NZ752865B2 - Calpain modulators and therapeutic uses thereof - Google Patents
Calpain modulators and therapeutic uses thereof Download PDFInfo
- Publication number
- NZ752865B2 NZ752865B2 NZ752865A NZ75286517A NZ752865B2 NZ 752865 B2 NZ752865 B2 NZ 752865B2 NZ 752865 A NZ752865 A NZ 752865A NZ 75286517 A NZ75286517 A NZ 75286517A NZ 752865 B2 NZ752865 B2 NZ 752865B2
- Authority
- NZ
- New Zealand
- Prior art keywords
- compound
- group
- alkyl
- optionally substituted
- ghmatters
- Prior art date
Links
- 230000000051 modifying Effects 0.000 title abstract description 9
- 102000007590 Calpain Human genes 0.000 title abstract description 5
- 108010032088 Calpain Proteins 0.000 title abstract description 5
- 230000001225 therapeutic Effects 0.000 title description 11
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 32
- 150000001875 compounds Chemical class 0.000 claims description 1025
- 125000000217 alkyl group Chemical group 0.000 claims description 143
- -1 cyano, hydroxy Chemical group 0.000 claims description 121
- 125000004452 carbocyclyl group Chemical group 0.000 claims description 113
- 229910052799 carbon Inorganic materials 0.000 claims description 101
- 125000003118 aryl group Chemical group 0.000 claims description 84
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 78
- 201000010099 disease Diseases 0.000 claims description 77
- 229910052739 hydrogen Inorganic materials 0.000 claims description 75
- 206010016654 Fibrosis Diseases 0.000 claims description 65
- 230000004761 fibrosis Effects 0.000 claims description 65
- 125000001188 haloalkyl group Chemical group 0.000 claims description 64
- 125000003545 alkoxy group Chemical group 0.000 claims description 62
- 125000000623 heterocyclic group Chemical group 0.000 claims description 59
- 239000011780 sodium chloride Substances 0.000 claims description 57
- 150000003839 salts Chemical class 0.000 claims description 52
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 42
- 230000003176 fibrotic Effects 0.000 claims description 40
- 229910052757 nitrogen Inorganic materials 0.000 claims description 39
- 125000004438 haloalkoxy group Chemical group 0.000 claims description 27
- 229910052760 oxygen Inorganic materials 0.000 claims description 27
- 239000003814 drug Substances 0.000 claims description 25
- 229910052717 sulfur Inorganic materials 0.000 claims description 24
- 125000006714 (C3-C10) heterocyclyl group Chemical group 0.000 claims description 23
- 125000003342 alkenyl group Chemical group 0.000 claims description 23
- 230000001684 chronic Effects 0.000 claims description 19
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 15
- 239000000546 pharmaceutic aid Substances 0.000 claims description 13
- 229910052727 yttrium Inorganic materials 0.000 claims description 13
- 239000002202 Polyethylene glycol Substances 0.000 claims description 10
- 210000000056 organs Anatomy 0.000 claims description 10
- 229920001223 polyethylene glycol Polymers 0.000 claims description 10
- 210000004185 Liver Anatomy 0.000 claims description 9
- 108009000252 Lung fibrosis Proteins 0.000 claims description 9
- 208000005069 Pulmonary Fibrosis Diseases 0.000 claims description 9
- 206010039073 Rheumatoid arthritis Diseases 0.000 claims description 9
- 230000000747 cardiac effect Effects 0.000 claims description 9
- 201000004044 liver cirrhosis Diseases 0.000 claims description 9
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 9
- 201000002793 renal fibrosis Diseases 0.000 claims description 9
- 201000009594 systemic scleroderma Diseases 0.000 claims description 9
- 208000006897 Interstitial Lung Disease Diseases 0.000 claims description 8
- 208000002780 Macular Degeneration Diseases 0.000 claims description 8
- 208000002805 Mediastinal Fibrosis Diseases 0.000 claims description 8
- 206010028537 Myelofibrosis Diseases 0.000 claims description 8
- 208000003476 Primary Myelofibrosis Diseases 0.000 claims description 8
- 206010036805 Progressive massive fibrosis Diseases 0.000 claims description 8
- 206010038748 Restrictive cardiomyopathy Diseases 0.000 claims description 8
- 210000000952 Spleen Anatomy 0.000 claims description 8
- 201000010048 endomyocardial fibrosis Diseases 0.000 claims description 8
- 201000001155 extrinsic allergic alveolitis Diseases 0.000 claims description 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 8
- 239000007924 injection Substances 0.000 claims description 8
- 238000002347 injection Methods 0.000 claims description 8
- 230000036407 pain Effects 0.000 claims description 8
- 238000001356 surgical procedure Methods 0.000 claims description 8
- 208000003510 Nephrogenic Fibrosing Dermopathy Diseases 0.000 claims description 7
- 206010067467 Nephrogenic systemic fibrosis Diseases 0.000 claims description 7
- 206010038979 Retroperitoneal fibrosis Diseases 0.000 claims description 7
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 7
- 238000007879 vasectomy Methods 0.000 claims description 7
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 6
- 206010022114 Injury Diseases 0.000 claims description 5
- 125000004104 aryloxy group Chemical group 0.000 claims description 5
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 5
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 5
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 4
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 4
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 229920000728 polyester Polymers 0.000 claims description 3
- 125000003542 3-methylbutan-2-yl group Chemical group [H]C([H])([H])C([H])(*)C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 125000005213 alkyl heteroaryl group Chemical group 0.000 claims description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 125000001475 halogen functional group Chemical group 0.000 claims 15
- 239000000203 mixture Substances 0.000 abstract description 237
- 238000002360 preparation method Methods 0.000 abstract description 13
- 150000003384 small molecules Chemical class 0.000 abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 297
- 239000007787 solid Substances 0.000 description 156
- 101710040879 CAPN9 Proteins 0.000 description 152
- 102100015629 CAPN9 Human genes 0.000 description 152
- 102000003900 Calpain-2 Human genes 0.000 description 125
- 108090000232 Calpain-2 Proteins 0.000 description 125
- 102000003895 Calpain-1 Human genes 0.000 description 124
- 108090000236 Calpain-1 Proteins 0.000 description 124
- 235000019439 ethyl acetate Nutrition 0.000 description 112
- ODUCDPQEXGNKDN-UHFFFAOYSA-N Nitroxyl Chemical compound O=N ODUCDPQEXGNKDN-UHFFFAOYSA-N 0.000 description 111
- 239000000543 intermediate Substances 0.000 description 94
- 230000000875 corresponding Effects 0.000 description 88
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 86
- 239000000243 solution Substances 0.000 description 84
- 230000027455 binding Effects 0.000 description 75
- 229940093499 ethyl acetate Drugs 0.000 description 73
- 239000011541 reaction mixture Substances 0.000 description 71
- 125000004429 atoms Chemical group 0.000 description 69
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 69
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 67
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 66
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 63
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 63
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 62
- 125000005843 halogen group Chemical group 0.000 description 61
- 235000002639 sodium chloride Nutrition 0.000 description 55
- 239000012267 brine Substances 0.000 description 52
- 239000003208 petroleum Substances 0.000 description 49
- 230000002829 reduced Effects 0.000 description 47
- 150000003857 carboxamides Chemical class 0.000 description 46
- 230000003993 interaction Effects 0.000 description 44
- 239000012044 organic layer Substances 0.000 description 43
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 43
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 38
- 230000002401 inhibitory effect Effects 0.000 description 38
- UIIMBOGNXHQVGW-UHFFFAOYSA-M buffer Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 36
- 125000001072 heteroaryl group Chemical group 0.000 description 34
- WMFOQBRAJBCJND-UHFFFAOYSA-M lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 34
- 102000004190 Enzymes Human genes 0.000 description 33
- 108090000790 Enzymes Proteins 0.000 description 33
- 239000003795 chemical substances by application Substances 0.000 description 32
- 125000004435 hydrogen atoms Chemical class [H]* 0.000 description 32
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 32
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 31
- JIZCCIASPUFEIE-UHFFFAOYSA-N 4-phenyl-1,2-oxazole-3-carboxamide Chemical compound NC(=O)C1=NOC=C1C1=CC=CC=C1 JIZCCIASPUFEIE-UHFFFAOYSA-N 0.000 description 31
- 239000001257 hydrogen Substances 0.000 description 31
- 239000003921 oil Substances 0.000 description 31
- 235000019198 oils Nutrition 0.000 description 31
- 125000004432 carbon atoms Chemical group C* 0.000 description 30
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 29
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 26
- 125000004122 cyclic group Chemical group 0.000 description 25
- 238000006243 chemical reaction Methods 0.000 description 23
- 238000004440 column chromatography Methods 0.000 description 23
- 125000005842 heteroatoms Chemical group 0.000 description 23
- 239000000460 chlorine Substances 0.000 description 22
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 21
- 238000007792 addition Methods 0.000 description 21
- 230000035492 administration Effects 0.000 description 21
- OKTJSMMVPCPJKN-UHFFFAOYSA-N carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 21
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 21
- 125000001424 substituent group Chemical group 0.000 description 21
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 19
- 210000004027 cells Anatomy 0.000 description 19
- 239000002904 solvent Substances 0.000 description 19
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 19
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 18
- LIVNPJMFVYWSIS-UHFFFAOYSA-N silicon monoxide Inorganic materials [Si-]#[O+] LIVNPJMFVYWSIS-UHFFFAOYSA-N 0.000 description 18
- 150000001408 amides Chemical class 0.000 description 17
- 125000000304 alkynyl group Chemical group 0.000 description 16
- 239000000047 product Substances 0.000 description 16
- 239000007858 starting material Substances 0.000 description 16
- 125000002947 alkylene group Chemical group 0.000 description 15
- 239000010410 layer Substances 0.000 description 15
- 238000000034 method Methods 0.000 description 15
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- 239000000651 prodrug Substances 0.000 description 15
- 229940002612 prodrugs Drugs 0.000 description 15
- NINIDFKCEFEMDL-UHFFFAOYSA-N sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 15
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N DMSO-d6 Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 14
- 238000009472 formulation Methods 0.000 description 14
- 125000004404 heteroalkyl group Chemical group 0.000 description 14
- 210000000651 myofibroblasts Anatomy 0.000 description 14
- 239000000126 substance Substances 0.000 description 14
- 150000001413 amino acids Chemical group 0.000 description 13
- 239000002552 dosage form Substances 0.000 description 13
- KVXNKFYSHAUJIA-UHFFFAOYSA-M ethoxyethane;acetate Chemical compound CC([O-])=O.CCOCC KVXNKFYSHAUJIA-UHFFFAOYSA-M 0.000 description 13
- 239000003112 inhibitor Substances 0.000 description 13
- 125000004043 oxo group Chemical group O=* 0.000 description 13
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 12
- VZYJYKJYUQHDMJ-UHFFFAOYSA-N 4-phenyl-1,3-thiazole-2-carboxamide Chemical compound S1C(C(=O)N)=NC(C=2C=CC=CC=2)=C1 VZYJYKJYUQHDMJ-UHFFFAOYSA-N 0.000 description 12
- 235000001014 amino acid Nutrition 0.000 description 12
- 230000004069 differentiation Effects 0.000 description 12
- 239000003937 drug carrier Substances 0.000 description 12
- 239000000725 suspension Substances 0.000 description 12
- BZLVMXJERCGZMT-UHFFFAOYSA-N MeOtBu Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 11
- 229940079593 drugs Drugs 0.000 description 11
- 239000012074 organic phase Substances 0.000 description 11
- 238000003786 synthesis reaction Methods 0.000 description 11
- RAXXELZNTBOGNW-UHFFFAOYSA-N Imidazole Chemical compound C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 10
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 10
- 102000004887 Transforming Growth Factor beta Human genes 0.000 description 9
- 108090001012 Transforming Growth Factor beta Proteins 0.000 description 9
- 239000012298 atmosphere Substances 0.000 description 9
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 description 9
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 9
- 239000008079 hexane Substances 0.000 description 9
- 239000004615 ingredient Substances 0.000 description 9
- 239000002609 media Substances 0.000 description 9
- 239000001301 oxygen Substances 0.000 description 9
- MYMOFIZGZYHOMD-UHFFFAOYSA-N oxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 9
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 9
- 239000011593 sulfur Substances 0.000 description 9
- 210000002540 Macrophages Anatomy 0.000 description 8
- 241000124008 Mammalia Species 0.000 description 8
- 210000000274 Microglia Anatomy 0.000 description 8
- LEHBURLTIWGHEM-UHFFFAOYSA-N Pyridinium chlorochromate Chemical compound [O-][Cr](Cl)(=O)=O.C1=CC=[NH+]C=C1 LEHBURLTIWGHEM-UHFFFAOYSA-N 0.000 description 8
- CFOAUYCPAUGDFF-UHFFFAOYSA-N TosMIC Chemical compound CC1=CC=C(S(=O)(=O)C[N+]#[C-])C=C1 CFOAUYCPAUGDFF-UHFFFAOYSA-N 0.000 description 8
- UQYZFNUUOSSNKT-UHFFFAOYSA-N [benzotriazol-1-yloxy(dimethylamino)methylidene]-dimethylazanium;hexafluorophosphate Chemical compound F[P-](F)(F)(F)(F)F.C1=CC=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 UQYZFNUUOSSNKT-UHFFFAOYSA-N 0.000 description 8
- 210000003008 brain-resident macrophage Anatomy 0.000 description 8
- CURLTUGMZLYLDI-UHFFFAOYSA-N carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 8
- LCGLNKUTAGEVQW-UHFFFAOYSA-N dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 8
- 230000000670 limiting Effects 0.000 description 8
- 239000007788 liquid Substances 0.000 description 8
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 8
- 210000002569 neurons Anatomy 0.000 description 8
- 125000004433 nitrogen atoms Chemical group N* 0.000 description 8
- 230000003647 oxidation Effects 0.000 description 8
- 238000007254 oxidation reaction Methods 0.000 description 8
- DBSMXZFYDNXILM-UHFFFAOYSA-N 1-methylpyrazole-3-carboxamide Chemical compound CN1C=CC(C(N)=O)=N1 DBSMXZFYDNXILM-UHFFFAOYSA-N 0.000 description 7
- NNHQFKJWBLHANC-UHFFFAOYSA-N 1-phenylpyrazole-3-carboxamide Chemical compound N1=C(C(=O)N)C=CN1C1=CC=CC=C1 NNHQFKJWBLHANC-UHFFFAOYSA-N 0.000 description 7
- HXITXNWTGFUOAU-UHFFFAOYSA-N Phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 7
- 238000010168 coupling process Methods 0.000 description 7
- 238000005859 coupling reaction Methods 0.000 description 7
- 239000003085 diluting agent Substances 0.000 description 7
- 230000000813 microbial Effects 0.000 description 7
- 125000004430 oxygen atoms Chemical group O* 0.000 description 7
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 7
- 230000002335 preservative Effects 0.000 description 7
- 239000003755 preservative agent Substances 0.000 description 7
- 125000006239 protecting group Chemical group 0.000 description 7
- 230000011664 signaling Effects 0.000 description 7
- 238000010898 silica gel chromatography Methods 0.000 description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 7
- 239000003826 tablet Substances 0.000 description 7
- 150000004799 α-ketoamides Chemical class 0.000 description 7
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-hydroxy-Succinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 6
- JOXIMZWYDAKGHI-UHFFFAOYSA-N P-Toluenesulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 6
- 239000003153 chemical reaction reagent Substances 0.000 description 6
- 239000003086 colorant Substances 0.000 description 6
- 230000001808 coupling Effects 0.000 description 6
- 239000012043 crude product Substances 0.000 description 6
- 150000002148 esters Chemical class 0.000 description 6
- 239000000796 flavoring agent Substances 0.000 description 6
- 235000013355 food flavoring agent Nutrition 0.000 description 6
- 229910052740 iodine Inorganic materials 0.000 description 6
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 6
- 239000011734 sodium Substances 0.000 description 6
- 239000012453 solvate Substances 0.000 description 6
- 230000002194 synthesizing Effects 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- JQAMICDVFNNDKP-UHFFFAOYSA-N 4-phenyl-1,3-oxazole-2-carboxamide Chemical compound O1C(C(=O)N)=NC(C=2C=CC=CC=2)=C1 JQAMICDVFNNDKP-UHFFFAOYSA-N 0.000 description 5
- 125000006163 5-membered heteroaryl group Chemical group 0.000 description 5
- FBPFZTCFMRRESA-KAZBKCHUSA-N D-Mannitol Natural products OC[C@@H](O)[C@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KAZBKCHUSA-N 0.000 description 5
- CZMRCDWAGMRECN-UGDNZRGBSA-N D-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 5
- FBPFZTCFMRRESA-KVTDHHQDSA-N Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 5
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 5
- 125000004093 cyano group Chemical group *C#N 0.000 description 5
- 201000009910 diseases by infectious agent Diseases 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 238000003818 flash chromatography Methods 0.000 description 5
- 229910052731 fluorine Inorganic materials 0.000 description 5
- PEDCQBHIVMGVHV-UHFFFAOYSA-N glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 5
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 5
- 238000001990 intravenous administration Methods 0.000 description 5
- HPQVWDOOUQVBTO-UHFFFAOYSA-N lithium aluminum hydride Chemical compound [Li+].[Al-] HPQVWDOOUQVBTO-UHFFFAOYSA-N 0.000 description 5
- 239000000594 mannitol Substances 0.000 description 5
- 235000010355 mannitol Nutrition 0.000 description 5
- 230000004048 modification Effects 0.000 description 5
- 238000006011 modification reaction Methods 0.000 description 5
- 239000002808 molecular sieve Substances 0.000 description 5
- 239000002244 precipitate Substances 0.000 description 5
- 238000002560 therapeutic procedure Methods 0.000 description 5
- 230000000699 topical Effects 0.000 description 5
- VZCYOOQTPOCHFL-OWOJBTEDSA-N (E)-but-2-enedioate;hydron Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 4
- RFFLAFLAYFXFSW-UHFFFAOYSA-N 1,2-Dichlorobenzene Chemical compound ClC1=CC=CC=C1Cl RFFLAFLAYFXFSW-UHFFFAOYSA-N 0.000 description 4
- ZUHBIVLGBDHHSW-UHFFFAOYSA-N 1-pyridin-2-ylpyrazole-3-carboxamide Chemical compound N1=C(C(=O)N)C=CN1C1=CC=CC=N1 ZUHBIVLGBDHHSW-UHFFFAOYSA-N 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- NSYQSHFVAUTBDK-UHFFFAOYSA-N 3-phenylfuran-2-carboxamide Chemical compound O1C=CC(C=2C=CC=CC=2)=C1C(=O)N NSYQSHFVAUTBDK-UHFFFAOYSA-N 0.000 description 4
- NKNDPYCGAZPOFS-UHFFFAOYSA-M Copper(I) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 description 4
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 4
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 4
- 229910004373 HOAc Inorganic materials 0.000 description 4
- 206010061218 Inflammation Diseases 0.000 description 4
- GUBGYTABKSRVRQ-UUNJERMWSA-N Lactose Natural products O([C@@H]1[C@H](O)[C@H](O)[C@H](O)O[C@@H]1CO)[C@H]1[C@@H](O)[C@@H](O)[C@H](O)[C@H](CO)O1 GUBGYTABKSRVRQ-UUNJERMWSA-N 0.000 description 4
- 229910010082 LiAlH Inorganic materials 0.000 description 4
- LXCFILQKKLGQFO-UHFFFAOYSA-N Methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 4
- QIQXTHQIDYTFRH-UHFFFAOYSA-N Stearic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 4
- CZMRCDWAGMRECN-GDQSFJPYSA-N Sucrose Natural products O([C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](CO)O1)[C@@]1(CO)[C@H](O)[C@@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-GDQSFJPYSA-N 0.000 description 4
- LWIHDJKSTIGBAC-UHFFFAOYSA-K Tripotassium phosphate Chemical class [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 239000002671 adjuvant Substances 0.000 description 4
- 230000000240 adjuvant Effects 0.000 description 4
- 239000003963 antioxidant agent Substances 0.000 description 4
- 239000001768 carboxy methyl cellulose Substances 0.000 description 4
- 239000000969 carrier Substances 0.000 description 4
- 229910052801 chlorine Inorganic materials 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- LKYXEULZVGJVTG-UHFFFAOYSA-N chloromethane Chemical compound Cl[CH] LKYXEULZVGJVTG-UHFFFAOYSA-N 0.000 description 4
- 238000005516 engineering process Methods 0.000 description 4
- DBPFRRFGLYGEJI-UHFFFAOYSA-N ethyl glyoxylate Chemical compound CCOC(=O)C=O DBPFRRFGLYGEJI-UHFFFAOYSA-N 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 235000003599 food sweetener Nutrition 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- 230000004054 inflammatory process Effects 0.000 description 4
- 239000011630 iodine Substances 0.000 description 4
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 4
- 239000008101 lactose Substances 0.000 description 4
- GUBGYTABKSRVRQ-XLOQQCSPSA-N 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
- 239000000314 lubricant Substances 0.000 description 4
- 235000019359 magnesium stearate Nutrition 0.000 description 4
- 230000001404 mediated Effects 0.000 description 4
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 4
- 238000002600 positron emission tomography Methods 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N propionic acid Chemical compound CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 4
- DNIAPMSPPWPWGF-UHFFFAOYSA-N propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 238000002603 single-photon emission computed tomography Methods 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 239000000600 sorbitol Substances 0.000 description 4
- 235000010356 sorbitol Nutrition 0.000 description 4
- 238000006467 substitution reaction Methods 0.000 description 4
- 239000005720 sucrose Substances 0.000 description 4
- 239000003765 sweetening agent Substances 0.000 description 4
- 230000001131 transforming Effects 0.000 description 4
- WQZGKKKJIJFFOK-VFUOTHLCSA-N β-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 4
- POYYYLGRSJIILJ-UHFFFAOYSA-N 1-(trifluoromethyl)pyrazole-3-carboxamide Chemical compound NC(=O)C=1C=CN(C(F)(F)F)N=1 POYYYLGRSJIILJ-UHFFFAOYSA-N 0.000 description 3
- BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical compound C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 description 3
- RQCBPOPQTLHDFC-UHFFFAOYSA-N 2-phenyl-1,3-oxazole Chemical compound C1=COC(C=2C=CC=CC=2)=N1 RQCBPOPQTLHDFC-UHFFFAOYSA-N 0.000 description 3
- 241000283690 Bos taurus Species 0.000 description 3
- 230000037261 ClH Effects 0.000 description 3
- 108010010803 Gelatin Proteins 0.000 description 3
- JNWBBCNCSMBKNE-UHFFFAOYSA-N HATU Chemical compound F[P-](F)(F)(F)(F)F.C1=CN=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 JNWBBCNCSMBKNE-UHFFFAOYSA-N 0.000 description 3
- KRKPYFLIYNGWTE-UHFFFAOYSA-N N,O-Dimethylhydroxylamine Chemical compound CNOC KRKPYFLIYNGWTE-UHFFFAOYSA-N 0.000 description 3
- LAKGQQOHHAREIL-UHFFFAOYSA-N N1=C(N=CC=C1)N1N=C(C=C1)C(=O)N Chemical compound N1=C(N=CC=C1)N1N=C(C=C1)C(=O)N LAKGQQOHHAREIL-UHFFFAOYSA-N 0.000 description 3
- 206010063837 Reperfusion injury Diseases 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 3
- 235000011054 acetic acid Nutrition 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 125000003710 aryl alkyl group Chemical group 0.000 description 3
- 125000005110 aryl thio group Chemical group 0.000 description 3
- 239000011230 binding agent Substances 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 235000012970 cakes Nutrition 0.000 description 3
- 201000011510 cancer Diseases 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 239000002738 chelating agent Substances 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- 235000015165 citric acid Nutrition 0.000 description 3
- 239000012230 colorless oil Substances 0.000 description 3
- HEDRZPFGACZZDS-MICDWDOJSA-N deuterated chloroform Substances [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 3
- YZCKVEUIGOORGS-OUBTZVSYSA-N deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 3
- 239000008121 dextrose Substances 0.000 description 3
- 239000003995 emulsifying agent Substances 0.000 description 3
- 239000000839 emulsion Substances 0.000 description 3
- 230000002255 enzymatic Effects 0.000 description 3
- 239000000284 extract Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000011737 fluorine Substances 0.000 description 3
- YCKRFDGAMUMZLT-UHFFFAOYSA-N fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 3
- 239000008273 gelatin Substances 0.000 description 3
- 229920000159 gelatin Polymers 0.000 description 3
- 235000019322 gelatine Nutrition 0.000 description 3
- 235000011852 gelatine desserts Nutrition 0.000 description 3
- 235000011187 glycerol Nutrition 0.000 description 3
- 239000008187 granular material Substances 0.000 description 3
- 229910052736 halogen Inorganic materials 0.000 description 3
- 150000002367 halogens Chemical class 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- 230000001976 improved Effects 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 230000001965 increased Effects 0.000 description 3
- 230000002503 metabolic Effects 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 239000007800 oxidant agent Substances 0.000 description 3
- 230000001717 pathogenic Effects 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 238000009117 preventive therapy Methods 0.000 description 3
- LCDCPQHFCOBUEF-UHFFFAOYSA-N pyrrolidine-1-carboxamide Chemical compound NC(=O)N1CCCC1 LCDCPQHFCOBUEF-UHFFFAOYSA-N 0.000 description 3
- 150000003254 radicals Chemical class 0.000 description 3
- 239000002464 receptor antagonist Substances 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 239000000377 silicon dioxide Substances 0.000 description 3
- 235000012239 silicon dioxide Nutrition 0.000 description 3
- FPTVEOPNJVOJBF-UHFFFAOYSA-M sodium;oxolane;hydroxide Chemical compound [OH-].[Na+].C1CCOC1 FPTVEOPNJVOJBF-UHFFFAOYSA-M 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- 239000004094 surface-active agent Substances 0.000 description 3
- 238000000844 transformation Methods 0.000 description 3
- 239000003981 vehicle Substances 0.000 description 3
- RRHGBEAONBPBMW-VIFPVBQESA-N (1S)-1-amino-1-phenylpropan-1-ol Chemical compound CC[C@](N)(O)C1=CC=CC=C1 RRHGBEAONBPBMW-VIFPVBQESA-N 0.000 description 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 2
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 2
- WBYWAXJHAXSJNI-VOTSOKGWSA-M .beta-Phenylacrylic acid Natural products [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 2
- BPXKZEMBEZGUAH-UHFFFAOYSA-N 2-(chloromethoxy)ethyl-trimethylsilane Chemical compound C[Si](C)(C)CCOCCl BPXKZEMBEZGUAH-UHFFFAOYSA-N 0.000 description 2
- GVNVAWHJIKLAGL-UHFFFAOYSA-N 2-(cyclohexen-1-yl)cyclohexan-1-one Chemical compound O=C1CCCCC1C1=CCCCC1 GVNVAWHJIKLAGL-UHFFFAOYSA-N 0.000 description 2
- VUKAUDKDFVSVFT-UHFFFAOYSA-N 2-[6-[4,5-bis(2-hydroxypropoxy)-2-(2-hydroxypropoxymethyl)-6-methoxyoxan-3-yl]oxy-4,5-dimethoxy-2-(methoxymethyl)oxan-3-yl]oxy-6-(hydroxymethyl)-5-methoxyoxane-3,4-diol Chemical compound COC1C(OC)C(OC2C(C(O)C(OC)C(CO)O2)O)C(COC)OC1OC1C(COCC(C)O)OC(OC)C(OCC(C)O)C1OCC(C)O VUKAUDKDFVSVFT-UHFFFAOYSA-N 0.000 description 2
- CZPWVGJYEJSRLH-UHFFFAOYSA-N 289-95-2 Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 2
- COZQDNPLORIALF-UHFFFAOYSA-N 3-hydroxy-2-methylpropanenitrile Chemical compound OCC(C)C#N COZQDNPLORIALF-UHFFFAOYSA-N 0.000 description 2
- GPGKNEKFDGOXPO-UHFFFAOYSA-N 4-phenyl-1H-pyrazole Chemical compound C1=NNC=C1C1=CC=CC=C1 GPGKNEKFDGOXPO-UHFFFAOYSA-N 0.000 description 2
- WRIWBZLJIGBNSQ-RLICGFIPSA-N 5-hydroxy-2-(4-methoxyphenyl)-7-[(3R,4S,5S,6S)-3,4,5,6-tetrahydroxyoxan-2-yl]oxychromen-4-one Chemical compound C1=CC(OC)=CC=C1C(OC1=C2)=CC(=O)C1=C(O)C=C2OC1[C@H](O)[C@@H](O)[C@H](O)[C@@H](O)O1 WRIWBZLJIGBNSQ-RLICGFIPSA-N 0.000 description 2
- XJKJWTWGDGIQRH-BFIDDRIFSA-N Alginic acid Chemical compound O1[C@@H](C(O)=O)[C@@H](OC)[C@H](O)[C@H](O)[C@@H]1O[C@@H]1[C@@H](C(O)=O)O[C@@H](C)[C@@H](O)[C@H]1O XJKJWTWGDGIQRH-BFIDDRIFSA-N 0.000 description 2
- 239000005695 Ammonium acetate Substances 0.000 description 2
- 241000416162 Astragalus gummifer Species 0.000 description 2
- 206010060945 Bacterial infection Diseases 0.000 description 2
- 229960000686 Benzalkonium Chloride Drugs 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N Benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 102100004554 CAST Human genes 0.000 description 2
- 102100000129 CHURC1 Human genes 0.000 description 2
- 101710014631 CHURC1 Proteins 0.000 description 2
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L Calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 2
- 241000282472 Canis lupus familiaris Species 0.000 description 2
- 241000283707 Capra Species 0.000 description 2
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 2
