Intermediate H, 1.6 g, 4.14 mmol) and t-BuONa (863 mg, 8.98 mmol) in 1,4-dioxane (20 mL) was added chloro(2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (232 mg, 0.30 mmol), 2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl (139 mg, 0.30 mmol). The mixture was heated to 120° C. for 16 h under a nitrogen atmosphere. After cooling the reaction to room temperature, the mixture was filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (DCM/MeOH=20/1) to give the title compound (1 g, 58%) as a brown solid. LCMS M/Z (M+H) 573.
-
- To a solution of tert-butyl 3-(7-cyano-3,4-dimethyl-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinoxalin-1(2H)-yl)-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (1 g, 1.75 mmol) in DCM (15 mL) at 0° C. was added trifluoroacetic acid (1.53 mL, 17.46 mmol). The mixture was stirred at room temperature for 2 h and concentrated in vacuo to give the title compound (800 mg, crude) as a brown oil that required no further purification. LCMS M/Z (M+H) 473.
-
- To a solution of 1,2-dimethyl-7-(1-methyl-1H-pyrazol-4-yl)-4-(1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-1,2,3,4-tetrahydroquinoxaline-6-carbonitrile (400 mg, 0.85 mmol) in DCM (15 mL) at 0° C. was added triethylamine (0.35 mL, 2.54 mmol) and acetic anhydride (0.16 mL, 1.69 mmol). The mixture was stirred at 17° C. for 1 h and concentrated in vacuo. The crude residue was purified by reverse phase chromatography (acetonitrile 38-68%/0.225% formic acid in water) to give racemic 4-(5-acetyl-1-tetrahydropyran-4-yl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-3-yl)-1,2-dimethyl-7-(1-methylpyrazol-4-yl)-2,3-dihydroquinoxaline-6-carbonitrile (230 mg, 51%) as a white solid that was separated using chiral SFC (Chiralcel OJ 250 mm×30 mm, 10 um, I.D., 3 um Mobile phase: ethanol (0.05% diethylamine) in CO2 from 5% to 40% Flow rate: 80 mL/min) to give (R)-4-(5-acetyl-1-tetrahydropyran-4-yl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-3-yl)-1,2-dimethyl-7-(1-methylpyrazol-4-yl)-2,3-dihydroquinoxaline-6-carbonitrile (55 mg, first peak) and (S)-4-(5-acetyl-1-tetrahydropyran-4-yl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-3-yl)-1,2-dimethyl-7-(1-methylpyrazol-4-yl)-2,3-dihydroquinoxaline-6-carbonitrile (62 mg, second peak). Absolute configuration was arbitrarily assigned to each enantiomer. Example 264: 1H NMR (400 MHz, CDCl3) δ 7.90-7.84 (m, 1H), 7.77-7.76 (m, 1H), 6.65-6.61 (m, 1H), 6.58-6.52 (m, 1H), 4.57-4.10 (m, 5H), 4.06-3.95 (m, 4H), 3.80-3.60 (m, 3H), 3.55-3.50 (m, 3H), 3.06-3.03 (m. 3H), 2.83-2.76 (m, 2H), 2.32-2.27 (m, 2H), 2.17-2.08 (m, 3H), 1.91-1.82 (m, 2H), 1.28 (d, J=6.4 Hz, 3H). LCMS M/Z (M+H) 515. Example 265: 1H NMR (400 MHz, CDCl3) δ 7.90-7.84 (m, 1H), 7.77-7.76 (m, 1H), 6.65-6.61 (m, 1H), 6.58-6.52 (m, 1H), 4.57-4.10 (m, 5H), 4.06-3.95 (m, 4H), 3.80-3.60 (m, 3H), 3.55-3.50 (m, 3H), 3.06-3.03 (m. 3H), 2.83-2.76 (m, 2H), 2.32-2.27 (m, 2H), 2.17-2.08 (m, 3H), 1.91-1.82 (m, 2H), 1.28 (d, J=6.4 Hz, 3H). LCMS M/Z (M+H) 515.
-
- To a solution of 1,2-dimethyl-7-(1-methyl-1H-pyrazol-4-yl)-4-(1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-1,2,3,4-tetrahydroquinoxaline-6-carbonitrile (400 mg, 0.85 mmol) in DCM (15 mL) was added triethylamine (0.35 mL, 2.54 mmol) and N-methyl-1H-imidazole-1-carboxamide (213 mg, 1.69 mmol). The mixture was stirred at 20° C. for 16 h and concentrated in vacuo. DCM (100 mL) was added, washed with water (50 mL×3) and brine (50 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by reverse phase chromatography (acetonitrile 24-54%/0.05% NH4OH in water) to give racemic 3-[7-cyano-3,4-dimethyl-6-(1-methylpyrazol-4-yl)-2,3-dihydroquinoxalin-1-yl]-N-methyl-1-tetrahydropyran-4-yl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxamide (220 mg, 49%) as a white solid which was separated by using chiral SFC (AD 250 mm×30 mm, 5 um, I.D., 3 um Mobile phase: ethanol (0.05% diethylamine) in CO2 from 5% to 40% Flow rate: 80 mL/min) to give (R)-3-[7-cyano-3,4-dimethyl-6-(1-methylpyrazol-4-yl)-2,3-dihydroquinoxalin-1-yl]-N-methyl-1-tetrahydropyran-4-yl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxamide (51 mg, first peak) and (S)-3-[7-cyano-3,4-dimethyl-6-(1-methylpyrazol-4-yl)-2,3-dihydroquinoxalin-1-yl]-N-methyl-1-tetrahydropyran-4-yl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxamide (72 mg, second peak). Absolute configuration was arbitrarily assigned to each diastereomer. Example 266: 1H NMR (400 MHz, CDCl3) δ 7.89 (s, 1H), 7.77 (s, 1H), 6.63 (s, 1H), 6.56 (s, 1H), 4.44-4.40 (m, 1H), 4.15-4.10 (m, 3H), 4.00-3.85 (m, 6H), 3.74-3.60 (m, 3H), 3.55-3.50 (m. 3H), 3.05 (s, 3H), 2.81-2.77 (m, 5H), 2.29-2.26 (m, 2H), 1.91-1.82 (m, 2H), 1.28 (d, J=6.0 Hz, 3H). LCMS M/Z (M+H) 530. Example 267: 1H NMR (400 MHz, CDCl3) δ 7.89 (s, 1H), 7.77 (s, 1H), 6.63 (s, 1H), 6.56 (s, 1H), 4.43-4.39 (m, 1H), 4.15-4.10 (m, 3H), 4.00-3.85 (m, 6H), 3.74-3.60 (m, 3H), 3.56-3.50 (m. 3H), 3.05 (s, 3H), 2.81-2.77 (m, 5H), 2.32-2.26 (m, 2H), 1.91-1.82 (m, 2H), 1.28 (d, J=6.0 Hz, 3H). LCMS M/Z (M+H) 530.
-
-
- To a solution of 1-bromo-5-fluoro-4-nitro-2-(trifluoromethyl)benzene (7.0 g, 24.3 mmol) in DMF (50 mL) was added N,N-diisopropylethylamine (12.9 mL, 72.9 mmol) and 2-(methylamino)ethanol (2.2 g, 29.2 mmol). The mixture was heated to 80° C. for 16 h. After cooling the reaction to room temperature, water (50 mL) was added and extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine (50 mL×3), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc=3:1) to give the title compound (7.5 g, 90%) as a yellow solid.
-
- To a solution of 2-((5-bromo-2-nitro-4-(trifluoromethyl)phenyl)(methyl)amino)ethanol (4 g, 11.7 mmol) and pyridine (0.94 mL, 11.7 mmol) in DCM (40 mL) at 0° C. was added thionylchloride (1.7 mL, 23.3 mmol) dropwise. The mixture was stirred at room temperature for 16 h. DCM (50 mL) was added and the mixture was washed with sat. aq. NaHCO3 (50 mL×3) and brine (50 mL×2). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc=3:1) to give the title compound (2.7 g, 64%) as a yellow oil.
-
- To a solution of 5-bromo-N-(2-chloroethyl)-N-methyl-2-nitro-4-(trifluoromethyl)aniline (2.7 g, 7.5 mmol) in AcOH (20 mL) was added Fe powder (2.1 g, 37.3 mmol). The mixture was stirred at room temperature for 1 h. Insoluble solid was filtered off, the filtrate was adjusted to pH 8 by addition of sat. aq. NaHCO3 and the mixture was extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine (50 mL×3), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (2.2 g, crude) as a brown solid that required no further purification. LCMS M/Z (M+H) 333.
-
- To a solution of 5-bromo-N1-(2-chloroethyl)-N1-methyl-4-(trifluoromethyl)benzene-1,2-diamine (2.0 g, 6.0 mmol) in DMF (20 mL) was added potassium iodide (2.0 g, 12.1 mmol) and potassium carbonate (2.5 g, 18.1 mmol). The mixture was heated to 80° C. for 3 h. After cooling the reaction to room temperature, water (50 mL) was added and the mixture was extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine (100 mL×2), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc=3:1) to give the title compound (830 mg, 47%) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 6.72 (s, 1H), 6.63 (s 1H), 6.07 (s, 1H), 3.29-3.26 (m, 2H), 3.24-3.21 (m, 2H), 2.83 (s, 3H).
-
- To a solution of 7-bromo-1-methyl-6-(trifluoromethyl)-1,2,3,4-tetrahydroquinoxaline (830 mg, 2.8 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (702 mg, 3.4 mmol) and sodium carbonate (894 mg, 8.4 mmol) in THF (10 mL) and water (2 mL) was added chloro(2-dicyclohexylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl) palladium(II) (221 mg, 0.28 mmol) and 2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (134 mg, 0.28 mmol). The mixture was heated to 60° C. for 16 h under a nitrogen atmosphere. After cooling the reaction to room temperature, the mixture was filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc=1:1) to give the title compound (383 mg, 46%) as a brown solid. LCMS M/Z (M+H) 297.
-
- To a solution of 1-methyl-7-(1-methyl-1H-pyrazol-4-yl)-6-(trifluoromethyl)-1,2,3,4-tetrahydroquinoxaline (384 mg, 1.3 mmol), tert-butyl 3-bromo-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (Intermediate H, 0.5 g, 1.3 mmol) and t-BuONa (373 mg, 3.9 mmol) in 1,4-dioxane (5 mL) was added chloro(2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (101 mg, 0.13 mmol) and 2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl (373 mg, 3.9 mmol). The mixture was heated to 120° C. for 16 h under a nitrogen atmosphere. After cooling the reaction to room temperature, the mixture was filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (DCM/MeOH=20/1) to give the title compound (0.66 g, 85%) as a yellow solid. LCMS M/Z (M+H) 601.
-
- To a solution of tert-butyl 3-(4-methyl-6-(1-methyl-1H-pyrazol-4-yl)-7-(trifluoromethyl)-3,4-dihydroquinoxalin-1(2H)-yl)-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (240 mg, 0.4 mmol) in DCM (4 mL) at 0° C. was added trifluoroacetic acid (1 mL, 13.3 mmol). The mixture was stirred at room temperature for 1 h and concentrated in vacuo to give the title compound (320 mg, crude) as a brown oil that required no further purification. LCMS M/Z (M+H) 502.
-
- To a solution of 1-methyl-7-(1-methyl-1H-pyrazol-4-yl)-4-(1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-6-(trifluoromethyl)-1,2,3,4-tetrahydroquinoxaline (270 mg, 0.54 mmol) in DCM (2 mL) was added triethylamine (0.37 mL, 2.7 mmol) and N-methyl-1H-imidazole-1-carboxamide (135 mg, 1.1 mmol). The mixture was stirred at room temperature for 16 h and concentrated in vacuo. DCM (10 mL) was added, washed with water (10 mL×3) and brine (10 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by reverse phase chromatography (acetonitrile 30-60%/0.225% formic acid in water) to give the title compound (40 mg, 13%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.75 (s, 1H), 7.46 (s, 1H), 6.79 (s, 1H), 6.55-6.51 (m, 2H), 4.28-4.25 (m, 1H), 4.01 (s, 2H), 3.96-3.93 (m, 2H), 3.86 (s, 3H), 3.71-3.67 (m, 2H), 3.60-3.56 (m, 2H), 3.48-3.42 (m, 4H), 2.96 (s, 3H), 2.74-2.71 (m, 2H), 2.54-2.52 (m, 3H), 2.01-1.95 (m, 2H), 1.81-1.76 (m, 2H). LCMS M/Z (M+H) 559.
-
- To a solution of 1-methyl-7-(1-methyl-1H-pyrazol-4-yl)-4-(1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-6-(trifluoromethyl)-1,2,3,4-tetrahydroquinoxaline (Step 7 of Example 268, 270 mg, 0.54 mmol) in DCM (2 mL) was added triethylamine (0.37 mL, 2.7 mmol) and acetic anhydride (0.05 mL, 0.54 mmol). The mixture was stirred at room temperature for 0.5 h and concentrated in vacuo. The crude residue was purified by reverse phase chromatography (acetonitrile 30-60%/0.05% NH4HCO3 in water) to give the title compound (77 mg, 26%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.77 (s, 1H), 7.47 (s, 1H), 6.82-6.78 (m, 1H), 6.52 (s, 1H), 4.29-4.24 (m, 1H), 4.17-4.10 (m, 2H), 3.96-3.92 (m, 2H), 3.86 (s, 3H), 3.70-3.62 (m, 4H), 3.48-3.42 (m, 4H), 2.96 (s, 3H), 2.88-2.74 (m, 2H), 2.07-1.95 (m, 5H), 1.83-1.78 (m, 2H). LCMS M/Z (M+H) 544.
-
-
- To a solution of 7-bromo-1-methyl-6-(trifluoromethyl)-1,2,3,4-tetrahydroquinoxaline (1.0 g, 3.4 mmol), tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinate (1.2 g, 4.1 mmol) and K3PO4 (1.8 g, 8.5 mmol) in dioxane (20 mL) and water (4 mL) was added [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (248 mg, 0.34 mmol). The mixture was heated to 90° C. for 2 h under a nitrogen atmosphere. After cooling the reaction to room temperature, the mixture was filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc=2:1) to give the title compound (1.27 g, 95%) as a yellow solid. LCMS M/Z (M+H) 394.
-
- To a solution of tert-butyl 5-(4-methyl-7-(trifluoromethyl)-1,2,3,4-tetrahydroquinoxalin-6-yl)picolinate (599 mg, 1.5 mmol), 1-(3-bromo-1-tetrahydropyran-4-yl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl)ethanone (Intermediate I, 0.5 g, 1.5 mmol) and K3PO4 (970 mg, 4.6 mmol) in t-AmOH (10 mL) was added methanesulfonato(2-dicyclohexylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (129 mg, 0.15 mmol). The mixture was heated to 105° C. for 16 h under an argon atmosphere. After cooling the reaction to room temperature, the mixture was filtered and concentrated in vacuo. The crude residue was purified by reverse phase chromatography (acetonitrile 14-44%/0.225% formic acid in water) to give the title compound (63 mg, 7%) as a yellow oil. LCMS M/Z (M+H) 585.
-
- To a solution of 5-(1-(5-acetyl-1-(tetrahydro-2H-pyran-4-yl)-4, 5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-4-methyl-7-(trifluoromethyl)-1,2,3,4-tetrahydroquinoxalin-6-yl)picolinic acid (63 mg, 0.11 mmol), methanamine hydrochloride (9 mg, 0.13 mmol) and N,N-diisopropylethylamine (0.08 mL, 0.43 mmol) in DCM (2 mL) was added HATU (53 mg, 0.14 mmol). The mixture was stirred at room temperature for 2 h. Water (5 mL) was added and the mixture was extracted with DCM (5 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by reverse phase chromatography (acetonitrile 35-65%/0.05% NH4HCO3 in water) to give the title compound (17 mg, 26%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 8.81-8.78 (m, 1H), 8.53-8.51 (m, 1H), 8.04-8.02 (m, 1H), 7.91-7.88 (m, 1H), 6.88-6.82 (m, 1H), 6.51 (s, 1H), 4.31-4.27 (m, 1H), 4.22-4.14 (m, 2H), 3.95-3.91 (m, 2H), 3.73-3.69 (m, 4H), 3.47-3.42 (m, 4H), 2.95 (s, 3H), 2.88-2.74 (m, 5H), 2.07-1.93 (m, 5H), 1.82-1.78 (m, 2H). LCMS M/Z (M+H) 598.
-
-
- To a solution of 1-bromo-5-fluoro-4-nitro-2-(trifluoromethyl)benzene (5.0 g, 17.36 mmol) in DMF (50 mL) was added N,N-diisopropylethylamine (6.2 mL, 17.36 mmol) and 2-(methylamino)propan-1-ol (3.0 g, 33.66 mmol). The mixture was heated to 80° C. for 12 h. After cooling the reaction to room temperature, water (150 mL) was added and extracted with EtOAc (100 mL×3). The combined organic layers were washed with brine (100 mL×3), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc=1:1) to give the title compound (5 g, 80%) as a brown oil. LCMS M/Z (M+H) 357.
-
- To a solution of 2-((5-bromo-2-nitro-4-(trifluoromethyl)phenyl)(methyl)amino)propan-1-ol (5.0 g, 14 mmol) and pyridine (1.1 mL, 14 mmol) in DCM (30 mL) at 0° C. was added thionylchloride (2.0 mL, 28 mmol) dropwise. The mixture was stirred at room temperature for 16 h. DCM (200 mL) was added and the mixture was washed with sat. aq. NaHCO3 (150 mL×3) and brine (150 mL×2). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (5 g, crude) as a brown oil that required no further purification. LCMS M/Z (M+H) 375.
-
- To a solution of 5-bromo-N-(1-chloropropan-2-yl)-N-methyl-2-nitro-4-(trifluoromethyl)aniline (5 g, 13.3 mmol) in AcOH (20 mL) was added Fe powder (3.7 g, 66.6 mmol). The mixture was stirred at room temperature for 2 h. Insoluble solid was filtered off, the filtrate was adjusted to pH 8 by the addition of sat. aq. NaHCO3 and the mixture was extracted with EtOAc (100 mL×3). The combined organic layers were washed with brine (100 mL×3), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (3.8 g, crude) as a brown oil that required no further purification. LCMS M/Z (M+H) 345.
-
- To a solution of 5-bromo-N1-(1-chloropropan-2-yl)-N1-methyl-4-(trifluoromethyl)benzene-1,2-diamine (3.8 g, 11 mmol) in DMF (50 mL) was added potassium iodide (3.7 g, 22 mmol) and potassium carbonate (4.6 g, 33 mmol). The mixture was heated to 80° C. for 5 h. After cooling the reaction to room temperature, EtOAc (200 mL) was added and washed with brine (100 mL×3). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc=3:1) to give the title compound (1.6 g, 47%) as a brown oil. LCMS M/Z (M+H) 309.
-
- To a solution of 7-bromo-1,2-dimethyl-6-(trifluoromethyl)-1,2,3,4-tetrahydroquinoxaline (800 mg, 2.59 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (646 mg, 3.11 mmol) and sodium carbonate (823 mg, 7.76 mmol) in THF (10 mL) and water (2 mL) was added chloro(2-dicyclohexylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl) palladium(II) (203 mg, 0.26 mmol) and 2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (123 mg, 0.26 mmol). The mixture was heated to 60° C. for 16 h under a nitrogen atmosphere. After cooling the reaction to room temperature, water (100 mL) was added and the mixture was extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine (50 mL×2), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc=1:1) to give the title compound (0.5 g, 62%) as yellow oil. LCMS M/Z (M+H) 311.
-
- To a solution of 1,2-dimethyl-7-(1-methyl-1H-pyrazol-4-yl)-6-(trifluoromethyl)-1,2,3,4-tetrahydroquinoxaline (200 mg, 0.64 mmol), tert-butyl 3-bromo-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (Intermediate H, 373 mg, 0.97 mmol) and t-BuONa (185 mg, 1.93 mmol) in 1,4-dioxane (5 mL) was added chloro(2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (50 mg, 0.06 mmol) and 2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl (30 mg, 0.06 mmol). The mixture was heated to 120° C. for 16 h under a nitrogen atmosphere. After cooling the reaction to room temperature, water (50 mL) was added and the mixture was extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine (30 mL×2), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (DCM/MeOH=20/1) to give the title compound (0.2 g, 50%) as a yellow oil. LCMS M/Z (M+H) 616.
-
- To a solution of tert-butyl 3-(3,4-dimethyl-6-(1-methyl-1H-pyrazol-4-yl)-7-(trifluoromethyl)-3,4-dihydroquinoxalin-1(2H)-yl)-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (0.2 g, 0.32 mmol) in DCM (5 mL) at 0° C. was added trifluoroacetic acid (0.28 mL, 3.25 mmol). The mixture was stirred at 0° C. for 2 h and concentrated in vacuo to give the title compound (0.1 g, crude) as a brown oil that required no further purification. LCMS M/Z (M+H) 516.
-
- To a solution of 1,2-dimethyl-7-(1-methyl-1H-pyrazol-4-yl)-4-(1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-6-(trifluoromethyl)-1,2,3,4-tetrahydroquinoxaline (150 mg, 0.29 mmol) in DCM (5 mL) was added triethylamine (0.12 mL, 0.87 mmol) and N-methyl-1H-imidazole-1-carboxamide (73 mg, 0.58 mmol). The mixture was stirred at room temperature for 16 h and concentrated in vacuo. The crude residue was purified by reverse phase chromatography (acetonitrile 35-65%/0.225% formic acid in water) to give racemic 3-[3,4-dimethyl-6-(1-methylpyrazol-4-yl)-7-(trifluoromethyl)-2,3-dihydroquinoxalin-1-yl]-N-methyl-1-tetrahydropyran-4-yl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxamide (70 mg, 42%) as a white solid that was separated by chiral SFC (AD 250 mm×30 mm, 5 um, I.D., 3 um Mobile phase: ethanol (0.05% diethylamine) in CO2 from 5% to 40% Flow rate: 80 mL/min) to give (S)-3-[3,4-dimethyl-6-(1-methylpyrazol-4-yl)-7-(trifluoromethyl)-2,3-dihydroquinoxalin-1-yl]-N-methyl-1-tetrahydropyran-4-yl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxamide (18 mg, first peak) and (R)-3-[3,4-dimethyl-6-(1-methylpyrazol-4-yl)-7-(trifluoromethyl)-2,3-dihydroquinoxalin-1-yl]-N-methyl-1-tetrahydropyran-4-yl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxamide (24 mg, second peak). Absolute configuration was arbitrarily assigned to each enantiomer. Example 271: 1H NMR (400 MHz, CDCl3) δ 7.57 (s, 1H), 7.45 (s, 1H), 6.79 (s, 1H), 6.48 (s, 1H), 4.40-4.36 (m, 1H), 4.14-4.08 (m, 3H), 3.95-3.80 (m, 6H), 3.78-3.70 (m, 2H), 3.62-3.50 (m, 4H), 2.98 (s, 3H), 2.80-2.75 (m, 5H), 2.31-2.26 (m, 2H), 1.92-1.85 (m, 2H), 1.26-1.22 (m, 3H). LCMS M/Z (M+H) 573. Example 272: 1H NMR (400 MHz, CDCl3) δ 7.57 (s, 1H), 7.45 (s, 1H), 6.79 (s, 1H), 6.48 (s, 1H), 4.40-4.36 (m, 1H), 4.14-4.08 (m, 3H), 3.96-3.80 (m, 6H), 3.78-3.70 (m, 2H), 3.62-3.50 (m, 4H), 2.98 (s, 3H), 2.80-2.75 (m, 5H), 2.31-2.26 (m, 2H), 1.92-1.85 (m, 2H), 1.26-1.22 (m, 3H). LCMS M/Z (M+H) 573.
-
- To a solution of 1,2-dimethyl-7-(1-methyl-1H-pyrazol-4-yl)-4-(1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-6-(trifluoromethyl)-1,2,3,4-tetrahydroquinoxaline (100 mg, 0.19 mmol) in DCM (5 mL) at 0° C. was added triethylamine (0.054 mL, 0.39 mmol) and acetic anhydride (0.037 mL, 0.39 mmol). The mixture was stirred at room temperature for 1 h and concentrated in vacuo. The crude residue was purified by reverse phase chromatography (acetonitrile 45-75%/0.225% formic acid in water) to give racemic 1-[3-[3,4-dimethyl-6-(1-methylpyrazol-4-yl)-7-(trifluoromethyl)-2,3-dihydroquinoxalin-1-yl]-1-tetrahydropyran-4-yl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (60 mg, 55%) as a white solid that was separated by chiral SFC (OJ 250 mm×30 mm, 5 um, I.D, 3 um Mobile phase: ethanol (0.05% diethylamine) in CO2 from 5% to 40% Flow rate: 80 mL/min) to give (S)-1-[3-[3,4-dimethyl-6-(1-methylpyrazol-4-yl)-7-(trifluoromethyl)-2,3-dihydroquinoxalin-1-yl]-1-tetrahydropyran-4-yl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (23 mg, first peak) and (R)-1-[3-[3,4-dimethyl-6-(1-methylpyrazol-4-yl)-7-(trifluoromethyl)-2, 3-dihydroquinoxalin-1-yl]-1-tetrahydropyran-4-yl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (25 mg, second peak). Absolute configuration was arbitrarily assigned to each enantiomer. Example 273: 1H NMR (400 MHz, CDCl3) δ 7.57-7.55 (m, 1H), 7.45-7.43 (m, 1H), 6.79 (s, 1H), 6.49-6.44 (m, 1H), 4.16-4.05 (m, 4H), 4.02-3.91 (m, 5H), 3.88-3.75 (m, 2H), 3.61-3.50 (m, 4H), 2.99-2.95 (m, 3H), 2.82-2.75 (m, 2H), 2.32-2.25 (m, 2H), 2.17-2.04 (m, 3H), 1.92-1.86 (m, 2H), 1.26-1.23 (m, 3H). Example 274: 1H NMR (400 MHz, CDCl3) δ 7.57-7.55 (m, 1H), 7.45-7.43 (m, 1H), 6.79 (s, 1H), 6.49-6.44 (m, 1H), 4.16-4.05 (m, 4H), 4.02-3.91 (m, 5H), 3.88-3.75 (m, 2H), 3.61-3.50 (m, 4H), 2.99-2.95 (m, 3H), 2.82-2.75 (m, 2H), 2.32-2.25 (m, 2H), 2.17-2.04 (m, 3H), 1.92-1.86 (m, 2H), 1.26-1.23 (m, 3H). LCMS M/Z (M+H) 558.
-
-
- To a solution of 2-chloroethanol (1.25 mL, 18.6 mmol) in THF (18 mL) at 0° C. was added lithium diisopropylamide (2 M, 9.31 mL, 18.62 mmol) dropwise. After stirring at room temperature for 15 min, 2-bromo-4-fluoro-5-nitro-benzonitrile (3.8 g, 15.51 mmol) in THF (7 mL) was added dropwise. The mixture was stirred at room temperature for additional 16 h. Water (30 mL) was added and the mixture was extracted with EtOAc (30 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc=2:1) to give the title compound (4 g, 84%) as a yellow solid.
-
- To a solution of 2-bromo-4-(2-chloroethoxy)-5-nitrobenzonitrile (4.8 g, 15.8 mmol) in AcOH (50 mL) was added Fe powder (4.4 g, 78.8 mmol). The mixture was stirred at room temperature for 1 h. Insoluble solid was filtered off, the filtrate was adjusted to pH 8 by the addition of sat. aq. NaHCO3 and the mixture was extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine (50 mL×3), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc=2:1) to give the title compound (3.6 g, 83%) as a yellow oil. LCMS M/Z (M+H) 275.
-
- To a solution of 5-amino-2-bromo-4-(2-chloroethoxy)benzonitrile (3.1 g, 11.3 mmol) in DMF (20 mL) was added potassium iodide (3.7 g, 22.5 mmol) and potassium carbonate (4.7 g, 33.8 mmol). The mixture was heated to 80° C. for 7 h. After cooling the reaction to room temperature, water (50 mL) was added and extracted with EtOAc (150 mL×3). The combined organic layers were washed with brine (100 mL×2), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (2.68 g, crude) as a brown solid that required no further purification. LCMS M/Z (M+H) 239.
-
- To a solution of 7-bromo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carbonitrile (0.6 g, 2.5 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.63 g, 3.0 mmol) and sodium carbonate (0.8 g, 7.5 mmol) in THF (10 mL) and water (2 mL) was added chloro(2-dicyclohexylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl) palladium(II) (0.2 g, 0.25 mmol) and 2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (120 mg, 0.25 mmol). The mixture was heated to 60° C. for 16 h under a nitrogen atmosphere. After cooling the reaction to room temperature, the mixture was filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc=1:2) to give the title compound (0.47 g, 78%) as a brown solid. LCMS M/Z (M+H) 241.
-
- To a solution of 7-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carbonitrile (230 mg, 0.96 mmol), tert-butyl 3-bromo-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (Intermediate H, 0.37 g, 0.96 mmol) and t-BuONa ((276 mg, 2.87 mmol) in 1,4-dioxane (5 mL) was added chloro(2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (74 mg, 0.1 mmol), 2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl (45 mg, 0.1 mmol). The mixture was heated to 120° C. for 16 h under an argon atmosphere. After cooling the reaction to room temperature, the mixture was filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc=1:2) to give the title compound (0.44 g, 84%) as a yellow solid. LCMS M/Z (M+H) 546.
-
- To a solution of tert-butyl 3-(6-cyano-7-(1-methyl-1H-pyrazol-4-yl)-2H-benzo[b][1,4]oxazin-4(3H)-yl)-1-(tetrahydro-2H-pyran-4-yl)-6, 7-dihydro-1H-pyrazolo[4,3-c]pyridine-5 (4H)-carboxylate (200 mg, 0.37 mmol) in DCM (2 mL) at 0° C. was added trifluoroacetic acid (0.27 mL, 3.7 mmol). The mixture was stirred at room temperature for 1 h and concentrated in vacuo to give the title compound (163 mg, crude) as a yellow oil that required no further purification. LCMS M/Z (M+H) 446.
-
- To a solution of 7-(1-methyl-1H-pyrazol-4-yl)-4-(1-(tetrahydro-2H-pyran-4-yl)-4, 5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carbonitrile (163 mg, 0.37 mmol) in DCM (4 mL) was added triethylamine (0.15 mL, 1.1 mmol) and N-methyl-1H-imidazole-1-carboxamide (92 mg, 0.73 mmol). The mixture was stirred at room temperature for 16 h and concentrated in vacuo. The crude residue was purified by reverse phase chromatography (acetonitrile 20-50%/0.225% formic acid in water) to give the title compound (62 mg, 33%) as a white solid. 1H NMR (400 MHz, DMSO) δ 8.11 (s, 1H), 7.83 (s, 1H), 7.11 (s, 1H), 6.98 (s, 1H), 6.56-6.52 (m, 1H), 4.42-4.30 (m, 3H), 4.12 (s, 2H), 3.95-3.90 (m, 2H), 3.88 (s, 3H), 3.70-3.65 (m, 2H), 3.64-3.60 (m, 2H), 3.48-3.44 (m, 2H), 2.74-2.62 (m, 2H), 2.56 (d, J=4.0 Hz, 3H), 1.99-1.90 (m, 2H), 1.85-1.80 (m, 2H). LCMS M/Z (M+H) 503.
-
-
- To a solution of 2-chloroethanol (1.7 mL, 25 mmol) in THF (25 mL) at 0° C. was added lithium diisopropylamide (2 M, 12.5 mL, 25 mmol) dropwise. After stirring at room temperature for 15 min, 1-bromo-5-fluoro-4-nitro-2-(trifluoromethyl)benzene (6.0 g, 20.8 mmol) in THF (10 mL) was added dropwise. The mixture was stirred at room temperature for additional 16 h. Water (30 mL) was added and extracted with EtOAc (30 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc=4:1) to give the title compound (6.8 g, 94%) as a yellow oil.
-
- To a solution of 1-bromo-5-(2-chloroethoxy)-4-nitro-2-(trifluoromethyl)benzene (6.8 g, 19.5 mmol) in AcOH (20 mL) was added Fe powder (5.45 g, 97.6 mmol). The mixture was stirred at room temperature for 1 h. Insoluble solid was filtered off, the filtrate was adjusted to pH 8 by the addition of sat. aq. NaHCO3 and extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine (50 mL×3), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc=3:1) to give the title compound (6 g, 97%) as a brown oil. LCMS M/Z (M+H) 318.
-
- To a solution of 4-bromo-2-(2-chloroethoxy)-5-(trifluoromethyl)aniline (6.0 g, 18.8 mmol) in DMF (20 mL) was added potassium iodide (6.25 g, 37.7 mmol) and potassium carbonate (7.8 g, 56.5 mmol). The mixture was heated to 80° C. for 7 h. After cooling the reaction to room temperature, water (50 mL) was added and the mixture was extracted with EtOAc (150 mL×3). The combined organic layers were washed with brine (100 mL×2), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc=3:1) to give the title compound (5.3 g, 99%) as a brown oil. LCMS M/Z (M+H) 282.
-
- To a solution of 7-bromo-6-(trifluoromethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (1.0 g, 3.55 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.89 g, 4.25 mmol) and sodium carbonate (1.13 g, 10.6 mmol) in THF (20 mL) and water (4 mL) was added chloro(2-dicyclohexylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl) palladium(II) (279 mg, 0.35 mmol) and 2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (169 mg, 0.35 mmol). The mixture was heated to 60° C. for 16 h under a nitrogen atmosphere. After cooling the reaction to room temperature, the mixture was filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc=1:1) to give the title compound (0.95 g, 95%) as a brown oil. LCMS M/Z (M+H) 284.
-
- To a solution of 7-(1-methyl-1H-pyrazol-4-yl)-6-(trifluoromethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (450 mg, 1.59 mmol), tert-butyl 3-bromo-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (Intermediate H, 0.61 g, 1.59 mmol) and t-BuONa (458 mg, 4.77 mmol) in 1,4-dioxane (15 mL) was added chloro(2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (123 mg, 0.16 mmol) and 2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl (74 mg, 0.16 mmol). The mixture was heated to 120° C. for 16 h under an argon atmosphere. After cooling the reaction to room temperature, the mixture was filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc=1:2) to give the title compound (670 mg, 72%) as a yellow solid. LCMS M/Z (M+H) 589.
-
- To a solution of tert-butyl 3-(7-(1-methyl-1H-pyrazol-4-yl)-6-(trifluoromethyl)-2H-benzo[b][1,4]oxazin-4(3H)-yl)-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (340 mg, 0.58 mmol) in DCM (4 mL) at 0° C. was added trifluoroacetic acid (1.72 mL, 23.1 mmol). The mixture was stirred at room temperature for 2 h and concentrated in vacuo to give the title compound (282 mg, crude) as a brown oil that required no further purification. LCMS M/Z (M+H) 489.
-
- To a solution of 7-(1-methyl-1H-pyrazol-4-yl)-4-(1-(tetrahydro-2H-pyran-4-yl)-4, 5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-6-(trifluoromethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (141 mg, 0.29 mmol) in DCM (4 mL) was added triethylamine (0.12 mL, 0.87 mmol) and N-methyl-1H-imidazole-1-carboxamide (144 mg, 1.15 mmol). The mixture was stirred at room temperature for 18 h and concentrated in vacuo. The crude residue was purified by reverse phase chromatography (acetonitrile 18-48%/0.225% formic acid in water) to give the title compound (40 mg, 25%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.55 (s, 1H), 7.44 (s, 1H), 7.00 (s, 1H), 6.89 (s, 1H), 4.42-4.38 (m, 3H), 4.16-4.10 (m, 3H), 4.05 (s, 2H), 3.95 (s, 3H), 3.85-3.80 (m, 4H), 3.55-3.50 (m, 2H), 2.81-2.75 (m, 5H), 2.31-2.25 (m, 2H), 1.87-1.85 (m, 2H). LCMS M/Z (M+H) 546.
-
- To a solution of 7-(1-methyl-1H-pyrazol-4-yl)-4-(1-(tetrahydro-2H-pyran-4-yl)-4, 5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-6-(trifluoromethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (141 mg, 0.29 mmol) in DCM (2 mL) was added triethylamine (0.12 mL, 0.87 mmol) and acetic anhydride (0.11 mL, 1.15 mmol). The mixture was stirred at room temperature for 18 h and concentrated in vacuo. The crude residue was purified by reverse phase chromatography (acetonitrile 18-48%/0.225% formic acid in water) to give the title compound (52 mg, 33%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.55 (s, 1H), 7.45-7.42 (m, 1H), 7.05-6.99 (m, 1H), 6.90-6.86 (m, 1H), 4.43-4.35 (m, 3H), 4.20-4.13 (m, 4H), 3.95-3.90 (m, 4H), 3.83-3.75 (m, 3H), 3.56-3.53 (m, 2H), 2.85-2.75 (m, 2H), 2.32-2.26 (m, 2H), 2.19-2.08 (m, 3H), 1.88-1.85 (m, 2H). LCMS M/Z (M+H) 531.
-
-
- To a solution of 2-chloroethanol (0.3 mL, 4.44 mmol) in THF (5 mL) at 0° C. was added lithium diisopropylamide (2 M, 2.22 mL, 4.44 mmol) dropwise. After stirring at room temperature for 15 min, 1-bromo-2-(difluoromethyl)-5-fluoro-4-nitro-benzene (1.0 g, 3.7 mmol) in THF (5 mL) was added dropwise. The mixture was stirred at room temperature for an additional 16 h. Water (30 mL) was added and the mixture was extracted with EtOAc (30 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc=9:1) to give the title compound (1 g, 82%) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.18 (s, 1H), 7.35 (s, 1H), 6.85 (t, J=54.8 Hz, 1H), 4.41 (t, J=6.0 Hz, 2H), 3.89 (t, J=6.0 Hz, 2H).
-
- To a solution of 1-bromo-5-(2-chloroethoxy)-2-(difluoromethyl)-4-nitro-benzene (1.0 g, 3.03 mmol) in AcOH (10 mL) was added Fe powder (0.84 g, 15.1 mmol). The mixture was stirred at room temperature for 2 h. Insoluble solid was filtered off, the filtrate was adjusted to pH 8 by the addition of sat. aq. NaHCO3 and the mixture was extracted with EtOAc (100 mL×3). The combined organic layers were washed with brine (100 mL×3), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (700 mg, 77%) as a red oil that required no further purification. 1H NMR (400 MHz, CDCl3) δ 7.00 (s, 1H), 6.93 (s, 1H), 6.81 (t, J=55.2 Hz, 1H), 4.28 (t, J=5.6 Hz, 2H), 3.86 (t, J=5.6 Hz, 2H).
-
- To a solution of 4-bromo-2-(2-chloroethoxy)-5-(difluoromethyl)aniline (700 mg, 2.33 mmol) in DMF (14 mL) was added potassium iodide (773 mg, 4.66 mmol) and potassium carbonate (966 mg, 6.99 mmol). The mixture was heated to 80° C. for 24 h. After cooling the reaction to room temperature, water (100 mL) was added and the mixture was extracted with EtOAc (100 mL×3). The combined organic layers were washed with brine (100 mL×2), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (700 mg, crude) as a brown oil. LCMS M/Z (M+H) 264.
-
- To a solution of 7-bromo-6-(difluoromethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (700 mg, 2.65 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (662 mg, 3.18 mmol) and sodium carbonate (843 mg, 7.95 mmol) in THF (10 mL) in water (2 mL) was added chloro(2-dicyclohexylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl) palladium(II) (209 mg, 0.27 mmol) and 2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (130 mg, 0.27 mmol). The mixture was heated to 60° C. for 16 h under a nitrogen atmosphere. After cooling the reaction to room temperature, the mixture was filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc=1:1) to give the title compound (300 mg, 43%) as a brown solid. 1H NMR (400 MHz, CDCl3) δ 7.51 (s, 1H), 7.39 (s, 1H), 6.93 (s, 1H), 6.76 (s, 1H), 6.52 (t, J=55.6 Hz, 1H), 4.28 (t, J=4.4 Hz, 2H), 3.93 (s, 3H), 3.44 (t, J=4.4 Hz, 2H).
-
- To a solution of 6-(difluoromethyl)-7-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (100 mg, 0.38 mmol), 1-(3-bromo-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone (Intermediate I, 136 mg, 0.41 mmol) and t-BuONa (109 mg, 1.13 mmol) in 1,4-dioxane (3 mL) was added chloro(2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (29 mg, 0.04 mmol), 2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl (18 mg, 0.04 mmol). The mixture was heated to 120° C. for 16 h under an argon atmosphere. After cooling the reaction to room temperature, the mixture was filtered and concentrated in vacuo. The crude residue was purified by reverse phase chromatography (acetonitrile 25-55%/0.05% NH4OH in water) to give the title compound (38 mg, 20%) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 7.79 (s, 1H), 7.53 (s, 1H), 7.08-7.04 (m, 1H), 6.97-6.64 (m, 2H), 4.38-4.18 (m, 5H), 3.97-3.93 (m, 2H), 3.87 (s, 3H), 3.79-3.63 (m, 4H), 3.46 (t, J=11.6 Hz, 2H), 2.92-2.71 (m, 2H), 2.13-1.91 (m, 5H), 1.83-1.80 (m, 2H). LCMS M/Z (M+H) 513.
-
-
- To a solution of 6-(1-methylpyrazol-4-yl)-1,2,3,4-tetrahydro-1,7-naphthyridine (180 mg, 0.84 mmol) and tert-butyl 3-bromo-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (Intermediate H, 389 mg, 1.01 mmol) and t-BuONa (161 mg, 1.68 mmol) in 1,4-dioxane (2 mL) was added dichloro[1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II) (100 mg, 0.13 mmol). The mixture was heated to 120° C. for 16 h under an argon atmosphere. After cooling the reaction to room temperature, the mixture was filtered and concentrated in vacuo. The crude residue was purified by Prep-TLC (DCM/MeOH=10:1) to give the title compound (80 mg, 18%) as a yellow oil. LCMS M/Z (M+H) 520.
-
- To a solution of tert-butyl 3-(6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydro-1,7-naphthyridin-1(2H)-yl)-1-(tetrahydro-2H-pyran-4-yl)-6, 7-dihydro-1H-pyrazolo[4,3-c]pyridine-5 (4H)-carboxylate (80 mg, 0.15 mmol) in DCM (1.5 mL) at 0° C. was added trifluoroacetic acid (0.3 mL, 4.04 mmol). The mixture was stirred at room temperature for 1 h and concentrated in vacuo. DCM (10 mL) was added and washed with sat. aq. NaHCO3 (5 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (60 mg, 93%) as a brown oil that required no further purification. LCMS M/Z (M+H) 420.
-
- To a solution of 6-(1-methyl-1H-pyrazol-4-yl)-1-(1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-1,2,3,4-tetrahydro-1,7-naphthyridine (60 mg, 0.14 mmol) in DCM (2 mL) was added triethylamine (0.06 mL, 0.43 mmol) and N-methyl-1H-imidazole-1-carboxamide (27 mg, 0.21 mmol). The mixture was stirred at room temperature for 16 h and concentrated in vacuo. The crude residue was purified by reverse phase chromatography (acetonitrile 15-45%/0.05% NH4OH in water) to give the title compound (24 mg, 35%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.15 (s, 1H), 7.89 (s, 1H), 7.81 (s, 1H), 7.49 (s, 1H), 6.59-6.55 (m, 1H), 4.32-4.28 (m, 1H), 4.11 (s, 2H), 3.98-3.93 (m, 2H), 3.86 (s, 3H), 3.62-3.57 (m, 4H), 3.46 (t, J=11.6 Hz, 2H), 2.89-2.70 (m, 4H), 2.55 (d, J=4.0 Hz, 3H), 1.99-1.91 (m, 4H), 1.83-1.77 (m, 2H). LCMS M/Z (M+H) 477.
-
-
- To a solution of 6-methoxy-1,2,3,4-tetrahydro-1,7-naphthyridine (1.2 g, 7.31 mmol), 1-(3-bromo-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone (Intermediate I, 2.0 g, 6.09 mmol) and t-BuONa (1.7 g, 18.3 mmol) in 1,4-dioxane (20 mL) was added dichloro[1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II) (484 mg, 0.6 mmol). The mixture was heated to 120° C. for 16 h under an argon atmosphere. After cooling the reaction to room temperature, the mixture was filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (DCM/MeOH=10/1) to give the title compound (1.7 g, 68%) as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ 7.39 (s, 1H), 6.50 (s, 1H), 4.46-4.13 (m, 3H), 4.01-3.92 (m, 2H), 3.77-3.72 (m, 4H), 3.57-3.41 (m, 4H), 3.08 (s, 3H), 2.81-2.78 (m, 3H), 2.09-2.00 (m, 4H), 1.98-1.90 (m, 2H), 1.87-1.75 (m, 2H). LCMS M/Z (M+H) 412.
-
- A mixture of 1-(3-(6-methoxy-3,4-dihydro-1,7-naphthyridin-1(2H)-yl)-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone (1.3 g, 3.16 mmol) and pyridine hydrochloride (3.0 g, 26.2 mmol) was heated to 150° C. for 0.5 h. After cooling the reaction to room temperature, DCM (30 mL) was added and the mixture was made basic with triethylamine to pH 8 before being concentrated in vacuo. The crude residue was purified by silica gel chromatography (DCM/MeOH=10/1) to give the title compound (400 mg, 32%) as a brown oil. 1H NMR (400 MHz, DMSO-d6) δ 10.65 (s, 1H), 6.76-6.71 (m, 1H), 6.16 (s, 1H), 4.29-4.18 (m, 1H), 4.17-4.09 (m, 2H), 3.98-3.94 (m, 2H), 3.76-3.64 (m, 2H), 3.51-3.39 (m, 4H), 2.86-2.65 (m, 4H), 2.11-1.92 (m, 5H), 1.91-1.71 (m, 4H). LCMS M/Z (M+H) 398.
-
- To a solution of 1-(3-(6-hydroxy-3,4-dihydro-1,7-naphthyridin-1(2H)-yl)-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone (200 mg, 0.5 mmol) in DCM (5 mL) at 0° C. was added triethylamine (0.21 mL, 1.51 mmol) and 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (270 mg, 0.75 mmol). The mixture was stirred at room temperature for 16 h. DCM (50 mL) was added and washed with water (40 mL×2). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (200 mg, crude) as a brown oil that required no further purification.
-
- To a solution of 1-(5-acetyl-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-1,2,3,4-tetrahydro-1,7-naphthyridin-6-yl trifluoromethanesulfonate (100 mg, 0.19 mmol), N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinamide (59 mg, 0.23 mmol) and sodium carbonate (60 mg, 0.6 mmol) in THF (5 mL) and water (1 mL) was added chloro(2-dicyclohexylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl) palladium(II) (16 mg, 0.02 mmol) and 2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (8 mg, 0.02 mmol). The mixture was irradiated in a microwave at 60° C. for 0.5 h. After cooling the reaction to room temperature, DCM (50 mL) was added and washed with water (40 mL×2). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by Prep-TLC (DCM/MeOH=20/1) to give the title compound (40 mg, 38%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 9.17 (s, 1H), 8.79-8.72 (m, 1H), 8.47-8.45 (m, 1H), 8.04 (d, J=8.4 Hz, 1H), 7.96-7.87 (m, 1H), 7.83 (s, 1H), 4.35-4.29 (m, 1H), 4.26-4.18 (m, 2H), 4.00-3.92 (m, 2H), 3.81-3.71 (m, 2H), 3.66-3.58 (m, 2H), 3.50-3.44 (m, 2H), 2.93-2.86 (m, 3H), 2.83 (d, J=4.8 Hz, 3H), 2.78-2.71 (m, 1H), 2.11-1.94 (m, 7H), 1.86-1.83 (m, 2H). LCMS M/Z (M+H) 516.
-
- To a solution of 1-(5-acetyl-1-tetrahydropyran-4-yl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-3-yl)-6-bromo-3,4-dihydro-2H-quinoline-7-carbonitrile (Intermediate M, 150 mg, 0.3 mmol) in THF (5 mL) and water (1 mL) was added chloro(2-dicyclohexylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl) palladium(II) (24 mg, 0.03 mmol), 2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (15 mg, 0.03 mmol) and pyridin-3-ylboronic acid (46 mg, 0.37 mmol), Na2CO3 (65 mg, 0.6 mmol). The mixture was heated to 60° C. for 16 h under a nitrogen atmosphere. After cooling the reaction to room temperature, the mixture was filtered and concentrated in vacuo. DCM (50 mL) was added and the mixture was washed with water (30 mL×3) and brine (30 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by reverse phase chromatography (acetonitrile 24-54%/0.05% NH4OH in water) to give the title compound (30 mg, 20%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 8.71 (s, 1H), 8.60-8.59 (m, 1H), 7.94 (d, J=8.0 Hz, 1H), 7.52-7.48 (m, 1H), 7.36 (s, 1H), 6.89-6.82 (m, 1H), 4.35-4.30 (m, 1H), 4.25-4.20 (m, 2H), 3.98-3.95 (m, 2H), 3.81-3.71 (m, 2H), 3.66-3.57 (m, 2H), 3.49-3.43 (m, 2H), 2.96-2.74 (m, 4H), 2.16-1.94 (m, 7H), 1.87-1.83 (m, 2H). LCMS M/Z (M+H) 483.
- The following compounds were prepared in a similar fashion to Example 281:
-
-
Example Compound Name NMR m/z Example N-[5-[1-(5-acetyl-1- 1H NMR (400 MHz, DMSO-d6) δ 540 282 tetrahydropyran-4-yl- 10.63 (s, 1H), 8.44-8.43 (m, 1H), 6,7-dihydro-4H- 8.15-8.12 (m, 1H), 7.93-7.90 (m, 1H), 7.33 (s, 1H), pyrazolo[4,3-c]pyridin- 6.86-6.75 (m, 1H), 4.38-4.27 (m, 1H), 3-yl)-7-cyano-3,4- 4.25-4.18 (m, 2H), 3.97-3.95 (m, 2H), dihydro-2H-quinolin-6- 3.81-3.70 (m, 2H), 3.64-3.57 (m, 2H), yl]-2-pyridyl]acetamide 3.48-3.46 (m, 2H), 2.94-2.74 (m, 4H), 2.11 (s, 3H), 2.10-1.92 (m, 7H), 1.88-1.81 (m, 2H) Example 1-(5-acetyl-1- 1H NMR (400 MHz, DMSO-d6) δ 483 283 tetrahydropyran-4-yl- 8.73-8.57 (m, 2H), 7.60-7.48 (m, 2H), 7.39 (s, 6,7-dihydro-4H- 1H), 6.91-6.79 (m, 1H), 4.37-4.29 (m, pyrazolo[4,3-c]pyridin- 1H), 4.27-4.19 (m, 2H), 3.98-3.95 (m, 3-yl)-6-(4-pyridyl)-3,4- 2H), 3.79-3.72 (m, 2H), 3.66-3.57 (m, dihydro-2H-quinoline-7- 2H), 3.49-3.43 (m, 2H), 2.96-2.74 (m, carbonitrile 4H), 2.12-1.93 (m, 7H), 1.90-1.80 (m, 2H) Example 1-(5-acetyl-1- 1H NMR (400 MHz, DMSO-d6) δ 8.92 (s, 508 284 tetrahydropyran-4-yl- 1H), 8.23 (d, J = 8.0 Hz, 1H), 8.16 (d, J = 8.0 Hz, 6,7-dihydro-4H- 1H), 7.46 (s, 1H), 6.93-6.82 (m, pyrazolo[4,3-c]pyridin- 1H), 4.39-4.28 (m, 1H), 4.27-4.18 (m, 3-yl)-6-(6-cyano-3- 2H), 3.97-3.93 (m, 2H), 3.82-3.69 (m, pyridyl)-3,4-dihydro- 2H), 3.67-3.57 (m, 2H), 3.46 (t, J = 12.0 Hz, 2H-quinoline-7- 2H), 2.98-2.73 (m, 4H), carbonitrile 2.13-1.91 (m, 7H), 1.90-1.80 (m, 2H) Example 1-(5-acetyl-1- 1H NMR (400 MHz, DMSO-d6) δ 8.51 (s, 523 285 tetrahydropyran-4-yl- 1H), 7.79-7.76 (m, 1H), 7.39 (d, J = 8.0 Hz, 6,7-dihydro-4H- 1H), 7.30 (s, 1H), 6.85-6.79 (m, 1H), pyrazolo[4,3-c]pyridin- 4.38-4.27 (m, 1H), 4.24-4.17 (m, 2H), 3-yl)-6-(6-cyclopropyl- 3.97-3.94 (m, 2H), 3.80-3.70 (m, 2H), 3-pyridyl)-3,4-dihydro- 3.64-3.56 (m, 2H), 3.49-3.43 (m, 2H), 2H-quinoline-7- 2.94-2.75 (m, 4H), 2.18-2.11 (m, 1H), carbonitrile 2.10-1.96 (m, 7H), 1.86-1.83 (m, 2H), 0.99-0.94 (m, 4H) Example 1-(5-acetyl-1- 1H NMR (400 MHz, DMSO-d6) δ 8.57 (s, 497 286 tetrahydropyran-4-yl- 1H), 7.83-7.80 (m, 1H), 7.38-7.29 (m, 6,7-dihydro-4H- 2H), 6.88-6.76 (m, 1H), 4.39-4.27 (m, pyrazolo[4,3-c]pyridin- 1H), 4.26-4.15 (m, 2H), 3.97-3.93 (m, 3-yl)-6-(6-methyl-3- 2H), 3.82-3.68 (m, 2H), 3.65-3.54 (m, pyridyl)-3,4-dihydro- 2H), 3.46 (t, J = 11.6 Hz, 2H), 2H-quinoline-7- 2.97-2.72 (m, 4H), 2.52 (s, 3H), 2.14-1.90 (m, 7H), carbonitrile 1.89-1.78 (m, 2H) Example 1-(5-acetyl-1- 1H NMR (400 MHz, DMSO-d6) δ 9.21 (s, 484 287 tetrahydropyran-4-yl- 1H), 8.99 (s, 2H), 7.45 (s, 1H), 6,7-dihydro-4H- 6.93-6.82 (m, 1H), 4.39-4.28 (m, 1H), pyrazolo[4,3-c]pyridin- 4.27-4.18 (m, 2H), 3.97-3.95 (m, 2H), 3-yl)-6-pyrimidin-5-yl- 3.83-3.70 (m, 2H), 3.65-3.57 (m, 2H), 3,4-dihydro-2H- 3.49-3.43 (m, 2H), 2.96-2.74 (m, 4H), quinoline-7-carbonitrile 2.10-1.96 (m, 7H), 1.90-1.81 (m, 2H) -
- To a solution of 3-(6-bromo-7-cyano-3,4-dihydro-2H-quinolin-1-yl)-N-methyl-1-tetrahydropyran-4-yl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxamide (Intermediate N, 100 mg, 0.2 mmol) in THF (2.5 mL) and water (0.5 mL) was added chloro(2-dicyclohexylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl) palladium(II) (16 mg, 0.02 mmol), 2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (10 mg, 0.02 mmol), 6-methylpyridine-3-boronicacid (41 mg, 0.3 mmol) and Na2CO3 (42 mg, 0.4 mmol). The mixture was heated to 60° C. for 16 h under a nitrogen atmosphere. After cooling the reaction to room temperature, the mixture was filtered and concentrated in vacuo. DCM (50 mL) was added and the mixture was washed with water (30 mL×3) and brine (30 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by reverse phase chromatography (acetonitrile 22-52%/0.05% NH4OH in water) to give the title compound (37 mg, 36%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.55-8.54 (m, 1H), 7.81-7.79 (m, 1H), 7.35-7.33 (m, 1H), 7.30 (s, 1H), 6.78 (s, 1H), 6.56-6.55 (m, 1H), 4.38-4.25 (m, 1H), 4.06 (s, 2H), 3.97-3.94 (m, 2H), 3.64-3.58 (m, 4H), 3.49-3.43 (m, 2H), 2.93-2.90 (m, 2H), 2.78-2.72 (m, 2H), 2.55 (d, J=4.0 Hz, 3H), 2.52 (s, 3H), 2.02-1.92 (m, 4H), 1.85-1.82 (m, 2H). LCMS M/Z (M+H) 512.
- The following compounds were prepared in a similar fashion to Example 288:
-
-
Example Compound Name NMR m/z Example 3-[7-cyano-6-[6- 1H NMR (400 MHz, CDCl3) δ 8.68 (s, 555 289 (methylcarbamoyl)-3- 1H), 8.25 (d, J = 8.0 Hz, 1H), pyridyl]-3,4-dihydro- 8.03-7.96 (m, 2H), 7.15 (s, 1H), 6.82 (s, 1H), 2H-quinolin-1-yl]-N- 4.46-4.44 (m, 1H), 4.15-4.09 (m, 5H), methyl-1- 3.78-3.76 (m, 2H), 3.72-3.69 (m, 2H), 3.53 (t, tetrahydropyran-4-yl- J = 8.0 Hz, 2H), 3.06 (d, J = 4.8 Hz, 3H), 6,7-dihydro-4H- 2.97-2.91 (m, 2H), 2.83-2.80 (m, 5H), pyrazolo[4,3-c]pyridine- 2.30-2.26 (m, 2H), 2.13-2.10 (m, 2H), 5-carboxamide 1.90-1.88 (m, 2H). Example 3-[6-(6-acetamido-3- 1H NMR (400 MHz, CDCl3) δ 8.39 (d, J = 2.4 Hz, 555 290 pyridyl)-7-cyano-3,4- 1H), 8.28 (d, J = 8.4 Hz, 1H), dihydro-2H-quinolin-1- 8.11 (s, 1H), 7.89-7.84 (m, 1H), 7.11 (s, 1H), yl]-N-methyl-1- 6.79 (s, 1H), 4.46-4.39 (m, 1H), tetrahydropyran-4-yl- 4.21-4.10 (m, 3H), 4.07 (s, 2H), 3.79 (t, J = 5.6 Hz, 6,7-dihydro-4H- 2H), 3.70 (t, J = 5.6 Hz, 2H), 3.53 (t, J = 11.2 Hz, pyrazolo[4,3-c]pyridine- 2H), 2.93 (t, J = 6.0 Hz, 2H), 5-carboxamide 2.87-2.77 (m, 5H), 2.36-2.26 (m, 2H), 2.24 (s, 3H), 2.15-2.07 (m, 2H), 1.93-1.84 (m, 2H) Example 3-[7-cyano-6-(6- 1H NMR (400 MHz, DMSO-d6) δ 528 291 methoxy-3-pyridyl)-3,4- 8.30-8.29 (m, 1H), 7.87-7.84 (m, 1H), 7.29 (s, dihydro-2H-quinolin-1- 1H), 6.93 (d, J = 9.2 Hz, 1H), 6.79 (s, 1H), yl]-N-methyl-1- 6.59-6.51 (m, 1H), 4.33-4.32 (m, 1H), tetrahydropyran-4-yl- 4.08 (s, 2H), 3.95-3.94 (m, 2H), 3.90 (s, 6,7-dihydro-4H- 3H), 3.63-3.58 (m, 4H), 3.46-3.43 (m, pyrazolo[4,3-c]pyridine- 2H), 2.93-2.90 (m, 2H), 2.76-2.74 (m, 5-carboxamide 2H), 2.56 (d, J = 4.4 Hz, 3H), 2.06-1.91 (m, 4H), 1.87-1.78 (m, 2H). Example 3-[7-cyano-6-(5-methyl- 1H NMR (400 MHz, DMSO-d6) δ 512 292 3-pyridyl)-3,4-dihydro- 8.54-8.51 (m, 1H), 8.44 (s, 1H), 7.75 (s, 1H), 2H-quinolin-1-yl]-N- 7.34 (s, 1H), 6.81 (s, 1H), 6.60-6.52 (m, methyl-1- 1H), 4.35-4.29 (m, 1H), 4.09 (s, 2H), tetrahydropyran-4-yl- 3.97-3.95 (m, 2H), 3.63-3.59 (m, 4H), 6,7-dihydro-4H- 3.49-3.43 (m, 2H), 2.94-2.91 (m, 2H), pyrazolo[4,3-c]pyridine- 2.75-2.76 (m, 2H), 2.56 (d, J = 4.0 Hz, 5-carboxamide 3H), 2.36 (s, 3H), 2.05-1.90 (m, 4H), 1.86-1.78 (m, 2H) Example 3-[7-cyano-6-(2-methyl- 1H NMR (400 MHz, CDCl3) δ 512 293 3-pyridyl)-3,4-dihydro- 8.55-8.48 (m, 1H), 7.51 (d, J = 8.0 Hz, 1H), 2H-quinolin-1-yl]-N- 7.23-7.16 (m, 1H), 6.98 (s, 1H), 6.78 (s, 1H), methyl-1- 4.51-4.45 (m, 1H), 4.23-4.08 (m, 5H), tetrahydropyran-4-yl- 3.78 (t, J = 5.6 Hz, 2H), 3.70 (t, J = 5.6 Hz, 6,7-dihydro-4H- 2H), 3.53 (t, J = 12.0 Hz, 3H), 2.91 (t, pyrazolo[4,3-c]pyridine- J = 6.0 Hz, 2H), 2.84-2.79 (m, 5H), 5-carboxamide 2.46 (s, 3H), 2.36-2.23 (m, 2H), 2.16-2.08 (m, 2H), 1.93-1.83 (m, 2H) Example 3-[7-cyano-6-(2- 1H NMR (400 MHz DMSO-d6) δ 8.24 (d, 528 294 methoxy-4-pyridyl)-3,4- J = 5.2 Hz, 1H), 7.37 (s, 1H), dihydro-2H-quinolin-1- 7.13-7.11 (m, 1H), 6.93 (s, 1H), 6.79 (s, 1H), yl]-N-methyl-1- 6.57-6.49 (m, 1H), 4.41-4.24 (m, 1H), 4.08 (s, tetrahydropyran-4-yl- 2H), 3.99-3.91 (m, 2H), 3.87 (s, 3H), 6,7-dihydro-4H- 3.67-3.55 (m, 4H), 3.46 (t, J = 11.2 Hz, pyrazolo[4,3-c]pyridine- 2H), 2.90 (t, J = 6.0 Hz, 2H), 5-carboxamide 2.75-2.72 (m, 2H), 2.54 (d, J = 4.4 Hz, 3H), 2.05-1.91 (m, 4H), 1.85-1.80 (m, 2H) Example 3-[7-cyano-6-(2-methyl- 1H NMR (400 MHz DMSO-d6) δ 8.51 (d, 512 295 4-pyridyl)-3,4-dihydro- J = 4.8 Hz, 1H), 8.12 (s, 1H), 7.39 (s, 1H), 2H-quinolin-1-yl]-N- 7.38-7.32 (m, 2H), 6.80 (s, 1H), methyl-1- 6.58-6.50 (m, 1H), 4.42-4.26 (m, 1H), 4.08 (s, tetrahydropyran-4-yl- 2H), 3.95-3.90 (m, 2H), 3.70-3.54 (m, 6,7-dihydro-4H- 4H), 3.44 (t, J = 12.0 Hz, 2H), 2.92 (t, J = 6.0 Hz, pyrazolo[4,3-c]pyridine- 2H), 2.80-2.71 (m, 2H), 2.56 (d, 5-carboxamide J = 4.4 Hz, 3H), 2.50 (s, 3H), 2.06-1.90 (m, 4H), 1.88-1.78 (m, 2H) Example 3-[7-cyano-6-[6- 1H NMR (400 MHz, DMSO-d6) δ 8.11 (d, 527 296 (methylamino)-3- J = 2.4 Hz, 1H), 7.55-7.50 (m, 1H), pyridyl]-3,4-dihydro- 7.20 (s, 1H), 6.74 (s, 1H), 6.71-6.65 (m, 1H), 2H-quinolin-1-yl]-N- 6.58-6.53 (m, 1H), 6.51 (d, J = 9.2 Hz, methyl-1- 1H), 4.37-4.24 (m, 1H), 4.06 (s, 2H), tetrahydropyran-4-yl- 3.99-3.92 (m, 2H), 3.64-3.60 (s, 2H), 6,7-dihydro-4H- 3.58-3.54 (m, 2H), 3.45 (t, J = 12.0 Hz, pyrazolo[4,3-c]pyridine- 2H), 2.91-2.88 (m, 2H), 2.80 (d, J = 4.8 Hz, 5-carboxamide 3H), 2.77-2.72 (m, 2H), 2.55 (d, J = 4.4 Hz, 3H), 2.04-1.92 (m, 4H), 1.87-1.81 (m, 2H) Example 3-[7-cyano-6-(4-methyl- 1H NMR (400 Hz, DMSO-d6) δ 8.46 (d, J = 4.8 Hz, 512 297 3-pyridyl)-3,4-dihydro- 1H), 8.34 (s, 1H), 7.37 (d, J = 4.8 Hz, 2H-quinolin-1-yl]-N- 1H), 7.18 (s, 1H), 6.84 (s, 1H), methyl-1- 6.61-6.53 (m, 1H), 4.38-4.24 (m, 1H), tetrahydropyran-4-yl- 4.12 (s, 2H), 3.98-3.94 (m, 2H), 6,7-dihydro-4H- 3.67-3.54 (m, 4H), 3.46 (t, J = 11.2 Hz, 2H), pyrazolo[4,3-c]pyridine- 2.93-2.89 (m, 2H), 2.78-2.74 (m., 2H), 5-carboxamide 2.56 (d, J = 4.0 Hz, 3H), 2.20 (s, 3H), 2.06-1.90 (m, 4H), 1.86-1.80 (m, 2H). Example 3-[7-cyano-6-(3-methyl- 1H NMR (400 MHz, DMSO-d6) δ 8.54 (s, 512 298 4-pyridyl)-3,4-dihydro- 1H), 8.46 (d, J = 4.8 Hz, 1H), 7.22 (d, J = 4.8 Hz, 2H-quinolin-1-yl]-N- 1H), 7.17 (s, 1H), 6.83 (s, 1H), methyl-1- 6.58-6.51 (m, 1H), 4.35-4.27 (m, 1H), tetrahydropyran-4-yl- 4.11 (s, 2H), 3.99-3.91 (m, 2H), 6,7-dihydro-4H- 3.65-3.58 (m, 4H), 3.52-3.41 (m, 2H), pyrazolo[4,3-c]pyridine- 2.92-2.88 (m, 2H), 2.78-2.72 (m, 2H), 2.56 (d, 5-carboxamide J = 4.4 Hz, 3H), 2.18 (s, 3H), 2.04-1.94 (m, 4H), 1.88-1.80 (m, 2H) Example 3-[7-cyano-6-(6-cyano- 1H NMR (400 MHz, DMSO-d6) δ 8.91 (s, 523 299 3-pyridyl)-3,4-dihydro- 1H), 8.23-8.20 (m, 1H), 8.15 (d, J = 8.8 Hz, 2H-quinolin-1-yl]-N- 1H), 7.44 (s, 1H), 6.84 (s, 1H), methyl-1- 6.79 (s, 1H), 6.60-6.51 (m, 1H), tetrahydropyran-4-yl- 4.34-4.30 (m, 1H), 4.07 (s, 2H), 3.95-3.91 (m, 2H), 6,7-dihydro-4H- 3.61-3.58 (m, 4H), 3.47-3.41 (m, 2H), pyrazolo[4,3-c]pyridine- 2.95-2.87 (m, 2H), 2.78-2.72 (m, 2H), 5-carboxamide 2.54 (d, J = 4.4 Hz, 3H), 2.02-1.91 (m, 4H), 1.84-1.81 (m, 2H). -
- To a solution of 3-(7-cyano-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinolin-1(2H)-yl)-N-methyl-1-(tetrahydro-2H-pyran-4-yl)-6, 7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxamide (Intermediate O, 100 mg, 0.2 mmol) in THF (2.5 mL) and water (0.5 mL) was added chloro(2-dicyclohexylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl) palladium(II) (16 mg, 0.02 mmol), 2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (10 mg, 0.02 mmol), 2-bromopyridine (48 mg, 0.3 mmol) and Na2CO3 (66 mg, 0.6 mmol). The mixture was heated to 60° C. for 16 h under a nitrogen atmosphere. After cooling the reaction to room temperature, the mixture was filtered and concentrated in vacuo. DCM (50 mL) was added and the mixture was washed with water (30 mL×3) and brine (30 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by Prep-TLC (DCM/MeOH=20:1) to give the title compound (21 mg, 20%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.66-8.63 (m, 1H), 7.93-7.86 (m, 1H), 7.76 (d, J=7.6 Hz, 1H), 7.59 (s, 1H), 7.39-7.35 (m, 1H), 6.80 (s, 1H), 6.60-6.52 (m, 1H), 4.37-4.27 (m, 1H), 4.08 (s, 2H), 3.99-3.93 (m, 2H), 3.65-3.59 (m, 4H), 3.49-3.43 (m, 2H), 2.95-2.92 (m, 2H), 2.77-2.75 (m, 2H), 2.55 (d, J=4.0 Hz, 3H), 2.03-1.93 (m, 4H), 1.89-1.82 (m, 2H). LCMS M/Z (M+H) 498.