- OSASVXMJTNOKOY-UHFFFAOYSA-N Chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 2
- 229960004926 Chlorobutanol Drugs 0.000 description 2
- 229920002261 Corn starch Polymers 0.000 description 2
- NKLCNNUWBJBICK-UHFFFAOYSA-N Dess–Martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 description 2
- VILAVOFMIJHSJA-UHFFFAOYSA-N Dicarbon monoxide Chemical compound [C]=C=O VILAVOFMIJHSJA-UHFFFAOYSA-N 0.000 description 2
- 239000001856 Ethyl cellulose Substances 0.000 description 2
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 2
- 241000282326 Felis catus Species 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 2
- FEWJPZIEWOKRBE-XIXRPRMCSA-N Mesotartaric acid Chemical compound OC(=O)[C@@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-XIXRPRMCSA-N 0.000 description 2
- NHQDETIJWKXCTC-UHFFFAOYSA-N Meta-Chloroperoxybenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- 241000283973 Oryctolagus cuniculus Species 0.000 description 2
- 241000283898 Ovis Species 0.000 description 2
- 229960002553 Phenylmercuric nitrate Drugs 0.000 description 2
- 239000004698 Polyethylene (PE) Substances 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- 125000005631 S-sulfonamido group Chemical group 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N Salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N Sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 2
- 235000021355 Stearic acid Nutrition 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 241000282898 Sus scrofa Species 0.000 description 2
- 229940033663 Thimerosal Drugs 0.000 description 2
- RTKIYNMVFMVABJ-UHFFFAOYSA-L Thiomersal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 2
- 230000036335 Tissue distribution Effects 0.000 description 2
- 229940116362 Tragacanth Drugs 0.000 description 2
- 229920001615 Tragacanth Polymers 0.000 description 2
- 241000251539 Vertebrata <Metazoa> Species 0.000 description 2
- 239000003070 absorption delaying agent Substances 0.000 description 2
- 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 2
- 239000012190 activator Substances 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- 235000010443 alginic acid Nutrition 0.000 description 2
- 229920000615 alginic acid Polymers 0.000 description 2
- 239000000783 alginic acid Substances 0.000 description 2
- 229960001126 alginic acid Drugs 0.000 description 2
- 125000004183 alkoxy alkyl group Chemical group 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 150000003862 amino acid derivatives Chemical class 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- USFZMSVCRYTOJT-UHFFFAOYSA-N ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 2
- 235000019257 ammonium acetate Nutrition 0.000 description 2
- 229940043376 ammonium acetate Drugs 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 230000000111 anti-oxidant Effects 0.000 description 2
- 108090001123 antibodies Proteins 0.000 description 2
- 102000004965 antibodies Human genes 0.000 description 2
- 239000003429 antifungal agent Substances 0.000 description 2
- 230000003078 antioxidant Effects 0.000 description 2
- 244000052616 bacterial pathogens Species 0.000 description 2
- 238000004166 bioassay Methods 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- 108010044208 calpastatin Proteins 0.000 description 2
- 125000002837 carbocyclic group Chemical group 0.000 description 2
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 2
- 125000002843 carboxylic acid group Chemical group 0.000 description 2
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 2
- 235000010980 cellulose Nutrition 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 125000003636 chemical group Chemical group 0.000 description 2
- 229910052681 coesite Inorganic materials 0.000 description 2
- 238000011109 contamination Methods 0.000 description 2
- 239000010949 copper Substances 0.000 description 2
- 239000008120 corn starch Substances 0.000 description 2
- 229940099112 cornstarch Drugs 0.000 description 2
- 229910052906 cristobalite Inorganic materials 0.000 description 2
- 125000000392 cycloalkenyl group Chemical group 0.000 description 2
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 2
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 229910052805 deuterium Inorganic materials 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- 239000002612 dispersion media Substances 0.000 description 2
- KCXVZYZYPLLWCC-UHFFFAOYSA-N edta Chemical group OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 125000004185 ester group Chemical group 0.000 description 2
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 2
- 235000019325 ethyl cellulose Nutrition 0.000 description 2
- 229920001249 ethyl cellulose Polymers 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 238000005755 formation reaction Methods 0.000 description 2
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 2
- 239000001530 fumaric acid Substances 0.000 description 2
- 235000011087 fumaric acid Nutrition 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- 150000004677 hydrates Chemical class 0.000 description 2
- 150000002430 hydrocarbons Chemical group 0.000 description 2
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 2
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 2
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 2
- 238000003384 imaging method Methods 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 200000000018 inflammatory disease Diseases 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- 239000007972 injectable composition Substances 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- MGFYSGNNHQQTJW-UHFFFAOYSA-N iodonium Chemical compound [IH2+] MGFYSGNNHQQTJW-UHFFFAOYSA-N 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 2
- 239000007951 isotonicity adjuster Substances 0.000 description 2
- 238000002372 labelling Methods 0.000 description 2
- ZEABYRLMGDTEAI-UHFFFAOYSA-M lithium;methanol;hydroxide Chemical compound [Li+].[OH-].OC ZEABYRLMGDTEAI-UHFFFAOYSA-M 0.000 description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 239000002207 metabolite Substances 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- BKBMACKZOSMMGT-UHFFFAOYSA-N methanol;toluene Chemical compound OC.CC1=CC=CC=C1 BKBMACKZOSMMGT-UHFFFAOYSA-N 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 2
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 2
- 229960002216 methylparaben Drugs 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 150000002829 nitrogen Chemical group 0.000 description 2
- PDTFCHSETJBPTR-UHFFFAOYSA-N nitrooxy(phenyl)mercury Chemical compound [O-][N+](=O)O[Hg]C1=CC=CC=C1 PDTFCHSETJBPTR-UHFFFAOYSA-N 0.000 description 2
- 239000006186 oral dosage form Substances 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 235000005985 organic acids Nutrition 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 230000001575 pathological Effects 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- 239000008363 phosphate buffer Substances 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 229910052698 phosphorus Inorganic materials 0.000 description 2
- 230000035790 physiological processes and functions Effects 0.000 description 2
- 229920001690 polydopamine Polymers 0.000 description 2
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 2
- 229920000053 polysorbate 80 Polymers 0.000 description 2
- 235000015320 potassium carbonate Nutrition 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Inorganic materials [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 2
- 230000001737 promoting Effects 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 235000013772 propylene glycol Nutrition 0.000 description 2
- 230000002633 protecting Effects 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- YZCKVEUIGOORGS-IGMARMGPSA-N protium Chemical compound [1H] YZCKVEUIGOORGS-IGMARMGPSA-N 0.000 description 2
- LCTONWCANYUPML-UHFFFAOYSA-N pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 description 2
- 229910052904 quartz Inorganic materials 0.000 description 2
- 230000002285 radioactive Effects 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 230000019491 signal transduction Effects 0.000 description 2
- 239000001187 sodium carbonate Substances 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 2
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 2
- BZKBCQXYZZXSCO-UHFFFAOYSA-N sodium hydride Inorganic materials [H-].[Na+] BZKBCQXYZZXSCO-UHFFFAOYSA-N 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 239000008117 stearic acid Substances 0.000 description 2
- 229910052682 stishovite Inorganic materials 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 235000000346 sugar Nutrition 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 239000000375 suspending agent Substances 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 235000012222 talc Nutrition 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- 235000002906 tartaric acid Nutrition 0.000 description 2
- 239000011975 tartaric acid Substances 0.000 description 2
- 229960001367 tartaric acid Drugs 0.000 description 2
- 229910052713 technetium Inorganic materials 0.000 description 2
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- IOGXOCVLYRDXLW-UHFFFAOYSA-N tert-butyl nitrite Chemical compound CC(C)(C)ON=O IOGXOCVLYRDXLW-UHFFFAOYSA-N 0.000 description 2
- 239000012414 tert-butyl nitrite Substances 0.000 description 2
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 2
- 150000003536 tetrazoles Chemical class 0.000 description 2
- 125000003396 thiol group Chemical group [H]S* 0.000 description 2
- 210000001519 tissues Anatomy 0.000 description 2
- 235000010487 tragacanth Nutrition 0.000 description 2
- 239000000196 tragacanth Substances 0.000 description 2
- 229910052905 tridymite Inorganic materials 0.000 description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 2
- 235000019798 tripotassium phosphate Nutrition 0.000 description 2
- 229910000404 tripotassium phosphate Inorganic materials 0.000 description 2
- 239000000080 wetting agent Substances 0.000 description 2
- NOOLISFMXDJSKH-UTLUCORTSA-N (+)-Neomenthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@@H]1O NOOLISFMXDJSKH-UTLUCORTSA-N 0.000 description 1
- AQFLVLHRZFLDDV-VIFPVBQESA-N (1S)-1-phenylpropan-1-amine Chemical compound CC[C@H](N)C1=CC=CC=C1 AQFLVLHRZFLDDV-VIFPVBQESA-N 0.000 description 1
- PMATZTZNYRCHOR-CGLBZJNRSA-N (3S,6S,9S,12R,15S,18S,21S,24S,30S,33S)-30-ethyl-33-[(E,1R,2R)-1-hydroxy-2-methylhex-4-enyl]-1,4,7,10,12,15,19,25,28-nonamethyl-6,9,18,24-tetrakis(2-methylpropyl)-3,21-di(propan-2-yl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotritriacontane-2,5,8,11,14,17 Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 description 1
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 description 1
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 description 1
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-Bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 1
- LBUJPTNKIBCYBY-UHFFFAOYSA-N 1,2,3,4-tetrahydroquinoline Chemical compound C1=CC=C2CCCNC2=C1 LBUJPTNKIBCYBY-UHFFFAOYSA-N 0.000 description 1
- FTNJQNQLEGKTGD-UHFFFAOYSA-N 1,3-Benzodioxole Chemical compound C1=CC=C2OCOC2=C1 FTNJQNQLEGKTGD-UHFFFAOYSA-N 0.000 description 1
- IGERFAHWSHDDHX-UHFFFAOYSA-N 1,3-dioxanyl Chemical group [CH]1OCCCO1 IGERFAHWSHDDHX-UHFFFAOYSA-N 0.000 description 1
- JPRPJUMQRZTTED-UHFFFAOYSA-N 1,3-dioxolanyl Chemical group [CH]1OCCO1 JPRPJUMQRZTTED-UHFFFAOYSA-N 0.000 description 1
- FLOJNXXFMHCMMR-UHFFFAOYSA-N 1,3-dithiolanyl Chemical group [CH]1SCCS1 FLOJNXXFMHCMMR-UHFFFAOYSA-N 0.000 description 1
- KFHQOZXAFUKFNB-UHFFFAOYSA-N 1,3-oxathiolanyl Chemical group [CH]1OCCS1 KFHQOZXAFUKFNB-UHFFFAOYSA-N 0.000 description 1
- VPVXHAANQNHFSF-UHFFFAOYSA-N 1,4-dioxan-2-one Chemical compound O=C1COCCO1 VPVXHAANQNHFSF-UHFFFAOYSA-N 0.000 description 1
- XIVUBGOYMBSEMA-UHFFFAOYSA-N 1,4-dioxane;methylsulfinylmethane Chemical compound CS(C)=O.C1COCCO1 XIVUBGOYMBSEMA-UHFFFAOYSA-N 0.000 description 1
- 125000005940 1,4-dioxanyl group Chemical group 0.000 description 1
- KPWQQJVVMNLBEI-UHFFFAOYSA-N 1-(3-methylphenyl)pyrazole-3-carboxylic acid Chemical compound CC1=CC=CC(N2N=C(C=C2)C(O)=O)=C1 KPWQQJVVMNLBEI-UHFFFAOYSA-N 0.000 description 1
- JLPULHDHAOZNQI-ZTIMHPMXSA-N 1-hexadecanoyl-2-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/C\C=C/CCCCC JLPULHDHAOZNQI-ZTIMHPMXSA-N 0.000 description 1
- GCSJOZFHZGHGTJ-UHFFFAOYSA-N 2-[2-[3,4-bis(2-hydroxyethoxy)oxolan-2-yl]-2-(2-hydroxyethoxy)ethoxy]ethyl formate Chemical compound O=COCCOCC(OCCO)C1OCC(OCCO)C1OCCO GCSJOZFHZGHGTJ-UHFFFAOYSA-N 0.000 description 1
- QOWAMIUFBNBINS-UHFFFAOYSA-N 2-[6-[4,5-diethoxy-2-(ethoxymethyl)-6-methoxyoxan-3-yl]oxy-4,5-dimethoxy-2-(methoxymethyl)oxan-3-yl]oxy-6-(hydroxymethyl)-5-methoxyoxane-3,4-diol Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(OC)C(OC)C(OC2C(C(O)C(OC)C(CO)O2)O)C(COC)O1 QOWAMIUFBNBINS-UHFFFAOYSA-N 0.000 description 1
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 1
- 125000001340 2-chloroethyl group Chemical group [H]C([H])(Cl)C([H])([H])* 0.000 description 1
- VVQNEPGJFQJSBK-UHFFFAOYSA-N 2-methyl-2-propenoic acid methyl ester Chemical compound COC(=O)C(C)=C VVQNEPGJFQJSBK-UHFFFAOYSA-N 0.000 description 1
- JAYYJZZOYTVNHH-UHFFFAOYSA-N 3-amino-2-hydroxy-4-phenylbutanamide Chemical compound NC(=O)C(O)C(N)CC1=CC=CC=C1 JAYYJZZOYTVNHH-UHFFFAOYSA-N 0.000 description 1
- 125000006201 3-phenylpropyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000005986 4-piperidonyl group Chemical group 0.000 description 1
- LVXOXXGCJHYEOS-UHFFFAOYSA-N 5-phenylpyrimidine Chemical compound C1=CC=CC=C1C1=CN=CN=C1 LVXOXXGCJHYEOS-UHFFFAOYSA-N 0.000 description 1
- HRZFUMHJMZEROT-UHFFFAOYSA-L 7681-57-4 Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
- 229940045942 ACETONE SODIUM BISULFITE Drugs 0.000 description 1
- 229960004308 ACETYLCYSTEINE Drugs 0.000 description 1
- 229940035676 ANALGESICS Drugs 0.000 description 1
- MWFMGBPGAXYFAR-UHFFFAOYSA-N Acetone cyanohydrin Chemical compound CC(C)(O)C#N MWFMGBPGAXYFAR-UHFFFAOYSA-N 0.000 description 1
- 241000251468 Actinopterygii Species 0.000 description 1
- 206010001584 Alcohol abuse Diseases 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 206010003441 Asbestosis Diseases 0.000 description 1
- 229960001230 Asparagine Drugs 0.000 description 1
- IAOZJIPTCAWIRG-QWRGUYRKSA-N Aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 description 1
- 229960003438 Aspartame Drugs 0.000 description 1
- 108010011485 Aspartame Proteins 0.000 description 1
- 229960005261 Aspartic Acid Drugs 0.000 description 1
- 206010003816 Autoimmune disease Diseases 0.000 description 1
- 229960002170 Azathioprine Drugs 0.000 description 1
- 229960001950 Benzethonium Chloride Drugs 0.000 description 1
- UREZNYTWGJKWBI-UHFFFAOYSA-M Benzethonium chloride Chemical compound [Cl-].C1=CC(C(C)(C)CC(C)(C)C)=CC=C1OCCOCC[N+](C)(C)CC1=CC=CC=C1 UREZNYTWGJKWBI-UHFFFAOYSA-M 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 229940043253 Butylated Hydroxyanisole Drugs 0.000 description 1
- 229940095259 Butylated Hydroxytoluene Drugs 0.000 description 1
- 239000004255 Butylated hydroxyanisole Substances 0.000 description 1
- CZBZUDVBLSSABA-UHFFFAOYSA-N Butylated hydroxyanisole Chemical compound COC1=CC=C(O)C(C(C)(C)C)=C1.COC1=CC=C(O)C=C1C(C)(C)C CZBZUDVBLSSABA-UHFFFAOYSA-N 0.000 description 1
- 239000004322 Butylated hydroxytoluene Substances 0.000 description 1
- NLZUEZXRPGMBCV-UHFFFAOYSA-N Butylhydroxytoluene Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 NLZUEZXRPGMBCV-UHFFFAOYSA-N 0.000 description 1
- 125000000041 C6-C10 aryl group Chemical group 0.000 description 1
- BHAROVLESINHSM-UHFFFAOYSA-N CC1=CC=CC=C1.CC1=CC=CC=C1 Chemical compound CC1=CC=CC=C1.CC1=CC=CC=C1 BHAROVLESINHSM-UHFFFAOYSA-N 0.000 description 1
- 102100005862 CCR2 Human genes 0.000 description 1
- 125000006414 CCl Chemical group ClC* 0.000 description 1
- 108060001122 CRTISO Proteins 0.000 description 1
- 229960005069 Calcium Drugs 0.000 description 1
- 229960003563 Calcium Carbonate Drugs 0.000 description 1
- 210000000845 Cartilage Anatomy 0.000 description 1
- 102000003952 Caspase 3 Human genes 0.000 description 1
- 108090000397 Caspase 3 Proteins 0.000 description 1
- 210000000170 Cell Membrane Anatomy 0.000 description 1
- 229920000623 Cellulose acetate phthalate Polymers 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- OPQARKPSCNTWTJ-UHFFFAOYSA-L Copper(II) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 description 1
- 229940013361 Cresol Drugs 0.000 description 1
- 229960001681 Croscarmellose Sodium Drugs 0.000 description 1
- 229920002785 Croscarmellose sodium Polymers 0.000 description 1
- 229960004397 Cyclophosphamide Drugs 0.000 description 1
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 1
- 229940119017 Cyclosporine Drugs 0.000 description 1
- 108010036949 Cyclosporine Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N D-Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- WHUUTDBJXJRKMK-GSVOUGTGSA-N D-glutamic acid Chemical compound OC(=O)[C@H](N)CCC(O)=O WHUUTDBJXJRKMK-GSVOUGTGSA-N 0.000 description 1
- MTCFGRXMJLQNBG-UWTATZPHSA-N D-serine Chemical compound OC[C@@H](N)C(O)=O MTCFGRXMJLQNBG-UWTATZPHSA-N 0.000 description 1
- QIVBCDIJIAJPQS-SECBINFHSA-N D-tryptophane Chemical compound C1=CC=C2C(C[C@@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-SECBINFHSA-N 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- 206010012601 Diabetes mellitus Diseases 0.000 description 1
- JXTHNDFMNIQAHM-UHFFFAOYSA-N Dichloroacetic acid Chemical compound OC(=O)C(Cl)Cl JXTHNDFMNIQAHM-UHFFFAOYSA-N 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N Diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 229960001484 Edetic Acid Drugs 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- 241001125671 Eretmochelys imbricata Species 0.000 description 1
- 229920003134 Eudragit® polymer Polymers 0.000 description 1
- 108010037362 Extracellular Matrix Proteins Proteins 0.000 description 1
- 102000010834 Extracellular Matrix Proteins Human genes 0.000 description 1
- 241000287828 Gallus gallus Species 0.000 description 1
- 210000001035 Gastrointestinal Tract Anatomy 0.000 description 1
- 229940065521 Glucocorticoid inhalants for obstructive airway disease Drugs 0.000 description 1
- 229960002989 Glutamic Acid Drugs 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 230000036499 Half live Effects 0.000 description 1
- 206010019641 Hepatic cirrhosis Diseases 0.000 description 1
- 241001272567 Hominoidea Species 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
- 229960004171 Hydroxychloroquine Drugs 0.000 description 1
- 206010020880 Hypertrophy Diseases 0.000 description 1
- 229960003444 IMMUNOSUPPRESSANTS Drugs 0.000 description 1
- 229960000310 ISOLEUCINE Drugs 0.000 description 1
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 1
- 210000000987 Immune System Anatomy 0.000 description 1
- PQNFLJBBNBOBRQ-UHFFFAOYSA-N Indane Chemical compound C1=CC=C2CCCC2=C1 PQNFLJBBNBOBRQ-UHFFFAOYSA-N 0.000 description 1
- 102000010781 Interleukin-6 Receptors Human genes 0.000 description 1
- 108010038501 Interleukin-6 Receptors Proteins 0.000 description 1
- SNHMUERNLJLMHN-UHFFFAOYSA-N Iodobenzene Chemical compound IC1=CC=CC=C1 SNHMUERNLJLMHN-UHFFFAOYSA-N 0.000 description 1
- JJWLVOIRVHMVIS-UHFFFAOYSA-N Isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
- PWKSKIMOESPYIA-BYPYZUCNSA-N L-N-acetyl-Cysteine Chemical compound CC(=O)N[C@@H](CS)C(O)=O PWKSKIMOESPYIA-BYPYZUCNSA-N 0.000 description 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 1
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- XUJNEKJLAYXESH-REOHCLBHSA-N L-cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 1
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-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
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 description 1
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 1
- 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 1
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 1
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 1
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 description 1
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 1
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 1
- 229960004873 LEVOMENTHOL Drugs 0.000 description 1
- 229940067606 Lecithin Drugs 0.000 description 1
- VHOGYURTWQBHIL-UHFFFAOYSA-N Leflunomide Chemical compound O1N=CC(C(=O)NC=2C=CC(=CC=2)C(F)(F)F)=C1C VHOGYURTWQBHIL-UHFFFAOYSA-N 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 108090000642 Lysophosphatidic Acid Receptors Proteins 0.000 description 1
- 102000004137 Lysophosphatidic Acid Receptors Human genes 0.000 description 1
- 229940014456 MYCOPHENOLATE Drugs 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N Mandelic acid Chemical compound OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 229940041616 Menthol Drugs 0.000 description 1
- 230000036650 Metabolic stability Effects 0.000 description 1
- 230000035633 Metabolized Effects 0.000 description 1
- GMPKIPWJBDOURN-UHFFFAOYSA-N Methoxyamine Chemical compound CON GMPKIPWJBDOURN-UHFFFAOYSA-N 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 210000002027 Muscle, Skeletal Anatomy 0.000 description 1
- 229960000951 Mycophenolic Acid Drugs 0.000 description 1
- CZFNISFYDPIDNM-UHFFFAOYSA-N N,N-dimethylformamide;oxolane Chemical compound CN(C)C=O.C1CCOC1 CZFNISFYDPIDNM-UHFFFAOYSA-N 0.000 description 1
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-Chlorosuccinimide Substances ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 1
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinylpyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 1
- 102000004722 NADPH Oxidases Human genes 0.000 description 1
- 108010002998 NADPH Oxidases Proteins 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 239000007832 Na2SO4 Substances 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 108010061543 Neutralizing Antibodies Proteins 0.000 description 1
- HYIMSNHJOBLJNT-UHFFFAOYSA-N Nifedipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1[N+]([O-])=O HYIMSNHJOBLJNT-UHFFFAOYSA-N 0.000 description 1
- 229960001597 Nifedipine Drugs 0.000 description 1
- 206010053159 Organ failure Diseases 0.000 description 1
- 229940100467 POLYVINYL ACETATE PHTHALATE Drugs 0.000 description 1
- 241000282579 Pan Species 0.000 description 1
- 210000000496 Pancreas Anatomy 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 102000003728 Peroxisome Proliferator-Activated Receptors Human genes 0.000 description 1
- 108090000029 Peroxisome Proliferator-Activated Receptors Proteins 0.000 description 1
- 229960005190 Phenylalanine Drugs 0.000 description 1
- HKOOXMFOFWEVGF-UHFFFAOYSA-N Phenylhydrazine Chemical compound NNC1=CC=CC=C1 HKOOXMFOFWEVGF-UHFFFAOYSA-N 0.000 description 1
- 102000030951 Phosphotransferases Human genes 0.000 description 1
- 108091000081 Phosphotransferases Proteins 0.000 description 1
- 229960003073 Pirfenidone Drugs 0.000 description 1
- 229920002413 Polyhexanide Polymers 0.000 description 1
- 229940068968 Polysorbate 80 Drugs 0.000 description 1
- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- UVSMNLNDYGZFPF-UHFFFAOYSA-N Pomalidomide Chemical compound O=C1C=2C(N)=CC=CC=2C(=O)N1C1CCC(=O)NC1=O UVSMNLNDYGZFPF-UHFFFAOYSA-N 0.000 description 1
- 229940069328 Povidone Drugs 0.000 description 1
- 241000288906 Primates Species 0.000 description 1
- 229960002429 Proline Drugs 0.000 description 1
- YORCIIVHUBAYBQ-UHFFFAOYSA-N Propargyl bromide Chemical compound BrCC#C YORCIIVHUBAYBQ-UHFFFAOYSA-N 0.000 description 1
- QELSKZZBTMNZEB-UHFFFAOYSA-N Propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 1
- 102000014961 Protein Precursors Human genes 0.000 description 1
- 108010078762 Protein Precursors Proteins 0.000 description 1
- 241000720974 Protium Species 0.000 description 1
- 229940107700 Pyruvic Acid Drugs 0.000 description 1
- 102000004215 Relaxin receptors Human genes 0.000 description 1
- 108090000728 Relaxin receptors Proteins 0.000 description 1
- 241000220010 Rhode Species 0.000 description 1
- XWGJFPHUCFXLBL-UHFFFAOYSA-M Rongalite Chemical compound [Na+].OCS([O-])=O XWGJFPHUCFXLBL-UHFFFAOYSA-M 0.000 description 1
- MNOALXGAYUJNKX-UHFFFAOYSA-N S-chloro chloromethanethioate Chemical compound ClSC(Cl)=O MNOALXGAYUJNKX-UHFFFAOYSA-N 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N Saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 229940081974 Saccharin Drugs 0.000 description 1
- 229920001800 Shellac Polymers 0.000 description 1
- 208000007056 Sickle Cell Anemia Diseases 0.000 description 1
- BNRNXUUZRGQAQC-UHFFFAOYSA-N Sildenafil Chemical compound CCCC1=NN(C)C(C(N2)=O)=C1N=C2C(C(=CC=1)OCC)=CC=1S(=O)(=O)N1CCN(C)CC1 BNRNXUUZRGQAQC-UHFFFAOYSA-N 0.000 description 1
- 229940005550 Sodium alginate Drugs 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M Sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L Sodium thiosulphate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 208000004190 Stiff Skin Syndrome Diseases 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N Sulfuryl chloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 229940037128 Systemic Glucocorticoids Drugs 0.000 description 1
- 206010042953 Systemic sclerosis Diseases 0.000 description 1
- 108009000039 TGF-beta Signaling Pathway Proteins 0.000 description 1
- 108091005711 TGF-beta receptors Proteins 0.000 description 1
- ZVQXQPNJHRNGID-UHFFFAOYSA-N Tetramethylsuccinonitrile Chemical compound N#CC(C)(C)C(C)(C)C#N ZVQXQPNJHRNGID-UHFFFAOYSA-N 0.000 description 1
- 229960003433 Thalidomide Drugs 0.000 description 1
- UEJJHQNACJXSKW-UHFFFAOYSA-N Thalidomide Chemical compound O=C1C2=CC=CC=C2C(=O)N1C1CCC(=O)NC1=O UEJJHQNACJXSKW-UHFFFAOYSA-N 0.000 description 1
- 235000002423 Theobroma angustifolium Nutrition 0.000 description 1
- 240000006474 Theobroma bicolor Species 0.000 description 1
- 235000002425 Theobroma bicolor Nutrition 0.000 description 1
- 235000002424 Theobroma grandiflorum Nutrition 0.000 description 1
- 235000002323 Theobroma simiarum Nutrition 0.000 description 1
- YUKQRDCYNOVPGJ-UHFFFAOYSA-N Thioacetamide Chemical compound CC(N)=S YUKQRDCYNOVPGJ-UHFFFAOYSA-N 0.000 description 1
- UMGDCJDMYOKAJW-UHFFFAOYSA-N Thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 1
- 239000004473 Threonine Substances 0.000 description 1
- 102000016715 Transforming Growth Factor beta Receptors Human genes 0.000 description 1
- GETTZEONDQJALK-UHFFFAOYSA-N Trifluorotoluene Chemical compound FC(F)(F)C1=CC=CC=C1 GETTZEONDQJALK-UHFFFAOYSA-N 0.000 description 1
- GETQZCLCWQTVFV-UHFFFAOYSA-N Trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 1
- 210000003462 Veins Anatomy 0.000 description 1
- JAVRSTADGYIZFV-UHFFFAOYSA-N [2-fluoro-3-(hydroxymethyl)phenyl]boronic acid Chemical compound OCC1=CC=CC(B(O)O)=C1F JAVRSTADGYIZFV-UHFFFAOYSA-N 0.000 description 1
- FIQIEWYXLLEXNR-UHFFFAOYSA-N [O-][N+](=O)S(=O)(=O)[N+]([O-])=O Chemical group [O-][N+](=O)S(=O)(=O)[N+]([O-])=O FIQIEWYXLLEXNR-UHFFFAOYSA-N 0.000 description 1
- DLFVBJFMPXGRIB-UHFFFAOYSA-N acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 1
- 239000008351 acetate buffer Substances 0.000 description 1
- AUALQMFGWLZREY-UHFFFAOYSA-N acetonitrile;methanol Chemical compound OC.CC#N AUALQMFGWLZREY-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 229960001138 acetylsalicylic acid Drugs 0.000 description 1
- 230000002378 acidificating Effects 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 125000000641 acridinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3C=C12)* 0.000 description 1
- 239000011149 active material Substances 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 description 1
- 230000002730 additional Effects 0.000 description 1
- 235000004279 alanine Nutrition 0.000 description 1
- 150000001294 alanine derivatives Chemical class 0.000 description 1
- 201000003082 alcohol use disease Diseases 0.000 description 1
- 230000001476 alcoholic Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 125000004450 alkenylene group Chemical group 0.000 description 1
- 125000004414 alkyl thio group Chemical group 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminum Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- WMGSQTMJHBYJMQ-UHFFFAOYSA-N aluminum;magnesium;silicate Chemical compound [Mg+2].[Al+3].[O-][Si]([O-])([O-])[O-] WMGSQTMJHBYJMQ-UHFFFAOYSA-N 0.000 description 1
- 150000001414 amino alcohols Chemical class 0.000 description 1
- 125000006620 amino-(C1-C6) alkyl group Chemical group 0.000 description 1
- 125000004103 aminoalkyl group Chemical group 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 230000000202 analgesic Effects 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000003042 antagnostic Effects 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 125000002178 anthracenyl group Chemical group C1(=CC=CC2=CC3=CC=CC=C3C=C12)* 0.000 description 1
- 230000003110 anti-inflammatory Effects 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 230000000692 anti-sense Effects 0.000 description 1
- 230000002622 anti-tumorigenesis Effects 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 1
- 238000007080 aromatic substitution reaction Methods 0.000 description 1
- 125000005418 aryl aryl group Chemical group 0.000 description 1
- 235000009582 asparagine Nutrition 0.000 description 1
- 239000000605 aspartame Substances 0.000 description 1