- The following compounds were prepared in a similar fashion to Example 300:
-
-
Example Compound Name NMR m/z Example 3-[7-cyano-6-[2- 1H NMR (400 MHz, DMSO-d6) δ 8.01 (d, 527 301 (methylamino)-4- J = 5.6 Hz, 1H), 7.26 (s, 1H), 6.76 (s, 1H), pyridyl]-3,4-dihydro- 6.59-6.52 (m, 3H), 4.34-4.27 (m, 1H), 2H-quinolin-1-yl]-N- 4.06 (s, 2H), 3.95-3.93 (m, 2H), methyl-1- 3.61-3.56 (m, 4H), 3.47-3.41 (m, 2H), tetrahydropyran-4-yl- 2.92-2.88 (m, 2H), 2.78-2.73 (m, 5H), 2.55 (d, 6,7-dihydro-4H- J = 4.4 Hz, 3H), 1.99-1.83 (m, 4H), pyrazolo[4,3-c]pyridine- 1.82-1.78 (m, 2H). 5-carboxamide Example 3-[7-cyano-6-[4-methyl- 1H NMR (400 MHz, DMSO-d6) δ 569 302 6-(methylcarbamoyl)-3- 8.88-8.80 (m, 1H), 8.41 (s, 1H), 8.01 (s, 1H), pyridyl]-3,4-dihydro- 7.24 (s, 1H), 6.85 (s, 1H), 6.60-6.52 (m, 2H-quinolin-1-yl]-N- 1H), 4.35-4.25 (m, 1H), 4.12 (s, 2H), methyl-1- 3.96-3.93 (m, 2H), 3.69-3.54 (m, 4H), tetrahydropyran-4-yl- 3.46 (t, J = 11.2 Hz, 2H), 2.93-2.91 (m, 6,7-dihydro-4H- 2H), 2.83 (d, J = 4.8 Hz, 3H), pyrazolo[4,3-c]pyridine- 2.75-2.70 (m, 2H), 2.56 (d, J = 4.4 Hz, 3H), 2.29 (s, 5-carboxamide 3H), 2.06-1.90 (m, 4H), 1.88-1.78 (m, 2H) Example 3-[7-cyano-6-[5-methyl- 1H NMR (400 MHz, DMSO-d6) δ 569 303 6-(methylcarbamoyl)-3- 8.67-8.64 (m, 1H), 8.58 (s, 1H), 7.89 (d, J = 1.6 Hz, pyridyl]-3,4-dihydro- 1H), 7.40 (s, 1H), 6.83 (s, 1H), 2H-quinolin-1-yl]-N- 6.60-6.52 (m, 1H), 4.33-4.30 (m, 1H), 4.09 (s, methyl-1- 2H), 3.95-3.90 (m, 2H), 3.63-3.59 (m, tetrahydropyran-4-yl- 4H), 3.46 (t, J = 11.2 Hz, 2H), 6,7-dihydro-4H- 2.93-2.90 (m, 2H), 2.80-2.75 (m, 5H), 2.60 (s, 3H), pyrazolo[4,3-c]pyridine- 2.56 (d, J = 4.0 Hz, 3H), 2.06-1.91 (m, 5-carboxamide 4H), 1.88-1.79 (m, 2H) Example 3-[7-cyano-6-(6-methyl- 1H NMR (400 MHz, DMSO-d6) δ 512 304 2-pyridyl)-3,4-dihydro- 7.81-7.74 (m, 1H), 7.58 (s, 1H), 7.56-7.55 (m, 2H-quinolin-1-yl]-N- 1H), 7.23-7.22 (m, 1H), 6.78 (s, 1H), methyl-1- 6.57-6.56 (m, 1H), 4.37-4.27 (m, 1H), tetrahydropyran-4-yl- 4.07 (s, 2H), 3.97-3.95 (m, 2H), 6,7-dihydro-4H- 3.64-3.59 (m, 4H), 3.49-3.43 (m, 2H), 2.93 (t, pyrazolo[4,3-c]pyridine- J = 6.0 Hz, 2H), 2.81-2.72 (m, 2H), 5-carboxamide 2.55 (d, J = 4.0 Hz, 3H), 2.45 (s, 3H), 2.05-1.92 (m, 4H), 1.88-1.81 (m, 2H) Example 3-[7-cyano-6-(5-methyl- 1H NMR (400 MHz, DMSO-d6) δ 8.47 (s, 512 305 2-pyridyl)-3,4-dihydro- 1H), 7.70-7.63 (m, 2H), 7.54 (s, 1H), 2H-quinolin-1-yl]-N- 6.76 (s, 1H), 6.57-6.51 (m, 1H), methyl-1- 4.33-4.27 (m, 1H), 4.06 (s, 2H), 3.95-3.93 (m, tetrahydropyran-4-yl- 2H), 3.61-3.57 (m, 4H), 3.47-3.44 (m, 6,7-dihydro-4H- 2H), 2.93-2.90 (m, 2H), 2.74-2.73 (m, pyrazolo[4,3-c]pyridine- 2H), 2.53 (d, J = 4.0 Hz, 3H), 2.32 (s, 3H), 5-carboxamide 2.00-1.95 (m, 4H), 1.84-1.81 (m, 2H) Example 3-[7-cyano-6-(4-methyl- 1H NMR (400 MHz, DMSO-d6) δ 8.49 (d, 512 306 2-pyridyl)-3,4-dihydro- J = 4.4 Hz, 1H), 7.62-7.54 (m, 2H), 2H-quinolin-1-yl]-N- 7.20 (d, J = 4.4 Hz, 1H), 6.79 (s, 1H), methyl-1- 6.61-6.53 (m, 1H), 4.35-4.25 (m, 1H), 4.08 (s, tetrahydropyran-4-yl- 2H), 3.97-3.94 (m, 2H), 3.70-3.60 (m, 6,7-dihydro-4H- 4H), 3.46 (t, J = 11.2 Hz, 2H), 2.93 (t, J = 6.0 Hz, pyrazolo[4,3-c]pyridine- 2H), 2.77-2.73 (m, 2H), 2.55 (d, 5-carboxamide J = 4.0 Hz, 3H), 2.38 (s, 3H), 2.05-1.93 (m, 4H), 1.91-1.85 (m, 2H) Example 3-[7-cyano-6-(1,3- 1H NMR (400 MHz, DMSO-d6) δ 7.74 (s, 515 307 dimethylpyrazol-4-yl)- 1H), 7.11 (s, 1H), 6.73 (s, 1H), 3,4-dihydro-2H- 6.57-6.56 (m, 1H), 4.33-4.27 (m, 1H), 4.07 (s, 2H), quinolin-1-yl]-N-methyl- 3.96-3.94 (m, 2H), 3.79 (s, 3H), 1-tetrahydropyran-4-yl- 3.65-3.53 (m, 4H), 3.48-3.43 (m, 2H), 2.87 (t, 6,7-dihydro-4H- J = 6.0 Hz, 2H), 2.78-2.72 (m, 2H), pyrazolo[4,3-c]pyridine- 2.55 (d, J = 4.0 Hz, 3H), 2.14 (s, 3H), 5-carboxamide 2.02-1.90 (m, 4H), 1.84-1.81 (m, 2H) Example 3-[7-cyano-6-(1,5- 1H NMR (400 MHz, DMSO-d6) δ 7.44 (s, 515 308 dimethylpyrazol-4-yl)- 1H), 7.09 (s, 1H), 6.75 (s, 1H), 3,4-dihydro-2H- 6.59-6.55 (m, 1H), 4.34-4.31 (m, 1H), 4.07 (s, 2H), quinolin-1-yl]-N-methyl- 3.95-3.94 (m, 2H), 3.79 (s, 3H), 1-tetrahydropyran-4-yl- 3.64-3.57 (m, 4H), 3.54-3.42 (m, 2H), 6,7-dihydro-4H- 2.79-2.86 (m, 2H), 2.76-2.73 (m, 2H), 2.56 (d, pyrazolo[4,3-c]pyridine- J = 4.0 Hz, 3H), 2.24 (s, 3H), 5-carboxamide 2.04-1.91 (m, 4H), 1.87-1.78 (m, 2H). -
-
- To a solution of 3-(7-cyano-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinolin-1(2H)-yl)-N-methyl-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxamide (Intermediate O, 200 mg, 0.37 mmol) in THF (2.5 mL) and water (0.5 mL) was added chloro(2-dicyclohexylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl) palladium(II) (29 mg, 0.04 mmol), 2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (17 mg, 0.04 mmol), 2,4-dichloropyrimidine (81 mg, 0.55 mmol) and Na2CO3 (78 mg, 0.73 mmol). The mixture was heated to 60° C. for 16 h under a nitrogen atmosphere. After cooling the reaction to room temperature, the mixture was filtered and concentrated in vacuo. DCM (50 mL) was added and the mixture was washed with water (30 mL×3) and brine (30 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (DCM/MeOH=50:1) to give the title compound (180 mg, 92%) as a yellow solid. LCMS M/Z (M+H) 533.
-
- To a solution of 3-(6-(2-chloropyrimidin-4-yl)-7-cyano-3,4-dihydroquinolin-1(2H)-yl)-N-methyl-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxamide (130 mg, 0.24 mmol) in MeOH (2 mL) was added 10% Pd/C (13 mg). The reaction mixture was stirred at 25° C. for 12 h under hydrogen atmosphere (15 psi). The mixture was filtered and concentrated in vacuo. The crude residue was purified by reverse phase chromatography (acetonitrile 22-55%/0.05% NH4OH in water) to give the title compound (14 mg, 12%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 9.23 (s, 1H), 8.87 (d, J=5.6 Hz, 1H), 7.94-7.93 (m, 1H), 7.79 (s, 1H), 6.85 (s, 1H), 6.58-6.57 (m, 1H), 4.39-4.28 (m, 1H), 4.09 (s, 2H), 4.03-3.91 (m, 2H), 3.68-3.59 (m, 4H), 3.51-3.43 (m, 2H), 2.98-2.94 (m, 2H), 2.78-2.76 (m, 2H), 2.56 (d, J=4.0 Hz, 3H), 2.07-1.93 (m, 4H), 1.87-1.81 (m, 2H). LCMS M/Z (M+H) 499.
-
- To a solution of 1-(3-(6-bromo-7-(difluoromethyl)-3,4-dihydroquinolin-1(2H)-yl)-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone (Intermediate P, 210 mg, 0.41 mmol) in THF (5 mL) and water (1 mL) was added N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)acetamide (130 mg, 0.49 mmol), chloro(2-dicyclohexylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl) palladium (II) (32 mg, 0.04 mmol), 2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (20 mg, 0.04 mmol) and Na2CO3 (130 mg, 1.23 mmol). The mixture was heated to 60° C. for 16 h under a nitrogen atmosphere. After cooling the reaction to room temperature, the mixture was concentrated in vacuo. The crude residue was purified by reverse phase chromatography (acetonitrile 30-60%/0.05% NH4OH in water) to give the title compound (131 mg, 56%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.29-8.19 (m, 2H), 8.05-8.03 (m, 1H), 7.69-7.66 (m, 1H), 6.99-6.95 (m, 1H), 6.90 (s, 1H), 6.53-6.23 (m, 1H), 4.28 (s, 1H), 4.16-4.13 (m, 4H), 3.93-3.91 (m, 1H), 3.77-3.72 (m, 3H), 3.56-3.50 (m, 2H), 2.92-2.88 (m, 3H), 2.84-2.77 (m, 1H), 2.33-2.30 (m, 5H), 2.18-2.07 (m, 4H), 1.90-1.87 (m, 2H). LCMS M/Z (M+H) 565.
- The following compounds were prepared in a similar fashion to Example 310:
-
-
Example Compound Name NMR m/z Example 311 1-[3-[7- 1H NMR (400 MHz, CDCl3) δ 8.06 (s, 1H), 537 (difluoromethyl)-6-[6- 7.43-7.41 (m, 1H), 6.98-6.93 (m, 1H), (methylamino)-3- 6.88 (s, 1H), 6.60-6.28 (m, 2H), pyridyl]-3,4-dihydro- 4.66-4.57 (m, 1H), 4.29-4.07 (m, 5H), 3.95-3.90 (m, 2H-quinolin-1-yl]-1- 1H), 3.78-3.69 (m, 3H), 3.58-3.48 (m, tetrahydropyran-4-yl- 2H), 2.98 (d, J = 4.8 Hz, 3H), 6,7-dihydro-4H- 2.91-2.76 (m, 4H), 2.39-2.25 (m, 2H), 2.30-2.17 (m, pyrazolo[4,3- 5H), 1.92-1.85 (m, 2H) c]pyridin-5- yl]ethanone Example 312 1-[3-[7- 1H NMR (400 MHz, CDCl3) δ 8.13 (d, J = 2.0 Hz, 551 (difluoromethyl)-6-[6- 1H), 7.46-7.40 (m, 1H), (dimethylamino)-3- 6.97-6.93 (m, 1H), 6.89 (s, 1H), 6.61-6.29 (m, 2H), pyridyl]-3,4-dihydro- 4.30-4.09 (m, 5H), 3.95-3.89 (m, 1H), 2H-quinolin-1-yl]-1- 3.79-3.74 (m, 3H), 3.58-3.49 (m, 2H), tetrahydropyran-4-yl- 3.13 (s, 6H), 2.93-2.74 (m, 4H), 6,7-dihydro-4H- 2.38-2.26 (m, 2H), 2.19-2.01 (m, 5H), 1.92-1.84 (m, pyrazolo[4,3- 2H) c]pyridin-5- yl]ethanone -
- To a solution of 1-(3-(7-(difluoromethyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinolin-1(2H)-yl)-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone (Intermediate Q, 200 mg, 0.36 mmol) in THF (5 mL) and water (1 mL) was added 3-bromo-1-methyl-pyrazole (58 mg, 0.36 mmol), chloro(2-dicyclohexylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl) palladium (II) (28 mg, 0.04 mmol), Na2CO3 (76 mg, 0.72 mmol) and 2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (17 mg, 0.04 mmol). The mixture was heated to 60° C. for 16 h under a nitrogen atmosphere. After cooling the reaction to room temperature, the mixture was concentrated in vacuo. The crude residue was purified by reverse phase chromatography (acetonitrile 40-70%/0.225% formic acid in water) to give the title compound (13 mg, 7%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.73 (s, 1H), 7.62-7.29 (m, 2H), 6.86 (s, 1H), 6.47 (s, 1H), 4.40-4.24 (m, 1H), 4.22-4.11 (m, 2H), 3.97-3.94 (m, 2H), 3.86 (s, 3H), 3.78-3.67 (m, 2H), 3.63-3.58 (m, 2H), 3.51-3.44 (m, 2H), 2.93-2.75 (m, 4H), 2.07-1.90 (m, 7H), 1.84-1.74 (m, 2H). LCMS M/Z (M+H) 511.
- The following compounds were prepared in a similar fashion to Example 313:
-
-
Example Compound Name NMR m/z Example 314 1-[3-[6-(5-chloro-3- 1H NMR (400 MHz, DMSO-d6) δ 8.62 (d, J = 2.4 Hz, 542 pyridyl)-7- 1H), 8.46 (s, 1H), 7.91-7.84 (m, (difluoromethyl)-3,4- 1H), 7.12 (s, 1H), 6.95-6.62 (m, 2H), dihydro-2H-quinolin- 4.36-4.26 (m, 1H), 4.23-4.14 (m, 2H), 1-yl]-1- 3.97-3.94 (m, 2H), 3.79-3.68 (m, 2H), tetrahydropyran-4-yl- 3.66-3.59 (m, 2H), 3.46 (t, J = 12 Hz, 2H), 6,7-dihydro-4H- 2.94-2.73 (m, 4H), 2.08-1.92 (m, 7H), pyrazolo[4,3- 1.85-1.78 (m, 2H) c]pyridin-5- yl]ethanone Example 315 1-[3-[6-(3-chloro-4- 1H NMR (400 MHz, DMSO-d6) δ 8.71 (s, 542 pyridyl)-7- 1H), 8.54 (d, J = 4.4 Hz, 1H), (difluoromethyl)-3,4- 7.39-7.32 (m, 1H), 6.96 (s, 1H), 6.90-6.83 (m, 1H), dihydro-2H-quinolin- 6.70-6.39 (m, 1H), 4.40-4.28 (m, 1H), 1-yl]-1- 4.23-4.17 (m, 2H), 3.97-3.93 (m, 2H), tetrahydropyran-4-yl- 3.79-3.69 (m, 2H), 3.65-3.60 (m, 2H), 6,7-dihydro-4H- 3.50-3.45 (m, 2H), 2.89-2.75 (m, 4H), pyrazolo[4,3- 2.09-1.92 (m, 7H), 1.85-1.78 (m, 2H) c]pyridin-5- yl]ethanone Example 316 4-[1-(5-acetyl-1- 1H NMR (400 MHz, DMSO-d6) δ 8.75 (d, J = 4.4 Hz, 533 tetrahydropyran-4-yl- 1H), 8.00 (s, 1H), 7.70-7.58 (m, 6,7-dihydro-4H- 1H), 7.18 (s, 1H), 7.05-6.72 (m, 2H), pyrazolo[4,3- 4.40-4.31 (m, 1H), 4.25-4.12 (m, 2H), c]pyridin-3-yl)-7- 3.97-3.93 (m, 2H), 3.80-3.68 (m, 2H), (difluoromethyl)-3,4- 3.65-3.62 (m, 2H), 3.46-3.42 (m, 2H), dihydro-2H-quinolin- 2.94-2.74 (m, 4H), 2.09-1.92 (m, 7H), 6-yl]pyridine-2- 1.85-1.72 (m, 2H) carbonitrile Example 317 1-[3-[7- 1H NMR (400 MHz, CDCl3) δ 522 (difluoromethyl)-6-(2- 8.55-8.49 (m, 1H), 7.13 (s, 1H), 7.08-7.06 (m, 1H), methyl-4-pyridyl)-3,4- 7.02-6.97 (m, 1H), 6.90 (s, 1H), dihydro-2H-quinolin- 6.60-6.26 (m, 1H), 4.32-4.08 (m, 5H), 3.97-3.89 (m, 1-yl]-1- 1H), 3.81-3.69 (m, 3H), 3.54 (t, J = 12.0 Hz, tetrahydropyran-4-yl- 2H), 2.96-2.74 (m, 4H), 2.61 (s, 3H), 6,7-dihydro-4H- 2.37-2.25 (m, 2H), 2.23-2.07 (m, 5H), pyrazolo[4,3- 1.94-1.83 (m, 2H) c]pyridin-5- yl]ethanone -
- To a solution of 3-(6-bromo-7-(difluoromethyl)-3,4-dihydroquinolin-1(2H)-yl)-N-methyl-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5 (4H)-carboxamide (Intermediate R, 100 mg, 0.2 mmol) in THF (2.5 mL) and water (0.5 mL) was added chloro(2-dicyclohexylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl) palladium(II) (16 mg, 0.02 mmol), 2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (9 mg, 0.02 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one (70 mg, 0.3 mmol) and Na2CO3 (42 mg, 0.4 mmol). The mixture was heated to 60° C. for 16 h under a nitrogen atmosphere. After cooling the reaction to room temperature, the mixture was concentrated in vacuo. DCM (50 mL) was added and the mixture was washed with water (30 mL×3) and brine (30 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by reverse phase chromatography (acetonitrile 20-50%/0.05% NH4OH in water) to give the title compound (43 mg, 20%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.73-7.71 (m, 1H), 7.07 (s, 1H), 6.86 (s, 1H), 6.81 (t, J=54.8 Hz, 1H), 6.56-6.55 (m, 1H), 6.24 (s, 1H), 6.20-6.18 (m, 1H), 4.35-4.25 (m, 1H), 4.05 (s, 2H), 3.98-3.91 (m, 2H), 3.61-3.60 (m, 4H), 3.50-3.40 (m, 5H), 2.92-2.72 (m, 4H), 2.55 (d, J=4.0 Hz, 3H), 2.06-1.90 (m, 4H), 1.83-1.81 (m, 2H). LCMS M/Z (M+H) 553.
-
- To a solution of 3-(7-(difluoromethyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinolin-1(2H)-yl)-N-methyl-1-(tetrahydro-2H-pyran-4-yl)-6, 7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxamide (Intermediate S, 100 mg, 0.2 mmol) in THF (2.5 mL) and water (0.5 mL) was added chloro(2-dicyclohexylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl) palladium (II) (16 mg, 0.02 mmol), 2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (9 mg, 0.02 mmol), 3-bromo-1-methyl-pyrazole (48 mg, 0.3 mmol) and Na2CO3 (42 mg, 0.4 mmol). The reaction was heated to 60° C. for 16 h under a nitrogen atmosphere. After cooling the reaction to room temperature, the mixture was concentrated in vacuo. DCM (50 mL) was added and the mixture was washed with water (30 mL×3) and brine (30 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by reverse phase chromatography (acetonitrile 40-70%/0.05% NH4OH in water) to give the title compound (11 mg, 11%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.73 (d, J=2.0 Hz, 1H), 7.44 (t, J=55.6 Hz, 1H), 7.32 (s, 1H), 6.86 (s, 1H), 6.55 (d, J=4.0 Hz, 1H), 6.46 (s, 1H), 4.33-4.23 (m, 1H), 4.02 (s, 2H), 3.95-3.93 (m, 2H), 3.86 (s, 3H), 3.61-3.58 (m, 4H), 3.48-3.42 (m, 2H), 2.89-2.71 (m, 4H), 2.53 (d, J=4.4 Hz, 3H), 2.01-1.93 (m, 4H), 1.82-1.80 (m, 2H). LCMS M/Z (M+H) 526.
- The following compounds were prepared in a similar fashion to Example 319:
-
-
Example Compound Name NMR m/z Example 320 3-[7-(difluoromethyl)- 1H NMR (400 MHz, DMSO-d6) δ 7.50 (s, 540 6-(1,3- 1H), 6.92 (s, 1H), 6.83 (s, 1H), dimethylpyrazol-4-yl)- 6.56-6.39 (m, 2H), 4.34-4.23 (m, 1H), 4.05 (s, 2H), 3,4-dihydro-2H- 3.95-3.93 (m, 2H), 3.77 (s, 3H), quinolin-1-yl]-N- 3.64-3.54 (m, 4H), 3.49-3.40 (m, 2H), 2.87-2.71 (m, methyl-1- 4H), 2.54 (d, J = 4.0 Hz, 3H), 2.05 (s, 3H), tetrahydropyran-4-yl- 2.01-1.91 (m, 4H), 1.82-1.79 (m, 2H) 6,7-dihydro-4H- pyrazolo[4,3- c]pyridine-5- carboxamide Example 321 3-[7-(difluoromethyl)- 1H NMR (400 MHz, DMSO-d6) δ 7.44 (t, J = 56.0 Hz, 540 6-(1,5- 1H), 7.27 (s, 1H), 6.84 (s, 1H), dimethylpyrazol-3-yl)- 6.53 (d, J = 4.4 Hz, 1H), 6.26 (s, 1H), 3,4-dihydro-2H- 4.31-4.25 (m, 1H), 4.02 (s, 2H), 3.98-3.91 (m, quinolin-1-yl]-N- 2H), 3.74 (s, 3H), 3.63-3.55 (m, 4H), methyl-1- 3.48-3.42 (m, 2H), 2.87-2.72 (m, 4H), 2.53 (d, J = 4.0 Hz, tetrahydropyran-4-yl- 3H), 2.27 (s, 3H), 2.02-1.92 (m, 6,7-dihydro-4H- 4H), 1.82-1.80 (m, 2H) pyrazolo[4,3- c]pyridine-5- carboxamide -
-
- To a solution of 7-(difluoromethyl)-1,2,3,4-tetrahydroquinoline (422 mg, 2.3 mmol) in dioxane (20 mL) was added tert-butyl 3-bromo-1-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (Intermediate K, 1.0 g, 2.3 mmol), chloro(2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (179 mg, 0.23 mmol), 2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl (107 mg, 0.23 mmol) and t-BuONa (664 mg, 6.9 mmol). The mixture was heated to 120° C. for 16 h under a nitrogen atmosphere. After cooling the reaction to room temperature, the mixture was filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (DCM/MeOH=100:1) to give the title compound (1.1 g, 89%) as a light yellow solid. LCMS M/Z (M+H) 537.
-
- To a solution of tert-butyl 3-(7-(difluoromethyl)-3,4-dihydroquinolin-1(2H)-yl)-1-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-6,7-dihydro 1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (1.1 g, 1.6 mmol) in DCM (10 mL) at 0° C. was added N-bromosuccinimide (281 mg, 1.6 mmol) portionwise. The mixture was stirred at room temperature for 2 h. The mixture was poured into water (20 mL) and extracted with DCM (20 mL×2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (1.32 g, crude) as a brown solid that required no further purification. LCMS M/Z (M+H) 617.
-
- To a solution of tert-butyl 3-(6-bromo-7-(difluoromethyl)-3,4-dihydroquinolin-1(2H)-yl)-1-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-6,7-dihydro 1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (400 mg, 0.65 mmol) in THF (2 mL) and water (0.4 mL) was added Na2CO3 (207 mg, 1.9 mmol), chloro(2-dicyclohexylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl) palladium(II) (51 mg, 0.06 mmol), 2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (32 mg, 0.06 mmol) and 1,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (173 mg, 0.78 mmol). The mixture was heated to 60° C. for 16 h under a nitrogen atmosphere. After cooling the reaction to room temperature, the mixture was concentrated in vacuo. The crude residue was purified by silica gel chromatography (DCM/MeOH=100:3) to give the title compound (240 mg, 59%) as a yellow solid. LCMS M/Z (M+H) 631.
-
- To a solution of tert-butyl 3-(7-(difluoromethyl)-6-(1,5-dimethyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-6, 7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (242 mg, 0.38 mmol) in DCM (2 mL) at 0° C. was added trifluoroacetic acid (0.5 mL, 6.8 mmol) dropwise. The mixture was stirred at 25° C. for 1 h and concentrated in vacuo to give the title compound (212 mg, crude) as a brown oil that required no further purification. LCMS M/Z (M+H) 531.
-
- To a solution of 4-(3-(7-(difluoromethyl)-6-(1,5-dimethyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-
thiopyran 1,1-dioxide (106 mg, 0.2 mmol) in DCM (2 mL) at 0° C. was added triethylamine (0.14 mL, 1.0 mmol) and acetic anhydride (0.02 mL, 0.2 mmol). The mixture was stirred at room temperature for 0.5 h. Water (5 mL) was added and the mixture was extracted with DCM (5 mL×2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by reverse phase chromatography (acetonitrile 28-58%/0.05% NH4OH in water) to give the title compound (16 mg, 14%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.37 (s, 1H), 6.91-6.87 (m, 1H), 6.85 (s, 1H), 6.57-6.27 (m, 1H), 4.34-4.30 (m, 1H), 4.27-4.14 (m, 2H), 3.92-3.91 (m, 1H), 3.86-3.85 (m, 3H), 3.77-3.72 (m, 5H), 3.06-3.03 (m, 2H), 2.89-2.85 (m, 2H), 2.79-2.73 (m, 2H), 2.56-2.51 (m, 4H), 2.20-2.17 (m, 3H), 2.15-2.07 (m, 5H). LCMS M/Z (M+H) 573. - The following compound was prepared in a similar fashion to Example 322:
-
-
Example Compound Name NMR m/z Example 323 1-[3-[7- 1H NMR (400 MHz, DMSO-d6) δ 7.76 (s, 559 (difluoromethyl)-6-(1- 1H), 7.50 (s, 1H), 7.11 (s, 1H), methylpyrazol-4-yl)- 6.94-6.65 (m, 2H), 4.52-4.48 (m, 1H), 4.16-4.11 (m, 3,4-dihydro-2H- 2H), 3.86 (s, 3H), 3.75-3.69 (m, 2H), quinolin-1-yl]-1-(1,1- 3.60-3.58 (m, 2H), 3.35-3.30 (m, 2H), dioxothian-4-yl)-6,7- 3.25-3.22 (m, 2H), 2.84-2.73 (m, 4H), dihydro-4H- 2.43-2.41 (m, 2H), 2.23-2.20 (m, 2H), pyrazolo[4,3- 2.07-1.96 (m, 5H) c]pyridin-5- yl]ethanone -
- To a solution of 4-(3-(7-(difluoromethyl)-6-(1,5-dimethyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4, 5,6, 7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-
thiopyran 1,1-dioxide (106 mg, 0.2 mmol) in DCM (2 mL) at 0° C. was added triethylamine (0.14 mL, 1.0 mmol) and N-methyl-1H-imidazole-1-carboxamide (50 mg, 0.4 mmol). The mixture was stirred at room temperature for 16 h. Water (5 mL) was added and the mixture was extracted with DCM (5 mL×2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by reverse phase chromatography (acetonitrile 29-59%/0.05% NH4OH in water) to give the title compound (8 mg, 7%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.37 (s, 1H), 6.91 (s, 1H), 6.85 (s, 1H), 6.44 (t, J=56.0 Hz, 1H), 4.43-4.42 (m, 1H), 4.33-4.32 (m, 1H), 4.00 (s, 2H), 3.86 (s, 3H), 3.81-3.72 (m, 6H), 3.08-3.05 (m, 2H), 2.87-2.86 (m, 2H), 2.79 (d, J=4.4 Hz, 3H), 2.74-2.72 (m, 2H), 2.56-2.54 (m, 4H), 2.21 (s, 3H), 2.10-2.05 (m, 2H). LCMS M/Z (M+H) 588. - The following compounds were prepared in a similar fashion to Example 324:
-
-
Example Compound Name NMR m/z Example 3-[7-(difluoromethyl)-6- 1H NMR (400 MHz, CDCl3) δ 7.55 (s, 574 325 (1-methylpyrazol-4-yl)- 1H), 7.43 (s, 1H), 7.08 (s, 1H), 6.85 (s, 3,4-dihydro-2H- 1H), 6.57 (t, J = 55.6 Hz, 1H), 4.47-4.38, quinolin-1-yl]-1-(1,1- (m, 1H), 4.35-4.30 (m, 1H), dioxothian-4-yl)-N- 3.97-3.94 (m, 5H), 3.83-3.62 (m, 6H), methyl-6,7-dihydro-4H- 3.10-3.00 (m, 2H), 2.88-2.84 (m, 2H), 2.79 (d, J = 4.4 Hz, pyrazolo[4,3-c]pyridine- 3H), 2.74-2.68 (m, 2H), 5-carboxamide 2.57-2.53 (m, 4H), 2.11-2.06 (m, 2H) Example 3-[7-(difluoromethyl)-6- 1H NMR (400 MHz, CDCl3) δ 7.39 (s, 642 326 [1-methyl-3- 1H), 6.99 (s, 1H), 6.82 (s, 1H), 6.35 (t, J = 55.2 Hz, (trifluoromethyl)pyrazol- 1H), 4.38-4.33 (m, 2H), 4.01 (s, 4-yl]-3,4-dihydro-2H- 3H), 3.95 (s, 2H), 3.81-3.72 (m, 6H), quinolin-1-yl]-1-(1,1- 3.07-3.03 (m, 2H), 2.88-2.84 (m, 2H), dioxothian-4-yl)-N- 2.79 (d, J = 4.0 Hz, 3H), 2.74-2.72 (m, methyl-6,7-dihydro-4H- 2H), 2.57-2.50 (m, 4H), 2.10-2.06 (m, pyrazolo[4,3-c]pyridine- 2H) 5-carboxamide -
-
- To a solution of 7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinoline (370 mg, 1.4 mmol) in dioxane (10 mL) was added tert-butyl 1-(1-acetyl-4-piperidyl)-3-bromo-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate (Intermediate L, 500 mg, 1.2 mmol), dichloro[1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II) (93 mg, 0.12 mmol) and t-BuONa (562 mg, 5.9 mmol). The mixture was heated to 120° C. for 12 h under a nitrogen atmosphere. After cooling the reaction to room temperature, the mixture was concentrated in vacuo. The crude residue was purified by silica gel chromatography (DCM/MeOH=20:1) to give the title compound (300 mg, 42%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 7.75 (s, 1H), 7.49 (s, 1H), 7.10 (s, 1H), 6.92-6.65 (m, 2H), 4.48-4.41 (m, 1H), 4.31 (s, 2H), 4.02 (s, 2H), 3.94-3.90 (m, 1H), 3.86 (s, 3H), 3.61-3.56 (m, 2H), 3.24-3.09 (m, 1H), 2.84-2.74 (m, 4H), 2.73-2.63 (m, 2H), 2.02 (s, 3H), 1.98-1.85 (m, 6H), 1.41-1.37 (m, 9H).
-
- To a solution of tert-butyl 1-(1-acetylpiperidin-4-yl)-3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5 (4H)-carboxylate (300 mg, 0.5 mmol) in DCM (2 mL) at 0° C. was added trifluoroacetic acid (0.4 mL, 4.9 mmol) dropwise. The mixture was stirred at room temperature for 1 h. The mixture was concentrated in vacuo. The crude residue was diluted with DCM (50 mL) and washed with sat. aq. NaHCO3 (30 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (200 mg, 70%) as a white solid that required no further purification. LCMS M/Z (M+H) 510.
-
- To a solution of 1-(4-(3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4, 5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)ethanone (100 mg, 0.17 mmol) in DCM (2 mL) at 0° C. was added triethylamine (0.07 mL, 0.52 mmol) and acetic anhydride (0.021 mL, 0.21 mmol). The mixture was stirred at room temperature for 1 h. The mixture was diluted with DCM (50 mL), and washed with water (40 mL) and brine (40 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by Prep-TLC (DCM/MeOH=20:1) to give the title compound (53 mg, 52%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.75 (s, 1H), 7.50 (s, 1H), 7.10 (s, 1H), 6.94-6.64 (m, 2H), 4.46-4.42 (m, 1H), 4.39-4.26 (m, 1H), 4.21-4.08 (m, 2H), 3.93-3.89 (m, 1H), 3.86 (s, 3H), 3.79-3.65 (m, 2H), 3.63-3.52 (m, 2H), 3.25-3.11 (m, 1H), 2.90-2.83 (m, 3H), 2.80-2.64 (m, 2H), 2.08-1.96 (m, 6H), 1.95-1.83 (m, 5H), 1.80-1.67 (m, 1H). LCMS M/Z (M+H) 552.
-
- To a solution of 1-(4-(3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)ethanone (100 mg, 0.17 mmol) in DCM (3 mL) was added triethylamine (0.07 mL, 0.52 mmol) and N-methyl-1H-imidazole-1-carboxamide (26 mg, 0.21 mmol). The mixture was stirred at room temperature for 3 h. The mixture was diluted with DCM (50 mL), and washed with water (40 mL) and brine (40 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by Prep-TLC (DCM/MeOH=20:1) to give the title compound (29 mg, 29%) as a white solid 1H NMR (400 MHz, DMSO-d6) δ 7.75 (s, 1H), 7.49 (s, 1H), 7.09 (s, 1H), 6.94-6.62 (m, 2H), 6.55 (d, J=4.4 Hz, 1H), 4.45-4.42 (m, 1H), 4.37-4.25 (m, 1H), 4.01 (s, 2H), 3.94-3.87 (m, 1H), 3.86 (s, 3H), 3.66-3.52 (m, 4H), 3.22-3.15 (m, 1H), 2.89-2.78 (m, 2H), 2.78-2.62 (m, 3H), 2.54 (d, J=4.4 Hz, 3H), 2.02 (s, 3H), 2.00-1.81 (m, 5H), 1.79-1.65 (m, 1H). LCMS M/Z (M+H) 567.
- The following compound was prepared in a similar fashion to Example 328:
-
-
Example Compound Name NMR m/z Example 329 1-(1-acetyl-4- 1H NMR (400 MHz, CDCl3) δ 7.57 (s, 1H), 600 piperidyl)-N-methyl-3- 7.45 (s, 1H), 6.77 (s, 1H), 6.52 (s, 1H), [4-methyl-6-(1- 4.78-4.70 (m, 1H), 4.40-4.30 (m, 1H), methylpyrazol-4-yl)-7- 4.17-4.07 (m, 1H), 4.04-3.93 (m, 6H), (trifluoromethyl)-2,3- 3.84-3.76 (m, 4H), 3.49-3.47 (m, 2H), dihydroquinoxalin-1- 3.26-3.20 (m, 1H), 3.00 (s, 3H), 2.81-2.71 (m, yl]-6,7-dihydro-4H- 6H), 2.23-1.90 (m, 7H) pyrazolo[4,3- c]pyridine-5- carboxamide -
-
- To a solution of tert-butyl 3-bromo-1-(1-(oxetan-3-yl)piperidin-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (Intermediate V, 150 mg, 0.34 mmol), 4-methyl-6-(1-methylpyrazol-4-yl)-7-(trifluoromethyl)-2,3-dihydro-1H-quinoxaline (100 mg, 0.34 mmol) and t-BuONa (97 mg, 1.01 mmol) in 1,4-dioxane (4 mL) was added chloro(2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (26 mg, 0.03 mmol) and 2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl (16 mg, 0.03 mmol). The mixture was heated to 120° C. for 16 h under a nitrogen atmosphere. After cooling the reaction to room temperature, the reaction was filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (DCM/MeOH=50/1) to give the title compound (140 mg, 63%) as a yellow oil. LCMS M/Z (M+H) 657.
-
- To a solution of tert-butyl 3-(4-methyl-6-(1-methyl-1H-pyrazol-4-yl)-7-(trifluoromethyl)-3,4-dihydroquinoxalin-1(2H)-yl)-1-(1-(oxetan-3-yl)piperidin-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (140 mg, 0.21 mmol) in DCM (2 mL) at 0° C. was added trifluoroacetic acid (0.32 mL, 4.26 mmol). The mixture was stirred at room temperature for 1 h. The reaction was quenched with sat. aq. NaHCO3 (10 mL) and extracted with DCM (20 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (80 mg, crude) as a brown oil. LCMS M/Z (M+H) 557.
-
- To a solution of 1-methyl-7-(1-methylpyrazol-4-yl)-4-[1-[1-(oxetan-3-yl)-4-piperidyl]-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]-6-(trifluoromethyl)-2,3-dihydroquinoxaline (80 mg, 0.14 mmol) and triethylamine (0.08 mL, 0.57 mmol) in DCM (2 mL) was added N-methyl-1H-imidazole-1-carboxamide (54 mg, 0.43 mmol). The mixture was stirred at room temperature for 16 h. Water (10 mL) was added and extracted with DCM (20 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by reverse phase chromatography (acetonitrile 20-50%/0.05% NH4OH in water) to give the title compound (35 mg, 40%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.75 (s, 1H), 7.46 (s, 1H), 6.77 (s, 1H), 6.58-6.52 (m, 1H), 6.51 (s, 1H), 4.53 (t, J=6.4 Hz, 2H), 4.42 (t, J=6.4 Hz, 2H), 4.12-3.94 (m, 3H), 3.86 (s, 3H), 3.73-3.65 (m, 2H), 3.60-3.57 (m, 2H), 3.49-3.42 (m, 3H), 2.96 (s, 3H), 2.81-2.64 (m, 4H), 2.54-2.52 (m, 3H), 2.07-1.77 (m, 6H). LCMS M/Z (M+H) 614.
- The following compound was prepared in a similar fashion to Example 330:
-
Example 331 3-[7-chloro-6-(1- 1H NMR (400 MHz, DMSO-d6) δ 7.96 (s, 565 methylpyrazol-4-yl)- 1H), 7.67 (s, 1H), 7.19 (s, 1H), 3,4-dihydro-2H- 6.56-6.52 (m, 1H), 6.50 (s, 1H), 4.53 (t, J = 6.8 Hz, quinolin-1-yl]-N- 2H), 4.42 (t, J = 6.4 Hz, 2H), 4.05-4.01 (m, methyl-1-[1-(oxetan- 3H), 3.85 (s, 3H), 3.63-3.50 (m, 4H), 3-yl)-4-piperidyl]-6,7- 3.48-3.46 (m, 1H), 2.83-2.64 (m, 6H), 2.54 (d, dihydro-4H- J = 4.4 Hz., 3H), 2.03-1.78 (m, 8H) pyrazolo[4,3- c]pyridine-5- carboxamide -
-
- A mixture of tert-butyl 3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (Intermediate T, 100 mg, 0.16 mmol) and formic acid (1.48 mL, 40 mmol) was stirred at 16° C. for 16 h. The reaction solution was concentrated in vacuo to give the title compound (80 mg, crude) as a yellow oil that required no further purification. LCMS M/Z (M+H) 515.
-
- To a solution of 7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-1,2,3,4-tetrahydroquinoline (80 mg, 0.16 mmol) in DCM (15 mL) at 16° C. was added triethylamine (0.07 mL, 0.47 mmol) and N-methyl-1H-imidazole-1-carboxamide (39 mg, 0.31 mmol). The mixture was stirred at 16° C. for 16 h. The reaction solution was diluted with DCM (50 mL) and washed with brine (30 mL×3). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by Prep-TLC (DCM/MeOH=20:1) to give the title compound (40 mg, 45%) as a white solid. LCMS M/Z (M+H) 572.
-
- To a solution of 3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-N-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxamide (30 mg, 0.05 mmol) in DCM (10 mL) was added trifluoroacetic acid (1.5 mL, 17.54 mmol). The mixture was stirred at 16° C. for 4 h and concentrated in vacuo. The crude residue was purified by reverse phase chromatography (acetonitrile 15-45%/0.225% formic acid in water) to give the title compound (8 mg, 34%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.63 (s, 1H), 7.51 (s, 1H), 7.17 (s, 1H), 7.01 (s, 1H), 6.61 (t, J=55.6 Hz, 1H), 4.03-4.00 (m, 5H), 3.90 (s, 2H), 3.70 (t, J=5.6 Hz, 2H), 3.02 (t, J=4.0 Hz, 2H), 2.87-2.84 (m, 2H), 2.78 (s, 3H), 2.14-2.11 (m, 2H). LCMS M/Z (M+H) 442.
-
-
- To a solution of tert-butyl 3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (Intermediate U, 2.0 g, 4.13 mmol) in DCM (5 mL) at 0° C. was added trifluoroacetic acid (4.0 mL, 4.13 mmol). The mixture was stirred at 20° C. for 16 h and concentrated in vacuo to give the title compound (2.0 g, crude) as a brown oil that required no further purification. LCMS M/Z (M+H) 385.
-
- To a solution of 7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-1-(4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-1,2,3,4-tetrahydroquinoline (120 mg, 0.31 mmol) in DCM (5 mL) at 0° C. was added triethylamine (0.09 mL, 0.62 mmol) and acetic anhydride (0.04 mL, 0.62 mmol). The mixture was stirred at 20° C. for 1 h. DCM (50 mL) was added and the mixture was washed with water (30 mL×3) and brine (30 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by reverse phase chromatography (acetonitrile 26-56%/0.05% NH4OH in water) to give the title compound (19 mg, 14%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 12.42-12.31 (m, 1H), 7.75 (s, 1H), 7.50 (s, 1H), 7.10 (s, 1H), 6.96-6.62 (m, 2H), 4.21-4.04 (m, 2H), 3.86 (s, 3H), 3.76-3.51 (m, 4H), 2.88-2.66 (m, 4H), 2.07-1.87 (m, 5H). LCMS M/Z (M+H) 427.
-
-
- To a solution of tert-butyl 3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-6, 7-dihydro-1H-pyrazolo[4,3-c]pyri dine-5 (4H)-carboxylate (Intermediate U, 700 mg, 1.44 mmol) in 1,4-dioxane (10 mL) was added benzyl 4-(2-tosylhydrazono)piperidine-1-carboxylate (696 mg, 1.73 mmol), Cs2CO3 (1.04 g, 3.18 mmol) and copper (II) acetylacetonate (38 mg, 0.14 mmol). The mixture was heated to 100° C. for 16 h under a nitrogen atmosphere. After cooling the reaction to room temperature, the mixture was filtered. The filtrate was concentrated in vacuo. The crude residue was purified by silica gel chromatography (DCM/MeOH=20:1) to give the title compound (650 mg, 65%) as a brown solid. LCMS M/Z (M+H) 702.
-
- To a solution of tert-butyl 1-(1-((benzyloxy)carbonyl)piperidin-4-yl)-3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-6,7-dihydro-H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (650 mg, 0.93 mmol) in MeOH (10 mL) was added 10% Pd/C (50 mg). The mixture was stirred at 25° C. for 6 h under a hydrogen atmosphere (15 psi). The mixture was filtered and concentrated in vacuo to give the title compound (420 mg, 80%) as a white solid that required no further purification. LCMS M/Z (M+H) 568
-
- To a solution of tert-butyl 3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1-(piperidin-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (70.0 mg, 0.12 mmol) in MeCN (2 mL) was added triethylamine (0.052 mL, 0.37 mmol) and 2,2,2-trifluoroethyltrifluoromethanesulfonate (0.036 mL, 0.25 mmol). The mixture was stirred at 25° C. for 2 h. Water (10 mL) was added and the mixture was extracted with EtOAc (10 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (70 mg, crude) as a yellow solid that required no further purification. LCMS M/Z (M+H) 650.
-
- To a solution of tert-butyl 3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)-6, 7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (70 mg, 0.11 mmol) in DCM (1 mL) at 0° C. was added trifluoroacetic acid (0.08 mL, 1.1 mmol). The mixture was stirred at 25° C. for 2 h and concentrated in vacuo to give the title compound (50 mg, crude) as a brown oil that required no further purification. LCMS M/Z (M+H) 550.
-
- To a solution of 7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-1-(1-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)-4, 5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-1,2,3,4-tetrahydroquinoline (50 mg, 0.09 mmol) in DCM (3 mL) was added triethylamine (0.038 mL, 0.27 mmol) and N-methyl-1H-imidazole-1-carboxamide (23 mg, 0.18 mmol). The mixture was stirred at 25° C. for 3 h and concentrated in vacuo. The crude residue was purified by reverse phase chromatography (acetonitrile 30-60%/0.225% formic acid in water) to give the title compound (19 mg, 34%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.55 (s, 1H), 7.42 (s, 1H), 7.05 (s, 1H), 6.86 (s, 1H), 6.55 (d, J=55.6 Hz, 1H), 4.39-4.38 (m, 1H), 3.96-3.80 (m, 6H), 3.79-3.72 (m, 4H), 3.13-3.04 (m, 4H), 2.88-2.87 (m, 2H), 2.79-2.75 (m, 5H), 2.58-2.57 (m, 2H), 2.31-2.29 (m, 2H), 2.08-2.07 (m, 2H), 1.91-1.88 (m, 2H). LCMS M/Z (M+H) 607.
- The following compounds were prepared in a similar fashion to Example 334:
-
-
Example Compound Name NMR m/z Example 335 1-[1-(2,2- 1H NMR (400 MHz, CDCl3) δ 7.54 (s, 1H), 589 difluoroethyl)-4- 7.41(s, 1H), 7.04 (s, 1H), 6.86 (s, 1H), 6.55 piperidyl]-3-[7- (t, J = 55.6 Hz, 1H), 6.04-5.74 (m, 1H), (difluoromethyl)-6-(1- 4.40-4.39 (m, 1H), 3.96-3.80 (m, 6H), methylpyrazol-4-yl)- 3.78-3.72 (m, 4H), 3.10-3.07 (m, 2H), 3,4-dihydro-2H- 2.87-2.73 (m, 9H), 2.39-2.25 (m, 4H), quinolin-1-yl]-N- 2.06-2.01 (m, 2H), 1.92-1.90 (m, 2H) methyl-6,7-dihydro- 4H-pyrazolo[4,3- c]pyridine-5- carboxamide Example 336 3-[7-(difluoromethyl)- 1H NMR (400 MHz, CDCl3) δ 7.54 (s, 1H), 581 6-(1-methylpyrazol-4- 7.42 (s, 1H), 7.05 (s, 1H), 6.86 (s, 1H), 6.55 yl)-3,4-dihydro-2H- (d, J = 55.6 Hz, 1H), 4.69-4.62 (m, 4H), quinolin-1-yl]-N- 4.40-4.39 (s, 1H), 3.96-3.95 (m, 6H), methyl-1-[1-(oxetan-3- 3.80-3.72 (m, 4H), 3.54-3.52 (m, 1H), yl)-4-piperidyl]-6,7- 2.89-2.87 (m, 4H), 2.79-2.74 (m, 5H), dihydro-4H- 2.08-2.05 (m, 2H), 1.99-1.93 (m, 6H) pyrazolo[4,3- c]pyridine-5- carboxamide Example 337 3-[7-(difluoromethyl)- 1H NMR (400 MHz, CDCl3) δ 7.54 (s, 1H), 603 6-(1-methylpyrazol-4- 7.42 (s, 1H), 7.06 (s, 1H), 6.87 (s, 1H), 6.55 yl)-3,4-dihydro-2H- (t, J = 55.6 Hz, 1H), 4.44-4.37 (m, 1H), quinolin-1-yl]-N- 4.13-4.03 (m, 1H), 3.99-3.91 (m, 7H), methyl-1-(1- 3.84-3.76 (m, 2H), 3.74-3.70 (m, 2H), methylsulfonyl-4- 2.97 (t, J = 11.2 Hz, 2H), 2.91-2.87 (m, piperidyl)-6,7-dihydro- 2H), 2.85 (s, 3H), 2.79 (d, J = 4.0 Hz, 3H), 4H-pyrazolo[4,3- 2.78-2.72 (m, 2H), 2.38-2.24 (m, 2H), c]pyridine-5- 2.11-2.01 (m, 4H) carboxamide Example 338 (S,S)-3-[7- 1H NMR (400 MHz, CDCl3) δ 7.54 (s, 1H), 540 (difluoromethyl)-6-(1- 7.42 (s, 1H), 7.04 (s, 1H), 6.86 (s, 1H), 6.55 methylpyrazol-4-yl)- (t, J = 55.6 Hz, 1H), 4.41-4.40 (m, 1H), 3,4-dihydro-2H- 4.15-4.12 (m, 2H), 3.97-3.95 (m, 5H), quinolin-1-yl]-N- 3.81-3.72 (m, 4H), 3.58-3.54 (m, 2H), methyl-1-(2- 2.88-2.86 (m, 2H), 2.79-2.74(m, 5H), methyltetrahydropyran- 2.08-2.06 (m, 1H), 1.96-1.70 (m, 5H), 4-yl)-6,7-dihydro-4H- 1.27 (d, J = 6.0 Hz, 3H) pyrazolo[4,3- c]pyridine-5- carboxamide Example 339 (R,R)-3-[7- 1H NMR (400 MHz, CDCl3) δ 7.54 (s, 1H), 540 (difluoromethyl)-6-(1- 7.41 (s, 1H), 7.04 (s, 1H), 6.86 (s, 1H), 6.54 methylpyrazol-4-yl)- (t, J = 55.6 Hz, 1H), 4.40-4.39 (m, 1H), 3,4-dihydro-2H- 4.15-4.12 (m, 2H), 3.97-3.95 (m, 5H), quinolin-1-yl]-N- 3.81-3.72 (m, 4H), 3.58-3.54 (m, 2H), methyl-1-(2- 2.87-2.86 (m, 2H), 2.79-2.74 (m, 5H), methyltetrahydropyran- 2.08-2.06 (m, 1H), 1.96-1.70 (m, 5H), 4-yl)-6,7-dihydro-4H- 1.26 (d, J = 6.0 Hz, 3H). pyrazolo[4,3- c]pyridine-5- carboxamide -
-
- To a solution of tert-butyl 3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-6, 7-dihydro-1H-pyrazolo[4,3-c]pyridine-5 (4H)-carboxylate (Intermediates U, 200 mg, 0.41 mmol) in DCM (8 mL) was added phenylboronic acid (50 mg, 0.41 mmol), copper(II) acetate (75 mg, 0.41 mmol) and triethylamine (0.139 mL, 1 mmol). The mixture was stirred at room temperature for 16 h under an oxygen atmosphere (15 psi). Water (10 mL) was added and extracted with EtOAc (15 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc=1:1) to give the title compound (135 mg, 58%) as colorless oil. LCMS M/Z (M+H) 561.
-
- To a solution of tert-butyl 3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1-phenyl-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5 (4H)-carboxylate (135 mg, 0.24 mmol) in DCM (2 mL) at 0° C. was added trifluoroacetic acid (1.8 mL, 24.1 mmol). The mixture was stirred at 25° C. for 2 h and concentrated in vacuo to give the title compound (110 mg, crude) as a brown oil that required no further purification. LCMS M/Z (M+H) 461.
-
- To a solution of 7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-1-(1-phenyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-1,2,3,4-tetrahydroquinoline (110 mg, 0.24 mmol) in DCM (2 mL) was added triethylamine (0.1 mL, 0.72 mmol) and N-methyl-1H-imidazole-1-carboxamide (60 mg, 0.48 mmol). The mixture was stirred at 25° C. for 16 h and concentrated in vacuo. The crude residue was purified by reverse phase chromatography (acetonitrile 23-53%/0.225% formic acid in water) to give the title compound (37 mg, 29%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.57 (s, 1H), 7.52-7.44 (m, 5H), 7.36-7.29 (m, 1H), 7.09 (s, 1H), 7.00 (s, 1H), 6.73 (t, J=55.2 Hz, 1H), 4.47-4.39 (m, 1H), 4.05 (s, 2H), 3.98 (s, 3H), 3.87 (t, J=5.6 Hz, 2H), 3.77 (t, J=5.6 Hz, 2H), 2.93-2.89 (m, 4H), 2.82 (d, J=4.4 Hz, 3H), 2.13-2.09 (m, 2H). LCMS M/Z (M+H) 518.
- The following compounds were prepared in a similar fashion to Example 340:
-
-
Example Compound Name NMR m/z Example 341 3-[7-(difluoromethyl)- 1H NMR (400 MHz, DMSO-d6) δ 8.84 (d, J = 519 6-(1-methylpyrazol-4- 2.4 Hz, 1H), 8.53 (d, J = 4.4 Hz, 1H), 8.01 yl)-3,4-dihydro-2H- (d, J = 8.4 Hz, 1H), 7.77 (s, 1H), 7.55-7.52 quinolin-1-yl]-N- (m, 2H), 7.15 (s, 1H), 6.91 (s, 1H), 6.83 (t, J = methyl-1-(3-pyridyl)- 55.2 Hz, 1H), 6.62-6.57 (m, 1H), 4.07 (s, 6,7-dihydro-4H- 2H), 3.86 (s, 3H), 3.70-3.68 (m, 2H), 3.59- pyrazolo[4,3- 3.57 (m, 2H), 2.92-2.86 (m, 4H), 2.54 (d, J = c]pyridine-5- 4.4 Hz, 3H), 2.01-1.98 (m, 2H). carboxamide Example 342 3-[7-(difluoromethyl)- 1H NMR (400 MHz, CDCl3) δ 8.66 (d, J = 519 6-(1-methylpyrazol-4- 6.0 Hz, 2H), 7.57 (s, 1H), 7.51 (d, J = 6.4 yl)-3,4-dihydro-2H- Hz, 2H), 7.45 (s, 1H), 7.12 (s, 1H), 7.00 (s, quinolin-1-yl]-N- 1H), 6.60 (t, J = 55.6 Hz, 1H), 4.48-4.42 methyl-1-(4-pyridyl)- (m, 1H), 4.02 (s, 2H), 3.98 (s, 3H), 3.87 (t, J = 6,7-dihydro-4H- 5.6 Hz, 2H), 3.78 (t, J = 5.6 Hz, 2H), 3.08- pyrazolo[4,3- 3.02 (m, 2H), 2.91-2.88 (m, 2H), 2.81 (d, c]pyridine-5- J = 4.4 Hz, 3H), 2.14-2.07 (m, 2H) carboxamide -
-
- To a solution of tert-butyl 3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5 (4H)-carboxylate (Intermediates U, 600 mg, 1.24 mmol) in MeCN (10 mL) was added 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (942 mg, 6.19 mmol) and 1-(2-trimethylsilylethoxymethyl)-2,3-dihydropyridin-6-one (845 mg, 3.71 mmol). The mixture was heated to 100° C. for 48 h. The reaction solution was diluted with EtOAc (150 mL), washed with brine (50 mL×3), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by Prep-TLC (DCM/MeOH=20:1) to give the title compound (400 mg, 45%) as a colorless oil. LCMS M/Z (M+23) 734.
-
- To a solution of tert-butyl 3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1-(2-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (100 mg, 0.14 mmol) in DCM (6 mL) was added trifluoroacetic acid (2 mL, 7.02 mmol). The mixture was stirred at 16° C. for 4 h and concentrated in vacuo. The crude residue was re-dissolved in MeOH (10 mL) and K2CO3 (86 mg, 0.63 mmol) was added. The mixture was stirred at 16° C. for 16 h. The reaction solution was filtered and concentrated in vacuo. The crude residue was purified by Prep-TLC (DCM/MeOH=20:1) to give the title compound (40 mg, 53%) as a white solid. LCMS M/Z (M+H) 482.
-
- To a solution of 4-(3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-2-one (100 mg, 0.21 mmol) in DCM (10 mL) at 0° C. was added triethylamine (0.044 mL, 0.31 mmol) and acetic anhydride (0.02 mL, 0.21 mmol). The mixture was stirred at 0° C. for 1 h. The reaction solution was diluted with DCM (50 mL), washed with brine (30 mL×3), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by reverse phase chromatography (acetonitrile 15-45%/0.225% formic acid in water) to give racemic 4-[5-acetyl-3-[7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-1-yl]piperidin-2-one (30 mg, 28%) as a white solid which was separated by using chiral SFC (AD(250 mm×30 mm, 10 um), I.D., 3 um Mobile phase: ethanol (Neu) in CO2 from 5% to 40%; Flow rate: 80 mL/min) to give (R)-4-[5-acetyl-3-[7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-1-yl]piperidin-2-one (4 mg, first peak) and (S)-4-[5-acetyl-3-[7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-1-yl]piperidin-2-one (4 mg, second peak). Absolute configuration was arbitrarily assigned to each enantiomer. Example 343: 1H NMR (400 MHz, CDCl3) δ 7.55-7.53 (m, 1H), 7.42-7.40 (m, 1H), 7.07-7.01 (m, 1H), 6.89-6.87 (m, 1H), 6.69-6.38 (m, 1H), 5.90-5.82 (m, 1H), 4.48-4.45 (m, 1H), 4.26-4.03 (m, 3H), 3.96 (s, 3H), 3.83-3.68 (m, 3H), 3.47-3.40 (m, 2H), 3.08-3.02 (m, 1H), 2.88-2.74 (m, 5H), 2.37-2.30 (m, 1H), 2.17-2.06 (m, 6H). LCMS M/Z (M+H) 524. Example 344: 1H NMR (400 MHz, CDCl3) δ 7.55-7.53 (m, 1H), 7.42-7.40 (m, 1H), 7.07-7.01 (m, 1H), 6.88-6.87 (m, 1H), 6.69-6.38 (m, 1H), 5.98-5.89 (m, 1H), 4.48-4.45 (m, 1H), 4.26-4.03 (m, 3H), 3.96 (s, 3H), 3.82-3.68 (m, 3H), 3.50-3.40 (m, 2H), 3.08-3.01 (m, 1H), 2.88-2.74 (m, 5H), 2.37-2.31 (m, 1H), 2.17-2.06 (m, 6H). LCMS M/Z (M+H) 524.
-
-
- To a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (5.0 g, 24.84 mmol) in DCM (40 mL) at 0° C. was added triethylamine (10.33 mL, 74.53 mmol) and methanesulfonyl chloride (2.6 mL, 33.44 mmol) dropwise. The mixture was stirred at room temperature for 12 h. The reaction was quenched with water (60 mL) and extracted with DCM (50 mL×2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (7.25 g, crude) as a light yellow solid that required no further purification. 1H NMR (400 MHz, CDCl3) δ 4.93-4.82 (m, 1H), 3.75-3.62 (m, 2H), 3.40-3.23 (m, 2H), 3.04 (s, 3H), 2.00-1.90 (m, 2H), 1.87-1.76 (m, 2H), 1.46 (s, 9H).
-
- To a solution of 1-[3-[7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-yl]ethanone (Example 333, 850 mg, 2.0 mmol) in DMF (10 mL) was added Cs2CO3 (1.30 g, 3.99 mmol) and tert-butyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (835 mg, 2.99 mmol). The mixture was heated to 80° C. for 12 h. After cooling the reaction to room temperature, the mixture was filtered and concentrated in vacuo. The crude residue was purified by reverse phase chromatography (acetonitrile 37-67%/0.05% NH4OH in water) to give the title compound (210 mg, 17%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.55-7.53 (m, 1H), 7.42-7.40 (m, 1H), 7.06-7.00 (m, 1H), 6.86 (s, 1H), 6.68-6.37 (m, 1H), 4.38-4.12 (m, 3H), 4.08-3.99 (m, 1H), 3.96 (s, 3H), 3.95-3.89 (m, 2H), 3.75-3.67 (m, 3H), 2.89-2.70 (m, 6H), 2.17-2.03 (m, 7H), 1.92-1.88 (m, 2H), 1.48 (s, 9H). LCMS M/Z (M+H) 610.
-
- To a solution of tert-butyl 4-(5-acetyl-3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate (80 mg, 0.13 mmol) in DCM (2 mL) at 0° C. was added trifluoroacetic acid (0.1 mL, 1.3 mmol). The mixture was stirred at room temperature for 2 h and concentrated in vacuo to give the title compound (73 mg, crude) as a brown oil that required no further purification. LCMS M/Z (M+H) 510.
-
- To a solution of 1-(3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1-(piperidin-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone (73 mg, 0.14 mmol) in MeCN (2 mL) was added triethylamine (0.06 mL, 0.43 mmol) and 2,2-difluoroethyl trifluoromethanesulfonate (46 mg, 0.21 mmol). The mixture was stirred at room temperature for 3 h and concentrated in vacuo. The crude residue was purified by reverse phase chromatography (acetonitrile 30-60%/0.225% formic acid in water) to give the title compound (19 mg, 23%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.73 (s, 1H), 7.48 (s, 1H), 7.08 (s, 1H), 6.92-6.63 (m, 2H), 6.12 (t, J=56.0 Hz, 1H), 4.15-4.10 (m, 2H), 4.04-3.98 (m, 1H), 3.85 (s, 3H), 3.74-3.62 (m, 2H), 3.58-3.55 (m, 2H), 2.98-2.96 (m, 2H), 2.83-2.70 (m, 6H), 2.34-2.31 (m, 2H), 2.05-1.88 (m, 7H), 1.82-1.79 (m, 2H). LCMS M/Z (M+H) 574.
- The following compound was prepared in a similar fashion to Example 345:
-
-
Example Compound Name NMR m/z Example 346 1-[3-[7- 1H NMR (400 MHz, DMSO-d6) δ 7.70 (s, 592 (difluoromethyl)-6-(1- 1H), 7.47 (s, 1H), 7.10 (s, 1H), 6.82 (s, 1H), methylpyrazol-4-yl)- 6.75 (t, J = 55.6 Hz, 1H), 4.17-4.13 (m, 3,4-dihydro-2H- 3H), 3.87 (s, 3H), 3.73-3.70 (m, 2H), 3.61 quinolin-1-yl]-1-[1- (t, J = 6.0 Hz, 2H), 3.47-3.38 (m, 2H), 3.17- (2,2,2-trifluoroethyl)- 3.13 (m, 2H), 2.89-2.64 (m, 6H), 2.35- 4-piperidyl]-6,7- 1.87 (m, 9H) dihydro-4H- pyrazolo[4,3- c]pyridin-5- yl]ethanone -
- To a solution of 1-(3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1-(piperidin-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone (80 mg, 0.16 mmol) in DCE (2 mL) was added sodium cyanoborohydride (30 mg, 0.47 mmol), AcOH (0.05 mL, 0.87 mmol) and formaldehyde (37% in water, 0.035 mL, 0.47 mmol). The mixture was stirred at room temperature for 1 h. The reaction was quenched with sat. aq. NaHCO3 (10 mL) and the mixture was extracted with DCM (10 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by reverse phase chromatography (acetonitrile 24-54%/0.05% NH4OH in water) to give the title compound (19 mg, 23%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.73 (s, 1H), 7.48 (s, 1H), 7.08 (s, 1H), 6.92-6.62 (m, 2H), 4.15-4.10 (m, 2H), 4.02-3.94 (m, 1H), 3.85 (s, 3H), 3.72-3.65 (m, 2H), 3.60-3.55 (m, 2H), 2.83-2.71 (m, 6H), 2.18 (s, 3H), 2.05-1.90 (m, 9H), 1.84-1.75 (m, 2H). LCMS M/Z (M+H) 524.
-
-
- To a solution of 4,4-difluorocyclohexanol (800 mg, 5.88 mmol) in DCM (10 mL) at 0° C. was added triethylamine (2.44 mL, 17.63 mmol) and methanesulfonyl chloride (0.65 mL, 8.38 mmol) dropwise. The mixture was stirred at room temperature for 12 h. The reaction was quenched with water (30 mL) and the mixture was extracted with DCM (30 mL×2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (1.2 g, 95%) as a light red oil. 1H NMR (400 MHz, CDCl3) δ 4.92-4.91 (m, 1H), 3.05 (s, 3H), 2.15-2.04 (m, 4H), 2.02-1.96 (m, 4H).
-
- To a solution of 1-[3-[7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-yl]ethanone (Example 333, 100 mg, 0.23 mmol) in DMF (3 mL) was added Cs2CO3 (230 mg, 0.71 mmol) and 4,4-difluorocyclohexyl methanesulfonate (75 mg, 0.35 mmol). The mixture was heated to 80° C. for 16 h. After cooling the reaction to room temperature, the mixture was filtered. The filtrate was diluted with EtOAc (20 mL), washed with brine (20 mL×2). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by reverse phase chromatography (acetonitrile 37-67%/0.05% NH4OH in water) to give the title compound (23 mg, 18%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.55-7.53 (m, 1H), 7.42-7.40 (m, 1H), 7.06-7.01 (m, 1H), 6.86 (s, 1H), 6.68-6.38 (m, 1H), 4.29-4.12 (m, 2H), 4.10-4.01 (m, 1H), 3.96 (s, 3H), 3.93-3.66 (m, 4H), 2.93-2.61 (m, 4H), 2.41-2.25 (m, 4H), 2.17-1.81 (m, 9H). LCMS M/Z (M+H) 545.
- The following compounds were prepared in a similar fashion to Example 348:
-
-
Example Compound Name NMR m/z Example 349 1-[3-[7- 1H NMR (400 MHz, CDCl3) δ 7.57-7.54 588 (difluoromethyl)-6-(1- (m, 1H), 7.44-7.39 (m, 1H), 7.07-7.01 (m, methylpyrazol-4-yl)- 1H), 6.90-6.87 (m, 1H), 6.71-6.37 (m, 3,4-dihydro-2H- 1H), 4.28-4.13 (m, 2H), 4.10-4.02 (m, quinolin-1-yl]-1-(1- 1H), 3.99-3.91 (m, 6H), 3.75-3.69 (m, methylsulfonyl-4- 3H), 3.02-2.92 (m, 2H), 2.90-2.83 (m, piperidyl)-6,7- 5H), 2.81-2.71 (m, 2H), 2.39-2.24 (m, dihydro-4H- 2H), 2.17-2.05 (m, 7H) pyrazolo[4,3- c]pyridin-5- yl]ethanone Example 350 1-[3-[6-(1- 1H NMR (400 MHz, DMSO-d6) δ 7.71 (s, 606 methylpyrazol-4-yl)-7- 1H), 7.42 (s, 1H), 7.10 (s, 1H), 6.97-6.93 (trifluoromethyl)-3,4- (m, 1H), 4.25-4.16 (m, 3H), 3.84 (s, 3H), dihydro-2H-quinolin- 3.74-3.55 (m, 6H), 2.89-2.73 (m, 9H), 1-yl]-1-(1- 2.07-1.95 (m, 9H) methylsulfonyl-4- piperidyl)-6,7- dihydro-4H- pyrazolo[4,3- c]pyridin-5- yl]ethanone -
-
- To a solution of 4-(benzyloxy)cyclohexanol (4 g, 19.4 mmol) and triethylamine (5.4 mL, 38.8 mmol) in DCM (20 mL) at 0° C. was added methanesulfonyl chloride (3.5 mL, 44.8 mmol).
- DCM (50 mL) was added and washed with water (40 mL×2). The organic phase was dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (5 g, crude) as a white solid that required no further purification. 1H-NMR (400 MHz, CDCl3) δ 7.35-7.26 (m, 5H), 4.80-4.76 (m, 1H), 4.53 (s, 2H), 3.52-3.48 (m, 1H), 3.01 (s, 3H), 2.11-1.89 (m, 4H), 1.80-1.60 (m, 4H).
-
- To a solution of 1-[3-[7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-yl]ethanone (Example 333, 400 mg, 0.9 mmol) in DMF was added Cs2CO3 (917 mg, 2.8 mmol) and 4-(benzyloxy)cyclohexyl methanesulfonate (320 mg, 1.13 mmol). The mixture was heated to 80° C. for 12 h. After cooling the reaction to room temperature, the mixture was filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc=from 10:1 to 1:1) to give the mixture of title compounds (350 mg, ˜3:1) as a white solid. LCMS M/Z (M+H) 615.
-
- To a solution of 1-(1-(4-(benzyloxy)cyclohexyl)-3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone and 1-(2-(4-(benzyloxy)cyclohexyl)-3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-6,7-dihydro-2H-pyrazolo[4,3-c]pyridin-5 (4H)-yl)ethanone (200 mg, 0.3 mmol) in MeOH (10 mL) was added 10% Pd(OH)2/C (50 mg). The mixture was stirred at room temperature for 9 days under a hydrogen atmosphere (15 psi). The mixture was filtered and concentrated in vacuo. The crude residue was purified by reverse phase chromatography (acetonitrile 20-50%/0.225% formic acid in water) to give (S,S)-1-[3-[7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-1-(4-hydroxycyclohexyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (16 mg, 78% purity) and (R,R)-1-[3-[7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-1-(4-hydroxycyclohexyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (26 mg, 51% purity). The impure compounds were further separated by using chiral SFC (OD (250 mm×30 mm, 10 um), Mobile phase: 30% ethanol (0.05% diethylamine) in CO2, Flow rate: 80 mL/min) to give (S,S)-1-[3-[7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-1-(4-hydroxycyclohexyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (3 mg) as a white solid and (R,R)-1-[3-[7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-1-(4-hydroxycyclohexyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (10 mg) as a white solid, respectively. Example 351: 1H NMR (400 MHz, CDCl3) δ 7.55-7.53 (m, 1H), 7.42-7.39 (m, 1H), 7.08-6.96 (m, 1H), 6.87 (s, 1H), 6.69-6.36 (m, 1H), 4.27-4.12 (m, 2H), 4.11-4.08 (m, 1H), 4.03-3.87 (m, 5H), 3.78-3.68 (m, 2H), 2.94-2.80 (m, 3H), 2.77-2.75 (m, 1H), 2.40-2.30 (m, 2H), 2.21-1.94 (m, 7H), 1.81-1.78 (m, 2H), 1.72-1.69 (m, 2H). LCMS M/Z (M+H) 525. Example 352: 1H NMR (400 MHz, CDCl3) δ 7.55-7.52 (m, 1H), 7.42-7.39 (m, 1H), 7.07-6.96 (m, 1H), 6.87-6.85 (m, 1H), 6.69-6.35 (m, 1H), 4.31-4.10 (m, 2H), 4.01-3.85 (m, 5H), 3.81-3.65 (m, 4H), 2.92-2.72 (m, 4H), 2.22-2.03 (m, 7H), 2.02-1.93 (m, 2H), 1.65-1.61 (m, 2H), 1.53-1.40 (m, 2H). LCMS M/Z (M+H) 525.
-
-
- To a solution of 1-(3-bromo-1-tetrahydropyran-4-yl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl)ethanone (Intermediates I, 0.4 g, 1.2 mmol) in 1,4-dioxane (10 mL) was added 7-chloro-1,2,3,4-tetrahydroquinoline (482 mg, 3 mmol), chloro(2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (95 mg, 0.12 mmol), 2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl (67 mg, 0.12 mmol) and t-BuONa (351 mg, 3.7 mmol). The mixture was heated to 120° C. for 12 h under a nitrogen atmosphere. After cooling the reaction to room temperature, the mixture was filtered and concentrated in vacuo. The crude residue was diluted with DCM (100 mL) and the mixture was washed with water (50 mL×3) and brine (50 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (DCM/MeOH=50:1) to give the title compound (320 mg, 63%) as a yellow solid. LCMS M/Z (M+H) 415.
-
- To a solution of 1-(3-(7-chloro-3,4-dihydroquinolin-1(2H)-yl)-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone (400 mg, 0.37 mmol) in DCM (5 mL) was added N-bromosuccinimide (65 mg, 0.37 mmol) portionwise. The mixture was stirred at 0° C. for 1 h. DCM (50 mL) was added and the mixture was washed with water (30 mL×3) and brine (30 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (480 mg, crude) as a yellow solid. LCMS M/Z (M+H) 495.
-
- To a solution of 1-(3-(6-bromo-7-chloro-3,4-dihydroquinolin-1(2H)-yl)-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone (100 mg, 0.2 mmol) in THF (5 mL) and water (1 mL) was added chloro(2-dicyclohexylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl) palladium(II) (16 mg, 0.02 mmol), 2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (10 mg, 0.02 mmol), N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinamide (81 mg, 0.3 mmol) and Na2CO3 (65 mg, 0.6 mmol). The mixture was heated to 60° C. for 16 h under a nitrogen atmosphere. After cooling the reaction to room temperature, the mixture was filtered and concentrated in vacuo. DCM (50 mL) was added and the mixture was washed with water (30 mL×3) and brine (30 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by reverse phase chromatography (acetonitrile 45-75%/0.05% NH4OH in water) to give the title compound (31 mg, 27%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 8.81-8.79 (m, 1H), 8.67-8.62 (m, 1H), 8.08-7.97 (m, 2H), 7.19 (s, 1H), 6.64-6.55 (m, 1H), 4.36-4.27 (m, 1H), 4.26-4.19 (m, 2H), 3.98-3.95 (m, 2H), 3.81-3.70 (m, 2H), 3.63-3.55 (m, 2H), 3.49-3.43 (m, 2H), 2.91-2.76 (m, 7H), 2.11-1.92 (m, 7H), 1.86-1.83 (m, 2H). LCMS M/Z (M+H) 549.
- The following compound was prepared in a similar fashion to Example 353:
-
-
Example Compound Name NMR m/z Example 354 1-[3-[7-chloro-6-(1- 1H NMR (400 MHz, DMSO-d6) δ 7.96 (s, 495 methylpyrazol-4-yl)-3,4- 1H), 7.68 (s, 1H), 7.20 (s, 1H), 6.54-6.46 dihydro-2H-quinolin-1- (m, 1H), 4.35-4.23 (m, 1H), 4.21-4.13 yl]-1-tetrahydropyran-4- (m, 2H), 3.97-3.94 (m, 2H), 3.85 (s, 3H), yl-6,7-dihydro-4H- 3.80-3.68 (m, 2H), 3.58-3.51 (m, 2H), pyrazolo[4,3-c]pyridin- 3.48-3.42 (m, 2H), 2.91-2.71 (m, 4H), 5-yl]ethanone 2.12-1.90 (m, 7H), 1.84-1.81 (m, 2H) -
-
- To a solution of 1-[3-[7-chloro-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-1-tetrahydropyran-4-yl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (Example 354, 3.8 g, 7.68 mmol) in 1,4-dioxane (150 mL) was added chloro(2-dicyclohexylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl) palladium(II) (604 mg, 0.77 mmol), 2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (366 mg, 0.77 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (5.85 g, 23.03 mmol) and potassium acetate (1.5 g, 15.35 mmol). The mixture was heated to 90° C. for 16 h under a nitrogen atmosphere. After cooling the reaction to room temperature, the mixture was filtered and concentrated in vacuo. EtOAc (150 mL) was added, washed with water (100 mL×3) and brine (100 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (DCM/MeOH=20:1) to give the title compound (1.64 g, 36%) as a brown solid. LCMS M/Z (M+H) 587.
-
- To a solution of 1-(3-(6-(1-methyl-1H-pyrazol-4-yl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinolin-1(2H)-yl)-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone (1.64 g, 2.8 mmol) in THF (30 mL) and water (15 mL) was added sodium periodate (1.79 g, 8.39 mmol) and acetic ammonia (0.65 g, 8.39 mmol). The mixture was stirred at room temperature for 48 h. Water (100 mL) was added and the mixture was extracted with DCM (80 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (DCM/MeOH=20:1) to give the title compound (560 mg, 40%) as a yellow solid. LCMS M/Z (M+H) 505.
-
- To a solution of (1-(5-acetyl-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinolin-7-yl)boronic acid (250 mg, 0.50 mmol) in 1,4-dioxane (3 mL) was added 4-methoxy-N-(oxetan-3-ylideneamino)benzenesulfonamide (127 mg, 0.50 mmol) and cesium carbonate (200 mg, 0.61 mmol). The mixture was heated to 110° C. for 16 h under an argon atmosphere. After cooling the reaction to room temperature, the mixture was filtered and concentrated in vacuo. EtOAc (50 mL) was added and the mixture was washed with water (30 mL×3) and brine (30 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by Prep-TLC (DCM/MeOH=20:1) to give the title compound (12 mg, 5%) as a yellow solid. 1H NMR (400 MHz, CD3OD) δ 7.56-7.48 (m, 1H), 7.37 (s, 1H), 6.95-6.93 (m, 1H), 6.72-6.71 (m, 1H), 4.83-4.75 (m, 2H), 4.60-4.46 (m, 3H), 4.40-4.28 (m, 3H), 4.07-4.04 (m, 2H), 3.91-3.82 (m, 5H), 3.66-3.60 (m, 4H), 2.93-2.84 (m, 4H), 2.30-2.05 (m, 7H), 1.90-1.88 (m, 2H).
-
- Racemic 1-(5-acetyl-1-tetrahydropyran-4-yl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-3-yl)-3-methyl-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinoline-7-carbonitrile (Example 85, 50 mg) was separated using HPLC-chiral normal phase (Chiralpak AD 250×30 mm I.D., 5 um; Mobile Phase A: Heptane; Mobile Phase B: Ethanol w/ 0.1% Formic Acid; Conditions: Isocratic at 20% B; Run; time: 30 minutes; Flow rate: 40 ml/min; Column oven: 40° C.; Wavelength: 254 nm) to afford (R)-1-(5-acetyl-1-tetrahydropyran-4-yl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-3-yl)-3-methyl-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinoline-7-carbonitrile (7.7 mg, first peak) and (S)-1-(5-acetyl-1-tetrahydropyran-4-yl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-3-yl)-3-methyl-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinoline-7-carbonitrile (6.2 mg, second peak). Absolute configuration was arbitrarily assigned to each enantiomer. Example 356: 1H NMR (400 MHz, DMSO-d6) δ 8.06 (s, 1H), 7.79 (s, 1H), 7.35 (s, 1H), 6.73-6.67 (m, 1H), 4.34-4.26 (m, 1H), 4.19-4.16 (m, 2H), 3.97-3.94 (m, 2H), 3.87 (s, 3H), 3.73-3.71 (m, 2H), 3.58-3.48 (m, 2H), 3.35-3.15 (m, 2H), 2.88-2.74 (m, 2H), 2.56-2.54 (m, 2H), 2.08-1.95 (m, 6H), 1.84-1.81 (m, 2H), 1.04-1.02 (m, 3H). LCMS M/Z (M+H) 500. Example 357: 1H NMR (400 MHz, DMSO-d6) δ 8.05 (s, 1H), 7.79 (s, 1H), 7.34 (s, 1H), 6.72-6.68 (m, 1H), 4.34-4.26 (m, 1H), 4.18-4.16 (m, 2H), 3.96-3.93 (m, 2H), 3.87 (s, 3H), 3.73-3.71 (m, 2H), 3.58-3.48 (m, 2H), 3.35-3.15 (m, 2H), 2.88-2.74 (m, 2H), 2.56-2.54 (m, 2H), 2.08-1.95 (m, 6H), 1.84-1.81 (m, 2H), 1.04-1.02 (m, 3H). LCMS M/Z (M+H) 500.
-
- Racemic 3-[7-(difluoromethyl)-4-methyl-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-N-methyl-1-tetrahydropyran-4-yl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxamide (Example 248, 50 mg) was separated using HPLC-chiral normal phase (Chiralpak AD 250×30 mm I.D., 5 um; Mobile Phase A: Heptane; Mobile Phase B: Ethanol w/ 0.1% Formic Acid; Conditions: Isocratic at 20% B; Run; time: 30 minutes; Flow rate: 40 ml/min; Column oven: 40° C.; Wavelength: 254 nm) to afford (R)-3-[7-(difluoromethyl)-4-methyl-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-N-methyl-1-tetrahydropyran-4-yl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxamide (13.7 mg, first peak) and (S)-3-[7-(difluoromethyl)-4-methyl-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-N-methyl-1-tetrahydropyran-4-yl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxamide (29.1 mg, second peak). Absolute configuration was arbitrarily assigned to each enantiomer. Example 358: 1H NMR (400 MHz, DMSO-d6) δ 7.78 (s, 1H), 7.52 (s, 1H), 7.17 (s, 1H), 6.82 (s, 1H), 6.80 (t, J=55.6 Hz, 1H), 6.56-6.52 (m, 1H), 4.34-4.28 (m, 1H), 4.03-3.90 (m, 4H), 3.87 (s, 3H), 3.71-3.51 (m, 4H), 3.48-3.42 (m, 2H), 3.00-2.95 (m, 1H), 2.75-2.72 (m, 2H), 2.53 (d, J=4.0 Hz, 3H), 2.10-1.90 (m, 3H), 1.88-1.68 (m, 3H), 1.32 (d, J=6.8 Hz, 3H). LCMS M/Z (M+H) 540. Example 359: 1H NMR (400 MHz, DMSO-d6) δ 7.77 (s, 1H), 7.51 (s, 1H), 7.17 (s, 1H), 6.82 (s, 1H), 6.79 (t, J=55.6 Hz, 1H), 6.56-6.53 (m, 1H), 4.33-4.28 (m, 1H), 4.03-3.90 (m, 4H), 3.87 (s, 3H), 3.71-3.51 (m, 4H), 3.48-3.42 (m, 2H), 3.00-2.95 (m, 1H), 2.75-2.72 (m, 2H), 2.54 (d, J=4.0 Hz, 3H), 2.10-1.90 (m, 3H), 1.88-1.68 (m, 3H), 1.32 (d, J=6.8 Hz, 3H). LCMS M/Z (M+H) 540.
-
-
- To a vial was added tert-butyl 3-[6-bromo-7-(difluoromethyl)-3,4,4a,8a-tetrahydro-2H-quinolin-1-yl]-1-tetrahydropyran-4-yl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate (Intermediate R, 35.0 mg, 0.0617 mmol), 4,4,5,5-tetramethyl-2-(5-methyl-2-thienyl)-1,3,2-dioxaborolane (20.7 mg, 0.0925 mmol), K2CO3 (39.3 mg, 0.185 mmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (1.7 mg, 0.0037 mmol) and (2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl)]palladium(II) chloride (1.4 mg, 0.0018 mmol). THF (0.4 mL) and water (0.1 mL) were added and the mixture was sparged with an argon ballon before being heated to 100° C. for 16 h under argon atmosphere. After cooling the reaction to room temperature, DCM (1 mL) was added and the reaction was filtered through celeit and concentrated in vacuo to give crude product that was purified by reverse phase preparative HPLC (acetonitrile 50-90%/0.1% formic acid in water) to give the title compound (25.1 mg, 70% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.11 (d, J=1.3 Hz, 1H), 6.99-6.56 (m, 4H), 4.35-4.23 (m, 1H), 4.06 (d, J=1.9 Hz, 2H), 4.00-3.90 (m, 2H), 3.67-3.55 (m, 4H), 3.49-3.41 (m, 2H), 2.88-2.81 (m, 2H), 2.79 (ddddd, J=5.1, 3.6, 3.1, 1.5, 1.0 Hz, 2H), 2.46 (d, J=1.0 Hz, 3H), 2.08-1.91 (m, 4H), 1.82 (d, J=12.7 Hz, 2H), 1.37 (s, 9H). LCMS M/Z (M+H) 585.
-
- To a solution of tert-butyl 3-[7-(difluoromethyl)-6-(5-methyl-2-thienyl)-3,4-dihydro-2H-quinolin-1-yl]-1-tetrahydropyran-4-yl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate (25.1 mg, 0.0429 mmol) in DCM (1.0 mL) at 0° C. was added trifluoroacetic acid (0.5 mL) dropwise. The mixture was stirred at rt for 1.5 h, then concentrated in vacuo to give crude product that was used in the subsequent step without further purification. LCMS M/Z (M+H) 485.
-
- To a solution of 7-(difluoromethyl)-6-(5-methyl-2-thienyl)-1-(1-tetrahydropyran-4-yl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl)-3,4-dihydro-2H-quinoline in DCM (2 mL) was added TEA (23.9 μL, 0.172 mmol) and N-methyl-1H-imidazole-1-carboxamide (11.3 mg, 0.0859 mmol). The mixture was heated in a microwave reactor at 100° C. for 10 min then concentrated in vacuo to give crude product that was purified by reverse phase preparative HPLC (acetonitrile 30-70%/0.1% formic acid in water) to give the title compound (10.5 mg, 45% yield, 2 steps) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.10 (s, 1H), 6.96-6.63 (m, 4H), 6.57-6.50 (m, 1H), 4.30 (td, J=11.1, 5.5 Hz, 1H), 4.04 (s, 2H), 4.00-3.88 (m, 2H), 3.65-3.55 (m, 4H), 3.45 (ddddd, J=11.7, 11.1, 2.0, 1.0, 0.5 Hz, 2H), 2.85 (s, 2H), 2.74 (s, 2H), 2.54 (d, J=4.2 Hz, 3H), 2.46 (d, J=1.0 Hz, 3H), 1.98 (dt, J=11.9, 6.0 Hz, 4H), 1.81 (d, J=11.2 Hz, 2H). LCMS M/Z (M+H) 542.
- The following compounds were prepared in a similar fashion to Example 360:
-
-
Example Compound Name NMR m/z Example 361 3-[6-(2- 1H NMR (400 MHz, DMSO-d6) δ 7.42 (s, 569 cyclopropylthiazol-5- 1H), 7.12 (d, J = 1.3 Hz, 1H), 6.97-6.65 yl)-7-(difluoromethyl)- (m, 2H), 6.54 (q, J = 4.3 Hz, 1H), 4.29 (td, 3,4-dihydro-2H- J = 11.2, 5.5 Hz, 1H), 4.04 (s, 2H), 4.00- quinolin-1-yl]-N- 3.88 (m, 2H), 3.60 (ddddd, J = 4.6, 4.1, 3.1, methyl-1- 2.0, 1.5 Hz, 4H), 3.50-3.42 (m, 2H), 2.88- tetrahydropyran-4-yl- 2.79 (m, 2H), 2.77-2.70 (m, 2H), 2.54 6,7-dihydro-4H- (d, J = 4.3 Hz, 3H), 2.39 (tt, J = 8.2, 4.8 pyrazolo[4,3- Hz, 1H), 1.97 (ddt, J = 17.2, 12.0, 5.7 Hz, c]pyridine-5- 4H), 1.81 (d, J = 12.6 Hz, 2H), 1.16-1.08 carboxamide (m, 2H), 1.01-0.95 (m, 2H). Example 362 3-[7-(difluoromethyl)- 1H NMR (400 MHz, DMSO-d6) δ 7.58 (dd, 528 6-(2-thienyl)-3,4- J = 5.2, 1.1 Hz, 1H), 7.15 (s, 1H), 7.12 (dd, dihydro-2H-quinolin-1- J = 5.2, 3.5 Hz, 1H), 7.01 (dd, J = 3.5, 1.2 yl]-N-methyl-1- Hz, 1H), 6.90 (d, J = 19.1 Hz, 2H), 6.54 (q, tetrahydropyran-4-yl- J = 5.1, 4.6 Hz, 1H), 4.35-4.22 (m, 1H), 6,7-dihydro-4H- 4.05 (s, 2H), 3.97-3.87 (m, 2H), 3.66- pyrazolo[4,3- 3.57 (m, 4H), 3.50-3.42 (m, 2H), 2.87 (t, c]pyridine-5- J = 6.1 Hz, 2H), 2.75 (t, J = 5.7 Hz, 2H), carboxamide 2.55 (d, J = 4.3 Hz, 3H), 2.08-1.89 (m, 4H), 1.82 (d, J = 12.0 Hz, 2H). Example 363 3-[7-(difluoromethyl)- 1H NMR (400 MHz, DMSO-d6) δ 8.52 (s, 554 6-(2- 2H), 7.07 (s, 1H), 6.94-6.60 (m, 2H), 6.60- methoxypyrimidin-5- 6.49 (m, 1H), 4.36-4.23 (m, 1H), 4.10- yl)-3,4-dihydro-2H- 4.01 (m, 2H), 4.00-3.85 (m, 5H), 3.61 (t, quinolin-1-yl]-N- J = 5.3 Hz, 4H), 3.51-3.38 (m, 2H), 2.87 methyl-1- (t, J = 6.3 Hz, 2H), 2.75 (t, J = 5.7 Hz, 2H), tetrahydropyran-4-yl- 2.55 (d, J = 4.2 Hz, 3H), 2.08-1.88 (m, 6,7-dihydro-4H- 4H), 1.86-1.76 (m, 2H). pyrazolo[4,3- c]pyridine-5- carboxamide Example 364 3-[6-(5-cyano-2- 1H NMR (400 MHz, DMSO-d6) δ 7.96 (d, J = 553 thienyl)-7- 3.9 Hz, 1H), 7.23 (s, 1H), 7.17 (d, J = 3.9 (difluoromethyl)-3,4- Hz, 1H), 7.05-6.69 (m, 2H), 6.54 (d, J = dihydro-2H-quinolin-1- 4.5 Hz, 1H), 4.37-4.23 (m, 1H), 4.05 (s, yl]-N-methyl-1- 2H), 4.00-3.89 (m, 2H), 3.66-3.55 (m, tetrahydropyran-4-yl- 4H), 3.49-3.39 (m, 2H), 2.87 (t, J = 6.5 6,7-dihydro-4H- Hz, 2H), 2.75 (t, J = 5.7 Hz, 2H), 2.55 (d, J = pyrazolo[4,3- 4.1 Hz, 3H), 1.98 (dt, J = 11.7, 5.5 Hz, c]pyridine-5- 4H), 1.83 (s, 2H). carboxamide Example 365 3-[6-(5-chloro-2- 1H NMR (400 MHz, DMSO-d6) δ 7.16- 562 thienyl)-7- 7.10 (m, 2H), 6.99-6.68 (m, 3H), 6.53 (t, (difluoromethyl)-3,4- J = 4.4 Hz, 1H), 4.38-4.22 (m, 1H), 4.04 dihydro-2H-quinolin-1- (s, 2H), 3.98-3.86 (m, 2H), 3.60 (td, J = yl]-N-methyl-1- 5.9, 3.3 Hz, 4H), 3.45 (td, J = 11.7, 2.0 Hz, tetrahydropyran-4-yl- 2H), 2.86 (t, J = 6.4 Hz, 2H), 2.75 (t, J = 6,7-dihydro-4H- 5.8 Hz, 2H), 2.54 (d, J = 4.2 Hz, 3H), 2.06- pyrazolo[4,3- 1.90 (m, 4H), 1.87-1.77 (m, 2H). c]pyridine-5- carboxamide Example 366 3-[7-(difluoromethyl)- 1H NMR (400 MHz, DMSO-d6) δ 7.07 (s, 572 6-[2- 1H), 6.96 (s, 1H), 6.95-6.64 (m, 2H), 6.57- (dimethylamino)thiazol- 6.49 (m, 1H), 4.34-4.24 (m, 1H), 4.03 5-yl]-3,4-dihydro-2H- (s, 2H), 4.00-3.90 (m, 2H), 3.59 (q, J = quinolin-1-yl]-N- 5.9 Hz, 4H), 3.51-3.39 (m, 2H), 3.04 (s, methyl-1- 6H), 2.84 (t, J = 6.3 Hz, 2H), 2.76-2.70 tetrahydropyran-4-yl- (m, 2H), 2.54 (d, J = 4.3 Hz, 3H), 2.04- 6,7-dihydro-4H- 1.91 (m, 4H), 1.86-1.71 (m, 2H). pyrazolo[4,3- c]pyridine-5- carboxamide Example 367 3-[7-(difluoromethyl)- 1H NMR (400 MHz, DMSO-d6) δ 7.00 (s, 557 6-(2,4-dimethylthiazol- 1H), 6.85 (s, 1H), 6.72-6.37 (m, 2H), 4.37- 5-yl)-3,4-dihydro-2H- 4.22 (m, 1H), 4.07 (s, 2H), 3.94 (dd, J = quinolin-1-yl]-N- 11.8, 4.3 Hz, 2H), 3.60 (q, J = 5.6 Hz, 4H), methyl-1- 3.45 (td, J = 11.9, 1.9 Hz, 2H), 2.84 (d, J = tetrahydropyran-4-yl- 6.6 Hz, 2H), 2.75 (t, J = 5.7 Hz, 2H), 2.61 6,7-dihydro-4H- (s, 3H), 2.55 (d, J = 4.2 Hz, 3H), 2.10 (s, pyrazolo[4,3- 3H), 2.02-1.91 (m, 4H), 1.85-1.78 (m, c]pyridine-5- 2H). carboxamide Example 368 3-[7-(difluoromethyl)- 1H NMR (400 MHz, DMSO-d6) δ 7.48 (s, 543 6-(2-methylthiazol-5- 1H), 7.12 (s, 1H), 6.97-6.65 (m, 2H), 6.54 yl)-3,4-dihydro-2H- (q, J = 4.3 Hz, 1H), 4.29 (tt, J = 11.2, 4.4 quinolin-1-yl]-N- Hz, 1H), 4.04 (s, 2H), 4.01-3.90 (m, 2H), methyl-1- 3.60 (dq, J = 5.9, 3.4 Hz, 4H), 3.51-3.43 tetrahydropyran-4-yl- (m, 2H), 2.85 (t, J = 6.4 Hz, 2H), 2.75 (t, J = 6,7-dihydro-4H- 5.8 Hz, 2H), 2.66 (s, 3H), 2.54 (d, J = 4.2 pyrazolo[4,3- Hz, 3H), 1.98 (ddd, J = 12.2, 7.5, 5.4 Hz, c]pyridine-5- 4H), 1.81 (dd, J = 13.3, 4.2 Hz, 2H). carboxamide -
- To a vial was added 1-(5-acetyl-1-tetrahydropyran-4-yl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-3-yl)-6-bromo-3,4-dihydro-2H-quinoline-7-carbonitrile (Intermediate M, 15.0 mg, 0.0310 mmol), 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole (10.6 mg, 0.0465 mmol), K3PO4 (19.2 mg, 0.0929 mmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (0.9 mg, 0.002 mmol), (2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl)]palladium(II) chloride (0.7 mg, 0.001 mmol), then THF (0.4 mL) and water (0.1 mL). The mixture was sparged with an argon ballon, and then heated to 100° C. for 1 h under argon atmosphere. After cooling the reaction to room temperature, DCM (1 mL) was added and the reaction was filtered through celite and concentrated in vacuo to give crude product that was purified by reverse phase preparative HPLC (acetonitrile 20-60%/0.1% formic ammonium hydroxide in water) to give the title compound (5.7 mg, 37% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.85 (s, 1H), 7.37 (s, 1H), 6.77 (s, 1H), 4.31 (td, J=11.2, 5.5 Hz, 1H), 4.21 (d, J=10.9 Hz, 2H), 3.96 (d, J=12.7 Hz, 2H), 3.80-3.70 (m, 2H), 3.60 (dt, J=11.0, 5.4 Hz, 2H), 3.55-3.40 (m, 2H), 2.94-2.73 (m, 4H), 2.69 (s, 3H), 2.09 (s, 2H), 2.02-1.94 (m, 5H), 1.84 (d, J=13.0 Hz, 2H). LCMS M/Z (M+H) 503.2.
-
- To a vial was added 6-(1-methylpyrazol-4-yl)-1-(1-tetrahydropyran-4-yl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl)-3,4-dihydro-2H-quinoline (Intermediate XX, 30.3 mg, 0.0724 mmol), 2-bromo-5-methyl-1,3,4-thiadiazole (27.3 mg, 0.145 mmol), dichloro[1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II) (12.1 mg, 0.0145 mmol), t-BuONa (13.9 mg, 0.145 mmol), then 1,4-dioxane (0.4 mL). The mixture was sparged with an argon ballon, and then heated to 120° C. for 16 h under argon atmosphere. After cooling the reaction to room temperature, DCM (1 mL) was added and the reaction was filtered through celite and concentrated in vacuo to give crude product that was purified by reverse phase preparative HPLC (acetonitrile 20-60%/0.1% ammonium hydroxide in water) to give the title compound (10.3 mg, 23% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.92 (d, J=0.8 Hz, 1H), 7.68 (d, J=0.8 Hz, 1H), 7.21 (d, J=2.1 Hz, 1H), 7.11 (dd, J=8.4, 2.2 Hz, 1H), 6.44 (d, J=8.4 Hz, 1H), 4.34-4.24 (m, 1H), 4.11 (s, 2H), 3.95 (d, J=11.6 Hz, 2H), 3.82 (d, J=1.3 Hz, 3H), 3.78 (t, J=5.8 Hz, 2H), 3.62-3.53 (m, 2H), 3.49-3.41 (m, 2H), 2.92 (t, J=5.9 Hz, 2H), 2.81 (t, J=6.2 Hz, 2H), 2.48 (s, 3H), 1.97 (tt, J=11.7, 5.2 Hz, 4H), 1.81 (d, J=12.3 Hz, 2H). LCMS M/Z (M+H) 517.
-
- To a vial was added 6-(1-methylpyrazol-4-yl)-1-(1-tetrahydropyran-4-yl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl)-3,4-dihydro-2H-quinoline (Intermediate J, 30.3 mg, 0.0724 mmol), 2-bromo-5-methyl-1,3,4-oxadiazole (24.8 mg, 0.145 mmol), dichloro[1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II) (12.1 mg, 0.0145 mmol), t-BuONa (13.9 mg, 0.145 mmol), then 1,4-dioxane (0.4 mL). The mixture was sparged with an argon ballon, and then heated to 120° C. for 16 h under argon atmosphere. After cooling the reaction to room temperature, DCM (1 mL) was added and the reaction was filtered through celite and concentrated in vacuo to give crude product which was purified by reverse phase preparative HPLC (acetonitrile 20-60%/0.1% ammonium hydroxide in water) to give the title compound (3.5 mg, 8% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.91 (d, J=0.8 Hz, 1H), 7.67 (d, J=0.8 Hz, 1H), 7.21 (d, J=2.1 Hz, 1H), 7.11 (dd, J=8.4, 2.2 Hz, 1H), 6.42 (d, J=8.4 Hz, 1H), 4.34-4.25 (m, 1H), 4.07 (s, 2H), 3.94 (d, J=4.2 Hz, 2H), 3.82 (s, 3H), 3.73 (t, J=5.8 Hz, 2H), 3.61-3.52 (m, 2H), 3.50-3.43 (m, 2H), 2.90 (t, J=4.5 Hz, 2H), 2.81 (t, J=6.4 Hz, 2H), 2.31 (s, 3H), 2.06-1.90 (m, 4H), 1.81 (dd, J=11.4, 2.4 Hz, 2H). LCMS M/Z (M+H) 501.
-
-
- To a stirred solution of tert-butyl 3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5 (4H)-carboxylate (Intermediate U, 500 mg, 1.03 mmol) in dichloromethane (5 mL) at 0° C. was added trifluoroacetic acid (1.56 g, 13.6 mmol) and the resulting solution was stirred for 2 h at room temperature. The crude mixture was concentrated in vacuo to remove the excess trifluoroacetic acid. The mixture was dissolved in acetonitrile (3.4 mL, 65 mmol) and a 5.25% solution of sodium bicarbonate in water (2.06 mL, 1.34 mmol) was added at room temperature before acetic anhydride (116 mg, 1.14 mmol) was added dropwise at 0° C. The reaction mixture was stirred at 0° C. for 1 h and the reaction mixture was slowly warmed up to room temperature and stirred for an additional 1 h. The reaction mixture was cooled down to 0° C. and acetic anhydride (116 mg, 1.14 mmol) was added dropwise at this temperature. Following the addition, the reaction mixture was slowly warmed up to room temperature and stirred for an additional 16 h. The mixture was concentrated in vacuo. Saturated aqueous NH4Cl solution (60 mL) was added and the mixture was extracted with EtOAc (50 mL×3). The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (1% Et3N in Heptanes/25% MeOH in iPrOAc=3:1) to afford a mixture of products containing the title compound (220 mg, 50%) as a white solid that was used without any further purification in the next step. LCMS M/Z (M+H) 427.
-
- To a vial was added 1-(3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)ethan-1-one (30 mg, 0.070 mmol), (4-(trifluoromethoxy)phenyl)boronic acid (18 mg, 0.085 mmol) and copper(II) acetate (2.6 mg, 0.01407 mmol) in methanol (0.5 mL). The reaction mixture was stirred overnight at room temperature under air. The crude mixture was concentrated in vacuo and partioned between DCM (15 mL) and water (10 mL). The two phases were separated and the aqueous layer was washed with DCM (15 mL). The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated in vacuo. The crude residue was purified by reverse phase chromatography (acetonitrile 30-90%/0.1% NH4OH in water) to give the title compound (7.3 mg, 18%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.83-7.69 (m, 3H), 7.52 (q, J=6.3, 4.8 Hz, 3H), 7.18 (d, J=3.2 Hz, 1H), 7.01-6.63 (m, 2H), 4.19 (d, J=25.8 Hz, 2H), 3.88 (d, J=1.7 Hz, 3H), 3.71 (dq, J=11.9, 6.1 Hz, 4H), 3.05 (t, J=5.7 Hz, 1H), 2.90 (d, J=21.1 Hz, 3H), 2.10 (s, 2H), 2.06-1.81 (m, 3H). LCMS M/Z (M+H) 587.
-
-
- To a stirred solution of oxepan-4-one (500 mg, 4.38 mmol) in methanol (10 mL) was added 4-methylbenzene sulfonohydrazide (841 mg, 4.38 mmol) and the reaction mixture was stirred at room temperature for 4 h. The mixture was concentrated in vacuo. The crude residue was washed with tert-butyl methyl ether (10 mL) to give the title compound (1.10 g, 90%) as white crystals. 1H NMR (400 MHz, CDCl3) δ 7.87-7.80 (m, 2H), 7.30 (d, J=8.1 Hz, 2H), 7.13 (s, 1H), 3.83-3.75 (m, 1H), 3.75-3.68 (m, 2H), 3.68-3.62 (m, 1H), 2.69-2.52 (m, 2H), 2.42 (s, 3H), 2.47-2.33 (m, 2H), 1.89-1.79 (m, 1H), 1.74-1.63 (m, 1H). LCMS M/Z (M+H) 283.
-
- To a stirred solution of tert-butyl 3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-6, 7-dihydro-1H-pyrazolo[4,3-c]pyridine-5 (4H)-carboxylate (Intermediate U, 25 mg, 0.052 mmol) was added 4-methyl-N-(oxepan-4-ylidene)benzenesulfonohydrazide (29 mg, 0.10 mmol), copper(II) acetylacetonate (3 mg, 0.01 mmol) and cesium carbonate (59 mg, 0.18 mmol) in 1,4-dioxane (0.5 mL) and the reaction mixture was stirred at 100° C. for 16 h under a nitrogen atmosphere. The reaction mixture was diluted with DCM (5 mL), filtered through celite and concentrated in vacuo. The brown solid obtained was used without any further purification in the next step. LCMS M/Z (M+H) 583.
-
- To a stirred solution of tert-butyl 3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1-(oxepan-4-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (crude mixture obtained from step 2) in dichloromethane (0.2 mL) at 0° C. was added trifluoroacetic acid (99 mg, 0.87 mmol) and the resulting solution was stirred for 2 h at room temperature. The crude mixture was concentrated in vacuo to remove the excess of trifluoroacetic acid. The black residue was redissolved in dichloromethane (0.2 mL). To this solution was added triethylamine (17 mg, 0.17 mmol) and acetic anhydride (13 mg, 0.12 mmol) and the reaction mixture was stirred at room temperature for an additional 3 h. The mixture was concentrated in vacuo. The crude residue was purified by reverse phase chromatography (acetonitrile 20-60%/0.1% formic acid in water) to give the racemic mixture of the title compounds. Then, the two enantiomers were separated by using chiral SFC (
Chiralcel OJ 250×21.2 mm I.D., 5 m; Supercritical CO2/EtOH (0.1% NH3H2O)=80:20 at 70 mL/min) to give (S)-1-(3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1-(oxepan-4-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)ethan-1-one (3.4 mg, first peak) and (R)-1-(3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1-(oxepan-4-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)ethan-1-one (5.2 mg, second peak). Absolute configuration was arbitrarily assigned to each enantiomer. Example 251: 1H NMR (400 MHz, DMSO-d6) δ 7.75 (s, 1H), 7.49 (s, 1H), 7.10 (d, J=2.7 Hz, 1H), 6.84-6.80 (m, 1H), 6.95-6.58 (m, 1H), 4.38-4.26 (m, 1H), 4.20-4.06 (m, 2H), 3.86 (s, 3H), 3.80-3.54 (m, 8H), 2.84 (q, J=5.8 Hz, 4H), 2.77-2.65 (m, 1H), 2.24-2.11 (m, 1H), 2.11-2.00 (m, 3H), 1.97 (d, J=6.5 Hz, 4H), 1.85-1.69 (m, 2H). LCMS M/Z (M+H) 525. Example 252: 1H NMR (400 MHz, DMSO-d6) δ 7.75 (s, 1H), 7.49 (s, 1H), 7.10 (d, J=2.7 Hz, 1H), 6.84-6.80 (m, 1H), 6.95-6.58 (m, 1H), 4.38-4.26 (m, 1H), 4.20-4.06 (m, 2H), 3.86 (s, 3H), 3.80-3.54 (m, 8H), 2.84 (q, J=5.8 Hz, 4H), 2.77-2.65 (m, 1H), 2.24-2.11 (m, 1H), 2.11-2.00 (m, 3H), 1.97 (d, J=6.5 Hz, 4H), 1.85-1.69 (m, 2H). LCMS M/Z (M+H) 525. -
-
- To a stirred solution of cyclohexanone (1.00 g, 10.2 mmol) in methanol (20 mL) was added 4-methylbenzene sulfonohydrazide (1.96 g, 10.2 mmol) and the reaction mixture was stirred at room temperature for 4 h. A white solid precipitated in the reaction mixture. The solution was cooled down to 0° C. The solid was filtered under vacuum to give the title compound (1.94 g, 72%) as white crystals. 1H NMR (400 MHz, CDCl3) δ 7.87-7.79 (m, 2H), 7.29 (d, J=8.0 Hz, 2H), 7.06 (s, 1H), 2.42 (s, 3H), 2.28-2.16 (m, 4H), 1.69-1.51 (m, 6H). LCMS M/Z (M+H) 267.
-
- To a stirred solution of tert-butyl 3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5 (4H)-carboxylate (Intermediate U, 60 mg, 0.12 mmol) was N-cyclohexylidene-4-methylbenzenesulfonohydrazide (66 mg, 0.25 mmol), copper(II) acetylacetonate (7 mg, 0.025 mmol) and cesium carbonate (141 mg, 0.433 mmol) in 1,4-dioxane (1.2 mL) and the reaction mixture was stirred at 100° C. for 16 h under a nitrogen atmosphere. The reaction mixture was diluted with DCM (5 mL), filtered through celite and concentrated in vacuo. The brown solid obtained was used without any further purification in the next step. LCMS M/Z (M+H) 567.
-
- To a stirred solution of tert-butyl 3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1-(oxepan-4-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (crude mixture obtained from step 2) in dichloromethane (0.4 mL) at 0° C. was added trifluoroacetic acid (200 mg, 1.75 mmol) and the resulting solution was stirred for 2 h at room temperature. The crude mixture was concentrated in vacuo to remove the excess of trifluoroacetic acid The black residue was redissolved in dichloromethane (0.4 mL). To this solution was added triethylamine (35 mg, 0.34 mmol) and N-methyl-1H-imidazole-1-carboxamide (23 mg, 0.17 mmol). The reaction mixture was irradiated in a microwave at 100° C. for 10 min. The mixture was concentrated in vacuo. The crude residue was purified by reverse phase chromatography (acetonitrile 30-70%/0.1% NH4OH in water) to give the title compounds (30 mg, 43% over 2 steps) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.74 (s, 1H), 7.49 (d, J=0.8 Hz, 1H), 7.08 (s, 1H), 6.80 (s, 1H), 6.77 (t, J=55.3 Hz, 1H), 6.52 (q, J=4.3 Hz, 1H), 4.06-3.94 (m, 3H), 3.86 (s, 3H), 3.63-3.53 (m, 4H), 2.88-2.80 (m, 2H), 2.71 (t, J=5.8 Hz, 2H), 2.54 (d, J=4.2 Hz, 3H), 2.03-1.92 (m, 2H), 1.90-1.59 (m, 7H), 1.45-1.31 (m, 2H), 1.18 (q, J=13.3 Hz, 1H). LCMS M/Z (M+H) 524.
- The following compounds were prepared in a similar fashion to Example 375:
-
-
Example Compound Name NMR m/z Example 376 1-(1-(cyanomethyl)piperidin- 1H NMR (400 MHz, DMSO-d6) δ 564 4-yl)-3-(7-(difluoromethyl)-6- 7.74 (s, 1H), 7.49 (d, J = 0.8 Hz, (1-methyl-1H-pyrazol-4-yl)- 1H), 7.09 (s, 1H), 6.83 (s, 1H), 6.77 3,4-dihydroquinolin-1(2H)- (t, J = 55.4 Hz, 1H), 6.53 (q, J = 4.3 yl)-N-methyl-1,4,6,7- Hz, 1H), 4.13-3.99 (m, 3H), 3.86 tetrahydro-5H-pyrazolo[4,3- (s, 3H), 3.76 (s, 2H), 3.58 (q, J = 5.7 c]pyridine-5-carboxamide Hz, 4H), 2.93-2.80 (m, 4H), 2.73 (t, J = 5.7 Hz, 2H), 2.54 (d, J = 4.2 Hz, 3H), 2.41-2.30 (m, 2H), 2.10- 1.92 (m, 4H), 1.92-1.84 (m, 2H). Example 377 1-(1- 1H NMR (400 MHz, DMSO-d6, 36/ 593 (cyclopropanecarbonyl)piperidin- 38 H) δ 7.74 (s, 1H), 7.49 (s, 1H), 4-yl)-3-(7-(difluoromethyl)- 7.09 (s, 1H), 6.80 (s, 1H), 6.79 (t, J = 6-(1-methyl-1H-pyrazol-4-yl)- 55.2 Hz, 1H), 6.53 (q, J = 4.3 Hz, 3,4-dihydroquinolin-1(2H)- 1H), 4.58-4.29 (m, 3H), 4.02 (s, yl)-N-methyl-1,4,6,7- 2H), 3.86 (s, 3H), 3.59 (dt, J = 14.0, tetrahydro-5H-pyrazolo[4,3- 5.7 Hz, 4H), 2.83 (t, J = 6.4 Hz, 2H), c]pyridine-5-carboxamide 2.75 (t, J = 5.9 Hz, 2H), 2.54 (d, J = 4.2 Hz, 3H), 2.06-1.84 (m, 6H), 1.74 (s, 1H), 0.71 (tt, J = 7.9, 2.9 Hz, 4H). Example 378 3-(7-(difluoromethyl)-6-(1- 1H NMR (400 MHz, DMSO-d6) δ 484 methyl-1H-pyrazol-4-yl)-3,4- 7.74 (d, J = 0.8 Hz, 1H), 7.49 (d, J = dihydroquinolin-1(2H)-yl)-1- 0.8 Hz, 1H), 7.09 (s, 1H), 6.83 (s, isopropyl-N-methyl-1,4,6,7- 1H), 6.77 (s, 1H), 6.53 (p, J = 4.4, tetrahydro-5H-pyrazolo[4,3- 3.9 Hz, 1H), 4.39 (hept, J = 6.6 Hz, c]pyridine-5-carboxamide 1H), 4.02 (s, 2H), 3.86 (s, 3H), 3.58 (q, J = 5.8 Hz, 4H), 2.88-2.80 (m, 2H), 2.71 (t, J = 5.7 Hz, 2H), 2.54 (d, J = 4.2 Hz, 3H), 2.03-1.92 (m, 2H), 1.35 (d, J = 6.6 Hz, 6H). -
- To a stirred solution of tert-butyl 3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1-(oxepan-4-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (crude mixture obtained from
step 2 of Examples 373 & 374) in dichloromethane (0.2 mL) at 0° C. was added trifluoroacetic acid (99 mg, 0.87 mmol) and the resulting solution was stirred for 2 h at room temperature. The crude mixture was concentrated in vacuo to remove the excess trifluoroacetic acid. The black residue was redissolved in dichloromethane (0.2 mL). To this solution was added triethylamine (17 mg, 0.17 mmol) and N-methyl-1H-imidazole-1-carboxamide (11 mg, 0.083 mmol). The reaction mixture was irradiated in a microwave at 100° C. for 10 min. The mixture was concentrated in vacuo. The crude residue was purified by reverse phase chromatography (acetonitrile 20-60%/0.1% formic acid in water) to give the racemic mixture of the title compounds. Then, the two enantiomers were separated by using chiral SFC (Phenomenex Cellulose-3 250×21.2 mm I.D., 5 m; Supercritical CO2/EtOH (0.1% NH3H2O)=85:15 at 70 mL/min) to give (S)-3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-N-methyl-1-(oxepan-4-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxamide (6.5 mg, first peak) and (R)-3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-N-methyl-1-(oxepan-4-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxamide (6.0 mg, second peak). Absolute configuration was arbitrarily assigned to each enantiomer. Example 379: 1H NMR (400 MHz, DMSO-d6) δ 7.74 (s, 1H), 7.49 (d, J=0.8 Hz, 1H), 7.09 (s, 1H), 6.82 (s, 1H), 6.77 (t, J=55.2 Hz, 1H), 6.52 (q, J=4.3 Hz, 1H), 4.32 (tt, J=9.3, 4.4 Hz, 1H), 4.02 (s, 2H), 3.86 (s, 3H), 3.80-3.69 (m, 2H), 3.69-3.52 (m, 6H), 2.88-2.80 (m, 2H), 2.72 (t, J=5.7 Hz, 2H), 2.54 (d, J=4.2 Hz, 3H), 2.21-1.86 (m, 6H), 1.85-1.66 (m, 2H). LCMS M/Z (M+H) 540. Example 380: 1H NMR (400 MHz, DMSO-d6) δ 7.74 (s, 1H), 7.49 (d, J=0.8 Hz, 1H), 7.09 (s, 1H), 6.82 (s, 1H), 6.77 (t, J=55.2 Hz, 1H), 6.52 (q, J=4.3 Hz, 1H), 4.32 (tt, J=9.3, 4.4 Hz, 1H), 4.02 (s, 2H), 3.86 (s, 3H), 3.80-3.69 (m, 2H), 3.69-3.52 (m, 6H), 2.88-2.80 (m, 2H), 2.72 (t, J=5.7 Hz, 2H), 2.54 (d, J=4.2 Hz, 3H), 2.21-1.86 (m, 6H), 1.85-1.66 (m, 2H). LCMS M/Z (M+H) 540. - The following compounds were prepared in a similar fashion to Example 379 & 380:
-
-
Example Compound Name NMR m/z Example 381 (R)-1-(1-cyclopropylethyl)-3- 1H NMR (400 MHz, DMSO-d6) δ 510 (7-(difluoromethyl)-6-(1- 7.74 (s, 1H), 7.49 (d, J = 0.8 Hz, methyl-1H-pyrazol-4-yl)-3,4- 1H), 7.08 (s, 1H), 6.86 (s, 1H), 6.77 dihydroquinolin-1(2H)-yl)-N- (t, J = 55.2 Hz, 1H), 6.52 (q, J = 4.3 methyl-1,4,6,7-tetrahydro-5H- Hz, 1H), 4.12-3.96 (m, 2H), 3.86 pyrazolo[4,3-c]pyridine-5- (s, 3H), 3.70-3.47 (m, 5H), 2.84 (t, carboxamide J = 6.1 Hz, 2H), 2.74-2.60 (m, 2H), 2.54 (d, J = 4.2 Hz, 3H), 1.99 (p, J = 6.3 Hz, 2H), 1.45 (d, J = 6.6 Hz, 3H), 1.26 (ddt, J = 13.3, 8.2, 4.4 Hz, 1H), 0.60-0.49 (m, 1H), 0.44- 0.34 (m, 1H), 0.28 (dt, J = 4.8, 2.5 Hz, 2H). Example 382 (S)-1-(1-cyclopropylethyl)-3- 1H NMR (400 MHz, DMSO-d6) δ 510 (7-(difluoromethyl)-6-(1- 7.74 (s, 1H), 7.49 (d, J = 0.8 Hz, methyl-1H-pyrazol-4-yl)-3,4- 1H), 7.08 (s, 1H), 6.86 (s, 1H), 6.77 dihydroquinolin-1(2H)-yl)-N- (t, J = 55.2 Hz, 1H), 6.52 (q, J = 4.3 methyl-1,4,6,7-tetrahydro-5H- Hz, 1H), 4.12-3.96 (m, 2H), 3.86 pyrazolo[4,3-c]pyridine-5- (s, 3H), 3.70-3.47 (m, 5H), 2.84 (t, carboxamide J = 6.1 Hz, 2H), 2.74-2.60 (m, 2H), 2.54 (d, J = 4.2 Hz, 3H), 1.99 (p, J = 6.3 Hz, 2H), 1.45 (d, J = 6.6 Hz, 3H), 1.26 (ddt, J = 13.3, 8.2, 4.4 Hz, 1H), 0.60-0.49 (m, 1H), 0.44- 0.34 (m, 1H), 0.28 (dt, J = 4.8, 2.5 Hz, 2H). Example 383 3-(7-(difluoromethyl)-6-(1- 1H NMR (400 MHz, DMSO-d6) δ 554 methyl-1H-pyrazol-4-yl)-3,4- 7.74 (s, 1H), 7.49 (s, 1H), 7.09 (s, dihydroquinolin-1(2H)-yl)-1- 1H), 6.79 (s, 0H), 6.77 (t, J = 55.2 ((Z)-4-methoxycyclohexyl)-N- Hz, 1H), 6.76 (s, 1H), 6.52 (q, J = methyl-1,4,6,7-tetrahydro-5H- 4.4 Hz, 1H), 4.11-4.03 (m, 1H), pyrazolo[4,3-c]pyridine-5- 4.01 (s, 2H), 3.86 (s, 3H), 3.64- carboxamide 3.39 (m, 4H), 3.23-3.20 (m, 3H), 2.88-2.80 (m, 2H), 2.70 (t, J = 5.6 Hz, 2H), 2.54 (d, J = 4.3 Hz, 3H), 2.10-1.92 (m, 6H), 1.66-1.45 (m, 4H). Example 384 3-(7-(difluoromethyl)-6-(1- 1H NMR (400 MHz, DMSO-d6) δ 554 methyl-1H-pyrazol-4-yl)-3,4- 7.74 (s, 1H), 7.49 (d, J = 0.8 Hz, dihydroquinolin-1(2H)-yl)-1- 1H), 7.09 (s, 1H), 6.79 (s, 1H), 6.77 ((E)-4-methoxycyclohexyl)- (t, J = 55.2 Hz, 1H), 6.52 (q, J = 4.3 N-methyl-1,4,6,7-tetrahydro- Hz, 1H), 4.11-4.01 (m, 1H), 4.01 5H-pyrazolo[4,3-c]pyridine-5- (s, 2H), 3.86 (s, 3H), 3.57 (dt, J = carboxamide 8.3, 5.6 Hz, 4H), 3.25 (s, 3H), 3.25- 3.11 (m, 1H), 2.84 (t, J = 6.8 Hz, 2H), 2.71 (t, J = 5.7 Hz, 2H), 2.54 (d, J = 4.2 Hz, 3H), 2.12-2.04 (m, 2H), 2.01-1.93 (m, 2H), 1.93- 1.74 (m, 4H), 1.29 (qd, J = 12.9, 4.0 Hz, 2H). Example 385 1-((Z)-4-cyanocyclohexyl)-3- 1H NMR (400 MHz, DMSO-d6) δ 549 (7-(difluoromethyl)-6-(1- 7.75 (s, 1H), 7.49 (d, J = 0.8 Hz, methyl-1H-pyrazol-4-yl)-3,4- 1H), 7.09 (s, 1H), 6.78 (s, 1H), 6.77 dihydroquinolin-1(2H)-yl)-N- (t, J = 55.2 Hz, 1H), 6.53 (q, J = 4.3 methyl-1,4,6,7-tetrahydro-5H- Hz, 1H), 4.14-4.03 (m, 1H), 4.01 pyrazolo[4,3-c]pyridine-5- (s, 2H), 3.86 (s, 3H), 3.59 (td, J = carboxamide 5.9, 2.8 Hz, 4H), 3.17 (q, J = 3.8 Hz, 1H), 2.85 (t, J = 6.3 Hz, 2H), 2.71 (t, J = 5.7 Hz, 2H), 2.54 (d, J = 4.3 Hz, 3H), 1.99 (dd, J = 10.7, 4.4 Hz, 6H), 1.91 (dt, J = 13.7, 6.0 Hz, 2H), 1.81-1.69 (m, 2H). Example 386 1-((E)-4-cyanocyclohexyl)-3- 1H NMR (400 MHz, DMSO-d6) δ 549 (7-(difluoromethyl)-6-(1- 7.74 (d, J = 0.8 Hz, 1H), 7.49 (d, J = methyl-1H-pyrazol-4-yl)-3,4- 0.8 Hz, 1H), 7.09 (s, 1H), 6.77 (t, J = dihydroquinolin-1(2H)-yl)-N- 55.2 Hz, 1H), 6.75 (s, 1H), 6.52 methyl-1,4,6,7-tetrahydro-5H- (q, J = 4.3 Hz, 1H), 4.09 (tt, J = pyrazolo[4,3-c]pyridine-5- 11.0, 4.2 Hz, 1H), 4.00 (s, 2H), 3.86 carboxamide (s, 3H), 3.57 (dt, J = 11.3, 5.7 Hz, 4H), 2.87-2.76 (m, 3H), 2.76- 2.65 (m, 2H), 2.53 (d, J = 4.2 Hz, 3H), 2.17-2.07 (m, 2H), 2.02- 1.62 (m, 8H). - His/Flag epitope tagged CBP was cloned, expressed, and purified to homogeneity. CBP binding and inhibition was assessed by monitoring the engagement of a biotinylated small molecule compound with the target using the TR-FRET assay technology (Perkin-Elmer). Specifically, in a 384 well ProxiPlate CBP (4 nM final) was combined with biotin-ligand (60 nM final) in 50 mM HEPES (pH 7.5), 50 mM NaCl, 1 mM TCEP, 0.01% (w/v) BSA, and 0.008% (w/v) Brij-35 either in the presence of DMSO (final 0.2% DMSO) or compound dilution series in DMSO. After 10 minutes incubation at room temperature, a mixture Eu-W1024 Anti-6×His antibody (Perkin Elmer ADO 110) and SureLight™ Allophycocyanin-Streptavidin (APC-SA, Perkin Elmer CR130-100) were added to a final concentrations of 0.2 nMolar antibody and 50 nMolar APC-SA, respectively. After twenty minutes of equilibration, the plates were read on an Envision instrument and IC50s calculated using a four parameter non-linear curve fit.
- His/Flag epitope-tagged BRD4 BD1 (bromo domain 1) was cloned, expressed, and purified to homogeneity. BRD4 BD1 binding and inhibition were assessed by monitoring the engagement of a biotinylated small molecule compound with the target using TR-FRET assay technology (PerkinElmer). Specifically, BRD4 BD1 (2.5 nM final) in 50 mM HEPES (pH 7.5), 50 mM NaCl, 1 mM TCEP, 0.01% (w/v) BSA, and 0.008% (w/v) Brij-35 was added to the wells of a 384-well white ProxiPlate containing DMSO alone or compound dilution series in DMSO (final 0.2% DMSO). After 10 minutes of incubation at room temperature, biotin-ligand (25 nM final) was added and allowed to incubate for an additional 10 minutes. Then a mixture of Eu-W 1024 Anti-6×His antibody (PerkinElmer ADO 110) and SureLight™ Allophycocyanin-Streptavidin (APC-SA, PerkinElmer CR130-100) was added to final concentrations of 0.2 nM antibody and 100 nM APC-SA, respectively. After 40 minutes of equilibration under ambient conditions, the plates were read on an Envision plate reader, and IC50 values were calculated using four-parameter, non-linear curve fitting.
- QuantiGene 2.0 Reagent system, Affymetrix: HUMAN MYCN; V-myc myelocytomatosis viral related oncogene, neuroblastoma derived (avian); NM_005378 SA-15008. 10,000 MV-4-11 cells (GNE in-house) were plated in 75 ul complete media: RPMI-1640 (GNE in-house), 10% FBS (Life Technologies, cat. no. 10082), 1% Pen-strep (GNE in-house), in 96 well clear flat bottom plates (Costar, cat. no. 3595). 25 ul compound was added for 4 hours at 37 deg C. in a 1:3 serial dilution 10-point dose response, with a final DMSO concentration=0.2%. The cells were then lysed according to the assay kit's protocol and frozen at −80 deg C. The following day, an appropriate volume of Working Probe Set was prepared by combining the following reagents in the order listed: Nuclease-free water, Lysis Mixture, Blocking Reagent, and 2.0 Probe Set (MYC or RPL19). 20 ul of the working probe set was added into each assay well on the capture plate, and then 80 ul of the lysates were transferred into the assay plates. The capture plate was placed in a 55 deg C. incubator for overnight hybridization (16-20 hours). The following day, wash buffer was prepared according to manufacturer's recommendations. The capture plates were washed with 300 ul per well of 1× wash buffer three times. Then 100 ul Pre-Amplifier was added to the plate for a 60 minute incubation at 55 deg C. After the incubation, the capture plate was washed with 300 ul per well of 1× wash buffer three times, and 100 ul Amplifier was added to the plate for a 60 minute incubation at 55 deg C. The capture plate was again washed with 300 ul per well of 1× wash buffer three times, and 100 ul Label Probe was added to the plate for a 60 minute incubation at 50 deg C. Then the capture plate was washed with 300 ul per well of 1× wash buffer three times, and 100 ul 2.0 Substrate was added to each well of the plate. The plates were incubated at RT for 5 minutes in the dark and read on the Envision using the luminescence protocol, with an integration time set at 0.2 seconds.
- Data for representative compounds of formula (I) from the three assays described above is provided in the following table (all units in μM).
-
CBP HTRF BRD4 HTRF Myc Example IC50 (μM) IC50 (μM) IC50 (μM) 1 1.181 >20.0 2 1.593 >20.0 3 1.575 >20.0 4 0.627 >20.0 5 0.994 >20.0 6 0.029 >20.0 0.375 7 0.046 >20.0 8 0.050 >20.0 9 0.032 >20.0 5.058 10 0.025 >20.0 2.130 11 0.051 >20.0 12 0.063 9.8 13 0.048 16.7 1.237 14 0.074 >20.0 15 0.026 >20.0 1.350 16 0.115 >20.0 17 0.014 8.8 1.141 18 0.050 >20.0 1.555 19 0.034 >20.0 2.598 20 0.258 >20.0 21 0.071 >20.0 22 0.115 >20.0 23 0.051 1.8 1.711 24 0.035 >20.0 4.647 25 0.107 >20.0 26 0.064 >20.0 27 0.070 >20.0 28 0.063 >20.0 29 0.083 >20.0 30 0.043 >20.0 18.449 31 0.033 >20.0 32 0.021 >20.0 7.043 33 0.009 >20.0 1.583 34 0.058 >20.0 35 0.023 >20.0 0.202 36 0.039 >20.0 1.857 37 0.074 >20.0 38 0.089 >20.0 39 0.187 >20.0 40 0.424 >20.0 41 0.065 >20.0 42 0.054 >20.0 43 0.091 >20.0 44 0.080 >20.0 45 0.237 >20.0 46 0.005 14.5 1.531 47 0.049 18.7 19.238 48 0.004 7.7 0.669 49 0.011 14.3 1.127 50 1.523 >20.0 51 0.007 >20.0 0.729 52 0.020 >20.0 3.277 53 0.011 18.0 0.721 54 0.010 15.2 9.556 55 0.023 >20.0 0.254 56 0.020 18.1 1.845 57 0.008 >20.0 0.037 58 0.004 >20.0 0.199 59 0.004 >20.0 0.188 60 0.001 7.4 0.089 61 0.003 >20.0 62 0.003 >20.0 0.598 63 0.008 >20.0 0.019 64 0.007 >20.0 0.334 65 0.029 18.0 0.401 66 0.020 14.2 4.913 67 0.040 >20.0 0.744 68 0.148 13.7 69 0.070 >20.0 4.860 70 0.024 17.2 1.341 71 0.016 18.2 0.582 72 0.025 >20.0 0.681 73 0.035 >20.0 1.567 74 0.041 >20.0 1.474 75 0.008 >20.0 0.411 76 0.007 >20.0 0.652 77 0.080 >20.0 78 0.021 10.5 3.498 79 0.082 >20.0 80 0.020 12.1 4.749 81 0.024 >20.0 0.280 82 0.019 >20.0 1.338 83 0.024 >20.0 0.830 84 0.006 16.5 0.088 85 0.002 11.4 86 0.030 >20.0 6.103 87 0.041 >20.0 14.335 88 0.031 >20.0 0.354 89 0.057 >20.0 90 0.276 >20.0 91 0.024 >20.0 7.873 92 0.026 >20.0 0.937 93 0.025 >20.0 1.249 94 2.190 >20.0 95 0.005 >20.0 0.474 96 0.511 >20.0 97 0.014 >20.0 0.149 98 0.008 >20.0 0.673 99 0.019 >20.0 5.653 100 0.026 >20.0 0.232 101 0.021 >20.0 0.110 102 0.003 9.7 0.154 103 0.006 >20.0 0.224 104 0.003 16.7 0.085 105 0.012 >20.0 0.364 106 0.031 >20.0 2.148 107 0.073 >20.0 108 0.034 >20.0 5.167 109 0.071 >20.0 110 0.019 >20.0 8.932 111 0.018 >20.0 4.246 112 0.058 >20.0 113 0.023 >20.0 0.250 114 0.016 >20.0 0.126 115 0.019 >20.0 2.622 116 0.101 >20.0 117 0.010 >20.0 0.256 118 0.022 16.0 0.809 119 0.026 >20.0 0.657 120 0.021 18.4 1.500 121 0.001 4.9 0.011 122 0.008 9.4 0.274 123 0.006 3.3 0.233 124 0.001 4.9 0.006 125 0.006 4.3 0.259 126 0.006 8.6 0.087 127 0.006 >20.0 0.693 128 0.001 8.8 0.027 129 0.002 10.6 0.028 130 0.009 >20.0 0.323 131 0.005 19.7 0.051 132 0.015 >20.0 0.737 133 0.005 >20.0 0.047 134 0.005 9.2 0.957 135 0.041 >20.0 1.073 136 0.0646 >20.0 137 0.085 >20.0 138 0.069 >20.0 139 0.159 >20.0 140 0.686 >20.0 141 0.002 11.1 0.206 142 0.008 8.7 1.348 143 0.009 8.8 0.160 144 0.017 >20.0 1.021 145 0.005 1.9 0.055 146 0.001 1.9 0.051 147 0.004 7.9 0.135 148 0.001 2.3 0.023 149 0.001 2.9 0.004 150 0.017 >20.0 14.416 151 0.058 >20.0 152 0.002 7.9 0.072 153 0.0034 >20.0 0.119 154 0.001 9.8 0.017 155 0.001 10.9 0.014 156 0.004 14.3 0.706 157 0.001 5.4 0.015 158 0.002 11.5 0.046 159 0.001 11.2 0.016 160 0.003 >20.0 0.150 161 0.001 4.3 0.009 162 0.001 6.3 0.004 163 0.001 5.8 0.005 164 0.001 7.8 0.018 165 0.001 8.9 0.013 166 3.218 13.1 167 0.001 3.5 0.237 168 0.025 6.5 0.478 169 0.041 11.8 0.980 170 0.011 1.5 0.499 171 0.043 8.4 2.947 172 0.128 14.4 1.691 173 0.757 >20.0 174 0.027 4.6 0.478 175 0.068 13.5 176 0.038 5.8 0.523 177 0.0688 7.6 0.892 178 0.040 4.0 0.209 179 0.015 2.0 2.457 180 0.015 2.6 0.549 181 0.025 3.7 0.188 182 0.018 1.7 0.135 183 0.016 2.1 0.667 184 0.021 3.2 0.982 185 0.025 5.0 0.565 186 0.032 6.9 1.282 187 0.025 3.6 0.284 188 0.027 5.1 1.311 189 0.026 4.3 1.760 190 0.025 9.2 0.562 191 0.016 7.2 0.329 192 0.034 12.8 0.745 193 0.219 12.0 194 0.031 7.0 0.915 195 0.161 9.1 196 0.027 3.6 3.599 197 0.023 3.9 1.575 198 0.137 7.7 199 0.222 >20.0 1.792 200 0.028 6.1 0.228 201 0.020 13.9 1.434 202 0.314 >20.0 203 0.151 >20.0 204 0.010 >20.0 >20.0 205 0.067 >20.0 206 0.119 9.9 207 0.041 4.1 1.219 208 0.107 >20.0 209 0.032 5.9 3.364 210 0.044 2.5 0.564 211 0.014 >20.0 >20.0 212 0.041 >20.0 4.497 213 0.050 3.0 214 0.343 >20.0 215 0.054 5.3 7.648 216 0.069 7.8 1.284 217 0.040 14.6 0.395 218 0.010 5.1 0.551 219 0.004 >20.0 0.192 220 0.041 7.0 3.840 221 0.070 10.4 222 0.201 >20.0 223 0.159 >20.0 224 0.112 >20.0 >4.0 225 0.055 19.3 0.535 226 0.047 10.4 0.514 227 2.125 228 0.115 >20.0 >4.0 229 0.461 >20.0 230 0.005 >20.0 0.236 231 0.031 >20.0 232 0.088 >20.0 233 2.318 6.1 234 2.547 >20.0 235 0.163 >20.0 236 1.245 >20.0 237 2.886 >20.0 238 0.0011 4.7 0.028 239 0.0047 9.7 0.176 240 0.0020 7.8 0.035 241 0.0013 6.8 0.02 242 0.0033 7.0 0.112 243 0.0007 1.9 0.016 244 0.0016 4.4 0.086 245 0.0011 3.9 0.011 246 0.0029 6.2 0.094 247 0.0011 1.3 0.018 248 0.0009 4.1 0.017 249 0.0006 2.5 0.011 250 0.0008 3.7 0.006 251 0.0007 3.8 0.006 252 0.0007 3.7 0.005 253 0.0012 7.3 0.028 254 0.0007 3.8 0.004 255 0.0017 5.7 0.047 256 0.0010 2.2 0.011 257 0.0012 4.9 0.008 258 0.0011 2.0 0.011 259 0.0014 2.9 0.019 260 0.0025 4.7 0.039 261 0.0014 8.1 0.029 262 0.0008 7.5 0.005 263 0.0012 4.5 0.015 264 0.0013 2.8 0.016 265 0.0134 >20.0 0.358 266 0.0009 4.6 0.004 267 0.0085 >20.0 0.082 268 0.0010 4.0 0.007 269 0.0013 1.5 0.007 270 0.0012 2.0 0.019 271 0.0042 >20.0 2.077 272 0.0010 3.6 0.006 273 0.0014 1.4 0.027 274 0.0175 >20.0 275 0.0020 15.3 0.046 276 0.0017 7.7 0.013 277 0.0017 4.6 0.021 278 0.0016 5.8 0.029 279 0.0026 >20.0 0.104 280 0.0052 >20.0 0.057 281 0.0036 19.3 0.062 282 0.0014 13.0 0.019 283 0.0024 15.4 0.051 284 0.0029 19.9 0.052 285 0.0014 7.3 0.040 286 0.0022 10.3 0.043 287 0.0080 >20.0 0.069 288 0.0016 11.0 0.025 289 0.0017 14.2 0.016 290 0.0009 10.3 0.007 291 0.0014 11.8 0.027 292 0.0029 11.2 0.033 293 0.0039 11.9 0.073 294 0.0012 4.5 0.031 295 0.0014 2.8 0.027 296 0.0011 7.9 0.011 297 0.0080 16.9 0.070 298 0.0021 12.8 0.083 299 0.0024 >20.0 0.038 300 0.0021 17.2 0.053 301 0.0014 6.0 0.038 302 0.0041 12.9 0.032 303 0.0040 11.8 0.028 304 0.0028 11.8 0.086 305 0.0017 7.0 0.030 306 0.0036 7.1 0.106 307 0.0063 11.9 0.075 308 0.0017 10.5 0.015 309 0.0023 >20.0 0.063 310 0.0009 3.6 0.004 311 0.0015 3.1 0.019 312 0.0015 >7.0 0.017 313 0.0015 3.5 0.015 314 0.0016 3.8 0.059 315 0.0027 4.2 0.022 316 0.0020 6.4 0.034 317 0.0017 2.6 0.017 318 0.0012 6.3 0.005 319 0.0008 4.2 0.008 320 0.0020 3.9 0.021 321 0.0010 2.4 0.011 322 0.0012 5.1 0.019 323 0.0012 5.4 0.021 324 0.0007 4.6 0.011 325 0.0010 8.1 0.017 326 0.0059 6.9 0.078 327 0.0007 3.8 0.006 328 0.0007 3.6 0.007 329 0.0009 3.9 0.007 330 0.0010 4.7 0.015 331 0.0010 3.7 0.018 332 0.0039 >20.0 0.062 333 0.0037 15.9 0.063 334 0.0009 5.9 0.009 335 0.0009 3.4 0.005 336 0.0010 4.5 0.005 337 0.0010 4.9 0.012 338 0.0008 6.2 0.008 339 0.0008 5.2 0.006 340 0.0011 8.7 0.021 341 0.0030 16.2 0.038 342 0.0021 9.7 0.023 343 0.0070 10.6 0.285 344 0.0022 12.7 0.009 345 0.0010 3.4 0.013 346 0.0013 4.8 0.012 347 0.0020 4.2 >1.0 348 0.0009 3.9 0.019 349 0.0008 3.6 0.026 350 0.0014 4.4 0.041 351 0.0011 3.6 0.008 352 0.0011 2.7 0.007 353 0.0023 5.3 0.029 354 0.0013 4.8 0.024 355 0.0060 4.0 0.070 356 0.0044 >20.0 0.049 357 0.0061 19.2 358 0.0007 3.6 0.010 359 0.0009 4.7 0.019 360 0.0011 3.6 0.113 361 0.0010 1.4 0.007 362 0.0009 4.8 0.056 363 0.0011 10.4 0.048 364 0.0010 2.8 0.095 365 0.0019 8.8 0.235 366 0.0013 1.2 0.008 367 0.0012 1.1 0.070 368 0.0011 2.8 0.006 369 0.0021 9.3 0.067 370 1.6582 >20.0 371 0.3836 >20.0 372 0.0108 >20.0 373 0.0012 4.9 0.023 374 0.0012 4.2 0.010 375 0.0010 4.1 0.008 376 0.0009 4.2 0.014 377 0.0007 3.5 0.006 378 0.0008 3.2 0.004 379 0.0009 4.2 0.006 380 0.0008 2.7 0.004 381 0.0010 1.7 0.006 382 0.0009 2.8 0.007 383 0.0009 4.0 0.006 384 0.0009 3.6 0.003 385 0.0009 3.0 0.016 386 0.0009 3.5 0.004 - While a number of embodiments have been described, these examples may be altered to provide other embodiments that utilize the compounds and methods described herein. Therefore, the scope of this invention is to be defined by the appended claims rather than by the specific embodiments that have been represented by way of example.