- 235000010357 aspartame Nutrition 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- 230000001363 autoimmune Effects 0.000 description 1
- 201000009596 autoimmune hypersensitivity disease Diseases 0.000 description 1
- LMEKQMALGUDUQG-UHFFFAOYSA-N azathioprine Chemical compound CN1C=NC([N+]([O-])=O)=C1SC1=NC=NC2=C1NC=N2 LMEKQMALGUDUQG-UHFFFAOYSA-N 0.000 description 1
- 125000002785 azepinyl group Chemical group 0.000 description 1
- 125000003828 azulenyl group Chemical group 0.000 description 1
- 230000003385 bacteriostatic Effects 0.000 description 1
- 238000010945 base-catalyzed hydrolysis reactiony Methods 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 102000006635 beta-Lactamases Human genes 0.000 description 1
- 108020004256 beta-Lactamases Proteins 0.000 description 1
- 150000001576 beta-amino acids Chemical class 0.000 description 1
- 201000002393 blood protein disease Diseases 0.000 description 1
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 235000019282 butylated hydroxyanisole Nutrition 0.000 description 1
- 235000010354 butylated hydroxytoluene Nutrition 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 239000003537 cannabinoid receptor agonist Substances 0.000 description 1
- 229940121376 cannabinoid receptor agonists Drugs 0.000 description 1
- 239000007963 capsule composition Substances 0.000 description 1
- 125000000609 carbazolyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3NC12)* 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 150000001722 carbon compounds Chemical class 0.000 description 1
- 150000001728 carbonyl compounds Chemical class 0.000 description 1
- 229920003090 carboxymethyl hydroxyethyl cellulose Polymers 0.000 description 1
- 230000024881 catalytic activity Effects 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000033077 cellular process Effects 0.000 description 1
- 229940081734 cellulose acetate phthalate Drugs 0.000 description 1
- 229910052729 chemical element Inorganic materials 0.000 description 1
- 239000007910 chewable tablet Substances 0.000 description 1
- 238000010568 chiral column chromatography Methods 0.000 description 1
- 229960001265 ciclosporin 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
- 239000007979 citrate buffer Substances 0.000 description 1
- 238000005037 combinatorial chemistry Methods 0.000 description 1
- 230000002860 competitive Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 235000005687 corn oil Nutrition 0.000 description 1
- 239000002285 corn oil Substances 0.000 description 1
- 239000006184 cosolvent Substances 0.000 description 1
- 235000012343 cottonseed oil Nutrition 0.000 description 1
- 239000002385 cottonseed oil Substances 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 150000001896 cresols Chemical class 0.000 description 1
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 1
- 125000001651 cyanato group Chemical group [*]OC#N 0.000 description 1
- 125000004850 cyclobutylmethyl group Chemical group C1(CCC1)C* 0.000 description 1
- 125000006622 cycloheptylmethyl group Chemical group 0.000 description 1
- 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000004851 cyclopentylmethyl group Chemical group C1(CCCC1)C* 0.000 description 1
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 description 1
- 235000018417 cysteine Nutrition 0.000 description 1
- 230000002354 daily Effects 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 231100000517 death Toxicity 0.000 description 1
- 230000001419 dependent Effects 0.000 description 1
- 230000000779 depleting Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 230000001627 detrimental Effects 0.000 description 1
- OKKJLVBELUTLKV-VMNATFBRSA-N deuteriooxymethane Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 1
- 229960005215 dichloroacetic acid Drugs 0.000 description 1
- FHHZOYXKOICLGH-UHFFFAOYSA-N dichloromethane;ethanol Chemical compound CCO.ClCCl FHHZOYXKOICLGH-UHFFFAOYSA-N 0.000 description 1
- SYZWSSNHPZXGML-UHFFFAOYSA-N dichloromethane;oxolane Chemical compound ClCCl.C1CCOC1 SYZWSSNHPZXGML-UHFFFAOYSA-N 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- STRNXFOUBFLVIN-UHFFFAOYSA-N diethyl but-2-ynedioate Chemical compound CCOC(=O)C#CC(=O)OCC STRNXFOUBFLVIN-UHFFFAOYSA-N 0.000 description 1
- 125000000723 dihydrobenzofuranyl group Chemical group O1C(CC2=C1C=CC=C2)* 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- 125000005879 dioxolanyl group Chemical group 0.000 description 1
- 229940042397 direct acting antivirals Cyclic amines Drugs 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 238000009510 drug design Methods 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 239000003974 emollient agent Substances 0.000 description 1
- 239000002308 endothelin receptor antagonist Substances 0.000 description 1
- 230000029578 entry into host Effects 0.000 description 1
- BRLQWZUYTZBJKN-UHFFFAOYSA-N epichlorohydrin Chemical compound ClCC1CO1 BRLQWZUYTZBJKN-UHFFFAOYSA-N 0.000 description 1
- 210000002919 epithelial cells Anatomy 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-N ethanesulfonic acid Chemical compound CCS(O)(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-N 0.000 description 1
- ZRSDQBKGDNPFLT-UHFFFAOYSA-N ethanol;oxolane Chemical compound CCO.C1CCOC1 ZRSDQBKGDNPFLT-UHFFFAOYSA-N 0.000 description 1
- HZAXFHJVJLSVMW-UHFFFAOYSA-N ethanolamine Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 1
- HZNQVAOLVRFZBE-UHFFFAOYSA-N ethenylcyclohexane Chemical group C=C[C]1CCCCC1 HZNQVAOLVRFZBE-UHFFFAOYSA-N 0.000 description 1
- 238000006266 etherification reaction Methods 0.000 description 1
- LIIIIFGKOFQGDN-UHFFFAOYSA-N ethyl 2-(5-oxocyclohexa-1,3-dien-1-yl)propanoate Chemical compound CCOC(=O)C(C)C1=CC=CC(=O)C1 LIIIIFGKOFQGDN-UHFFFAOYSA-N 0.000 description 1
- 229960004667 ethyl cellulose Drugs 0.000 description 1
- 235000010944 ethyl methyl cellulose Nutrition 0.000 description 1
- 239000001761 ethyl methyl cellulose Substances 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 102000036690 extracellular matrix enzymes Human genes 0.000 description 1
- 108091007011 extracellular matrix enzymes Proteins 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 239000011888 foil Substances 0.000 description 1
- ISXSFOPKZQZDAO-UHFFFAOYSA-N formaldehyde;sodium Chemical compound [Na].O=C ISXSFOPKZQZDAO-UHFFFAOYSA-N 0.000 description 1
- 239000008369 fruit flavor Substances 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N fumaric acid Chemical compound OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 230000001408 fungistatic Effects 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 230000002068 genetic Effects 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000003862 glucocorticoid Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 150000004676 glycans Polymers 0.000 description 1
- 150000002332 glycine derivatives Chemical class 0.000 description 1
- 239000003966 growth inhibitor Substances 0.000 description 1
- 125000004475 heteroaralkyl group Chemical group 0.000 description 1
- 125000004446 heteroarylalkyl group Chemical group 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 101710028323 hisS Proteins 0.000 description 1
- 150000002429 hydrazines Chemical class 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 229920003132 hydroxypropyl methylcellulose phthalate Polymers 0.000 description 1
- 229940031704 hydroxypropyl methylcellulose phthalate Drugs 0.000 description 1
- 229960001680 ibuprofen Drugs 0.000 description 1
- 125000002632 imidazolidinyl group Chemical group 0.000 description 1
- 125000002636 imidazolinyl group Chemical group 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 230000001861 immunosuppresant Effects 0.000 description 1
- 239000003018 immunosuppressive agent 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
- 125000001041 indolyl group Chemical group 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 102000006495 integrins Human genes 0.000 description 1
- 108010044426 integrins Proteins 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 238000007917 intracranial administration Methods 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 230000000302 ischemic Effects 0.000 description 1
- 125000001261 isocyanato group Chemical group *N=C=O 0.000 description 1
- BMYJKRSSTXJRLI-UHFFFAOYSA-N isocyanomethylsulfonylmethylbenzene Chemical compound [C-]#[N+]CS(=O)(=O)CC1=CC=CC=C1 BMYJKRSSTXJRLI-UHFFFAOYSA-N 0.000 description 1
- 125000004594 isoindolinyl group Chemical group C1(NCC2=CC=CC=C12)* 0.000 description 1
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 description 1
- FZWBNHMXJMCXLU-BLAUPYHCSA-N isomaltotriose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O)O1 FZWBNHMXJMCXLU-BLAUPYHCSA-N 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 125000001810 isothiocyanato group Chemical group *N=C=S 0.000 description 1
- 230000000155 isotopic Effects 0.000 description 1
- 125000003965 isoxazolidinyl group Chemical group 0.000 description 1
- 125000003971 isoxazolinyl group Chemical group 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 229960000681 leflunomide Drugs 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 239000006193 liquid solution Substances 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium;hydroxide;hydrate Chemical compound [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 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
- 239000011976 maleic acid Substances 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- PWHULOQIROXLJO-UHFFFAOYSA-N manganese Chemical compound [Mn] PWHULOQIROXLJO-UHFFFAOYSA-N 0.000 description 1
- 229910052748 manganese Inorganic materials 0.000 description 1
- 239000011572 manganese Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 1
- GRWIABMEEKERFV-UHFFFAOYSA-N methanol;oxolane Chemical compound OC.C1CCOC1 GRWIABMEEKERFV-UHFFFAOYSA-N 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 230000003278 mimic Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 125000002757 morpholinyl group Chemical group 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
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000001326 naphthylalkyl group Chemical group 0.000 description 1
- 239000005445 natural product Substances 0.000 description 1
- 229930014626 natural products Natural products 0.000 description 1
- 230000002988 nephrogenic Effects 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 125000006574 non-aromatic ring group Chemical group 0.000 description 1
- 230000000269 nucleophilic Effects 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 239000002997 ophthalmic solution Substances 0.000 description 1
- 238000006053 organic reaction Methods 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 125000000160 oxazolidinyl group Chemical group 0.000 description 1
- 125000005968 oxazolinyl group Chemical group 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 125000003551 oxepanyl group Chemical group 0.000 description 1
- 230000001590 oxidative Effects 0.000 description 1
- 125000000466 oxiranyl group Chemical group 0.000 description 1
- LVSJDHGRKAEGLX-UHFFFAOYSA-N oxolane;2,2,2-trifluoroacetic acid Chemical compound C1CCOC1.OC(=O)C(F)(F)F LVSJDHGRKAEGLX-UHFFFAOYSA-N 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 239000003961 penetration enhancing agent Substances 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000007967 peppermint flavor Substances 0.000 description 1
- 230000000737 periodic Effects 0.000 description 1
- 229960003742 phenol Drugs 0.000 description 1
- 150000002993 phenylalanine derivatives Chemical class 0.000 description 1
- 125000000286 phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- 229940067157 phenylhydrazine Drugs 0.000 description 1
- ABLZXFCXXLZCGV-UHFFFAOYSA-N phosphorous acid Chemical compound OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 description 1
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 1
- 125000005633 phthalidyl group Chemical group 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- ISWRGOKTTBVCFA-UHFFFAOYSA-N pirfenidone Chemical compound C1=C(C)C=CC(=O)N1C1=CC=CC=C1 ISWRGOKTTBVCFA-UHFFFAOYSA-N 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 230000004983 pleiotropic Effects 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
- 229920001308 poly(aminoacid) Polymers 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 229920000023 polynucleotide Polymers 0.000 description 1
- 239000002157 polynucleotide Substances 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 150000004804 polysaccharides Polymers 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 235000019422 polyvinyl alcohol Nutrition 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229960000688 pomalidomide Drugs 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- OZAIFHULBGXAKX-UHFFFAOYSA-N precursor Substances N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 150000003147 proline derivatives Chemical class 0.000 description 1
- 125000001325 propanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- 229960003415 propylparaben Drugs 0.000 description 1
- 150000003815 prostacyclins Chemical class 0.000 description 1
- 230000001681 protective Effects 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 1
- 125000002755 pyrazolinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- QIEQDFYXVYQLLU-UHFFFAOYSA-N pyrimidin-4-ylhydrazine Chemical compound NNC1=CC=NC=N1 QIEQDFYXVYQLLU-UHFFFAOYSA-N 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000004929 pyrrolidonyl group Chemical group N1(C(CCC1)=O)* 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 150000004728 pyruvic acid derivatives Chemical class 0.000 description 1
- SMWDFEZZVXVKRB-UHFFFAOYSA-N quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 239000000018 receptor agonist Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000001172 regenerating Effects 0.000 description 1
- 239000011369 resultant mixture Substances 0.000 description 1
- 239000011435 rock Substances 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 238000007127 saponification reaction Methods 0.000 description 1
- 201000000306 sarcoidosis Diseases 0.000 description 1
- 231100000241 scar Toxicity 0.000 description 1
- 230000002784 sclerotic Effects 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 125000000467 secondary amino group Chemical group [H]N([*:1])[*:2] 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- 231100000486 side effect Toxicity 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 229960003310 sildenafil Drugs 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- MSXHSNHNTORCAW-UHFFFAOYSA-M sodium 3,4,5,6-tetrahydroxyoxane-2-carboxylate Chemical compound [Na+].OC1OC(C([O-])=O)C(O)C(O)C1O MSXHSNHNTORCAW-UHFFFAOYSA-M 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 239000007974 sodium acetate buffer Substances 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- 229940001607 sodium bisulfite Drugs 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 229940001584 sodium metabisulfite Drugs 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 235000011008 sodium phosphates Nutrition 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 229940001474 sodium thiosulfate Drugs 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- AIWXQURDQHMMDO-UHFFFAOYSA-M sodium;hydrogen sulfite;propan-2-one Chemical compound [Na+].CC(C)=O.OS([O-])=O AIWXQURDQHMMDO-UHFFFAOYSA-M 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 210000000130 stem cell Anatomy 0.000 description 1
- 230000000707 stereoselective Effects 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 235000011044 succinic acid Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 1
- 230000000153 supplemental Effects 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000007916 tablet composition Substances 0.000 description 1
- GKLVYJBZJHMRIY-UHFFFAOYSA-N technetium Chemical compound [Tc] GKLVYJBZJHMRIY-UHFFFAOYSA-N 0.000 description 1
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000003507 tetrahydrothiofenyl group Chemical group 0.000 description 1
- 125000004632 tetrahydrothiopyranyl group Chemical group S1C(CCCC1)* 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 125000002769 thiazolinyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000001583 thiepanyl group Chemical group 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 125000000858 thiocyanato group Chemical group *SC#N 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 230000036962 time dependent Effects 0.000 description 1
- 230000000451 tissue damage Effects 0.000 description 1
- 231100000827 tissue damage Toxicity 0.000 description 1
- 108020000411 toll-like receptors Proteins 0.000 description 1
- 102000002689 toll-like receptors Human genes 0.000 description 1
- 239000012049 topical pharmaceutical composition Substances 0.000 description 1
- 230000002588 toxic Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 125000002306 tributylsilyl group Chemical group C(CCC)[Si](CCCC)(CCCC)* 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 239000002750 tryptase inhibitor Substances 0.000 description 1
- 201000008827 tuberculosis Diseases 0.000 description 1
- 230000029069 type 2 immune response Effects 0.000 description 1
- 150000003667 tyrosine derivatives Chemical class 0.000 description 1
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 1
- 229940121358 tyrosine kinase inhibitors Drugs 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- 230000000261 vasodilator Effects 0.000 description 1
- 239000003071 vasodilator agent Substances 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 230000003612 virological Effects 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
- A61K31/4155—1,2-Diazoles non condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/42—Oxazoles
- A61K31/422—Oxazoles 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/426—1,3-Thiazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/427—Thiazoles 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/433—Thidiazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/02—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
- C07C233/04—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with carbon atoms of carboxamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
- C07C233/05—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with carbon atoms of carboxamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D209/20—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals substituted additionally by nitrogen atoms, e.g. tryptophane
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/18—Benzimidazoles; Hydrogenated benzimidazoles with aryl radicals directly attached in position 2
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/04—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
- C07D249/06—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles with aryl radicals directly attached to ring atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
- C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
- C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
- C07D261/10—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D261/18—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
- C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
- C07D271/04—1,2,3-Oxadiazoles; Hydrogenated 1,2,3-oxadiazoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
- C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
- C07D271/08—1,2,5-Oxadiazoles; Hydrogenated 1,2,5-oxadiazoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D275/00—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings
- C07D275/02—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings not condensed with other rings
- C07D275/03—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings not condensed with other rings with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
- C07D285/01—Five-membered rings
- C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
- C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
- C07D285/06—1,2,3-Thiadiazoles; Hydrogenated 1,2,3-thiadiazoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
- C07D285/01—Five-membered rings
- C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
- C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
- C07D285/10—1,2,5-Thiadiazoles; Hydrogenated 1,2,5-thiadiazoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
- C07D307/84—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D319/04—1,3-Dioxanes; Hydrogenated 1,3-dioxanes
- C07D319/08—1,3-Dioxanes; Hydrogenated 1,3-dioxanes condensed with carbocyclic rings or ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Abstract
Disclosed herein are small molecule calpain modulator compositions, pharmaceutical compositions, the use and preparation thereof.
Description
BLADT.004WO PATENT
CALPAIN MODULATORS AND THERAPEUTIC USES THEREOF
BACKGROUND
Field of the Invention
The present invention relates to the fields of chemistry and medicine. More
particularly, the present invention relates to non-macrocyclic α-keto amide compounds as small
molecule calpain modulators, compositions, their preparation, and their use as therapeutic agents.
Description of the Related Art
Fibrotic disease accounts for an estimated 45% of deaths in the developed
world but the development of therapies for such diseases is still in its infancy. The current
treatments for fibrotic diseases, such as for idiopathic lung fibrosis, renal fibrosis, systemic
sclerosis, and liver cirrhosis, are few in number and only alleviate some of the symptoms of
fibrosis while failing to treat the underlying cause.
Despite the current limited understanding of the diverse etiologies responsible
for these conditions, similarities in the phenotype of the affected organs, across fibrotic diseases,
strongly support the existence of common pathogenic pathways. At present, it is recognized that
a primary driver of fibrotic disease is a high transforming growth factor-beta (TGFβ) signaling
pathway which can promote the transformation of normally functioning cells into fibrosis-
promoting cells. Termed "myofibroblasts," these transformed cells can secrete large amounts of
extracellular matrix proteins and matrix degrading enzymes, resulting in the formation of scar
tissue and eventual organ failure. This cellular process is transformative and termed
"myofibroblast differentiation" (which includes Epithelial-to-Mesenchymal Transition (EpMT)
and its variations like Endothelial-to-Mesenchymal Transition (EnMT) and Fibroblast-to-
Myofibroblast Transition (FMT)). This process is a major target for the treatment of fibrotic
diseases. Myofibroblast differentiation has also been shown to occur within cancer cells that
have been chronically exposed to high TGFβ, causing stationary epithelial cells to become
motile, invasive, and metastasize. Thus, within the context of cancer, the signaling has been
documented to associate with the acquisition of drug resistance, immune system evasion, and
development of stem cell properties.
17681897_1 (GHMatters) P110989.NZ
Despite the tremendous potential of myofibroblast differentiation-inhibiting
drugs, and the numerous attempts to develop a working treatment, the data gathered thus far has
yet to translate into practical therapy. This is partly due to the lack of an ideal target protein.
Initial strategies to target the myofibroblast differentiation process focused on proximal
inhibition of the TGFβ signaling pathway by various methods, including targeting ligand
activators (e.g. alpha-v integrins), ligand-receptor interactions (e.g., using neutralizing
antibodies) or TGFβ receptor kinase activity (e.g., small molecule chemical compound drugs to
block signal transduction). Unfortunately, TGFβ is a pleiotropic cytokine with many
physiological functions such that global suppression of TGFβ signaling was also associated with
severe side effects. Additionally, current data suggests that such proximal inhibition may be
vulnerable to pathologic workaround strategies (i.e., due to redundancy or compensation), that
would limit the utility of such drugs. Further complicating matters is that, in cancer,
TGFβ signaling early on functions as an anti-tumorigenic growth inhibitor but later becomes
tumor promoting and is another reason why selective inhibition of pathogenic elements of
signaling is so strongly desired. In light of these inherent limitations, current treatment strategies
have refocused on identification and inhibition of critical distal events in TGFβ signaling, which
in theory would preferentially target the pathologic, but not physiological functions of TGFβ
signaling.
Summary
A compound having the structure of the formula I:
or a pharmaceutically acceptable salt thereof, wherein:
17681897_1 (GHMatters) P110989.NZ
A is selected from the group consisting of optionally substituted 5-10 membered heterocyclyl
provided the 5-10 membered heterocyclyl is not substituted with oxo, optionally substituted 5-,
8-, or 9- membered heteroaryl, and optionally substituted C carbocyclyl;
3-10
A is selected from the group consisting of optionally substituted 3-10 membered heterocyclyl,
optionally substituted C aryl, optionally substituted 5-10 membered heteroaryl, and optionally
6-10
substituted C carbocyclyl, -CR -, -S-, -S(=O)-, -SO -, -O-, -C(=S)-, -C(=O)-, -NR-, -CH=CH-,
3-10 2 2
-C≡C-, -OC(O)NH-, -NHC(O)NH-, -NHC(O)O-, -NHC(O)-, -NHC(S)NH-, -NHC(S)O-, -
NHC(S)-, and single bond;
A is selected from the group consisting of optionally substituted C aryl, optionally substituted
4 6-10
-10 membered heteroaryl, optionally substituted 3-10 membered heterocyclyl, optionally
substituted C carbocyclyl, optionally substituted C - alkyl, -(CR ) -S-(CR ) -, -(CR ) -S(=O)-
3-10 1 4 2 n 2 n 2 n
(CR ) -, -(CR ) -SO -(CR ) -, -(CR ) O-(CR ) -, -(CR ) -C(=S)-(CR ) -, -(CR ) -C(=O)-
2 n 2 n 2 2 n 2 n- 2 n 2 n 2 n 2 n
(CR ) -, -(CR ) -NR-(CR ) -, -(CR ) -CH=CH-(CR ) -, -(CR ) -OC(O)NH-(CR ) -, -(CR ) -
2 n 2 n 2 n 2 n 2 n 2 n 2 n 2 n
NHC(O)NH-(CR ) -, -(CR ) -NHC(O)O-(CR ) -, -(CR ) -NHC(O)-(CR ) -, -(CR ) -
2 n 2 n 2 n 2 n 2 n 2 n
NHC(S)NH-(CR ) -, -(CR ) -NHC(S)O-(CR ) -, -(CR ) -NHC(S)-(CR ) -, and single bond;
2 n 2 n 2 n 2 n 2 n
when A and A are single bond, A is directly attached to A ;
2 4 3 8
A is selected from the group consisting of optionally substituted C aryl, optionally substituted
3 6-10
-10 membered heteroaryl, optionally substituted 3-10 membered heterocyclyl, and optionally
substituted C carbocyclyl, or if A is selected from optionally substituted 3-10 membered
3-10 2
heterocyclyl, optionally substituted C aryl, optionally substituted 5-10 membered heteroaryl,
6-10
and optionally substituted C carbocyclyl, then A is selected from the group consisting of
3-10 3
hydrogen, optionally substituted C aryl, optionally substituted 5-10 membered heteroaryl,
6-10
optionally substituted 3-10 membered heterocyclyl, optionally substituted C carbocyclyl,-
3-10
C≡CH, and optionally substituted 2- to 5-membered polyethylene glycol;
A is selected from the group consisting of optionally substituted 3-10 membered heterocyclyl,
optionally substituted C aryl, optionally substituted 5-10 membered heteroaryl, optionally
6-10
substituted C carbocyclyl, optionally substituted C alkyl, -S-, -S(=O)-, -SO -, -O-, -C(=S)-, -
3-10 1-8 2
C(=O)-, -NR-, -CH=CH-, -OC(O)NH-, -NHC(O)NH-, -NHC(O)O-, -NHC(O)-, -NHC(S)NH-, -
NHC(S)O-, -NHC(S)-, and single bond;
17681897_1 (GHMatters) P110989.NZ
A is selected from the group consisting of optionally substituted C aryl, optionally substituted
6 6-10
-10 membered heteroaryl, optionally substituted 3-10 membered heterocyclyl, and optionally
substituted C carbocyclyl, optionally substituted C alkyl, optionally substituted C alkenyl,
3-10 1-8 2-8
optionally substituted –O-C alkyl, optionally substituted –O C alkenyl, -OSO CF , and any
1-6 2-6 2 3
natural or non-natural amino acid side chain;
A is selected from the group consisting of optionally substituted C aryl, optionally substituted
7 6-10
-10 membered heteroaryl, optionally substituted 3-10 membered heterocyclyl, optionally
substituted C carbocyclyl, optionally substituted C - alkyl, -S-, S(=O)-, -SO -, -O-, -C(=S)-, -
3-10 1 8 2
C(=O)-, -NR-, -CH=CH-, -OC(O)NH-, -NHC(O)NH-, -NHC(O)O-, -NHC(O)-, -NHC(S)NH-, -
NHC(S)O-, -NHC(S)-, and single bond;
when A and A are single bond, A is directly attached to the carbon to which R is attached;
7 6
A is a ring member of A and selected from the group consisting of C, CH, and N;
R is selected from the group consisting of -COR , -CN, -CH=CHSO R, and -CH NO ;
2 2 2
R is selected from the group consisting of H, -OH, C haloalkyl, -COOH, -CH NO -
1-4 2 2,
2 3 2 3
C(=O)NOR, -NH , -CONR R , -CH(CH )=CH , -CH(CF )NR R ,
2 3 2 3
-C(F)=CHCH CH , , , , , ,
R N N
O O H
, , , , , ,
, , and ;
R is halo;
each R, R , and R are independently selected from –H, optionally substituted
C - alkyl, optionally substituted C - alkoxyalkyl, optionally substituted 2- to 5-membered
1 4 1 8
polyethylene glycol, optionally substituted C carbocyclyl, optionally substituted 5-10
17681897_1 (GHMatters) P110989.NZ
membered heterocyclyl, optionally substituted C aryl, and optionally substituted 5-10
6-10
membered heteroaryl; and
R is independently selected from –H and optionally substituted C - alkyl.