- As depicted in the Examples below, in certain exemplary embodiments, compounds of Formula (II) are prepared according to the following general procedures. It will be appreciated that, although the general methods depict the synthesis of certain compounds of the present invention, the following general methods, and other methods known to one of ordinary skill in the art, can be applied to all compounds and subclasses and species of each of these compounds, as described herein.
- Compounds of Formula (II) may be prepared by general synthetic methods as shown in
Scheme 1. - Reaction between α-cyanoketone (1) and hydrazine in a suitable solvent such as, but not limited to, ethanol at a temperature ranging from about room temperature to reflux temperature and for a time varying from about 30 minutes to about 2 hours can provide amino pyrazole (2). The bromo pyrazole (3) can be formed by diazatization of the amino pyrazole (2) using a isoamylnitrite, sodium nitrite, or tert-butyl nitrite and copper(ll) bromide in a suitable organic solvent such as, but not limited to, acetonitrile at a temperature of about 20° C. to about 60° C. for about 5 hours. The alkylation of pyraozle N1 nitrogen to form compounds of formula (5) can be carried out using an alkyl iodide, bromide, mesylate or triflate in the presense of an inorganic base such as, but not limited to, sodium hydride or cesium carbonate, in a suitable solvent such as, but not limited to, N,N-dimethylformamide (DMF) or tetrahydrofuran (THF), and at a temperature ranging from about 0° C. to 120° C. and for a time varying from about 30 minutes to about 16 hours. Compounds of formula (3) can also be formed by treatment with alkyl boronic acids or boronate esters such as cyclopropylboronic acid in the presence of copper(II) acetate and an organic base such as, but not limited to, triethylamine or pyridine in a suitable solvent such as, but not limited to, THF at around 60° C. for 12 hours. Deprotection of N-tert-butoxycarbonyl (Boc) group using a protic acid such as, but not limited to, trifluoroacetic acid or hydrochloric acid followed by N-acetylation with acetic anhydride in the presence of an organic base such as, but not limited to, triethylamine can afford compounds of formula (5). Compounds of formula (5) can cross-couple with aryl, heteroaryl, alkyl or cycloalkyl amines under a palladium catalyst conditions such as, but not limited to, Ruphos pre-catalyst in combination with Brettphos/Ruphos ligand in the presence of inorganic base such as, but not limited to, sodium tert-butoxide or cesium carbonate in a suitable organic solvent such as, but not limited to, 1,4-dioxane at an elevated temperature to yield compounds of Formula (II).
- Compounds of formula (12) wherein R2 has the values as shown in Formula II, may be prepared by general synthetic methods as shown in
Scheme 2. It is to be understood that the “—R1′” group as shown inScheme 2 corresponds to the list of one or more substituents that may be optionally substituted on the R1 group as shown in Formula II. - Reaction between a compound of formula (8) and ketone (7) in the presence of a base such as, but not limited to, potassium tert-butoxide in a suitable organic solvent such as, but not limited to, THF at about 20° C. for about 3 hours followed by addition of methyl iodide and stirring for approximately 1 hour can produce the compounds of formula (9). Reaction between a compound of formula (9) and hydrazine in a suitable solvent such as, but not limited to, ethanol at reflux temperature for about 2 hours can produce compounds of formula (10). Compounds of formula (11) can be produced by treatment with alkyl iodide, bromide, mesylate or triflate in the presense of an inorganic base such as, but not limited to, sodium hydride or cesium carbonate, in a suitable solvent such as, but not limited to, N,N-dimethylformamide (DMF) or tetrahydrofuran (THF) at a temperature ranging from about 0° C. to 120° C. and for a time varying from about 30 minutes to about 16 hours. Compounds of formula (11) can cross-couple with aryl/heteroaryl boronic acids or boronate esters under palladium catalyst conditions such as, but not limited to, Pd(dppf)Cl2 in the presence of inorganic base such as, but not limited to, sodium carbonate in a suitable organic solvent such as, but not limited to, 1,4-dioxane at an elevated temperature to yield compounds of formula (12).
-
-
- To ethyl 3-aminopropanoate hydrochloride (366.5 g, 2.39 mol) in MeOH (1.2 L) at rt was added NaOH (95.6 g, 2.39 mol) in portions. The mixture was heated to 70° C., acrylonitrile (158 g, 2.98 mol) was added dropwise and the reaction mixture stirred for 6 h. The solution was cooled to 0° C. before (Boc)2O (521 g, 2.39 mol) was added. The reaction was stirred at rt for 6 h, filtered, and washed with MeOH (200 mL). The filtrate was concentrated in vacuo to give a yellow oil residue that was re-dissolved in EtOAc and water (500 mL). The aqueous layer was extracted with EtOAc (800 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (638 g) as light yellow oil that required no further purification. 1H NMR (400 MHz, CDCl3) δ 4.17 (q, J=7.2 Hz, 2H), 3.68-3.62 (m, 4H), 2.57-2.53 (m, 4H), 1.49 (s, 9H), 1.29 (t, J=7.2 Hz, 3H).
-
- To toluene (2.7 L) at 25° C. was added NaH (80 g, 2.0 mol) portion-wise and the suspension was heated to 80° C. Ethyl 3-((tert-butoxycarbonyl)(2-cyanoethyl)amino)propanoate (270 g, crude) in anhydrous toluene (270 mL) was added dropwise. The mixture was heated to 100° C. and stirred for 5 h. The mixture was cooled to rt, quenched with sat. aq. ammonium chloride (800 mL) and washed with hexanes (800 mL). The aqueous phase was acidified with HCl (2 N) to
pH 6 and then extracted with EtOAc (1 L×2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (310 g) as yellow oil that required no further purification. 1H NMR (400 MHz, CDCl3) δ 4.17-4.14 (m, 1H), 3.59-3.56 (m, 2H), 3.43-3.41 (m, 2H), 2.70-2.66 (m, 2H), 1.51 (s, 9H). -
- A mixture of tert-butyl 3-cyano-4-oxopiperidine-1-carboxylate (310 g, 1.38 mol) and hydrazine mono-hydrate (140 mL, 2.08 mol) in EtOH (1.5 L) was heated to 60° C. for 2 h. The mixture was concentrated in vacuo to give the crude product that was dissolved in EtOAc (1 L) and washed with water (1 L×2). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo to afford the title compound (230 g, 70%) as a colorless solid. 1H NMR (400 MHz, CD3OD) δ 4.28 (s, 2H), 3.66-3.63 (m, 2H), 2.62-2.59 (m, 2H), 1.49 (s, 9H).
-
- To a stirred mixture of tert-butyl 3-amino-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (120 g, 503.6 mmol), CuBr2 (112.5 g, 503.6 mmol) and MeCN (1.2 L) at 0° C. was added isopentyl nitrite (76.7 g, 654.7 mmol) and the reaction mixture stirred for 20 min. The temperature was raised to 60° C. and the reaction mixture was stirred for an additional 5 h. After cooling the reaction to room temperature, the reaction mixture was quenched with water (1 L) and the mixture was extracted with EtOAc (1 L×2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the crude product that was purified by silica gel chromatography (petroleum ether/EtOAc=4:1) to afford the title compound (Intermediate A, 52 g, 34%) as light yellow solid. LCMS M/Z (M+H) 302.
-
- To a stirred solution of tert-butyl 3-bromo-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (32 g, 105.9 mmol) in THF at 0° C. (350 mL) was added NaH (5.08 g, 127.1 mmol) and the mixture was stirred for 30 min. Methyliodide (18.05 g, 127.1 mmol) was added dropwise and the mixture stirred for an additional 2 h. The mixture was quenched with water and extracted with EtOAc (300 mL×2). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc=8:1) to afford the title compound (16 g, 48%) as a colorless oil. 1H NMR (400 MHz, CD3OD) δ 4.24 (s, 2H), 3.70 (s, 3H), 3.69-3.67 (m, 2H), 2.70-2.67 (m, 2H), 1.47 (s, 9H).
-
- A mixture of tert-butyl 3-bromo-1-methyl-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (12 g, 38.0 mmol) and trifluoroacetic acid (40 mL) in DCM (80 mL) was stirred at room temperature for 2 h. The mixture was concentrated in vacuo and the residue was re-dissolved in DCM (120 mL). The mixture was cooled to 0° C. before TEA (12.1 g, 120 mmol) and acetic anhydride (5.3 g, 52 mmol) were added dropwise. The mixture stirred at room temperature for an additional 2 h before water (100 mL) was added. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give crude product which was purified by silica gel chromatography (DCM/MeOH=20:1) to afford the title compound (Intermediate B, 8.5 g, 87%) as colorless solid. 1H NMR (400 MHz, CD3OD) δ 4.40-4.39 (m, 2H), 3.88-3.78 (m, 2H), 3.72 (s, 3H), 2.83-2.70 (m, 2H), 2.20-2.17 (m, 3H).
-
-
- To a mixture of 2-bromo-1-methyl-4-nitrobenzene (860 mg, 4.0 mmol), (1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (998 mg, 4.8 mmol) and cesium carbonate (2.6 g, 8 mmol) in dioxane (20 ml)/H2O (4 ml) was added [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (292 mg, 0.4 mmol). The mixture was heated to 90° C. for 10 hours under nitrogen atmosphere. After cooling to rt, the reaction mixture was concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether/EtOAc=5:1 to 3:1) to give the title compound (860 mg, 99%) as a yellow solid.
-
- To a mixture of 1-methyl-4-(2-methyl-5-nitrophenyl)-1H-pyrazole (434 mg, 2 mmol) and NH4Cl (530 mg, 10 mmol) in MeOH (20 ml) was added Fe powder (560 mg, 10 mmol) and the reaction mixture was heated to 60° C. for 10 hours. After filtration, the filtrate was concentrated, washed with water and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (370 mg, 98%) as a yellow solid that required no further purification.
-
- A mixture of 1-(3-bromo-1-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl)ethanone (Intermediate B, 200 mg, 0.77 mol), 4-methyl-3-(1-methylpyrazol-4-yl)aniline (145 mg, 0.77 mmol), 2-(dicyclohexylphosphino)3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl (42 mg, 0.08 mmol), Chloro-(2-Dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II) (63 mg, 0.08 mmol) and t-BuONa (223 mg, 2.32 mmol) in 1,4-dioxane (4 mL) was heated to 120° C. for 12 h. After cooling to rt, the reaction mixture was diluted with water (20 mL) and washed with DCM (20 mL×2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified reverse phase chromatography (acetonitrile 30-60%/0.1% NH4OH in water) to give the title compound (44 mg, 16%) as white solid. 1H NMR (400 MHz, CD3OD) δ 7.72 (s, 1H), 7.58 (s, 1H), 7.14-7.04 (m, 2H), 6.95-6.92 (m, 1H), 4.37-4.35 (m, 2H), 3.93 (s, 3H), 3.86-3.79 (m, 2H), 3.65-3.64 (m, 3H), 2.81-2.69 (m, 2H), 2.29-2.28 (m, 3H), 2.20-2.09 (m, 3H). LCMS M/Z (M+H) 365.
- The following Examples 2-7 were prepared in a similar fashion to Example 1.
-
Example Compound Name and Structure NMR m/z Example 2 1-[3-[2-fluoro-4-(1-methylpyrazol-4-yl)anilino]-1-methyl-6,7- dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone 1H NMR (400 MHz, CD3OD) δ 7.86 (d, J = 2.4 Hz, 1H), 7.73 (d, J = 2.0 Hz, 1H), 7.36- 7.17 (m, 3H), 4.40-4.39 (m, 2H), 3.90 (s, 3H), 3.89-3.80 (m, 2H), 3.68 (s, 3H), 2.84-2.71 (m, 2H), 2.20-2.13 (m, 3H) 369 Example 3 1-[3-[2-fluoro-3-(1-methylpyrazol-4-yl)anilino]-1-methyl-6,7- dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone 1H NMR (400 MHz, CD3OD) δ 8.04 (s, 1H), 7.71 (s, 1H), 7.90 (s, 1H), 7.20-7.06 (m, 3H), 4.43 (s, 2H), 3.97 (s, 3H), 3.93-3.83 (m, 2H), 3.72-3.71 (m, 3H), 2.87-2.74 (m, 2H), 2.22- 2.15 (m, 3H) 369 Example 4 1-[3-[2-fluoro-5-(1-methylpyrazol-4-yl)anilino]-1-methyl-6,7- dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone 1H NMR (400 MHz, CD3OD) δ 7.86 (s, 1H), 7.71 (s, 1H), 7.53-7.38 (m, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.01-7.03 (m, 2H), 4.43-4.41 (m, 2H), 3.90 (s, 3H), 3.88-3.82 (m, 2H), 3.71 (s, 3H), 2.86-2.73 (m, 2H), 2.21-2.10 (m, 3H) 369 Example 5 1-[3-[3-fluoro-5-(1-methylpyrazol-4-yl)anilino]-1-methyl-6,7- dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone 1H NMR (400 MHz, CD3OD) δ 7.92 (d, J = 2.8 Hz, 1H), 7.77 (s, 1H), 7.11-7.08 (m, 1H), 6.87 (dd, J = 8.0, 8.0 Hz, 1H), 6.70 (dd, J = 8.0, 8.0 Hz, 1H), 4.45-4.43 (m, 2H), 3.94 (s, 3H), 3.92-3.82 (m, 2H), 3.71 (s, 3H), 2.85- 2.72 (m, 2H), 2.23-2.15 (m, 3H) 369 Example 6 1-[3-[4-fluoro-3-(1-methylpyrazol-4-yl)anilino]-1-methyl-6,7- dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone 1H NMR (400 MHz, CD3OD) δ 7.92 (s, 1H), 7.78 (s, 1H), 7.39-7.37 (m, 1H), 7.00-6.95 (m, 2H), 4.38-4.36 (s, 2H), 3.92 (s, 3H), 3.85- 3.78 (m, 2H), 3.64 (s, 3H), 2.79-2.66 (m, 2H), 2.18-2.10 (s, 3H) 369 Example 7 1-[3-[3-fluoro-4-(1-methylpyrazol-4-yl)anilino]-1-methyl-6,7- dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone 1H NMR (400 MHz, CD3OD) δ 7.86 (s, 1H), 7.76 (s, 1H), 7.43-7.42 (m, 1H), 7.12 (dd, J = 9.6, 9.6 Hz, 1H), 6.95-6.91 (m, 1H), 4.42-4.41 (m, 2H), 3.92 (s, 3H), 3.91-3.79 (m, 2H), 3.68 (s, 3H), 2.82-2.69 (m, 2H), 2.20-2.15 (m, 3H) 369 -
- To a solution of 1-(3-bromo-1-methyl-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone (Intermediate B, 200 mg, 0.77 mmol) in dioxane (8.0 mL) was added 1-methyl-1H-pyrazol-4-amine (90 mg, 0.93 mmol), tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct (71.6 mg, 0.07 mmol), xantphos (41.2 mg, 0.07 mmol) and Cs2CO3 (504.9 mg, 1.55 mmol). The reaction mixture was purged with nitrogen atmosphere for 1 min and then stirred at 120° C. for 12 h. The mixture was concentrated in vacuo and the crude residue was purified by reverse phase chromatography (acetonitrile 1-28%/0.2% formic acid in water) to give the title compound (6.8 mg, 3%) as a white solid. 1H NMR (400 MHz, CD3OD) δ 7.35-7.34 (m, 1H), 5.95-5.93 (m, 1H), 4.37-4.36 (m, 2H), 3.87-3.76 (m, 2H), 3.77 (s, 3H), 3.61 (s, 3H), 2.78-2.65 (m, 2H), 2.18-2.13 (m, 3H). LCMS M/Z (M+H) 275.
- The following Examples 9-16 were prepared in a similar fashion to Step 3 of Example 1.
-
Example Compound Name and Structure NMR m/z Example 9 1H NMR (400 MHz, CD3OD) δ 8.90 (d, J = 2.8 Hz, 1H), 8.11 (d, J = 2.4 Hz, 1H), 7.57 (dd, J = 8.8, 7.2 Hz, 2H), 7.33 (dd, J = 11.2, 8.8 Hz, 2H), 4.42-4.41 (m, 2H), 3.90-3.79 (m, 2H), 3.68 (s, 3H), 2.82- 2.69 (m, 2 H), 2.20-2.15 (m, 3H) 338 Example 10 1H NMR (400 MHz, CD3OD) δ 9.00 (d, J = 3.6 Hz, 1H), 8.13 (d, J = 3.2 Hz, 1H), 7.66-7.62 (m, 1H), 7.35-7.31 (m, 1H), 7.17-7.14 (m, 1H), 4.43-4.41 (m, 2H), 3.90-3.79 (m, 2H), 3.69-3.68 (m, 3H), 2.83-2.70 (m, 2 H), 2.20-2.13 (m, 3H) 338 Example 11 1H NMR (400 MHz, CD3OD) δ 7.97 (d, J = 5.2 Hz, 1H), 7.50 (dd, J = 8.8, 7.2 Hz, 1H), 7.31 (s, 1H), 6.90 (d, J = 7.6 Hz, 1H), 4.41-4.39 (m, 2H), 4.09 (s, 3H), 3.91-3.80 (m, 2H), 3.69 (s, 3H), 2.84- 2.71 (m, 2H), 2.20-2.12 (m, 3H) 325 Example 12 1H NMR (400 MHz, CD3OD) δ 8.23- 8.22 (s, 1H), 7.54-7.51 (m, 1H), 7.43- 7.42 (m, 1H), 7.28-7.24 (m, 1H), 7.15- 7.12 (m, 2H), 4.41-4.40 (m, 2H), 3.90- 3.80 (m, 2H), 3.69 (s, 3H), 2.83-2.70 (m, 2H), 2.20-2.13 (m, 3H) 338 Example 13 1H NMR (400 MHz, CD3OD) δ 8.15 (s, 1H), 7.57-7.53 (m, 2H), 7.30-7.21 (m, 3H), 4.41-4.40 (m, 2H), 3.90-3.80 (m, 2H), 3.69-3.68 (m, 3H), 2.83-2.70 (m, 2H), 2.20-2.14 (m, 3H) 338 Example 14 1H NMR (400 MHz, CD3OD) δ 7.77 (s, 1H), 7.51 (dd, J = 8.8, 6.0 Hz, 1H), 7.37- 7.27 (s, 1H), 6.90 (d, J = 8.8 Hz, 1H), 4.42-4.41 (m, 2H), 3.92 (s, 3H), 3.91- 3.79 (m, 2H), 3.39 (s, 3H), 2.82-2.71 (m, 2H), 2.19-2.12 (m, 3H) 325 Example 15 1H NMR (400 MHz, CD3OD) δ 7.89 (d, J = 7.2 Hz, 1H), 7.45-7.42 (m, 2H), 7.17 (d, J = 7.2 Hz, 1H), 4.38, 4.36 (m, 2H), 4.11 (s, 3H), 3.87-3.76 (m, 2H), 3.65 (s, 3H), 2.79-2.69 (m, 2H), 2.18- 2.10 (m, 3H) 325 Example 16 1H NMR (400 MHz, CD3OD) δ 7.77 (d, J = 5.6 Hz, 1H), 7.53 (dd, J = 8.0, 8.0 Hz, 1H), 7.25 (d, J = 9.2 Hz, 1H), 4.35-4.33 (m, 2H), 3.98 (s, 3H), 3.85-3.75 (m, 2H), 3.63 (s, 3H), 2.78-2.67 (m, 2H), 2.17-2.08 (m, 3H) 325 -
-
- To a mixture of 3-bromo-5-nitrobenzoic acid (1.0 g, 4.1 mmol), propan-2-amine (0.29 g, 4.9 mmol and DIPEA (1.1 g, 8.2 mmol) in DCM (10.0 mL) was added HATU (1.6 g, 4.1 mmol). The mixture was stirred at rt for 12 h. The reaction mixture was filtered, concentrated in vacuo and the crude residue was purified by silica gel column chromatography (petroleum ether/EtOAc=1:1) to give the title compound (1.0 g, 86%) as a white solid.
-
- [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (0.13 g, 0.17 mmol) was added to a mixture of 3-bromo-N-isopropyl-5-nitrobenzamide (0.5 g, 1.7 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.43 g, 2.1 mmol) and Na2CO3 (0.37 g, 3.4 mmol) in 1,4-dioxane (5.0 mL) and water (1.3 mL). The mixture was stirred under nitrogen atmosphere at 120° C. for 12 h. The mixture was filtered, concentrated in vacuo and the residue was purified by silica gel column chromatography (petroleum ether/EtOAc=3:1 to 1:1) to give the title compound (0.30 g, 59%) as a light red solid.
-
- The title compound was prepared from N-isopropyl-3-(1-methyl-1H-pyrazol-4-yl)-5-nitrobenzamide in a similar fashion to Step 2 of Example 1. The residue was purified by silica gel chromatography (petroleum ether/EtOAc=1:1) to give the title compound (0.24 g, 90%) as a yellow solid. LCMS M/Z (M+H)=259.
-
- The title compound was prepared from 3-amino-N-isopropyl-5-(1-methyl-1H-pyrazol-4-yl)benzamide in a similar fashion to Step 3 of Example 1. The crude residue was purified by reverse phase chromatography (acetonitrile 32-62%/0.1% NH4OH in water) to give the title compound in 12% yield. 1H NMR (400 MHz, CD3OD) δ 7.95 (d, J=3.2 Hz, 1H), 7.82 (d, J=3.6 Hz, 1H), 7.46-7.36 (m, 3H), 4.42-4.40 (m, 2H), 4.23-4.19 (m, 1H), 3.94 (s, 3H), 3.89-3.80 (m, 2H), 3.70 (s, 3H), 2.84-2.72 (m, 2H), 2.21-2.12 (m, 3H), 1.26 (d, J=6.4 Hz, 6H). LCMS M/Z (M+H) 436.
-
-
- The title compound was prepared from 3-methyl-5-nitrobenzoic acid in a similar fashion to Step 1 of Example 17. The residue was purified by silica gel chromatography (petroleum ether/EtOAc=5:1 to 3:1) to give the title compound (560 mg, 84%) as yellow oil.
-
- The title compound was prepared N-isopropyl-3-methyl-5-nitrobenzamide in a similar fashion to Step 2 of Example 1. No purification was required to give the title compound (400 mg, 83%) as a yellow solid.
-
- The title compound was prepared from 3-amino-N-isopropyl-5-methylbenzamide in a similar fashion to Step 3 of Example 1. The crude residue was purified by reverse phase chromatography (acetonitrile 30-60%/0.1% NH4OH in water) to give the title compound in 22% yield. 1H NMR (400 MHz, CD3OD) δ 7.31 (d, J=7.6 Hz, 1H), 7.07-6.83 (m, 2H), 4.37-4.35 (m, 2H), 4.17-4.13 (m, 1H), 3.86-3.78 (m, 2H), 3.66 (s, 3H), 2.80-2.69 (m, 2H), 2.30 (s, 3H), 2.18-2.11 (m, 3H), 1.22 (d, J=6.4 Hz, 6H). LCMS M/Z (M+H) 369.
- The following Example 19 was prepared in a similar fashion to Example 18.
-
-
- To a solution of 3-amino-5-bromo-benzonitrile (1.4 g, 7.1 mmol) in dioxane (8 mL)/water (2 mL) was added 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyrazole (1.8 g, 8.5 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (0.5 g, 0.7 mmol) and Na2CO3 (1.5 g, 14.2 mmol). The reaction was heated to 120° C. for 16 h under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether:EtOAc=10:1 to 1:2) to give the title compound (1.3 g, 92%) as a brown solid. LCMS M/Z (M+H) 199.
-
- The title compound was prepared from 3-amino-5-(1-methyl-1H-pyrazol-4-yl)benzonitrile in a similar fashion to Step 3 of Example 1. The crude residue was purified by reverse phase chromatography (acetonitrile 35-65%/0.1% NH4OH in water) to give the title compound in 17% yield. 1H NMR (400 MHz, CD3OD) δ 8.00 (s, 1H), 7.83 (s, 1H), 7.64-7.60 (m, 1H), 7.47 (d, J=7.6 Hz, 1H), 7.31 (d, J=6.0 Hz, 1H), 4.47-4.45 (m, 2H), 3.95 (s, 3H), 3.93-3.82 (m, 2H), 3.73 (s, 3H), 2.84-2.74 (m, 2H), 2.23-2.17 (m, 3H). LCMS M/Z (M+H) 376.
- The following Examples 21-32 were prepared in a similar fashion to Example 20.
-
Example Compound Name and Structure NMR m/z Example 21 1H NMR (400 MHz, CD3OD) δ 7.82 (d, J = 3.2 Hz, 1H), 7.69 (d, J = 2.4 Hz, 1H), 7.07-7.04 (m, 1H), 6.80- 6.76 (m, 2H), 4.36-4.34 (m, 2H), 3.88 (s, 3H), 3.87-3.78 (m, 2H), 3.66 (s, 3H), 2.80-2.69 (m, 2H), 2.26 (s, 3H), 2.17-2.07 (m, 3H). 365 Example 22 1H NMR (400 MHz, DMSO-d6) δ 8.09-7.88 (m, 2H), 7.75-7.69 (m, 2H), 7.27-7.19 (m, 1H), 4.38- 4.32 (m, 2H), 3.87 (s, 3H), 3.73- 3.66 (m, 2H), 3.62 (s, 3H), 2.74- 2.59 (m, 2H), 2.08-2.03 (m, 3H) 387 Example 23 1H NMR (400 MHz, CD3OD) δ 8.21 (dd, J = 6.4, 2.0 Hz, 1H), 7.86 (d, J = 3.6 Hz, 1H), 7.73-7.70 (m, 2H), 6.98 (dd, J = 14.4, 4.8 Hz, 1H), 4.41- 4.39 (m, 2H), 3.89 (s, 3H), 3.87- 3.79 (m, 2H), 3.70 (s, 3H), 2.82- 2.71 (m, 2H), 2.17-2.10 (m, 3H) 352 Example 24 1H NMR (400 MHz, DMSO-d6) δ 8.18 (s, 1H), 8.02-7.92 (m, 1H), 7.88 (s, 1H), 7.42-7.38 (m, 1H), 7.12 (d, J = 8.4 Hz, 1H), 6.97 (d, J = 7.6 Hz, 1H), 4.32-4.28 (s, 2H), 3.91 (s, 3H), 3.74-3.67 (m, 2H), 3.64 (s, 3H), 2.78-2.64 (m, 2H), 2.09-2.03 (m, 3H) 376 Example 25 1H NMR (400 MHz, DMSO-d6) δ 8.62-8.57 (m, 1H), 7.85-7.81 (m, 1H), 7.77-7.71 (m, 1H), 7.41 (dd, J = 8.0, 8.0 Hz, 1H), 7.20 (dd, J = 6.4, 6.4 Hz, 1H), 4.33 (s, 2H), 3.71- 3.64 (m, 2H), 3.60 (s, 3H), 3.13 (s, 3H), 2.72-2.59 (m, 2H), 2.07- 2.05 (s, 3H) 349 Example 26 1H NMR (400 MHz, DMSO-d6) δ 8.13 (s, 1H), 7.81 (s, 1H), 7.60- 7.42 (m, 1H), 7.03 (dd, J = 9.6, 9.6 Hz, 1H), 4.39-4.32 (s, 2H), 3.92 (s 3H), 3.73-3.66 (m, 2H), 3.61 (s, 3H), 2.76-2.60 (m, 2H), 2.08- 2.04 (m, 3H) 387 Example 27 1H NMR (400 MHz, CD3OD) δ 8.01 (d, J = 4.4 Hz, 1H), 7.89 (s, 1H), 8.01 (dd, J = 8.0, 2.8 Hz, 1H), 6.99 (dd, J = 7.3, 2.9 Hz, 1H), 6.85-6.77 (m, 1H), 4.42-4.39 (m, 2H), 3.91 (s, 3H), 3.90-3.81 (m, 2H), 3.69 (s, 3H), 2.85-2.72 (m, 2 H), 2.01- 1.96 (m, 3H) 352 Example 28 1H NMR (400 MHz, CD3OD) δ 8.11- 8.03 (m, 1H), 8.02 (d, J = 3.2 Hz, 1H), 7.89 (d, J = 2.0 Hz, 1H), 7.39- 7.34 (m, 1H), 6.98-6.95 (m, 1H), 4.45-4.43 (m, 2H), 3.93 (s, 3H), 3.92-3.79 (m, 2H), 3.72 (s, 3H), 2.83-2.70 (m, 2H), 2.20-2.14 (m, 3H) 352 Example 29 1H NMR (400 MHz, CD3OD) δ 8.30 (d, J = 2.4 Hz, 1H), 8.14 (d, J = 4.4 Hz, 1H), 8.02 (d, J = 3.6 Hz, 1H), 7.94-7.87 (m, 1H), 7.84 (d, J = 2.4 Hz, 1H), 4.46-4.44 (m, 2H), 3.94 (s, 3H), 3.89-3.80 (m, 2H), 3.70 (s, 3H), 2.83-2.70 (m, 2 H), 2.21- 2.16 (m, 3H) 352 Example 30 1H NMR (400 MHz, CD3OD) δ 8.10 (s, 1H), 8.00-7.97 (m, 1H), 7.90 (s, 1H), 7.12-7.09 (m, 1H), 6.97 (d, J = 5.6 Hz, 1H), 4.42 (s, 2H), 3.94 (s, 3H), 3.89-3.81 (m, 2H), 3.72- 3.71 (m, 3H), 2.85-2.72 (m, 2 H), 2.19-2.11 (m, 3H) 352 Example 31 1H NMR (400 MHz, CD3OD) δ 7.90 (d, J = 3.2 Hz, 1H), 7.75 (d, J = 2.2 Hz, 1H), 7.22-7.19 (m, 1H), 7.19 (s, 1H), 6.94 (d, J = 6.8 Hz, 1H), 4.42-4.40 (m, 2H), 3.92 (s, 3H), 3.95-3.70 (m, 2H), 3.69 (s, 3H), 2.83-2.70 (m, 2H), 2.21-2.13 (m, 3H) 385 Example 32 1H NMR (400 MHz, CD3OD) δ 8.24 (dd, J = 6.4, 2.0 Hz, 1H), 7.89 (d, J = 3.2 Hz, 1H), 7.75-7.73 (m, 2H), 7.03-6.97 (m, 1H), 4.43-4.41 (m, 2H), 3.92 (s, 3H), 3.89 3.81 (m, 2H), 3.70-3.69 (m, 3H), 2.85- 2.72 (m, 2H), 2.19-2.13 (m, 3H) 352 -
-
- [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (0.13 g, 0.17 mmol) was added to a mixture of 3-bromo-N-isopropyl-5-nitrobenzamide (0.5 g, 1.7 mmol), cyclopropylboronic acid (0.18 g, 2.1 mmol) and K2CO3 (0.48 g, 3.5 mmol) in 1,4-dioxane (5.0 mL) and water (1.3 mL). The reaction mixture was stirred under nitrogen atmosphere at 120° C. for 12 h before it was filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel chromatography (petroleum ether/EtOAc=3:1 to 1:1) to give the title compound (0.24 g, 55%) as a light red solid.
-
- The title compound was prepared from 3-cyclopropyl-N-isopropyl-5-nitrobenzamide in a similar fashion to Step 2 of Example 1. The residue was purified by silica gel column chromatography (petroleum ether/EtOAc=1:1) to give the title compound (0.18 g, 85%) as a yellow solid. LCMS M/Z (M+H) 219.
-
- The title compound was prepared from 3-amino-5-cyclopropyl-N-isopropylbenzamide in a similar fashion to Step 3 of Example 1. The crude residue was purified by reverse phase chromatography (acetonitrile 35-65%/0.1% HCl in water) to give the title compound in 1% yield. 1H NMR (400 MHz, CD3OD) δ 7.38-7.37 (m, 1H), 7.16-7.13 (m, 1H), 7.05-7.04 (m, 1H), 4.42-4.41 (m, 2H), 4.21-4.17 (m, 1H), 3.91-3.85 (m, 2H), 3.74-3.73 (m, 3H), 2.89-2.76 (m, 2H), 2.22-2.15 (m, 3H), 1.97-1.95 (m, 1H), 1.25 (d, J=6.8 Hz, 6H), 1.03-0.99 (m, 2H), 0.79-0.76 (m, 2H). LCMS M/Z (M+H) 396.
-
-
- [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (0.64 g, 0.87 mmol) was added to a mixture of 4-bromo-1-methyl-3-(trifluoromethyl)-1H-pyrazole (2.0 g, 8.7 mmol), 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (2.1 g, 8.7 mmol) and Na2CO3 (1.8 g, 17.4 mmol) in 1,4-dioxane (20 mL) and water (4 mL). The reaction mixture was stirred under nitrogen atmosphere at 120° C. for 12 h. After cooling to room temperature the reaction mixture was filtered, concentrated in vacuo and the residue was purified by silica gel chromatography (petroleum ether/EtOAc=3:1 to 1:1) to give the title compound (1.2 g, 55%) as a light yellow solid. LCMS M/Z (M+H) 260.
-
- The title compound was prepared from 2-fluoro-4-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)aniline in a similar fashion to Step 3 of Example 1. The crude residue was purified by reverse phase chromatography (acetonitrile 44-74%/0.1% HCl in water) to give the title compound in 4% yield as a white solid. 1H NMR (400 MHz, CD3OD) δ 7.81 (s, 1H), 7.39-7.13 (m, 1H), 7.12-7.04 (m, 2H), 4.41 (s, 2H), 3.95 (s, 3H), 3.88-3.79 (m, 2H), 3.68 (s, 3H), 2.83-2.71 (m, 2H), 2.19-2.13 (m, 3H). LCMS M/Z (M+H) 437.
- The following Example 35 was prepared in a similar fashion to Example 34.
-
Example Compound Name and Structure NMR m/z Example 35 1H NMR (400 MHz, DMSO-d6) δ 8.19 (s, 1H), 8.08 (s, 1H) 7.47-7.43 (m, 1H), 7.33 (d, J = 8.0 Hz, 1H), 7.24-7.19 (m, 1H), 6.74 (d, J = 7.2 Hz, 1H), 4.37-4.34 (s, 2H), 3.94 (s, 3H), 3.73-3.66 (m, 2H), 3.60-3.59 (m, 3H), 2.74-2.59 (m, 2H), 2.09-2.04 (m, 3H) 441 [M + Na] -
-
- [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (39.7 mg, 0.054 mmol) was added to a mixture of 6-bromopyridin-3-amine (94.0 mg, 0.54 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)-1H-pyrazole (150.0 mg, 0.54 mmol) and K2CO3 (149.0 mg, 1.1 mmol) in 1,4-dioxane (2.0 mL) and water (0.5 mL). The reaction mixture was stirred under nitrogen atmosphere at 120° C. for 12 h. The mixture was filtered, concentrated in vacuo and the residue was purified by silica gel chromatography (petroleum ether/EtOAc=3:1 to 1:1) to give the title compound (80 mg, 60%) as a red solid. LCMS M/Z (M+H)=243.
-
- The title compound was prepared from 6-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)pyridin-3-amine in a similar fashion to Step 3 of Example 1. The crude residue was purified by reverse phase chromatography (acetonitrile 16-46%/0.1% formic acid in water) to give the title compound in 29% yield as a white. 1H NMR (400 MHz, DMSO-d6) δ 8.66-8.64 (m, 1H), 8.49-8.45 (m, 1H), 8.23 (s, 1H), 7.92 (dd, J=8.8, 2.4 Hz, 1H), 7.37 (dd, J=8.8, 5.6 Hz, 1H), 4.38 (s, 2H), 3.94 (s, 3H), 3.74-3.66 (m, 2H), 3.62 (s, 3H), 2.74-2.59 (m, 2H), 2.10-2.07 (m, 3H). LCMS M/Z (M+H) 420.
-
-
- To a stirred solution of tert-butyl 3-bromo-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (Intermediate A, 6.0 g, 19.8 mmol) in DMF (40 mL) was added Cs2CO3 (9.70 g, 29.8 mmol) and (bromomethyl)cyclopropane (4.0 g, 29.8 mmole). The reaction mixture was heated to 80° C. for 12 h. The mixture was diluted with EtOAc (200 mL), washed with brine (100 mL×3), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (eluent gradient from petroleum ether to petroleum ether/MTBE/THF=10:1:1) to give the title compound (3.0 g, 42%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 4.29 (s, 2H), 3.85 (d, J=3.4 Hz, 2H), 3.71 (t, J=5.2 Hz, 2H), 2.67 (t, J=5.2 Hz, 2H), 1.49 (s, 9H), 1.25-1.18 (m, 1H), 0.61-0.55 (m, 2H), 0.35-0.31 (m, 2H).
-
- A mixture of tert-butyl 3-bromo-1-(cyclopropylmethyl)-6,7-dihydro-1H-pyrazolo[4, 3-c]pyridine-5(4H)-carboxylate (3.0 g, 8.4 mmol) and trifluoroacetic acid (30 mL) in DCM (30 mL) was stirred at room temperature for 2 h. The solvent was removed by evaporation and the crude product was re-dissolved in DCM (120 mL). The solution was cooled to 0° C. before TEA (2.49 g, 24.6 mmol) and acetic anhydride (1.26 g, 12.3 mmol) were added dropwise. The reaction mixture was stirred at room temperature for additional 2 h before it was quenched with water. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give crude product which was purified by silica gel chromatography (DCM/MeOH=20:1) to afford the title compound (2.40 g, 96%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 4.49-4.33 (m, 3H), 3.90-3.70 (m, 4H), 2.77-2.67 (m, 2H), 2.23-2.19 (m, 3H), 1.28-1.18 (m, 1H), 0.63-0.58 (m, 2H), 0.36-0.32 (m, 2H).
-
-
- The title compound was prepared from 1-bromo-2-fluoro-3-nitrobenzene in a similar fashion to Step 1 of Example 1. The residue was purified by silica gel chromatography (petroleum ether/EtOAc=5:1 to 3:1) to afford the title compound (9.5 g, 95%) as a yellow solid.
-
- The title compound was prepared from 4-(2-fluoro-3-nitrophenyl)-1-methyl-1H-pyrazole in a similar fashion to Step 2 of Example 1. The residue was purified by silica gel chromatography (petroleum ether/EtOAc=1:1) to give the title compound (7.9 g, 96% yield) as a red solid. 1H NMR (400 MHz, DMSO-d6) δ 7.99 (s, 1H), 7.76 (s, 1H), 6.81-6.58 (m, 3H), 5.08 (s, 2H), 3.84 (s, 3H).
-
- To a solution of 2-fluoro-3-(1-methyl-1H-pyrazol-4-yl)aniline (1.4 g, 7.0 mmol) and 1-(3-bromo-1-(cyclopropylmethyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone (1.8 g, 6.0 mmol) in 1,4-dioxane (40 mL) was added NaOtBu (1.9 g, 19.8 mmol), Chloro-(2-Dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II) (240 mg, 0.26 mmol) and 2-(dicyclohexylphosphino)3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl (160 mg, 0.24 mmol). The reaction mixture was heated to 120° C. for 12 h under N2 atmosphere. The mixture was filtered and concentrated in vacuo. The crude residue was purified reverse phase chromatography (acetonitrile 30-60%/0.1% NH4OH in water) to give the title compound (536 mg, 22%) as white solid. 1H NMR (400 MHz, CD3OD) δ 8.00 (s, 1H), 7.85 (s, 1H), 7.17-6.91 (m, 3H), 4.44 (s, 2H), 3.93 (s, 3H), 3.90-3.75 (m, 4H), 2.89-2.71 (m, 2H), 2.22-2.08 (m, 3H), 1.27-1.22 (m, 1H), 0.60-0.49 (m, 2H), 0.40-0.31 (m, 2H). LCMS M/Z (M+H) 409.
- The following Examples 38-40 were prepared in a similar fashion to Example 37.
-
Example Compound Name and Structure NMR m/z Example 38 1H NMR (400 MHz, DMSO-d6) δ 8.12- 8.07 (m, 1H), 8.00 (s, 1H), 7.72-7.71 (m, 2H), 7.30-7.26 (m, 1H), 7.10-7.03 (m, 1H), 4.36 (s, 2H), 3.90 (s, 3H), 3.78 (d, J = 6.8 Hz, 2H), 3.74-3.66 (m, 2H), 2.74- 2.62 (m, 2H), 2.11-2.07 (m, 3H), 1.25- 1.11 (m, 1H), 0.51-0.49 (m, 2H), 0.36- 0.35 (m, 2H) 409 Example 39 1H NMR (400 MHz, CD3OD) δ 7.75 (s, 1H), 7.61 (s, 1H), 7.22-7.17 (m, 1H), 7.09-7.08 (m, 1H), 7.06-6.95 (m, 1H), 3.95 (m, 2H), 3.88 (s, 3H), 3.84-3.79 (m, 4H), 2.85-2.74 (m, 2H), 2.31 (s, 3H), 2.30-2.12 (m, 3H), 1.24-1.21 (m, 1H), 0.59-0.56 (m, 2H), 0.39-0.37 (m, 2H) 405 Example 40 1H NMR (400 MHz, CD3OD) δ 7.82 (s, 1H), 7.66 (s, 1H), 7.58-7.42 (m, 1H), 7.06-7.02 (m, 1H), 6.95-6.93 (m, 1H), 4.45 (s, 2H), 3.91 (s, 3H), 3.90-3.84 (m, 4H), 2.90-2.76 (m, 2H), 2.22-2.13 (m, 3H), 1.27-1.23 (m, 1H), 0.62-0.60 (m, 2H), 0.43-0.41 (m, 2H) 431 (M + Na) -
-
- The title compound was prepared from 2-amino-6-bromobenzonitrile in a similar fashion to Step 1 of Example 20. The crude residue was purified by silica gel chromatography (petroleum ether:EtOAc=2:1) to give the title compound (900 mg, 89%) as a brown solid. 1H NMR (400 MHz, CDCl3) δ 7.94 (s, 1H), 7.82 (s, 1H), 7.32-7.26 (m, 1H), 6.85 (d, J=7.2 Hz, 1H), 6.62 (d, J=8.4 Hz, 1H), 4.48 (s, 2H), 3.97 (s, 3H).
-
- The title compound was prepared from 2-amino-6-(1-methyl-1H-pyrazol-4-yl)benzonitrile in a similar fashion to Step 3 of Example 1. The crude residue was purified by reverse phase chromatography (acetonitrile 25-55%/0.1% NH4OH in water) to give the title compound in 8% yield as a white solid. 1H NMR (400 MHz, CD3OD) δ 8.10 (s, 1H), 7.91 (s, 1H), 7.43-7.39 (m, 1H), 7.02-6.88 (m, 2H), 4.41-4.00 (m, 2H), 3.97 (s, 3H), 3.92-3.83 (m, 4H), 2.90-2.77 (m, 2H), 2.20-2.13 (m, 3H), 1.26-1.25 (m, 1H), 0.61-0.55 (m, 2H), 0.40-0.39 (m, 2H). LCMS M/Z (M+H) 416.
- The following Example 42 was prepared in a similar fashion to Example 41.
-
Example Compound Name and Structure NMR m/z Example 42 1H NMR (400 MHz, CD3OD) δ 8.52 (d, J = 2.8 Hz, 1H), 7.99 (s, 1H), 7.90 (s, 1H), 7.83-7.76 (m, 1H), 7.51 (dd, J = 8.8, 4.8 Hz, 1H), 4.46 (s, 2H), 3.93 (s, 3H), 3.90- 3.78 (m, 4H), 2.85-2.71 (m, 2H), 2.21- 2.17 (m, 3H), 1.30-1.20 (m, 1H), 0.61- 0.54 (m, 2H), 0.42-0.35 (m, 2H) 392 -
- The title compound was prepared from 2-methyl-2H-indazol-6-amine in a similar fashion to Step 3 of Example 37. The crude residue was purified by reverse phase chromatography (acetonitrile 20-50%/0.2% formic acid in water) to give the title compound in 8% yield as a white solid. 1H NMR (400 MHz, CD3OD) δ 8.41 (d, J=6.4 Hz, 1H), 7.70-7.59 (m, 2H), 7.13 (dd, J=8.8, 4.8 Hz, 1H), 4.47 (s, 2H), 4.21 (s, 3H), 3.90-3.80 (m, 4H), 2.87-2.75 (m, 2H), 2.21-2.15 (m, 3H), 1.28-1.26 (m, 1H), 0.62-0.58 (m, 2H), 0.42-0.39 (m, 2H). LCMS M/Z (M+H) 365.
- The following Examples 44-47 were prepared in a similar fashion to Example 43.
-
Example Compound Name and Structure NMR m/z Example 44 1H NMR (400 MHz, CD3OD) δ 7.20-7.08 (m, 4H), 6.78-6.73 (m, 1H), 4.38-4.37 (m, 2H), 3.87-3.78 (m, 4H), 2.84-2.71 (m, 2H), 2.20-2.12 (m, 3H), 1.25-1.20 (m, 1H), 0.58- 0.55 (m, 2H), 0.39-0.35 (m, 2H) 311 Example 45 1H NMR (400 MHz, CD3OD) δ 6.89-6.80 (m, 3H), 3.88 (s, 2H), 3.87-3.79 (m, 4H), 2.75-2.67 (m, 6H), 2.21-2.13 (m, 3H), 1.78 (m, 4H), 1.29-1.22 (m, 1H), 0.59-0.57 (m, 2H), 0.56-0.38 (m, 2H) 365 Example 46 1H NMR (400 MHz, CD3OD) δ 7.93-7.92 (m, 1H), 7.46-7.43 (m, 2H), 7.33-7.31 (m, 1H), 4.45 (s, 2H), 3.90-3.81 (m, 4H), 3.33 (s, 3H), 2.88-2.76 (m, 2H), 2.23-2.18 (m, 3H), 1.28-1.24 (m, 1H), 0.62-0.59 (m, 2H), 0.57-0.40 (m, 2H) 389 Example 47 1H NMR (400 MHz, CD3OD) δ 8.35 (s, 1H), 7.81 (s, 1H), 7.66-7.62 (m, 1H), 4.45 (s, 2H), 3.88-3.79 (m, 4H), 2.83 (t, J = 8.0 Hz, 1H), 2.73 (t, J = 8.0 Hz, 1H), 2.31 (s, 3H), 2.21- 2.17 (m, 3H) 326 -
-
- Sodium hydride (408 mg, 10.2 mmol) was added slowly to a stirring solution of 3,4-dihydroisoquinolin-1(2H)-one (1.00 g, 6.80 mmol) in THF (30 mL) at 0° C. The mixture stirred for 0.5 h before methyl iodide (1.45 mg, 10.2 mmol) was added and the mixture was heated to reflux for 16 hours. After cooling to room temperature, water (20 mL) was added and the mixture was extracted with EtOAc (20 mL×2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the crude product (1.2 g) as a yellow oil that required no further purification.
-
- To a mixture of 2-methyl-3,4-dihydroisoquinolin-1(2H)-one (500 mg, 3.10 mmol) in concentrated H2SO4 (10 mL) at 0° C. was added potassium nitrate (2.89 mg, 3.10 mmol). The mixture was heated to 15° C. for 16 h. After cooling to room temperature, the mixture was quenched with ice water (25 mL) and extracted with EtOAc (30 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (500 mg, 27%) as yellow oil that required no further purification. 1H NMR (400 MHz, CDCl3) δ 8.92 (d, J=2.4 Hz, 1H), 8.27 (dd, J=8.4, 2.4 Hz, 1H), 7.39 (d, J=8.4 Hz, 1H), 3.66 (t, J=6.8 Hz, 2H), 3.21 (s, 3H), 3.15 (d, J=6.8 Hz, 2H).
-
- To a solution of 2-methyl-7-nitro-3,4-dihydroisoquinolin-1(2H)-one (500 mg, 2.43 mmol) in EtOAc (20 mL) was added Pd/C (300 mg). The mixture was stirred under hydrogen atmosphere (20 Psi) at room temperature for 16 hours. The mixture was filtered and the filtrate was concentrated in vacuo to give the title compound (400 mg, crude) as yellow oil, which required no further purification.
-
- The title compound was prepared from 2-methyl-7-nitro-3,4-dihydroisoquinolin-1(2H)-one in a similar fashion to Step 3 of Example 37. The crude residue was purified by reverse phase chromatography (acetonitrile 20-50%/0.2% formic acid in water) to give the title compound in 4% yield as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.67-7.50 (m, 1H), 7.19-6.97 (m, 2H), 5.97-5.74 (m, 1H), 4.43-4.19 (m, 2H), 3.99-3.70 (m, 4H), 3.64-3.47 (m, 2H), 3.23-3.08 (m, 3H), 3.04-2.86 (m, 2H), 2.86-2.62 (m, 2H), 2.24-2.07 (m, 3H), 1.26-1.14 (m, 1H), 0.69-0.53 (m, 2H), 0.42-0.27 (m, 2H). LCMS M/Z (M+H) 394.
-
- The title compound was prepared from 3-amino-N-isopropyl-5-methylbenzamide (
Step 2 of Example 18) in a similar fashion to Step 3 of Example 37. The crude residue was purified by reverse phase chromatography (acetonitrile 30-60%/0.2% formic acid in water) to give the title compound in 4% yield as a white solid. 1H NMR (400 MHz, CD3OD) δ 7.4 (d, J=6.8 Hz, 1H), 7.09 (d, J=8.4 Hz, 1H), 7.02 (d, J=6.4 Hz, 1H), 4.16 (d, J=4.4 Hz, 2H), 4.23-4.12 (m, 1H), 3.92-3.79 (m, 4H), 2.86-2.69 (m, 2H), 2.34 (d, J=4.0 Hz, 3H), 2.25-2.18 (m, 3H), 1.29 (d, J=6.4 Hz, 3H), 1.25 (d, J=6.4 Hz, 3H), 0.62-0.51 (m, 2H), 0.42-0.37 (m, 2H). LCMS M/Z (M+H) 410. -
-
- To a solution of tetrahydrofuran-3-ol (10 g, 113.5 mmol) in DCM (150 mL) was added MsCl (15.6 g, 136.2 mmol) and TEA (23 g, 227 mmol). The reaction mixture was stirred at room temperature for 18 h. Water (100 mL) was added and the mixture was extracted with DCM (100 mL×2). The combined organic layers was dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (16 g, 85%) as a brown oil. 1H NMR (400 MHz, CDCl3) δ 5.27-5.25 (m, 1H), 4.00-3.83 (m, 4H), 3.01 (s, 3H), 2.23-2.18 (m, 2H).
-
- To a solution of tert-butyl 3-bromo-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5 (4H)-carboxylate (Intermediate A, 20.0 g, 66.0 mmol) in DMF (100 mL) was added Cs2CO3 (40.0 g, 123 mmol) and tetrahydrofuran-3-yl methanesulfonate (16.0 g, 98.0 mmol). The mixture was heated to 80° C. for 12 h. The solution was concentrated in vacuo and the crude residue was purified by silica gel chromatography (eluent from petroleum ether/EtOAc=10:1 to 3:1) to give the title compound (17 g, 69%) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 4.78-4.69 (m, 1H), 4.26 (s, 2H), 4.18-3.86 (m, 4H), 3.72 (s, 2H), 2.72-2.62 (m, 2H), 2.44-2.22 (m, 2H), 1.48 (s, 9H).
-
- To a solution of tert-butyl 3-bromo-1-(tetrahydrofuran-3-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (17.0 g, 45.0 mmol) in DCM (60 mL) was added TFA (30 mL) dropwise. The reaction solution was stirred at room temperature for 2 h. The solvent was removed by evaporation and the crude product was re-dissolved in DMF (50 mL). The mixture was cooled to 0° C. before TEA (41.0 g, 40.5 mmol) and acetic anhydride (7.0 g, 68.0 mmol) were added dropwise. The ice bath was removed and the reaction was stirred at room temperature for additional 2 h. Water (50 mL) was added and the solution was extracted with EtOAc (150 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (DCM:MeOH=30:1) to give the title compound (12.0 g, 82%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 4.96-4.92 (m 1H), 4.28 (s, 2H), 3.99-3.95 (m, 2H), 3.80-3.68 (m, 4H), 2.82-2.70 (m, 2H), 2.29-2.19 (m, 2H), 2.10-2.08 (m, 3H).
-
- To a solution of 1-(3-bromo-1-(tetrahydrofuran-3-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone (Intermediate D, 300 mg, 0.96 mmol) in dioxane (8.0 mL) was added 2-fluoro-3-(1-methyl-1H-pyrazol-4-yl)aniline (
Step 2 of Example 37, 183 mg, 0.96 mmol), chloro-(2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II) (81.7 mg, 0.10 mmol), 2-(dicyclohexylphosphino)3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl (53.6 mg, 0.10 mmol) and tBuONa (277 mg, 2.9 mmol). The reaction mixture was purged with nitrogen atmosphere for 1 min and then heated to 120° C. for 18 h. The mixture was concentrated in vacuo and the crude residue was purified by reverse phase chromatography (acetonitrile 25-55%/0.1% NH4OH in water) to give the title compound (67 mg, 16%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.09 (s, 1H), 7.85-7.77 (m, 2H), 7.57-7.38 (m, 1H), 7.04-6.95 (m, 2H), 4.89-4.82 (m, 1H), 4.39-4.32 (m, 2H), 4.02-3.95 (m, 2H), 3.90 (s, 3H), 3.85-3.68 (m, 4H), 2.79-2.63 (m, 2H), 2.33-2.22 (m, 2H), 2.08-2.05 (m, 3H). LCMS M/Z (M+H) 425. - The following Examples 51-54 were prepared in a similar fashion to Example 50.
-
Example Compound Name and Structure NMR m/z Example 51 1H NMR (400 MHz, DMSO-d6) δ 8.02 (s, 1H), 7.83-7.74 (m, 2H), 7.68 (dd, J = 8.0, 8.0 Hz, 1H), 7.36-7.33 (m, 1H), 7.21 (dd, J = 8.0, 8.0 Hz, 1H), 4.87-4.82 (m, 1H), 4.40-4.33 (m, 2H), 4.01 (t, J = 7.6 Hz, 2H), 3.84-3.77 (m, 5H), 3.72-3.67 (m, 2H), 2.78-2.66 (m, 2H), 2.26-2.22 (m, 2H), 2.08-2.05 (m, 3H) 425 Example 52 1H NMR (400 MHz, CD3OD) δ 7.88 (s, 1H), 7.78 (s, 1H), 7.46-7.41 (m, 1H), 7.33-7.30 (m, 1H), 7.05 (d, J = 6.0 Hz, 1H), 4.93-4.92 (m, 1H), 4.45-4.44 (m, 2H), 4.22-4.10 (m, 2H), 3.99-3.82 (m, 7H), 2.85-2.75 (m, 2H), 2.38-2.34 (m, 2H), 2.22-2.18 (m, 3H) 425 Example 53 1H NMR (400 MHz, CD3OD) δ 8.33- 8.11 (m, 1H), 7.93 (d, J = 3.6 Hz, 1H), 7.77 (d, J = 8.0 Hz, 1H), 6.99-6.93 (m, 1H), 4.90-4.88 (m, 1H), 4.45-4.43 (m, 2H), 4.22-4.19 (m, 1H), 4.04 (d, J = 6.4 Hz, 2H), 3.91-3.78 (m, 6H), 2.85- 2.72 (m, 2H), 2.37-2.29 (m, 2H), 2.19- 2.13 (m, 3H) 443 Example 54 1H NMR (400 MHz, CD3OD) δ 8.31 (s, 1H), 8.18 (s, 1H), 7.42-7.33 (m, 1H), 7.14 (dd, J = 9.6, 9.6 Hz, 1H), 5.10 (s, 1H), 4.44-4.41 (m, 2H), 4.20-4.15 (m, 1H), 4.07-4.03 (m, 4H), 3.95-3.88 (m, 3H), 3.81-3.75 (m, 1H), 3.02-2.87 (m, 2H), 2.61-2.48 (m, 1H), 2.26-2.15 (m, 4H) 443 -
- The title compound was prepared from 2-fluoro-4-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)aniline (
Step 1 of Example 34) and Intermediate D in a similar fashion to Example 50. The crude residue was purified by reverse phase chromatography (acetonitrile 20-50%/0.2% formic acid in water) to give the title compound in 29% yield as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.11 (s, 1H), 7.99-7.92 (m, 1H), 7.85-7.68 (m, 1H), 7.17-7.12 (m, 1H), 7.06 (dd, J=8.0, 8.0 Hz, 1H), 4.92-4.80 (m, 1H), 4.41-4.35 (m, 2H), 4.03-3.80 (m, 5H), 3.87-3.75 (m, 2H), 3.73-3.68 (m, 2H), 2.79-2.67 (m, 2H), 2.27-2.23 (m, 2H), 2.09-2.05 (m, 3H). LCMS M/Z (M+H) 493. - The following Examples 56-57 were prepared in a similar fashion to Example 55.
-
Example Compound Name and Structure NMR m/z Example 56 1H NMR (400 MHz, DMSO-d6) δ 8.31- 8.25 (m, 1H), 8.02 (s, 1H), 7.41 (dd, J = 8.8, 8.8 Hz, 2H), 7.20 (dd, J = 7.6, 7.6 Hz, 2H), 4.87-4.82 (m, 1H), 4.36 (s, 2H), 4.03-3.95 (m, 2H), 3.86 (s, 3H), 3.84- 3.66 (m, 4H), 2.78-2.60 (m, 2H), 2.26- 2.20 (m, 2H), 2.07 (s, 3H) 475 Example 57 1H NMR (400 MHz, CD3OD) δ 8.67 (dd, J = 3.2, 3.2 Hz, 1H), 7.98-7.93 (m, 2H), 7.39 (dd, J = 7.6, 1.6 Hz, 1H), 4.93-4.90 (m, 1H), 4.48 (s, 2H), 4.20-4.00 (m, 2H), 3.99-3.95 (m, 5H), 3.89-3.81 (m, 2H), 2.85-2.75 (m, 2H), 2.39-2.33 (m, 2H), 2.22-2.18 (m, 3H) 476 -
-
- To a solution of tert-butyl 3-bromo-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5 (4H)-carboxylate (Intermediate A, 4.0 g, 13.2 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (1.5 g, 19.9 mmole) in DMF (20 mL) was added Cs2CO3 (10.8 g, 33.1 mmol). The reaction mixture was stirred at 80° C. for 16 h. The mixture was diluted with EtOAc (200 mL), washed with brine (100 mL×3), dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (eluent gradient from petroleum ether to petroleum ether/MTBE/THF=10:1:1) to give the title compound (1.4 g, 27%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 4.56 (q, J=8.4 Hz, 2H), 4.30 (s, 2H), 3.73 (s, 2H), 2.68 (s, 2H), 1.50 (s, 9H).
-
- To a solution of tert-butyl 3-bromo-1-(2,2,2-trifluoroethyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (1.4 g, 3.6 mmol) in DCM (20 mL) was added TFA (20 mL). The reaction mixture was stirred at room temperature for 2 h. The solution was concentrated in vacuo and the resulting residue was dissolved in DMF (20 mL). TEA (1.05 g, 10.5 mmol) and Ac2O (700 mg, 7.0 mmol) were added and reaction mixture was stirred at room temperature for 2 h. The mixture was diluted with EtOAc (200 mL), washed with brine (100 mL×3), dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (eluent from DCM to DCM/MeOH=25:1) to give the title compound (1.0 g, 89%) as a white solid. LCMS M/Z (M+H)+=328 (Br81).
-
- To a solution of 1-(3-bromo-1-(2,2,2-trifluoroethyl)-6,7-dihydro-1H-pyrazolo[4,3-c] pyridin-5(4H)-yl)ethanone (Intermediate E, 400 mg, 0.9 mmol) and 2-fluoro-3-(1-methyl-1H-pyrazol-4-yl)aniline (
Step 2 of Example 37, 260 mg, 1.4 mmol), tBuONa (220 mg, 1.4 mmol) in 1,4-dioxane (20 mL) was added chloro-(2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II) (50 mg, 0.05 mmol) and 2-(dicyclohexylphosphino)3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl (30 mg, 0.05 mmol). The reaction mixture was heated to 120° C. for 12 h under N2 atmosphere. The mixture was filtered and concentrated. The crude residue was purified by reverse phase chromatography (acetonitrile 39-69%/0.1% HCl in water) to give the title compound (34 mg, 27%) yield as a white solid. 1H NMR (400 MHz, CD3OD) δ 8.38-8.30 (m, 2H), 7.54-7.42 (m, 1H), 7.24-7.10 (m, 2H), 4.81-4.74 (m, 2H), 4.48-4.46 (m, 2H), 4.10 (s, 3H), 3.81-3.90 (m, 2H), 2.88-2.73 (m, 2H), 2.21-2.16 (m, 3H). LCMS M/Z (M+H) 437. -
-
- Cyclopropylboronic acid (568 mg, 6.62 mmol), copper acetate (903 mg, 4.96 mmol), pyridine (915 mg, 11.58 mmol) and triethylamine (835 mg, 8.27 mmol) were added successively to a solution of tert-butyl 3-bromo-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (Intermediate A, 500 mg, 127 mmol) in THF (10 mL) and the resulting mixture was heated to 60° C. for 12 h. The reaction mixture was filtered over celite, the filtrate was concentrated in vacuo and diluted with EtOAc (50 mL). The organic layer was washed with 1N HCl (10 mL), washed with brine (25 mL×2), dried over Na2SO4 and concentrated in vacuo. The crude residue was purified by silica gel chromatography (THF/methyl tertiary butyl ether/petroleum ether=1/1/20) to afford the title compound (140 mg, 24%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 4.16 (s, 2H), 3.61 (t, J=5.6 Hz, 2H), 3.51-3.44 (m, 1H), 2.75 (t, J=5.6 Hz, 2H), 1.42 (s, 9H), 1.03-0.99 (m, 2H), 0.96-0.92 (m, 2H). LCMS M/Z (M+H) 344.
-
- To tert-butyl 3-bromo-1-cyclopropyl-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (140 mg, 0.41 mmol) in EtOAc (5 mL) was added HCl (2 mL, 4 M in EtOAc). The reaction was stirred at room temperature for 2 h. The solvent was concentrated in vacuo and the crude product was re-dissolved in DCM (120 mL). The mixture was cooled to 0° C. and TEA (12.5 mg, 1.24 mmol) and acetic anhydride (84 mg, 0.82 mmol) were added dropwise. The mixture stirred at room temperature for an additional 2 h before water (25 mL) was added. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the crude product that was purified by silica gel chromatography (petroleum ether/EtOAc=2/1) to afford the title compound (100 mg, 85%) as white solid. 1H NMR (400 MHz, DMSO-d6) δ 4.26 (s, 2H), 3.74-3.67 (m, 2H), 3.49-3.43 (m, 1H), 2.85-2.71 (m, 2H), 2.09-2.07 (s, 3H), 1.03-0.99 (m, 2H), 0.97-0.92 (m, 2H).
-
-
- To a mixture of 3-bromoaniline (500 mg, 2.9 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (601 mg, 2.9 mmol) and Na2CO3 (613 mg, 5.8 mmol) in dioxane (4 mL)/H2O (1 mL) was added [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (219 mg, 0.3 mmol). The mixture was heated to 120° C. for 16 h under nitrogen atmosphere. After cooling to room temperature, the solvent was concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc=5:1) to give the title compound (380 mg, 75%) as a white solid. LCMS M/Z (M+H) 174.
-
- To a solution of 1-(3-bromo-1-cyclopropyl-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone (200 mg, 0.70 mmol) in dioxane (8.0 mL) was added 3-(1-methyl-1H-pyrazol-4-yl) aniline (122 mg, 0.70 mmol), chloro-(2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II) (57.2 mg, 0.07 mmol), 2-(dicyclohexylphosphino)3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl (37.6 mg, 0.07 mmol) and t-BuONa (135 mg, 1.41 mmol). The reaction mixture was purged with nitrogen atmosphere for 1 min. The reaction mixture was heated to 120° C. for 16 h. After cooling to rt, the reaction mixture was diluted with water (20 mL) and washed with DCM (20 mL×2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by reverse phase chromatography (acetonitrile 28-48%/0.1% NH4OH in water) to give the title compound (77 mg, 30%) as white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.11-8.06 (m, 1H), 7.98-7.97 (m, 1H), 7.70-7.68 (m, 1H), 7.50 (s, 1H), 7.25-7.22 (m, 1H), 7.17-7.12 (m, 1H), 6.91-6.87 (m, 1H), 4.33 (s, 2H), 3.86 (s, 3H), 3.76-3.67 (m, 2H), 3.42-3.36 (m, 1H), 2.82-2.67 (m, 2H), 2.10-2.05 (m, 3H), 1.05-0.85 (m, 4H). LCMS M/Z (M+H) 377.
- The following Example 60 was prepared in a similar fashion to Example 59.
-
-
- To a solution of 1-acetylpiperidin-4-one (10.0 g, 70.8 mmol) in anhydrous THE (100 mL) was added t-BuOK (9.5 g, 85.0 mmol) portionwise. The mixture was allowed to stir for 3 h at rt. A solution of 1-bromo-3-isothiocyanatobenzene (18.2 g, 85.0 mmol) in anhydrous THE (100 mL) was added dropwise at 40° C. and stirred for 2 h. Then MeI (30.2 g, 212.5 mmol) was added dropwise and the reaction was stirred for another 1 h. After cooling to room temperature, the mixture was poured into water (200 mL) and extracted with EtOAc (100 mL×3). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether/EtOAc=1/1) to afford the title compound (16.4 g, 63%) as yellow oil. LCMS M/Z (M+H) 371 (Br81).
-
- To a solution of (Z)-1-acetyl-3-(((3-bromophenyl)amino)(methylthio)methylene)piperidin-4-one (13.4 g, 36.3 mmol) in EtOH (100 mL) was added hydrazine hydrate (1.8 g, 36.3 mmol). The mixture was heated to reflux for 2 h. The solvent was concentrated in vacuo to afford the title compound (11.4 g, 94%) as a yellow solid that required no further purification. LCMS M/Z (M+H) 337 (Br81).
-
- To a solution of 1-(3-((3-bromophenyl)amino)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone (Intermediate G, 6.0 g, 17.9 mmol) in DMF (30 mL) was added (bromomethyl)cyclopropane (3.6 g, 26.9 mmol) and Cs2CO3 (11.7 g, 35.8 mmol). The mixture was heated to 80° C. for 12 h. The mixture was diluted with EtOAc (100 mL) and washed with water (100 mL×3). The organic layer was separated, dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel chromatography (DCM/MeOH=50/1 to 20/1) to afford the title compound (3.3 g, 47%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 8.36-8.31 (m, 1H), 7.75-7.73 (m, 1H), 7.32-7.29 (m, 1H), 7.11 (dd, J=15.2, 7.6 Hz, 1H), 6.86-6.83 (m, 1H), 4.35 (s, 2H), 3.78 (d, J=6.4 Hz, 2H), 3.74-3.66 (m, 2H), 2.74-2.61 (m, 2H), 2.10-2.07 (m, 3H), 1.23-1.09 (m, 1H), 0.50-0.49 (m, 2H), 0.36-0.32 (m, 2H). LCMS M/Z (M+H) 389.
-
- To a solution of 1-(3-((3-bromophenyl)amino)-1-(cyclopropylmethyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone (Example 61, 100 mg, 0.26 mmol) in dioxane (10 mL) and water (3 mL) was added (3-(hydroxymethyl) phenyl)boronic acid (47 mg, 0.31 mmol), Na2CO3 (55 mg, 0.52 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (20 mg). The mixture was degassed with nitrogen and the mixture was heated to reflux for 2 h. The reaction mixture was concentrated in vacuo and the crude product was redissolved in EtOAc (50 mL). The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by reverse phase chromatography (acetonitrile 38-68%/0.1% NH4OH in water) to give the title compound (29.3 mg, 29%) as white solid. 1H NMR (400 MHz, CD3OD): 7.58-7.56 (m, 2H), 7.44-7.38 (m, 3H), 7.25-7.23 (m, 1H), 7.06-7.01 (m, 2H), 4.62 (s, 2H), 4.42-4.40 (m, 2H), 3.88-3.78 (m, 4H), 2.84-2.82 (m, 1H), 2.74-2.71 (m, 1H), 2.19-2.11 (m, 3H), 1.24-1.21 (m, 1H), 0.60-0.54 (m, 2H), 0.40-0.38 (m, 2H). LCMS M/Z (M+H) 417.
- The following Examples 63-73 were prepared in a similar fashion to Example 62.
-
Example Compound Name and Structure NMR m/z Example 63 1H NMR (400 MHz, CD3OD) δ 8.77 (s, 1H), 8.49 (t, J = 2.4 Hz, 1H), 8.07 (d, J = 8.0 Hz, 1H), 7.59-7.48 (m, 2H), 7.32-7.18 (m, 1H), 7.09-7.06 (m, 1H), 7.05-7.03 (m, 1H), 4.43 (d, J = 6.0 Hz, 2H), 3.87-3.78 (m, 4H), 2.84-2.81 (m, 1H), 2.74-2.71 (m, 1H), 2.20-2.12 (m, 3H), 1.28-1.20 (m, 1H), 0.59-0.53 (m, 2H), 0.39- 0.37 (m, 2H) 388 Example 64 1H NMR (400 MHz, CD3OD) δ 8.56- 8.54 (m, 1H), 7.69-7.60 (m, 3H), 7.34-7.33 (m, 1H), 7.31-7.23 (m, 1H), 7.17-7.15 (m, 1H), 4.44 (d, J = 4.8 Hz, 2H), 3.90-3.82 (m, 4H), 2.86- 2.85 (m, 1H), 2.83-2.75 (m, 1H), 2.21-2.14 (m, 3H), 1.26-1.24 (m, 1H), 0.59-0.57 (m, 2H), 0.41-0.39 (m, 2H) 388 Example 65 1H NMR (400 MHz, CD3OD) δ 7.60 (s, 1H), 7.50-7.42 (m, 2H), 7.40- 7.28 (m, 2H), 7.26-7.18 (m, 1H), 7.11-6.97 (m, 2H), 4.91-4.89 (m, 1H), 4.42 (d, J = 10.4 Hz, 2H), 3.89- 3.78 (m, 4H), 2.84-2.83 (m, 1H), 2.82-2.17 (m, 1H), 2.20-2.10 (m, 3H), 1.48 (d, J = 6.4 Hz, 3H), 1.25- 1.23 (m, 1H), 0.58-0.55 (m, 2H), 0.40-0.37 (m, 2H) 431 Example 66 1H NMR (400 MHz, CD3OD) δ 7.73 (d, J = 1.2 Hz, 1H), 7.47-7.43 (m, 3H), 7.37-7.35 (m, 1H), 7.26-7.24 (m, 1H), 7.09-7.03 (m, 2H), 4.41 (d, J = 10.4 Hz, 2H), 3.88-3.78 (m, 4H), 2.84-2.81 (m, 1H), 2.74-2.71 (m, 1H), 2.19-2.10 (m, 3H), 1.57 (s, 6H), 1.25-1.20 (m, 1H), 0.58-0.54 (m, 2H), 0.39-0.36 (m, 2H) 445 Example 67 1H NMR (400 MHz, CD3OD) δ 7.85 (d, J = 2.4 Hz, 1H), 7.72 (d, J = 2.4 Hz, 1H), 7.35-7.30 (m, 1H), 7.18- 7.13 (m, 1H), 3.96-6.92 (m, 2H), 4.40-4.38 (m, 2H), 3.90 (s, 3H), 3.89- 3.80 (m, 4H), 2.84-2.81 (m, 1H), 2.74-2.72 (m, 1H), 2.19-2.11 (m, 3H), 1.24-1.21 (m, 1H), 0.60-0.54 (m, 2H), 0.40-0.38 (m, 2H) 391 Example 68 1H NMR (400 MHz, DMSO-d6) δ 8.25- 8.19 (m, 1H), 7.79 (s, 1H), 7.52- 7.38 (m, 4H), 7.27 (dd, J = 15.6, 7.6 Hz, 1H), 7.20-7.16 (m, 1H), 7.04- 7.01 (m, 1H), 4.38 (s, 2H), 3.78 (d, J = 6.8 Hz, 2H), 3.75-3.67 (m, 2H), 2.76- 2.62 (m, 2H), 2.11-2.07 (m, 3H), 1.23-1.10 (m, 1H), 0.52-0.47 (m, 2H), 0.37-0.31 (m, 2H) 405 Example 69 1H NMR (400 MHz, DMSO-d6) δ 8.22- 8.16 (m, 1H), 7.62-7.60 (m, 1H), 7.51-7.47 (m, 1H), 7.43-7.37 (m, 2H), 7.31-7.23 (m, 3H), 6.86 (d, J = 7.0 Hz, 1H), 4.37 (s, 2H), 3.76 (d, J = 6.8 Hz, 2H), 3.73-3.66 (m, 2H), 2.76- 2.61 (m, 2H), 2.10-2.06 (m, 3H), 1.19-1.11 (m, 1H), 0.50-0.44 (m, 2H), 0.34-0.30 (m, 2H) 405 Example 70 1H NMR (400 MHz, DMSO-d6) δ 12.90 (s, 1H), 8.08-8.03 (m, 2H), 7.77 (s, 1H), 7.61 (s, 1H), 7.22-7.20 (m, 1H), 7.14 (dd, J = 15.6, 7.6 Hz, 1H), 6.96-6.92, (m, 1H), 4.36 (s, 2H), 3.79 (d, J = 6.8 Hz, 2H), 3.75- 3.67 (m, 2H), 2.76-2.61 (m, 2H), 2.10-2.07 (m, 3H), 1.22-1.18 (m, 1H), 0.51-0.48 (m, 2H), 0.38-0.35 (m, 2H) 377 Example 71 1H NMR (400 MHz, DMSO-d6) δ 9.30 (d, J = 6.4 Hz, 1H), 8.98 (d, J = 6.0 Hz, 1H), 8.25-8.19 (m, 1H), 7.60 (s, 1H), 7.38-7.32 (m, 1H), 7.23 (dd, J = 8.0, 8.0 Hz, 1H), 7.03-7.00 (m, 1H), 4.35 (s, 2H), 3.79 (d, J = 6.8 Hz, 2H), 3.73-3.67 (m, 2H), 2.75-2.63 (m, 2H), 2.10-2.06 (m, 3H), 1.40-1.22 (m, 1H), 0.52-0.47 (m, 2H), 0.37- 0.33 (m, 2H) 338 Example 72 1H NMR (400 MHz, DMSO-d6) δ 8.21- 8.16 (m, 1H), 7.70 (s, 1H), 7.62- 7.61 (m, 2H), 7.38 (dd, J = 7.8, 1.8 Hz, 1H), 7.31-7.23 (m, 3H), 6.98- 6.95 (m, 1H), 4.37 (s, 2H), 3.78 (d, J = 6.8 Hz, 2H), 3.76-3.67 (m, 2H), 2.77- 2.62 (m, 2H), 2.11-2.07 (m, 3H), 1.21-1.13 (m, 1H), 0.53-0.47 (m, 2H), 0.37-0.32 (m, 2H) 405 Example 73 1H NMR (400 MHz, CD3OD) δ 7.47- 7.29 (m, 3H), 7.26 (dd, J = 7.2, 7.2 Hz, 1H), 6.85 (dd, J = 7.2, 7.2 Hz, 1H), 6.32 (d, J = 2.0 Hz, 1H), 4.42 (s, 2H), 3.86 (s, 3H), 3.84-3.78 (m, 4H), 2.83-2.71 (m, 2H), 2.19-2.13 (m, 3H), 1.22-1.18 (m, 1H), 0.55-0.52 (m, 2H), 0.37-0.33 (m, 2H) 391 -
-
- The title compound was prepared from 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in a similar fashion to Example 62. The residue was purified by silica gel chromatography (DCM/MeOH=50/1 to 20/1) to afford the title compound in 68% yield as a white solid. LCMS M/Z (M+Na) 483.
-
- To a solution of 1-(1-(cyclopropylmethyl)-3-((3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)phenyl)amino)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone (400 mg) in methanol (4.0 mL) at 0° C. was added HCl (2.0 mL, 1.0 N). The mixture was stirred at 0° C. for 1 h before it was concentrated in vacuo. The crude residue was purified by reverse phase chromatography (acetonitrile 22-52%/0.1% NH4OH in water) to give the title compound (25.6 mg, 12%) as white solid. 1H NMR (400 MHz, CD3OD) δ 7.63-7.51 (m, 2H), 7.21-7.07 (m, 3H), 6.57 (m, 1H), 4.38 (s, 2H), 4.01-3.69 (m, 4H), 2.81-2.72 (m, 2H), 2.17-2.08 (m, 3H), 1.37-1.25 (m, 1H), 0.55-0.52 (m, 2H), 0.37-0.33 (m, 2H). LCMS M/Z (M+H) 377.
-
-
- To a solution of 1-(3-((3-bromophenyl)amino)-1-(cyclopropylmethyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone (Example 61, 600 mg, 1.54 mmol) in dioxane (20 mL) was added KOAc (300 mg, 3.06 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (110 mg, 0.15 mmol) and 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (600 mg, 2.31 mmol). The reaction mixture was purged with nitrogen atmosphere for 1 min and then heated to 110° C. for 18 h. The mixture was concentrated in vacuo and the crude residue was purified by silica gel chromatography (petroleum ether:EtOAc=1:1) to give the title compound (600 mg, 85%) as a brown oil.
-
- To a solution of 1-(1-(cyclopropylmethyl)-3-((3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)amino)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl) ethanone (200 mg, 0.46 mmol) in dioxane (4 mL) and water (1 mL) was added Na2CO3 (98 mg, 0.92 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (34 mg, 0.05 mmol) and 3-bromo-1-methyl-1H-pyrazole (111 mg, 0.69 mmol). The reaction mixture was purged with nitrogen atmosphere for 1 min and heated to 110° C. for 18 h. The mixture was concentrated in vacuo and the crude residue was purified by silica gel chromatography (DCM:MeOH=10:1) to give the crude product (100 mg). The residue was further purified by reverse phase chromatography (acetonitrile 40-70%/0.1% NH4OH in water) to give the title compound (21.2 mg, 12%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.15-8.10 (m, 1H), 7.79-7.75 (m, 1H), 7.70 (s, 1H), 7.41-7.36 (m, 1H), 7.18-7.09 (m, 2H), 6.55-6.52 (m, 1H), 4.36-4.35 (m, 2H), 3.86 (s, 3H), 3.79-3.66 (m, 4H), 2.76-2.63 (m, 2H), 2.10-2.06 (m, 3H), 1.28-1.10 (m, 1H), 0.51-0.47 (m, 2H), 0.37-0.34 (m, 2H). LCMS M/Z (M+H) 391.
- The following Example 76 was prepared in a similar fashion to Example 75.
-
Example Compound Name and Structure NMR m/z Example 76 1H NMR (400 MHz, DMSO-d6) δ 8.22- 8.17 (m, 1H), 7.79 (s, 1H), 7.56 (s., 1H), 7.46 (d, J = 6.8 Hz, 1H), 7.39 (d, J = 6.8 Hz, 2H), 7.31-7.20 (m, 2H), 7.04-6.95 (m, 1H), 5.18 (d, J = 4.0 Hz, 1H), 4.51-4.50 (m, 1H), 4.38 (s, 2H), 3.82-3.64 (m, 4H), 2.76-2.60 (m, 2H), 2.11-2.07 (m, 3H), 1.71- 1.59 (m, 2H), 1.25-1.16 (m, 1H), 0.85 (t, J = 7.2 Hz, 3H), 0.51-0.48 (m, 2H), 0.35-0.30 (m, 2H) 445 -
- To a solution of 1-(3-((3-bromophenyl)amino)-1-(cyclopropylmethyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone (Example 61, 100 mg, 0.26 mmol) in dioxane (5 mL) and water (1 mL) was added cyclohex-1-en-1-ylboronic acid (65 mg, 0.51 mmol), KOAc (50 mg, 0.51 mmol) and Pb(dppf)Cl2 (20 mg, 0.03 mmol). The reaction mixture was heated to 120° C. for 12 h. The mixture was poured into water (20 mL) and extracted with EtOAc (3×30 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The crude residue was purified reverse phase chromatography (acetonitrile 46-76%/0.2% formic acid in water) to give the title compound (15 mg, 15%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.03-7.98 (m, 1H), 7.46 (s, 1H), 7.26 (d, J=8.0 Hz, 1H), 7.12-7.06 (m, 1H), 6.74 (d, J=6.8 Hz, 1H), 6.09 (s, 1H), 4.34 (s, 2H), 3.76 (d, J=6.4 Hz, 2H), 3.73-3.67 (m, 2H), 2.73-2.62 (m, 2H), 2.40-2.30 (m, 2H), 2.18-2.14 (m, 2H), 2.10-2.06 (m, 3H), 1.71-1.70 (m, 2H), 1.61-1.60 (m, 2H), 1.10-1.20 (m, 1H), 0.49-0.48 (m, 2H), 0.35-0.30 (m, 2H). LCMS M/Z (M+H) 391.
-
- To a solution of 1-(1-(cyclopropylmethyl)-3-((2′,3′,4′,5′-tetrahydro-[1,1′-biphenyl]-3-yl)amino)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone (Example 77, 100 mg, 0.26 mmol) in EtOH (10 mL) was added Pd/C (10%, 15 mg). The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred under a H2 balloon at 25° C. for 16 h. The suspension was filtered through a pad of Celite, washed with EtOH (50 mL×3) and the organic layer was concentrated in vacuo. The crude residue was purified by reverse phase chromatography (acetonitrile 46-76%/0.2% formic acid in water) to give the title compound (22 mg, 21%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.97-7.91 (m, 1H), 7.23 (s, 1H), 7.18 (d, J=8.4 Hz, 1H), 7.34 (dd, J=15.6, 7.6 Hz, 1H), 6.57-6.53 (m, 1H), 4.32 (s, 2H), 3.76 (d, J=6.4 Hz, 2H), 3.72-3.67 (m, 2H), 2.73-2.61 (m, 2H), 2.38-2.33 (m, 1H), 2.09-2.06 (m, 3H), 1.79-1.68 (m, 5H), 1.37-1.16 (m, 6H), 0.50-0.48 (m, 2H), 0.40-0.31 (m, 2H). LCMS M/Z (M+H) 393.
-
- To a solution of 1-(3-((3-bromophenyl)amino)-1-(cyclopropylmethyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone (Example 61, 100 mg, 0.26 mmol) and 2-(tributylstannyl)pyridine (94 mg, 0.26 mmol) in toluene (10 mL) was added Pd(PPh3)4(30 mg, 0.026 mmol). The reaction was heated to reflux for 12 h. The mixture was poured into water (20 mL) and extracted with EtOAc (30 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by reverse phase chromatography (acetonitrile 18-48%/0.2% formic acid in water) to give the title compound (31 mg, 31%) as a white solid. 1H NMR (400 MHz, CD3OD) δ 8.59-8.57 (m, 1H), 7.90-7.86 (m, 1H), 7.80 (d, J=8.0 Hz, 1H), 7.74-7.72 (m, 1H), 7.37-7.30 (m, 3H), 7.24-7.20 (m, 1H), 4.43-4.41 (m, 2H), 3.90-3.80 (m, 4H), 2.87-2.75 (m, 2H), 2.20-2.11 (m, 3H), 1.27-1.22 (m, 1H), 0.60-0.54 (m, 2H), 0.41-0.36 (m, 2H). LCMS M/Z (M+H) 388.
-
-
- To a solution of 1-(3-((3-bromophenyl)amino)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone (Intermediate G, 5.0 g, 15.5 mmol) in DMF (30 mL) was added iodomethane (3.8 g, 22.3 mmol) and Cs2CO3 (9.7 g, 29.8 mmol). The mixture was allowed to stir at room temperature for 5 h. The mixture was diluted with EtOAc (100 mL) and washed with water (100 mL×3). The organic layer was separated, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (DCM/MeOH=50/1 to 20/1) to afford the title compound (2.1 g, 40%) as a yellow solid. LCMS M/Z (M+H) 351 (Br81).
-
- To a solution of 1-(3-((3-bromophenyl)amino)-1-methyl-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone (Intermediate H, 100 mg, 0.28 mmol) in 1,4-dioxane (5.0 mL) and water (1.0 mL) was added 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole (84 mg, 0.43 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (20.9 mg, 0.03 mmol) and Na2CO3 (60.7 mg, 0.57 mmol). The mixture was heated to 120° C. for 12 h. The reaction mixture was filtered and concentrated in vacuo. The crude residue was purified by reverse phase chromatography (acetonitrile 25-55%/0.2% formic acid in water) to give the title compound (5.5 mg, 5%) as a white solid. 1H NMR (400 MHz, CD3OD) δ 8.91 (d, J=3.6 Hz, 1H), 8.09 (d, J=2.8 Hz, 1H), 7.51-7.48 (m, 1H), 7.26 (dd, J=14.0, 6.4 Hz, 1H), 7.17-7.13 (m, 1H), 7.08-7.05 (m, 1H), 4.42-4.41 (m, 2H), 3.90-3.80 (m, 2H), 3.69-3.68 (m, 3H), 2.83-2.70 (m, 2H), 2.21-2.13 (m, 3H). LCMS M/Z (M+H) 354.
- The following Examples 81-82 were prepared in a similar fashion to Example 80.
-
Compound Name and Example Structure NMR m/z Example 81 1-[1-methyl-3-[3-(1-methylpyrazol-4- yl)anilino]-6,7-dihydro-4H-pyrazolo[4,3- c]pyridin-5-yl]ethanone 1H NMR (400 MHz, CD3OD) δ 7.88 (d, J = 2.8 Hz, 1H), 7.72 (d, J = 2.8 Hz, 1H), 7.22- 7.19 (m, 1H), 6.95 (dd, J = 8.0, 8.0 Hz, 1H), 6.91-6.95 (m, 2H), 4.37-4.35 (m, 2H), 3.92 (s, 3H), 3.90-3.78 (m, 2H), 3.67 (s, 3H), 2.78-2.67 (m, 2H), 2.21-2.11 (m, 3H) 351 Example 82 1-(3-((3-(1H-pyrazol-4-yl)phenyl)amino)-1- methyl-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin- 5(4H)-yl)ethanone 1H NMR (400 MHz, DMSO-d6) δ 12.89 (s, 1H), 8.06-8.01 (m, 1H), 7.79 (s, 1H), 7.49 (s, 1H), 7.29-7.24 (m, 1H), 7.15 (dd, J = 15.6, 7.6 Hz, 1H), 6.95-6.92, (m, 1H), 4.34 (s, 2H), 3.74-3.66 (m, 2H), 3.61 (s, 3H), 2.73-2.59 (m, 2H), 2.10-2.05 (m, 3H) 337 -
-
- To a solution of 1-(3-((3-bromophenyl)amino)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone (Intermediate G, 1.0 g, 3.0 mmol) in 1,4-dioxane (10.0 mL) and water (2.5 mL) was added [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (0.22 g, 0.30 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.74 g, 3.6 mmol) and Na2CO3 (0.63 g, 6.0 mmol). The mixture was stirred under N2 atmosphere at 120° C. for 12 h. The reaction mixture was filtered, concentrated in vacuo and purified by silica gel chromatography (dichloromethane/methanol=20:1 to 3:1) to give the title compound (0.82 g, 82%) as a white solid.
-
- To a stirred solution of 1-(3-((3-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone (Intermediate I, 0.3 g, 0.89 mmol) in DMF (5.0 mL) was added Cs2CO3 (0.58 g, 1.8 mmol) and 1,1,1-trifluoro-2-iodoethane (0.37 g, 1.8 mmol). The mixture was heated to 110° C. for 8 h. The mixture was quenched with water and extracted with EtOAc (50 mL×2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified reverse phase chromatography (acetonitrile 39-59%/0.1% NH4OH in water) to give the title compound (6 mg, 2%) as a white solid. 1H NMR (400 MHz, CD3OD) δ 7.84 (s, 1H), 7.72 (s, 1H), 7.55 (d, J=13.2 Hz, 1H), 7.18-7.09 (m, 2H), 6.99-6.96 (m, 1H), 4.72 (q, J=8.8 Hz, 2H), 4.43-4.42 (m, 2H), 3.90 (s, 3H), 3.87-3.78 (m, 2H), 2.82-2.70 (m, 2H), 2.19-2.14 (m, 3H). LCMS M/Z (M+H) 419.
- The following Examples 84-86 were prepared in a similar fashion to Example 83.
-
Compound Name and Example Structure NMR m/z Example 84 1-[3-[3-(1-methylpyrazol-4-yl)anilino]-1-(3,3,3- trifluoropropyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin- 5-yl]ethanone 1H NMR (400 MHz, CD3OD) δ 7.84 (s, 1H), 7.71 (s, 1H), 7.38 (s, 1H), 7.19- 7.14 (m, 1H), 6.96 (dd, J = 6.8, 6.8 Hz, 1H), 4.40-4.38 (m, 2H), 4.20 (t, J = 7.2 Hz, 2H), 3.90 (s, 3H), 3.87-3.79 (m, 2H), 2.80-2.70 (m, 4H), 2.19-2.11 (m, 3H) 433 Example 85 1-[1-[(2,2-difluorocyclopropyl)methyl]- 3-[3-(1-methylpyrazol-4-yl)anilino]-6,7-dihydro-4H- pyrazolo[4,3-c]pyridin-5-yl]ethanone 1H NMR (400 MHz, DMSO-d6) δ 8.17- 8.11 (m, 1 H), 7.98-7.96 (m, 1H), 7.72- 7.70 (m, 1H), 7.62 (s, 1H), 7.24-7.22 (m, 1H), 7.18-7.11 (m, 1H), 6.95-6.85 (m, 1H), 4.36 (s, 2H), 4.13-3.94 (m, 2H), 3.86 (s, 3H), 3.79-3.65 (m, 2H), 2.76-2.59 (m, 2H), 2.22-2.11 (m, 1H), 2.10-2.07 (m, 3H), 1.70-1.65 (m, 1 H), 1.53-1.36 (m, 1 H) 427 Example 86 1-[3-[3-(1-methylpyrazol-4-yl)anilino]-1-(oxetan-3- ylmethyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5- yl]ethanone 1H NMR (400 MHz, DMSO-d6) δ 8.12- 8.07 (m, 1H), 7.97 (d, J = 4.4 Hz, 1H), 7.69 (d, J =4.8 Hz, 1H), 7.54 (s, 1H), 7.21-7.11 (m, 1H), 6.93-6.85 (m, 1H), 4.67 (dd, J = 7.6, 6.0 Hz, 2H), 4.49 (dd, J = 8.8, 6.4 Hz, 2H), 4.34 (s, 2H), 4.18 (d, J = 6.8 Hz, 2H), 3.86 (s, 3H), 3.77-3.64 (m, 2H), 2.7-2.58 (m, 2H), 2.10-2.06 (m, 3H) 407 -
- To a solution of (1-(3-((3-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone (Intermediate I, 300 mg, 0.89 mmol) in bromocyclopropane (5 mL) was added Cs2CO3 (1.45 g, 4.46 mmol). The reaction mixture was heated to 100° C. for 16 h in an autoclave. The mixture was concentrated in vacuo and the crude residue was purified by reverse phase chromatography (acetonitrile 32-62%/0.1% NH4OH in water) to give the title compound (13 mg, 4%) as a white solid. 1H NMR (400 MHz, CD3OD) δ 7.84 (s, 1H), 7.71 (s, 1H), 7.33 (d, J=14.8 Hz, 1H), 7.15 (dd, J=14.8, 8.0 Hz, 1H), 6.96-6.92 (m, 1H), 6.01-5.94 (m, 1H), 5.19 (d, J=10.0 Hz, 1H), 5.03 (d, J=17.2 Hz, 1H), 4.60-4.59 (m, 2H), 4.39 (d, J=9.2 Hz, 1H), 3.89 (s, 3H), 3.86-3.79 (m, 2H), 2.78-2.62 (m, 2H), 2.18-2.10 (m, 3H). LCMS M/Z (M+Na) 399.
-
-
- To a solution of 1-acetylpiperidin-4-one (15.0 g, 106.3 mmol) in anhydrous THF (100 mL) was added t-BuOK (14.3 g, 127.5 mmol) portionwise. The mixture was allowed to stir for 3 h before a solution of 1-bromo-4-isothiocyanatobenzene (27.3 g, 127.5 mmol) in anhydrous THF (100 mL) was added dropwise at 40° C. The mixture stirred for an additional 2 h at this temperature. Then MeI (45.3 g, 318.8 mmol) was added dropwise and the reaction was stirred for another 1 h. After cooling to room temperature, the mixture was poured into water (200 mL) and extracted with EtOAc (150 mL×3). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether/EtOAc=1/1) to afford the title compound (24.3 g, 62%) as a yellow solid. LCMS M/Z (M+H) 371 (Br81).
-
- To a solution of 1-(3-((4-bromophenyl)amino)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone (24.3 g, 65.8 mmol) in EtOH (200 mL) was added hydrazine hydrate (3.3 g, 65.8 mmol). The mixture was heated to reflux for 2 h. The solvent was removed to afford the title compound (20.0 g, 91%) as a yellow solid. LCMS M/Z (M+H) 335.
-
- To a solution of 1-(3-((4-bromophenyl)amino)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone (Intermediate J, 7.0 g, 20.9 mmol) in DMF (30 mL) was added (bromomethyl)cyclopropane (4.2 g, 31.3 mmol) and Cs2CO3 (13.6 g, 41.8 mmol). The mixture was heated to 80° C. for 12 h. The mixture was diluted with EtOAc (100 mL) and washed with water (100 mL×3). The organic layer was separated, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (DCM/MeOH=50/1 to 20/1, Rf=0.2) to afford the title compound as a yellow solid (4.0 g, 49%). 1H NMR (400 MHz, DMSO-d6, T=80° C.) δ 7.97 (s, 1H), 7.34-7.28 (m, 4H), 4.35 (s, 2H), 3.80 (d, J=6.8 Hz, 2H), 3.71 (s, 2H), 2.72 (s, 2H), 2.09 (s, 3H), 1.27-1.17 (m, 1H), 0.54-0.49 (m, 2H), 0.35-0.33 (m, 2H). LCMS M/Z (M+H) 389.
-
- To a solution of 1-(3-((4-bromophenyl)amino)-1-(cyclopropylmethyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone (Example 88, 300 mg, 0.77 mmol) in dioxane (3.0 mL) and water (1.0 mL) was added 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (192.4 mg, 0.92 mmol), [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II), complex with dichloromethane (56.29 mg, 0.07 mmol) and Na2CO3 (161.7 mg, 1.5 mmol). The reaction was heated to 120° C. for 12 h. After cooling to room temperature, the reaction was filtered and concentrated in vacuo. The crude residue was purified by reverse phase chromatography (acetonitrile 32-62%/0.1% NH4OH in water) to give the title compound (61 mg, 20%) as a white solid. 1H NMR (400 MHz, CD3OD) δ 7.54 (dd, J=6.4, 6.4 Hz, 2H), 7.82 (s, 1H), 7.71 (s, 1H), 7.38 (dd, J=8.0, 8.0 Hz, 2H), 7.15 (dd, J=8.8, 8.8 Hz, 2H), 4.42-4.40 (m, 2H), 3.92 (s, 3H), 3.90-3.80 (m, 4H), 2.86-2.73 (m, 2H), 2.22-2.15 (m, 3H), 1.26-1.25 (m, 1H), 0.62-0.56 (m, 2H), 0.40-0.39 (m, 2H). LCMS M/Z (M+H) 391.
- The following Examples 90-97 were prepared in a similar fashion to Example 89.
-
Compound Name and Example Structure NMR m/z Example 90 1-(1-(cyclopropylmethyl)-3-((3′-(2-hydroxypropan-2- yl)-[1,1′-biphenyl]-4-yl)amino)-6,7-dihydro-1H- pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone 1H NMR (400 MHz, CD3OD) δ 7.72 (s, 1H), 7.52-7.48 (m, 2H), 7.42-7.41 (m, 1H), 7.36-7.34 (m, 2H), 7.22- 7.20 (m, 2H), 4.41-4.40 (m, 2H), 3.92- 3.81 (m, 4H), 2.86-2.84 (m, 1H), 2.77-2.74 (m, 1H), 2.22-2.16 (m, 3H), 1.59 (s, 6H), 1.24-1.21 (m, 1H), 0.61-0.58 (m, 2H), 0.41-0.40 (m, 2H) 445 Example 91 1-(1-(cyclopropylmethyl)-3-((3′-(1-hydroxyethyl)- [1,1′-biphenyl]-4-yl)amino)-6,7-dihydro-1H- pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone 1H NMR (400 MHz, CD3OD): 7.57 (s, 1H), 7.50-7.43 (m, 3H), 7.35-7.33 (m, 1H), 7.26-7.18 (m, 3H), 4.42- 4.41 (m, 2H), 3.88-3.79 (m, 4H), 2.85- 2.82 (m, 1H), 2.75-2.72 (m, 1H), 2.20-2.14 (m, 3H), 1.48-1.47 (m, 3H), 1.25-1.24 (m, 1H), 0.59-0.56 (m, 2H), 0.39-0.38 (m, 2H) 431 Example 92 1-(1-(cyclopropylmethyl)-3-((3′-(hydroxymethyl)-[1, 1′-biphenyl]-4-yl)amino)-6,7-dihydro-1H- pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone 1H NMR (400 MHz, CD3OD): 7.55 (s, 1H), 7.50-7.45 (m, 3H), 7.35-7.33 (m, 1H), 7.24-7.18 (m, 2H), 4.64- 4.59 (m, 2H), 4.41-4.40 (m, 2H), 3.88- 3.80 (m, 4H), 2.83-2.81 (m, 1H), 2.73-2.71 (m, 1H), 2.19-2.14 (m, 3H), 1.24-1.21 (m, 1H), 0.58-0.55 (m, 2H), 0.38-0.37 (m, 2H) 417 Example 93 1-(1-(cyclopropylmethyl)-3-((4-(pyridin-4- yl)phenyl)amino)-6,7-dihydro-1H-pyrazolo [4,3-c]pyridin-5(4H)-yl)ethanone 1H NMR (400 MHz, DMSO-d6) δ 8.64- 8.62 (m, 2H), 8.28-8.26 (m, 2H), 7.95-7.93 (m, 2H), 7.43-7.40 (m, 1H), 7.37-7.34 (m, 1H), 3.90-3.80 (m, 4H), 2.90-2.75 (m, 2H), 2.23- 2.12 (m, 3H) 388 Example 94 1-(1-(cyclopropylmethyl)-3-((2′-fluoro-[1,1′- biphenyl′-4-yl)amino)-6,7-dihydro-1H-pyrazolo [4,3-c]pyridin-5(4H)-yl)ethanone 1H NMR (400 MHz, DMSO-d6) δ 8.29- 8.24 (m, 1H), 7.51-7.47 (m, 3H), 7.41-7.37 (m, 2H), 7.33-7.29 (m, 1H), 7.27-7.23 (m, 2H), 4.38 (s, 2H), 3.80 (d, J = 6.8 Hz, 2H), 3.76-3.67 (m, 2H), 2.77-2.62 (m, 2 H), 2.11-2.08 (m, 3H), 1.23-1.15 (m, 1H), 0.52- 0.47 (m, 2H), 0.36-0.32 (m, 2H) 405 Example 95 1-(1-(cyclopropylmethyl)-3-((3′-fluoro-[1,1′- biphenyl]-4-yl)amino)-6,7-dihydro-1H-pyrazolo[4,3- c]pyridin-5(4H)-yl)ethanone 1H NMR (400 MHz, DMSO-d6) δ 8.30- 8.25 (m, 1H), 7.58-7.39 (m, 7H), 7.08-7.04 (m, 1H), 4.37 (s, 2H), 3.80 (d, J = 6.8 Hz, 2H), 3.76-3.67 (m, 2H), 2.76-2.62 (m, 2 H), 2.10-2.08 (m, 3H), 1.23-1.16 (m, 1H), 0.52-0.47 (m, 2H), 0.36-0.31 (m, 2H) 405 Example 96 1-(1-(cyclopropylmethyl)-3-((4-(1-methyl-1H- pyrazol-5-yl)phenyl)amino)-6,7- dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone 1H NMR (400 MHz, DMSO-d6) δ 8.34- 8.30 (m, 1H), 7.51-7.48 (m, 2H), 7.39 (d, J = 1.6 Hz, 1H), 7.34-7.30 (m, 2H), 6.27 (d, J = 1.6 Hz, 1H), 4.37 (s, 2H), 3.82 (s, 3H), 3.74 (d, J = 5.2 Hz, 2H), 3.72-3.66 (m, 2H), 2.76-2.61 (m, 2 H), 2.10-2.08 (m, 3H), 1.25- 1.15 (m, 1H), 0.51-0.47 (m, 2H), 0.35- 0.33 (m, 2H) 391 Example 97 1-[1-(cyclopropylmethyl)-3-[4-(4-fluorophenyl)anilino]- 6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone 1H NMR (400 MHz, CD3OD) δ 7.54 (dd, J = 6.4, 6.4 Hz, 2H), 7.42 (dd, J = 8.4, 8.4 Hz, 2H), 7.20 (dd, J = 9.2, 9.2 Hz, 2H), 7.09 (dd, J = 2.0, 2.0 Hz, 2H), 4.40-4.39 (m, 2H), 3.87-3.78 (m, 4H), 2.83-2.71 (m, 2H), 2.19-2.13 (m, 3H), 1.24-1.23 (m, 1H), 0.59- 0.54 (m, 2H), 0.38-0.37 (m, 2H) 405 -
-
- The title compound was prepared in 80% yield from tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate in a similar fashion to Example 89.
-
- To a solution of tert-butyl 4-(4-((5-acetyl-1-(cyclopropylmethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)amino)phenyl)-1H-pyrazole-1-carboxylate (500 mg, 0.24 mmol) in DCM (2 mL) was added TFA (2 mL) dropwise. The reaction was stirred at room temperature for 2 h. The mixture was concentrated in vacuo and the crude residue was purified by reverse phase chromatography (acetonitrile 18-48%/0.1% NH4OH in water) to give the title compound (24 mg, 6%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 12.76 (s, 1H), 8.08-8.03 (m, 1H), 8.00 (s, 1H), 7.78 (s, 1H), 7.40-7.39 (m, 4H), 4.35 (s, 2H), 3.77 (d, J=7.2 Hz, 2H), 3.74-3.66 (m, 2H), 2.75-2.60 (m, 2H), 2.10-2.07 (m, 3H), 1.19-1.17 (m, 1H), 0.50-0.47 (m, 2H), 0.35-0.33 (m, 2H). LCMS M/Z (M+H) 377.
-
- The title compound was prepared from 1-(3-((4-bromophenyl)amino)-1-(cyclopropylmethyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone (Example 88) in a similar fashion to Example 89. The crude residue was purified by reverse phase chromatography (acetonitrile 46-76%/0.2% formic acid in water) to give the title compound in 15% yield. 1H NMR (400 MHz, DMSO-d6) δ 8.08-8.03 (m, 1H), 7.33 (d, J=8.8 Hz, 2H), 7.25-7.20 (m, 2H), 6.00 (s, 1H), 4.34 (s, 2H), 3.77 (d, J=6.8 Hz, 2H), 3.74-3.65 (m, 2H), 2.74-2.61 (m, 2H), 2.35-2.25 (m, 2H), 2.15-2.14 (m, 2H), 2.10-2.06 (m, 3H), 1.71-1.69 (m, 2H), 1.59-1.57 (m, 2H), 1.17-1.16 (m, 1H), 0.49-0.46 (m, 2H), 0.33-0.32 (m, 2H). LCMS M/Z (M+H) 391.
-
- The title compound was prepared from 1-(1-(cyclopropylmethyl)-3-((2′,3′,4′,5′-tetrahydro-[1,1′-biphenyl]-4-yl) amino)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone in a similar fashion to Example 78. The crude residue was purified by reverse phase chromatography (acetonitrile 52-82%/0.2% formic acid in water) to give the title compound in 15% yield. 1H NMR (400 MHz, DMSO-d6) δ 7.91-7.86 (m, 1H), 7.28 (d, J=8.4 Hz, 2H), 7.03-6.99 (m, 2H), 4.33 (s, 2H), 3.76 (d, J=6.8 Hz, 2H), 3.72-3.65 (m, 2H), 2.74-2.61 (m, 2H), 2.34-2.33 (m, 2H), 2.10-2.09 (m, 3H), 1.76-1.67 (m, 5H), 1.37-1.16 (m, 6H), 0.49-0.46 (m, 2H), 0.33-0.30 (m, 2H). LCMS M/Z (M+H) 393.
-
-
- To a solution of (3-bromophenyl)methanamine (0.5 g, 2.69 mmol) in DCM (6 mL) at 0° C. was added 3-methoxypropanoic acid (0.28 g, 2.69 mmol), HATU (1.23 g, 3.22 mmol) and DIPEA (1.04 g, 8.10 mmol). The reaction was allowed to stir at room temperature for 16 h. The reaction mixture was washed with DCM (10 mL×3) and water (10 mL) and the combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether/EtOAc=10:1-1:2) to afford the title compound (0.5 g, 68%) as a yellow oil. LCMS M/Z (M+H) 274.
-
- To a solution of 1-(3-((4-bromophenyl)amino)-1-(cyclopropylmethyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone (1 g, 2.57 mmol) in dioxane (5 mL), was added 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (0.78 g, 3.08 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (0.19 g, 0.26 mmol) and KOAc (0.50 g, 5.14 mmol). The reaction was heated to 120° C. for 16 h. After cooling to room temperature, the reaction was filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (DCM:MeOH=0-5%) to afford the title compound (0.64 g, 57%) as a light yellow solid. LCMS M/Z (M+H) 437.
-
- To a solution of 1-(1-(cyclopropylmethyl)-3-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)amino)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone (0.2 g, 0.46 mmol) in dioxane (2 mL) and water (0.5 mL) was added N-(3-bromobenzyl)-3-methoxypropanamide (0.15 g, 0.55 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (0.03 g, 0.05 mmol) and Na2CO3 (0.15 g, 1.38 mmol). The reaction was heated to 120° C. for 16 h. After cooling to room temperature, the reaction was filtered and concentrated in vacuo. The crude residue was purified by reverse phase chromatography (acetonitrile 20-50%/0.1% NH4OH in water) to give the title compound (47 mg, 20%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.39 (s, 1H), 8.25-8.20 (m, 1H), 7.49-7.34 (m, 7H), 7.13 (d, J=5.6 Hz, 1H), 4.37-4.33 (m, 4H), 3.80-3.68 (m, 6H), 3.23 (s, 3H), 2.75-2.63 (m, 2H), 2.40 (s, 2H), 2.11-2.08 (m, 3H), 1.26-1.10 (m, 1H), 0.57-0.40 (m, 2H), 0.36-0.25 (m, 2H). LCMS M/Z (M+Na) 524.
-
- The title compound was prepared from 1-(3-((4-bromophenyl)amino)-1-(cyclopropylmethyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone in a similar fashion to Example 74. The crude residue was purified by reverse phase chromatography (acetonitrile 46-76%/0.1% NH4OH in water) to give the title compound in 6% yield. 1H NMR (400 MHz, CD3OD) δ 7.61-7.48 (m, 3H), 7.24-7.15 (m, 2H), 6.55-6.45 (m, 1H), 4.42-4.41 (m, 2H), 3.89-3.81 (m, 4H), 2.85-2.73 (m, 1H), 2.21-2.14 (m, 3H), 1.28-1.24 (m, 1H), 0.61-0.56 (m, 2H), 0.41-0.37 (m, 2H). LCMS M/Z (M+H) 337.
-
- The title compound was prepared from 1-(3-((4-bromophenyl)amino)-1-(cyclopropylmethyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone in a similar fashion to Example 75. The crude residue was purified by reverse phase chromatography (acetonitrile 34-64%/0.1% NH4OH in water) to give the title compound in 5% yield. 1H NMR (400 MHz, DMSO-d6) δ 8.16-8.11 (m, 1H), 7.61-7.52 (m, 2H), 7.38 (d, J=8.8 Hz, 2H), 6.51 (d, J=2.0 Hz, 1H), 4.35 (s, 2H), 3.83 (s, 3H), 3.78 (d, J=6.8 Hz, 2H), 3.76-3.62 (m, 2H), 2.78-2.65 (m, 2H), 2.10-2.07 (m, 1H), 1.18-1.15 (m, 1H), 0.53-0.45 (m, 2H), 0.36-0.31 (m, 2H). LCMS M/Z (M+H) 391.
-
- The title compound was prepared from 1-(3-((4-bromophenyl)amino)-1-(cyclopropylmethyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone and 2-(tributylstannyl)pyridine in a similar fashion to Example 79. The crude residue was purified by reverse phase chromatography (acetonitrile 18-48%/0.1% NH4OH in water) to give the title compound in 8% yield. 1H NMR (400 MHz, CD3OD) δ 8.54-8.53 (m, 1H), 7.85-7.80 (m, 4H), 7.30-7.26 (m, 3H), 4.46-4.42 (m, 2H), 3.91-3.81 (m, 4H), 2.88-2.76 (m, 2H), 2.21-2.15 (m, 3H), 1.26-1.25 (m, 1H), 0.61-0.56 (m, 2H), 0.41-0.37 (m, 2H). LCMS M/Z (M+H) 338. (dd, J=8.8, 8.8 Hz, 2H), 7.20 (dd, J=7.6, 7.6 Hz, 2H), 4.87-4.82 (m, 1H), 4.36 (s, 2H), 4.03-3.95 (m, 2H), 3.86 (s, 3H), 3.84-3.66 (m, 4H), 2.78-2.60 (m, 2H), 2.26-2.20 (m, 2H), 2.07 (s, 3H). LCMS M/Z (M+H) 475.
-
-
- To a solution of 1-(3-((4-bromophenyl)amino)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone (Intermediate J, 5.0 g, 14.92 mmol) and Cs2CO3 (14.58 g, 44.75 mmol) in DMF (30 mL) was added iodomethane (3.18 g, 22.37 mmol) dropwise at 0° C. The reaction stirred at room temperature for 5 hours. The mixture was diluted with EtOAc (100 mL) and washed with brine (100 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (DCM/MeOH=100/1) to afford 1-(3-((4-bromophenyl)amino)-1-methyl-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone (2.7 g, 51%) as a light yellow solid. 1H NMR (400 MHz, CD3OD) δ 7.27-7.24 (m, 2H), 7.10-7.06 (m, 2H), 4.37-4.35 (m, 2H), 3.87-3.76 (m, 2H), 3.64-3.63 (m, 3H), 2.79-2.67 (m, 2H), 2.18-2.12 (m, 3H).
-
- To a mixture of 1-(3-((4-bromophenyl)amino)-1-methyl-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone (Intermediate K, 0.1 g, 0.29 mmol) and 1,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.076 g, 0.34 mmol) was added [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (0.021 g, 0.029 mmol) and Na2CO3 (0.061 g, 0.57 mmol) in 1,4-Dioxane/water (4:1, 5 mL). The reaction mixture was heated to 120° C. for 12 h. The reaction mixture was cooled to room temperature, filtered and concentrated in vacuo. The crude residue was purified by reverse phase chromatography (acetonitrile 27-57%/0.1% NH4OH in water) to give the title compound (0.022 g, 21%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.09-8.04 (s, 1H), 7.44-7.41 (m, 3H), 7.19 (dd, J=7.6, 7.6 Hz, 2H), 4.35 (s, 2H), 3.75-3.66 (m, 5H), 3.60 (s, 3H), 2.73-2.58 (m, 2H), 2.32 (s, 3H), 2.10-2.06 (s, 3H). LCMS M/Z (M+H) 387 [M+Na].
- The following Examples 106-114 were prepared in a similar fashion to Example 105.
-
Example Compound Name NMR m/z Example 106 1-[3-[4-[3-(1-hydroxyethyl)phenyl]anilino]- 1-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5- yl]ethanone 1H NMR (400 MHz, CD3OD) δ 7.61 (s, 1H), 7.55-7.54 (m, 2H), 7.47-7.30 (m, 2H), 7.27-7.23 (m, 3H), 4.85- 4.82 (m, 1H), 4.45-4.43 (s, 2H), 3.93- 3.84 (m, 2H), 3.71 (s, 3H), 2.87- 2.73 (m, 2H), 2.23-2.17 (m, 3H), 1.50 (d, J = 6.8 Hz, 3H) 391 Example 107 1-[3-[4-[3-(1-hydroxy-1-methyl-ethyl)phenyl]anilino]- 1-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5- yl]ethanone 1H NMR (400 MHz, CD3OD) δ 7.72 (s, 1H), 7.52-7.50 (m, 2H), 7.48-7.35 (m, 3H), 7.25-7.21 (m, 2H), 4.44- 4.42 (m, 2H), 3.93-3.82 (m, 2H), 3.70 (s, 3H), 2.85-2.73 (m, 2H), 2.23- 2.16 (m, 3H), 1.59 (s, 6H) 405 Example 108 1-[1-methyl-3-[4-[1-(2,2,2-trifluoroethyl)pyrazol-4- yl]anilino]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone 1H NMR (400 MHz, CDCl3) δ 7.80- 7.79 (m 1H), 7.66-7.64 (m, 1H), 7.38- 7.34 (m, 2H), 7.12-6.96 (m, 2H), 5.71 (s, 1H), 4.76-4.70 (m, 2H), 4.43- 4.24 (m, 2H), 3.93-3.70 (m, 2H), 2.22 (s, 1H), 2.76-2.68 (m, 2H), 2.20- 2.10 (m, 3H) 419 Example 109 1-[1-methyl-3-[4-(2-methylpyrazol-3-yl)anilino]- 6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone 1H NMR (400 MHz, DMSO-d6) δ 8.34- 8.29 (m, 1H), 7.49 (dd, J = 8.4, 4.8 Hz, 2H), 7.40 (d, J = 1.6 Hz, 1 H), 7.33 (dd, J = 8.4, 8.4 Hz, 2H), 6.27 (s, 1H), 4.37 (s, 2H), 3.82 (s, 3H), 3.77-3.66 (m, 2H), 3.61 (s, 3H), 2.75-2.59 (m, 1H), 2.10-2.07 (m, 3H) 351 Example 110 1-[1-methyl-3-(4-thiazol-5-ylanilino)-6,7-dihydro-4H- pyrazolo[4,3-c]pyridin-5-yl]ethanone 1H NMR (400 MHz, DMSO-d6) δ 8.93 (s, 1H), 8.37-8.32 (m, 1H), 8.10 (s, 1H), 7.55-7.41 (m, 4H), 4.35-4.33 (s, 2H), 3.77-3.64 (m, 2 H), 3.61 (s, 3H), 2.76-2.58 (m, 1H), 2.10-2.06 (m, 3H) 354 Example 111 1-[3-[4-(1,3-dimethylpyrazol-4-yl)anilino]-1-methyl-6,7- dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone 1H NMR (400 MHz, CD3OD) δ 7.56- 7.55 (m, 1H), 7.24-7.13 (m, 4H), 4.38- 4.36 (m, 2H), 3.87-3.75 (m, 5H), 3.65-3.64 (m, 3H), 2.77-2.60 (m, 2H), 2.30 (s, 3H), 2.18-2.11 (s, 3H) 365 Example 112 1-(1-methyl-3-((4-(1-methyl-3-(trifluoromethyl)-1H- pyrazol-4-yl)phenyl)amino)-6,7-dihydro-1H-pyrazolo[4,3- c]pyridin-5(4H)-yl)ethanone 1H NMR (400 MHz, CD3OD) δ 7.76 (s, 1H), 7.26-7.22 (m, 2H), 7.18-7.14 (m, 2H), 4.40-4.39 (m, 2H), 3.95 (s, 3H), 3.89-3.79 (m, 2H), 3.67-3.66 (m, 3H), 2.82-2.69 (m, 2H), 2.20- 2.13 (m, 3H) 419 Example 113 1-(1-methyl-3-((4-(1,3,5-trimethyl-1H-pyrazol-4- yl)phenyl)amino)-6,7-dihydro-1H-pyrazolo[4,3- c]pyridin-5(4H)-yl)ethanone 1H NMR (400 MHz, CD3OD) δ 7.22- 7.16 (m, 2H), 7.08-7.04 (m, 2H), 4.41 (s, 2H), 3.90-3.80 (m, 2H), 3.74 (s, 3H), 3.76-3.66 (m, 3H), 2.83-2.70 (m, 2H), 2.22-2.15 (m, 9H) 379 Example 114 1-(3-((4-(1-(difluoromethyl)-1H-pyrazol-4- yl)phenyl)amino)-1-methyl-6,7-dihydro-1H-pyrazolo[4,3- c]pyridin-5(4H)-yl)ethanone 1H NMR (400 MHz, CD3OD) δ 8.25 (d, J = 3.6 Hz, 1H), 7.99 (s, 1H), 7.47- 7.43 (m, 2H), 7.46 (t, J = 60.0 Hz, 1H), 7.20-7.16 (m, 2H), 4.40-4.39 (m, 2H), 3.90-3.79 (m, 2H), 3.68-3.67 (s, 3H), 2.82-2.70 (m, 2H), 2.20- 2.14 (m, 3H) 387 -
- To an 8 mL vial was added 1-[3-(4-bromoanilino)-1-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (Intermediate K, 35 mg, 0.10 mmol), (2-fluorophenyl)boronic acid (28 mg, 0.20 mmol), potassium phosphate tribasic (2.0 mol/L, 0.15 mL in water, 0.30 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (4.2 mg, 0.005 mmol) and 1,4-dioxane (0.3 mL). The reaction was capped and shaken at 85° C. for 1 h, then cooled to room temperature and filtered through celite. The filtrate phase was separated and the organic layer was concentrated in vacuo. The residue was purified by reverse phase HPLC (acetonitrile 20-60%/0.1% NH4OH in water) to give the title compound (19 mg, 53%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.32-8.15 (m, 1H), 7.52-7.44 (m, 3H), 7.44-7.35 (m, 2H), 7.35-7.29 (m, 1H), 7.29-7.20 (m, 2H), 4.37 (s, 2H), 3.79-3.65 (m, 2H), 3.65-3.58 (m, 3H), 2.76-2.58 (m, 2H), 2.15-2.03 (m, 3H). LCMS M/Z (M+H) 365.
- The following Examples 116-151 were prepared in a similar fashion to Example 115.
-
Compound Name and Example Structure NMR m/z Example 116 1-[3-[4-(3-fluorophenyl)anilino]-1- methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5- yl]ethanone 1H NMR (400 MHz, DMSO-d6) δ 8.33-8.19 (m, 1H), 7.62-7.51 (m, 2H), 7.51-7.37 (m, 5H), 7.12- 6.98 (m, 1H), 4.36 (s, 2H), 3.76- 3.65 (m, 2H), 3.65-3.59 (m, 3H), 2.77-2.56 (m, 2H), 2.16-2.05 (m, 3H) 365 Example 117 1-[1-methyl-3-[4-(m-tolyl)anilino]-6,7-dihydro-4H- pyrazolo[4,3-c]pyridin-5-yl]ethanone 1H NMR (400 MHz, DMSO-d6) δ 8.21-8.11 (m, 1H), 7.60-7.34 (m, 6H), 7.32-7.24 (m, 1H), 7.10- 7.03 (m, 1H), 3.78-3.64 (m, 2H), 3.61 (d, J = 2.0 Hz, 3H), 2.78- 2.57 (m, 2H), 2.35 (s, 3H), 2.13- 2.03 (m, 3H) 361 Example 118 1-[1-methyl-3-[4-(o-tolyl)anilino]-6,7-dihydro-4H- pyrazolo[4,3-c]pyridin-5-yl]ethanone 1H NMR (400 MHz, DMSO-d6) δ 8.18-8.07 (m, 1H), 7.60-7.40 (m, 2H), 7.28-7.11 (m, 6H), 4.37 (s, 2H), 3.79-3.65 (m, 2H), 3.63- 3.58 (m, 3H), 2.77-2.58 (m, 2H), 2.26 (s, 3H), 2.13-2.06 (m, 3H) 361 Example 119 1-[1-methyl-3-[4-(3-pyridyl)anilino]-6,7-dihydro- 4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone 1H NMR (400 MHz, DMSO-d6) δ 8.88-8.80 (m, 1H), 8.50-8.42 (m, 1H), 8.33-8.21 (m, 1H), 8.04- 7.93 (m, 1H), 7.62-7.47 (m, 4H), 7.44-7.31 (m, 1H), 4.42- 4.30 (m, 2H), 3.79-3.65 (m, 3H), 3.60-3.57 (m, 1H), 2.79-2.56 (m, 3H), 2.13-2.01 (m, 3H) 348 Example 120 1-[1-methyl-3-[4-(p-tolyl)anilino]-6,7-dihydro-4H- pyrazolo[4,3-c]pyridin-5-yl]ethanone 1H NMR (400 MHz, DMSO-d6) δ 8.21-8.08 (m, 1H), 7.52-7.42 (m, 6H), 7.26-7.17 (m, 2H), 4.36 (s, 2H), 3.78-3.64 (m, 2H), 3.61 (d, J = 2.0 Hz, 3H), 2.77-2.57 (m, 2H), 2.31 (s, 3H), 2.13-2.03 (m, 3H) 361 Example 121 1-[1-methyl-3-[4-[4-(4-methylpiperazine-1-carbonyl)phenyl]anilino]-6,7- dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone 1H NMR (400 MHz, DMSO-d6) δ 8.29-8.20 (m, 1H), 7.70-7.63 (m, 2H), 7.60-7.52 (m, 2H), 7.51- 7.45 (m, 2H), 7.43-7.38 (m, 2H), 4.37 (s, 2H), 3.77-3.65 (m, 2H), 3.64-3.60 (m, 3H), 2.77- 2.58 (m, 2H), 2.52-2.47 (m, 4H), 2.40-2.26 (m, 4H), 2.20 (s, 3H), 2.13-2.05 (m, 3H) 473 Example 122 3-[4-[(5-acetyl-1-methyl-6,7-dihydro-4H-pyrazolo[4,3- c]pyridin-3-yl)amino]phenyl]benzonitrile 1H NMR (400 MHz, DMSO-d6) δ 8.35-8.24 (m, 1H), 8.08-8.03 (m, 1H), 7.99-7.92 (m, 1H), 7.74- 7.66 (m, 1H), 7.65-7.56 (m, 3H), 7.53-7.47 (m, 2H), 4.37 (d, J = 1.7 Hz, 2H), 3.77-3.65 (m, 2H), 3.62 (d, J = 2.0 Hz, 3H), 2.77- 2.57 (m, 2H), 2.14-2.05 (m, 3H) 372 Example 123 1-[3-[4-(1-ethylpyrazol-4-yl)anilino]-1-methyl-6,7- dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone 1H NMR (400 MHz, DMSO-d6) δ 8.07-7.95 (m, 2H), 7.72-7.68 (m, 1H), 7.40-7.32 (m, 4H), 4.34 (s, 2H), 4.12 (q, J = 7.3 Hz, 2H), 3.77-3.64 (m, 2H), 3.63-3.57 (m, 3H), 2.75-2.56 (m, 2H), 2.12- 2.04 (m, 3H), 1.39 (t, J = 7.3 Hz, 3H) 365 Example 124 1-[3-[4-(4-fluorophenyl)anilino]-1-methyl- 6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone 1H NMR (400 MHz, DMSO-d6) δ 8.23-8.13 (m, 1H), 7.65-7.58 (m, 2H), 7.51-7.42 (m, 4H), 7.27- 7.17 (m, 2H), 4.36 (s, 2H), 3.77- 3.66 (m, 2H), 3.64-3.58 (m, 3H), 2.76-2.58 (m, 2H), 2.13-2.05 (m, 3H) 365 Example 125 1-[3-[4-(4-methoxyphenyl)anilino]-1- methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone 1H NMR (400 MHz, DMSO-d6) δ 8.16-8.06 (m, 1H), 7.55-7.49 (m, 2H), 7.46-7.42 (m, 4H), 7.00- 6.94 (m, 2H), 4.36 (s, 2H), 3.77 (s, 3H), 3.76-3.65 (m, 2H), 3.63- 3.59 (m, 3H), 2.76-2.57 (m, 2H), 2.12-2.04 (m, 3H) 377 Example 126 4-[4-[(5-acetyl-1-methyl-6,7-dihydro-4H-pyrazolo[4,3- c]pyridin-3-yl)amino]phenyl]benzonitrile 1H NMR (400 MHz, DMSO-d6) δ 8.41-8.32 (m, 1H), 7.86-7.80 (m, 4H), 7.67-7.60 (m, 2H), 7.54- 7.47 (m, 2H), 4.41-4.33 (m, 2H), 3.77-3.65 (m, 2H), 3.65- 3.59 (m, 3H), 2.78-2.59 (m, 2H), 2.12-2.04 (m, 3H) 372 Example 127 1-[3-[4-(2-methoxyphenyl)anilino]-1- methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5- yl]ethanone 1H NMR (400 MHz, DMSO-d6) δ 8.18-8.01 (m, 1H), 7.46-7.36 (m, 2H), 7.34-7.20 (m, 4H), 7.08- 7.02 (m, 1H), 7.02-6.94 (m, 1H), 4.36 (s, 2H), 3.80-3.64 (m, 5H), 3.64-3.56 (m, 3H), 2.79- 2.56 (m, 2H), 2.13-2.03 (m, 3H) 377 Example 128 1-[3-[4-(3-methoxyphenyl)anilino]-1- methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone 1H NMR (400 MHz, DMSO-d6) δ 8.24-8.14 (m, 1H), 7.56-7.43 (m, 4H), 7.34-7.26 (m, 1H), 7.20- 7.09 (m, 2H), 6.86-6.79 (m, 1H), 4.40-4.34 (m, 2H), 3.81 (s, 3H), 3.78-3.65 (m, 2H), 3.64- 3.58 (m, 3H), 2.77-2.58 (m, 2H), 2.15-2.04 (m, 3H) 377 Example 129 1-[3-[4-(4-chlorophenyl)anilino]-1- methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone 1H NMR (400 MHz, DMSO-d6) δ 8.30-8.17 (m, 1H), 7.67-7.38 (m, 8H), 4.36 (s, 2H), 3.79-3.65 (m, 2H), 3.65-3.59 (m, 3H), 2.78- 2.58 (m, 2H), 2.15-2.04 (m, 3H) 381 Example 130 1-[3-[4-[4-(hydroxymethyl)phenyl]anilino]- 1-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone 1H NMR (400 MHz, DMSO-d6) δ 8.24-8.10 (m, 1H), 7.58-7.42 (m, 6H), 7.38-7.28 (m, 2H), 4.50 (d, J = 4.4 Hz, 2H), 4.36 (s, 2H), 3.78-3.65 (m, 2H), 3.63-3.56 (m, 3H), 2.76-2.57 (m, 2H), 2.13- 2.04 (m, 3H) 377 Example 131 1-[3-[4-(3,5-difluorophenyl)anilino]-1- methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5- yl]ethanone 1H NMR (400 MHz, DMSO-d6) δ 8.38-8.27 (m, 1H), 7.65-7.45 (m, 5H), 7.39-7.30 (m, 2H), 7.10- 7.01 (m, 1H), 4.37 (s, 2H), 3.79- 3.65 (m, 2H), 3.65-3.57 (m, 3H), 2.78-2.58 (m, 2H), 2.15-2.03 (m, 3H) 383 Example 132 1-[3-[4-(3-chlorophenyl)anilino]-1- methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5- yl]ethanone 1H NMR (400 MHz, DMSO-d6) δ 8.31-8.21 (m, 1H), 7.65-7.38 (m, 7H), 7.33-7.27 (m, 1H), 4.36 (s, 2H), 3.78-3.65 (m, 2H), 3.65- 3.59 (m, 3H), 2.77-2.57 (m, 2H), 2.13-2.04 (m, 3H) 381 Example 133 1-[3-[4-(3,4-difluorophenyl)anilino]-1- methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone 1H NMR (400 MHz, DMSO-d6) δ 8.30-8.19 (m, 1H), 7.70-7.60 (m, 1H), 7.57-7.41 (m, 6H), 4.36 (s, 2H), 3.77-3.65 (m, 2H), 3.65- 3.58 (m, 3H), 2.77-2.57 (m, 2H), 2.13-2.04 (m, 3H) 383 Example 134 1-[3-[4-(2,5-difluorophenyl)anilino]-1- methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone 1H NMR (400 MHz, DMSO-d6) δ 8.35-8.25 (m, 1H), 7.51-7.39 (m, 4H), 7.38-7.25 (m, 2H), 7.18- 7.09 (m, 1H), 4.40-4.33 (m, 2H), 3.77-3.64 (m, 2H), 3.64- 3.58 (m, 3H), 2.77-2.57 (m, 2H), 2.13-2.05 (m, 3H) 383 Example 135 4-[4-[(5-acetyl-1-methyl-6,7-dihydro-4H-pyrazolo[4,3- c]pyridin-3-yl)amino]phenyl]benzamide 1H NMR (400 MHz, DMSO-d6) δ 8.31-8.22 (m, 1H), 7.95-7.87 (m, 3H), 7.71-7.65 (m, 2H), 7.63- 7.55 (m, 2H), 7.52-7.45 (m, 2H), 7.27 (s, 1H), 4.41-4.30 (m, 2H), 3.77-3.64 (m, 2H), 3.64- 3.60 (m, 3H), 3.60-3.56 (m, 1H), 2.77-2.56 (m, 2H), 2.13-2.03 (m, 3H) 390 Example 136 1-[1-methyl-3-[4-[3-(trifluoromethyl)phenyl]anilino]- 6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone 1H NMR (400 MHz, DMSO-d6) δ 8.33-8.24 (m, 1H), 7.94-7.85 (m, 2H), 7.67-7.57 (m, 4H), 7.53- 7.47 (m, 2H), 4.37 (s, 2H), 3.78- 3.64 (m, 2H), 3.65-3.60 (m, 3H), 2.78-2.57 (m, 2H), 2.14-2.04 (m, 3H) 415 Example 137 1-[3-[4-[3-(dimethylamino)phenyl]anilino]- 1-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone 1H NMR (400 MHz, DMSO-d6) δ 8.20-8.09 (m, 1H), 7.51-7.41 (m, 4H), 7.23-7.16 (m, 1H), 6.90- 6.84 (m, 2H), 6.67-6.60 (m, 1H), 4.36 (s, 2H), 3.78-3.65 (m, 2H), 3.64-3.58 (m, 3H), 2.94 (s, 6H), 2.67 (d, J = 47.2, 5.8 Hz, 2H), 2.13-2.04 (m, 3H) 390 Example 138 4-[4-[(5-acetyl-1-methyl-6,7-dihydro-4H-pyrazolo[4,3- c]pyridin-3-yl)amino]phenyl]-N,N-dimethyl-benzamide 1H NMR (400 MHz, DMSO-d6) δ 8.28-8.19 (m, 1H), 7.68-7.63 (m, 2H), 7.60-7.53 (m, 2H), 7.52- 7.46 (m, 2H), 7.45-7.40 (m, 2H), 4.40-4.34 (m, 2H), 3.78- 3.64 (m, 2H), 3.64-3.58 (m, 3H), 2.98 (s, 7H), 2.77-2.57 (m, 2H), 2.13-2.04 (m, 3H) 419 Example 139 1-[1-methyl-3-[4-[4-(trifluoromethyl)phenyl]anilino]- 6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone 1H NMR (400 MHz, DMSO-d6) δ 8.36-8.27 (m, 1H), 7.85-7.79 (m, 2H), 7.77-7.70 (m, 2H), 7.64- 7.57 (m, 2H), 7.54-7.47 (m, 2H), 4.37 (s, 2H), 3.79-3.66 (m, 2H), 3.65-3.58 (m, 3H), 2.79- 2.58 (m, 2H), 2.14-2.05 (m, 3H) 415 Example 140 3-[4-[(5-acetyl-1-methyl-6,7-dihydro-4H-pyrazolo[4,3- c]pyridin-3-yl)amino]phenyl]-N,N-dimethyl-benzamide 1H NMR (400 MHz, DMSO-d6) δ 8.28-8.17 (m, 1H), 7.71-7.63 (m, 1H), 7.60-7.51 (m, 3H), 7.50- 7.42 (m, 3H), 7.29-7.23 (m, 1H), 4.36 (s, 2H), 3.77-3.65 (m, 2H), 3.64-3.59 (m, 3H), 2.98 (d, J = 19.1 Hz, 6H), 2.76-2.58 (m, 2H), 2.08 (d, J = 13.2 Hz, 3H) 419 Example 141 1-[1-methyl-3-[4-[3-(trifluoromethoxy)phenyl]anilino]- 6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone 1H NMR (400 MHz, DMSO-d6) δ 8.35-8.22 (m, 1H), 7.69-7.62 (m, 1H), 7.61-7.44 (m, 6H), 7.26- 7.19 (m, 1H), 4.37 (s, 2H), 3.78- 3.65 (m, 2H), 3.65-3.59 (m, 3H), 2.77-2.57 (m, 2H), 2.13-2.05 (m, 3H) 431 Example 142 1-[1-methyl-3-[4-[4-(trifluoromethoxy)phenyl]anilino]- 6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone 1H NMR (400 MHz, DMSO-d6) δ 8.29-8.19 (m, 1H), 7.74-7.67 (m, 2H), 7.56-7.45 (m, 4H), 7.41- 7.34 (m, 2H), 4.40-4.32 (m, 2H), 3.77-3.65 (m, 2H), 3.64- 3.59 (m, 3H), 2.77-2.57 (m, 2H), 2.12-2.05 (m, 3H) 431 Example 143 N-[3-[4-[(5-acetyl-1-methyl-6,7-dihydro-4H-pyrazolo[4,3- Not Determined 440 c]pyridin-3-yl)amino]phenyl]phenyl]-methanesulfonamide Example 144 N-[4-[4-[(5-acetyl-1-methyl-6,7-dihydro-4H-pyrazolo[4,3- c]pyridin-3-yl)amino]phenyl]phenyl]-methanesulfonamide 1H NMR (400 MHz, DMSO-d6) δ 8.21-8.11 (m, 1H), 7.59-7.53 (m, 2H), 7.51-7.42 (m, 4H), 7.26- 7.20 (m, 2H), 4.36 (s, 2H), 3.78- 3.64 (m, 2H), 3.64-3.57 (m, 3H), 2.97 (s, 3H), 2.77-2.58 (m, 2H), 2.14-2.04 (m, 3H) 440 Example 145 5-[4-[(5-acetyl-1-methyl-6,7-dihydro-4H-pyrazolo[4,3- c]pyridin-3-yl)amino]phenyl]pyridine-2-carbonitrile 1H NMR (400 MHz, DMSO-d6) δ 9.08-9.03 (m, 1H), 8.50-8.41 (m, 1H), 8.28-8.20 (m, 1H), 8.05- 7.99 (m, 1H), 7.77-7.69 (m, 2H), 7.59-7.50 (m, 2H), 4.37 (s, 2H), 3.71 (dt, J = 20.4, 5.8 Hz, 2H), 3.66-3.61 (m, 3H), 2.78-2.56 (m, 2H), 2.14-2.02 (m, 3H) 373 Example 146 5-[4-[(5-acetyl-1-methyl-6,7-dihydro-4H-pyrazolo[4,3- c]pyridin-3-yl)amino]phenyl]pyridine-3-carbonitrile 1H NMR (400 MHz, DMSO-d6) δ 9.14 (t, J = 2.0 Hz, 1H), 8.86 (t, J = 2.0 Hz, 1H), 8.55-8.50 (m, 1H), 8.42-8.32 (m, 1H), 7.72-7.65 (m, 2H), 7.57-7.48 (m, 2H), 4.37 (s, 2H), 3.79-3.66 (m, 2H), 3.65- 3.61 (m, 3H), 2.77-2.57 (m, 2H), 2.14-2.05 (m, 3H) 373 Example 147 1-[1-methyl-3-[4-[4-(morpholine-4-carbonyl) phenyl]anilino]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone 1H NMR (400 MHz, DMSO-d6) δ 8.30-8.20 (m, 1H), 7.70-7.64 (m, 2H), 7.60-7.52 (m, 2H), 7.52- 7.40 (m, 4H), 4.37 (s, 2H), 3.78- 3.65 (m, 2H), 3.65-3.57 (m, 6H), 3.57-3.43 (m, 5H), 2.77-2.57 (m, 2H), 2.12-2.03 (m, 3H) 460 Example 148 5-[4-[(5-acetyl-1-methyl-6,7-dihydro-4H-pyrazolo[4,3- c]pyridin-3-yl)amino]phenyl]-N-methyl-pyridine-2-carboxamide 1H NMR (400 MHz, DMSO-d6) δ 8.91-8.84 (m, 1H), 8.74-8.66 (m, 1H), 8.41-8.30 (m, 1H), 8.21- 8.11 (m, 1H), 8.06-7.98 (m, 1H), 7.72-7.62 (m, 2H), 7.57- 7.49 (m, 2H), 4.37 (s, 2H), 3.78- 3.65 (m, 2H), 3.65-3.60 (m, 3H), 2.88-2.80 (m, 3H), 2.77-2.57 (m, 2H), 2.14-2.06 (m, 3H) 405 Example 149 4-[4-[(5-acetyl-1-methyl-6,7-dihydro-4H-pyrazolo[4,3- c]pyridin-3-yl)amino]phenyl]-N-methyl-benzamide 1H NMR (400 MHz, DMSO-d6) δ 8.43-8.36 (m, 1H), 8.31-8.22 (m, 1H), 7.89-7.83 (m, 2H), 7.72- 7.66 (m, 2H), 7.63-7.55 (m, 2H), 7.52-7.46 (m, 2H), 4.37 (s, 2H), 3.78-3.64 (m, 2H), 3.64- 3.60 (m, 3H), 2.83-2.77 (m, 3H), 2.76-2.59 (m, 2H), 2.13-2.06 (m, 3H) 404 Example 150 3-[4-[(5-acetyl-1-methyl-6,7-dihydro-4H-pyrazolo[4,3- c]pyridin-3-yl)amino]phenyl]-N-methyl-benzamide 1H NMR (400 MHz, DMSO-d6) δ 8.54-8.45 (m, 1H), 8.29-8.18 (m, 1H), 8.07-8.02 (m, 1H), 7.79- 7.68 (m, 2H), 7.63-7.53 (m, 2H), 7.53-7.44 (m, 3H), 4.36 (s, 2H), 3.78-3.65 (m, 2H), 3.64- 3.60 (m, 3H), 2.81 (d, J = 4.5 Hz, 3H), 2.77-2.59 (m, 2H), 2.13- 2.06 (m, 3H) 404 Example 151 1-[3-[4-[3-(hydroxymethyl)phenyl]anilino]-1- methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone 1H NMR (400 MHz, DMSO-d6) δ 8.24-8.11 (m, 1H), 7.57-7.42 (m, 6H), 7.38-7.31 (m, 1H), 7.24- 7.17 (m, 1H), 5.21-5.12 (m, 1H), 4.59-4.51 (m, 2H), 4.36 (s, 2H), 3.78-3.65 (m, 2H), 3.65- 3.59 (m, 3H), 2.77-2.55 (m, 2H), 2.08 (d, J = 13.4 Hz, 3H) 377 -
- A microwave vial was charged with 1-[3-(4-bromoanilino)-1-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (Intermediate K, 30 mg, 0.08591 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine (27.71 mg, 0.1117 mmol), SiliaCat DPP-Pd (17 mg, 0.004296 mmol) and potassium carbonate (23.75 mg, 0.1718 mmol). Methanol (2 mL) was added and the mixture was irradiated at 120° C. for 15 min before being filtered. The solution was concentrated in vacuo to yield the crude residue that was purified by reverse phase HPLC to afford the title compound (20.4 mg, 59%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.09-7.95 (m, 1H), 7.57 (d, J=2.4 Hz, 1H), 7.45-7.19 (m, 3H), 4.34 (s, 2H), 4.07 (t, J=6.1 Hz, 2H), 3.78-3.63 (m, 2H), 3.59 (d, J=2.0 Hz, 3H), 2.87 (t, J=6.3 Hz, 2H), 2.77-2.55 (m, 2H), 2.13-2.02 (m, 3H), 2.02-1.91 (m, 2H), 1.88-1.76 (m, 2H). LCMS M/Z (M+H) 391.