[0005a] In one aspect, the present invention provides a compound having the structure
selected from the formulas:
A A A A
X 2 Y
Z X Z
2 Z 6
I-e I-f
X Y Y X
I-g I-h
or a pharmaceutically acceptable salt thereof, wherein:
A is a single bond;
17681897_1 (GHMatters) P110989.NZ
A is -CH - or a single bond;
when A is single bond, A is directly attached to the ring-atom to which A is attached;
4 3 2
A is selected from the group consisting of optionally substituted C aryl, optionally
3 6-10
substituted 5-10 membered heteroaryl, optionally substituted 3-10 membered heterocyclyl, and
optionally substituted C carbocyclyl;
3-10
A is C alkyl;
1-4
A is selected from the group consisting of C aryl, 5-10 membered heteroaryl, C
6 6-10 1-4
alkyl, and C alkenyl, each optionally substituted with one or more halo, hydroxyl, C alkyl,
2-4 1-4
O–C alkyl , or O–C alkenyl;
1-6 2-6
A is single bond;
1 2 3
R is selected from the group consisting of H and -CONR R ,
each R and R are independently selected from –H, optionally substituted C - alkyl, 2-
to 5-membered polyethylene glycol, C carbocyclyl, optionally substituted C aryl(C -
3-7 6-10 1
C )alkyl, and 5-10 membered heteroaryl;
R is –H; and
X and Z are each independently selected from the group consisting of C(R )and N; and
each R is independently selected from the group consisting of –H, C alkyl, C
1-4 1-2
haloalkyl, C carbocyclyl, halo, hydroxy, and C -C alkoxy;
3-7 1 3
Y is selected from the group consisting of O, S, and SO ;
wherein an optionally substituted group can be substituted, unless otherwise specified,
with one or more subsitutents independently selected from C -C alkyl, C -C carbocyclyl, 5-10
1 6 3 7
membered heterocyclyl, aryl (optionally substituted with halo and C -C alkyl), 5-10 membered
heteroaryl (optionally substituted with halo, C -C alkyl, and C -C haloalkyl), halo, cyano,
1 6 1 6
hydroxy, C -C alkoxy, C -C alkoxy(C -C )alkyl (i.e., ether), aryloxy, halo(C -C )alkyl (e.g., –
1 6 1 6 1 6 1 6
CF3), halo(C1-C6)alkoxy (e.g., –OCF3), amino, amino(C1-C6)alkyl, C-amido, N-amido, N-
sulfonamido, and sulfonyl.
[0005b] In another aspect, the present invention provides a pharmaceutical composition
comprising: a pharmaceutically acceptable excipient; and an effective amount of at least one
compound as defined herein.
17681897_1 (GHMatters) P110989.NZ
[0005c] In another aspect, the present invention provides a use of a compound as defined
herein, or a pharmaceutical composition as defined herein, in the manufacture of a medicament
for treating fibrotic disease or a secondary disease state or condition thereof, wherein the disease
is selected from the group consisting of liver fibrosis, renal fibrosis, lung fibrosis,
hypersensitivity pneumonitis, interstitial fibrosis, systemic scleroderma, macular degeneration,
pancreatic fibrosis, fibrosis of the spleen, cardiac fibrosis, mediastinal fibrosis, myelofibrosis,
endomyocardial fibrosis, retroperitoneal fibrosis, progressive massive fibrosis, nephrogenic
systemic fibrosis, fibrotic complications of surgery, chronic allograft vasculopathy and/or chronic
rejection in transplanted organs, ischemic-reperfusion injury associated fibrosis, injection
fibrosis, cirrhosis, diffuse parenchymal lung disease, post-vasectomy pain syndrome, and
rheumatoid arthritis.
Other embodiments disclosed herein include a pharmaceutical composition
comprising a therapeutically effective amount of a compound disclosed herein and a
pharmaceutically acceptable excipient.
Other embodiments disclosed herein include a method of treating diseases and
conditions mediated at least in part by the physiologic effects of CAPN1, CAPN2, or CAP9, or
combinations thereof, comprising administering to a subject in need thereof a compound
disclosed herein.
In some embodiments, compounds disclosed herein are specific inhibitors of
one of: CAPN1, CAPN2 or CAPN9.
In some embodiments, compounds disclosed herein are selective inhibitors of
one of: CAPN1, CAPN2 or CAPN9.
In some embodiments, compounds disclosed herein are selective inhibitors of:
CAPN1 and CAPN2, or CAPN1 and CAPN9, or CAPN2 and CAPN9.
In some embodiments, compounds disclosed herein are effective inhibitors of
CAPN1, CAPN2 and/or CAPN9.
In some embodiments, the non-macrocyclic α-keto amide compounds disclosed
herein are broadly effective in treating a host of conditions arising from fibrosis or inflammation,
and specifically including those associated with myofibroblast differentiation. Accordingly,
compounds disclosed herein are active therapeutics for a diverse set of diseases or disorders that
17681897_1 (GHMatters) P110989.NZ
include or that produces a symptom which include, but are not limited to: liver fibrosis, renal
fibrosis, lung fibrosis, hypersensitivity pneumonitis, interstitial fibrosis, systemic scleroderma,
macular degeneration, pancreatic fibrosis, fibrosis of the spleen, cardiac fibrosis, mediastinal
fibrosis, myelofibrosis, endomyocardial fibrosis, retroperitoneal fibrosis, progressive massive
fibrosis, nephrogenic systemic fibrosis, fibrotic complications of surgery, chronic allograft
vasculopathy and/or chronic rejection in transplanted organs, ischemic-reperfusion injury
associated fibrosis, injection fibrosis, cirrhosis, diffuse parenchymal lung disease, post-
vasectomy pain syndrome, and rheumatoid arthritis diseases or disorders. In other embodiments,
the compounds disclosed herein can be used can be used in metabolic and reaction kinetic
studies, detection and imaging techniques and radioactive treatments.
In some embodiments, the compounds disclosed herein are used to treat
diseases or conditions or that produces a symptom in a subject which include, but not limited to:
liver fibrosis, renal fibrosis, lung fibrosis, hypersensitivity pneumonitis, interstitial fibrosis,
systemic scleroderma, macular degeneration, pancreatic fibrosis, fibrosis of the spleen, cardiac
fibrosis, mediastinal fibrosis, myelofibrosis, endomyocardial fibrosis, retroperitoneal fibrosis,
progressive massive fibrosis, nephrogenic systemic fibrosis, fibrotic complications of surgery,
chronic allograft vasculopathy and/or chronic rejection in transplanted organs, ischemic-
reperfusion injury associated fibrosis, injection fibrosis, cirrhosis, diffuse parenchymal lung
disease, post-vasectomy pain syndrome, and rheumatoid arthritis diseases.
In certain embodiments methods are provided for alleviating or ameliorating a
condition or disorder, affected at least in part by the enzymatic activity of calpain 1 (CAPN1),
calpain 2 (CAPN2), and/or calpain 9 (CAPN9), or mediated at least in part by the enzymatic
activity of CAPN1, CAPN2, and/or CAPN9 wherein the condition includes or produces a
symptom which includes: liver fibrosis, renal fibrosis, lung fibrosis, hypersensitivity
pneumonitis, interstitial fibrosis, systemic scleroderma, macular degeneration, pancreatic
fibrosis, fibrosis of the spleen, cardiac fibrosis, mediastinal fibrosis, myelofibrosis,
endomyocardial fibrosis, retroperitoneal fibrosis, progressive massive fibrosis, nephrogenic
systemic fibrosis, fibrotic complications of surgery, chronic allograft vasculopathy and/or chronic
rejection in transplanted organs, ischemic-reperfusion injury associated fibrosis, injection
17681897_1 (GHMatters) P110989.NZ
fibrosis, cirrhosis, diffuse parenchymal lung disease, post-vasectomy pain syndrome, and/or
rheumatoid arthritis.
In some embodiments, the methods, compounds, and/or compositions of the
present invention are used for prophylactic therapy.
In some embodiments, the CAPN1, CAPN2, and/or CAPN9 inhibiting
compounds demonstrate efficacy in animal models of human disease. Specifically, in-vivo
treatment of mice, rabbits, and other mammalian subjects with compounds disclosed herein
establish the utility of these compounds as therapeutic agents to modulate CAPN1, CAPN2,
and/or CAPN9 activities in humans and thereby ameliorate corresponding medical conditions.
Some embodiments provide compounds, pharmaceutical compositions, and
methods of use to inhibit myofibroblast differentiation. Some embodiments provide compounds,
pharmaceutical compositions, and methods of use for inhibiting CAPN1, CAPN2, and/or
CAPN9 or combinations of these enzyme activities such as CAPN1 and CAPN2, or CAPN1 and
CAPN9, or CAPN2 and CAPN9. Some embodiments provide methods for treatment of diseases
and disorders by inhibiting CAPN1, CAPN2, and/or CAPN9 or combinations of these enzymatic
activities.
DETAILED DESCRIPTION
In some embodiments, compounds that are non-macrocyclic α-keto amides are
provided that act as calpain modulators. Various embodiments of these compounds include
compounds having the structures of Formula I as described above or pharmaceutically acceptable
salts thereof. The structure of Formula I encompasses all stereoisomers and racemic mixtures,
including the following structures and mixtures thereof:
3 A 3 A
A A A A
N R N R
17681897_1 (GHMatters) P110989.NZ
In some embodiments of compounds of Formula (I), the compound is not
selected from the group consisting of:
O NH
N O N O N O
H H H
N NH N NH N NH
2 2 2
O O O O O O
, , ,
N NH
N NH
, and .
17681897_1 (GHMatters) P110989.NZ
In some embodiments of compounds of Formula (I):
A is selected from the group consisting of optionally substituted 6-10 membered heterocyclyl
provided the 6membered heterocyclyl is not substituted with oxo; optionally substituted 5-,
8-, or 9- membered heteroaryl; and optionally substituted C carbocyclyl;
3-10
A is selected from the group consisting of optionally substituted 3-10 membered heterocyclyl,
optionally substituted C aryl, optionally substituted 5-10 membered heteroaryl, optionally
6-10
substituted C carbocyclyl, -CR -, -S-, -S(=O)-, -SO -, -O-, -C(=S)-, -C(=O)-, -NR-, -CH=CH-,
3-10 2 2
-OC(O)NH-, -NHC(O)NH-, -NHC(O)O-, -NHC(O)-, -NHC(S)NH-, -NHC(S)O-, -NHC(S)-, and
single bond;
A is selected from the group consisting of optionally substituted C aryl, optionally substituted
4 6-10
-10 membered heteroaryl, optionally substituted 3-10 membered heterocyclyl, optionally
substituted C carbocyclyl, optionally substituted C - alkyl, -S-, S(=O)-, -SO -, -O-, -C(=S)-, -
3-10 1 4 2
C(=O)-, -NR-, -CH=CH-, -OC(O)NH-, -NHC(O)NH-, -NHC(O)O-, -NHC(O)-, -NHC(S)NH-, -
NHC(S)O-, -NHC(S)-, and single bond;
A is selected from the group consisting of optionally substituted C aryl, optionally substituted
3 6-10
-10 membered heteroaryl, optionally substituted 3-10 membered heterocyclyl, and optionally
substituted C carbocyclyl;
3-10
A is selected from the group consisting of optionally substituted C aryl, optionally substituted
6 6-10
-10 membered heteroaryl, optionally substituted 3-10 membered heterocyclyl, optionally
substituted C carbocyclyl, optionally substituted C alkyl, optionally substituted –O-C
3-10 1-8 1-6
alkyl, optionally substituted –O C2-6 alkenyl, and any natural or non-natural amino acid side
chain; and
each R, R , and R are independently selected from –H, optionally substituted C - alkyl,
optionally substituted C carbocyclyl, optionally substituted 5-10 membered heterocyclyl,
optionally substituted C aryl, and optionally substituted 5-10 membered heteroaryl.
6-10
Some embodiments of compounds of Formula (I) include compounds having
the structure of Formula (I-a):
17681897_1 (GHMatters) P110989.NZ
or a pharmaceutically acceptable salt thereof, wherein:
A, B, and D are each independently selected from the group consisting of C(R ) and N; and each
R is independently selected from the group consisting of –H, C alkyl, C haloalkyl, C
1-4 1-4 3-7
carbocyclyl (optionally substituted with halo, C -C alkyl, C -C alkoxy, C -C haloalkyl, and C -
1 6 1 6 1 6 1
C haloalkoxy), halo, hydroxy, and C -C alkoxy.
6 1 6
In some embodiments of compounds of Formula (I-a) or their pharmaceutically
acceptable salts; A, B, and D are independently selected from the group consisting of CH and N.
In some embodiments, A is N, B is CH, and D is CH. In some embodiments, A is CH, B is N,
and D is CH.
Some embodiments of compounds of Formula (I) include compounds having
the structure of Formula (I-b):
or a pharmaceutically acceptable salt thereof, wherein:
17681897_1 (GHMatters) P110989.NZ
A, B, and D are each independently selected from the group consisting of C(R ) and N; and each
R is independently selected from the group consisting of –H, C alkyl, C haloalkyl, C
1-4 1-4 3-7
carbocyclyl (optionally substituted with halo, C -C alkyl, C -C alkoxy, C -C haloalkyl, and C -
1 6 1 6 1 6 1
C haloalkoxy), halo, hydroxy, and C -C alkoxy.
6 1 6
In some embodiments of compounds of Formula (I-b) or their pharmaceutically
acceptable salts; A, B, and D are independently selected from the group consisting of CH and N.
Some embodiments of compounds of Formula (I) include compounds having
the structure of Formula (I-c):
or a pharmaceutically acceptable salt thereof, wherein:
Y is selected from the group consisting of NR , O, S, and SO ; X and Z are each independently
selected from the group consisting of C(R ) and N; each R is independently selected from the
group consisting of –H, C alkyl, C haloalkyl, C carbocyclyl (optionally substituted with
1-4 1-4 3-7
halo, C -C alkyl, C -C alkoxy, C -C haloalkyl, and C -C haloalkoxy), halo, hydroxy, and C -
1 6 1 6 1 6 1 6 1
C alkoxy; and R is selected from the group consisting of –H, C alkyl, C haloalkyl, and C
6 1-4 1-4 3-7
carbocyclyl.
In some embodiments of compounds of Formula (I-c) or their pharmaceutically
acceptable salts; X and Z are independently selected from the group consisting of CH and N.
Some embodiments of compounds of Formula (I) include compounds having
the structure of Formula (I-d):
17681897_1 (GHMatters) P110989.NZ
or a pharmaceutically acceptable salt thereof, wherein:
Y is selected from the group consisting of NR , O, S, and SO ; X and Z are each independently
selected from the group consisting of C(R ) and N; each R is independently selected from the
group consisting of –H, C alkyl, C haloalkyl, C carbocyclyl (optionally substituted with
1-4 1-4 3-7
halo, C -C alkyl, C -C alkoxy, C -C haloalkyl, and C -C haloalkoxy), halo, hydroxy, and C -
1 6 1 6 1 6 1 6 1
C alkoxy; and R is selected from the group consisting of –H, C alkyl, C haloalkyl, and C
6 1-4 1-4 3-7
carbocyclyl.
In some embodiments of compounds of Formula (I-d) or their pharmaceutically
acceptable salts; X and Z are independently selected from the group consisting of CH and N.
Some embodiments of compounds of Formula (I) include compounds having
the structure of Formula (I-e):
or a pharmaceutically acceptable salt thereof, wherein:
17681897_1 (GHMatters) P110989.NZ
Y is selected from the group consisting of NR , O, S, and SO ; X and Z are each independently
selected from the group consisting of C(R ) and N; each R is independently selected from the
group consisting of –H, C alkyl, C haloalkyl, C carbocyclyl (optionally substituted with
1-4 1-4 3-7
halo, C -C alkyl, C -C alkoxy, C -C haloalkyl, and C -C haloalkoxy), halo, hydroxy, and C -
1 6 1 6 1 6 1 6 1
C alkoxy; and R is selected from the group consisting of –H, C alkyl, C haloalkyl, and C
6 1-4 1-4 3-7
carbocyclyl.
In some embodiments of compounds of Formula (I-e) or their pharmaceutically
acceptable salts; X and Z are independently selected from the group consisting of CH and N.
Some embodiments of compounds of Formula (I) include compounds having
the structure of Formula (I-f):
or a pharmaceutically acceptable salt thereof, wherein:
Y is selected from the group consisting of NR , O, S, and SO ; X and Z are each independently
selected from the group consisting of C(R ) and N; each R is independently selected from the
group consisting of –H, C - alkyl, C haloalkyl, C carbocyclyl (optionally substituted with
1 4 1-4 3-7
halo, C -C alkyl, C -C alkoxy, C -C haloalkyl, and C -C haloalkoxy), halo, hydroxy, and C -
1 6 1 6 1 6 1 6 1
C alkoxy; and R is selected from the group consisting of –H, C alkyl, C haloalkyl, and C
6 1-4 1-4 3-7
carbocyclyl.
In some embodiments of compounds of Formula (I-f), Z is N, Y is NR , and X
is CH.
In some embodiments of compounds of Formula (I-f), R is selected from the
group consisting of –H, C alkyl, C -C haloalkyl, and cyclopropyl.
1-4 1 4
17681897_1 (GHMatters) P110989.NZ
In some embodiments of compounds of Formula (I-f), Z is N, Y is O, and X is
C(R ). In some embodiments of compounds of Formula (I-f), Z is N, Y is S, and X is C(R ). In
some embodiments of compounds of Formula (I-f), Z is C(R ), Y is S, and X is C(R ).
In some embodiments of compounds of Formula (I-f), Z is C(R ), Y is O, and
X is C(R ).
In some embodiments of compounds of Formula (I-f), Z is N, Y is S, and X is
N. In some embodiments of compounds of Formula (I-f), Z is N, Y is O, and X is N.
Some embodiments of compounds of Formula (I) include compounds having
the structure of formula (I-g):
or a pharmaceutically acceptable salt thereof, wherein:
Y is selected from the group consisting of NR , O, S, and SO ; X and Z are each independently
selected from the group consisting of C(R ) and N; each R is independently selected from the
group consisting of –H, C alkyl, C haloalkyl C carbocyclyl (optionally substituted with
1-4 1-4 3-7
halo, C -C alkyl, C -C alkoxy, C -C haloalkyl, and C -C haloalkoxy), halo, hydroxy, and C -
1 6 1 6 1 6 1 6 1
C alkoxy; and R is selected from the group consisting of –H, C alkyl, C haloalkyl and C
6 1-4 1-4 3-7
carbocyclyl (optionally substituted with halo, C -C alkyl, C -C alkoxy, C -C haloalkyl, and C -
1 6 1 6 1 6 1
C haloalkoxy).
In some embodiments of compounds of Formula (I-g) or their pharmaceutically
acceptable salts; X and Z are independently selected from the group consisting of CH and N. In
some embodiments of compounds of Formula (I-g), Y is NR , Z is N, and X is CH.
17681897_1 (GHMatters) P110989.NZ
Some embodiments of compounds of Formula (I) include compounds having
the structure of Formula (I-h):
or a pharmaceutically acceptable salt thereof, wherein:
Y is selected from the group consisting of NR , O, S, and SO ; X and Z are each independently
selected from the group consisting of C(R ) and N; each R is independently selected from the
group consisting of –H, C - alkyl, C haloalkyl, C carbocyclyl (optionally substituted with
1 4 1-4 3-7
halo, C -C alkyl, C -C alkoxy, C -C haloalkyl, and C -C haloalkoxy), halo, hydroxy, and C -
1 6 1 6 1 6 1 6 1
C alkoxy; and R is selected from the group consisting of –H, C alkyl, C haloalkyl, and C
6 1-4 1-4 3-7
carbocyclyl (optionally substituted with halo, C -C alkyl, C -C alkoxy, C -C haloalkyl, and C -
1 6 1 6 1 6 1
C haloalkoxy).
In some embodiments of compounds of Formula (I-h) or their pharmaceutically
acceptable salts; X and Z are independently selected from the group consisting of CH and N. In
some embodiments of compounds of Formula (I-h), X is CH, Z is N, and Y is NR .
In some embodiments of compounds of Formula (I-h), X is CH, Z is N, and Y
is NR . In some embodiments of compounds of Formula (I-h), X is N, Z is C(R ), and Y is O.
In some embodiments of compounds of Formula (I-h), wherein R is selected
from –H and C alkyl.
In some embodiments of compounds of Formula (I-h), X is N, Z is C(R ), and
Y is S. In some embodiments of compounds of Formula (I-h), X is N, Z is N, and Y is S.
17681897_1 (GHMatters) P110989.NZ
Some embodiments of compounds of Formula (I) include compounds having
the structure of formula (I-j):
or a pharmaceutically acceptable salt thereof.
Some embodiments of compounds of Formula (I) include compounds having
the structure of Formula (I-k):
A O A
or a pharmaceutically acceptable salt thereof, wherein:
4 4
X is selected from the group consisting of C(OR ), -C(R ), and N; R is selected from the group
consisting of –H, C alkyl, C haloalkyl, C carbocyclyl (optionally substituted with halo, C -
1-4 1-4 3-7 1
C alkyl, C -C alkoxy, C -C haloalkyl, and C -C haloalkoxy), halo, hydroxy, and C -C
6 1 6 1 6 1 6 1 6
alkoxy; and R is selected from the group consisting of –H, C alkyl, C haloalkyl, and C
1-4 1-4 3-7
17681897_1 (GHMatters) P110989.NZ
carbocyclyl (optionally substituted with halo, C -C alkyl, C -C alkoxy, C -C haloalkyl, and C -
1 6 1 6 1 6 1
C haloalkoxy).
In some embodiments of compounds of Formula (I-k) or their pharmaceutically
acceptable salts; X and Z are independently selected from the group consisting of CH and N.
Some embodiments of compounds of Formula (I) include compounds having
the structure of Formula (I-m):
or a pharmaceutically acceptable salt thereof, wherein:
X and Z are independently selected from the group consisting of C(R ) and N; E is selected from
the group consisting of an optionally substituted C carbocyclyl and an optionally substituted 5-
to 6-membered heterocyclyl; and each R is independently selected from the group consisting of
–H, C - alkyl, C haloalkyl, C carbocyclyl (optionally substituted with halo, C -C alkyl, C -
1 4 1-4 3-7 1 6 1
C alkoxy, C -C haloalkyl, and C -C haloalkoxy), halo, hydroxy, and C -C alkoxy.
6 1 6 1 6 1 6
Some embodiments of compounds of Formula (I) include compounds having
the structure of Formula (I-n):
17681897_1 (GHMatters) P110989.NZ
or a pharmaceutically acceptable salt thereof, wherein:
A is selected from the group consisting of C(R ) and N; E is selected from the group consisting
of an optionally substituted C carbocyclyl, an optionally substituted 5- to 6-membered
heterocyclyl, an optionally substituted 5- to 6- membered heteroaryl, and an optionally
substituted phenyl; and each R is independently selected from the group consisting of –H, C -
alkyl, C haloalkyl, C carbocyclyl (optionally substituted with halo, C -C alkyl, C -C
1-4 3-7 1 6 1 6
alkoxy, C -C haloalkyl, and C -C haloalkoxy), halo, hydroxy, and C -C alkoxy.
1 6 1 6 1 6
Some embodiments include compounds of Formula (III)
or a pharmaceutically acceptable salt thereof, wherein:
A is selected from the group consisting of optionally substituted 5-10 membered heterocyclyl
provided the 6membered heterocyclyl is not substituted with oxo; optionally substituted 5-,
8-, or 9- membered heteroaryl; and optionally substituted C carbocyclyl;
3-10
17681897_1 (GHMatters) P110989.NZ
A is selected from the group consisting of optionally substituted 3-10 membered heterocyclyl,
optionally substituted C aryl, optionally substituted 5-10 membered heteroaryl, optionally
6-10
substituted C carbocyclyl, -CR -, -S-, -S(=O)-, -SO -, -O-, -C(=S)-, -C(=O)-, -NR-, -CH=CH-,
3-10 2 2
-C≡C-, -OC(O)NH-, -NHC(O)NH-, -NHC(O)O-, -NHC(O)-, -NHC(S)NH-, -NHC(S)O-, -
NHC(S)-, and single bond;
A is selected from the group consisting of optionally substituted C aryl, optionally substituted
4 6-10
-10 membered heteroaryl, optionally substituted 3-10 membered heterocyclyl, optionally
substituted C carbocyclyl, optionally substituted C - alkyl, -(CR ) -S-(CR ) -, -(CR ) -S(=O)-
3-10 1 4 2 n 2 n 2 n
(CR ) -, -(CR ) -SO -(CR ) -, -(CR ) O-(CR ) -, -(CR ) -C(=S)-(CR ) -, -(CR ) -C(=O)-
2 n 2 n 2 2 n 2 n- 2 n 2 n 2 n 2 n
(CR ) -, -(CR ) -NR-(CR ) -, -(CR ) -CH=CH-(CR ) -, -(CR ) -OC(O)NH-(CR ) -, -(CR ) -
2 n 2 n 2 n 2 n 2 n 2 n 2 n 2 n
NHC(O)NH-(CR ) -, -(CR ) -NHC(O)O-(CR ) -, -(CR ) -NHC(O)-(CR ) -, -(CR ) -
2 n 2 n 2 n 2 n 2 n 2 n
NHC(S)NH-(CR ) -, -(CR ) -NHC(S)O-(CR ) -, -(CR ) -NHC(S)-(CR ) -, and single bond;
2 n 2 n 2 n 2 n 2 n
when A and A are single bond, A is directly attached to A ;
2 4 3 8
A is selected from the group consisting of optionally substituted C aryl, optionally substituted
3 6-10
-10 membered heteroaryl, optionally substituted 3-10 membered heterocyclyl, and optionally
substituted C carbocyclyl, or if A is selected from optionally substituted 3-10 membered
3-10 2
heterocyclyl, optionally substituted C aryl, optionally substituted 5-10 membered heteroaryl,
6-10
and optionally substituted C carbocyclyl, then A is selected from the group consisting of
3-10 3
hydrogen, optionally substituted C aryl, optionally substituted 5-10 membered heteroaryl,
6-10
optionally substituted 3-10 membered heterocyclyl, optionally substituted C carbocyclyl, -
3-10
C≡CH, and optionally substituted 2- to 5-membered polyethylene glycol;
G is an optionally substituted C to C carbocyclyl or an optionally substituted 4- to 7-membered
heterocyclyl;
A8 is a ring member of A1 and is selected from the group consisting of C and N;
R is selected from the group consisting of -COR , -CN, -CH=CHSO R, -CH NO ;
2 2 2
R is selected from the group consisting of H, -OH, C haloalkyl, -COOH, -CH NO -
1-4 2 2,
2 3 2 3
C(=O)NOR, -NH , -CONR R , -CH(CH )=CH , -CH(CF )NR R ,
2 3 2 3
17681897_1 (GHMatters) P110989.NZ
-C(F)=CHCH CH , , , , , ,
O O H
, , , , , ,
, , and ;
R is halo; and
each R, R , and R are independently selected from –H, optionally substituted C - alkyl,
optionally substituted C - alkoxyalkyl, optionally substituted 2- to 5-membered polyethylene
glycol, optionally substituted C carbocyclyl, optionally substituted 5-10 membered
heterocyclyl, optionally substituted C aryl, optionally substituted C aryl(C -C )alkyl, and
6-10 6-10 1 6
optionally substituted 5-10 membered heteroaryl; R is independently selected from –H and
optionally substituted C - alkyl; and each n is independently selected to be an integer from 0 to
Some embodiments of compounds of Formulas (III) include compounds
having the structure of Formula (III-a):
III-a
or a pharmaceutically acceptable salt thereof.