- The following Examples 153-167 were prepared in a similar fashion to Example 152.
-
Compound Name and Example Structure NMR m/z Example 153 1-[3-[4-(1-cyclopropylpyrazol-4-yl)anilino]-1-methyl-6,7- dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone 1H NMR (400 MHz, DMSO-d6) δ 8.08-7.95 (m, 2H), 7.74-7.66 (m, 1H), 7.36 (d, J = 3.3 Hz, 4H), 4.34 (s, 2H), 3.79-3.62 (m, 3H), 3.60 (d, J = 2.1 Hz, 3H), 2.80- 2.55 (m, 3H), 2.07 (d, J = 14.8 Hz, 3H), 1.08-1.01 (m, 2H), 1.00- 0.89 (m, 2H) 377 Example 154 1-[3-[4-(3-cyclopropyl-1-methyl-pyrazol-4-yl)anilino]-1- methyl-6,7-dihydro-4H-pyrazolo[4,3- c]pyridin-5-yl]ethanone 1H NMR (400 MHz, DMSO-d6) δ 8.10-7.97 (m, 1H), 7.66 (d, J = 2.2 Hz, 1H), 7.47-7.36 (m, 2H), 7.33 (dd, J = 8.8, 6.9 Hz, 2H), 4.35 (s, 2H), 3.78-3.55 (m, 8H), 2.77- 2.56 (m, 2H), 2.08 (d, J = 14.0 Hz, 3H), 1.89 (tt, J = 8.3, 5.1 Hz, 1H), 0.90-0.79 (m, 2H), 0.79- 0.71 (m, 2H) 391 Example 1-[1-methyl-3-[4-(4-pyridyl)anilino]-6,7-dihydro-4H- Not Determined 348 155 pyrazolo[4,3-c]pyridin-5-yl]ethanone Example 156 1-[1-methyl-3-(4-pyrimidin-5-ylanilino)-6,7-dihydro-4H- pyrazolo[4,3-c]pyridin-5-yl]ethanone 1H NMR (400 MHz, DMSO-d6) δ 9.08-9.04 (m, 3H), 8.40-8.31 (m, 1H), 7.70-7.63 (m, 2H), 7.58- 7.51 (m, 2H), 4.37 (s, 2H), 3.78- 3.57 (m, 5H), 2.79-2.58 (m, 2H), 2.14-2.03 (m, 3H) 349 Example 157 1-[3-[4-(6-amino-3-pyridyl)anilino]-1-methyl-6,7- dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone 1H NMR (400 MHz, DMSO-d6) δ 8.18-7.99 (m, 2H), 7.64-7.56 (m, 1H), 7.46-7.32 (m, 4H), 6.51- 6.46 (m, 1H), 5.88-5.80 (m, 2H), 4.38-4.30 (m, 2H), 3.78- 3.63 (m, 2H), 3.63-3.56 (m, 3H), 2.77-2.56 (m, 2H), 2.14-2.02 (m, 3H) 363 Example 158 1-[1-methyl-3-[4-(5-methylsulfonyl-3-pyridyl) anilino]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone 1H NMR (400 MHz, DMSO-d6) δ 9.20-9.15 (m, 1H), 8.95-8.89 (m, 1H), 8.47-8.39 (m, 1H), 7.76- 7.68 (m, 1H), 7.59-7.51 (m, 2H), 7.40-7.32 (m, 1H), 7.21- 7.10 (m, 1H), 4.41-4.30 (m, 2H), 3.81-3.55 (m, 6H), 3.38 (d, J = 0.8 Hz, 3H), 2.79-2.56 (m, 1H), 2.15-2.03 (m, 3H) 427 Example 159 1-[3-[4-(2-isopropoxy-3-pyridyl)anilino]-1-methyl-6,7- dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone 1H NMR (400 MHz, DMSO-d6) δ 8.22-8.11 (m, 1H), 8.07-8.02 (m, 1H), 7.66 (dt, J = 7.3, 1.5 Hz, 1H), 7.46-7.37 (m, 4H), 7.02- 6.96 (m, 1H), 5.34 (hept, J = 6.1 Hz, 1H), 4.36 (d, J = 2.8 Hz, 2H), 3.81-3.65 (m, 2H), 3.61 (d, J = 1.9 Hz, 3H), 2.78-2.57 (m, 2H), 2.15-1.99 (m, 3H), 1.29 (d, J = 6.2 Hz, 6H) 406 Example 160 1-[1-methyl-3-[4-(6-methyl-3-pyridyl)anilino]-6,7-dihydro-4H- pyrazolo[4,3-c]pyridin-5-yl]ethanone 1H NMR (400 MHz, DMSO-d6) δ 8.70-8.66 (m, 1H), 8.27-8.17 (m, 1H), 7.86 (dt, J = 8.1, 2.2 Hz, 1H), 7.57-7.39 (m, 5H), 7.29- 7.23 (m, 1H), 4.36 (s, 2H), 3.78- 3.66 (m, 2H), 3.61 (d, J = 2.1 Hz, 3H), 2.78-2.58 (m, 2H), 2.47 (s, 3H), 2.13-2.04 (m, 3H) 362 Example 1-[1-methyl-3-[4-(2-methyl-3-pyridyl)anilino]-6,7-dihydro- Not Determined 362 161 4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone Example 1-[3-[4-(2,4-dimethylpyrazol-3-yl)anilino]-1-methyl-6,7- Not Determined 365 162 dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone Example 163 N-[5-[4-[(5-acetyl-1-methyl-6,7-dihydro-4H-pyrazolo[4,3- c]pyridin-3-yl)amino]phenyl]-2-pyridyl]acetamide 1H NMR (400 MHz, DMSO-d6) δ 10.45 (s, 1H), 8.59-8.52 (m, 1H), 8.21 (d, J = 20.0 Hz, 1H), 8.09 (d, J = 8.7 Hz, 1H), 7.98 (dt, J = 8.7, 2.2 Hz, 1H), 7.58-7.43 (m, 4H), 4.36 (s, 2H), 3.71 (dt, J = 21.2, 5.8 Hz, 2H), 3.64-3.57 (m, 3H), 2.77- 2.57 (m, 2H), 2.08 (d, J = 13.5 Hz, 6H) 405 Example 164 1-[3-[4-(1-isobutylpyrazol-4-yl)anilino]-1-methyl-6,7-dihydro- 4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone 1H NMR (400 MHz, DMSO-d6) δ 8.08-7.97 (m, 1H), 7.96-7.92 (m, 1H), 7.73-7.69 (m, 1H), 7.41- 7.32 (m, 4H), 4.34 (s, 2H), 3.89 (d, J = 7.2 Hz, 2H), 3.79-3.63 (m, 2H), 3.60 (d, J = 2.0 Hz, 3H), 2.77-2.56 (m, 2H), 2.19-2.01 (m, 4H), 0.86 (d, J = 6.7 Hz, 6H) 393 Example 1-[3-[4-(6-hydroxy-3-pyridyl)anilino]-1-methyl-6,7- Not Determined 364 165 dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone Example 1-[1-methyl-3-[4-(4-methyl-3-pyridyl)anilino]-6,7-dihydro- Not Determined 362 166 4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone Example 1-[3-[4-(2,6-dimethyl-3-pyridyl)anilino]-1-methyl-6,7- Not Determined 376 167 dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone -
-
- To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2 g, 10.3 mol) in MeCN (30 mL) was added tert-butyl (2-bromoethyl)carbamate (3.46 g, 15.5 mmol) and Cs2CO3 (10.1 g, 30.9 mmol). The mixture was heated to 60° C. for 12 h. After cooling to rt, the reaction was diluted in water (80 mL) and washed with EtOAc (80 mL×2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (petroleum ether/EtOAc=8/1) to give the title compound (1.2 g, 35%) as a white solid.
-
- To a stirred of solution of tert-butyl (2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethyl)carbamate (500 mg, 1.48 mmol) in THF (10 mL) was added NaH (77 mg, 1.93 mmol) in an ice bath. After being stirred at 0° C. for 30 min, MeI (274 mg, 1.93 mmol) was added and the reaction mixture stirred at room temperature for 3 h. The reaction was quenched by water (20 ml) and extracted with EtOAc (20 mL×2). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (petroleum ether:EtOAc=5:1) to afford the title compound (200 mg, 38%) as a white solid.
-
- The title compound was prepared from 1-(3-((4-bromophenyl)amino)-1-methyl-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone (Intermediate K, 201 mg, 0.57 mmol) and tert-butyl methyl(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethyl)carbamate in a similar fashion to Example 105. The crude product was purified by silica gel chromatography (DCM/MeOH=20/1) to afford the title compound (110 mg, 39%) as a white solid.
-
- To a stirred solution of tert-butyl N-[2-[4-[4-[(5-acetyl-1-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-3-yl)amino]phenyl]pyrazol-1-yl]ethyl]-N-methyl-carbamate (100 mg, 0.2 mmol) in DCM (4 mL) was added TFA (2 mL) dropwise. The mixture was stirred at room temperature for 3 h. The mixture was concentrated in vacuo and the crude residue was purified by reverse phase chromatography (acetonitrile 27-57%/0.1% NH4OH in water) to give the title compound (26 mg, 33%) as a white solid. 1H NMR (400 MHz, CD3OD) δ 7.86 (d, J=3.6 Hz, 1H), 7.75 (d, J=2.0 Hz, 1H), 7.38 (dd, J=8.0, 8.0 Hz, 1H), 7.14 (dd, J=8.0, 8.0 Hz, 1H), 4.39-4.37 (m, 2H), 4.27 (t, J=6.0 Hz, 3H), 3.87-3.78 (m, 2H), 3.66 (s, 3H), 3.03 (t, J=6.0 Hz, 3H), 2.81-2.36 (m, 2H), 2.40 (s, 3H), 2.19-2.12 (m, 3H). LCMS M/Z (M+H) 394.
-
- The title compound was prepared from 1-(3-((4-bromophenyl)amino)-1-methyl-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone in a similar fashion to Example 74. The crude residue was purified by reverse phase chromatography (acetonitrile 30-60%/0.1% NH4OH in water) to give the title compound in 70% yield. 1H NMR (400 MHz, DMSO-d6) δ 13.0 (s, 1H), 12.6 (s, 1H), 8.33-8.07 (m, 1H), 7.76-7.33 (m, 5H), 6.58-6.42 (m, 1H), 4.36 (s, 2H), 3.76-3.66 (m, 2H), 3.62 (s, 3H), 2.75-2.60 (m, 2H), 2.09-2.07 (m, 3H). LCMS M/Z (M+H) 337.
-
- The title compound was prepared from 1-(3-((4-bromophenyl)amino)-1-methyl-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone in a similar fashion to Example 75. The crude residue was purified by reverse phase chromatography (acetonitrile 26-56%/0.1% NH4OH in water) to give the title compound in 43% yield. 1H NMR (400 MHz, DMSO-d6) δ 7.59 (dd, J=8.4, 6.0 Hz, 2H), 7.54 (dd, J=6.8, 6.0 Hz, 1H), 7.16 (dd, J=8.8, 5.2 Hz, 2H), 6.49 (dd, J=6.4, 2.4 Hz, 1H), 4.40-4.38 (m, 2H), 3.90 (s, 3H), 3.88-3.78 (m, 2H), 3.67 (s, 3H), 2.81-2.69 (m, 1H), 2.20-2.13 (m, 3H). LCMS M/Z (M+H) 351.
-
-
- To a solution of 1-[3-(4-bromoanilino)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-yl]ethanone (Intermediate J, 7.0 g, 20.88 mmol) in 1,4-dioxane (40.0 mL) and water (10.0 mL) was added 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (5.21 g, 25.06 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1.52 g, 2.09 mmol) and Na2CO3 (4.43 g, 41.77 mmol). The mixture was heated to 120° C. for 12 h. The reaction mixture was filtered, concentrated in vacuo and purified by silica gel chromatography (dichloromethane/methanol=50:1 to 10:1) to give the title compound (4.80 g, 65%) as a white solid. 1H NMR (400 MHz, CD3OD) δ 7.80-7.79 (m, 1H), 7.69-7.68 (m, 1H), 7.38-7.34 (m, 2H), 7.12-6.97 (m, 2H), 4.40-4.39 (m, 2H), 3.89 (s, 3H), 3.88-3.77 (m, 2H), 2.82-2.69 (m, 2H), 2.19-2.12 (m, 3H). LCMS M/Z (M+H) 337.
-
- A mixture of 1-(3-((4-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone (Intermediate L, 0.4 g, 1.19 mmol), 3-chloropropanamide (0.14 g, 1.31 mmol), Cs2CO3 (0.77 g, 2.38 mmol) in DMF (2 mL) was heated to 90° C. for 16 hours. The reaction mixture was washed with EtOAc (5 mL×3) and brine (5 mL). The combined organic layers were concentrated in vacuo and the crude residue was purified by reverse phase chromatography (acetonitrile 17-47%/0.1% NH4OH in water) to give the title compound (38.3 mg, 8%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.10-8.06 (m, 1H), 7.95-7.89 (m, 1H), 7.70 (s, 1H), 7.45-7.33 (m, 4H), 6.95-6.87 (m, 1H), 6.64-6.59 (m, 1H), 4.33 (s, 1H), 4.11-4.03 (m, 3H), 3.83 (s, 3H), 3.71-3.65 (m, 2H), 2.74-2.67 (m, 2H), 2.57 (t, J=3.6 Hz, 2H), 2.08-2.06 (m, 3H). LCMS M/Z (M+H) 408.
- The following Examples 172-177 were prepared in a similar fashion to Example 171.
-
Example Compound Name and Structure NMR m/z Example 172 1H NMR (400 MHz, DMSO-d6) δ 8.15-8.10 (m, 1H), 7.93 (d, J = 2.4 Hz, 1H), 7.71 (d, J = 2.0 Hz, 1H), 7.41-7.34 (m, 4H), 4.43 (s, 2H), 4.13 (t, J = 6.8 Hz, 2H), 3.83 (s, 3H), 3.72-3.65 (m, 2H), 2.82- 2.73 (m, 2H), 2.09-2.06 (m, 3H) 433 Example 173 1H NMR (400 MHz, DMSO-d6) δ 8.08-8.04 (m, 1H), 7.93 (s, 1H), 7.70 (s, 1H), 7.39-7.33 (m, 4H), 4.34 (s, 2H), 3.83 (s, 3H), 3.72- 3.66 (m, 2H), 3.60 (s, 3H), 2.73- 2.58 (m, 2H), 2.09-2.06 (m, 3H) 351 Example 174 1H NMR (400 MHz, DMSO-d6) δ 8.27-8.22 (m, 1H), 7.95 (m, 1H), 7.72 (s, 1H), 7.46 (dd, J = 8.4, 8.4 Hz, 1H), 7.38 (dd, J = 8.4, 8.4 Hz, 1H), 4.89 (q, J = 9.2 Hz, 1H), 4.38 (s, 2H), 3.83 (s, 3H), 3.74-3.67 (m, 2H), 2.75-2.67 (m, 2H), 2.11- 2.09 (m, 3H) 419 Example 175 1H NMR (400 MHz, DMSO-d6) δ 8.15-8.11 (m, 1H), 7.93 (s, 1H), 7.71 (s, 1H), 7.40-7.34 (m, 4H), 4.86-4.80 (m, 1H), 4.34 (s, 2H), 4.03-4.00 (m, 2H), 3.86-3.81 (m, 5H), 3.73-3.67 (m, 2H), 2.76- 2.64 (m, 2H), 2.26-2.21 (m, 2H), 2.09-2.06 (m, 3H) 407 Example 176 1H NMR (400 MHz, DMSO-d6) δ 8.16-8.11 (m, 1H), 7.94 (s, 1H), 7.71 (s, 1H), 7.44-7.41 (m, 2H), 7.39-7.34 (m, 2H), 4.36 (s, 2H), 4.01 (d, J = 7.2 Hz, 2H), 3.83 (s, 3H), 3.76-3.65 (m, 2H), 2.74-2.59 (m, 2H), 2.41-2.20 (m, 1H), 2.10- 2.07 (m, 3H), 1.68-1.65 (m, 1H), 1.45-1.35 (m, 1H) 427 Example 177 1H NMR (400 MHz, DMSO-d6) δ 8.12-8.07 (m, 1H), 7.94 (s, 1H), 7.71 (s, 1H), 7.41-7.34 (m, 4H), 4.66 (dd, J = 8.0, 6.0 Hz, 2H), 4.48 (dd, J = 9.6, 6.0 Hz, 2H), 4.34 (s, 2H), 4.17 (d, J = 7.2 Hz, 2H), 3.83 (s, 3H), 3.75-3.60 (m, 2H), 2.75- 2.59 (m, 2H), 2.10-2.07 (m, 3H) 407 -
- Racemic 1-[3-[4-(1-methylpyrazol-4-yl)anilino]-1-tetrahydrofuran-3-yl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (35 mg) was separated using chiral SFC (Chiralpak AD 21.2×150 mm, 5 micron, mobile phase: carbon dioxide, methanol w/ 0.1% NH4OH, method: Isocratic at 45% B for 6 min, flow rate: 70 ml/min, pressure: 100 bar, temperature: 40° C., wavelength: 211 nm) to afford (S)-1-[3-[4-(1-methylpyrazol-4-yl)anilino]-1-tetrahydrofuran-3-yl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (12.2 mg, first peak) and (R)-1-[3-[4-(1-methylpyrazol-4-yl)anilino]-1-tetrahydrofuran-3-yl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (9.3 mg, second peak). Absolute configuration was arbitrarily assigned to each enantiomer. Example 178: 1H NMR (400 MHz, DMSO-d6) δ 8.17-8.07 (m, 1H), 7.96-7.92 (m, 1H), 7.73-7.70 (m, 1H), 7.42-7.33 (m, 4H), 4.88-4.78 (m, 1H), 4.34 (s, 2H), 4.08-3.96 (m, 2H), 3.90-3.63 (m, 7H), 2.82-2.60 (m, 2H), 2.35-2.19 (m, 2H), 2.13-2.05 (m, 3H). LCMS M/Z (M+H) 407. Example 179: 1H NMR (400 MHz, DMSO-d6) δ 8.16-8.08 (m, 1H), 7.95-7.92 (m, 1H), 7.73-7.69 (m, 1H), 7.42-7.33 (m, 4H), 4.89-4.78 (m, 1H), 4.34 (s, 2H), 4.07-3.96 (m, 2H), 3.90-3.64 (m, 7H), 2.80-2.60 (m, 2H), 2.29-2.17 (m, 2H), 2.13-2.03 (m, 3H). LCMS M/Z (M+H) 407.
-
- To a solution of 1-(3-((4-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone (Intermediate L, 0.20 g, 0.595 mmol) and DBU (0.18 g, 1.19 mmol) in MeCN (2 mL) was added (methylsulfonyl)ethane (0.095 g, 0.892 mmol) and the reaction mixture was heated to 90° C. for 16 h. The reaction mixture was concentrated in vacuo and washed with EtOAc (5 mL×3) and brine (5 mL). The combined organic layers were dried over anhydrous MgSO4 and concentrated in vacuo. The crude residue was purified by reverse phase chromatography (acetonitrile 5-35%/0.1% NH4OH in water) to give the title compound (2 mg, 1%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.19-8.14 (m, 1H), 7.93 (s, 1H), 7.70 (s, 1H), 7.42 (dd, J=8.4, 8.4 Hz, 2H), 7.37 (dd, J=8.4, 8.4 Hz, 2H), 4.35 (s, 2H), 4.30 (t, J=6.8 Hz, 2H), 3.83 (s, 3H), 3.72-3.66 (m, 2H), 3.63 (t, J=6.8 Hz, 2H), 2.89 (s, 3H), 2.77-2.66 (m, 2H), 2.10-2.07 (m, 3H). LCMS M/Z (M+H) 443.
-
-
- To a stirred solution of (1R, 2S)-ethyl 2-fluorocyclopropanecarboxylate (1 g, 7.57 mmol) in THF (20 mL) was added LiAlH4 (862 mg, 22.7 mmol) in an ice bath and the mixture was stirred at room temperature for 12 h. The reaction was quenched with water (1 mL) and 1N NaOH (1 mL) and dried over anhydrous Na2SO4. The mixture was filtered and concentrated in vacuo to afford the title compound (0.8 g, crude) as a light yellow oil.
-
- To a stirred solution of ((1R, 2S)-2-fluorocyclopropyl)methanol (400 mg, 2.24 mol) and TEA (681 mg, 6.73 mmol) in DCM at 0° C. (8 mL) was added MsCl (379 mg, 3.37 mmol). The mixture was stirred at room temperature for 12 h. The reaction was quenched with water (20 mL), washed with DCM (20 mL×2) and the combined organic layers were dried over anhydrous Na2SO4. The solution was concentrated in vacuo to give the title compound (300 mg, 52%) as a light yellow oil.
-
- To a stirred solution of 1-(3-((4-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone (Intermediate L, 200 mg, 0.59 mol) in DMF (5 mL), was added ((1R, 2S)-2-fluorocyclopropyl)methyl methanesulfonate (150 mg, 0.89 mmol) and Cs2CO3 (581 mg, 1.81 mmol). The mixture was heated to 100° C. for 12 hours. After cooling to rt, the reaction mixture was diluted in water (40 mL) and washed with EtOAc (40 mL×2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by reverse phase chromatography (acetonitrile 40-60%/0.2% formic acid in water) to give the title compound (15 mg, 6%) as a white solid. 1H NMR (400 MHz, CD3OD) δ 7.81 (d, J=3.2 Hz, 1H), 7.71 (d, J=2.4 Hz, 1H), 7.41-7.37 (m, 2H), 7.21-7.17 (m, 2H), 4.71-4.55 (m, 1H), 4.42-4.41 (m, 2H), 3.91 (s, 3H), 3.87-3.80 (m, 4H), 2.84-2.72 (m, 2H), 2.21-2.15 (m, 3H), 1.73-1.69 (m, 1H), 1.13-1.07 (m, 1H), 0.74-1.69 (m, 1H). LCMS M/Z (M+H) 409.
-
- The title compound was prepared from 1-(3-((4-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone (Intermediate L) and (1-methylcyclopropyl)methyl methanesulfonate in a similar fashion to Example 183. The crude residue was purified by reverse phase chromatography (acetonitrile 40-60%/0.2% formic acid in water) to give the title compound in 6% yield. 1H NMR (400 MHz, CD3OD) δ 7.83 (d, J=3.6 Hz, 1H), 7.72 (d, J=2.8 Hz, 1H), 7.41-4.37 (m, 2H), 7.19 (dd, J=8.0, 8.0 Hz, 2H), 4.43 (s, 2H), 3.92 (m, 3H), 3.90-3.82 (m, 4H), 2.87-2.75 (m, 2H), 2.23-2.17 (m, 3H), 1.05 (s, 3H), 0.66-0.64 (m, 2H), 0.44-0.41 (m, 2H). LCMS M/Z (M+H) 405.
-
- The title compound was prepared from 1-(3-((4-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone (Intermediate L) and bromocyclopropane in a similar fashion to Example 87. The crude residue was purified by reverse phase chromatography (acetonitrile 27-57%/0.2% formic acid in water) to give the title compound in 4% yield. 1H NMR (400 MHz, CD3OD) δ 7.81 (d, J=3.2 Hz, 1H), 7.70 (d, J=2.0 Hz, 1H), 7.39-7.35 (m, 2H), 7.17-7.13 (m, 2H), 6.02-5.95 (m, 1H), 5.19 (d, J=10.8 Hz, 1H), 5.03 (d, J=16.8 Hz, 1H), 4.60 (s, 2H), 4.40 (d, J=4.8 Hz, 2H), 3.90 (s, 3H), 3.87-3.78 (m, 2H), 2.80-2.67 (m, 2H), 2.20-2.14 (m, 3H). LCMS M/Z (M+H) 377.
-
- The title compound was prepared from 1-(3-((4-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone (Intermediate L) and acrylonitrile in a similar fashion to Example 182. The crude residue was purified by reverse phase chromatography (acetonitrile 17-42%/0.05% HCl in water) to give the title compound in 5% yield. 1H NMR (400 MHz, DMSO-d6) δ 8.07 (s, 1H), 7.86 (s, 1H), 7.45 (dd, J=8.4, 8.4 Hz, 2H), 7.39 (dd, J=8.4, 8.4 Hz, 2H), 4.41-4.36 (m, 2H), 4.17 (t, J=6.4 Hz, 2H), 3.87 (s, 3H), 3.73-3.68 (m, 2H), 2.77-2.66 (m, 2H), 2.09-2.07 (m, 3H). LCMS M/Z (M+H) 390.
-
-
- To a solution of 1-(3-((4-bromophenyl)amino)-1-methyl-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5 (4H)-yl)ethanone (Intermediate K, 500 mg, 1.43 mmol) in dioxane (12 mL) and H2O (3 mL) was added Na2CO3 (303 mg, 2.86 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (103 mg, 0.14 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (630 mg, 2.14 mmol). After being purged with nitrogen atmosphere for 1 min, the reaction mixture was heated to 110° C. for 18 h. The mixture was evaporated to dryness and the crude compound was purified by silica gel chromatography (DCM:MeOH=20:1) to give the title compound (500 mg, 80% yield) as a brown solid.
-
- To a solution of tert-butyl 4-(4-((5-acetyl-1-methyl-4, 5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)amino) phenyl)-1H-pyrazole-1-carboxylate (500 mg, 0.24 mmol) in DCM (2 mL), was added TFA (2 mL) dropwise. The reaction mixture was stirred at room temperature for 2 h. The mixture was concentrated in vacuo and purified by reverse phase chromatography (acetonitrile 18-48%/0.1% NH4OH in water) to give the title compound (24.2 mg, 6%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 12.76 (br s, 1H), 8.06-8.01 (m, 1H), 7.98 (br s, 1H), 7.79 (br s, 1H), 7.46-7.33 (m, 4H), 4.34 (s, 2H), 3.75-3.64 (m, 2H), 3.60 (s, 3H), 2.73-2.56 (m, 2H), 2.09-2.06 (m, 3H). LCMS M/Z (M+H) 337.
-
- To a solution of 1-[1-methyl-3-[4-(1H-pyrazol-4-yl)anilino]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (Example 187, 100 mg, 0.30 mmol) in DMF (2.0 mL) was added 2-bromo-N,N-dimethylethanamine (86 mg, 0.60 mmol) and Cs2CO3 (200 mg, 0.60 mmol). The reaction mixture was heated to 120° C. for 24 h. The crude residue was purified by reverse phase chromatography (acetonitrile 22-42%/0.1% NH4OH in water) to give the title compound (41 mg, 34% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.07-8.03 (m, 1H), 7.97 (s, 1H), 7.70 (s, 1H), 7.39-7.32 (m, 4H), 4.34 (s, 2H), 4.17 (t, J=6.4 Hz, 2H), 3.74-3.60 (m, 1H), 2.73-2.63 (m, 2H), 2.17 (s, 6H), 2.09-2.06 (m, 3H). LCMS M/Z (M+H) 408.
-
- The title compound was prepared from 1-[1-methyl-3-[4-(1H-pyrazol-4-yl)anilino]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (Example 186) and 2-bromoethanol in a similar fashion to Example 188. The crude residue was purified by reverse phase chromatography (acetonitrile 21-41%/0.1% NH4OH in water) to give the title compound in 6% yield. 1H NMR (400 MHz, DMSO-d6) δ 7.87 (s, 1H), 7.74 (s, 1H), 7.40-7.33 (m, 2H), 7.15-7.11 (m, 2H), 4.39-4.37 (m, 2H), 4.23 (t, J=5.6 Hz, 2H), 3.93-3.85 (m, 4H), 3.66-3.65 (m, 3H), 2.81-2.68 (m, 2H), 2.19-2.12 (m, 3H). LCMS M/Z (M+H) 381.
-
-
- To a solution of tert-butyl 4-oxopiperidine-1-carboxylate (9.0 g, 45.17 mmol) in anhydrous THF (100 mL) was added t-BuOK (6.1 g, 54.20 mmol) portionwise. The reaction mixture was allowed to stir at room temperature for 5 h before being warmed to 40° C. A solution of 1-isothiocyanato-3-methylbenzene (8.1 g, 54.20 mmol) in anhydrous THF (50 mL) was added dropwise and stirred for an additional 2 h at this temperature before MeI (19.23 g, 135.51 mmol) was added dropwise. The reaction mixture was stirred for another 1 h. After cooling to room temperature, the mixture was poured into water (100 mL) and extracted with EtOAc (3×100 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether/EtOAc=10/1 to 5/1) to afford the title compound (9.5 g, 58%) as a yellow oil.
-
- To a solution of (Z)-tert-butyl 3-((methylthio)(m-tolyl amino)methylene)-4-oxopiperidine-1-carboxylate (9.5 g, 26.21 mmol) in EtOH (50 mL) was added hydrazine hydrate (1.7 g, 28.83 mmol). The reaction was heated to reflux for 2 h. The solvent was removed and the residue was extracted with DCM (50 mL×3) and washed with water (50 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether/EtOAc=3/1 to 1/1) to afford the title compound (5.8 g, 67%) as a yellow solid.
-
- To a solution of tert-butyl 3-(m-tolylamino)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (5.8 g, 17.66 mmol) in EtOAc at 0° C. (30 mL) was added HCl/EtOAc (20 mL) dropwise. The reaction was allowed to stir at room temperature for 2 h. The mixture was concentrated in vacuo to afford the title compound (8.5 g, DCM:MeOH=20:1) as a yellow solid that required no further purification. LCMS M/Z (M+H) 229.
-
- To a solution of N-(m-tolyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-amine (8.5 g) and TEA (5.36 g, 52.96 mmol) in DMF (30 mL) at 0° C. was added a solution of Ac2O (1.8 g, 17.65 mmol) in DMF (5 mL) dropwise. The reaction mixture was stirred at 0° C. for 10 min and quenched by the addition of brine (50 mL). The mixture was extracted with EtOAc (3×30 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The crude residue was purified by silica gel chromatography (DCM/MeOH=50/1 to 20/1) to afford the title compound (3.7 g, 77%, two steps) as a white solid. 1H NMR (400 MHz, CD3OD) δ 8.62-8.53 (m, 1H), 7.46-7.42 (m, 2H), 7.09 (dd, J=7.6, 7.6 Hz, 1H), 6.64-6.62 (m, 1H), 4.37-4.27 (m, 2H), 3.66-3.59 (m, 2H), 2.99-2.87 (m, 2H), 2.22 (s, 3H), 2.06 (s, 3H). LCMS M/Z (M+H) 271.
-
- To a solution of 1-(3-(m-tolylamino)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone (Intermediate M, 200 mg, 0.74 mmol) and Cs2CO3 (481 mg, 1.48 mmol) in DMF (4 mL) was added chloro-2-methoxyethane (73.5 mg, 0.77 mmol). The mixture was heated to 80° C. for 2 h. The reaction mixture was filtered and concentrated in vacuo. The crude residue was purified by reverse phase chromatography (acetonitrile 1-28%/0.2% formic acid in water) to give the title compound (49 mg, 20%) as a white solid. 1H NMR (400 MHz, T=80° C., DMSO-d6) δ 7.67 (br s, 1H), 7.14-7.01 (m, 3H), 6.54 (d, J=7.2 Hz, 1H), 4.32 (s, 2H), 4.05-4.02 (m, 2H), 3.75-3.63 (m, 4H), 3.25 (s, 3H), 2.71 (br s, 2H), 2.23 (s, 3H), 2.08 (s, 3H). LCMS M/Z (M+H) 329.
- The following Examples 189-207 were prepared in a similar fashion to Example 188.
-
Example Compound Name and Structure NMR m/z Example 189 1H NMR (400 MHz, T = 80° C., DMSO-d6) δ 8.23 (s, 1H), 7.73 (br s, 1H), 7.12-7.10 (m, 3H), 7.05-7.01 (m, 1H), 6.54 (d, J = 6.8 Hz, 1H), 5.23 (s, 2H), 4.32 (s, 2H), 3.72 (br s, 2H), 2.76 (br s, 2H), 2.23 (s, 3H), 2.08 (s, 3H) 352 Example 190 1H NMR (400 MHz, T = 80° C., DMSO-d6) δ 7.71 (br s, 2H), 7.15-7.01 (m, 3H), 6.54 (d, J = 7.8 Hz, 1H), 4.52 (s, 2H), 4.34 (s, 2H), 3.71 (br s, 2H), 3.17- 3.11 (m, 2H), 2.70 (br s, 2H), 2.24 (s, 3H), 2.09 (s, 3H), 1.06 (t, J = 7.4 Hz, 3H) 356 Example 191 1H NMR (400 MHz, DMSO- d6) δ 7.72 (s, 1H), 7.21-7.11 (m, 4H), 7.10-6.94 (m, 1H), 6.55-6.52 (m, 1H), 6.38-6.31 (m, 2H), 4.11-4.02 (m, 4H), 3.71-3.63 (m, 2H), 3.15 (d, J = 5.2 Hz, 1H), 2.96 (t, J = 8.0 Hz, 2H), 2.67 (t, J = 8.0 Hz, 1H), 2.60-2.51 (m, 1H), 2.17 (s, 3H), 2.04 (s, 3H) 375 Example 192 1H NMR (400 MHz, DMSO- d6) δ 8.5 (s, 1H), 7.90 (m, 1H), 7.70-7.60 (m, 1H), 7.25-7.06 (m, 6H), 6.53-6.45 (m, 1H), 4.34-4.21 (m, 4H), 3.64-3.52 (m, 2H), 3.19-3.11 (m, 2H), 2.47-2.42 (m, 1H), 2.38-2.31 (m, 1H), 2.22 (s, 3H), 2.04 (s, 3H) 376 Example 193 1H NMR (400 MHz, DMSO- d6) δ 8.42-8.41 (m, 2H), 7.99 (s, 1H), 7.07-7.01 (m, 5 H), 6.54-6.51 (m, 1H), 4.28 (s, 2H), 4.16-4.13 (m, 2H), 3.60- 3.50 (m, 2H), 3.05 (t, J = 6.8 Hz, 2H), 2.39-2.32 (m, 1H), 2.22 (s, 3H), 2.03 (s, 3H) 376 Example 194 1H NMR (400 MHz, T = 80° C., DMSO-d6) δ 7.71 (br s, 1H), 7.61 (br s, 1H), 7.15-7.01 (m, 3H), 6.54 (d, J = 7.2 Hz, 1H), 4.52 (s, 2H), 4.33 (s, 2H), 3.70 (br s, 2H), 2.75-2.55 (m, 5H), 2.23 (s, 3H), 2.08 (s, 3H) 342 Example 195 1H NMR (400 MHz, T = 80° C., DMSO-d6) δ 8.52-8.51 (m, 1H), 7.76-7.68 (m, 2H), 7.28-7.27 (m, 1H), 7.15-6.99 (m, 4H), 6.52 (d, J = 7.2 Hz), 5.21 (s, 2H), 4.34 (s, 2H), 3.70 (br s, 2H), 2.71 (br s, 2H), 2.21 (s, 3H), 2.07 (s, 3H) 362 Example 196 1H NMR (400 MHz, T = 80° C., DMSO-d6) δ 8.48 (m, 2H), 8.14 (br s, 1H), 7.75 (br s, 1H), 7.62-7.61 (m, 1H), 7.36-7.33 (m, 1H), 7.11 (s, 2H), 7.04- 7.00 (m, 1H), 6.53 (d, J = 7.2 Hz, 1H), 5.17 (s, 2H), 4.34 (s, 2H), 3.70 (br s, 2H), 2.72 (br s, 2H), 2.22 (s, 3H), 2.07 (s, 3H) 362 Example 197 1H NMR (400 MHz, T = 80° C., DMSO-d6) δ 7.71 (br s, 1H), 7.34-7.24 (m, 5 H), 7.15-7.07 (m, 2H), 7.05-7.04 (m, 3H), 6.54 (d, J = 7.2 Hz, 1H), 5.43- 5.38 (m, 1H), 4.38-4.26 (m, 2H), 3.65 (br s, 2H), 2.75 (br s, 2H), 2.24 (s, 3H), 2.05 (s, 3H), 1.80 (d, J = 6.8 Hz, 3H) 375 Example 198 1H NMR (400 MHz, T = 80° C., DMSO-d6) δ 7.62 (br s, 1H), 7.12-7.01 (m, 3H), 6.53 (d, J = 7.2 Hz, 1H), 4.31 (s, 2H), 3.71 (br s, 2H), 3.60 (s, 3H), 2.67 (br s, 2H), 2.23 (s, 3H), 2.07 (br s, 3H) 285 Example 199 1H NMR (400 MHz, T = 80° C., DMSO-d6) δ 7.63 (br s, 1H), 7.12-7.01 (m, 3H), 6.53 (d, J = 7.2 Hz, 1H), 4.32 (s, 2H), 3.95-3.89 (m, 2H), 3.72 (br s, 2H), 2.71 (br s, 2H), 2.24 (s, 3H), 2.08 (br s, 3H), 1.32 (t, J = 7.4 Hz, 3H) 299 Example 200 1H NMR (400 MHz, T = 80° C., DMSO-d6) δ 7.64 (br s, 1H), 7.08 (s, 2H), 7.05-7.01 (m, 1H), 6.52 (d, J = 7.2 Hz, 1H), 4.36-4.30 (m, 3H), 3.71 (br s, 2H), 2.73 (br s, 2H), 2.23 (s, 3H), 2.06 (br s, 3H), 1.38 (d, J = 6.8 Hz, 3H) 313 Example 201 1H NMR (400 MHz, T = 80° C., DMSO-d6) δ 7.63 (br s, 1H), 7.12-7.11 (m, 2H), 7.05-7.01 (m, 1H), 6.53 (d, J = 7.6 Hz, 1H), 4.33 (s, 2H), 3.79 (d, J = 6.8 Hz, 1H), 3.71 (br s, 2H), 2.72 (br s, 2H), 2.24 (s, 3H), 2.08 (br s, 3H), 1.22-1.43 (m, 1H), 0.54-0.49 (m, 2H), 0.36- 0.33 (m, 2H) 325 Example 202 1H NMR (400 MHz, DMSO- d6) δ 8.57-8.51 (m, 2H), 7.78 (s, 1H), 7.15-7.11 (m, 4H), 7.00-7.05 (m, 1H), 6.55-6.53 (m, 1H), 5.18 (s, 2H), 4.36 (s, 2H), 3.75-3.65 (m, 2H), 2.55- 2.75 (m, 2H), 2.22 (s, 3H), 2.07 (s, 3H) 362 Example 203 1H NMR (400 MHz, T = 80° C., DMSO-d6) δ 7.70 (br s, 1H), 7.35-7.32 (m, 1H), 7.28-7.21 (m, 2H), 7.15-7.10 (m, 2H), 7.05-7.00 (s, 1H), 6.53 (d, J = 7.2 Hz, 1H), 5.13 (s, 2H), 4.33 (s, 2H), 3.69 (br s, 2H), 2.66 (br s, 2H), 2.22 (s, 3H), 2.06 (s, 3H) 361 Example 204 1H NMR (400 MHz, DMSO- d6) δ 7.17-7.07 (m, 3H), 6.60 (dd, J = 7.2, 7.2 Hz, 1H), 4.34- 4.30 (s, 2H), 3.97 (t, J = 4.8 Hz, 2H), 3.71-3.67 (m, 4H), 2.78-2.65 (m, 2H), 2.23 (s, 3H), 2.09-2.05 (s, 3H) 315 Example 205 1H NMR (400 MHz, DMSO- d6) δ 7.97-7.92 (m, 1H), 7.40 (s, 1H), 7.19 (d, J = 7.2 Hz, 1H), 7.11 (s, 1H) 7.07-7.01 (m, 1H), 6.86 (s, 1H), 6.52 (dd, J = 6.8, 6.8 Hz, 1H), 4.30 (s, 2H), 4.04 (t, J = 6.8 Hz, 2H), 3.70-3.64 (m, 2H), 2.74-2.62 (m, 2H), 2.57 (t, J = 6.8 Hz, 2H), 2.23-2.22 (m, 3H), 2.09-2.05 (m, 3H) 342 Example 206 1H NMR (400 MHz, DMSO- d6) δ 7.16-7.06 (m, 3H), 6.59 (d, J = 7.2 Hz, 1H), 4.60-4.35 (m, 2H), 4.00-3.95 (m, 2H), 3.72-3.66 (m, 2H), 3.37 (t, J = 6.0 Hz, 2H), 2.76-2.63 (m, 2H), 2.23 (s, 3H), 2.09-2.05 (m, 3H), 1.88-1.83 (m, 2H) 329 Example 207 1H NMR (400 MHz, DMSO- d6) δ 8.02-7.97 (m, 1H), 7.17 (s, 2H), 7.07-7.01 (m, 1H), 6.53 (dd, J = 6.4, 6.4 Hz, 2H), 4.32 (s, 2H), 3.95 (t, J = 6.4 Hz, 2H), 3.74-3.66 (m, 2H), 2.74-2.52 (m, 2H), 2.51-2.49 (m, 2H), 2.23-2.22 (m, 3H), 2.09-2.05 (m, 3H), 2.02 (t, J = 6.8 Hz, 2H) 360 [M + Na] -
-
- To a stirred solution of 1-cyclopropylethanol (5 g, 58.1 mmol) and TEA (17.6 g, 174.4 mmol) in DCM (100 mL) at 0° C. was added MsCl (8.02 g, 69.7 mmol). The reaction mixture was stirred at room temperature for 0.5 h. The mixture was diluted in DCM (100 mL), washed with 1 N HCl, washed with sat. aq. NaHCO3 and washed with brine (120 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (6.5 g) as a colorless oil that required no further purification.
-
- To a solution of 1-(3-(m-tolylamino)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone (Intermediate M, 200 mg, 0.74 mmol) in DMF (5 mL) was added 1-cyclopropylethyl methanesulfonate (607 mg, 3.70 mol) and K2CO3 (306 mg, 2.22 mmol). The mixture was heated to 100° C. for 16 hours under an autoclave. After cooling the reaction mixture to rt, the reaction mixture was diluted with water (30 mL) and washed with EtOAc (30 mL×2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by reverse phase chromatography (acetonitrile 40-60%/0.2% formic acid in water to give the title compound (11 mg, 4%) as a white solid. 1H NMR (400 MHz, CD3OD) δ 7.10-7.14 (m, 1H), 6.92-6.87 (m, 2H), 6.61 (dd, J=6.8, 6.8 Hz, 1H), 5.46-5.43 (m, 2H), 4.37-4.36 (s, 2H), 3.98-3.95 (m, 2H), 3.88-3.79 (m, 2H), 2.82-2.71 (m, 2H), 2.46-2.44 (m, 2H), 2.28 (s, 3H), 2.21-2.13 (m, 3H), 1.64-1.57 (m, 3H). LCMS M/Z (M+H) 339.
-
-
- To a solution of 1-(3-(m-tolylamino)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone (Intermediate M, 150 mg, 0.56 mmol) in DMF (10 mL) was added tert-butyl 3-(bromomethyl)piperidine-1-carboxylate (169 mg, 0.61 mmol) and Cs2CO3 (362 mg, 1.11 mmol). The reaction mixture was heated to 80° C. for 2 h. The reaction mixture was diluted with EtOAc (30 mL) and washed with water (30 mL×3). The organic layer was separated, dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether/EtOAc (1/1)) to afford the title compound (200 mg, 77%).
-
- To a solution of tert-butyl 3-((5-acetyl-3-(m-tolylamino)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)piperidine-1-carboxylate (0.2 g, 0.428 mmol) in EtOAc (10 mL) was added HCl/EtOAc (2.0 ml). The mixture was allowed to stir at room temperature for 2 h. The solvent was concentrated in vacuo and the crude product required no further purification.
-
- To a solution of 1-(1-(piperidin-3-ylmethyl)-3-(m-tolylamino)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone hydrochloride in DCM (5.0 ml) was added HCHO (26 mg, 0.856 mmol) and Et3N (0.5 ml). The mixture was heated to 30° C. for 1 h before NaBH(OAc)3 (181 mg, 0.86 mmol) was added. The mixture stirred for an additional 1 h at 30° C. The reaction mixture was quenched by the addition of brine (10 ml) and the solution was extracted with DCM (20 ml×2) and washed with water (10 ml×3). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by reverse phase chromatography (acetonitrile 30-60%/0.1% NH4OH in water) to give the title compound (47 mg, 28%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.98 (s, 1H), 7.19-7.14 (m, 2H), 7.06-7.01 (m, 1H), 6.54-6.50 (m, 1H), 4.37-4.26 (m, 2H), 3.82-3.70 (m, 4H), 2.72-2.60 (m, 5H), 2.35-2.30 (m, 5H), 2.20-1.95 (m, 5H), 1.65-1.60 (m, 1H), 1.58-1.55 (m, 1H), 1.49-1.47 (m, 1H), 1.23-1.1 (m, 1H), 1.04-1.02 (m, 1H). LCMS M/Z (M+H) 382.
-
-
- To a solution of 1-methylpyrazole-3-carbaldehyde (1 g, 9.1 mmol) in THF (5 mL) at 0° C. was added MeMgBr (4.54 ml, 13.62 mmol) dropwise. The reaction mixture was allowed to stir at room temperature for 12 h. The reaction was quenched with sat. aq. NH4Cl (10 mL) and extracted with EtOAc (10 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo to afford the title compound (0.55 g) that required no further purification.
-
- To a solution of 1-(1-methylpyrazol-3-yl)ethanol (0.55 g, 4.36 mmol) in DCM (10 ml) at 0° C. was added SOCl2 (0.57 g, 4.80 mmol) dropwise and the reaction mixture was stirred at for 10 min. The reaction was quenched with brine (10 mL) and extracted with EtOAc (10 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to afford the title compound (0.6 g) that required no further purification.
-
- The title compound was prepared from 1-(3-(m-tolylamino)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone (Intermediate M) and 3-(1-chloroethyl)-1-methyl-1H-pyrazole in a similar fashion to Example 188. The crude residue was purified by reverse phase chromatography (acetonitrile 31-61%/0.1% NH4OH in water) to give the title compound in 4% yield. 1H NMR (400 MHz, DMSO-d6) δ 7.98-7.93 (m, 1H), 7.56 (s, 1H), 7.14-7.11 (m, 2H), 7.02 (dd, J=7.6, 7.6 Hz, 1H), 6.51 (dd, J=6.0, 6.0 Hz, 1H), 6.04 (d, J=2.0 Hz, 1H), 5.34 (q, J=6.4 Hz, 1H), 4.37-4.20 (m, 2H), 3.77 (s, 3H), 3.73-3.62 (m, 2H), 2.79-2.64 (m, 2H), 2.22-2.21 (m, 3H), 2.08-2.04 (m, 3H), 1.72 (d, J=6.8 Hz, 3H). LCMS M/Z (M+H) 401 [M+Na].
-
-
- The title compound was prepared from 1-(3-(m-tolylamino)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone (Intermediate M) and ethyl 2-bromopropanoate in a similar fashion to Example 188. The residue was purified by silica gel chromatography (DCM:MeOH=2%-50%) to afford the title compound (0.185 g, 27%) as a yellow oil. LCMS M/Z (M+Na) 393.
-
- To a solution of ethyl 2-(5-acetyl-3-(m-tolylamino)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-1-yl)propanoate (0.23 g, 0.62 mmol) in MeOH (5 mL) at 0° C. was added NaBH4 (0.094 mg, 2.48 mmol) portionwise and stirred at room temperature for 4 h. The reaction mixture was quenched by sat. aq. NH4Cl (5 mL) and extracted with EtOAc (5 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The crude residue was purified by reverse phase chromatography (acetonitrile 20-50%/0.1% NH4OH in water) to give the title compound (0.049 g, 22%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.98-7.93 (m, 1H), 7.16-7.10 (m, 2H), 7.06-7.00 (m, 1H), 6.51 (dd, J=6.8, 6.8 Hz, 1H), 4.83-4.75 (m, 1H), 4.36-4.28 (m, 2H), 4.12-4.11 (m, 1H), 3.67-3.65 (m, 2H), 3.60-3.54 (m, 2H), 2.76-2.63 (m, 2H), 2.23-2.21 (m, 3H), 2.09-2.05 (m, 3H), 1.33-1.31 (m, 3H). LCMS M/Z (M+H) 329.
-
- Racemic 1-(1-(1-hydroxypropan-2-yl)-3-(m-tolylamino)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone (45 mg) was separated using chiral SFC (SFC80;
Chiralpak AD 250×30 mm I.D., 5 um; Supercritical CO2/MEOH+NH3.H2O=55/45; 50 ml/min) to afford (S)-1-(1-(1-hydroxypropan-2-yl)-3-(m-tolylamino)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone (12.0 mg, first peak) and (R)-1-(1-(1-hydroxy propan-2-yl)-3-(m-tolylamino)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone (12.4 mg, second peak). Absolute configuration was arbitrarily assigned to each enantiomer. Example 212: 1H NMR (400 MHz, DMSO-d6) δ 7.98-7.93 (m, 1H), 7.15-7.09 (m, 2H), 7.06-7.00 (m, 1H), 6.51 (dd, J=6.4, 6.4 Hz, 1H), 4.84-4.79 (m, 1H), 4.32-4.27 (m, 2H), 4.12-4.10 (m, 1H), 3.67-3.64 (m, 2H), 3.58-3.54 (m, 2H), 2.76-2.63 (m, 2H), 2.22-2.21 (m, 3H), 2.08-2.05 (m, 3H), 1.33-1.31 (m, 3H). LCMS M/Z (M+H) 329. Example 213: 1H NMR (400 MHz, DMSO-d6) δ 7.97-7.92 (s, 1H), 7.15-7.09 (m, 2H), 7.05-6.99 (m, 1H), 6.50 (dd, J=6.4, 6.4 Hz, 1H), 4.83-4.80 (m, 1H), 4.31-4.27 (m, 2H), 4.12-4.10 (m, 1H), 3.66-3.58 (m, 2H), 3.57-3.53 (m, 2H), 2.75-2.62 (m, 2H), 2.22-2.21 (m, 3H), 2.08-2.04 (m, 3H), 1.33-1.30 (m, 3H). LCMS M/Z (M+H) 329. -
- The title compound was prepared from 1-(3-(m-tolylamino)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone (Intermediate M) and acrylonitrile in a similar fashion to Example 180. The residue was purified by reverse phase chromatography (acetonitrile 35-65%/0.1% NH4OH in water) to afford the title compound in 27% yield. 1H NMR (400 MHz, DMSO-d6) δ 8.07-8.01 (m, 1H), 7.22 (s, 2H), 7.06-7.01 (m, 1H), 6.53 (dd, J=6.8, 6.8 Hz, 2H), 4.33 (s, 2H), 4.16 (t, J=6.4 Hz, 2H), 3.74-3.66 (m, 2H), 2.96 (t, J=6.4 Hz, 2H), 2.76-2.65 (m, 2H), 2.23-2.22 (m, 3H), 2.09-2.06 (m, 3H). LCMS M/Z (M+H) 324.
-
- The title compound was prepared from 1-(3-(m-tolylamino)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone (Intermediate M) and tert-butyl 3-(2-((methylsulfonyl)oxy)ethyl)piperidine-1-carboxylate in a similar fashion to Example 209. The residue was purified by reverse phase chromatography (acetonitrile 20-50%/0.1% HCl in water) to afford the title compound in 13% yield. 1H NMR (400 MHz, DMSO-d6) δ 7.25 (dd, J=7.6, 7.6 Hz, 1H), 7.11-6.86 (m, 3H), 4.38 (s, 2H), 4.19-4.11 (m, 2H), 3.96-3.82 (m, 2H), 3.38-3.28 (m, 2H), 3.01-2.61 (m, 4H), 2.33 (s, 3H), 2.20-2.13 (m, 3H), 2.01-1.60 (m, 6H), 1.40-1.19 (m, 1H). LCMS M/Z (M+H) 382.
-
- The title compound was prepared from 1-(3-(m-tolylamino)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone (Intermediate M) in a similar fashion to Example 209. The residue was purified by reverse phase chromatography (acetonitrile 20-50%/0.1% HCl in water) to afford the title compound in 20% yield. 1H NMR (400 MHz, CD3OD) δ 7.30 (dd, J=7.2, 3.6 Hz, 1H), 7.15-6.98 (m, 3H), 4.43 (s, 2H), 4.26-4.10 (m., 2H), 3.97-3.90 (m, 2H), 3.50-3.45 (m, 2H), 3.05-2.68 (m, 7H), 2.37 (s, 3H), 2.24-2.17 (m, 3H), 2.06-1.75 (m, 6H), 1.29-1.25 (m, 1H). LCMS M/Z (M+H) 396.
-
-
- To a solution of (Z)-tert-butyl 3-((methylthio)(m-tolylamino)methylene)-4-oxopiperidine-1-carboxylate (0.2 g, 0.55 mmol) in ethanol (10 mL) was added cyclopropylhydrazine hydrochloride (77.5 mg, 0.71 mmol) and Et3N (71 mg, 0.71 mmol). The mixture was heated to reflux for 2 h. The mixture was concentrated in vacuo and dissolved in EtOAc. The white solid was filtered and the filtrate was concentrated in vacuo to give crude mixture of the title compounds (0.2 g, 99%) as yellow oil.
-
- The mixture of tert-butyl 1-cyclopropyl-3-(m-tolylamino)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5 (4H)-carboxylate and tert-butyl 2-cyclopropyl-3-(phenylamino)-6,7-dihydro-2H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (0.2 g, 0.54 mmol) in EtOAc (2 mL) was treated with 4N HCl/EtOAc (10 mL) and stirred for 2 h at rt. The resulting mixture was concentrated in vacuo to afford the crude mixture of the title compounds (164 mg, 100%) as a light brown solid.
-
- To a solution of 1-cyclopropyl-N-(m-tolyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-amine hydrochloride and 2-cyclopropyl-N-(m-tolyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-amine hydrochloride (164 mg, 0.54 mmol, from step 2) and Et3N (166.9 mg, 1.65 mmol) in DMF (2 mL) at rt was added acetic anhydride (56.1 mg, 0.55 mmol). The mixture stirred for 2 h before being filtered. The filtrate was concentrated in vacuo the residue was purified by reverse phase chromatography (acetonitrile 40-70%/0.1% NH4HCO3 in water) to afford the title compound (5.8 mg, 35%) as a white solid. 1H NMR (400 MHz, T=80° C., DMSO-d6) δ 7.63 (br s, 1H), 7.11-7.01 (m, 3H), 6.53 (d, J=7.2 Hz, 1H), 4.30 (s, 2H), 3.71 (br s, 2H), 3.36-3.34 (m, 1H), 2.78 (br s, 2H), 2.23 (s, 3H), 2.08 (s, 3H), 1.01-0.98 (m, 2H), 0.95-0.90 (m, 2H). LCMS M/Z (M+H) 311.
-
-
- To a solution of tert-butyl 4-oxopiperidine-1-carboxylate (5.0 g, 25.09 mmol) in anhydrous THF (180 mL) was added t-BuOK (3.4 g, 30.3 mmol) portionwise. The mixture was stirred at room temperature for 3 h before the mixture was heated to 40° C. and 1-isothiocyanato-3-methylbenzene (5.8 g, 30.1 mmol) was added dropwise. After the addition, the reaction mixture was allowed to stir for 2 h at the same temperature before MeI (10.68 g, 75.2 mol) was added dropwise. After cooling to room temperature, the mixture was poured into water (500 mL) and extracted with EtOAc (200 mL×4). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo to afford the title compound (10.0 g) as a brown oil.
-
- To a solution of (Z)-tert-butyl 3-((methylthio)(m-tolylamino)methylene)-4-oxopiperidine-1-carboxylate (10.0 g, 24.6 mmol) in ethanol (250 mL) was added hydrazine hydrate (85% aq., 10 g). After the addition, the mixture was heated to reflux for 5 h. The mixture was concentrated in vacuo and the residue was purified by silica gel chromatography (petroleum ether:EtOAc=9:1) to afford the title compound (7.5 g, 82%) as light yellow oil.
-
- To a solution of tert-butyl 3-((3-(methoxycarbonyl)phenyl)amino)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (6.1 g, 16.4 mmol) in EtOAc (60 mL) was added HCl/EtOAc (100 mL). The reaction mixture was stirred at room temperature for 1 h. The mixture was concentrated in vacuo to give the title compound (436 mg, crude) that required no further purification.
-
- To a solution of methyl 3-((4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl) amino)benzoate hydrochloride (3.8 g, 12.3 mmol) and TEA (3.7 g, 36.9 mmol) in DMF (50 mL) was added acetic anhydride (1.3 g, 12.3 mmol). The mixture was heated to 32° C. for 2 h. The reaction mixture was quenched by the addition of H2O (50 mL) and extracted with EtOAc (50 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo to afford the title compound (3.0 g, 78%) that required no further purification.
-
- To a solution of methyl 3-((5-acetyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl) amino)benzoate (1.0 g, 3.18 mmol) and Cs2CO3 (2.1 g, 6.35 mmol) in DMF (40 mL) was added (bromomethyl)cyclopropane (0.5 g, 3.33 mmol). The mixture was heated to 80° C. for 8 h. The reaction mixture was quenched with H2O (50 mL) and extracted with EtOAc (50 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo to give the title compound (1.1 g, 89%) that required no further purification.
-
- To a solution of KOH (0.8 g, 14.8 mmol) in MeOH/H2O (2:1, 12 mL) was added methyl 3-((5-acetyl-1-(cyclopropylmethyl)-4, 5,6,7-tetrahydro-1H-pyrazolo[4, 3-c]pyridin-3-yl)amino)benzoate (0.8 g, 2.27 mmol) in THF (20 mL). The reaction mixture was heated to 32° C. for 2 h. The reaction mixture was quenched with H2O (50 mL) and extracted with EtOAc (50 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo to give the title compound (410 mg, 53%) that required no further purification.