17681897_1 (GHMatters) P110989.NZ
In some embodiments of Formulas (I), (III), (III-a), (I-a), (I-b), (I-c), (I-d), (I-
e), (I-f), (I-g), (I-h), (I-j), (I-k), (I-m), (I-n), or (I-p), at least one of the optionally substituted
moieties of A , A , and A is substituted with F.
2 4 3
In some embodiments of Formulas (I), (III), (III-a), (I-a), (I-b), (I-c), (I-d), (I-
e), (I-f), (I-g), (I-h), (I-j), (I-k), (I-m), (I-n), or (I-p), at least one of the optionally substituted
moieties of A , A , and A is substituted with C -C alkyl containing one or more C.
2 4 3 1 6
In some embodiments of compounds of Formulas (I), (III), (III-a), (I-a), (I-b),
(I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-j), (I-k), (I-m), (I-n), or (I-p) or their pharmaceutically
2 X X
acceptable salts; A is selected from the group consisting of , ,
2 1 2
, , , ,
, , and
17681897_1 (GHMatters) P110989.NZ
; and A is selected from the group consisting of H, C aryl, 5-10
9 6-10
membered heteroaryl, 3-10 membered heterocyclyl, and C carbocyclyl, C - alkyl; X , X , and
3-10 1 4 2 1
Z are each independently selected from the group consisting of C(R ) and N; Y is selected from
the group consisting of NR , O, and S; J, L, M and M are each independently selected from the
group consisting of C(R ) and N; R is selected from the group consisting of –H, C alkyl, C
1-4 1-4
haloalkyl, C carbocyclyl, halo, hydroxy, and C -C alkoxy; R is selected from the group
3-7 1 6
consisting of –H, C alkyl, C haloalkyl, and C carbocyclyl.
1-4 1-4 3-7
In some embodiments of Formulas (I), (III), (III-a), (I-a), (I-b), (I-c), (I-d), (I-
e), (I-f), (I-g), (I-h), (I-j), (I-k), (I-m), (I-n), or (I-p), A is –CH -.
In some embodiments of Formulas (I), (III), (III-a), (I-a), (I-b), (I-c), (I-d), (I-
e), (I-f), (I-g), (I-h), (I-j), (I-k), (I-m), (I-n), or (I-p), A is –CH=CH-.
In some embodiments of Formulas (I), (III), (III-a), (I-a), (I-b), (I-c), (I-d), (I-
e), (I-f), (I-g), (I-h), (I-j), (I-k), (I-m), (I-n), or (I-p), A is –O-.
In some embodiments of Formulas (I), (III), (III-a), (I-a), (I-b), (I-c), (I-d), (I-
e), (I-f), (I-g), (I-h), (I-j), (I-k), (I-m), (I-n), or (I-p), A is S.
In some embodiments of Formulas (I), (III), (III-a), (I-a), (I-b), (I-c), (I-d), (I-
e), (I-f), (I-g), (I-h), (I-j), (I-k), (I-m), (I-n), or (I-p), A is single bond.
In some embodiments of Formulas (I), (III), (III-a), (I-a), (I-b), (I-c), (I-d), (I-
e), (I-f), (I-g), (I-h), (I-j), (I-k), (I-m), (I-n), or (I-p), A is phenyl.
In some embodiments of Formulas (I), (III), (III-a), (I-a), (I-b), (I-c), (I-d), (I-
e), (I-f), (I-g), (I-h), (I-j), (I-k), (I-m), (I-n), or (I-p), A is optionally substituted C aryl.
3 6-10
In some embodiments of Formulas (I), (III), (III-a), (I-a), (I-b), (I-c), (I-d), (I-
e), (I-f), (I-g), (I-h), (I-j), (I-k), (I-m), (I-n), or (I-p), A is selected from the group consisting of
optionally substituted 3-10 membered heterocyclyl, optionally substituted C aryl, optionally
6-10
substituted 5- or 7-10 membered heteroaryl, optionally substituted C carbocyclyl, -S-, -S(=O)-,
3-10
17681897_1 (GHMatters) P110989.NZ
-SO -, -C(=S)-, -C(=O)-, -NR-, -CH=CH-, -C≡C-, -OC(O)NH-, -NHC(O)NH-, -NHC(O)O-, -
NHC(S)NH-, -NHC(S)O-, and -NHC(S)-.
In some embodiments of Formulas (I), (III), (III-a), (I-a), (I-b), (I-c), (I-d), (I-
e), (I-f), (I-g), (I-h), (I-j), (I-k), (I-m), (I-n), or (I-p), A is selected from the group consisting of
optionally substituted 3-10 membered heterocyclyl, optionally substituted C aryl, optionally
6-10
substituted 5-10 membered heteroaryl, optionally substituted C carbocyclyl, and -C≡C-,
3-10
In some embodiments of Formulas (I), (III), (III-a), (I-a), (I-b), (I-c), (I-d), (I-
e), (I-f), (I-g), (I-h), (I-j), (I-k), (I-m), (I-n), or (I-p), A is selected from the group consisting of
optionally substituted 3-10 membered heterocyclyl, optionally substituted C aryl, optionally
6-10
substituted 5-10 membered heteroaryl, and optionally substituted C carbocyclyl.
3-10
In some embodiments of Formulas (I), (III), (III-a), (I-a), (I-b), (I-c), (I-d), (I-
e), (I-f), (I-g), (I-h), (I-j), (I-k), (I-m), (I-n), or (I-p), A is single bond.
In some embodiments of Formulas (I), (III), (III-a), (I-a), (I-b), (I-c), (I-d), (I-
e), (I-f), (I-g), (I-h), (I-j), (I-k), (I-m), (I-n), or (I-p), A is selected from the group consisting of
phenyl, , , , , , and
In some embodiments of Formulas (I), (III), (III-a), (I-a), (I-b), (I-c), (I-d), (I-
e), (I-f), (I-g), (I-h), (I-j), (I-k), (I-m), (I-n), or (I-p), A is optionally substituted 5-10
membered heteroaryl.
In some embodiments of Formulas (I), (III), (III-a), (I-a), (I-b), (I-c), (I-d), (I-
e), (I-f), (I-g), (I-h), (I-j), (I-k), (I-m), (I-n), or (I-p), A is selected from the group consisting of
17681897_1 (GHMatters) P110989.NZ
N S N O N N
, , , , , , and
In some embodiments of Formulas (I), (III), (III-a), (I-a), (I-b), (I-c), (I-d), (I-
e), (I-f), (I-g), (I-h), (I-j), (I-k), (I-m), (I-n), or (I-p), wherein A is a single bond, A is a single
bond, and A is an optionally substituted C aryl or an optionally substituted 5-10 membered
3 6-10
heteroaryl.
In some embodiments of Formulas (I), (III), (III-a), (I-a), (I-b), (I-c), (I-d), (I-
e), (I-f), (I-g), (I-h), (I-j), (I-k), (I-m), (I-n), or (I-p), wherein A has the structure:
, wherein J, L, M , M , and M are each independently selected from the group
1 2 3
consisting of C(R ) and N; and each R is independently selected from the group consisting of –
H, C - alkyl, C haloalkyl, C carbocyclyl (optionally substituted with halo, C -C alkyl, C -C
1 4 1-4 3-7 1 6 1 6
alkoxy, C -C haloalkyl, and C -C haloalkoxy), halo, hydroxy, and C -C alkoxy.
1 6 1 6 1 6
In some embodiments of Formulas (I), (III), (III-a), (I-a), (I-b), (I-c), (I-d), (I-
e), (I-f), (I-g), (I-h), (I-j), (I-k), (I-m), (I-n), or (I-p), wherein each of J, L, M , M , and M are
1 2 3
C(R )
In some embodiments of Formulas (I), (III), (III-a), (I-a), (I-b), (I-c), (I-d), (I-
e), (I-f), (I-g), (I-h), (I-j), (I-k), (I-m), (I-n), or (I-p), wherein each R is independently selected
from –H and halo.
17681897_1 (GHMatters) P110989.NZ
In some embodiments of Formulas (I), (III), (III-a), (I-a), (I-b), (I-c), (I-d), (I-
e), (I-f), (I-g), (I-h), (I-j), (I-k), (I-m), (I-n), or (I-p), wherein M is halo and each of J, L, M ,
and M are CH.
In some embodiments of Formulas (I), (III), (III-a), (I-a), (I-b), (I-c), (I-d), (I-
e), (I-f), (I-g), (I-h), (I-j), (I-k), (I-m), (I-n), or (I-p), wherein L is halo and each of J, M , M ,
and M are CH.
In some embodiments of Formulas (I), (III), (III-a), (I-a), (I-b), (I-c), (I-d), (I-
e), (I-f), (I-g), (I-h), (I-j), (I-k), (I-m), (I-n), or (I-p), wherein A has a structure selected from
the group consisting of:
and , wherein J, L, M , M , M , M , and M
1 2 3 4 5
are each independently selected from the group consisting of C(R ) and N; and each R is
independently selected from the group consisting of –H, C - alkyl, C haloalkyl, C
1 4 1-4 3-7
carbocyclyl (optionally substituted with halo, C -C alkyl, C -C alkoxy, C -C haloalkyl, and C -
1 6 1 6 1 6 1
C haloalkoxy), halo, hydroxy, and C -C alkoxy.
6 1 6
In some embodiments of Formulas (I), (III), (III-a), (I-a), (I-b), (I-c), (I-d), (I-
e), (I-f), (I-g), (I-h), (I-j), (I-k), (I-m), (I-n), or (I-p), wherein A has the structure:
, wherein X is selected from the group consisting of C(R ) and N; Y is selected from O
and S; and R is selected from the group consisting of –H, C - alkyl, C haloalkyl, C
1 4 1-4 3-7
carbocyclyl (optionally substituted with halo, C -C alkyl, C -C alkoxy, C -C haloalkyl, and C -
1 6 1 6 1 6 1
C haloalkoxy), halo, hydroxy, and C -C alkoxy.
6 1 6
17681897_1 (GHMatters) P110989.NZ
Some embodiments of compounds of Formula (I) include compounds having
the structure of Formula (I-o):
or a pharmaceutically acceptable salt thereof, wherein:
Y is selected from the group consisting of NR , O, S, and SO ; X is selected from the group
consisting of C(R ) and N; J, L, M , M , and M are each independently selected from the group
1 2 3
consisting of C(R ) and N; R is selected from the group consisting of –H, C - alkyl, C
1 4 1-4
haloalkyl, C carbocyclyl, halo, hydroxy, and C -C alkoxy; R is selected from the group
3-7 1 6
consisting of –H, C alkyl, C haloalkyl, and C carbocyclyl (optionally substituted with halo,
1-4 1-4 3-7
C -C alkyl, C -C alkoxy, C -C haloalkyl, and C -C haloalkoxy).
1 6 1 6 1 6 1 6
In some embodiments of compounds of Formula (I-o) or their pharmaceutically
acceptable salts; J, L, M , M , and M are independently selected from the group consisting of
1 2 3
CH and N.
In some embodiments of Formulas (I), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-
g), (I-h), (I-j), (I-k), (I-m), (I-n), (I-o), or (I-p), wherein at least one of the optionally substituted
moieties of A , A , and A is substituted with F.
7 6
In some embodiments of Formulas (I), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-
g), (I-h), (I-j), (I-k), (I-m), (I-n), (I-o), or (I-p), wherein at least one of the optionally substituted
moieties of A , A , and A is substituted with C -C alkyl containing one or more C.
7 6 1 6
In some embodiments of Formulas (I), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-
g), (I-h), (I-j), (I-k), (I-m), (I-n), (I-o), or (I-p), A is phenyl.
17681897_1 (GHMatters) P110989.NZ
In some embodiments of Formulas (I), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-
g), (I-h), (I-j), (I-k), (I-m), (I-n), (I-o), or (I-p), A is selected from the group consisting of
optionally substituted C aryl, optionally substituted 5-10 membered heteroaryl, optionally
6-10
substituted 3-10 membered heterocyclyl, optionally substituted C carbocyclyl, optionally
3-10
substituted C alkyl, optionally substituted –O-C alkyl, and optionally substituted –O C
1-8 1-6 2-6
alkenyl.
In some embodiments of Formulas (I), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-
g), (I-h), (I-j), (I-k), (I-m), (I-n), (I-o), or (I-p), A is -CH -.
In some embodiments of Formulas (I), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-
g), (I-h), (I-j), (I-k), (I-m), (I-n), (I-o), or (I-p), A is –CH=CH-.
In some embodiments of Formulas (I), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-
g), (I-h), (I-j), (I-k), (I-m), (I-n), (I-o), or (I-p), A is –O-.
In some embodiments of Formulas (I), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-
g), (I-h), (I-j), (I-k), (I-m), (I-n), (I-o), or (I-p), A is S.
In some embodiments of Formulas (I), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-
g), (I-h), (I-j), (I-k), (I-m), (I-n), (I-o), or (I-p), A is single bond.
In some embodiments of Formulas (I), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-
g), (I-h), (I-j), (I-k), (I-m), (I-n), (I-o), or (I-p), A is optionally substituted C aryl.
7 6-10
In some embodiments of Formulas (I), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-
g), (I-h), (I-j), (I-k), (I-m), (I-n), (I-o), or (I-p), A is phenyl.
In some embodiments of Formulas (I), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-
g), (I-h), (I-j), (I-k), (I-m), (I-n), (I-o), or (I-p), A is -CH -.
In some embodiments of Formulas (I), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-
g), (I-h), (I-j), (I-k), (I-m), (I-n), (I-o), or (I-p), wherein A is -CH - or -CH CH -; A is a single
2 2 2 7
bond; and A is selected from the group consisting of C -C alkyl, optionally substituted phenyl,
6 1 4
optionally substituted 5-10 membered heteroaryl.
In some embodiments of Formulas (I), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-
g), (I-h), (I-j), (I-k), (I-m), (I-n), (I-o), or (I-p), A6 is optionally substituted phenyl.
In some embodiments of Formulas (I), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-
g), (I-h), (I-j), (I-k), (I-m), (I-n), (I-o), or (I-p), wherein A is unsubstituted phenyl.
17681897_1 (GHMatters) P110989.NZ
In some embodiments of Formulas (I), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-
g), (I-h), (I-j), (I-k), (I-m), (I-n), (I-o), or (I-p), wherein A is phenyl optionally substituted with
one or more C - alkyl, C carbocyclyl, halo, hydroxy, and C -C alkoxy.
1 4 3-7 1 6
In some embodiments of Formulas (I), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-
g), (I-h), (I-j), (I-k), (I-m), (I-n), (I-o), or (I-p), A has the structure:
In some embodiments of Formulas (I), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-
g), (I-h), (I-j), (I-k), (I-m), (I-n), (I-o), or (I-p), wherein A is a single bond, A is a single bond;
and A is C -C alkyl.
6 1 5
In some embodiments of Formulas (I), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-
g), (I-h), (I-j), (I-k), (I-m), (I-n), (I-o), or (I-p), A is selected from the group consisting of ethyl,
n-propyl, isopropyl, isobutyl, 2,2-dimethylpropyl, and 1,2-dimethylpropyl.
In some embodiments of Formulas (I), (III), (III-a), (I-a), (I-b), (I-c), (I-d), (I-
1 2 3
e), (I-f), (I-g), (I-h), (I-j), (I-k), (I-o), or (I-p) R is CONR R .
In some embodiments of Formulas (I), (III), (III-a), (I-a), (I-b), (I-c), (I-d), (I-
e), (I-f), (I-g), (I-h), (I-j), (I-k), (I-o), or (I-p) R is –H and R is optionally substituted C1-4
alkyl.
In some embodiments of Formulas (I), (III), (III-a), (I-a), (I-b), (I-c), (I-d), (I-
e), (I-f), (I-g), (I-h), (I-j), (I-k), (I-o), or (I-p) wherein R is –H and R is selected from the group
consisting of –H, C -C alkyl optionally substituted with C-amido, and C -C cycloalkyl.
1 4 3 6
In some embodiments of Formulas (I), (III), (III-a), (I-a), (I-b), (I-c), (I-d), (I-
e), (I-f), (I-g), (I-h), (I-j), (I-k), (I-o), or (I-p) R is selected from ethyl or cyclopropyl.
In some embodiments of Formulas (I), (III), (III-a), (I-a), (I-b), (I-c), (I-d), (I-
e), (I-f), (I-g), (I-h), (I-j), (I-k), (I-o), or (I-p) R is methyl substituted with C-amido.
In some embodiments of Formulas (I), (III), (III-a), (I-a), (I-b), (I-c), (I-d), (I-
e), (I-f), (I-g), (I-h), (I-j), (I-k), (I-o), or (I-p) R is H.
17681897_1 (GHMatters) P110989.NZ
In some embodiments of Formulas (I), (III), (III-a), (I-a), (I-b), (I-c), (I-d), (I-
e), (I-f), (I-g), (I-h), (I-j), (I-k), (I-o), or (I-p) R is optionally substituted C alkyl.
In some embodiments of Formulas (I), (III), (III-a), (I-a), (I-b), (I-c), (I-d), (I-
e), (I-f), (I-g), (I-h), (I-j), (I-k), (I-o), or (I-p) R is benzyl.
In some embodiments of Formulas (I), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-
g), (I-h), (I-j), (I-k), (I-m), (I-n), (I-o), or (I-p), R is –H and optionally substituted C alkyl.
In some embodiments of Formulas (I), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-
g), (I-h), (I-j), (I-k), (I-m), (I-n), (I-o), or (I-p), R is optionally substituted C alkyl.
In some embodiments of Formulas (I), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-
g), (I-h), (I-j), (I-k), (I-m), (I-n), (I-o), or (I-p), R is methyl.
In some embodiments of Formula (I), A is selected from the group consisting
of optionally substituted 6-10 membered heterocyclyl; 5-membered heterocyclyl optionally
substituted with one or more C alkyl, C carbocyclyl, halo, hydroxy, or C -C alkoxy;
1-4 3-7 1 6
optionally substituted 5-, 8-, or 9- membered heteroaryl; and optionally substituted C3-10
carbocyclyl.
In some embodiments of Formula (I), A is selected from the group consisting
of 5-membered heterocyclyl optionally substituted with one or more C alkyl, C carbocyclyl,
1-4 3-7
halo, hydroxy, or C -C alkoxy and optionally substituted 5-membered heteroaryl.
In some embodiments of Formula (I), A is optionally substituted 5-membered
heteroaryl.
Some embodiments of compounds of Formula (I) include compounds having
the structure of Formula (I-p):
17681897_1 (GHMatters) P110989.NZ
or a pharmaceutically acceptable salt thereof.
Some embodiments provide a compound of Formula (II):
11 9
or a pharmaceutically acceptable salt thereof, wherein:
P is an optionally substituted cyclic moiety having a size and configuration
such that, upon binding of the compound to calpain 9, at least one atom of P forms a non-polar
interaction with, and is within 5 Å or less of, at least one calpain 9 P2 pocket moiety selected
from the group consisting of Gly190, Phe233, Gly253, His254, and Ala255;
L is a bond or a moiety consisting of from 1 to 25 atoms selected from the
group consisting of carbon, oxygen, nitrogen, hydrogen, and sulfur;
P is an optionally substituted cyclic moiety positioned by L and having a size
and configuration such that, upon binding of the compound to calpain 9, at least one atom of P
forms a non-polar interaction with, and is within 5 Å or less of, at least one calpain 9 P3 pocket
moiety selected from the group consisting of Gly189, Gly190, Ser191, Thr236, and Gly253;
R is oxo and is positioned by P such that, upon binding of the compound to
calpain 9, R forms a polar interaction with, and is within 4 Å or less of, calpain 9 Gly190
amide;
R is nitrogen and is positioned by the carbons to which it is bonded such that,
upon binding of the compound to calpain 9, R forms a polar interaction with, and is within 4 Å
or less of, calpain 9 Gly253 carbonyl;
L is a bond or a moiety consisting of from 1 to 25 atoms selected from the
group consisting of carbon, oxygen, nitrogen, hydrogen, and sulfur;
17681897_1 (GHMatters) P110989.NZ
P is a moiety positioned by L and having a size and configuration such that,
upon binding of the compound to calpain 9, at least one atom of P forms a non-polar interaction
with, and is within 5 Å or less of, at least one calpain 9 P1 pocket moiety selected from the group
consisting of Gly95, Lys188, Gly189, and Ser242;
R is a moiety positioned by the carbon to which it is attached such that, upon
binding of the compound to calpain 9, at least one atom of R forms a polar interaction with, and
is within 4 Å or less of, at least one calpain 9 moiety selected from the group consisting of
Gln91, Cys97, and His254; and
R is selected from –H and optionally substituted C - alkyl.
Some embodiments of compounds of Formula (II) include compounds
9 12 13 2 3
wherein; R is –(C=R )(C=R )NR R ;
R is oxo and is positioned such that, upon binding of the compound to calpain
9, R forms a polar interaction with, and is within 4 Å or less of, calpain 9 His254 imidazole;
R is oxo and is positioned such that, upon binding of the compound to calpain
9, R forms a polar interaction with, and is within 4 Å or less of, at least one calpain 9 moiety
selected from the group consisting of Gln91 side chain carboxamide and Cys97 backbone amide;
R and R are independently selected from –H, optionally substituted C1-4 alkyl,
optionally substituted C carbocyclyl, optionally substituted 5-10 membered heterocyclyl,
optionally substituted C aryl, optionally substituted C aryl(C -C )alkyl, and optionally
6-10 6-10 1 6
substituted 5-10 membered heteroaryl.
Some embodiments of compounds of Formula (II) include compound wherein
12 12
R is positioned such that, upon binding of the compound to calpain 9, R is within 2.6 to 3.2 Å
or less of, calpain 9 His254 imidazole.
Some embodiments of compounds of Formula (II) include compound wherein
12 12
R is positioned such that, upon binding of the compound to calpain 9, R is within 2.6 to 3.0 Å
or less of, calpain 9 His254 imidazole.
Some embodiments of compounds of Formula (II) include compound wherein
13 13
R is positioned such that, upon binding of the compound to calpain 9, R is within 2.6 to 3.5 Å
17681897_1 (GHMatters) P110989.NZ
to the calpain 9 moieties including both Gln91 side chain carboxamide and Cys97 backbone
amide.
Some embodiments of compounds of Formula (II) include compound wherein
13 13
R is positioned such that, upon binding of the compound to calpain 9, R is within 2.6 to 3.2 Å
to the calpain 9 moieties including both Gln91 side chain carboxamide and Cys97 backbone
amide.
Some embodiments of compounds of Formula (II) include compound wherein
R is positioned by the carbon to which it is attached such that, upon binding of the compound to
calpain 9, at least one atom of R forms a polar interaction with, and is within 3.6 Å or less of, at
least one calpain 9 moiety selected from the group consisting of Gln91, Cys97, and His254.
Some embodiments of compounds of Formula (II) include compound wherein
R is positioned by the carbon to which it is attached such that, upon binding of the compound to
calpain 9, at least one atom of R is within 2.6 to 3.6 Å to the calpain 9 moieties including both
Gln91 side chain carboxamide and Cys97 backbone amide.
Some embodiments of compounds of Formula (II) include compound wherein
R is positioned by the carbon to which it is attached such that, upon binding of the compound to
calpain 9, at least one atom of R is within 2.9 to 3.2 Å to the calpain 9 moieties including both
Gln91 side chain carboxamide and Cys97 backbone amide.
Some embodiments of compounds of Formula (II) include compound wherein
a carbon atom in R at its point of attachment forms a covalent bond with Cys97
Some embodiments of compounds of Formula (II) include compound wherein
the covalent bond length is between 1.7 and 1.9 Å.
Some embodiments of compounds of Formula (II) include compound wherein
P is an optionally substituted 5-membered heteroaryl.
Some embodiments of compounds of Formula (II) include compound wherein
R is positioned by the carbons to which it is bonded such that, upon binding of the compound
to calpain 9, R forms a polar interaction with, and is within 3.6 Å or less of, calpain 9 Gly253
carbonyl.
Some embodiments of compounds of Formula (II) include compound wherein,
P has a size and configuration such that, upon binding of the compound to calpain 1, at least one
17681897_1 (GHMatters) P110989.NZ
atom of P forms a non-polar interaction with, and is within 5 Å or less of, at least one calpain 1
P2 pocket moiety selected from the group consisting of Gly208, Ser251, Gly271, His272, and
Ala273;
P is positioned by L and has a size and configuration such that, upon binding
of the compound to calpain 1, at least one atom of P forms a non-polar interaction with, and is
within 5 Å or less of, at least one calpain 1 P3 pocket moiety selected from the group consisting
of Gly207, Gly208, Ser209, Ile254, and Gly271;
R is positioned by P such that, upon binding of the compound to calpain 1,
R forms a polar interaction with, and is within 4 Å or less of, calpain 1 Gly208 amide;
R is positioned by the carbons to which it is bonded such that, upon binding
of the compound to calpain 1, R forms a polar interaction with, and is within 4 Å or less of,
calpain 1 Gly271 carbonyl;
P is positioned by L and has a size and configuration such that, upon binding
of the compound to calpain 1, at least one atom of P forms a non-polar interaction with, and is
within 5 Å or less of, at least one calpain 1 P1 pocket moiety selected from the group consisting
of Gly113, Ser206, Gly207, and Met260; and
R is positioned by the carbon to which it is attached such that, upon binding of
the compound to calpain 1, at least one atom of R forms a polar interaction with, and is within 4
Å or less of, at least one calpain 1 moiety selected from the group consisting of Gln109, Cys115,
and His272.
Some embodiments of compounds of Formula (II) include compoundwherein:
P has a size and configuration such that, upon binding of the compound to
calpain 2, at least one atom of P forms a non-polar interaction with, and is within 5 Å or less of,
at least one calpain 2 P2 pocket moiety selected from the group consisting of Gly198, Ser241,
Gly261, His262, and Ala263;
P is positioned by L and has a size and configuration such that, upon binding
of the compound to calpain 2, at least one atom of P forms a non-polar interaction with, and is
within 5 Å or less of, at least one calpain 2 P3 pocket moiety selected from the group consisting
of Gly197, Gly198, Ala199, Ile244, and Gly261;
17681897_1 (GHMatters) P110989.NZ
R is positioned by P such that, upon binding of the compound to calpain 2,
R forms a polar interaction with, and is within 4 Å or less of, calpain 2 Gly198 amide;
R is positioned by the carbons to which it is bonded such that, upon binding
of the compound to calpain 2, R forms a polar interaction with, and is within 4 Å or less of,
calpain 2 Gly261 carbonyl;
P is positioned by L and has a size and configuration such that, upon binding
of the compound to calpain 2, at least one atom of P forms a non-polar interaction with, and is
within 5 Å or less of, at least one calpain 2 P1 pocket moiety selected from the group consisting
of Gly103, Ser196, Gly197, and Ser250; and
R is positioned by the carbon to which it is attached such that, upon binding of
the compound to calpain 2, at least one atom of R forms a polar interaction with, and is within 4
Å or less of, at least one calpain 2 moiety selected from the group consisting of Gln99, Cys105,
and His262.
Some embodiments of compounds of Formula (II) include compound wherein
P has a size and configuration such that, upon binding of the compound to calpain 9, at least one
atom of P is within 2.6 to 3.6 Å of Gly190 carbonyl oxygen.
Some embodiments of compounds of Formula (II) include compound wherein
P has a size and configuration such that, upon binding of the compound to calpain 9, at least one
atom of P2 is within 2.9 to 3.3 Å of Gly190 carbonyl oxygen.
Some embodiments of compounds of Formula (II) include compound wherein
P has a size and configuration such that, upon binding of the compound to calpain 9, at least one
atom of P is within 2.8 to 4.8 Å of a carbon atom in Phe233.
Some embodiments of compounds of Formula (II) include compound wherein
P has a size and configuration such that, upon binding of the compound to calpain 9, at least one
atom of P is within 2.9 to 3.3 Å of a carbon atom in Phe233.
Some embodiments of compounds of Formula (II) include compound wherein
P has a size and configuration such that, upon binding of the compound to calpain 9, at least one
atom of P is within 2.6 to 3.7 Å of Gly253 carbonyl oxygen.
17681897_1 (GHMatters) P110989.NZ
Some embodiments of compounds of Formula (II) include compound wherein
P has a size and configuration such that, upon binding of the compound to calpain 9, at least one
atom of P is within 2.9 to 3.3 Å of Gly253 carbonyl oxygen.
Some embodiments of compounds of Formula (II) include compound wherein
P has a size and configuration such that, upon binding of the compound to calpain 9, at least one
atom of P is within 2.9 to 4.8 Å of Ala255 nitrogen.
Some embodiments of compounds of Formula (II) include compound wherein
P has a size and configuration such that, upon binding of the compound to calpain 9, at least one
atom of P is within 3.2 to 4.0 Å of Ala255 nitrogen.
Some embodiments of compounds of Formula (II) include compound wherein
P has a size and configuration such that, upon binding of the compound to calpain 9, at least one
atom of P is within 3.1 to 4.3 Å of Gly189 C-alpha.
Some embodiments of compounds of Formula (II) include compound wherein
P has a size and configuration such that, upon binding of the compound to calpain 9, at least one
atom of P is within 3.2 to 4.0 Å of Gly189 C-alpha.
Some embodiments of compounds of Formula (II) include compound wherein
P has a size and configuration such that, upon binding of the compound to calpain 9, at least one
atom of P is within 3.0 to 4.3 Å of Gly190 carbonyl oxygen.
Some embodiments of compounds of Formula (II) include compound wherein
P has a size and configuration such that, upon binding of the compound to calpain 9, at least one
atom of P is within 3.2 to 4.0 Å of Gly190 carbonyl oxygen.
Some embodiments of compounds of Formula (II) include compound wherein
P has a size and configuration such that, upon binding of the compound to calpain 9, at least one
atom of P is within 3.2 to 4.8 Å of Ser191 nitrogen.
Some embodiments of compounds of Formula (II) include compound wherein
P has a size and configuration such that, upon binding of the compound to calpain 9, at least one
atom of P is within 3.2 to 4.0 Å of Ser191 nitrogen.
Some embodiments of compounds of Formula (II) include compound wherein
10
R is positioned by P such that, upon binding of the compound to calpain 9, R is within 2.6 to
3.5 Å of, calpain 9 Gly190 amide.
17681897_1 (GHMatters) P110989.NZ
Some embodiments of compounds of Formula (II) include compound wherein
10
R is positioned by P such that, upon binding of the compound to calpain 9, R is within 2.9 to
3.3 Å of, calpain 9 Gly190 amide.
Some embodiments of compounds of Formula (II) include compound wherein
R is positioned by the carbons to which it is bonded such that, upon binding of the compound
to calpain 9, R is within 2.6 to 3.6 Å or less of, calpain 9 Gly253 carbonyl.
Some embodiments of compounds of Formula (II) include compound wherein
R is positioned by the carbons to which it is bonded such that, upon binding of the compound
to calpain 9, R is within 2.9 to 3.3 Å or less of, calpain 9 Gly253 carbonyl.
Some embodiments of compounds of Formula (II) include compound wherein
P is positioned by L and has a size and configuration such that, upon binding of the compound
to calpain 9, at least one atom of P is within 3.2 to 4.4 Å Gly95 carbonyl oxygen.
Some embodiments of compounds of Formula (II) include compound wherein
P is positioned by L and has a size and configuration such that, upon binding of the compound
to calpain 9, at least one atom of P is within 3.2 to 4.0 Å Gly95 carbonyl oxygen.
Some embodiments of compounds of Formula (II) include compound wherein
P is positioned by L and has a size and configuration such that, upon binding of the compound
to calpain 9, at least one atom of P is within 3.2 to 4.7 Å of Lys188 carbonyl carbon.
Some embodiments of compounds of Formula (II) include compound wherein
P is positioned by L and has a size and configuration such that, upon binding of the compound
to calpain 9, at least one atom of P is within 2.6 to 4.0 Å of Lys188 carbonyl carbon.
Some embodiments of compounds of Formula (II) include compound wherein
P is positioned by L and has a size and configuration such that, upon binding of the compound
to calpain 9, at least one atom of P is within 3.0 to 4.1 Å of Gly189 C-alpha.
Some embodiments of compounds of Formula (II) include compound wherein
P is positioned by L and has a size and configuration such that, upon binding of the compound
to calpain 9, at least one atom of P is within 3.2 to 4.0 Å of Gly189 C-alpha.
Some embodiments provide a compound of Formula (II):
17681897_1 (GHMatters) P110989.NZ
11 9
or a pharmaceutically acceptable salt thereof, wherein:
P is an optionally substituted cyclic moiety having a size and configuration
such that, upon binding of the compound to calpain 1, at least one atom of P forms a non-polar
interaction with, and is within 5 Å or less of, at least one calpain 1 P2 pocket moiety selected
from the group consisting of Gly208, Ser251, Gly271, His272, and Ala273;
L is a bond or a moiety consisting of from 1 to 25 atoms selected from the
group consisting of carbon, oxygen, nitrogen, hydrogen, and sulfur;
P is an optionally substituted cyclic moiety positioned by L and having a size
and configuration such that, upon binding of the compound to calpain 1, at least one atom of P
forms a non-polar interaction with, and is within 5 Å or less of, at least one calpain 1 P3 pocket
moiety selected from the group consisting of Gly207, Gly208, Ser209, Ile254, and Gly271;
R is oxo and is positioned by P such that, upon binding of the compound to
calpain 1, R forms a polar interaction with, and is within 4 Å or less of, calpain 1 Gly208
amide;
R is nitrogen and is positioned by the carbons to which it is bonded such that,
upon binding of the compound to calpain 1, R forms a polar interaction with, and is within 4 Å
or less of, calpain 1 Gly271 carbonyl;
L is a bond or a moiety consisting of from 1 to 25 atoms selected from the
group consisting of carbon, oxygen, nitrogen, hydrogen, and sulfur;
P is a moiety positioned by L and having a size and configuration such that,
upon binding of the compound to calpain 1, at least one atom of P forms a non-polar interaction
17681897_1 (GHMatters) P110989.NZ
with, and is within 5 Å or less of, at least one calpain 1 P1 pocket moiety selected from the group
consisting of Gly113, Ser206, Gly207, and Met260;
R is a moiety positioned by the carbon to which it is attached such that, upon
binding of the compound to calpain 1, at least one atom of R forms a polar interaction with, and
is within 4 Å or less of, at least one calpain 1 moiety selected from the group consisting of
Gln109, Cys115, and His272; and R is selected from –H and optionally substituted C - alkyl.
Some embodiments of compounds of Formula (II) include compound wherein
9 12 13 2 3
R is –(C=R )(C=R )NR R ;
R is oxo and is positioned such that, upon binding of the compound to calpain
1, R forms a polar interaction with, and is within 4 Å or less of, calpain 1 His272 imidazole;
R is oxo and is positioned such that, upon binding of the compound to calpain
1, R forms a polar interaction with, and is within 4 Å or less of, at least one calpain 1 moiety
selected from the group consisting of Gln109 side chain carboxamide and Cys115 backbone
amide; and
R and R are independently selected from –H, optionally substituted C - alkyl,
optionally substituted C carbocyclyl, optionally substituted 5-10 membered heterocyclyl,
optionally substituted C aryl, optionally substituted C aryl(C -C )alkyl, and optionally
6-10 6-10 1 6
substituted 5-10 membered heteroaryl.
Some embodiments of compounds of Formula (II) include compound wherein
R is positioned by the carbon to which it is attached such that, upon binding of the compound to
calpain 1, at least one atom of R forms a polar interaction with, and is within 3.5 Å or less of, at
least one calpain 1 moiety selected from the group consisting of Gln109, Cys115, and His272.
Some embodiments of compounds of Formula (II) include compound wherein
a carbon atom in R at its point of attachment forms a covalent bond with Cys115.
Some embodiments of compounds of Formula (II) include compound wherein
the covalent bond length is between 1.7 and 1.9 Å.
Some embodiments of compounds of Formula (II) include compound wherein
P is an optionally substituted 5-membered heteroaryl.
Some embodiments of compounds of Formula (II) include compound wherein
R is positioned by the carbons to which it is bonded such that, upon binding of the compound
17681897_1 (GHMatters) P110989.NZ
to calpain 1, R forms a polar interaction with, and is within 3.5 Å or less of, calpain 1 Gly271
carbonyl.
Some embodiments provide a compound of Formula (II):
11 9
or a pharmaceutically acceptable salt thereof, wherein
P is an optionally substituted cyclic moiety having a size and configuration
such that, upon binding of the compound to calpain 2, at least one atom of P forms a non-polar
interaction with, and is within 5 Å or less of, at least one calpain 2 P2 pocket moiety selected
from the group consisting of Gly198, Ser241, Gly261, His262, and Ala263;
L is a bond or a moiety consisting of from 1 to 25 atoms selected from the
group consisting of carbon, oxygen, nitrogen, hydrogen, and sulfur;
P is an optionally substituted cyclic moiety positioned by L and having a size
and configuration such that, upon binding of the compound to calpain 2, at least one atom of P
forms a non-polar interaction with, and is within 5 Å or less of, at least one calpain 2 P3 pocket
moiety selected from the group consisting of Gly197, Gly198, Ala199, Ile244, and Gly261;
R is oxo and is positioned by P2 such that, upon binding of the compound to
calpain 2, R forms a polar interaction with, and is within 4 Å or less of, calpain 2 Gly198
amide;
R is nitrogen and is positioned by the carbons to which it is bonded such that,
upon binding of the compound to calpain 2, R forms a polar interaction with, and is within 4 Å
or less of, calpain 2 Gly261 carbonyl;
L is a bond or a moiety consisting of from 1 to 25 atoms selected from the
group consisting of carbon, oxygen, nitrogen, hydrogen, and sulfur;
17681897_1 (GHMatters) P110989.NZ
P is a moiety positioned by L and having a size and configuration such that,
upon binding of the compound to calpain 2, at least one atom of P forms a non-polar interaction
with, and is within 5 Å or less of, at least one calpain 2 P1 pocket moiety selected from the group
consisting of Gly103, Ser196, Gly197, and Ser250;
R is a moiety positioned by the carbon to which it is attached such that, upon
binding of the compound to calpain 2, at least one atom of R forms a polar interaction with, and
is within 4 Å or less of, at least one calpain 2 moiety selected from the group consisting of
Gln99, Cys105, and His262; and R is selected from –H and optionally substituted C - alkyl.
Some embodiments of compounds of Formula (II) include compound wherein
9 12 13 2 3
R is –(C=R )(C=R )NR R ;
R is oxo and is positioned such that, upon binding of the compound to calpain
2, R forms a polar interaction with, and is within 4 Å or less of, calpain 2 His262 imidazole;
R is oxo and is positioned such that, upon binding of the compound to calpain
2, R forms a polar interaction with, and is within 4 Å or less of, at least one calpain 2 moiety
selected from the group consisting of Gln99 side chain carboxamide and Cys105 backbone
amide; and
R and R are independently selected from –H, optionally substituted C - alkyl,
optionally substituted C carbocyclyl, optionally substituted 5-10 membered heterocyclyl,
optionally substituted C6-10 aryl, optionally substituted C6-10aryl(C1-C6)alkyl, and optionally
substituted 5-10 membered heteroaryl.
Some embodiments of compounds of Formula (II) include compound wherein
R is positioned by the carbon to which it is attached such that, upon binding of the compound to
calpain 2, at least one atom of R forms a polar interaction with, and is within 3.5 Å or less of, at
least one calpain 2 moiety selected from the group consisting of Gln99, Cys105, and His262.
Some embodiments of compounds of Formula (II) include compound wherein
a carbon atom in R at its point of attachment forms a covalent bond with Cys195.
Some embodiments of compounds of Formula (II) include compound wherein
the covalent bond length is between 1.7 and 1.9 Å.
Some embodiments of compounds of Formula (II) include compound wherein
P is an optionally substituted 5-membered heteroaryl.
17681897_1 (GHMatters) P110989.NZ
Some embodiments of compounds of Formula (II) include compound wherein
R is positioned by the carbons to which it is bonded such that, upon binding of the compound
to calpain 2, R forms a polar interaction with, and is within 3.5 Å or less of, calpain 2 Gly261
carbonyl.
Some embodiments include a compound selected from the group consisting of
compounds 1 to 90, compounds 92-94, compound 195, compounds 197 to 235, compounds 238
to 273, compounds 276 to 281, compounds 283 to 299, compounds 303 to 309, compounds 313
to 363, compound 365, compounds 367-410, compounds 413-424, compounds 428-445,
compounds 447-448, compounds 454-532, compound 540, compounds 546-588, compounds
591-605, compounds 607-611, compounds 613-630, and pharmaceutically acceptable salts
thereof, as such compounds are described herein.
Some embodiments include a compound selected from the group consisting of
compounds 91, 196, 274, 282, 310 to 312, 364, 366, 411, 536, 541, and pharmaceutically
acceptable salts thereof, as such compounds are described herein.
Some embodiments include a compound selected from the group consisting of:
N O N
N N N N
H H H
H O O
N N N
N N N N
O NH
17681897_1 (GHMatters) P110989.NZ
O H C O O O
N N NH
N N N N NH
NH 2
11
O O O O H
O C O
N N NH N N NH N N
2 NH
H H H
O S O O
O O O O
N N NH
N N NH N N NH
2 2 2
O S O
16 17
OCF O
O O O O
N N NH O N
2 NH
O O O
N N N NH
O N NH
S N O
17681897_1 (GHMatters) P110989.NZ
N N NH
N N NH
N N NH 2
O O O
N N NH
S N NH 2
N N N
N N NH
N N NH
N N N
O O O
N N N NH
O N NH
O N O
34 35 36
N O O O O O O
N N NH N N NH N N NH
O O O
37 39
17681897_1 (GHMatters) P110989.NZ
N O O O O O O
N N NH N NH N NH
H H H
S N N
O O O
41 42
O O O O
N NH N N NH
N N S
O O H N
43 44
O O O O
O N NH O N NH
N N NH
46 47
N N NH
O N NH
49 N
S N NH
N NH
N NH
N O 54
O N NH
N N NH
O N NH
17681897_1 (GHMatters) P110989.NZ
N N NH
N NH
O N NH H
O O O O
N N NH O N NH
2 N N NH
S O O
61 62
N N NH
N N NH
N N NH H
N N NH
N NH
N NH
N NH
N NH
O O O O
N NH N N NH
2 N NH 2
N O S N O
70 72
O N NH
N NH
17681897_1 (GHMatters) P110989.NZ
N O O
O O O O
N N N NH
N NH H
N NH
O O O O
HN N NH N N NH
2 2 N N NH
N N NH
N N NH H
2 N N NH
O O N
N O O
N N NH
N N NH
N N NH
HN N
N NH
N NH
17681897_1 (GHMatters) P110989.NZ
NH O
N NH
N 2 N NH
N NH
N NH
O 2 2 N
O O O
N N N
H H H
N 2 N NH
103 104
17681897_1 (GHMatters) P110989.NZ
O O O
N N NH N
N N 2
N NH
109 111
N NH
NH N
N O O
N NH N NH
N N N
S H H
NH N
H 2 N
17681897_1 (GHMatters) P110989.NZ
CF CF
NH N
H H 2
125 2
N NH
N N 2
N N N NH
NH O
N N N
N H H
2 N NH
N N S O
17681897_1 (GHMatters) P110989.NZ
O O O
N NH
N N NH
2 H H H
HN O
CONH
N O O
N NH
139 N
HN O
N NH
NH N N
HN O
NH 2
H NH
N Cl
N NH N O
O 2 H H
17681897_1 (GHMatters) P110989.NZ
SO Me
SO Me
N O N
N NH
N 2 N
O NH
O S O
HN HN
O O O
N NH NH
NH N N
157 158
N NH
NH N
17681897_1 (GHMatters) P110989.NZ
N NH
N NH
163 164
N NH
N NH
N NH
165 O
O O O O
N NH N NH
2 N 2
N NH
N NH
N NH N 2
N NH
N NH N 2
N NH
175 176
17681897_1 (GHMatters) P110989.NZ
N NH
N NH
N 2 N NH
178 179
F O O
N NH
N NH
N 2 N 2
N NH
180 181
F C F CO CN
O O O O
N NH N NH N NH
N 2 N 2 N 2
H H H
N O N O N
O O O O
N NH
N NH
N NH
N 2 N 2
N NH
N NH N 2
N NH N 2
N NH N NH
N NH
17681897_1 (GHMatters) P110989.NZ
Br O O
O O O O
N NH
N NH N NH
2 N 2
O N O
N NH
N NH N
H N 2
N O S
N N N
202 203
N N NH
N N N
N NH
N NH 2
N NH
17681897_1 (GHMatters) P110989.NZ
CONH
H N NH
O O F O
N NH N
H N H
O 215
O O O
N N 2 N NH
N 2 2
N NH
N N NH
NH H
H O N
17681897_1 (GHMatters) P110989.NZ
N N N
N NH H H
N NH O
S 2 H
CONH N
N NH
N N H
OCH Ph
PhH CO
N NH
N NH
N N NH
O O N
N NH
N NH N
H N NH
O N 2
F C N
N NH
N NH
17681897_1 (GHMatters) P110989.NZ
N NH
N 2 H
N NH
2 N N
NH N 2
N N O
N NH
O O 2 2
244 245
N NH
N 2 H H
N NH
O NH
2 NH
250 251
17681897_1 (GHMatters) P110989.NZ
O O O O
N NH
N NH
O N NH
O O O
N NH
N NH
N 2 N NH
O O H
O O O O
N NH
N NH
N NH
N 2 N 2
N O N
O N O
F 260
N NH
N NH NH
N NH
2 N NH
N NH
N 2 N 2
264 266
F O O
N NH
N NH
N NH 2
N 2 H
H N O
17681897_1 (GHMatters) P110989.NZ
O O N
N NH
N NH
N NH N NH
H N H
N NH
N NH N 2
N NH
N NH
N O N 2
N NH
N NH
N NH
N H N 2 O
17681897_1 (GHMatters) P110989.NZ
N NH
N NH
N N 2
3 287
N NH
N NH
N NH
N NH
N NH
N NH 2
N NH
N N N
NH N
N 2 N
N NH
N NH
N NH
17681897_1 (GHMatters) P110989.NZ
N NH
N NH
N NH
O O O
O 305
N NH
N NH
H 2 N
N N NH
H N NH
O N NH
309 O
O O O O
N NH N NH
N 2 N NH 2
O N O
Cl 314
O O O
N NH
N N NH
N 316
17681897_1 (GHMatters) P110989.NZ
N N O O
N NH
2 N NH
O N NH
O S 2
N NH H
N NH
322 323
N NH
N NH
N NH
N 2 2
F O O
N NH N
CONH N NH
2 N 2
H N O
N NH O
N N O
O H H
N H H
N N O
17681897_1 (GHMatters) P110989.NZ
O O O
N N NH
N O O
336 337 338
O O O
2 N N
N N N
H H H
O O O
HN O
N NH O
NH 2
CF CF
O O O O
N NH N NH
N NH
2 N 2
N O O
345 346 Cl
N N N
F O O
N NH
N NH
N NH
N 2 N 2
F C 349
348 350
O O O O
N NH N N
N NH
H 2 H
351 353
17681897_1 (GHMatters) P110989.NZ
OSO CF
N NH
N NH
N NH
H N 2
N NH
N NH
N NH
N NH
N NH
O OH
361 H
Cl O O
N NH
N 2 N NH
N NH
Br O O F O O
N NH
N NH N NH
N 2 N N 2
O S O
367 368
17681897_1 (GHMatters) P110989.NZ
N NH N NH
N NH
N 2 N 2
N OH N
S N O
F O O
N NH N NH
N NH
2 N 2
N O O
N O S
O O O
N NH N NH
N NH
N O O
N O S
N NH
N NH
N NH
379 F 380
F O O
N NH N NH
N NH N 2
N O N
382 383
17681897_1 (GHMatters) P110989.NZ
N NH
N NH
N NH N 2
384 386
N NH
N NH
N 2 N NH
O O O
387 388
O O O
N NH N
N NH
H NH
390 O
CONH
N NH
N NH
O O O
394 395
17681897_1 (GHMatters) P110989.NZ
F O O
N NH N NH
N NH N 2
403 405
O O O
CONH
N NH N
N NH
H H N 2
406 407
N NH
N N N
N NH
17681897_1 (GHMatters) P110989.NZ
N NH
N NH
N NH 2
N 2 N
O O O
N N NH
N NH N
O O O O
N NH
N NH N NH
421 422
N NH
N O O
N NH
N NH
N NH
O S 2
O O O O
N NH
2 N NH
N NH
N 2 N 2
430 432
17681897_1 (GHMatters) P110989.NZ
N Cl N
O O O
N NH
N F N NH H
PhH CO
NC N
N NH
N 2 N NH
N NH
PhO O
O O O O O O
N NH NH NH N NH
2 2 2
N N N
O O O
439 440
O O O O
N NH NH
N NH
N N 2
442 444
N NH
N NH
N N 2
H N O
O 447
17681897_1 (GHMatters) P110989.NZ
N NH
O O O O
N N N N
N N N
H H H H
455 456
N H N N
O H H H H
460 S
N NH
2 N NH
N NH
S N O
463 464
17681897_1 (GHMatters) P110989.NZ
N NH
N NH
N NH H
H N O
466 468
F O O O O
N NH N NH
N NH
N 2 N 2
469 470
F O O
O O O O
N NH N NH
N NH
N 2 N 2
H H H
N N O
472 474
N N F
475 476 477
N F N
N N NH
478 480
17681897_1 (GHMatters) P110989.NZ
O O O O
CONH
N NH
N NH
N 2 N
O N N
481 482
N N NH
N NH
N N 2
H N O
2 486
CONH
N NH
N NH
N N 2
N O O
N NH
N N NH
490 492
O O O O
N N N NH NH NH
O N 2
17681897_1 (GHMatters) P110989.NZ
O O O
N N NH
NH N 2 N NH
2 N 2
496 497 498
N NH
N NH
2 N NH
N N 2
N N O
499 500
N NH
N NH N 2 N NH
O O F
N NH
N NH
N NH
N 2 N 2
N NH 2
N NH
17681897_1 (GHMatters) P110989.NZ
F C O O
O F C O O
O O 3
N NH
N NH N NH
N 2 N 2
O O N
512 513
O O O O F
N NH N NH
N NH
N 2 N 2
N N O
515 516
F CF
F O O O
F O O
N NH
N NH N 2
F O O O
N NH
N N 2
O N O
N NH
N NH
N NH N 2
F 524
523 525
17681897_1 (GHMatters) P110989.NZ
N NH
N NH
N NH N 2
N 2 2
N O N
527 528
N NH
N NH 2
N NH O
O O O O
NH NH
N NH N NH
S 546
N NH
N NH
H N NH
17681897_1 (GHMatters) P110989.NZ
O O F
N NH
N NH 2
N NH N
N NH
N NH
N NH N 2
553 554
F O O
N NH
N NH 2 N NH
2 O 2
N O N N
557 558
N NH
N NH
N NH
N 561
O O O O
N NH
N NH N NH
562 563
N NH
N NH
N NH 2
N 2 N
565 566
O O O O O
N NH
N NH N NH
N 2 N 2
O N O
568 570
17681897_1 (GHMatters) P110989.NZ
O O O O
N N NH
N NH N 2
N O O
571 572 573
F O O O O
N NH N NH
N 2 N NH N 2
574 576
F O O
N NH N NH
2 2 NH
N N 2
N S O
577 578 579
F O O
N NH
2 N NH
N NH N 2
N 2 H
O O O O
F O O
N NH N NH
N NH
N 2 2
N NH
N NH
N NH N 2
O N NH
N N 2
586 587 588
F O O O O O O
N NH
N NH N NH
N 2 2
O O O
592 593 594
17681897_1 (GHMatters) P110989.NZ
O O O O
N NH N NH
2 N NH
O N N 2
596 597
O O O O
N NH
N NH
N NH
N O O
599 600
N O O
N O O
N NH
N NH
N NH N 2
N N O
601 603
Cl O O O O
N NH
N NH
604 605
O O O O
N NH N NH
N NH
O O O
607 609
O O O O
N NH N NH
N O O N O O
N NH
N NH N NH
N 2 N 2
N O O
613 615
17681897_1 (GHMatters) P110989.NZ
O O O O
N NH N NH
2 N NH
O O O
616 618
O O O O
N NH
N NH N NH
620 621
O O O O
F O O
N NH N NH
N NH 2
N 2 N
N O N
622 624
O O O O
N NH
N NH
2 N NH 2
626 627
O O O O O O
N NH N NH N NH
628 629
or a pharmaceutically acceptable salt thereof. Various embodiments include
the S-enantiomer, the R-enantiomer, or the racemate of the above compounds.
Additional compounds suitable for use as described herein and that can be
made by using the methods described herein are presented in Table 1.