-
- To a mixture of 3-((5-acetyl-1-(cyclopropylmethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)amino)benzoic acid (Intermediate N, 110 mg, 0.35 mmol), isopropylamine (84 mg, 1.40 mmol) and DIEA (136 mg, 1.05 mmol) in DMF (5 mL) was added HATU (133 mg, 0.35 mmol). The reaction mixture was heated to 32° C. for 8 h before being filtered and concentrated in vacuo. The residue was purified by reverse phase chromatography (acetonitrile 28-58%/0.2% formic acid in water) to afford the title compound (48 mg, 35%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.94 (s, 1H), 7.75-7.61 (m, 2H), 7.57-7.45 (m, 1H), 7.25-7.16 (m, 1H), 7.13 (d, J=7.6 Hz, 1H), 4.36 (s, 2H), 4.15-4.05 (m, 1H), 3.80 (d, J=6.8 Hz, 2H), 3.76-3.63 (m, 2H), 2.77-2.58 (m, 2H), 2.08 (s, 3H), 1.25-1.14 (m, 7H), 0.55-0.48 (m, 2H), 0.48-0.32 (m, 2H). LCMS M/Z (M+H) 396.
- The following Examples 219-222 were prepared in a similar fashion to Example 218.
-
Example Compound Name and Structure NMR m/z Example 219 1H NMR (400 MHz, DMSO- d6) δ 8.05-7.90 (m, 1H), 7.69 (s, 2H), 7.58-7.45 (m, 1H), 7.25-7.11 (m, 1H), 7.12 (d, J = 7.6 Hz, 1H), 4.34 (s, 2H), 3.81 (d, J = 6.8 Hz, 2H), 3.75- 3.65 (m, 2H), 2.78 (d, J = 4.4 Hz, 3H), 2.76-2.60 (m, 2H), 2.08 (s, 3H), 1.25-1.14 (m, 1H), 0.55-0.48 (m, 2H), 0.48- 0.32 (m, 2H) 368 Example 220 1H NMR (400 MHz, DMSO- d6) δ 8.05-7.90 (m, 1H), 7.40-7.35 (m, 2H), 7.23-7.18 (m, 1H), 6.71 (d, J = 7.2 Hz, 1H), 4.36 (s, 2H), 3.80 (d, J = 6.8 Hz, 2H), 3.75-3.65 (m, 2H), 2.96 (s, 6H), 2.76-2.60 (m, 2H), 2.09 (s, 3H), 1.25- 1.12 (m, 1H), 0.55-0.48 (m, 2H), 0.48-0.32 (m, 2H) 382 Example 221 1H NMR (400 MHz, DMSO- d6) δ 7.98 (s, 1H), 7.67 (s, 1H), 7.56-7.45 (m, 1H), 7.23- 7.18 (m, 1H), 7.09 (d, J = 7.6 Hz, 1H), 4.34 (s, 2H), 3.82- 3.78 (m, 2H), 3.75-3.65 (m, 2H), 2.92-2.70 (m, 1H), 2.69- 2.60 (m, 2H), 2.08 (s, 3H), 1.25-1.15 (m, 1H), 0.75-0.65 (m, 2H), 0.60-0.55 (m, 2H), 0.54-0.45 (m, 2H), 0.39- 0.30 (m, 2H) 394 Example 222 1H NMR (400 MHz, DMSO- d6) δ 8.05-7.90 (m, 1H), 7.71 (s, 1H), 7.55-7.45 (m, 1H), 7.23-7.18 (m, 1H), 7.14 (d, J = 8.0 Hz, 1H), 4.35 (s, 2H), 3.75-3.70 (m, 2H), 3.68-3.65 (m, 2H), 3.51-3.45 (m, 2H), 3.43-3.40 (m, 2H), 3.30 (s, 3H), 3.21 (s, 1H), 2.65-2.60 (m, 3H), 2.09 (s, 3H), 1.30- 1.15 (m, 1H), 0.60-0.45 (m, 2H), 0.48-0.32 (m, 2H) 412 -
- The title compound was prepared from tert-butyl 4-oxopiperidine-1-carboxylate and 1-isothiocyanato-3-(trifluoromethyl)benzene in a similar fashion to Intermediate N. The residue was purified by reverse phase chromatography (acetonitrile 53-63%/0.2% formic acid in water) to afford the title compound in 4% yield. 1H NMR (400 MHz, DMSO-d6) δ 8.27 (s, 1H), 7.84 (s, 1H), 7.58 (d, J=8.4 Hz, 1H), 7.37 (t, J=8.0 Hz, 1H), 7.00 (d, J=7.6 Hz, 1H), 4.38 (s, 2H), 3.81 (d, J=6.4 Hz, 2H), 3.72 (s, 2H), 2.79-2.65 (m, 2H), 2.10 (s, 3H), 1.21-1.17 (m, 1H), 0.53-0.50 (m, 2H), 0.37-0.34 (m, 2H). LCMS M/Z (M+H) 379.
-
-
- To a solution of tert-butyl 3-bromo-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (Intermediate A, 40.0 g, 132 mmol) in DMF (500 mL) was added Cs2CO3 (87 g, 264 mmol) and 3-iodooxetane (27 g, 146 mmol). The mixture was heated to 60° C. for 12 h before 3-iodooxetane (5 g, 27.0 mmol) was added and the mixture was stirred at 60° C. for an additional 6 h. After cooling the reaction to room temperature, the mixture was filtered, washed with EtOAc (500 mL) and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (petroleum ether:tert-butyl methyl ether:THF=from 100:1:1 to 5:1:1) to give the title compound (30 g, 64%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 5.30-5.25 (m 1H), 5.18-5.14 (m, 2H), 4.95-4.91 (m, 2H), 4.28 (s, 2H), 3.73-3.66 (m, 2H), 2.64 (t, J=5.6 Hz, 2H), 1.48 (s, 9H).
-
- To a solution of tert-butyl 3-bromo-1-(oxetan-3-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (25.0 g, 70.0 mmol) in DCM (50 mL) was added trifluoroacetic acid (50 mL) dropwise at 0° C. The mixture was stirred at room temperature for 2 h. The mixture was concentrated in vacuo and the residue was re-dissolved in DCM (500 mL). The mixture was cooled to 0° C. before triethylamine (36.0 g, 350 mmol) and acetic anhydride (7.2 g, 70.0 mmol) were added dropwise. The mixture was stirred at room temperature for an additional 2 h. The reaction was quenched with water. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (DCM/MeOH=80:1) to give the title compound (Intermediate O, 17.0 g, 81%) as a light yellow solid. 1H NMR (400 MHz, CDCl3) δ 5.32-5.27 (m 1H), 5.16-5.13 (m, 2H), 4.95-4.91 (m, 2H), 4.47-4.31 (m, 2H), 3.88-3.70 (m, 2H), 2.75-2.63 (m, 2H), 2.17 (s, 3H).
-
-
- To a stirred solution of 2-bromo-4-fluoro-benzaldehyde (10 g, 49.3 mmol) in concentrated H2SO4 (100 mL) was added KNO3 (5.5 g, 54.2 mmol) portionwise in an ice bath. The reaction mixture was stirred at 20° C. for 2 h. The reaction mixture was quenched by the addition of water (500 mL), and extracted with EtOAc (200 mL×2). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (12 g, 98%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 10.30 (s, 1H), 8.64 (d, J=8.0 Hz, 1H), 7.69 (d, J=9.6 Hz, 1H).
-
- To a stirred solution of 2-bromo-4-fluoro-5-nitro-benzaldehyde (11 g, 44.4 mmol) in DCM (110 mL) was added diethylaminosulfur trifluoride (14.3 g, 88.7 mmol) in an ice bath. The reaction mixture was stirred at 20° C. for 12 h. The reaction mixture was quenched by water (100 mL), and extracted with DCM (100 mL×2). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (petroleum ether/EtOAc=30:1) to give the title compound (7.2 g, 60%) as a light yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.40 (d, J=7.6 Hz, 1H), 7.65 (d, J=9.2 Hz, 1H), 6.89 (t, J=54.0 Hz, 1H).
-
- A mixture of 1-bromo-2-(difluoromethyl)-5-fluoro-4-nitro-benzene (7.2 g, 26.7 mmol), Fe powder (7.5 g, 133.3 mmol) and NH4Cl (8.6 g, 160.0 mmol) in EtOH (80 mL) and water (20 mL) was heated to 80° C. for 4 h. After cooling to room temperature, the reaction mixture was filtered over a celite pad. The filtrate was diluted in water (100 mL), and extracted with EtOAc (100 mL×2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (3.8 g, 59%) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 7.43 (d, J=10.8 Hz, 1H), 7.08 (d, J=9.2 Hz, 1H), 6.97 (t, J=54.4 Hz, 1H), 5.69 (s, 2H).
-
- A mixture of 4-bromo-5-(difluoromethyl)-2-fluoro-aniline (800 mg, 3.3 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (832 mg, 4 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (244 mg, 0.33 mmol) and Na2CO3 (1.06 g, 10.00 mmol) in 1,4-dioxane (10 mL) and water (2 mL) was heated to 90° C. for 12 h under a nitrogen atmosphere. After cooling to room temperature, water (40 mL) was added and the mixture was extracted with EtOAc (40 mL×2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (petroleum ether/EtOAc=5:1) to give the title compound (620 mg, 77%) as a light yellow solid. LCMS M/Z (M+H) 242.
-
- To a stirred solution of 5-(difluoromethyl)-2-fluoro-4-(1-methylpyrazol-4-yl)aniline (289 mg, 1.2 mmol) in 1,4-dioxane (3 mL) was added 1-(3-bromo-1-(oxetan-3-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone (300 mg, 1.0 mmol), 2-(dicyclohexylphosphino)3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl (54 mg, 0.1 mmol), chloro(2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl)[2-(2-aminoethylphenyl)]palladium(II), methyl-t-butylether adduct (82 mg, 0.1 mmol) and tBuONa (288 mg, 3 mmol). The reaction mixture was heated to 120° C. for 12 h under a nitrogen atmosphere. After cooling to room temperature, water (20 mL) was added and the mixture was extracted with DCM (20 mL×2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by reverse phase chromatography (acetonitrile 28-58%/0.2% formic acid in water) to give the title compound (61 mg, 13%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.42-8.23 (m, 2H), 7.86 (s, 1H), 7.60 (s, 1H), 7.33-7.27 (m, 1H), 6.91 (t, J=54.8, 1H), 5.46-5.39 (m, 1H), 4.95-4.92 (m, 2H), 4.86-4.84 (m, 2H), 4.42-4.37 (m, 2H), 3.88 (s, 3H), 3.71-3.64 (m, 2H), 2.74-2.59 (m, 2H), 2.07-2.04 (m, 3H). LCMS M/Z (M+H) 461.
- The following Examples 225-231 were prepared in a similar fashion to Example 224.
-
Example Compound Name and Structure NMR m/z Example 225 1H NMR (400 MHz, DMSO- d6) δ 8.47-8.38 (m, 1H), 8.07 (s, 1H), 8.00-7.95 (m, 1H), 7.91-7.86 (m, 1H), 7.19-7.12 (m, 1H), 5.45- 5.42 (m, 1H), 4.95-4.92 (m, 2H), 4.88-4.84 (m, 2H), 4.45-4.40 (m, 2H), 3.96 (s, 3H), 3.70-3.64 (m, 2H), 2.75-2.60 (m, 2H), 2.08- 2.05 (m, 3H). 497 Example 226 1H NMR (400 MHz, DMSO- d6) δ 8.61-8.55 (m, 1H), 7.89-7.84 (m, 1H), 7.79 (s, 1H), 7.72-7.70 (m, 1H), 7.55 (s, 1H), 7.36-7.32 (m, 1H), 6.92 (t, J = 55.2, 1H), 5.43-5.40 (m, 1H), 5.00- 4.97 (m, 2H), 4.86-4.82 (m, 2H), 4.37 (s, 2H), 3.88 (s, 3H), 3.73-3.66 (m, 2H), 2.73-2.59 (m, 2H), 2.09- 2.07 (m, 3H) 443 Example 227 1H NMR (400 MHz, DMSO- d6) δ 8.53-8.34 (m, 2 H), 8.20 (s, 1H), 7.92 (s, 1H), 7.63- 7.57 (m, 1H), 5.46-5.43 (m, 1H), 4.94-4.87 (m, 4H), 4.40- 4.39 (m, 2H), 3.90 (s, 3H), 3.70-3.66 (m, 2H), 2.74-2.62 (m, 2H), 2.08-2.06 (m, 3H) 436 Example 228 1H NMR (400 MHz, DMSO- d6) δ 8.69-8.60 (m, 1H), 8.48-8.38 (m, 1H), 8.20 (s, 1H), 7.38-7.33 (m, 1H), 5.49-5.42 (m, 1H), 4.95- 4.86 (m, 4H), 4.45-4.41 (m, 2H), 4.00 (s, 3H), 3.72-3.65 (m, 2H), 2.75-2.63 (m, 2H), 2.08-2.06 (m, 3H) 504 Example 229 1H NMR (400 MHz, DMSO- d6) δ 8.76-8.71 (m, 1H), 8.12 (s, 1H), 8.01-7.98 (m, 1H), 7.84 (s, 1H), 7.77-7.76 (m, 1H), 7.59-7.56 (m, 1H), 5.46-5.41 (m, 1H), 5.00-4.95 (m, 2H), 4.88-4.84 (m, 2H), 4.39-4.38 (m, 2H), 3.90 (s, 3H), 3.73-3.66 (m, 2H), 2.74-2.60 (m, 2H), 2.09-2.07 (m, 3H) 418 Example 230 1H NMR (400 MHz, DMSO- d6) δ 8.47-8.39 (m, 1H), 8.32-8.19 (m, 1H), 8.16 (s, 1H), 7.88 (s, 1H), 7.46-7.42 (m, 1H), 5.47-5.40 (m, 1H), 4.95-4.92 (m, 2H), 4.87- 4.83 (m, 2H), 4.42-4.38 (m, 2H), 3.91 (s, 3H), 3.71-3.64 (m, 2H), 2.75-2.61 (m, 2H), 2.08-2.05 (m, 3H) 436 Example 231 1H NMR (400 MHz, DMSO- d6) δ 7.89-7.85 (m, 2H), 7.62 (d, J = 4.8 Hz, 1H), 7.20- 7.18 (m, 2H), 4.30 (s, 2H), 3.87 (s, 3H), 3.72-3.59 (m, 2H), 3.46 (s, 3H), 2.87-2.81 (m, 4H), 2.72-2.50 (m, 2H), 2.09-2.03 (m, 3H), 2.01- 1.97 (m, 2H) 391 -
-
- To a solution of 4-bromo-2-fluoro-1-nitrobenzene (5 g, 22.73 mmol) in DMF (100 mL) at 0° C. was added a solution of NaSMe (1.8 g, 25 mmol) in H2O (40 mL) dropwise. The reaction mixture was stirred at 0° C. for 1 h. The reaction mixture was filtered and washed with H2O (50 mL×3). The resulting yellow solid was dissolved in DCM (200 mL), drived over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (5.4 g, 96%) as a yellow solid.
-
- To a solution of (5-bromo-2-nitrophenyl)(methyl)sulfane (3 g, 12.09 mmol) in DCM (50 mL) at −10° C. was added mCPBA (85%, 8.59 g, 42.32 mmol). The reaction mixture was stirred at −10° C. for 10 min. The temperature was raised to 20° C. and the reaction mixture was stirred for an additional 2 h. A solution of sat. aq. Na2S2O3 was added slowly until no peroxide existed (indicated by KI starch paper). The organic layer was separated and washed with sat. aq. NaHCO3 (50 mL×2), drived over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (3.1 g, crude) as a yellow solid that required no further purification. 1H NMR (400 MHz, DMSO-d6) δ 8.46 (d, J=2.0 Hz, 1H), 8.21-8.20 (m, 1H), 8.02 (d, J=8.4 Hz, 1H), 3.48 (s, 3H).
-
- To a solution of 4-bromo-2-(methylsulfonyl)-1-nitrobenzene (1 g, 3.57 mmol) in MeOH (27 mL) was added NH4Cl (2.9 g, 53.55 mmol) and Zn powder (2.3 g, 35.70 mmol). The reaction mixture was stirred at room temperature for 1 h. After filtration, the filtrate was concentrated, washed with water and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (0.8 g, 90%) as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ 7.43 (d, J=8.4 Hz, 1H), 7.11 (d, J=1.6 Hz, 1H), 6.86-6.83 (m, 1H), 6.28 (s, 2H), 3.11 (s, 3H).
-
- To a solution of 4-bromo-2-(methylsulfonyl)aniline (0.8 g, 3.2 mmol) in dioxane (20 mL) and H2O (4 mL) was added 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (666 mg, 3.2 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (250 mg, 0.34 mmol) and Na2CO3 (678 mg, 6.4 mmol). The reaction mixture was heated to 120° C. for 12 h under a nitrogen atmosphere. After cooling to room temperature, the mixture was filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH=20:1) to give the title compound (600 mg, 75%) as a yellow solid.
-
- To a solution of 1-(3-bromo-1-(tetrahydrofuran-3-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone (Intermediate D, 188 mg, 0.60 mmol) in dioxane (10 mL) was added 4-(1-methyl-1H-pyrazol-4-yl)-2-(methylsulfonyl)aniline (150 mg, 0.60 mmol), chloro-(2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II) (50 mg, 0.06 mmol), 2-(dicyclohexylphosphino)3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl (32 mg, 0.06 mmol) and tBuONa (230 mg, 2.39 mmol). The reaction mixture was purged with nitrogen for 1 min and then heated to 120° C. for 18 h. After cooling to room temperature, the mixture was concentrated in vacuo. The crude residue was purified by silica gel column chromatography (DCM/MeOH=20:1) to give the crude product which was further purified by recrystallization (MeOH) to give the title compound (99 mg, 35%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.12-8.03 (m, 2H), 7.84-7.65 (m, 4H), 4.94-4.91 (m, 1H), 4.27 (s, 2H), 4.03-3.99 (m, 2H), 3.85-3.70 (m, 7H), 3.31 (s, 3H), 2.82-2.70 (m, 2H), 2.31-2.23 (m, 2H), 2.09-2.03 (m, 3H). LCMS M/Z (M+H) 485.
- The following Examples 233-240 were prepared in a similar fashion to Example 232.
-
Example Compound Name and Structure NMR m/z Example 233 1H NMR (400 MHz, DMSO- d6) δ 8.74-8.68 (m, 1H), 8.09-8.06 (m, 1H), 7.66-7.61 (m, 1H), 7.46-7.40 (m, 1H), 7.23-7.20 (m, 1H), 4.87-4.81 (m, 1H), 4.35 (s, 2H), 4.04- 3.99 (m, 2H), 3.86-3.84 (m, 1H), 3.77-3.68 (m, 3H), 3.14 (s, 3H), 2.77-2.65 (m, 2H), 2.26-2.24 (m, 2H), 2.09- 2.06 (m, 3H) 405 Example 234 1H NMR (400 MHz, DMSO- d6) δ 8.39-8.30 (m, 1H), 7.77 (s, 1H), 7.32-7.26 (m, 1H), 7.24-7.18 (m, 1H), 6.87- 6.78 (m, 1H), 4.88-4.78 (m, 1H), 4.36 (s, 2H), 4.07-3.96 (m, 2H), 3.88-3.65 (m, 4H), 2.78-2.62 (m, 2H), 2.31- 2.20 (m, 2H), 2.10-2.07 (m, 3H), 1.70-1.58 (m, 6H). 394 Example 235 1H NMR (400 MHz, DMSO- d6) δ 8.73-8.67 (m, 1H), 8.12-8.08 (m, 1H), 7.63-7.60 (m, 1H), 7.45-7.41 (m, 1H), 7.21-7.18 (m, 1H), 4.87-4.84 (m, 1H), 4.37 (s, 2H), 4.06- 4.01 (m, 2H), 3.87-3.68 (m, 4H), 2.78-2.66 (m, 3H), 2.28-2.23 (m, 2H), 2.10- 2.07, (s, 3H), 1.09-1.02 (m, 4H) 431 Example 236 1H NMR (400 MHz, DMSO- d6) δ 8.00 (s, 1H), 7.73 (s, 1H), 7.33-7.32 (m, 1H), 7.18-7.13 (m, 1H), 7.12 (s, 1H), 7.04-6.97 (m, 1H), 4.84-4.81 (m, 1H), 4.16- 4.13 (m, 2H), 3.99-3.95 (m, 2H), 3.83 (s, 3H), 3.81-3.66 (m, 4H), 2.78-2.66 (m, 2H), 2.27-2.20 (m, 2H), 2.08-1.97 (m, 3H), 1.23-1.16 (m, 6H) 449 Example 237 1H NMR (400 MHz, DMSO- d6) δ 7.94 (s, 1H), 7.71 (s, 1H), 7.28 (s, 1H), 7.23-6.97 (m, 3H), 4.87-4.81 (m, 1H), 4.23-4.19 (m, 2H), 4.00-3.96 (m, 2H), 3.83 (s, 3H), 3.81- 3.67 (m, 4H), 2.79-2.67 (m, 2H), 2.29-2.19 (m, 5H), 2.08-2.00 (m, 3H) 421 Example 238 1H NMR (400 MHz, DMSO- d6) δ 8.20-8.12 (m, 1H), 8.01 (s, 1H), 7.85-7.74 (m, 2H), 7.52-7.48 (m, 1H), 4.89-4.85 (m, 1H), 4.44-4.38 (m, 2H), 4.03-3.99 (m, 2H), 3.86 (s, 3H), 3.80-3.67 (m, 4H), 2.79- 2.67 (m, 2H), 2.31-2.23 (m, 2H), 2.09-2.06 (m, 3H) 443 Example 239 1H NMR (400 MHz, DMSO- d6) δ 8.43-8.34 (m, 2H), 8.17 (d, J = 2.4 Hz, 1H), 7.90 (d, J = 2.4 Hz, 1H), 7.56-7.53 (m, 1H), 4.91-4.84 (m, 1H), 4.43-4.38 (m, 2H), 4.03-3.99 (m, 2H), 3.89 (s, 3H), 3.79- 3.67 (m, 4H), 2.78-2.66 (m, 2H), 2.33-2.23 (m, 2H), 2.08-2.05 (m, 3H) 450 Example 240 1H NMR (400 MHz, DMSO- d6) δ 8.38-8.30 (m, 1H), 8.17-8.02 (m, 2H), 7.87 (s, 1H), 7.41-7.37 (m, 1H), 4.91-4.85 (m, 1H), 4.41- 4.36 (m, 2H), 4.00-3.98 (m, 2H), 3.90 (s, 3H), 3.84- 3.79 (m, 2H), 3.77-3.68 (m, 2H), 2.79-2.67 (m, 2H), 2.28-2.22 (m, 2H), 2.09- 2.06 (m, 3H). 450 Example 241 1H NMR (400 MHz, DMSO- d6) δ 8.40-8.28 (m, 1H), 8.22-8.14 (m, 1H), 7.84 (s, 1H), 7.59 (s, 1H), 7.230-7.24 (m, 1H), 6.89 (t, J = 54.8, 1H), 4.88-4.85 (m, 1H), 4.44-4.38 (m, 2H), 4.06- 4.00 (m, 2H), 3.88-3.84 (m, 4H), 3.78-3.66 (m, 3H), 2.79-2.67 (m, 2H), 2.29- 2.25 (m, 2H), 2.09-2.06 (m, 3H) 475 -
-
- To a solution of tetrahydro-2H-pyran-4-ol (5 g, 49.0 mmol) and triethylamine (5.94 g, 58.7 mmol) in DCM (100 mL) was added mesyl chloride (16.8 g, 146.9 mmol) dropwise at 0° C. under a nitrogen atmosphere. The mixture was stirred at room temperature for 5 h. Water (100 mL) was added and washed with brine (100 mL×2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (4 g, 45%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 4.85-4.81 (m 1H), 3.90-3.87 (m, 2H), 3.52-3.46 (m, 2H), 2.99 (s, 3H), 2.01-1.97 (m, 2H), 1.83-1.80 (m, 2H).
-
- To a solution of tert-butyl 3-bromo-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (Intermediate A, 6 g, 19.8 mmol) in DMF (40 mL) was added Cs2CO3 (19.5 g, 59.6 mmol) and tetrahydro-2H-pyran-4-yl methanesulfonate (3.9 g, 21.8 mmol). The mixture was heated to 80° C. for 12 h under a nitrogen atmosphere. After cooling the reaction to room temperature, the mixture was filtered. The mixture was diluted with EtOAc (100 mL) and washed with brine (100 mL×2). The organic layer was concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether:tert-butyl methyl ether:THF=from 10:1:1 to 2:1:1) to give the title compound (Intermediate P, 3.2 g, 47%) as a clear oil. 1H NMR (400 MHz, DMSO-d6) δ 4.35-4.25 (m, 1H), 4.17 (s, 2H), 3.95-3.93 (m, 2H), 3.62-3.57 (m, 2H), 3.42 (t, J=11.2 Hz, 2H), 2.74-2.73 (m, 2H), 1.98-1.89 (m, 2H), 1.80-1.77 (m, 2H), 1.41 (s, 9H).
-
- To a solution of tert-butyl 3-bromo-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (Intermediate P, 3.2 g, 8.3 mmol) in DCM (20 mL) was added trifluoroacetic acid (20 mL) dropwise at 0° C. The mixture was stirred at room temperature for 2 h. The mixture was concentrated in vacuo and the residue was re-dissolved in DCM (30 mL). The mixture was cooled to 0° C. before triethylamine (2.1 g, 21 mmol) and acetic anhydride (0.93 g, 9.1 mmol) were added dropwise. The mixture was stirred at room temperature for an additional 0.5 h. The reaction was quenched with water (60 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (DCM/MeOH=50:1) to give the title compound (Intermediate Q, 2.1 g, 77%) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 4.33-4.29 (m, 1H), 4.28 (s 2H), 3.95-3.92 (m, 2H), 3.70-3.67 (m, 2H), 3.43-3.36 (m, 2H), 2.84-2.69 (m, 2H), 2.09-2.08 (m, 3H), 1.96-1.91 (m, 2H), 1.80-1.76 (m, 2H).
-
- To a stirred solution of 5-(difluoromethyl)-2-fluoro-4-(1-methylpyrazol-4-yl)aniline (176 mg, 0.73 mmol) in 1,4-dioxane (4 mL) was added 1-(3-bromo-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone (Intermediate Q, 200 mg, 0.61 mmol), 2-(dicyclohexylphosphino)3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl (33 mg, 0.06 mmol), chloro(2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl) [2-(2-aminoethylphenyl)]palladium(II), methyl-t-butylether adduct (50 mg, 0.06 mmol) and tBuONa (176 mg, 1.83 mmol). The reaction mixture was heated to 120° C. for 12 h under a nitrogen atmosphere. After cooling to room temperature, water (40 mL) was added, and extracted with DCM (40 mL×2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by reverse phase chromatography (acetonitrile 38-68%/0.225% formic acid in water) to give the title compound (28 mg, 9%) as a white solid. 1H NMR (400 MHz, CD3OD) δ 7.98-7.86 (m, 1H), 7.71 (s, 1H), 7.56 (s, 1H), 7.18-7.13 (m, 1H), 6.66 (t, J=55.6, 1H), 4.45-4.37 (m, 2H), 4.29-4.26 (m, 1H), 4.08-4.05 (m, 2H), 3.95 (s, 1H), 3.90-3.82 (m, 2H), 3.60-3.55 (m, 2H), 2.89-2.78 (m, 2H), 2.24-2.14 (m, 5H), 1.88-1.85 (m, 2H). LCMS M/Z (M+H) 489.
- The following Example 243 was prepared in a similar fashion to Example 242.
-
Example Compound Name and Structure NMR m/z Example 243 1H NMR (400 MHz, DMSO-d6) δ 8.06 (s, 1H), 7.90-7.70 (m, 2H), 7.26-7.14 (m, 1H), 7.04-6.91 (m, 2H), 4.41-4.35 (m, 2H), 4.25-4.22 (m, 1H), 3.97-3.94 (m, 2H), 3.88 (s, 3H), 3.73-3.66 (m, 2H), 3.48-3.42 (m, 2H), 2.79-2.67 (m, 2H), 2.08-1.98 (m, 5H), 1.80-1.76 (m, 2H) 489 -
-
- To a stirred solution of 1-acetylpiperidin-4-one (6.08 g, 43.09 mmol) in THF (100 mL) at 0° C. was added tBuOK (4.83 g, 43.09 mmol). After stirring at room temperature for 30 min, 4-bromo-2-fluoro-1-isothiocyanato-benzene (10 g, 43.09 mmol) was added. The mixture was stirred at room temperature for an additional 3 h before MeI (7.34 g, 51.71 mmol) was added. The reaction mixture was heated to 40° C. for 1 h. The mixture was quenched with sat. aq. ammonium chloride (100 mL) and washed with EtOAc (100 mL×2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (petroleum ether/EtOAc=1:1) to give the title compound (8.5 g, 51%) as a yellow oil.
-
- A mixture of (Z)-1-acetyl-3-(((4-bromo-2-fluorophenyl)amino)(methylthio)methylene)piperidin-4-one (8.5 g, 21.95 mmol) and hydrazine monohydrate (1.65 g, 32.92 mmol) in EtOH (85 mL) was heated to 60° C. for 2 h. The reaction mixture was concentrated in vacuo to give the title compound (Intermediate R, 7.5 g, crude) as a white solid that required no further purification.
-
-
- To a solution of 1-(3-((4-bromo-2-fluorophenyl)amino)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone (Intermediate R, 6 g, 16.99 mmol) in 1,4-dioxane (50 mL) and water (10 mL) was added 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (4.24 g, 20.39 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.24 g, 1.7 mmol) and Na2CO3 (3.6 g, 33.98 mmol). The reaction mixture was heated to 100° C. for 12 h under a nitrogen atmosphere. After cooling to room temperature, the mixture was filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH=30:1) to give the title compound (3.8 g, 63%) as a brown solid.
-
- To a solution of 1-(3-((2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone (500 mg, 1.4 mmol) and Cs2CO3 (600 mg, 1.8 mmol) in DMF (10 mL) was added ethyl 2-bromo-2-methylpropanoate (320 mg, 1.6 mmol). The reaction mixture was heated to 80° C. for 16 h. After cooling to room temperature, EtOAc (50 mL) was added and the mixture was washed with brine (100 mL×2), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (DCM/MeOH=20:1) to give the title compound (150 mg, 25%) as a brown solid. LCMS M/Z (M+H) 469.
-
- To a solution of ethyl 2-(5-acetyl-3-((2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)-2-methylpropanoate (150 mg, 0.3 mmol) in MeOH (20 mL) was added LiBH4 (150 mg, 7.0 mmol). The reaction mixture was heated to 60° C. for 16 h under nitrogen atmosphere. After cooling to room temperature, NaOH (1M, 10 mL) was added and the mixture was extracted with EtOAc (20 mL×2). The combined organic layers were washed with brine (20 mL×2), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (DCM/MeOH=15:1) to give the title compound (50 mg, 40%) as a pale brown solid. 1H NMR (400 MHz, DMSO-d6) δ 8.03 (s, 1H), 7.81-7.61 (m, 3H), 7.31-7.20 (m, 2H), 5.00 (s, 1H), 4.40-4.32 (m, 2H), 3.83 (s, 3H), 3.68-3.58 (m, 4H), 2.98-2.83 (m, 2H), 2.07-2.05 (m, 3H), 1.48 (s, 6H). LCMS M/Z (M+H) 427.
- The following Example 245 was prepared in a similar fashion to Example 244.
-
Compound Name and Example Structure NMR m/z Example 245 1H NMR (400 MHz, DMSO-d6) δ 7.86- 7.72 (m, 2H), 7.51 (s, 1H), 7.17- 7.03 (m, 2H), 4.67-4.63 (m, 2H), 4.46- 4.43 (m, 2H), 4.41-4.34 (m, 2H), 4.19 (d, J = 7.2 Hz, 2H), 3.75 (s, 3H), 3.73-3.65 (m, 2H), 3.38-3.34 (m, 1H), 2.76-2.63 (m, 2H), 2.34 (s, 3H), 2.09-2.05 (m, 3H) 439 -
-
- A mixture of 1-(3-((4-bromo-2-fluorophenyl)amino)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone (4.5 g, 12.74 mol), tetrahydrofuran-3-yl methanesulfonate (2.54 g, 15.29 mmol) and Cs2CO3 (8.31 g, 25.48 mmol) in DMF (45 mL) was heated to 90° C. for 12 h. After cooling to room temperature, water (50 mL) was added and the mixture was extracted with DCM (50 mL×2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (DCM/MeOH=30:1) to give the title compound (3.5 g, 65%) as a yellow solid. 1H NMR (400 MHz, CD3OD) δ 8.03-7.96 (m, 1H), 7.76-7.61 (m, 1H), 7.43-7.38 (m, 1H), 7.21-7.17 (m, 1H), 4.86-4.84 (m, 1H), 4.39-4.32 (m, 2H), 3.99-3.97 (m, 2H), 3.83-3.66 (m, 4H), 2.78-2.66 (m, 2H), 2.24-2.21 (m, 2H), 2.08-2.04 (m, 3H).
-
- A mixture of 1-(3-((4-bromo-2-fluorophenyl)amino)-1-(tetrahydrofuran-3-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone (2 g, 4.73 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (1.44 g, 5.67 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.35 g, 0.47 mmol) and KOAc (1.39 g, 14.18 mmol) in 1,4-dioxane (20 mL) was purged with nitrogen for 1 min. The reaction mixture was heated to 100° C. for 12 h. After cooling to room temperature, water (40 mL) was added and the mixture was extracted with DCM (40 mL×2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (DCM/MeOH=30:1) to give the title compound (Intermediate S, 1.5 g, 67%) as a yellow solid.
-
-
- To a solution 4-bromo-1H-pyrazole-3-carbaldehyde (2.0 g, 11.4 mmol) in DMF (20 mL) at 0° C. was added sodium hydride (60%, 0.55 g, 13.7 mmol) and the mixture was stirred for 30 min before 2-(trimethylsilyl)ethoxymethyl chloride (2.4 mL, 13.7 mmol) was added and the mixture stirred at room temperature for an additional 16 h. The mixture was quenched with water (25 mL) and extracted with DCM (30 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (petroleum ether/EtOAc=8:1) to give the title compound (1 g, 29%) as a yellow oil.
-
- To a solution of 4-bromo-1-(2-trimethylsilylethoxymethyl)pyrazole-3-carbaldehyde (800 mg, 2.6 mmol) in DCM (8 mL) at 0° C. was added diethylaminosulfur trifluoride (0.87 mL, 6.6 mmol) and the mixture was stirred for 16 h at 0° C. The mixture was quenched with sat. aq. NaHCO3 (10 mL) and the mixture was extracted with DCM (10 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (petroleum ether/EtOAc=100:1 to 50:1) to give the title compound (560 mg, 65%) as a yellow oil.
-
- To a solution of 1-(3-((2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)amino)-1-(tetrahydrofuran-3-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5 (4H)-yl)ethanone (Intermediate S, 300 mg, 0.64 mmol) in 1,4-dioxane (8 mL) and water (2 mL) was added 4-bromo-3-(difluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (251 mg, 0.77 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (47 mg, 0.06 mmol) and Na2CO3 (207 mg, 1.9 mmol). The reaction mixture was heated to 120° C. for 16 h. After cooling to room temperature, the reaction mixture was filtered and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (DCM/MeOH=50:1 to 20:1) to give the title compound (80 mg, 21%) as a yellow oil.
-
- To a solution of 1-(3-((4-(3-(difluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-2-fluorophenyl)amino)-1-(tetrahydrofuran-3-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone (150 mg, 0.25 mmol) in 1,4-dioxane (2 mL) was added HCl/dioxane (4 M, 4 mL) and the reaction mixture was stirred at 25° C. for 16 h. The mixture was concentrated in vacuo. Water (20 mL) was added and the mixture was made basic with sat. aq. NaHCO3 to pH 7 and then extracted with DCM (10 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by reverse phase chromatography (acetonitrile 23-53%/0.1% formic acid in water) to give the title compound (40 mg, 34%) as a colorless oil. 1H NMR (400 MHz, CD3OD) δ 7.87 (s, 1H), 7.62-7.49 (m, 1H), 7.27-7.23 (m, 1H), 7.20-7.15 (m, 1H), 6.85 (t, J=54 Hz, 1H), 4.89-4.86 (m, 1H), 4.44-4.42 (m, 2H), 4.18-4.15 (m, 1H), 4.09-4.06 (m, 1H), 3.98-3.88 (m, 3H), 3.84-3.79 (m, 1H), 2.88-2.76 (m, 2H), 2.39-2.33 (m, 2H), 2.20-2.14 (m, 3H). LCMS M/Z (M+H) 461.
- The following Examples 247-249 were prepared in a similar fashion to Example 246.
-
Compound Name and Example Structure NMR m/z Example 247 1H NMR (400 MHz, DMSO-d6) δ 7.98 (s, 1H), 7.85-7.64 (m, 2H), 7.52- 7.45 (m, 2H), 7.23-7.20 (m, 2H), 4.87- 4.84 (m, 1H), 4.41-4.35 (m, 2H), 4.03-3.99 (m, 2H), 3.87 (s, 3H), 3.84- 3.80 (m, 2H), 3.76-3.67 (m, 2H), 2.78-2.66 (m, 2H), 2.28-2.23 (m, 2H), 2.09-2.05 (m, 3H) 468 Example 248 1H NMR (400MHz, DMSO-d6) δ 12.84 (s, 1H), 8.10 (s, 1H), 7.91-7.79 (m, 2H), 7.76-7.67 (m, 1H), 7.42-7.38 (m, 1H), 7.31-7.26 (m, 1H), 4.90- 4.80 (m, 1H), 4.42-4.32 (m, 2H), 4.05- 3.96 (m, 2H), 3.88-3.76 (m, 2H), 3.74-3.64 (m, 2H), 2.81-2.63 (m, 2H), 2.31-2.19 (m, 2H), 2.08-2.05 (m, 3H). 411 Example 249 1H NMR (400MHz, DMSO-d6) δ 8.11- 7.99 (m, 1H), 7.93-7.72 (m, 1H), 7.34-7.18 (m, 2H), 4.91-4.82 (m, 1H), 4.44-4.31 (m, 2H), 4.06-3.95 (m, 2H), 3.88-3.76 (m, 2H), 3.74- 3.66 (m, 2H), 2.81-2.65 (m, 2H), 2.39 (s, 3H), 2.32-2.22 (s, 5H), 2.09-2.05 (m, 3H). 440 -
- To a solution (S)-1-[3-[4-(1-methylpyrazol-4-yl)anilino]-1-tetrahydrofuran-3-yl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (Examples 178, 100 mg, 0.25 mmol) in DMF (2 mL) at 0° C. was added sodium hydride (60%, 20 mg, 0.49 mmol) and the mixture was stirred for 30 min. Benzyl bromide (51 mg, 0.3 mmol) was added and the mixture stirred at room temperature for an additional 2 h. The mixture was quenched with water (10 mL) and extracted with EtOAc (10 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by reverse phase chromatography (acetonitrile 36-66%/0.1% NH4OH in water) to give the tittle compound (45 mg, 37%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.94 (s, 1H), 7.69 (s, 1H), 7.39-7.19 (m, 7H), 6.78-6.73 (m, 2H), 4.96 (s, 2H), 4.87-3.85 (m, 1H), 4.00-3.94 (m, 4H), 3.81-3.66 (m, 7H), 2.81-2.67 (m, 2H), 2.28-2.22 (m, 2H), 2.04-1.85 (m, 3H). LCMS M/Z (M+Na) 519.
- The following Example 251 was prepared in a similar fashion to Example 250.
-
Compound Name and Example Structure NMR m/z Example 251 1H NMR (400 MHz, DMSO-d6) δ 7.97 (s, 1H), 7.72 (s, 1H), 7.40-7.36 (m, 2H), 6.78-6.74 (m, 2H), 4.91-4.84 (m, 1H), 4.01-3.99 (m, 2H), 3.90 (s, 2H), 3.83 (s, 3H), 3.82-3.79 (m, 2H), 3.72-3.65 (m, 4H), 2.82-2.67 (m, 2H), 2.27-2.22 (m, 2H), 2.03-1.85 (m, 3H), 1.16-1.12 (m, 3H). 435 -
-
- To a stirred solution of 5-(difluoromethyl)-2-fluoro-4-(1-methylpyrazol-4-yl)aniline (500 mg, 2.1 mmol) in 1,4-dioxane (8 mL) was added tert-butyl 3-bromo-1-tetrahydropyran-4-yl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate (Intermediate P, 961 mg, 2.5 mmol), 2-(dicyclohexylphosphino)3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl (111 mg, 0.2 mmol), chloro(2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (161 mg, 0.2 mmol) and tBuONa (498 mg, 5.2 mmol). The reaction mixture was heated to 120° C. for 16 h under a nitrogen atmosphere. After cooling to room temperature, water (40 mL) was added and the mixture was extracted with EtOAc (40 mL×2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (DCM/MeOH=50:1) to give the title compound (600 mg, 53%). LCMS M/Z (M+H) 548.
-
- To a stirred solution of tert-butyl 3-((5-(difluoromethyl)-2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (150 mg, 0.2 mmol) in DCM (2 mL) at 0° C. was added a solution of trifluoroacetic acid (0.08 mL, 1.1 mmol) in DCM (2 mL). The mixture was stirred at 20° C. for 15 minutes and concentrated in vacuo to give the title compound (100 mg, crude) as a brown oil that required no further purification.
-
- To a stirred solution of N-(5-(difluoromethyl)-2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-amine (100 mg, 0.2 mmol) and N,N-diisopropylethylamine (0.12 mL, 0.7 mmol) in DCM (3 mL) at 0° C. was added a solution of propionyl chloride (0.02 mL, 0.25 mmol) in DCM (2 mL) dropwise. The reaction mixture was stirred at 20° C. for 10 minutes. Water (10 mL) was added and the mixture was extracted with DCM (10 mL×2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by reverse phase chromatography (acetonitrile 30-60%/0.225% formic acid in water) to give the title compound (22 mg, 19%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.38-8.24 (m, 1H), 8.19-8.10 (m, 1H), 7.84 (s, 1H), 7.59 (d, J=2.2 Hz, 1H), 7.30-7.24 (m, 1H), 6.90 (t, J=54.8 Hz, 1H), 4.44-4.38 (m, 2H), 4.27-4.18 (m, 1H), 4.00-3.92 (m, 2H), 3.88 (s, 3H), 3.76-3.67 (m, 2H), 3.48-4.42 (m, 2H), 2.81-2.67 (m, 2H), 2.44-2.34 (m, 2H), 1.95-2.06 (m, 2H), 1.83-1.75 (m, 2H), 1.02-0.98 (m, 3H). LCMS M/Z (M+H) 503.
- The following Examples 253-255 were prepared in a similar fashion to Example 252.
-
Compound Name and Example Structure NMR m/z Example 253 1H-NMR (400 MHz, DMSO-d6) δ 8.38-8.24 (m, 1H), 8.18-8.09 (m, 1H), 7.84 (s, 1H), 7.59 (d, J = 2.6 Hz, 1H), 7.30-7.24 (m, 1H), 6.89 (t, J = 55.2, 1H), 4.46-4.36 (m, 2H), 4.27-4.19 (m, 1H), 3.97- 3.94 (m, 2H), 3.88 (s, 3H), 3.77- 3.67 (m, 2H), 3.49-3.42 (m, 2H), 2.81-2.65 (m, 2H), 2.40-2.32 (m, 2H), 2.06-1.95 (m, 2H), 1.84- 1.75 (m, 2H), 1.57-1.49 (m, 2H), 0.92-0.87 (m, 3H) 517 Example 254 1H NMR (400MHz, DMSO-d6) δ 8.55-8.42 (m, 1H), 7.93-7.83 (m, 1H), 7.78 (s, 1H), 7.54-7.52 (m, 2H), 7.34-7.23 (m, 1H), 6.89 (t, J = 55.2, 1H), 4.88-4.79 (m, 1H), 4.38 (s., 2H), 4.09-3.98 (m, 2H), 3.88 (s, 3H), 3.86-3.67 (m, 4H), 2.80-2.62 (m, 2H), 2.47-2.35 (m, 2H), 2.25 (q, J = 7.2 Hz, 2H), 1.02 (t, J = 7.2 Hz, 3H) 471 Example 255 1H NMR (400MHz, DMSO-d6) δ 8.53-8.42 (m, 1H), 7.93-7.83 (m, 1H), 7.78 (s, 1H), 7.58-7.51 (m, 2H), 7.32-7.25 (m, 1H), 6.89 (t, J = 54.8, 1H), 4.91-4.79 (m, 1H), 4.38 (s, 2H), 4.08-3.97 (m, 2H), 3.88 (s, 3H), 3.86-3.68 (m, 4H), 2.78-2.63 (m, 2H), 2.41-2.33 (m, 2H), 2.25 (q, J = 6.4 Hz, 2H), 1.60- 1.48 (m, 2H), 0.93-0.86 (m, 3H) 485 -
- To a solution of N-(5-(difluoromethyl)-2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-amine (100 mg, 0.2 mmol) in DCM (2 mL) was added trimethylsilyl isocyanate (46 mg, 0.4 mmol). The reaction mixture was stirred at 26° C. for 4 h and concentrated in vacuo. The crude residue was purified by reverse phase chromatography (acetonitrile 30-60%/0.2% formic acid in water) to give the title compound (11 mg, 11%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.15 (d, J=8.8 Hz, 1H), 7.99 (s, 1H), 7.84 (s, 1H), 7.59 (s, 1H), 7.25 (d, J=12.4 Hz, 1H), 6.89 (t, J=54.8 Hz, 1H), 6.03 (s, 2H), 4.26-4.21 (m, 3H), 3.96-3.94 (m, 2H), 3.87 (s, 3H), 3.59-3.56 (m, 2H), 3.48-3.42 (m, 2H), 2.68-2.66 (m, 2H), 2.07-1.95 (m, 2H), 1.80-1.78 (m, 2H). LCMS M/Z (M+H) 490.
- The following Examples 257-259 were prepared in a similar fashion to Example 256.
-
Example Compound Name and Structure NMR m/z Example 257 1H NMR (400MHz, DMSO-d6) δ 8.20 (d, J = 8.8 Hz, 1H), 8.04 (s, 1H), 7.84 (s, 1H), 7.59 (s, 1H), 7.26 (d, J = 12.4 Hz, 1H), 6.89 (t, J = 54.8 Hz, 1H), 6.03 (s, 2H), 4.90-4.87 (m, 1H), 4.23 (s, 2H), 4.11-3.96 (m, 2H), 3.92-3.81 (m, 4H), 3.77- 3.75 (m, 1H), 3.59-3.56 (m, 2H), 2.68-2.65 (m, 2H), 2.31- 2.18 (m, 2H) 476 Example 258 1H NMR (400 MHz, DMSO-d6) δ 8.02 (s, 1H), 7.78 (s, 1H), 7.65-7.61 (m, 2H), 7.37-7.33 (m, 1H), 7.23 (d, J = 8.4 Hz, 1H), 6.03 (s, 2H), 4.89-4.85 (m, 1H), 4.20 (s, 2H), 4.01- 3.99 (m, 2H), 3.84 (s, 3H), 3.83-3.78 (m, 2H), 3.58-2.58 (m, 2H), 2.68-2.65 (m, 2H), 2.26- 2.21 (m, 2H) 426 Example 259 1H NMR (400MHz, DMSO-d6) δ 8.01 (s, 1H), 7.78 (s, 1H), 7.66-7.62 (m, 1H), 7.58 (s, 1H), 7.36-7.32 (m, 1H), 7.23 (d, J = 8.4 Hz, 1H), 6.01 (s, 2H), 4.31-4.13 (m, 3H), 3.97- 3.94 (m, 2H), 3.83 (s, 3H), 3.59-3.56 (m, 2H), 3.48-3.43 (m, 2H), 2.69-2.63 (m, 2H), 2.07-2.01 (m, 2H), 1.79-1.76 (m, 2H) 440 -
- To a solution of N-(5-(difluoromethyl)-2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-amine (200 mg, 0.4 mmol) and pyridine (0.06 mL, 2.02 mmol) in DMF (2 mL) was added 4-nitrophenylchloroformate (244 mg, 1.21 mmol). The reaction mixture was stirred at 26° C. for 4 h. Methanamine in THF (2 M, 0.77 mL, 1.54 mmol) was added and the reaction mixture was heated to 60° C. for an additional 12 h. The mixture was concentrated in vacuo. The crude residue was purified by reverse phase chromatography (acetonitrile 26-56%/0.2% formic acid in water) to give the title compound (15 mg, 19%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.12 (d, J=9.2 Hz, 1H), 8.01 (s, 1H), 7.83 (s, 1H), 7.58 (s, 1H), 7.25 (d, J=12.8 Hz, 1H), 6.88 (t, J=54.8 Hz, 1H), 6.49 (d, J=4.4 Hz, 1H), 4.25-4.20 (m, 3H), 3.96-3.93 (m, 2H), 3.87 (s, 3H), 3.58-3.56 (m, 2H), 3.45-3.42 (m, 2H), 2.68-2.66 (m, 2H), 2.57-2.55 (m, 3H), 2.04-1.94 (m, 2H), 1.79-1.77 (m, 2H). LCMS M/Z (M+H) 504.
- The following Examples 261-272 were prepared in a similar fashion to Example 260.
-
Example Compound Name and Structure NMR m/z Example 261 1H NMR (400MHz, DMSO- d6) δ 8.18 (d, J = 8.8 Hz, 1H), 8.06 (s, 1H), 7.84 (s, 1H), 7.59 (s, 1H), 7.26 (d, J = 12.8 Hz, 1H), 6.88 (t, J = 54.8 Hz, 1H), 6.50 (d, J = 4.5 Hz, 1H), 4.89- 4.86 (m, 1H), 4.22 (s, 2H), 4.10-3.96 (m, 2H), 3.90- 3.86 (m, 4H), 3.79-3.66 (m, 1H), 3.59-3.56 (m, 2H), 2.69- 2.65 (m, 2H), 2.58-2.54 (m, 3H), 2.34-2.20 (m, 2H) 490 Example 262 1H NMR (400 MHz, DMSO- d6) δ 7.99 (s, 1H), 7.75 (s, 1H), 7.61-7.54 (m, 2H), 7.33- 7.30 (m, 1H), 7.20-7.17 (m, 1H), 6.46-6.45 (m, 1H), 4.84-4.82 (m, 1H), 4.15 (s, 2H), 3.97-3.95 (m, 2H), 3.80 (s, 3H), 3.76-3.74 (m, 2H), 3.55-3.52 (m, 2H), 2.64- 2.62 (m, 2H), 2.54-2.52 (m, 3H), 2.22-2.17 (m, 2H) 440 Example 263 1H NMR (400MHz, DMSO- d6) δ 8.21-8.05 (m, 1H), 8.01 (s, 1H), 7.85-7.70 (m, 2H), 7.67-7.55 (m, 1H), 7.35 (d, J = 13.2 Hz, 1H), 7.26-7.23 (m, 1H), 6.49-6.48 (m, 1H), 4.32-4.18 (m, 3H), 3.97- 3.95 (m, 2H), 3.84 (s, 3H), 3.73-3.63 (m, 1H), 3.58- 3.42 (m, 3H), 2.80-2.66 (m, 2H), 2.57-2.55 (m, 3H), 2.04- 2.00 (m, 2H), 1.79-1.75 (m, 2H) 454 Example 264 1H NMR (400MHz, DMSO- d6) δ 8.15-7.95 (m, 2H), 7.78 (s, 1H), 7.54-7.25 (m, 2H), 6.49-6.48 (m, 1H), 4.33- 4.13 (m, 3H), 4.00-3.91 (m, 2H), 3.87 (s, 3H), 3.59-3.56 (m, 2H), 3.48-3.42 (m, 2H), 2.71-2.64 (m, 2H), 2.57- 2.55 (m, 3H), 2.08-1.93 (m, 2H), 1.80-1.76 (m, 2H) 472 Example 265 1H-NMR (400 MHz, DMSO- d6) δ 8.10 (s, 1H), 7.79 (s, 1H), 7.64-7.59 (m, 1H), 7.13 (d, J = 13.2 Hz, 1H), 7.06 (d, J = 8.4 Hz, 1H), 6.50-6.47 (m, 1H), 4.28-4.21 (m, 1H), 4.19 (s, 2H), 3.99-3.94 (m, 2H), 3.93 (s, 3H), 3.59-3.57 (m, 2H), 3.48-3.42 (m, 2H), 2.72-2.63 (m, 2H), 2.57-2.55 (m, 3H), 2.05-1.96 (m, 2H), 1.84-1.73 (m, 2H). 522 Example 266 1H NMR (400MHz, DMSO- d6) δ 8.23-8.21 (m, 2H), 8.15 (d, J = 8.8 Hz, 1H), 7.27 (d, J = 12.0 Hz, 1H), 6.98 (d, J = 4.4 Hz, 1H), 6.84 (t, J = 54.8 Hz, 1H), 6.78 (s, 1H), 6.50 (d, J = 4.0 Hz, 1H), 4.31-4.17 (m, 3H), 3.97-3.94 (m, 2H), 3.89 (s, 3H), 3.64-3.54 (m, 2H), 3.51-3.42 (m, 2H), 2.75-2.65 (m, 2H), 2.57-2.56 (m, 3H), 2.08-1.93 (m, 2H), 1.82-1.78 (m, 2H) 531 Example 267 1H NMR (400 MHz, DMSO- d6) δ 7.68-7.64 (m, 1H), 7.60 (s, 1H), 7.51 (s, 1H), 7.14 (d, J = 13.2 Hz, 1H), 7.06 (d, J = 8.4 Hz, 1H), 6.49-6.47 (m, 1H), 4.22-4.19 (m, 3H), 3.97- 3.95 (m, 2H), 3.76 (s, 3H), 3.58-3.57 (m, 2H), 3.48- 3.42 (m, 2H), 2.67-2.57 (m, 2H), 2.56-2.50 (m, 3H), 2.35 (s, 3H), 2.04-2.01 (m, 2H), 2.00-1.76 (m, 2H) 468 Example 268 1H NMR (400 MHz, DMSO- d6) δ 8.00 (s, 1H), 7.93 (s, 1H), 7.81 (s, 1H), 7.63-6.59 (m, 1H), 7.52-7.47 (m, 1H), 6.48 (s, 1H), 4.25-4.18 (m, 3H), 3.98-3.95 (m, 2H), 3.87 (s, 3H), 3.58-3.57 (m, 2H), 3.49-3.43 (m, 2H), 2.67- 2.60 (m, 2H), 2.58-2.57 (m, 3H), 2.05-1.97 (m, 2H), 1.81- 1.78 (m, 2H). 472 Example 269 1H-NMR (400 MHz, CDCl3) δ 8.01 (s, 1H), 7.96 (d, J = 8.4 Hz, 1H), 7.82 (s, 1H), 7.32 (s, 1H), 7.29 (d, J = 12.4 Hz, 1H), 5.91-5.89 (m, 1H), 4.56- 4.54 (m, 1H), 4.26 (s, 2H), 4.22-4.17 (m, 3H), 4.02 (s, 3H), 3.84-3.82 (m, 2H), 3.61-3.55 (m, 2H), 2.90 (d, J = 4.4 Hz, 3H), 2.83-2.80 (m, 2H), 2.36-2.23 (m, 2H), 1.92- 1.89 (m, 2H) 479 Example 270 1H NMR (400 MHz, CDCl3) δ 7.85 (s, 1H), 7.76 (s, 1H), 7.26- 7.24 (m, 1H), 6.96-7.05 (m, 2H), 5.88-5.87 (m, 1H), 4.50-4.49 (m, 1H), 4.15- 4.11 (m, 5H), 3.98 (s, 3H), 3.82-3.79 (m, 2H), 3.56- 3.50 (m, 2H), 2.82 (d, J = 4.8 Hz, 3H), 2.76-2.73 (m, 2H), 2.34-2.29 (m, 2H), 1.87- 1.83 (m, 2H). 454 Example 271 1H NMR (400 MHz, DMSO- d6) δ 8.62 (s, 1H), 8.18 (s, 1H), 7.85-7.70 (m, 3H), 7.16 (s, 1H), 6.55-6.54 (m, 1H), 4.25-4.22 (m, 3H), 3.97- 3.95 (m, 2H), 3.87 (s, 3H), 3.58-3.56 (m, 2H), 3.49- 3.43 (m, 2H), 2.67-2.65 (m, 8H), 2.58 (d, J = 4.8 Hz, 3H), 2.09-1.91 (m, 2H), 1.81- 1.75 (m, 2H). 543 Example 272 1H NMR (400 MHz, DMSO- d6) δ 8.87-8.84 (m, 1H), 8.60 (s, 1H), 8.24 (s, 1H), 8.17 (d, J = 9.2 Hz, 1H), 8.09 (d, J = 8.0 Hz, 1H), 7.97-7.95 (m, 1H), 7.35 (d, J = 12.0 Hz, 1H), 6.82 (t, J = 54.8 Hz, 1H), 6.52- 6.48 (m, 1H), 4.38-4.16 (m, 3H), 3.98-3.95 (m, 2H), 3.60- 3.58 (m, 2H), 3.50-3.44 (m, 2H), 2.85 (d, J = 4.4 Hz, 3H), 2.71-2.62 (m, 2H), 2.58 (d, J = 4.0 Hz, 3H), 2.09- 1.94 (m, 2H), 1.83-1.78 (m, 2H). 558 -
-
- To a solution of tetrahydrothiopyran-4-ol (10 g, 84.6 mmol) and triethylamine (35.4 mL, 253.8 mmol) in DCM (150 mL) at 0° C. was added methanesulfonyl chloride (10.7 mL, 138.8 mmol) dropwise. The reaction was stirred at 25° C. for 16 h. Water (100 mL) was added and the mixture was extracted with DCM (100 mL×2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (17 g, crude) as an orange oil that required no further purification. 1H NMR (400 MHz, DMSO-d6) δ 4.73-4.69 (m, 1H), 3.19 (s, 3H), 2.76-2.63 (m, 4H), 2.17-2.16 (m, 2H), 1.87-1.84 (m, 2H).
-
- A mixture of tert-butyl 3-bromo-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate (10 g, 33 mmol), tetrahydrothiopyran-4-yl methanesulfonate (8.4 g, 43 mmol) and Cs2CO3 (27 g, 83 mmol) in DMF (50 mL) was heated to 80° C. for 16 h. The reaction mixture was diluted with EtOAc (300 mL), washed with brine (200 mL×3), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent gradient from petroleum ether to petroleum ether/MTBE/THF=10:1:1) to give the title compound (5.9 g, 44%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 4.17 (s, 2H), 4.15-4.09 (m, 1H), 3.61-3.59 (m, 2H), 2.83-2.77 (m, 2H), 2.71-2.68 (m, 4H), 2.13-2.10 (m, 2H), 2.03-1.93 (m, 2H), 1.41 (s, 9H).
-
- To a solution of tert-butyl 3-bromo-1-tetrahydrothiopyran-4-yl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate (2 g, 5.0 mmol) in THF (8 mL) and water (2 mL) at 25° C. was added potassium peroxymonosulfate (5.8 g, 9.4 mmol). The reaction was stirred at 25° C. for 2 h. Water (20 mL) was added and the mixture was extracted with DCM (20 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (2.1 g, 99%) as a white solid that required no further purification. LCMS M/Z (M+H) 434.
-
- To a solution of tert-butyl 3-bromo-1-(1,1-dioxothian-4-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate (200 mg, 0.46 mmol) in 1,4-dioxane (2 mL) was added 5-(difluoromethyl)-2-fluoro-4-(1-methylpyrazol-4-yl)aniline (133 mg, 0.55 mmol), chloro(2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (36 mg, 0.05 mmol), tBuONa (133 mg, 1.4 mmol) and 2-(dicyclohexylphosphino)3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl (25 mg, 0.05 mmol). The reaction was heated to 120° C. for 16 h under a nitrogen atmosphere. After cooling to room temperature, the reaction was filtered and the filtrate was concentrated in vacuo. The crude residue was purified by silica gel column chromatography (DCM/MeOH=20:1) to give the title compound (148 mg, 54%) as a light yellow solid. LCMS M/Z (M+H) 595.
-
- A solution of tert-butyl 3-[5-(difluoromethyl)-2-fluoro-4-(1-methylpyrazol-4-yl)anilino]-1-(1,1-dioxothian-4-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate (130 mg, 0.22 mmol) in DCM (1 mL) and trifluoroacetic acid (1 mL) was stirred at 25° C. for 1 h. The reaction was concentrated in vacuo to give the title compound (70 mg, crude) as a yellow oil that required no further purification. LCMS M/Z (M+H) 495.
-
- To a solution of N-[5-(difluoromethyl)-2-fluoro-4-(1-methylpyrazol-4-yl)phenyl]-1-(1,1-dioxothian-4-yl)-4, 5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-amine (70 mg, 0.14 mmol), triethylamine (0.08 mL, 0.57 mmol) in DCM (1 mL) was added N-methylimidazole-1-carboxamide (21 mg, 0.17 mmol). The reaction was stirred at 25° C. for 16 h. Water (2 mL) was added and the mixture was extracted with DCM (2 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (DCM/MeOH=20:1) to give the title compound (33 mg, 41%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.76 (d, J=8.4 Hz, 1H), 7.57 (s, 1H), 7.47 (s, 1H), 7.09 (d, J=12.0 Hz, 1H), 6.60 (t, J=55.2, 1H), 5.91 (s, 1H), 4.50-4.49 (m, 1H), 4.32-4.30 (m, 1H), 4.18 (s, 2H), 3.98 (s, 3H), 3.81-3.71 (m, 4H), 3.07-3.04 (m, 2H), 2.84 (d, J=4.4 Hz, 3H), 2.74-2.72 (m, 2H), 2.56-2.53 (m, 4H). LCMS M/Z (M+H) 552.
- The following Example 274 was prepared in a similar fashion to Example 273.
-
Example Compound Name and Structure NMR m/z Example 274 1H NMR (400 MHz, DMSO- d6) δ 8.04 (d, J = 8.8 Hz, 1H), 8.01 (s, 1H), 7.84 (s, 1H), 7.59 (s, 1H), 7.25 (d, J = 12.4 Hz, 1H), 6.88 (t, J = 54.8, 1H), 6.50 (d, J = 4.0 Hz, 1H), 4.44- 4.41 (m, 1H), 4.33-4.24 (m, 1H), 4.21 (s, 2H), 3.96- 3.89 (m, 1H), 3.87 (s, 3H), 3.63-3.54 (m, 2H), 3.24- 3.17 (m, 1H), 2.75-2.65 (m, 3H), 2.56 (d, J = 4.0 Hz, 3H), 2.02 (s, 3H), 1.90-1.77 (m, 4H). 545 -
-
- To a solution of tert-butyl 3-bromo-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (20.0 g, 66.19 mmol) in dioxane (100 mL), was added ethyl 2-bromopropanoate (13.18 g, 72.81 mmol) and Cs2CO3 (64.7 g, 198.57 mmol). The reaction mixture was heated to 120° C. for 16 h. After cooling to room temperature, water (100 mL) was added and the mixture was extracted with EtOAc (100 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (eluent gradient from petroleum ether/MTBE/THF=10:1:1 to 2:1:1) to give the title compound (7.3 g, 27%) as clear oil. 1H NMR (400 MHz, DMSO-d6) δ 5.20 (q, J=7.2 Hz, 1H), 4.22-4.08 (m, 4H), 3.67-3.53 (m, 2H), 2.73-2.59 (m, 2H), 1.61 (d, J=7.2 Hz, 3H), 1.42 (s, 9H), 1.14 (t, J=7.2 Hz, 3H).
-
- To a solution of tert-butyl 3-bromo-1-(1-ethoxy-1-oxopropan-2-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (1.9 g, 4.7 mmol) in DCM (10 mL) at 0° C. was added trifluoroacetic acid (10 mL) dropwise. The mixture was stirred at room temperature for 2 h. The mixture was concentrated in vacuo and the residue was re-dissolved in DMF (10 mL). The mixture was cooled to 0° C. before triethylamine (2.7 g, 26.4 mmol) and acetic anhydride (0.68 g, 6.62 mmol) were added dropwise. The mixture was stirred at room temperature for an additional 0.5 h. The reaction was quenched with water (50 mL) and extracted with EtOAc (50 mL×3The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (DCM/MeOH=50:1) to give the title compound (1.3 g, 57%) as clear oil. LCMS M/Z (M+H) 344.
-
- To a solution of ethyl 2-(5-acetyl-3-bromo-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)propanoate (1.3 g, 3.78 mmol) in MeOH (10 mL) at 0° C. was added NaBH4 (0.71 g, 18.9 mmol). The reaction mixture was stirred at room temperature for 2 h. The reaction was quenched with brine (10 mL) and extracted with EtOAc (10 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (DCM/MeOH=20:1) to give the title compound (0.8 g, 70%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 4.92-4.87 (m, 1H), 4.34-4.19 (m, 3H), 3.74-3.65 (m, 2H), 3.55-3.51 (m, 2H), 2.80-2.66 (m, 2H), 2.09-2.88 (m, 3H), 1.30 (d, J=6.8 Hz, 3H).
-
- To a solution of 1-(3-bromo-1-(1-hydroxypropan-2-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone (0.25 g, 0.80 mmol) in 1,4-dioxane (3 mL) was added 2-fluoro-4-(1-methylpyrazol-4-yl) aniline (0.18 g, 0.95 mmol), chloro(2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl)[2-(2-aminoethylphenyl)]palladium(II), methyl-t-butylether adduct (0.07 g, 0.08 mmol), tBuONa (0.23 g, 2.39 mmol) and 2-(dicyclohexylphosphino)3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl (0.04 g, 0.08 mmol). The reaction was heated to 120° C. for 16 h under a nitrogen atmosphere. After cooling to room temperature, the reaction was filtered and the filtrate was concentrated in vacuo. The crude residue was purified by reverse phase chromatography (acetonitrile 26-56%/0.2% formic acid in water) to give the title compound (24 mg, 6%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.40-8.36 (m, 1H), 7.93 (s, 1H), 7.36 (s, 1H), 7.47-7.41 (m, 2H), 7.13-7.08 (m, 1H), 4.85-4.82 (m, 1H), 4.38-4.29 (m, 2H), 4.18-4.10 (m, 1H), 3.85 (s, 3H), 3.67-3.38 (m, 4H), 2.75-2.63 (m, 2H), 2.09-2.07 (m, 3H), 1.34-1.32 (m, 3H).
- The following Example 276 was prepared in a similar fashion to Example 275.
-
Example Compound Name and Structure NMR m/z Example 276 1H NMR (400MHz, DMSO- d6) δ 8.29-8.16 (m, 1H), 8.01 (s, 1H), 7.47-7.34 (m, 2H), 7.26-7.14 (m, 2H), 4.88- 4.77 (m, 1H), 4.45-4.26 (m, 2H), 4.19-4.04 (m, 1H), 3.93 (s, 3H), 3.83-3.49 (m, 4H), 2.81-2.60 (m, 2H), 2.10- 2.07 (m, 3 H), 1.34-1.32 (m, 3H). 463 -
-
- To a solution of 1-(3-((2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone (400 mg, 1.13 mmol) and Cs2CO3 (368 mg, 1.13 mmol) in DMF (4 mL) was added (E)-3-((phenylsulfonyl)methylene)tetrahydrofuran (506 mg, 2.26 mmol). The reaction mixture was stirred at 20° C. for 12 h. Water (20 mL) was added and the mixture was extracted with DCM (20 mL×2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (DCM/MeOH=20:1) to give the title compound (100 mg, 15%) as a light yellow solid. LCMS M/Z (M+H) 579.