17681897_1 (GHMatters) P110989.NZ
Table 1
N O N O
H N O NH
2 2 O
N O N
O NH
O O NH
2 NH
H N O
2 O NH
N O N O
2 O NH
O NH
17681897_1 (GHMatters) P110989.NZ
N O O
H N O
NH H
N NH
NH 2
O NH
17681897_1 (GHMatters) P110989.NZ
N O N O
NH NH
O NH
O NH
N N N
N O N O
O NH
NH NH
H N O
O NH
NH O
O NH
17681897_1 (GHMatters) P110989.NZ
N O N O
O O NH
N N O
NH NH N
O NH
N O N O
NH NH
N O N O
O NH O NH
17681897_1 (GHMatters) P110989.NZ
O NH
N O N O
NH NH
N O N O
NH NH
O NH
N O N O
NH O NH
N O N O
O NH
NH NH
17681897_1 (GHMatters) P110989.NZ
O NH N
O NH
O NH
N N
N O N
O NH
O NH
N O N O
O NH
NH O
NH 2
O NH
17681897_1 (GHMatters) P110989.NZ
O NH O
N N N
O O O
N O N O N O
N N N
H H H
O NH NH O NH
2 2 2
NH NH
N O N
NH NH
O NH
N O N
O NH O
2 O 2
N O N O
NH NH
17681897_1 (GHMatters) P110989.NZ
N NH
N O N
O NH NH
N O N O
H N H
N H N
O NH O NH
2 N 2
O NH
N S
O NH
O NH
17681897_1 (GHMatters) P110989.NZ
O N O
N O N O
H N H
N H N
O NH O
2 N 2
N S
N O O
N O N
O NH O
O NH NH
O NH O
17681897_1 (GHMatters) P110989.NZ
N O NH
O NH
NH N
O NH
O NH
NH O
O NH
O NH
N O N
N N N
O H N O
17681897_1 (GHMatters) P110989.NZ
H N O
O NH
O NH
H N O N
O NH
O HN
H N O
H N O
H N O
17681897_1 (GHMatters) P110989.NZ
H N O
N O N
H N O O NH
O NH
17681897_1 (GHMatters) P110989.NZ
N O N O
N N N
NH NH
2 2 H
O N O
O O NH
2 2 H
N O N O
O NH O
H N O
NH H
2 NH
17681897_1 (GHMatters) P110989.NZ
N N N
O NH
O O O
N O N O N
N N N
H H H
N N N
O NH O NH NH
2 2 2
N O N O
NH NH
O NH
N O N O
O O NH
NH NH
17681897_1 (GHMatters) P110989.NZ
N O N O
NH NH
NH 2 2
N O N
O N N
NH NH
O O O
N O N O N
N N N
H H H
O O NH
NH NH
O NH O
17681897_1 (GHMatters) P110989.NZ
O NH
H N O
HN NH
N O N O
NH O NH O
2 2 2
S N O
H N O
17681897_1 (GHMatters) P110989.NZ
O NH
H N O
NH 2
NH O
N N O N O
N H H
H N O
NH NH
NH N
O NH
17681897_1 (GHMatters) P110989.NZ
O NH
O NH
N O N O
NH O
O NH
O NH
N O N O 2
17681897_1 (GHMatters) P110989.NZ
N O N O
O O N
NH NH
O NH
O NH
NH NH
2 2 O
NH NH
2 2 O
17681897_1 (GHMatters) P110989.NZ
2 O NH
N N N
N N N
O O N
N O N O N O
N N N
O NH NH NH
N N N
N N N
N O N O N O
O NH O NH
N N N
O NH
O O O
N O N O
O NH NH
17681897_1 (GHMatters) P110989.NZ
O NH
N O N
N O O
NH NH
O NH
O NH
H 2 2
N N N
N N N
O O O
N O N O N O
O NH NH
17681897_1 (GHMatters) P110989.NZ
NH O
NH O
NH 2
O NH
17681897_1 (GHMatters) P110989.NZ
O N O
N O N
NH O
2 NH
O NH
N O O
O NH O
O 2 2
N O N
NH N
O NH
17681897_1 (GHMatters) P110989.NZ
O NH
N N N
N N N
O O O
N O N O N O
N N N
H H H
O O NH NH
NH O
N O N O
NH NH
O NH
N O N O
O NH NH
17681897_1 (GHMatters) P110989.NZ
N O N O
NH O NH
N N O O
NH NH
N N O
O NH
O NH
N N N
O O O
N O N O N O
NH NH O NH
2 2 2
17681897_1 (GHMatters) P110989.NZ
N O N O
N O N
O NH O NH
N O N
O NH NH
O NH
N O N O
NH O
NH O
17681897_1 (GHMatters) P110989.NZ
O NH
2 NH
H N N
O NH
NH O
O NH
N O N
17681897_1 (GHMatters) P110989.NZ
O NH
O NH
O NH
NH O NH
17681897_1 (GHMatters) P110989.NZ
N O N
N N N
O O NH
N H N
O NH
O NH
N N O
O NH
NH O
17681897_1 (GHMatters) P110989.NZ
N N O
NH NH
O NH
NH O
O N O
N O N O
H N H
O O NH
17681897_1 (GHMatters) P110989.NZ
N NH
N O N O
O NH
O NH
2 NH
2 N O
O NH
O NH
N HN
O NH
NH NH
N O N
N N H
O NH
17681897_1 (GHMatters) P110989.NZ
O NH
H N O
NH N
H N O
H N O
NH N
H N O
O NH
O NH N
17681897_1 (GHMatters) P110989.NZ
O NH
O NH
H N O
H N O
O NH
NH 2
17681897_1 (GHMatters) P110989.NZ
NH O NH
O NH
O NH
N O O
O N O
O NH O
NH NH
N N O
NH O
17681897_1 (GHMatters) P110989.NZ
N O N O
NH NH
O NH
O NH
O N O
O O NH
N O N O
O O NH
NH 2
O N O
O N O
O NH
17681897_1 (GHMatters) P110989.NZ
N O N O
NH NH
O NH
O NH
NH O
O NH
N O N
N NH
17681897_1 (GHMatters) P110989.NZ
N O N O
N NH
O NH
O N O
N O NH
O NH
O NH 2
N O N O
N NH
NH O
N O N O
O O NH
17681897_1 (GHMatters) P110989.NZ
N O N O N
NH NH
O NH
N O N
O NH
O NH
O NH
N O N
NH 2
17681897_1 (GHMatters) P110989.NZ
O NH
O NH
N NH
N N O
O NH NH
HN O
O NH
17681897_1 (GHMatters) P110989.NZ
O NH
O NH
O NH
N O N O
N N N
O NH
H 2 H
O NH H N O
H N O
17681897_1 (GHMatters) P110989.NZ
N O N O
NH NH
O NH
S NH
N N O
H N O
H N O
H N O
H N O
H N O
17681897_1 (GHMatters) P110989.NZ
N O N O
NH NH
O NH
O NH
2 NH
O O NH
N N O
O NH
17681897_1 (GHMatters) P110989.NZ
N N O
N N NH
N N O
O NH
O NH
2 NH
17681897_1 (GHMatters) P110989.NZ
N N N
O O N O
N O N O N O
N N N
N N N
H H H
O O O
NH NH NH
O NH
NH 2
N O N O
O NH
NH NH
17681897_1 (GHMatters) P110989.NZ
N O N O
O N N
N O O
NH NH
O NH
N O N O
O NH
NH NH
N O N O
O N N
O NH NH
O NH
17681897_1 (GHMatters) P110989.NZ
O NH
O NH
O NH
O NH
O NH O
17681897_1 (GHMatters) P110989.NZ
O NH
O NH
O NH
N O NH
O NH
N N N
O N O
N O N O
N N N
NH O NH
17681897_1 (GHMatters) P110989.NZ
N N O
NH O
N N N
N O N O
NH NH
NH O
17681897_1 (GHMatters) P110989.NZ
O O O
N O N O N O
N N N
N N N
H H H
O O O
NH NH NH
2 2 2
NH N
O NH N
O NH
O N O
N N O
N N O
NH NH
2 2 N
O NH
NH O N
17681897_1 (GHMatters) P110989.NZ
N O N O
NH NH
N O N O
O NH O NH
N 2 2
O NH
O O O
N O N O N O
N N N
H H H
N N N
O O O
NH NH NH
2 2 2
O NH
17681897_1 (GHMatters) P110989.NZ
O NH
NH O
O N O
O NH O NH
O NH
17681897_1 (GHMatters) P110989.NZ
2 NH
N N O
O NH NH
NH N
N N N
O NH
O NH
N N O
O NH NH
17681897_1 (GHMatters) P110989.NZ
NH NH
O NH
O NH
N NH
O NH NH
NH O
17681897_1 (GHMatters) P110989.NZ
O NH O NH
O NH
2 NH
2 O O
NH NH
O NH
O NH
2 2 O NH
17681897_1 (GHMatters) P110989.NZ
O NH
N N N
O O O
O O O
N N N
H H H
S S S
N N N
O O O
NH NH NH
2 2 2
O NH
O NH
O NH
O NH
17681897_1 (GHMatters) P110989.NZ
O NH
O N N
NH NH
NH 2 2
NH NH
O NH
N N N
O O O
O O O
N N N
H H H
O O O
N N N
O NH O O NH
2 2 2
17681897_1 (GHMatters) P110989.NZ
O NH
2 O NH
O NH
O NH
O NH
NH HN
O NH
17681897_1 (GHMatters) P110989.NZ
N N N
HN HN
NH NH
N N N
N N N
O O NH
O NH
O NH
O NH
17681897_1 (GHMatters) P110989.NZ
N HN
O NH
O NH
HN O
O NH
NH 2
N NH
O NH
O NH
O O O
HN HN
O O NH
NH NH
17681897_1 (GHMatters) P110989.NZ
HN HN
NH O NH
O NH
HN S
O NH O NH
HN S
NH NH
17681897_1 (GHMatters) P110989.NZ
2 NH O NH
N N N
NH NH
N N N
N N N
O O O
S N N
H H H
NH O NH O NH
N N N
O O O
O NH NH
17681897_1 (GHMatters) P110989.NZ
O O NH
N NH
2 NH
O NH NH
N NH
N O O
NH NH
H 2 2
17681897_1 (GHMatters) P110989.NZ
HN O
O NH
O NH
N N S
S HN O
NH NH
O NH
O NH
17681897_1 (GHMatters) P110989.NZ
O NH
O NH
NH NH
O NH
O NH
O NH
N N N
N N N
O O O
N N N
H H H
NH O NH
17681897_1 (GHMatters) P110989.NZ
N O O
NH NH
N N N
N N N
H H H
NH O O
NH NH
NH O
NH O
O NH
O O O
O O O
N N N
H H H
O HN N
O O O
NH NH NH
2 2 2
17681897_1 (GHMatters) P110989.NZ
NH NH
HN S
O NH
O NH O NH
N N N
N N N
HN S S
N N N
O O O
NH NH NH
2 2 2
N N N
O O O
O O O
N N N
S S S
H H H
N N N
O NH O NH O NH
2 2 2
17681897_1 (GHMatters) P110989.NZ
O NH
O NH
N NH
NH O
O NH
NH NH
17681897_1 (GHMatters) P110989.NZ
O NH NH
O NH
O NH NH 2
2 NH
NH 2
17681897_1 (GHMatters) P110989.NZ
NH O
O NH NH
O NH
NH O
2 NH
NH O
O O O
N N N
N N N
H H H
N N N
S S S
NH NH O NH
17681897_1 (GHMatters) P110989.NZ
O NH
O NH
O NH O NH
O NH
O NH
NH NH
O NH
17681897_1 (GHMatters) P110989.NZ
O NH 2
N N N
H N H
NH NH
O NH
NH N
O N O
H N H
O N NH
17681897_1 (GHMatters) P110989.NZ
NH N
NH H N
O NH
N N N
N H N
O NH
NH O
O O NH
NH NH
N N N
O S O
NH NH
O NH
17681897_1 (GHMatters) P110989.NZ
O NH H
O NH
O NH
S O NH
NH 2
O NH
O NH 2
17681897_1 (GHMatters) P110989.NZ
NH NH
O O 2
N N O
NH NH
NH N 2
N NH
17681897_1 (GHMatters) P110989.NZ
O NH
O NH
O NH
S O NH
N NH
N H 2
O NH
17681897_1 (GHMatters) P110989.NZ
H N O
2 NH
O NH
H N O S S
H N O
H N O
O NH
O NH
17681897_1 (GHMatters) P110989.NZ
O NH
NH N
H N O
N NH O
O NH
17681897_1 (GHMatters) P110989.NZ
O NH
O NH 2
N O NH
NH O
17681897_1 (GHMatters) P110989.NZ
O NH
N N N
O O O
O O O
O O O
O O NH O
NH NH
O NH
N NH
NH 2
N NH
O NH 2
17681897_1 (GHMatters) P110989.NZ
NH NH
O NH
O NH
O NH
N N N
O O O
N N N
N N N
H H H
O O O
O O O
NH NH NH
2 2 2
NH NH
17681897_1 (GHMatters) P110989.NZ
O NH
O O O
NH O O
NH NH
O NH
NH O
O NH
N N N
O O O
O O O
O NH O
NH NH
17681897_1 (GHMatters) P110989.NZ
N O O
NH NH
O NH
O NH
O NH
2 NH
17681897_1 (GHMatters) P110989.NZ
O O O
NH O
NH 2
O NH
N O O
NH NH
O NH
17681897_1 (GHMatters) P110989.NZ
O NH
O NH
O O NH
O NH O
2 O NH
17681897_1 (GHMatters) P110989.NZ
O NH O
O NH
N N N
O O O
O O O
N N N
HN HN
O NH O O NH
2 2 2
O NH
O NH
O NH
17681897_1 (GHMatters) P110989.NZ
O S N
O NH
O NH NH
O NH
N N N
O O O
S S S
O NH O O NH
2 2 2
17681897_1 (GHMatters) P110989.NZ
O NH
O NH N
O O O
O O O
O NH NH
N N N
O O O
O O O
N N N
H H H
O N N
O O O
NH NH NH
2 2 2
17681897_1 (GHMatters) P110989.NZ
O NH
O NH
2 2 O NH
N NH
NH O
O O O
NH NH
O NH
17681897_1 (GHMatters) P110989.NZ
O NH O NH
O NH
NH O
N NH
O NH O
2 NH
O NH
NH O
17681897_1 (GHMatters) P110989.NZ
O N O
N N O
NH NH
O NH
HN HN
NH NH
N N N
O O O
O O O
N N N
N N N
HN HN
O O NH O
NH NH
2 2 2
17681897_1 (GHMatters) P110989.NZ
HN HN
NH NH
O NH
HN HN
NH O NH
O NH
O NH O NH
O NH
17681897_1 (GHMatters) P110989.NZ
O O NH
O NH
O N N
HN HN
N O NH O
O NH
O NH O
NH NH
17681897_1 (GHMatters) P110989.NZ
HN HN
O NH O NH
2 2 N
HN O
O NH
HN N
O NH O
O NH
O NH
2 NH
17681897_1 (GHMatters) P110989.NZ
O NH
NH NH
N N N
O NH O NH
O NH
N N S
NH NH
17681897_1 (GHMatters) P110989.NZ
O NH
NH O
O NH
NH NH
HN N N
S HN
O NH O NH
17681897_1 (GHMatters) P110989.NZ
S N N
NH NH
2 2 NH
NH NH
2 2 NH
O NH
2 NH O
2 NH NH
17681897_1 (GHMatters) P110989.NZ
N N N
N H H
S O O
NH NH
O NH
O NH
O NH
O NH
O NH
S N O
NH NH
2 H 2
17681897_1 (GHMatters) P110989.NZ
N N N
H HN
O O N
NH NH
NH NH
NH 2
NH 2
17681897_1 (GHMatters) P110989.NZ
O NH
O O O
H H H
O NH NH O
O NH
O O NH
O NH
NH N
2 NH
17681897_1 (GHMatters) P110989.NZ
O HN
O NH O NH
N O NH
O NH
O O O
H H H
O O O
NH NH NH
2 2 2
O O O
O O O
N NH O
O NH O NH NH
2 2 2
17681897_1 (GHMatters) P110989.NZ
O O O
O N O
NH N N
NH O O
NH NH
2 2 2
O O O
N N N
H H H
NH O NH NH
O O O
O O N O
N N N
HN N
H H H
N S N
O O O
NH NH NH
2 2 2
S N HN
NH O NH
2 NH 2
17681897_1 (GHMatters) P110989.NZ
H N O
O NH
O NH
H N O H N O
NH NH
H N O H N O
O NH
17681897_1 (GHMatters) P110989.NZ
H N H N O
H N O
2 2 2
NH H
N NH
O H N O
N N O
O NH
H N H N O
2 O 2
17681897_1 (GHMatters) P110989.NZ
HN HN
O O O
O O O
N N N
HN N
H H H
O NH H N O H N O
2 2 2
NH N
N HN
H N O
O H N O 2
H N O
H N O
O NH 2
N O O
H N O
H N O 2
H N O
17681897_1 (GHMatters) P110989.NZ
NH O
O O O
O O O
N N N
N O N
H H H
HN N
H N O H N O H N O
2 2 2
NH O
H N O NH
H N O
NH O O
O O O
HN N
H H H
H N O H N
H N O O
N N O
N N N
H N O H N O H N O
2 H 2 2
17681897_1 (GHMatters) P110989.NZ
O O O
S HN
H H H
N N N
H N O O H N O
S NH
O O O
HN N N
N HN
H N O
H N O H N O
HN N
H N O H N O
H N O
S NH
O O O
N S N
H N O H N O
H N O
2 2 2
17681897_1 (GHMatters) P110989.NZ
H N O NH
H N O
H N O
H N O
H N O H N O
H N O
H N O
O O O
HN N
H H H
H N O
H N O H N O
2 2 2
17681897_1 (GHMatters) P110989.NZ
O NH N
H N O
H N O
H N O
H N O
H N O N
NH O NH
2 H N O
NH H
H N O O
H N O
17681897_1 (GHMatters) P110989.NZ
H N O
H N O
H N O
H N O
17681897_1 (GHMatters) P110989.NZ
17681897_1 (GHMatters) P110989.NZ
17681897_1 (GHMatters) P110989.NZ
17681897_1 (GHMatters) P110989.NZ
17681897_1 (GHMatters) P110989.NZ
17681897_1 (GHMatters) P110989.NZ
17681897_1 (GHMatters) P110989.NZ
17681897_1 (GHMatters) P110989.NZ
Where the compounds disclosed herein have at least one chiral center, they may
exist as individual enantiomers and diastereomers or as mixtures of such isomers, including
racemates. Separation of the individual isomers or selective synthesis of the individual isomers
is accomplished by application of various methods which are well known to practitioners in the
art. Unless otherwise indicated, all such isomers and mixtures thereof are included in the scope
of the compounds disclosed herein. Furthermore, compounds disclosed herein may exist in one
or more crystalline or amorphous forms. Unless otherwise indicated, all such forms are included
in the scope of the compounds disclosed herein including any polymorphic forms. In addition,
some of the compounds disclosed herein may form solvates with water (i.e., hydrates) or
common organic solvents. Unless otherwise indicated, such solvates are included in the scope of
the compounds disclosed herein.
The skilled artisan will recognize that some structures described herein may be
resonance forms or tautomers of compounds that may be fairly represented by other chemical
structures, even when kinetically; the artisan recognizes that such structures may only represent a
very small portion of a sample of such compound(s). Such compounds are considered within the
scope of the structures depicted, though such resonance forms or tautomers are not represented
herein.
Isotopically-Labeled Compounds
Isotopes may be present in the compounds described. Each chemical element
as represented in a compound structure may include any isotope of said element. The isotopes
may be isotopes of carbon, chlorine, fluorine, hydrogen, iodine, nitrogen, oxygen, phosphorous,
11 13 14 36 18 2 3 123 125 13 15 15 17 18
sulfur, and technetium, including C, C, C, Cl, F, H, H, I, I, N, N, O, O, O,
31 32 35 99m
P, P, S, and Tc. For example, in a compound structure a hydrogen atom may be explicitly
disclosed or understood to be present in the compound. At any position of the compound that a
hydrogen atom may be present, the hydrogen atom can be any isotope of hydrogen, including but
not limited to hydrogen-1 (protium) and hydrogen-2 (deuterium). Thus, reference herein to a
compound encompasses all potential isotopic forms unless the context clearly dictates otherwise.
Isotopically-labeled compounds of the present embodiments are useful in drug and substrate
tissue distribution and target occupancy assays. For example, isotopically labeled compounds are
17681897_1 (GHMatters) P110989.NZ
particularly useful in SPECT (single photon emission computed tomography) and in PET
(positron emission tomography), as discussed further herein.
Definitions
Unless defined otherwise, all technical and scientific terms used herein have
the same meaning as is commonly understood by one of ordinary skill in the art to which this
disclosure belongs. All patents, applications, published applications, and other publications are
incorporated by reference in their entirety. In the event that there is a plurality of definitions for a
term herein, those in this section prevail unless stated otherwise.
A “prodrug” refers to an agent that is converted into the parent drug in vivo.
Prodrugs are often useful because, in some situations, they may be easier to administer than the
parent drug. They may, for instance, be bioavailable by oral administration whereas the parent is
not. The prodrug may also have improved solubility in pharmaceutical compositions over the
parent drug. An example, without limitation, of a prodrug would be a compound which is
administered as an ester (the “prodrug”) to facilitate transmittal across a cell membrane where
water solubility is detrimental to mobility but which then is metabolically hydrolyzed to the
carboxylic acid, the active entity, once inside the cell where water-solubility is beneficial. A
further example of a prodrug might be a short peptide (polyaminoacid) bonded to an acid group
where the peptide is metabolized to reveal the active moiety. Conventional procedures for the
selection and preparation of suitable prodrug derivatives are described, for example, in Design of
Prodrugs, (ed. H. Bundgaard, Elsevier, 1985), which is hereby incorporated herein by reference
in its entirety.
The term “pro-drug ester” refers to derivatives of the compounds disclosed
herein formed by the addition of any of several ester-forming groups that are hydrolyzed under
physiological conditions. Examples of pro-drug ester groups include pivoyloxymethyl,
acetoxymethyl, phthalidyl, indanyl and methoxymethyl, as well as other such groups known in
the art, including a (5-Roxo-1,3-dioxolenyl)methyl group. Other examples of pro-drug ester
groups can be found in, for example, T. Higuchi and V. Stella, in "Pro-drugs as Novel Delivery
Systems", Vol. 14, A.C.S. Symposium Series, American Chemical Society (1975); and
"Bioreversible Carriers in Drug Design: Theory and Application", edited by E. B. Roche,
Pergamon Press: New York, 14-21 (1987) (providing examples of esters useful as prodrugs for
17681897_1 (GHMatters) P110989.NZ
compounds containing carboxyl groups). Each of the above-mentioned references is herein
incorporated by reference in their entirety.
“Metabolites” of the compounds disclosed herein include active species that are
produced upon introduction of the compounds into the biological milieu.
“Solvate” refers to the compound formed by the interaction of a solvent and a
compound described herein, a metabolite, or salt thereof. Suitable solvates are pharmaceutically
acceptable solvates including hydrates.
The term “pharmaceutically acceptable salt” refers to salts that retain the
biological effectiveness and properties of a compound, which are not biologically or otherwise
undesirable for use in a pharmaceutical. In many cases, the compounds herein are capable of
forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or
groups similar thereto. Pharmaceutically acceptable acid addition salts can be formed with
inorganic acids and organic acids. Inorganic acids from which salts can be derived include, for
example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the
like. Organic acids from which salts can be derived include, for example, acetic acid, propionic
acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric
acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid,
ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Pharmaceutically
acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases
from which salts can be derived include, for example, sodium, potassium, lithium, ammonium,
calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like; particularly
preferred are the ammonium, potassium, sodium, calcium and magnesium salts. Organic bases
from which salts can be derived include, for example, primary, secondary, and tertiary amines,
substituted amines including naturally occurring substituted amines, cyclic amines, basic ion
exchange resins, and the like, specifically such as isopropylamine, trimethylamine, diethylamine,
triethylamine, tripropylamine, and ethanolamine. Many such salts are known in the art, as
described in WO 87/05297, Johnston et al., published September 11, 1987 (incorporated by
reference herein in its entirety).
As used herein, “C to C ” or “C ” in which “a” and “b” are integers refer to
a b a-b
the number of carbon atoms in the specified group. That is, the group can contain from “a” to
17681897_1 (GHMatters) P110989.NZ
“b”, inclusive, carbon atoms. Thus, for example, a “C to C alkyl” or “C alkyl” group refers
1 4 1-4
to all alkyl groups having from 1 to 4 carbons, that is, CH -, CH CH -, CH CH CH -, (CH ) CH-
3 3 2 3 2 2 3 2
, CH CH CH CH -, CH CH CH(CH )- and (CH ) C-.
3 2 2 2 3 2 3 3 3
The term “halogen” or “halo,” as used herein, means any one of the radio-stable
atoms of column 7 of the Periodic Table of the Elements, e.g., fluorine, chlorine, bromine, or
iodine, with fluorine and chlorine being preferred.
As used herein, “alkyl” refers to a straight or branched hydrocarbon chain that
is fully saturated (i.e., contains no double or triple bonds). The alkyl group may have 1 to 20
carbon atoms (whenever it appears herein, a numerical range such as “1 to 20” refers to each
integer in the given range; e.g., “1 to 20 carbon atoms” means that the alkyl group may consist of
1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms,
although the present definition also covers the occurrence of the term “alkyl” where no numerical
range is designated). The alkyl group may also be a medium size alkyl having 1 to 9 carbon
atoms. The alkyl group could also be a lower alkyl having 1 to 4 carbon atoms. The alkyl group
of the compounds may be designated as “C alkyl” or similar designations. By way of example
only, “C alkyl” indicates that there are one to four carbon atoms in the alkyl chain, i.e., the
alkyl chain is selected from the group consisting of methyl, ethyl, propyl, iso-propyl, n-butyl, iso-
butyl, sec-butyl, and t-butyl. Typical alkyl groups include, but are in no way limited to, methyl,
ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, and the like.
As used herein, “haloalkyl” refers to a straight- or branched-chain alkyl group
having from 1 to 12 carbon atoms in the chain, substituting one or more hydrogens with
halogens. Examples of haloalkyl groups include, but are not limited to, -CF3, -CHF2, -CH2F, -
CH CF , -CH CHF , -CH CH F, -CH CH Cl, -CH CF CF and other groups that in light of the
2 3 2 2 2 2 2 2 2 2 3
ordinary skill in the art and the teachings provided herein, would be considered equivalent to any
one of the foregoing examples.
As used herein, “alkoxy” refers to the formula –OR wherein R is an alkyl as is
defined above, such as “C alkoxy”, including but not limited to methoxy, ethoxy, n-propoxy,
1-methylethoxy (isopropoxy), n-butoxy, iso-butoxy, sec-butoxy, and tert-butoxy, and the like.
17681897_1 (GHMatters) P110989.NZ
As used herein, “polyethylene glycol” refers to the formula
wherein n is an integer greater than one and R is a hydrogen or alkyl. The number of repeat units
“n” may be indicated by referring to a number of members. Thus, for example, “2- to 5-
membered polyethylene glycol” refers to n being an integer selected from two to five. In some
embodiments, R is selected from methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-
butoxy, iso-butoxy, sec-butoxy, and tert-butoxy.
As used herein, “heteroalkyl” refers to a straight or branched hydrocarbon chain
containing one or more heteroatoms, that is, an element other than carbon, including but not
limited to, nitrogen, oxygen and sulfur, in the chain backbone. The heteroalkyl group may have 1
to 20 carbon atoms although the present definition also covers the occurrence of the term
“heteroalkyl” where no numerical range is designated. The heteroalkyl group may also be a
medium size heteroalkyl having 1 to 9 carbon atoms. The heteroalkyl group could also be a
lower heteroalkyl having 1 to 4 carbon atoms. In various embodiments, the heteroalkyl may have
from 1 to 4 heteroatoms, from 1 to 3 heteroatoms, 1 or 2 heteroatoms, or 1 heteroatom. The
heteroalkyl group of the compounds may be designated as “C heteroalkyl” or similar
designations. The heteroalkyl group may contain one or more heteroatoms. By way of example
only, “C heteroalkyl” indicates that there are one to four carbon atoms in the heteroalkyl chain
and additionally one or more heteroatoms in the backbone of the chain.
The term “aromatic” refers to a ring or ring system having a conjugated pi
electron system and includes both carbocyclic aromatic (e.g., phenyl) and heterocyclic aromatic
groups (e.g., pyridine). The term includes monocyclic or fused-ring polycyclic (i.e., rings which
share adjacent pairs of atoms) groups provided that the entire ring system is aromatic.
As used herein, “aryl” refers to an aromatic ring or ring system (i.e., two or
more fused rings that share two adjacent carbon atoms) containing only carbon in the ring
backbone. When the aryl is a ring system, every ring in the system is aromatic. The aryl group
may have 6 to 18 carbon atoms, although the present definition also covers the occurrence of the
term “aryl” where no numerical range is designated. In some embodiments, the aryl group has 6
to 10 carbon atoms. The aryl group may be designated as “C aryl,” “C or C aryl,” or similar
6-10 6 10
17681897_1 (GHMatters) P110989.NZ
designations. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, azulenyl,
and anthracenyl.
As used herein, “aryloxy” and “arylthio” refers to RO- and RS-, in which R is
an aryl as is defined above, such as “C aryloxy” or “C arylthio” and the like, includingbut
6-10 6-10
not limited to phenyloxy.
An “aralkyl” or “arylalkyl” is an aryl group connected, as a substituent, via an
alkylene group, such “C aralkyl” and the like, including but not limited to benzyl, 2-
7-14
phenylethyl, 3-phenylpropyl, and naphthylalkyl. In some cases, the alkylene group is a lower
alkylene group (i.e., a C alkylene group).
As used herein, “heteroaryl” refers to an aromatic ring or ring system (i.e., two
or more fused rings that share two adjacent atoms) that contain(s) one or more heteroatoms, that
is, an element other than carbon, including but not limited to, nitrogen, oxygen and sulfur, in the
ring backbone. When the heteroaryl is a ring system, every ring in the system is aromatic. The
heteroaryl group may have 5-18 ring members (i.e., the number of atoms making up the ring
backbone, including carbon atoms and heteroatoms), although the present definition also covers
the occurrence of the term “heteroaryl” where no numerical range is designated. In some
embodiments, the heteroaryl group has 5 to 10 ring members or 5 to 7 ring members. The
heteroaryl group may be designated as “5-7 membered heteroaryl,” “5-10 membered heteroaryl,”
or similar designations. In various embodiments, a heteroaryl contains from 1 to 4 heteroatoms,
from 1 to 3 heteroatoms, from 1 to 2 heteroatoms, or 1 heteroatom. For example, in various
embodiments, a heteroaryl contains 1 to 4 nitrogen atoms, 1 to 3 nitrogen atoms, 1 to 2 nitrogen
atoms, 2 nitrogen atoms and 1 sulfur or oxygen atom, 1 nitrogen atom and 1 sulfur or oxygen
atom, or 1 sulfur or oxygen atom. Examples of heteroaryl rings include, but are not limited to,
furyl, thienyl, phthalazinyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl,
isothiazolyl, triazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl,
quinolinyl, isoquinlinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, indolyl, isoindolyl, and
benzothienyl.
A “heteroaralkyl” or “heteroarylalkyl” is heteroaryl group connected, as a
substituent, via an alkylene group. Examples include but are not limited to 2-thienylmethyl, 3-
thienylmethyl, furylmethyl, thienylethyl, pyrrolylalkyl, pyridylalkyl, isoxazollylalkyl, and
17681897_1 (GHMatters) P110989.NZ
imidazolylalkyl. In some cases, the alkylene group is a lower alkylene group (i.e., a C alkylene
group).
As used herein, “carbocyclyl” means a non-aromatic cyclic ring or ring system
containing only carbon atoms in the ring system backbone. When the carbocyclyl is a ring
system, two or more rings may be joined together in a fused, bridged or spiro-connected fashion.
Carbocyclyls may have any degree of saturation provided that at least one ring in a ring system is
not aromatic. Thus, carbocyclyls include cycloalkyls, cycloalkenyls, and cycloalkynyls. The
carbocyclyl group may have 3 to 20 carbon atoms, although the present definition also covers the
occurrence of the term “carbocyclyl” where no numerical range is designated. The carbocyclyl
group may also be a medium size carbocyclyl having 3 to 10 carbon atoms. The carbocyclyl
group could also be a carbocyclyl having 3 to 6 carbon atoms. The carbocyclyl group may be
designated as “C carbocyclyl” or similar designations. Examples of carbocyclyl rings include,
but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, 2,3-
dihydro-indene, bicycle[2.2.2]octanyl, adamantyl, and spiro[4.4]nonanyl.
A “(carbocyclyl)alkyl” is a carbocyclyl group connected, as a substituent, via an
alkylene group, such as “C (carbocyclyl)alkyl” and the like, including but not limited to,
4-10
cyclopropylmethyl, cyclobutylmethyl, cyclopropylethyl, cyclopropylbutyl, cyclobutylethyl,
cyclopropylisopropyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl,
cycloheptylmethyl, and the like. In some cases, the alkylene group is a lower alkylene group.
As used herein, “cycloalkyl” means a fully saturated carbocyclyl ring or ring
system. Examples include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
As used herein, “cycloalkenyl” means a carbocyclyl ring or ring system having
at least one double bond, wherein no ring in the ring system is aromatic. An example is
cyclohexenyl.
As used herein, “heterocyclyl” means a non-aromatic cyclic ring or ring system
containing at least one heteroatom in the ring backbone. Heterocyclyls may be joined together in
a fused, bridged or spiro-connected fashion. Heterocyclyls may have any degree of saturation
provided that at least one ring in the ring system is not aromatic. The heteroatom(s) may be
present in either a non-aromatic or aromatic ring in the ring system. The heterocyclyl group may
have 3 to 20 ring members (i.e., the number of atoms making up the ring backbone, including
17681897_1 (GHMatters) P110989.NZ
carbon atoms and heteroatoms), although the present definition also covers the occurrence of the
term “heterocyclyl” where no numerical range is designated. The heterocyclyl group may also be
a medium size heterocyclyl having 3 to 10 ring members. The heterocyclyl group could also be a
heterocyclyl having 3 to 6 ring members. The heterocyclyl group may be designated as “3-6
membered heterocyclyl” or similar designations.
In various embodiments, a heterocyclyl contains from 1 to 4 heteroatoms, from
1 to 3 heteroatoms, from 1 to 2 heteroatoms, or 1 heteroatom. For example, in various
embodiments, a heterocyclyl contains 1 to 4 nitrogen atoms, 1 to 3 nitrogen atoms, 1 to 2
nitrogen atoms, 2 nitrogen atoms and 1 sulfur or oxygen atom, 1 nitrogen atom and 1 sulfur or
oxygen atom, or 1 sulfur or oxygen atom. In preferred six membered monocyclic heterocyclyls,
the heteroatom(s) are selected from one up to three of O, N or S, and in preferred five membered
monocyclic heterocyclyls, the heteroatom(s) are selected from one or two heteroatoms selected
from O, N, or S. Examples of heterocyclyl rings include, but are not limited to, azepinyl,
acridinyl, carbazolyl, cinnolinyl, dioxolanyl, imidazolinyl, imidazolidinyl, morpholinyl, oxiranyl,
oxepanyl, thiepanyl, piperidinyl, piperazinyl, dioxopiperazinyl, pyrrolidinyl, pyrrolidonyl,
pyrrolidionyl, 4-piperidonyl, pyrazolinyl, pyrazolidinyl, 1,3-dioxinyl, 1,3-dioxanyl, 1,4-dioxinyl,
1,4-dioxanyl, 1,3-oxathianyl, 1,4-oxathiinyl, 1,4-oxathianyl, 2H-1,2-oxazinyl, trioxanyl,
hexahydro-1,3,5-triazinyl, 1,3-dioxolyl, 1,3-dioxolanyl, 1,3-dithiolyl, 1,3-dithiolanyl,
isoxazolinyl, isoxazolidinyl, oxazolinyl, oxazolidinyl, oxazolidinonyl, thiazolinyl, thiazolidinyl,
1,3-oxathiolanyl, indolinyl, isoindolinyl, tetrahydrofuranyl, tetrahydropyranyl,
tetrahydrothiophenyl, tetrahydrothiopyranyl, tetrahydro-1,4-thiazinyl, thiamorpholinyl,
dihydrobenzofuranyl, benzimidazolidinyl, and tetrahydroquinoline.
A “(heterocyclyl)alkyl” is a heterocyclyl group connected, as a substituent, via
an alkylene group. Examples include, but are not limited to, imidazolinylmethyl and
indolinylethyl.
As used herein, “acyl” refers to –C(=O)R, wherein R is hydrogen, C alkyl,
C alkenyl, C alkynyl, C carbocyclyl, aryl, 5-10 membered heteroaryl, and 5-10 membered
2-6 2-6 3-7
heterocyclyl, as defined herein. Non-limiting examples include formyl, acetyl, propanoyl,
benzoyl, and acryl.
17681897_1 (GHMatters) P110989.NZ
An “O-carboxy” group refers to a “-OC(=O)R” group in which R is selected
from hydrogen, C alkyl, C alkenyl, C alkynyl, C carbocyclyl, aryl, 5-10 membered
1-6 2-6 2-6 3-7
heteroaryl, and 5-10 membered heterocyclyl, as defined herein.
A “C-carboxy” group refers to a “-C(=O)OR” group in which R is selected
from hydrogen, C alkyl, C alkenyl, C alkynyl, C carbocyclyl, aryl, 5-10 membered
1-6 2-6 2-6 3-7
heteroaryl, and 5-10 membered heterocyclyl, as defined herein. A non-limiting example includes
carboxyl (i.e., -C(=O)OH).
A “cyano” group refers to a “-CN” group.
A “cyanato” group refers to an “-OCN” group.
An “isocyanato” group refers to a “-NCO” group.
A “thiocyanato” group refers to a “-SCN” group.
An “isothiocyanato” group refers to an “ -NCS” group.
A “sulfinyl” group refers to an “-S(=O)R” group in which R is selected from
hydrogen, C alkyl, C alkenyl, C alkynyl, C carbocyclyl, C aryl, 5-10 membered
1-6 2-6 2-6 3-7 6-10
heteroaryl, and 5-10 membered heterocyclyl, as defined herein.
A “sulfonyl” group refers to an “-SO2R” group in which R is selected from
hydrogen, C alkyl, C alkenyl, C alkynyl, C carbocyclyl, C aryl, 5-10 membered
1-6 2-6 2-6 3-7 6-10
heteroaryl, and 5-10 membered heterocyclyl, as defined herein.
An “S-sulfonamido” group refers to a “-SO NR R ” group in which R and R
2 A B A B
are each independently selected from hydrogen, C alkyl, C alkenyl, C alkynyl, C
1-6 2-6 2-6 3-7
carbocyclyl, C aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined
6-10
herein.
An “N-sulfonamido” group refers to a “-N(R )SO R ” group in which R and
A 2 B A
R are each independently selected from hydrogen, C alkyl, C alkenyl, C alkynyl, C
b 1-6 2-6 2-6 3-7
carbocyclyl, C aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined
6-10
herein.
An “O-carbamyl” group refers to a “-OC(=O)NR R ” group in which R and
A B A
R are each independently selected from hydrogen, C alkyl, C alkenyl, C alkynyl, C
B 1-6 2-6 2-6 3-7
carbocyclyl, C aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined
6-10
herein.
17681897_1 (GHMatters) P110989.NZ
An “N-carbamyl” group refers to an “-N(R )OC(=O)R ” group in which R
A B A
and R are each independently selected from hydrogen, C alkyl, C alkenyl, C alkynyl, C
B 1-6 2-6 2-6 3-7
carbocyclyl, C aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined
6-10
herein.
An “O-thiocarbamyl” group refers to a “-OC(=S)NR R ” group in which R
A B A
and R are each independently selected from hydrogen, C alkyl, C alkenyl, C alkynyl, C
B 1-6 2-6 2-6 3-7
carbocyclyl, C aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined
6-10
herein.
An “N-thiocarbamyl” group refers to an “-N(R )OC(=S)R ” group in which R
A B A
and R are each independently selected from hydrogen, C alkyl, C alkenyl, C alkynyl, C
B 1-6 2-6 2-6 3-7
carbocyclyl, C aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined
6-10
herein.
A “C-amido” group refers to a “-C(=O)NR R ” group in which R and R are
A B A B
each independently selected from hydrogen, C alkyl, C alkenyl, C alkynyl, C
1-6 2-6 2-6 3-7
carbocyclyl, C aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined
6-10
herein.
An “N-amido” group refers to a “-N(R )C(=O)R ” group in which R and R
A B A B
are each independently selected from hydrogen, C alkyl, C alkenyl, C alkynyl, C
1-6 2-6 2-6 3-7
carbocyclyl, C aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined
6-10
herein.
An “amino” group refers to a “-NR R ” group in which R and R are each
A B A B
independently selected from hydrogen, C alkyl, C alkenyl, C alkynyl, C carbocyclyl, C
1-6 2-6 2-6 3-7 6-
aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.
An “aminoalkyl” group refers to an amino group connected via an alkylene
group.
An “alkoxyalkyl” group refers to an alkoxy group connected via an alkylene
group, such as a “C alkoxyalkyl” and the like.
As used herein, a “natural amino acid side chain” refers to the side-chain
substituent of a naturally occuring amino acid. Naturally occurring amino acids have a
substituent attached to the α–carbon. Naturally occurring amino acids include Arginine, Lysine,
17681897_1 (GHMatters) P110989.NZ
Aspartic acid, Glutamic acid, Glutamine, Asparagine, Histidine, Serine, Threonine, Tyrosine,
Cysteine, Methionine, Tryptophan, Alanine, Isoleucine, Leucine, Phenylalanine, Valine, Proline,
and Glycine.
As used herein, a “non-natural amino acid side chain” refers to the side-chain
substituent of a non-naturally occurring amino acid. Non-natural amino acids include β-amino
acids (β and β ), Homo-amino acids, Proline and Pyruvic acid derivatives, 3-substituted Alanine
derivatives, Glycine derivatives, Ring-substituted Phenylalanine and Tyrosine Derivatives,
Linear core amino acids and N-methyl amino acids. Exemplary non-natural amino acids are
available from Sigma-Aldridge, listed under “unnatural amino acids & derivatives.” See also,
Travis S. Young and Peter G. Schultz, “Beyond the Canonical 20 Amino Acids: Expanding the
Genetic Lexicon,” J. Biol. Chem. 2010 285: 11039-11044, which is incorporated by reference in
its entirety.
As used herein, a substituted group is derived from the unsubstituted parent
group in which there has been an exchange of one or more hydrogen atoms for another atom or
group. Unless otherwise indicated, when a group is deemed to be “substituted,” it is meant that
the group is substituted with one or more subsitutents independently selected from C -C alkyl,
C -C alkenyl, C -C alkynyl, C -C heteroalkyl, C -C carbocyclyl (optionally substituted with
1 6 1 6 1 6 3 7
halo, C -C alkyl, C -C alkoxy, C -C haloalkyl, and C -C haloalkoxy), C -C -carbocyclyl-C -
1 6 1 6 1 6 1 6 3 7 1
C -alkyl (optionally substituted with halo, C -C alkyl, C -C alkoxy, C -C haloalkyl, and C -C
6 1 6 1 6 1 6 1 6
haloalkoxy), 5-10 membered heterocyclyl (optionally substituted with halo, C -C alkyl, C -C
1 6 1 6
alkoxy, C -C haloalkyl, and C -C haloalkoxy), 5-10 membered heterocyclyl-C -C -alkyl
1 6 1 6 1 6
(optionally substituted with halo, C -C alkyl, C -C alkoxy, C -C haloalkyl, and C -C
1 6 1 6 1 6 1 6
haloalkoxy), aryl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl,
and C -C haloalkoxy), aryl(C -C )alkyl (optionally substituted with halo, C -C alkyl, C -C
1 6 1 6 1 6 1 6
alkoxy, C -C haloalkyl, and C -C haloalkoxy), 5-10 membered heteroaryl (optionally
1 6 1 6
substituted with halo, C -C alkyl, C -C alkoxy, C -C haloalkyl, and C -C haloalkoxy), 5-10
1 6 1 6 1 6 1 6
membered heteroaryl(C -C )alkyl (optionally substituted with halo, C -C alkyl, C -C alkoxy,
1 6 1 6 1 6
C -C haloalkyl, and C -C haloalkoxy), halo, cyano, hydroxy, C -C alkoxy, C -C alkoxy(C -
1 6 1 6 1 6 1 6 1
C )alkyl (i.e., ether), aryloxy, sulfhydryl (mercapto), halo(C -C )alkyl (e.g., –CF ), halo(C -
6 1 6 3 1
C )alkoxy (e.g., –OCF ), C -C alkylthio, arylthio, amino, amino(C -C )alkyl, nitro, O-carbamyl,
6 3 1 6 1 6
17681897_1 (GHMatters) P110989.NZ
N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-
sulfonamido, C-carboxy, O-carboxy, acyl, cyanato, isocyanato, thiocyanato, isothiocyanato,
sulfinyl, sulfonyl, and oxo (=O). Wherever a group is described as “optionally substituted” that
group can be substituted with the above substituents.
In some embodiments, substituted group(s) is (are) substituted with one or
more substituent(s) individually and independently selected from C -C alkyl, amino, hydroxy,
and halogen.
It is to be understood that certain radical naming conventions can include either
a mono-radical or a di-radical, depending on the context. For example, where a substituent
requires two points of attachment to the rest of the molecule, it is understood that the substituent
is a di-radical. For example, a substituent identified as alkyl that requires two points of
attachment includes di-radicals such as –CH –, –CH CH –, –CH CH(CH )CH –, and the like.
2 2 2 2 3 2
Other radical naming conventions clearly indicate that the radical is a di-radical such as
“alkylene” or “alkenylene.”
When two R groups are said to form a ring (e.g., a carbocyclyl, heterocyclyl,
aryl, or heteroaryl ring) “together with the atom to which they are attached,” it is meant that the
collective unit of the atom and the two R groups are the recited ring. The ring is not otherwise
limited by the definition of each R group when taken individually. For example, when the
following substructure is present:
1 2 1
and R and R are defined as selected from the group consisting of hydrogen and alkyl, or R and
R together with the nitrogen to which they are attached form a heterocyclyl, it is meant that R
and R can be selected from hydrogen or alkyl, or alternatively, the substructure has structure:
where ring A is a heterocyclyl ring containing the depicted nitrogen.
Similarly, when two “adjacent” R groups are said to form a ring “together with
the atoms to which they are attached,” it is meant that the collective unit of the atoms,
17681897_1 (GHMatters) P110989.NZ
intervening bonds, and the two R groups are the recited ring. For example, when the following
substructure is present:
1 2 1
and R and R are defined as selected from the group consisting of hydrogen and alkyl, or R and
R together with the atoms to which they are attached form an aryl or carbocyclyl, it is meant that
R and R can be selected from hydrogen or alkyl, or alternatively, the substructure has structure:
where A is an aryl ring or a carbocyclyl containing the depicted double bond.
Wherever a substituent is depicted as a di-radical (i.e., has two points of
attachment to the rest of the molecule), it is to be understood that the substituent can be attached
in any directional configuration unless otherwise indicated. Thus, for example, a substituent
depicted as –AE– or includes the substituent being oriented such that the A is
attached at the leftmost attachment point of the molecule as well as the case in which A is
attached at the rightmost attachment point of the molecule.
As used herein, the substructure:
17681897_1 (GHMatters) P110989.NZ
means that the A atom can be in any ring atom position within the ring or ring
system A . The substructure: means that the A atom is in the ring atom
position immediately adjacent (i.e., alpha) to the point of attachment indicated by *.
As used herein, "isosteres" of a chemical group are other chemical groups that
exhibit the same or similar properties. For example, tetrazole is an isostere of carboxylic acid
because it mimics the properties of carboxylic acid even though they both have very different
molecular formulae. Tetrazole is one of many possible isosteric replacements for carboxylic
acid. Other carboxylic acid isosteres contemplated include -SO H, -SO HNR, -PO (R) , -
3 2 2 2
PO (R) , -CONHNHSO R, -COHNSO R, and –CONRCN, where R is selected from hydrogen,
3 2 2 2
C alkyl, C alkenyl, C alkynyl, C carbocyclyl, C aryl, 5-10 membered heteroaryl, and
1-6 2-6 2-6 3-7 6-10
3-10 membered heterocyclyl, as defined herein. In addition, carboxylic acid isosteres can include
-7 membered carbocycles or heterocycles containing any combination of CH , O, S, or N in any
chemically stable oxidation state, where any of the atoms of said ring structure are optionally
substituted in one or more positions. The following structures are non-limiting examples of
carbocyclic and heterocyclic isosteres contemplated. The atoms of said ring structure may be
optionally substituted at one or more positions with R as defined above.
N N N N N
N N N N N N
HN N N N HN N N NH NH
O C HS
17681897_1 (GHMatters) P110989.NZ
N N N
O N O
O N S N HN O
F OH
OH O O O
NH N NH NH
NH HN O S
O O O
It is also contemplated that when chemical substituents are added to a
carboxylic isostere, the compound retains the properties of a carboxylic isostere. It is
contemplated that when a carboxylic isostere is optionally substituted with one or more moieties
selected from R as defined above, then the substitution and substitution position is selected such
that it does not eliminate the carboxylic acid isosteric properties of the compound. Similarly, it is
also contemplated that the placement of one or more R substituents upon a carbocyclic or
heterocyclic carboxylic acid isostere is not a substitution at one or more atom(s) that maintain(s)
or is/are integral to the carboxylic acid isosteric properties of the compound, if such
substituent(s) would destroy the carboxylic acid isosteric properties of the compound.
Other carboxylic acid isosteres not specifically exemplified in this specification
are also contemplated.
The term “agent” or “test agent” includes any substance, molecule, element,
compound, entity, or a combination thereof. It includes, but is not limited to, e.g., protein,
polypeptide, peptide or mimetic, small organic molecule, polysaccharide, polynucleotide, and the
like. It can be a natural product, a synthetic compound, or a chemical compound, or a
combination of two or more substances. Unless otherwise specified, the terms “agent”,
“substance”, and “compound” are used interchangeably herein.
The term “analog” is used herein to refer to a molecule that structurally
resembles a reference molecule but which has been modified in a targeted and controlled manner,
by replacing a specific substituent of the reference molecule with an alternate substituent.
Compared to the reference molecule, an analog would be expected, by one skilled in the art, to
exhibit the same, similar, or improved utility. Synthesis and screening of analogs, to identify
variants of known compounds having improved characteristics (such as higher binding affinity
for a target molecule) is an approach that is well known in pharmaceutical chemistry.
17681897_1 (GHMatters) P110989.NZ
The term “mammal” is used in its usual biological sense. Thus, it specifically
includes, but is not limited to, primates, including simians (chimpanzees, apes, monkeys) and
humans, cattle, horses, sheep, goats, swine, rabbits, dogs, cats, rats and mice but also includes
many other species.
The term “microbial infection” refers to the invasion of the host organism,
whether the organism is a vertebrate, invertebrate, fish, plant, bird, or mammal, by pathogenic
microbes. This includes the excessive growth of microbes that are normally present in or on the
body of a mammal or other organism. More generally, a microbial infection can be any situation
in which the presence of a microbial population(s) is damaging to a host mammal. Thus, a
mammal is “suffering” from a microbial infection when excessive numbers of a microbial
population are present in or on a mammal’s body, or when the effects of the presence of a
microbial population(s) is damaging the cells or other tissue of a mammal. Specifically, this
description applies to a bacterial infection. Note that the compounds of preferred embodiments
are also useful in treating microbial growth or contamination of cell cultures or other media, or
inanimate surfaces or objects, and nothing herein should limit the preferred embodiments only to
treatment of higher organisms, except when explicitly so specified in the claims.
The term “pharmaceutically acceptable carrier” or “pharmaceutically
acceptable excipient” includes any and all solvents, dispersion media, coatings, antibacterial and
antifungal agents, isotonic and absorption delaying agents and the like. The use of such media
and agents for pharmaceutically active substances is well known in the art. Except insofar as any
conventional media or agent is incompatible with the active ingredient, its use in the therapeutic
compositions is contemplated. In addition, various adjuvants such as are commonly used in the
art may be included. Considerations for the inclusion of various components in pharmaceutical
compositions are described, e.g., in Gilman et al. (Eds.) (1990); Goodman and Gilman’s: The
Pharmacological Basis of Therapeutics, 8th Ed., Pergamon Press, which is incorporated herein by
reference in its entirety.
“Subject” as used herein, means a human or a non-human mammal, e.g., a dog,
a cat, a mouse, a rat, a cow, a sheep, a pig, a goat, a non-human primate or a bird, e.g., a chicken,
as well as any other vertebrate or invertebrate.
17681897_1 (GHMatters) P110989.NZ
An “effective amount” or a “therapeutically effective amount” as used herein
refers to an amount of a therapeutic agent that is effective to relieve, to some extent, or to reduce
the likelihood of onset of, one or more of the symptoms of a disease or condition, and includes
curing a disease or condition. “Curing” means that the symptoms of a disease or condition are
eliminated; however, certain long-term or permanent effects may exist even after a cure is
obtained (such as extensive tissue damage).
“Treat,” “treatment,” or “treating,” as used herein refers to administering a
pharmaceutical composition for prophylactic and/or therapeutic purposes. The term
“prophylactic treatment” refers to treating a subject who does not yet exhibit symptoms of a
disease or condition, but who is susceptible to, or otherwise at risk of, a particular disease or
condition, whereby the treatment reduces the likelihood that the patient will develop the disease
or condition. The term “therapeutic treatment” refers to administering treatment to a
Methods of Preparation
The compounds disclosed herein may be synthesized by methods described
below, or by modification of these methods. Ways of modifying the methodology include,
among others, temperature, solvent, reagents etc., known to those skilled in the art. In general,
during any of the processes for preparation of the compounds disclosed herein, it may be
necessary and/or desirable to protect sensitive or reactive groups on any of the molecules
concerned. This may be achieved by means of conventional protecting groups, such as those
described in Protective Groups in Organic Chemistry (ed. J.F.W. McOmie, Plenum Press, 1973);
and P.G.M. Green, T.W. Wutts, Protecting Groups in Organic Synthesis (3rd ed.) Wiley, New
York (1999), which are both hereby incorporated herein by reference in their entirety. The
protecting groups may be removed at a convenient subsequent stage using methods known from
the art. Synthetic chemistry transformations useful in synthesizing applicable compounds are
known in the art and include e.g. those described in R. Larock, Comprehensive Organic
Transformations, VCH Publishers, 1989, or L. Paquette, ed., Encyclopedia of Reagents for
Organic Synthesis, John Wiley and Sons, 1995, which are both hereby incorporated herein by
reference in their entirety. The routes shown and described herein are illustrative only and are not
intended, nor are they to be construed, to limit the scope of the claims in any manner whatsoever.
Those skilled in the art will be able to recognize modifications of the disclosed syntheses and to
17681897_1 (GHMatters) P110989.NZ
devise alternate routes based on the disclosures herein; all such modifications and alternate
routes are within the scope of the claims.
In the following schemes, protecting groups for oxygen atoms are selected for
their compatibility with the requisite synthetic steps as well as compatibility of the introduction
and deprotection steps with the overall synthetic schemes (P.G.M. Green, T.W. Wutts, Protecting
Groups in Organic Synthesis (3rd ed.) Wiley, New York (1999)).
If the compounds of the present technology contain one or more chiral centers,
such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual
enantiomers or d(l) stereoisomers, or as stereoisomer-enriched mixtures. All such stereoisomers
(and enriched mixtures) are included within the scope of the present technology, unless otherwise
indicated. Pure stereoisomers (or enriched mixtures) may be prepared using, for example,
optically active starting materials or stereoselective reagents well-known in the art.
Alternatively, racemic mixtures of such compounds can be separated using, for example, chiral
column chromatography, chiral resolving agents and the like.
The starting materials for the following reactions are generally known
compounds or can be prepared by known procedures or obvious modifications thereof. For
example, many of the starting materials are available from commercial suppliers such as Aldrich
Chemical Co. (Milwaukee, Wisconsin, USA), Bachem (Torrance, California , USA), Emka-
Chemce or Sigma (St. Louis, Missouri, USA). Others may be prepared by procedures, or
obvious modifications thereof, described in standard reference texts such as Fieser and Fieser's
Reagents for Organic Synthesis, Volumes 1-15 (John Wiley, and Sons, 1991), Rodd's Chemistry
of Carbon Compounds, Volumes 1-5, and Supplementals (Elsevier Science Publishers, 1989),
Organic Reactions, Volumes 1-40 (John Wiley, and Sons, 1991), March's Advanced Organic
Chemistry, (John Wiley, and Sons, 5th Edition, 2001), and Larock's Comprehensive Organic
Transformations (VCH Publishers Inc., 1989)..
Synthesis of Compounds of Formula I
In one embodiment, the method involves reacting an appropriately substituted
intermediate with an acidic hydrogen (IV) with an ester (V) under base catalyzed conditions to
yield the ester derivative (VI). The resulting product was then subjected to hydrolysis under
basic conditions to yield the carboxylic acid derivative (VII) which was then subjected to amide-
17681897_1 (GHMatters) P110989.NZ
coupling conditions with an amino acid derivative (VIII) wherein the carboxylic acid group is
functionalized with the R group (Scheme 1). Alternatively, the carboxylic acid product (VII) is
then subjected to amide coupling conditions with the amino alcohol derivative (VIII-a) to yield
the corresponding adduct (IX). The resulting adduct (IX) is subjected to oxidation conditions
with DMP oxidation (with hypervalent iodine) or by an oxidizing agent such as PCC (pyridinium
chlorochromate) to yield the α-ketoamide product (X). Alternately, the adduct (IX) was
subjected to oxidation conditions using EDC and dichloroacetic acid or using IBX as the
oxidizing agent to yield the α-ketoamide product (X). The skilled artisan will once again
appreciate that there are many other oxidizing conditions and agents which are within the scope
of this disclosure to oxidize the hydroxyl group. This synthesis route is generally shown in
Scheme 2.
Scheme 1:
Basic
4 Base Catalyzed hydrolysis
2 6 A O A
R 2 5
H N A R
A VIII
Amide Conditions O
Coupling
17681897_1 (GHMatters) P110989.NZ
Scheme 2:
A O A
8 1 H
VIII-a
Amide Conditions
Coupling
A O A
Oxidation
The following example schemes are provided for the guidance of the reader,
and collectively represent an example method for making the compounds encompassed herein.
Furthermore, other methods for preparing compounds described herein will be readily apparent
to the person of ordinary skill in the art in light of the following reaction schemes and examples.
Unless otherwise indicated, all variables are as defined above.
Uses of Isotopically-Labeled Compounds
Some embodiments provide a method of using isotopically labeled compounds
and prodrugs of the present disclosure in: (i) metabolic studies (preferably with C), reaction
kinetic studies (with, for example 2H or 3H); (ii) detection or imaging techniques [such as
positron emission tomography (PET) or single-photon emission computed tomography (SPECT)]
including drug or substrate tissue distribution assays; or (III) in radioactive treatment of patients.
Isotopically labeled compounds and prodrugs of the embodiments thereof can
generally be prepared by carrying out the procedures disclosed in the schemes or in the examples
and preparations described below by substituting a readily available isotopically labeled reagent
18 11
for a non-isotopically labeled reagent. An F or C labeled compound may be particularly
preferred for PET, and an I labeled compound may be particularly preferred for SPECT
17681897_1 (GHMatters) P110989.NZ
studies. Further substitution with heavier isotopes such as deuterium (i.e., H) may afford certain
therapeutic advantages resulting from greater metabolic stability, for example increased in vivo
half-life or reduced dosage requirements.
Synthesis of Isotopically Labeled Compounds
F labeled compounds are synthesized as shown in the schemes below. In one
embodiment, the method involves reacting the intermediate 450 with