-
- To a solution of 1-(3-((2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)-1-(3-((phenylsulfonyl)methyl)tetrahydrofuran-3-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone (90 mg, 0.16 mmol) in MeOH (2 mL) was added Mg (19 mg, 0.78 mmol) and HgCl2 (8 mg, 0.03 mmol). The reaction mixture was stirred at 20° C. under ultrasound for 20 min and stirred at 20° C. for an additional 12 h. Water (40 mL) was added and the mixture was extracted with DCM (40 mL×2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by reverse phase chromatography (acetonitrile 33-63%/0.2% formic acid in water) to give the title compound (10 mg, 15%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.85 (s, 1H), 7.31 (s, 1H), 7.57-7.45 (m, 1H), 7.28-7.20 (m, 2H), 4.47-4.30 (m, 3H), 4.04-3.97 (m, 3H), 3.90 (s, 3H), 3.82-3.75 (m, 2H), 2.95-2.84 (m, 2H), 2.72-2.71 (m, 1H), 2.33-2.30 (m, 1H), 2.20-2.14 (m, 3H), 1.55-1.54 (m, 3H). LCMS M/Z (M+H) 439.
- The following Examples 278-300, 301-302, 303-304, and 305-310 were prepared in a similar fashion to Example 50, 224, 244, and 246, respectively.
-
Example Compound Name and Structure NMR m/z Example 278 1H NMR (400MHz, CD3OD) δ 7.91 (s, 1H), 7.78 (s, 1H), 7.42-7.19 (m, 2H), 4.94- 4.87 (m, 1H), 4.44-4.42 (m, 2H), 4.16-4.08 (m, 2H), 3.96- 3.81 (m, 4H), 3.93 (s, 3H), 2.87-2.76 (m, 2H), 2.42- 2.33 (m, 2H), 2.20-2.15 (m, 3H) 443 Example 279 1H NMR (400MHz, CD3OD) δ 7.92 (s, 1H), 7.79 (s, 1H), 7.21-7.17 (m, 1H), 6.96- 6.89 (m, 1H), 4.86-4.75 (m, 1H), 4.33-4.32 (m, 2H), 4.04- 3.99 (m, 2H), 3.91 (s, 3H), 3.86-3.76 (m, 4H), 2.83- 2.72 (m, 2H), 2.29-2.21 (m, 2H), 2.17-2.08 (m, 3H) 443 Example 280 1H NMR (400MHz, CD3OD) δ 8.05 (s, 1H), 7.81 (s, 1H), 7.65-7.60 (m, 1H), 7.29- 7.23 (m, 1H), 7.07-7.01 (m, 1H), 4.79-4.76 (m, 1H), 4.30- 4.23 (m, 2H), 3.95-3.83 (m, 2H), 3.87 (s, 3H), 3.73- 3.65 (m, 4H), 2.74-2.63 (m, 2H), 2.22-2.10 (m, 2H), 2.07-2.01 (m, 3H) 443 Example 281 1H NMR (400MHz, CD3OD) δ 8.05 (s, 1H), 7.81 (s, 1H), 7.65-7.60 (m, 1H), 7.29- 7.23 (m, 1H), 7.06-7.01 (m, 1H), 4.79-4.74 (m, 1H), 4.30- 4.23 (m, 2H), 3.91-3.83 (m, 2H), 3.87 (s, 3H), 3.73- 3.63 (m, 4H), 2.76-2.63 (m, 2H), 2.18-2.09 (m, 2H), 2.07- 2.01 (m, 3H) 443 Example 282 1H NMR (400MHz, DMSO- d6) δ 8.68-8.63 (m, 1H), 8.17- 8.16 (m, 1H), 7.96 (s, 1H), 7.83-7.82 (m, 1H), 7.68- 7.67 (m, 1H), 7.22-7.20 (m, 1H), 4.90-4.85 (m, 1H), 4.39 (s, 2H), 4.06-4.00 (m, 2H), 3.89-3.79 (m, 2H), 3.87 (s, 3H), 3.73-3.68 (m, 2H), 2.79- 2.67 (m, 2H), 2.29-2.23 (m, 2H), 2.10-2.08 (m, 3H) 475 Example 283 1H NMR (400MHz, CD3OD) δ 7.87-7.83 (m, 1H), 7.77- 7.71 (m, 1H), 7.51 (s, 1H), 7.15-7.13 (m, 1H), 7.12- 7.03 (m, 1H), 4.88-4.82 (m, 1H), 4.40-4.34 (m, 2H), 4.02- 3.98 (m, 2H), 3.84-3.67 (m, 4H), 3.75 (s, 3H), 2.78- 2.66 (m, 2H), 2.34 (s, 3H), 2.26-2.22 (m, 2H), 2.08- 2.05 (m, 3H) 439 Example 284 1H NMR (400MHz, DMSO- d6) δ 7.87-7.83 (m, 1H), 7.77- 7.71 (m, 1H), 7.51 (s, 1H), 7.15-7.13 (m, 1H), 7.12- 7.03 (m, 1H), 4.88-4.82 (m, 1H), 4.40-4.34 (m, 2H), 4.02- 3.98 (m, 2H), 3.84-3.67 (m, 4H), 3.75 (s, 3H), 2.78- 2.66 (m, 2H), 2.34 (s, 3H), 2.26-2.22 (m, 2H), 2.09- 2.05 (m, 3H) 439 Example 285 1H NMR (400MHz, CD3OD) δ 7.88-7.83 (m, 1H), 7.77- 7.71 (m, 1H), 7.52 (s, 1H), 7.18-7.13 (m, 1H), 7.08- 7.03 (m, 1H), 4.88-4.84 (m, 1H), 4.41-4.35 (m, 2H), 4.03- 3.99 (m, 2H), 3.84-3.67 (m, 4H), 3.76 (s, 3H), 2.78- 2.66 (m, 2H), 2.35 (s, 3H), 2.28-2.23 (m, 2H), 2.09- 2.06 (m, 3H) 439 Example 286 1H NMR (400MHz, DMSO- d6) δ 8.38 (s, 1H), 7.99-7.93 (m, 1H), 7.88-7.67 (m, 1H), 7.60-7.47 (m, 2H), 4.90- 4.83 (m, 1H), 4.41-4.34 (m, 2H), 4.06 (s, 3H), 4.03-3.96 (m, 2H), 3.85-3.66 (m, 4H), 2.79-2.64 (m, 2H), 2.40- 2.17 (m, 2H), 2.09-2.05 (m, 3H) 426 Example 287 1H NMR (400MHz, DMSO- d6) δ 8.26-8.17 (m, 1H), 8.01 (s, 1H), 8.00-7.85 (m, 1H), 7.72 (s, 1H), 6.98-6.93 (m, 1H), 4.93-4.88 (m, 1H), 4.43- 4.37 (m, 2H), 4.04-4.01 (m, 2H), 3.88-3.84 (m, 2H), 3.86 (s, 3H), 3.83-3.69 (m, 2H), 2.81-2.68 (m, 2H), 2.30- 2.21 (m, 2H), 2.10-2.05 (m, 3H) 443 Example 288 1H NMR (400MHz, DMSO- d6) δ 8.22-8.17 (m, 1H), 8.00- 7.94 (m, 2H), 7.74-7.73 (m, 1H), 7.17-7.15 (m, 1H), 7.08-7.03 (m, 1H), 4.90- 4.80 (m, 1H), 4.36 (s, 2H), 4.06-4.01 (m, 2H), 3.89 (s, 3H), 3.86-3.84 (m, 2H), 3.74- 3.69 (m, 2H), 2.77-2.65 (m, 2H), 2.28-2.21 (m, 2H), 2.10-2.07 (m, 3H) 425 Example 289 1H NMR (400MHz, DMSO- d6) δ 8.51-8.46 (m, 1H), 7.91- 7.90 (m, 1H), 7.78 (s, 1H), 7.55-7.53 (m, 2H), 7.31- 7.27 (m, 1H), 6.89 (t, J = 56.0 Hz, 1H), 4.88-4.85 (m, 1H), 4.37 (s, 2H), 4.05-4.02 (m, 2H), 3.90-3.68 (m, 4H), 3.88 (s, 3H), 2.78-2.66 (m, 2H), 2.27-2.23 (m, 2H), 2.10- 2.08 (m, 3H) 457 Example 290 1H NMR (400MHz, DMSO- d6) δ 8.13 (s, 1H), 8.12-8.06 (m, 1H), 7.99-7.73 (m, 1H), 7.58-7.48 (m, 2H), 4.90- 4.84 (m, 1H), 4.41-4.35 (m, 2H), 4.15 (s, 3H), 4.03-4.00 (m, 2H), 3.85-3.78 (m, 2H), 3.73-3.68 (m, 2H), 2.80- 2.67 (m, 2H), 2.29-2.09 (m, 2H), 2.07-2.05 (m, 3H) 426 Example 291 1H NMR (400MHz, DMSO- d6) δ 8.49-8.45 (m, 1H), 8.05- 8.03 (m, 1H), 7.75-7.74 (m, 1H), 7.46-7.42 (m, 1H), 7.14-7.10 (m, 1H), 6.75- 6.71 (m, 1H), 4.89-4.83 (m, 1H), 4.36 (s, 2H), 4.07-3.99 (m, 2H), 3.90-3.80 (m, 2H), 3.85 (s, 3H), 3.75-3.67 (m, 2H), 2.78-2.66 (m, 2H), 2.32- 2.20 (m, 2H), 2.10-2.07 (m, 3H) 425 Example 292 1H NMR (400MHz, DMSO- d6) δ 8.25-8.05 (m, 1H), 7.95 (s, 1H), 7.91-7.84 (m, 1H), 7.66 (s, 1H), 7.11-7.06 (m, 1H), 6.91-6.88 (m, 1H), 4.90-4.86 (m, 1H), 4.43-4.36 (m, 2H), 4.03-3.99 (m, 2H), 3.88-3.83 (m, 2H), 3.85 (s, 3H), 3.71-3.68 (m, 2H), 2.79- 2.67 (m, 2H), 2.32-2.31 (m, 2H), 2.09-2.04 (m, 3H) 425 Example 293 1H NMR (400MHz, DMSO- d6) δ 8.05 (s, 1H), 7.79 (s, 1H), 7.56 (s, 1H), 7.51-7.29 (m, 3H), 4.92-4.82 (m, 1H), 4.35-4.28 (m, 2H), 4.03- 3.96 (m, 2H), 3.83 (s, 3H), 3.80-3.68 (m, 4H), 2.80- 2.68 (m, 2H), 2.33-2.22 (m, 2H), 2.09-2.04 (m, 3H) 441 Example 294 1H NMR (400MHz, DMSO- d6) δ 8.46-8.42 (m, 1H), 8.00 (s, 1H), 7.71 (s, 1H), 7.69 (s, 1H), 7.40-7.29 (m, 2H), 4.88- 4.82 (m, 1H), 4.36 (s, 2H), 4.05-4.01 (m, 2H), 3.88- 3.67 (m, 4H), 3.86 (s, 3H), 2.77-2.65 (m, 2H), 2.28- 2.24 (m, 2H), 2.10-2.07 (m, 3H) 441 Example 295 1H NMR (400MHz, DMSO- d6) δ 8.34-8.30 (m, 1H), 7.65 (s, 1H), 7.45-7.42 (m, 2H), 7.19-7.15 (m, 2H), 4.86- 4.83 (m, 1H), 4.36 (s, 2H), 4.05-3.99 (m, 5H), 3.88- 3.67 (m, 4H), 2.79-2.66 (m, 2H), 2.25-2.22 (m, 2H), 2.10- 2.07 (m, 3H) 475 Example 296 1H NMR (400MHz, DMSO- d6) δ 8.45-8.41 (m, 1H), 8.07- 8.06 (m, 1H), 7.76-7.75 (m, 1H), 7.60-7.57 (m, 1H), 7.34-7.29 (m, 1H), 4.89- 4.85 (m, 1H), 4.37 (s, 2H), 4.05-4.00 (m, 2H), 3.90 (s, 3H), 3.88-3.85 (m, 2H), 3.84- 3.67 (m, 2H), 2.78-2.64 (m, 2 H), 2.27-2.20 (m, 2H), 2.10-2.07 (m, 3H) 443 Example 297 1H NMR (400MHz, DMSO- d6) δ 8.11 (s, 1H), 8.00-7.93 (m, 1H), 7.86-7.69 (m, 1H), 7.16-7.13 (m, 1H), 7.12- 7.04 (m, 1H), 4.90-4.85 (m, 1H), 4.41-4.35 (m, 2H), 4.03- 3.99 (m, 2H), 3.93 (s, 3H), 3.84-3.68 (m, 4H), 2.80- 2.67 (m, 2H), 2.27-2.23 (m, 2H), 2.09-2.05 (m, 3H) 493 Example 298 1H NMR (400MHz, DMSO- d6) δ 8.11 (s, 1H), 7.99-7.93 (m, 1H), 7.86-7.69 (m, 1H), 7.16-7.12 (m, 1H), 7.08- 7.04 (m, 1H), 4.89-4.83 (m, 1H), 4.41-4.35 (m, 2H), 4.03- 3.98 (m, 2H), 3.93 (s, 3H), 3.84-3.68 (m, 4H), 2.79- 2.67 (m, 2H), 2.28-2.23 (m, 2H), 2.09-2.05 (m, 3H) 493 Example 299 1H NMR (400MHz, DMSO- d6) δ 8.03 (s, 1H), 7.83-7.67 (m, 3H), 7.39-7.34 (m, 1H), 7.26-7.21 (m, 1H), 4.87- 4.77 (m, 1H), 4.41-4.34 (m, 2H), 4.02-3.97 (m, 2H), 3.83 (s, 3H), 3.81-3.67 (m, 4H), 2.77-2.66 (m, 2H), 2.26- 2.22 (m, 2H), 2.08-2.05 (m, 3H) 425 Example 300 1H NMR (400MHz, DMSO- d6) δ 8.03 (s, 1H), 7.83-7.68 (m, 3H), 7.36-7.33 (m, 1H), 7.32-7.21 (m, 1H), 4.88- 4.84 (m, 1H), 4.40-4.33 (m, 2H), 4.03-3.99 (m, 2H), 3.84- 3.67 (m, 7H), 2.79-2.64 (m, 2H), 2.26-2.21 (m, 2H), 2.08-2.05 (m, 3H) 425 Example 301 1H NMR (400MHz, DMSO- d6) δ 8.12 (s, 1H), 8.01-7.84 (m, 2H), 7.20-7.09 (m, 2H), 5.44-5.38 (m, 1H), 4.96- 4.93 (m, 2H), 4.85-4.83 (m, 2H), 4.42-4.36 (m, 2H), 3.94 (s, 3H), 3.71-3.64 (m, 2H), 2.73-2.60 (m, 2H), 2.08- 2.05 (m, 3H) 479 Example 302 1H NMR (400MHz, DMSO- d6) δ 8.04 (s, 1H), 7.97-7.90 (m, 1H), 7.88-7.79 (m, 2H), 7.40-7.36 (m, 1H), 7.35- 7.26 (m, 1H), 5.44-5.37 (m, 1H), 4.96-4.93 (m, 2H), 4.86- 4.81 (m, 2H), 4.41-4.34 (m, 2H), 3.84 (s, 3H), 3.71- 3.63 (m, 2H), 2.71-2.58 (m, 2H), 2.07-2.05 (m, 3H) 411 Example 303 1H NMR (400MHz, DMSO- d6) δ 8.10 (s, 1H), 7.96-7.85 (m, 2H), 7.17-7.04 (m, 2H), 4.67-4.64 (m, 2H), 4.46- 4.36 (m, 4H), 4.21-4.19 (m, 2H), 3.93 (s, 3H), 3.72-3.67 (m, 2H), 3.41-3.39 (m, 1H), 2.76-2.64 (m, 2H), 2.09- 2.06 (m, 3H) 493 Example 304 1H NMR (400MHz, DMSO- d6) δ 8.01 (s, 1H), 7.87-7.67 (m, 3H), 7.37-7.32 (m, 1H), 7.26-7.21 (m, 1H), 4.40- 4.32 (m, 2H), 4.25-4.16 (m, 1H), 3.96-3.94 (m, 2H), 3.83 (s, 3H), 3.72-3.66 (m, 2H), 3.45-3.38 (m, 2H), 2.78- 2.66 (m, 2H), 2.08-1.99 (m, 5H), 1.78-1.75 (m, 2H) 439 Example 305 1H NMR (400MHz, DMSO- d6) δ 8.07 (s, 1H), 7.95-7.88 (m, 1H), 7.86-7.69 (m, 1H), 7.27-7.15 (m, 2H), 7.05 (t, J = 53.6 Hz, 1H), 4.89-4.83 (m, 1H), 4.41-4.35 (m, 2H), 4.03-3.97 (m, 2H), 3.89- 3.66 (m, 7H), 2.79-2.68 (m, 2H), 2.28-2.23 (m, 2H), 2.09- 2.05 (m, 3H) 475 Example 306 1H NMR (400MHz, DMSO- d6) δ 8.08 (s, 1H), 7.96-7.89 (m, 1H), 7.86-7.69 (m, 1H), 7.27-7.15 (m, 2H), 7.05 (t, J = 53.6 Hz, 1H), 4.87-4.83 (m, 1H), 4.41-4.35 (m, 2H), 4.03-3.97 (m, 2H), 3.89 (s, 3H), 3.88-3.66 (m, 4H), 2.79- 2.68 (m, 2H), 2.28-2.23 (m, 2H), 2.09-2.06 (m, 3H) 475 Example 307 1H NMR (400MHz, DMSO- d6) δ 8.07 (s, 1H), 7.95-7.88 (m, 1H), 7.86-7.69 (m, 1H), 7.27-7.15 (m, 2H), 7.05 (t, J = 53.6 Hz, 1H), 4.89-4.83 (m, 1H), 4.41-4.35 (m, 2H), 4.03-3.97 (m, 2H), 3.89 (s, 3H), 3.88-3.66 (m, 4H), 2.79- 2.66 (m, 2H), 2.28-2.23 (m, 2H), 2.09-2.05 (m, 3H) 475 Example 308 1H NMR (400MHz, DMSO- d6) δ 8.32 (s, 1H), 8.09-8.02 (m, 1H), 7.90-7.75 (m, 1H), 7.44-7.31 (m, 2H), 4.89- 4.85 (m, 1H), 4.42-4.35 (m, 2H), 4.03-3.99 (m, 2H), 3.96 (s, 3H), 3.85-3.68 (m, 4H), 2.79-2.67 (m, 2H), 2.29- 2.22 (m, 2H), 2.09-2.05 (m, 3H). 450 Example 309 1H NMR (400MHz, DMSO- d6) δ 7.85-7.76 (m, 3H), 7.19- 7.06 (m, 2H), 4.89-4.82 (m, 1H), 4.41-4.43 (m, 2H), 4.03-3.99 (m, 2H), 3.84- 3.67 (m, 4H), 3.75 (s, 3H), 2.79-2.65 (m, 2H), 2.24- 2.22 (m, 5H), 2.09-2.05 (m, 3H) 439 Example 310 1H NMR (400MHz, DMSO- d6) δ 13.67 (s, 1H), 8.16 (s, 1H), 7.97-7.13 (m, 2H), 7.21-7.07 (m, 2H), 4.88- 4.82 (m, 1H), 4.41-4.35 (m, 2H), 4.01-3.84 (m, 2H), 3.83- 3.68 (m, 4H), 2.79-2.67 (m, 2H), 2.25-2.23 (m, 2H), 2.09-2.05 (s, 3H) 479 - The inhibitory activity of representative compounds of Formula (II) against CBP/EP300 can be evaluated using known methods or using one of the following assay protocols.
- His/Flag epitope tagged CBP was cloned, expressed, and purified to homogeneity. CBP binding and inhibition was assessed by monitoring the engagement of a biotinylated small molecule compound with the target using the TR-FRET assay technology (Perkin-Elmer). Specifically, in a 384 well ProxiPlate CBP (4 nM final) was combined with biotin-ligand (60 nM final) in 50 mM HEPES (pH 7.5), 50 mM NaCl, 1 mM TCEP, 0.01% (w/v) BSA, and 0.008% (w/v) Brij-35 either in the presence of DMSO (final 0.2% DMSO) or compound dilution series in DMSO. After 10 minutes incubation at room temperature, a mixture Eu-W1024 Anti-6×His antibody (Perkin Elmer ADO 110) and SureLight™ Allophycocyanin-Streptavidin (APC-SA, Perkin Elmer CR130-100) were added to a final concentrations of 0.2 nMolar antibody and 50 nMolar APC-SA, respectively. After twenty minutes of equilibration, the plates were read on an Envision instrument and IC50s calculated using a four parameter non-linear curve fit.
- His/Flag epitope tagged BRD4 BD142-168 was cloned, expressed, and purified to. BRD4 binding and inhibition was assessed by monitoring the engagement of biotinylated H4-tetraacetyl peptide (New England Peptide, NEP2069-1/13) with the target using the AlphaLisa technology (Perkin-Elmer). Specifically, in a 384 well ProxiPlate BRD4(BD1) (30 nM final) was combined with peptide (200 nM final) in 40 mM HEPES (pH 7.0), 40 mM NaCl, 1 mM DTT, 0.01% (w/v) BSA, and 0.008% (w/v) Brij-35 either in the presence of DMSO (final 1.2% DMSO) or compound dilution series in DMSO. After 20 minutes incubation at room temperature Alpha streptavidin donor beads and AlphaLisa anti-Flag acceptor beads were added to a final concentration of 10 ug/mL each. After three hours equilibration plates were read on an Envision instrument and IC50s calculated using a four parameter non-linear curve fit.
- QuantiGene 2.0 Reagent system, Affymetrix: HUMAN MYCN; V-myc myelocytomatosis viral related oncogene, neuroblastoma derived (avian); NM_005378 SA-15008. 10,000 MV-4-11 cells (GNE in-house) were plated in 75 ul complete media: RPMI-1640 (GNE in-house), 10% FBS (Life Technologies, cat. no. 10082), 1% Pen-strep (GNE in-house), in 96 well clear flat bottom plates (Costar, cat. no. 3595). 25 ul compound was added for 4 hours at 37 deg C. in a 1:3 serial dilution 10-point dose response, with a final DMSO concentration=0.2%. The cells were then lysed according to the assay kit's protocol and frozen at −80 deg C. The following day, an appropriate volume of Working Probe Set was prepared by combining the following reagents in the order listed: Nuclease-free water, Lysis Mixture, Blocking Reagent, and 2.0 Probe Set (MYC or RPL19). 20 ul of the working probe set was added into each assay well on the capture plate, and then 80 ul of the lysates were transferred into the assay plates. The capture plate was placed in a 55 deg C. incubator for overnight hybridization (16-20 hours). The following day, wash buffer was prepared according to manufacturer's recommendations. The capture plates were washed with 300 ul per well of 1× wash buffer three times. Then 100 ul Pre-Amplifier was added to the plate for a 60 minute incubation at 55 deg C. After the incubation, the capture plate was washed with 300 ul per well of 1× wash buffer three times, and 100 ul Amplifier was added to the plate for a 60 minute incubation at 55 deg C. The capture plate was again washed with 300 ul per well of 1× wash buffer three times, and 100 ul Label Probe was added to the plate for a 60 minute incubation at 50 deg C. Then the capture plate was washed with 300 ul per well of 1× wash buffer three times, and 100 ul 2.0 Substrate was added to each well of the plate. The plates were incubated at RT for 5 minutes in the dark and read on the Envision using the luminescence protocol, with an integration time set at 0.2 seconds.
- Data for representative compounds of formula (II) from the three assays described above is provided in the following table (all units in μM).
-
CBP HTRF BRD4 Alpha Myc Example IC50 (μM) IC50 (μM) IC50 (μM) 1 0.06 7.32 0.88 2 0.06 12.50 0.70 3 0.12 7.73 4 0.03 10.24 0.98 5 0.02 4.98 0.68 6 0.02 4.77 0.65 7 0.02 6.22 0.29 8 1.43 >19.74 9 0.10 15.57 0.14 10 0.14 11.94 2.32 11 0.06 15.58 0.74 12 0.03 13 0.04 3.33 0.68 14 0.04 6.72 0.35 15 0.27 17.62 16 0.19 18.14 17 0.02 2.93 0.29 18 0.05 9.41 0.73 19 0.15 >19.74 20 0.02 3.82 0.33 21 0.01 2.87 0.24 22 0.02 7.80 0.34 23 0.16 >19.74 24 0.13 10.37 1.06 25 0.04 4.29 0.63 26 0.13 14.63 1.79 27 0.30 >19.74 28 0.17 >19.74 29 0.04 4.89 2.39 30 0.07 15.86 31 0.02 2.70 0.24 32 0.15 >19.74 2.46 33 >20.00 34 0.01 3.52 0.60 35 0.01 1.98 0.15 36 0.02 2.46 0.39 37 0.04 2.84 0.46 38 0.01 2.52 39 0.03 3.06 0.36 40 0.01 2.77 0.61 41 0.06 4.59 0.49 42 0.03 3.29 0.23 43 0.04 44 0.15 11.08 45 0.03 46 0.04 47 0.14 7.15 48 0.05 6.62 49 0.03 50 0.04 2.65 0.65 51 0.03 10.51 0.41 52 0.01 3.69 0.24 53 0.02 4.05 0.63 54 0.09 13.97 1.81 55 0.01 1.79 0.14 56 0.01 1.60 0.08 57 0.01 2.49 0.28 58 0.04 3.50 0.70 59 0.01 1.69 0.13 60 0.01 2.34 0.15 61 0.03 5.60 0.59 62 0.01 1.02 0.31 63 0.02 1.16 0.47 64 0.01 0.84 0.24 65 0.01 1.25 0.80 66 0.01 0.89 1.12 67 0.01 2.11 0.23 68 0.02 2.20 1.24 69 0.03 1.97 1.29 70 0.01 2.63 0.22 71 0.02 72 0.02 2.49 1.39 73 0.03 3.05 0.63 74 0.02 2.47 0.47 75 0.02 2.64 0.44 76 0.01 0.90 1.04 77 0.01 1.51 78 0.02 2.36 79 0.02 2.02 0.77 80 0.02 2.34 81 0.02 5.29 0.50 82 0.03 5.38 83 0.02 84 0.02 2.65 0.39 85 0.01 2.41 0.45 86 0.02 2.72 0.44 87 0.02 88 0.05 11.02 0.63 89 0.02 3.27 0.23 90 0.03 2.90 0.55 91 0.03 2.86 0.50 92 0.02 3.99 0.35 93 0.04 4.33 0.36 94 0.02 3.54 0.38 95 0.04 3.57 1.04 96 0.03 3.69 0.45 97 0.04 3.19 0.71 98 0.02 4.42 0.20 99 0.05 7.22 1.42 100 0.04 4.25 2.30 101 0.02 1.93 0.39 102 0.02 103 0.02 3.78 0.24 104 0.02 4.49 0.42 105 0.03 6.45 0.30 106 0.06 5.04 1.09 107 0.05 5.06 1.13 108 0.05 9.06 1.09 109 0.08 7.87 1.11 110 0.05 0.63 111 0.03 5.59 0.116 112 0.01 2.20 0.18 113 0.10 10.48 1.88 114 0.07 8.16 1.20 115 0.02 6.98 0.63 116 0.02 6.02 1.08 117 0.09 3.99 118 0.11 5.48 119 0.04 7.50 1.03 120 0.11 4.34 121 0.20 3.76 122 0.15 5.32 123 0.05 6.32 0.99 124 0.17 5.48 125 0.10 3.53 126 0.12 5.34 127 0.15 6.53 128 0.10 4.30 129 0.16 5.59 130 0.11 7.74 131 0.15 6.83 132 0.09 4.19 133 0.11 6.33 134 0.15 5.47 135 0.18 4.66 136 0.16 4.24 137 0.11 2.12 138 0.16 6.38 139 0.16 5.27 140 0.19 6.08 141 0.17 6.20 142 0.09 5.25 143 0.08 3.43 144 0.09 4.72 145 0.10 4.40 146 0.03 5.32 147 0.16 4.77 148 0.12 3.85 149 0.11 2.74 150 0.11 3.52 151 0.03 10.27 0.87 152 0.02 3.66 0.38 153 0.03 5.36 0.64 154 0.02 1.36 0.37 155 0.03 156 0.07 >19.74 2.29 157 0.03 4.52 0.69 158 0.06 7.77 1.86 159 0.03 2.63 1.89 160 0.02 3.68 0.41 161 0.03 162 0.03 163 0.02 4.14 0.44 164 0.04 5.10 1.07 165 0.08 166 0.08 167 0.04 168 0.11 10.22 169 0.06 11.72 1.05 170 0.04 8.25 0.52 171 0.06 15.94 4.55 172 0.04 0.44 173 0.04 6.47 0.63 174 0.03 2.92 0.44 175 0.03 8.09 0.89 176 0.03 3.85 0.60 177 0.04 6.66 0.36 178 0.03 5.18 0.61 179 0.02 2.54 0.42 180 0.15 181 0.03 3.98 0.31 182 0.02 183 0.02 4.06 184 0.08 9.65 185 0.05 11.42 0.86 186 0.12 6.75 187 0.08 12.33 188 0.36 19.38 189 0.20 5.48 0.81 190 0.87 28.37 191 3.38 192 1.65 >19.74 193 1.25 194 0.93 >19.74 195 0.28 3.45 196 0.29 2.72 197 0.22 4.07 1.17 198 0.26 25.68 2.74 199 0.18 14.07 2.89 200 0.05 15.81 1.48 201 0.13 9.08 2.38 202 0.22 5.19 203 0.17 2.63 204 0.31 >19.74 205 0.16 >19.74 206 0.16 13.08 207 0.27 >19.74 208 0.30 11.65 209 0.88 6.05 210 0.12 8.46 211 0.22 >19.74 212 0.23 >19.74 213 0.21 18.65 214 0.22 14.56 215 0.22 5.88 216 0.20 6.89 217 0.13 13.60 1.30 218 0.02 5.25 0.50 219 0.08 >10.53 0.79 220 0.29 9.72 1.72 221 0.03 6.18 0.41 222 3.28 >19.74 223 0.02 5.11 0.50 224 0.007 3.46 0.69 225 0.021 5.32 1.65 226 0.010 2.90 0.10 227 0.024 8.41 0.51 228 0.082 7.58 229 0.022 4.40 1.33 230 0.072 >6.67 231 0.017 2.61 0.03 232 0.067 15.03 233 0.063 2.13 234 0.018 2.72 0.38 235 0.034 2.18 0.91 236 0.031 5.90 0.78 237 0.022 11.06 0.37 238 0.021 3.19 0.39 239 0.015 5.07 0.44 240 0.035 5.01 2.84 241 0.007 2.14 0.02 242 0.002 2.48 0.20 243 0.013 2.99 2.75 244 0.074 6.66 245 0.031 5.93 3.47 246 0.016 4.27 0.49 247 0.141 9.08 248 0.028 5.80 1.09 249 0.032 2.78 4.09 250 0.159 >20 251 0.202 >20 252 0.004 4.81 0.18 253 0.239 >20 254 0.017 2.52 1.15 255 0.854 >20 256 0.002 >20 0.07 257 0.003 >20 0.10 258 0.061 >20 259 0.032 >20 4.72 260 0.001 11.69 0.03 261 0.003 14.47 0.07 262 0.016 >20 1.21 263 0.028 >20 1.88 264 0.015 >20 0.95 265 0.005 15.42 0.21 266 0.002 3.85 0.05 267 0.011 >20 0.60 268 0.004 12.24 >10 269 0.005 17.99 0.22 270 0.077 12.52 271 0.003 7.07 0.09 272 0.002 14.66 0.03 273 0.002 7.88 0.10 274 0.001 8.86 0.02 275 0.020 4.89 0.27 276 0.015 1.68 0.18 277 0.035 0.08 278 0.021 6.49 0.37 279 0.020 8.26 0.34 280 0.032 8.01 0.46 281 0.022 8.26 0.33 282 0.010 0.76 0.11 283 0.023 5.01 0.078 284 0.019 4.93 0.36 285 0.035 4.09 0.58 286 0.038 8.55 1.06 287 0.023 4.56 0.67 288 0.019 2.33 0.57 289 0.008 1.54 0.04 290 0.045 8.67 1.16 291 0.027 1.99 0.61 292 0.025 3.40 0.56 293 0.026 4.13 0.35 294 0.015 1.20 0.13 295 0.013 1.98 0.16 296 0.020 1.93 0.48 297 0.010 1.69 0.13 298 0.015 2.34 0.15 299 0.040 6.25 0.77 300 0.022 5.49 1.2 301 0.012 5.33 0.24 302 0.039 8.25 0.56 303 0.019 3.67 0.25 304 0.021 8.87 0.19 305 0.023 3.06 0.093 306 0.018 2.08 0.21 307 0.020 2.45 0.54 308 0.016 4.00 0.43 309 0.032 3.62 0.40 310 0.010 2.91 0.26 - The results of the fibrosis experiments described herein are shown in
FIGS. 1-14 . - Cell Culture:
- Collagen 1-coated 384-well plates (BD Biosciences cat #356667) were seeded with Normal Human Lung Fibroblasts (Lonza cat #CC-2512) at 2000 cells per well in 50 μl DMEM (Genentech) containing 0.5% fetal bovine serum (Sigma cat #F2442). After 16 hours, the indicated compounds were added to cells at final concentrations ranging from 10 μM to 0.005 nM in an 8-fold dilution series. After one hour, TGF beta (Genentech) was added to cells to a final concentration of 10 ng/ml. All treatments were performed in duplicate.
- Animal Study:
- Bleomycin was administered to mice via subcutaneous implantation of an osmotic pump (Alzet cat #1007D). After bleomycin administration, mice were treated with compounds by oral gavage. Mice received either MCT vehicle (0.5% w/v methylcellulose, 0.2% w/v polysorbate 80), G0272 in MCT at 5 mg/kg twice daily, G0272 in MCT at 15 mg/kg twice daily, G5049 in MCT at 5 mg/kg twice daily, G5049 in MCT at 15 mg/kg twice daily, G3486 in MCT at 15 mg/kg twice daily, or G3486 in MCT at 45 mg/kg twice daily. To label newly synthesized collagen, mice were injected intraperitoneally with 35 ml/kg heavy water (Sigma Aldrich, cat #151882) in two doses and heavy water was provided in drinking water. At study termination, blood samples were collected by retro-orbital bleed under isoflurane anesthesia and mice were euthanized. Upper right lung lobes were placed in glass vials and snap frozen in liquid nitrogen for mass spectrometry. The lower right lung lobe was placed in RNA later for expression analysis, and frozen at −20° C.
- Lung Hydroxyproline Determination:
- Lungs were thawed, dried overnight at 80° C., then hydrolyzed at 110° C. overnight in 6N HCl. The remainder of this paragraph was performed by KineMed, Emeryville Calif.). A 100 μl aliquot of tissue hydrolysate received a spike containing 1 μg 2H3-labeled hydroxyproline (D3-OHP; trans-4-Hydroxy-L-proline-2,5,5-d3; CDN), and then dried under vacuum and re-suspended in a solution of 50% acetonitrile, 50 mM K2HPO4 and pentafluorobenzyl bromide before incubation. Derivatives were extracted into ethyl acetate, and the top layer was removed and dried by vacuum centrifugation. In order to acetylate the hydroxyl moiety of hydroxyproline, samples were incubated with a solution of acetonitrile, N-Methyl-N-[tert-butyldimethyl-silyl]trifluoroacetamide and methylimidizole. This material was extracted in petroleum ether and dried with Na2SO4. The derivatized hydroxyproline was analyzed by GC/MS, performed in the negative chemical ionization mode. Selected ion monitoring was performed on ions with mass-to-charge ratios (m/z) 445, 446, 447, and 448 which include all of the carbon-hydrogen bonds from hydroxyproline. Incorporation of 2H into hydroxyproline was calculated as the molar fraction of molecules with one excess mass unit above the natural abundance fraction (EM1). Fractional collagen synthesis (f) was calculated as the ratio of the EM1 value in protein-bound hydroxyproline to the maximal value possible at the body water enrichment present. This method has previously been described (Gardner, J. L., et al., Measurement of liver collagen synthesis by heavy water labeling: effects of profibrotic toxicants and antifibrotic interventions. Am J Physiol Gastrointest Liver Physiol, 2007. 292(6): p. G1695-705). Additionally, hydroxyproline content in each tissue sample was determined by comparing the abundance in the m3 448 m/z channel representing the D3-OHP internal standard in each sample with that the m0 445 m/z ion. A set of standards with known OHP/D3-OHP concentration ratios was analyzed alongside the samples. 2H2O enrichment in plasma was determined using a previously described method (Previs S F, Hazey J W, Diraison F, Beylot M, David F, Brunengraber H (1996) Assay of the deuterium enrichment of water via acetylene. J Mass Spectrom 31:639-642.). Briefly body water is evaporated from plasma by overnight incubation at 80° C. Samples are then mixed in 10M NaOH and acetone followed by a second overnight incubation. This material was extracted in hexane and dried with Na2SO4 prior to GCMS analysis.
- RNA Isolation:
- For cultured cells, after 24 hours of treatment with TGF beta and CBP/p300 inhibitor, mRNA was isolated with the
Turbocapture 384 mRNA kit (Qiagen cat #72271) according to the manufacturers' instructions and eluted with 30 μl elution buffer. For lungs, tissues were thawed, removed from RNA later, homogenized in GentleMACS M tubes (Miltenyi Biotec cat #130-093-236) and RNA extracted with the RNeasy 96 kit (Qiagen cat #74182) according to the manufacturers instructions. - Expression Analysis:
- First-strand cDNA was synthesized using 14 μl mRNA for cultured cells and 150 ng RNA for lung. The High Capacity cDNA Reverse Transcription Kit (Life Technologies cat #4368814) was used according to the manufacturers protocol. Specific target amplification was performed using 1.25 μl cDNA, Taqman assays (Life Technologies cat #4331182) at a final concentration of 0.2×, and Taqman Preamp Master Mix (Life Technologies cat #4488593) and subsequently diluted according to the protocol for Fluidigm qPCR (Fluidigm Corp). Samples and assays were mixed with loading buffers and loaded onto 192.24 IFCs (Fluidigm cat #100-6266) according to the manufacturers instructions. Reactions were mixed using the IFC controller RX (Fluidigm) then amplified and measured using the Biomark system (Fluidigm). For cultured cells, relative expression of each target gene was determined using the ΔCt method, normalizing to the Ct for HPRT1 using Excel software (Microsoft). To generate heat maps, TGF beta-mediated expression increase for each gene in the presence of CBP/p300 inhibitor was divided by the increase in the absence of CBP/p300 inhibitor using Excel (i.e. (2−ΔCt, SMI+TGFb−2−ΔCt, SMI, no TGFb)/(2−ΔCt, TGFb−2−ΔCt, no TGFb)). Line graphs of 2−ΔCt values were generated using Prism software (Graphpad). For lung, relative expression of each target gene was determined using the ΔΔCt method, normalizing to the Ct for GAPDH and the vehicle control group. Heat maps were generated with Excel software (Microsoft).
- While a number of embodiments have been described, these examples may be altered to provide other embodiments that utilize the compounds and methods described herein. Therefore, the scope of this invention is to be defined by the appended claims rather than by the specific embodiments that have been represented by way of example.
Claims (8)
1. A method for treating a CBP and/or EP300-mediated disorder in an animal comprising administering a CBP and/or EP300 inhibitor, or a pharmaceutically acceptable salt thereof, to the animal.
2. The method of claim 1 wherein the CBP and/or EP300-mediated disorder is a fibrotic disease.
3. The method of claim 2 wherein the fibrotic disease is selected from the group consisting of pulmonary fibrosis, silicosis, cystic fibrosis, renal fibrosis, liver fibrosis, liver cirrhosis, primary sclerosing cholangitis, primary biliary cirrhosis, endomyocardial fibrosis, mediastinal fibrosis, myelofibrosis, retroperitoneal fibrosis, progressive massive fibrosis, nephrogenic systemic fibrosis, Crohn's disease, keloid, myocardial infarction, systemic sclerosis and arthro fibrosis.
4. The method of claim 1 wherein the CBP and/or EP300-mediated disorder is a fibrotic lung disease.
5. The method of claim 4 wherein the fibrotic lung disease is selected from the group consisting of idiopathic pulmonary fibrosis, fibrotic interstitial lung disease, interstitial pneumonia, fibrotic variant of non-specific interstitial pneumonia, cystic fibrosis, lung fibrosis, chronic obstructive pulmonary lung disease (COPD), and pulmonary arterial hypertension.
6. The method of claim 5 wherein the fibrotic lung disease is idiopathic pulmonary fibrosis.
7. The method of claim 1 wherein the CBP and/or EP300 inhibitor is a compound of formula (III):
or a pharmaceutically acceptable salt thereof, wherein:
X is NH, O, S, or —C(Ra)2—;
each Ra is independently selected from the group consisting of H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, and C3-6carbocyclyl;
ring A is a 6 membered heteroaryl ring or a benzo ring, wherein ring A is optionally substituted with one or more groups Rb that are independently selected from the group consisting of Rc, —F, —Cl, —Br, —I, —NO2, —N(Rd)2, —CN, —C(O)—N(Rd)2, —S(O)—N(Rd)2, —S(O)2—N(Rd)2, —O—Rd, —S—Rd, —O—C(O)—Rd, —O—C(O)—O—Rd, —C(O)—Rd, —C(O)—O—Rd, —S(O)—Rd, —S(O)2—Rd, —O—C(O)—N(Rd)2, —N(Rd)—C(O)—ORd, —N(Rd)—C(O)—N(Rd)2, —N(Rd)—C(O)—Rd, —N(Rd)—S(O)—Rd, —N(Rd)—S(O)2—Rd, —N(Rd)—S(O)—N(Rd)2, —CH═C(Re)2, and —N(Rd)—S(O)2—N(Rd)2;
each Rc is independently selected from the group consisting of hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 3-20 membered carbocyclyl, 3-20 membered heterocyclyl, wherein any C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 3-20 membered carbocyclyl, and 3-20 membered heterocyclyl is optionally substituted with one or more groups Rf;
each Rf is independently selected from the group consisting of oxo, 3-20 membered carbocyclyl, 3-20 membered heterocyclyl, halo, —NO2, —N(Rg)2, —CN, —C(O)—N(Rg)2, —S(O)—N(Rg)2, —S(O)2—N(Rg)2, —O—Rg, —S—Rg, —O—C(O)—Rg, —C(O)—Rg, —C(O)—O—Rg, —S(O)—Rg, —S(O)2—Rg, —C(O)—N(Rg)2, —N(Rg)—C(O)—Rg, —Si(Rh)3, —N(Rg)—C(O)—O—Rg, —N(Rg)—S(O)—Rg, N(Rg)—S(O)2—Rg, and C1-6alkyl, which 3-20 membered carbocyclyl, 3-20 membered heterocyclyl, and C1-6alkyl are optionally substituted with one or more groups Ri,
each Rg is independently selected from the group consisting of hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 3-20 membered carbocyclyl, and 3-20 membered heterocyclyl, wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkoxy, 3-20 membered carbocyclyl, and 3-20 membered heterocyclyl is optionally substituted with one or more groups Rj, or two Rg are taken together with the nitrogen to which they are attached to form a 3-20 membered heterocyclyl that is optionally substituted with one or more groups independently selected from the group consisting of oxo, halo and C1-3alkyl that is optionally substituted with one or more groups independently selected from the group consisting of oxo and halo;
each Rh is independently selected from the group consisting of H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, and C3-6carbocyclyl;
each Rj is independently selected from the group consisting of oxo, halo, amino, hydroxyl, —Si(Rk)3, 3-20 membered carbocyclyl, 3-20 membered heterocyclyl, and C1-C6 alkyl, wherein any 3-20 membered carbocyclyl, 3-20 membered heterocyclyl, and C1-C6 alkyl is optionally substituted with one or more groups independently selected from the group consisting of oxo, C1-C4alkyl, and halo;
each Rk is independently selected from the group consisting of H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, and C3-6carbocyclyl;
each Ri is independently selected from the group consisting of oxo, halo, C1-6alkyl, cyano, —N(R1)2, —O—R1, —S(O)—R1, —S(O)2—R1, —S(O)—N(R1)2, —S(O)2—N(R1)2, —N(R1)—S(O)—R1, —N(R1)—C(O)—R1, —N(R1)—C(O)—O—R1, —N(R1)—S(O)2—R1, 3-20 membered heterocyclyl, and 3-20 membered carbocyclyl that is optionally substituted with one or more groups independently selected from the group consisting of halo, and C1-6alkyl;
each R1 is independently selected from the group consisting of hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 3-20 membered carbocyclyl, and 3-20 membered heterocyclyl, wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkoxy, 3-20 membered carbocyclyl, and 3-20 membered heterocyclyl is optionally substituted with one or more groups Rm; or two R1 are taken together with the nitrogen to which they are attached to form a 3-20 membered heterocyclyl that is optionally substituted with one or more groups independently selected from the group consisting of oxo, halo and C1-3alkyl that is optionally substituted with one or more groups independently selected from the group consisting of oxo and halo; and
each Rm is independently selected from the group consisting of oxo, halo, amino, hydroxyl, —Si(Rn)3, 3-20 membered carbocyclyl, 3-20 membered heterocyclyl, and C1-C6 alkyl, wherein any 3-20 membered carbocyclyl, 3-20 membered heterocyclyl, and C1-C6 alkyl is optionally substituted with one or more groups independently selected from the group consisting of oxo, C1-C4alkyl, and halo;
each Rn is independently selected from the group consisting of H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, and C3-6carbocyclyl;
each Rd is independently selected from the group consisting of hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 3-20 membered carbocyclyl, and 3-20 membered heterocyclyl, wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 3-20 membered carbocyclyl, and 3-20 membered heterocyclyl is optionally substituted with one or more groups Ro, or two Rd are taken together with the nitrogen to which they are attached to form a 3-20 membered heterocyclyl that is optionally substituted with one or more groups independently selected from the group consisting of oxo, halo and C1-3alkyl that is optionally substituted with one or more groups independently selected from oxo and halo;
each Ro is independently selected from the group consisting of oxo, halo, amino, hydroxyl, cyano, —O—Rp, 3-20 membered carbocyclyl, 3-20 membered heterocyclyl, and C1-C6 alkyl, wherein any C1-C6 alkyl, 3-20 membered carbocyclyl and 3-20 membered heterocyclyl is optionally substituted with one or more groups independently selected from the group consisting of oxo, C1-C4 alkyl, —O—Rq, and halo;
each Rp is independently selected from the group consisting of hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 3-20 membered carbocyclyl, and 3-20 membered heterocyclyl, wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkoxy, 3-20 membered carbocyclyl, and 3-20 membered heterocyclyl is optionally substituted with one or more groups Rr,
each Rr is independently selected from the group consisting of oxo, halo, amino, hydroxyl, —Si(Rs)3, 3-20 membered carbocyclyl, 3-20 membered heterocyclyl, and C1-C6 alkyl, wherein any 3-20 membered carbocyclyl, 3-20 membered heterocyclyl, and C1-C6 alkyl is optionally substituted with one or more groups independently selected from the group consisting of oxo, C1-C4alkyl, and halo;
each Rs is independently selected from the group consisting of H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, and C3-6carbocyclyl;
each Rq is independently selected from the group consisting of hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 3-20 membered carbocyclyl, and 3-20 membered heterocyclyl, wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkoxy, 3-20 membered carbocyclyl, and 3-20 membered heterocyclyl is optionally substituted with one or more groups Rt,
each Rt is independently selected from the group consisting of oxo, halo, amino, hydroxyl, —Si(Ru)3, 3-20 membered carbocyclyl, 3-20 membered heterocyclyl, and C1-C6 alkyl, wherein any 3-20 membered carbocyclyl, 3-20 membered heterocyclyl, and C1-C6 alkyl is optionally substituted with one or more groups independently selected from the group consisting of oxo, C1-C4alkyl, and halo;
each Ru is independently selected from the group consisting of H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, and C3-6carbocyclyl; and
two Re groups taken together with the carbon to which they are attached form a 3-20 membered carbocyclyl;
or a salt thereof.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US15/667,227 US20170333406A1 (en) | 2014-11-27 | 2017-08-02 | Therapeutic compounds and uses thereof |
Applications Claiming Priority (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CNPCT/CN2014/092380 | 2014-11-27 | ||
CN2014092380 | 2014-11-27 | ||
CNPCT/CN2015/092965 | 2015-10-27 | ||
CN2015092965 | 2015-10-27 | ||
US14/952,821 US9763922B2 (en) | 2014-11-27 | 2015-11-25 | Therapeutic compounds and uses thereof |
US15/667,227 US20170333406A1 (en) | 2014-11-27 | 2017-08-02 | Therapeutic compounds and uses thereof |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US14/952,821 Continuation US9763922B2 (en) | 2014-11-27 | 2015-11-25 | Therapeutic compounds and uses thereof |
Publications (1)
Publication Number | Publication Date |
---|---|
US20170333406A1 true US20170333406A1 (en) | 2017-11-23 |
Family
ID=55024234
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US14/952,821 Active US9763922B2 (en) | 2014-11-27 | 2015-11-25 | Therapeutic compounds and uses thereof |
US15/667,227 Abandoned US20170333406A1 (en) | 2014-11-27 | 2017-08-02 | Therapeutic compounds and uses thereof |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US14/952,821 Active US9763922B2 (en) | 2014-11-27 | 2015-11-25 | Therapeutic compounds and uses thereof |
Country Status (6)
Country | Link |
---|---|
US (2) | US9763922B2 (en) |
EP (2) | EP3224258B1 (en) |
JP (1) | JP6771464B2 (en) |
CN (1) | CN107531690B (en) |
HK (1) | HK1248695A1 (en) |
WO (1) | WO2016086200A1 (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10807982B2 (en) | 2015-04-15 | 2020-10-20 | Celgene Quanticel Research, Inc. | Bromodomain inhibitors |
WO2021026059A1 (en) | 2019-08-05 | 2021-02-11 | Eli Lilly And Company | 7,8-DIHYDRO-4H-PYRAZOLO[4,3-c]AZEPINE-6-ONE COMPOUNDS |
Families Citing this family (38)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN107108613B (en) | 2014-11-10 | 2020-02-25 | 基因泰克公司 | Bromodomain inhibitors and uses thereof |
MA40940A (en) * | 2014-11-10 | 2017-09-19 | Constellation Pharmaceuticals Inc | SUBSTITUTED PYRROLOPYRIDINES USED AS BROMODOMA INHIBITORS |
MA40943A (en) | 2014-11-10 | 2017-09-19 | Constellation Pharmaceuticals Inc | SUBSTITUTED PYRROLOPYRIDINES USED AS BROMODOMA INHIBITORS |
CA2969417A1 (en) * | 2014-12-05 | 2016-06-09 | H. Lee Moffitt Cancer Center And Research Institute, Inc. | Bromodomain inhibitor as adjuvant in cancer immunotherapy |
EP3250571B1 (en) | 2015-01-29 | 2022-11-30 | Genentech, Inc. | Therapeutic compounds and uses thereof |
CN109476641B (en) * | 2016-05-24 | 2022-07-05 | 基因泰克公司 | Heterocyclic inhibitors of CBP/EP300 and their use in the treatment of cancer |
MA45146A (en) * | 2016-05-24 | 2021-03-24 | Constellation Pharmaceuticals Inc | PYRAZOLOPYRIDINE DERIVATIVES FOR THE TREATMENT OF CANCER |
EA201990370A1 (en) | 2016-07-25 | 2019-06-28 | Эпизайм, Инк. | CANCER THERAPY ASSOCIATED WITH CREBBP |
GB201617627D0 (en) * | 2016-10-18 | 2016-11-30 | Cellcentric Ltd | Pharmaceutical compounds |
GB201617630D0 (en) * | 2016-10-18 | 2016-11-30 | Cellcentric Ltd | Pharmaceutical compounds |
CA3049926A1 (en) | 2017-01-17 | 2018-07-26 | Heparegenix Gmbh | Protein kinase inhibitors for promoting liver regeneration or reducing or preventing hepatocyte death |
WO2018235966A1 (en) * | 2017-06-21 | 2018-12-27 | 第一三共株式会社 | Ep300/crebbp inhibitor |
MA50250A (en) | 2017-09-15 | 2020-07-22 | Forma Therapeutics Inc | TETRAHYDROIMIDAZO QUINOLEIN COMPOSITIONS USED AS CBP / P300 INHIBITORS |
EP3704119A1 (en) | 2017-11-02 | 2020-09-09 | AiCuris GmbH & Co. KG | Novel, highly active pyrazolo-piperidine substituted indole-2-carboxamides active against the hepatitis b virus (hbv) |
US11058688B2 (en) | 2018-03-29 | 2021-07-13 | Board Of Regents, The University Of Texas System | Imidazopiperazine inhibitors of transcription activating proteins |
WO2019195846A1 (en) | 2018-04-06 | 2019-10-10 | Board Of Regents, The University Of Texas System | Imidazopiperazinone inhibitors of transcription activating proteins |
GB201806320D0 (en) * | 2018-04-18 | 2018-05-30 | Cellcentric Ltd | Process |
GB201809295D0 (en) | 2018-06-06 | 2018-07-25 | Institute Of Cancer Res Royal Cancer Hospital | Lox inhibitors |
EP3587418B1 (en) * | 2018-06-29 | 2021-09-01 | Forma Therapeutics, Inc. | Inhibitors of creb binding protein (cbp) |
KR20210025631A (en) * | 2018-06-29 | 2021-03-09 | 포르마 세라퓨틱스 인크. | Inhibition of CREB binding protein (CBP) |
CN109187832B (en) * | 2018-09-30 | 2021-07-30 | 华润三九医药股份有限公司 | Method for determining phenylephrine concentration by LC-MS/MS (liquid chromatography-mass spectrometry/mass spectrometry) and sample pretreatment method |
GB201818750D0 (en) | 2018-11-16 | 2019-01-02 | Institute Of Cancer Res Royal Cancer Hospital | Lox inhibitors |
CN111320621B (en) * | 2018-12-14 | 2022-10-04 | 中国科学院广州生物医药与健康研究院 | Indolizine compound and preparation method and application thereof |
AU2020227742A1 (en) * | 2019-02-27 | 2021-09-16 | Constellation Pharmaceuticals, Inc. | P300/CBP hat inhibitors and methods for their use |
US20230073777A1 (en) * | 2019-02-27 | 2023-03-09 | Cullgen (Shanghai), Inc. | Cyclic-amp response element binding protein (cbp) and/or adenoviral e1a binding protein of 300 kda (p300) degradation compounds and methods of use |
MX2021011154A (en) * | 2019-03-15 | 2021-10-22 | Forma Therapeutics Inc | Compositions and methods for treating androgen receptor positive forms of cancer. |
TW202102494A (en) * | 2019-03-15 | 2021-01-16 | 美商弗瑪治療公司 | Inhibiting cyclic amp-responsive element-binding protein (creb) |
JP2022535743A (en) * | 2019-05-29 | 2022-08-10 | アイエフエム デュー インコーポレイテッド | Compounds and compositions for treating conditions associated with STING activity |
CN110170052B (en) * | 2019-06-21 | 2020-07-10 | 复旦大学 | Application of CBP-P300 inhibitor in intestinal injury diseases |
US20230159497A1 (en) | 2020-04-25 | 2023-05-25 | Pharmablock Sciences (Nanjing) , Inc. | Cbp/ep300 inhibitor and use thereof |
WO2022042707A1 (en) * | 2020-08-27 | 2022-03-03 | Cullgen (Shanghai) , Inc. | Cyclic-amp response element binding protein (cbp) and/or adenoviral e1a binding protein of 300 kda (p300) degradation compounds and methods of use |
US11795168B2 (en) | 2020-09-23 | 2023-10-24 | Forma Therapeutics, Inc. | Inhibiting cyclic amp-responsive element-binding protein (CREB) binding protein (CBP) |
US11801243B2 (en) | 2020-09-23 | 2023-10-31 | Forma Therapeutics, Inc. | Bromodomain inhibitors for androgen receptor-driven cancers |
KR20230080441A (en) * | 2020-10-02 | 2023-06-07 | 더 보드 오브 리젠츠 오브 더 유니버시티 오브 텍사스 시스템 | Imidazopiperazine Inhibitor of Transcription Activation Protein |
WO2022072647A1 (en) * | 2020-10-02 | 2022-04-07 | Board Of Regents, The University Of Texas System | Imidazopiperazine inhibitors of transcription activating proteins |
US20240122941A1 (en) * | 2020-12-25 | 2024-04-18 | National Cancer Center | Therapy based on synthetic lethality in swi/snf complex-dysfunction cancer |
TW202334142A (en) | 2021-11-12 | 2023-09-01 | 香港商英矽智能科技知識產權有限公司 | Small molecule inhibitors of ubiquitin specific protease 1 (usp1) and uses thereof |
US20240109868A1 (en) * | 2022-08-29 | 2024-04-04 | Miracure Biotechnology Limited | Ep300/cbp modulator, preparation method therefor and use thereof |
Family Cites Families (49)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CU22545A1 (en) | 1994-11-18 | 1999-03-31 | Centro Inmunologia Molecular | OBTAINING A CHEMICAL AND HUMANIZED ANTIBODY AGAINST THE RECEPTOR OF THE EPIDERMAL GROWTH FACTOR FOR DIAGNOSTIC AND THERAPEUTIC USE |
US4943533A (en) | 1984-03-01 | 1990-07-24 | The Regents Of The University Of California | Hybrid cell lines that produce monoclonal antibodies to epidermal growth factor receptor |
JP2975679B2 (en) | 1989-09-08 | 1999-11-10 | ザ・ジョーンズ・ホプキンス・ユニバーシティ | Structural change of EGF receptor gene in human glioma |
AU661533B2 (en) | 1992-01-20 | 1995-07-27 | Astrazeneca Ab | Quinazoline derivatives |
GB9314893D0 (en) | 1993-07-19 | 1993-09-01 | Zeneca Ltd | Quinazoline derivatives |
ES2166368T3 (en) | 1993-12-24 | 2002-04-16 | Merck Patent Gmbh | IMMUNOCONJUGADOS. |
IL112248A0 (en) | 1994-01-25 | 1995-03-30 | Warner Lambert Co | Tricyclic heteroaromatic compounds and pharmaceutical compositions containing them |
US5654307A (en) | 1994-01-25 | 1997-08-05 | Warner-Lambert Company | Bicyclic compounds capable of inhibiting tyrosine kinases of the epidermal growth factor receptor family |
IL112249A (en) | 1994-01-25 | 2001-11-25 | Warner Lambert Co | Pharmaceutical compositions containing di and tricyclic pyrimidine derivatives for inhibiting tyrosine kinases of the epidermal growth factor receptor family and some new such compounds |
WO1996003397A1 (en) | 1994-07-21 | 1996-02-08 | Akzo Nobel N.V. | Cyclic ketone peroxide formulations |
US5804396A (en) | 1994-10-12 | 1998-09-08 | Sugen, Inc. | Assay for agents active in proliferative disorders |
JP3088018B2 (en) | 1995-03-30 | 2000-09-18 | ファイザー・インコーポレーテッド | Quinazoline derivatives |
GB9508538D0 (en) | 1995-04-27 | 1995-06-14 | Zeneca Ltd | Quinazoline derivatives |
GB9508565D0 (en) | 1995-04-27 | 1995-06-14 | Zeneca Ltd | Quiazoline derivative |
US5747498A (en) | 1996-05-28 | 1998-05-05 | Pfizer Inc. | Alkynyl and azido-substituted 4-anilinoquinazolines |
EP0831880A4 (en) | 1995-06-07 | 2004-12-01 | Imclone Systems Inc | Antibody and antibody fragments for inhibiting the growth of tumors |
CZ1598A3 (en) | 1995-07-06 | 1998-04-15 | Novartis Ag | Pyrrolopyrimidines and process for preparing thereof |
US5760041A (en) | 1996-02-05 | 1998-06-02 | American Cyanamid Company | 4-aminoquinazoline EGFR Inhibitors |
GB9603095D0 (en) | 1996-02-14 | 1996-04-10 | Zeneca Ltd | Quinazoline derivatives |
CN100503580C (en) | 1996-04-12 | 2009-06-24 | 沃尼尔·朗伯公司 | Irreversible inhibitor of tyrosine kinase |
DK0912559T3 (en) | 1996-07-13 | 2003-03-10 | Glaxo Group Ltd | Condensed heterocyclic compounds as protein tyrosine kinase inhibitors |
ID18494A (en) | 1996-10-02 | 1998-04-16 | Novartis Ag | PIRAZOLA DISTRIBUTION IN THE SEQUENCE AND THE PROCESS OF MAKING IT |
UA73073C2 (en) | 1997-04-03 | 2005-06-15 | Уайт Холдінгз Корпорейшн | Substituted 3-cyan chinolines |
US6002008A (en) | 1997-04-03 | 1999-12-14 | American Cyanamid Company | Substituted 3-cyano quinolines |
US6235883B1 (en) | 1997-05-05 | 2001-05-22 | Abgenix, Inc. | Human monoclonal antibodies to epidermal growth factor receptor |
ES2201484T3 (en) | 1997-05-06 | 2004-03-16 | Wyeth Holdings Corporation | USE OF QUINAZOLINE COMPOUNDS FOR THE TREATMENT OF RENAL POLYCHYSTOSIS DISEASE. |
ZA986729B (en) | 1997-07-29 | 1999-02-02 | Warner Lambert Co | Irreversible inhibitors of tyrosine kinases |
ZA986732B (en) | 1997-07-29 | 1999-02-02 | Warner Lambert Co | Irreversible inhibitiors of tyrosine kinases |
TW436485B (en) | 1997-08-01 | 2001-05-28 | American Cyanamid Co | Substituted quinazoline derivatives |
BR9814116A (en) | 1997-11-06 | 2000-10-03 | American Cyanamid Co | Use of quinazoline derivatives as tyrosine kinase inhibitors for the treatment of colonic polyp |
ATE229008T1 (en) | 1998-11-19 | 2002-12-15 | Warner Lambert Co | N- 4-(3-CHLORO-4-FLUORO-PHENYLAMINO)-7-(3- MORFOLIN-4-YL-PROPOXY)-CHINAZOLINE-6-YL -AKRYLAMIDE, AN IRREVERSIBLE TYROSINE KINASE INHIBITOR |
US20060100233A1 (en) | 2002-07-25 | 2006-05-11 | Manuela Villa | Bicyclo-pyrazoles active as kinase inhibitors, process for their preparation and pharmaceutical compositions comprising them |
MXPA05000945A (en) | 2002-07-25 | 2005-05-16 | Pharmacia Italia Spa | Bicyclo-pyrazoles active as kinase inhibitors, process for their preparation and pharmaceutical compositions comprising them. |
US20070037790A1 (en) | 2003-03-11 | 2007-02-15 | Francesca Abrate | Bicyclo-pyrazole derivatives active as kinase inhibitors, process for their preparation and pharmaceutical compositions comprising them |
EP2418278A3 (en) | 2005-05-09 | 2012-07-04 | Ono Pharmaceutical Co., Ltd. | Human monoclonal antibodies to programmed death 1(PD-1) and methods for treating cancer using anti-PD-1 antibodies alone or in combination with other immunotherapeutics |
AU2006265108C1 (en) | 2005-07-01 | 2013-01-17 | E. R. Squibb & Sons, L.L.C. | Human monoclonal antibodies to programmed death ligand 1 (PD-L1) |
WO2007068619A1 (en) | 2005-12-12 | 2007-06-21 | Nerviano Medical Sciences S.R.L. | Substituted pyrazolo [4,3-c] pyridine derivatives active as kinase inhibitors |
WO2007099166A1 (en) | 2006-03-03 | 2007-09-07 | Nerviano Medical Sciences S.R.L. | Pyrazolo-pyridine derivatives active as kinase inhibitors |
CA2710740C (en) * | 2007-12-28 | 2016-07-19 | Shinji Miyoshi | Thienotriazolodiazepine compound as antitumor agent |
PT2242773T (en) | 2008-02-11 | 2017-09-15 | Cure Tech Ltd | Monoclonal antibodies for tumor treatment |
US8168757B2 (en) | 2008-03-12 | 2012-05-01 | Merck Sharp & Dohme Corp. | PD-1 binding proteins |
AR071780A1 (en) | 2008-05-15 | 2010-07-14 | Nerviano Medical Sciences Srl | BICYCLE CARBONILAMINO-PIRAZOLES CARBAMILILE DERIVATIVES AS PROFARMACOS |
CN102203125A (en) | 2008-08-25 | 2011-09-28 | 安普利穆尼股份有限公司 | Pd-1 antagonists and methods of use thereof |
PE20120341A1 (en) | 2008-12-09 | 2012-04-24 | Genentech Inc | ANTI-PD-L1 ANTIBODIES AND ITS USE TO IMPROVE T-CELL FUNCTION |
US20130017199A1 (en) | 2009-11-24 | 2013-01-17 | AMPLIMMUNE ,Inc. a corporation | Simultaneous inhibition of pd-l1/pd-l2 |
CN101812063B (en) | 2010-03-18 | 2012-04-25 | 中国医学科学院医药生物技术研究所 | Alpha-naphthalenesulfonamide base quintuple heterocyclic compound and anti-tumor activity thereof |
WO2013097052A1 (en) * | 2011-12-30 | 2013-07-04 | Abbott Laboratories | Bromodomain inhibitors |
WO2013148114A1 (en) | 2012-03-30 | 2013-10-03 | University Of Florida Research Foundation, Inc. | P300/cbp inhibitors and methods of use |
US9808505B2 (en) * | 2013-03-08 | 2017-11-07 | Board Of Regents, The University Of Texas System | Suppression of malignant mesothelioma by overexpression or stimulation of endothelial protein C receptors (EPCR) |
-
2015
- 2015-11-25 EP EP15816578.7A patent/EP3224258B1/en active Active
- 2015-11-25 CN CN201580074597.7A patent/CN107531690B/en active Active
- 2015-11-25 US US14/952,821 patent/US9763922B2/en active Active
- 2015-11-25 JP JP2017528520A patent/JP6771464B2/en active Active
- 2015-11-25 EP EP19191423.3A patent/EP3632915A1/en not_active Withdrawn
- 2015-11-25 WO PCT/US2015/062794 patent/WO2016086200A1/en active Application Filing
-
2017
- 2017-08-02 US US15/667,227 patent/US20170333406A1/en not_active Abandoned
-
2018
- 2018-06-28 HK HK18108300.8A patent/HK1248695A1/en unknown
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10807982B2 (en) | 2015-04-15 | 2020-10-20 | Celgene Quanticel Research, Inc. | Bromodomain inhibitors |
WO2021026059A1 (en) | 2019-08-05 | 2021-02-11 | Eli Lilly And Company | 7,8-DIHYDRO-4H-PYRAZOLO[4,3-c]AZEPINE-6-ONE COMPOUNDS |
AU2020324949B2 (en) * | 2019-08-05 | 2023-11-02 | Eli Lilly And Company | 7,8-dihydro-4h-pyrazolo(4,3-c)azepine-6-one compounds |
Also Published As
Publication number | Publication date |
---|---|
US9763922B2 (en) | 2017-09-19 |
EP3632915A1 (en) | 2020-04-08 |
EP3224258B1 (en) | 2019-08-14 |
US20160158207A1 (en) | 2016-06-09 |
JP2017537100A (en) | 2017-12-14 |
HK1248695A1 (en) | 2018-10-19 |
WO2016086200A1 (en) | 2016-06-02 |
JP6771464B2 (en) | 2020-10-21 |
CN107531690B (en) | 2020-11-06 |
CN107531690A (en) | 2018-01-02 |
WO2016086200A9 (en) | 2016-06-23 |
EP3224258A1 (en) | 2017-10-04 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US9763922B2 (en) | Therapeutic compounds and uses thereof | |
US11247989B2 (en) | Therapeutic compounds and uses thereof | |
US11168070B2 (en) | Therapeutic compounds and uses thereof | |
US10206931B2 (en) | Therapeutic compounds and uses thereof | |
US10308614B2 (en) | Therapeutic compounds and uses thereof | |
US10183009B2 (en) | Therapeutic compounds and uses thereof | |
US10301253B2 (en) | Therapeutic compounds and uses thereof | |
US10150767B2 (en) | Therapeutic compounds and uses thereof | |
US10258603B2 (en) | Therapeutic compounds and uses thereof | |
US10155764B2 (en) | Therapeutic compounds and uses thereof | |
US10202378B2 (en) | Therapeutic compounds and uses thereof |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
STCB | Information on status: application discontinuation |
Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION |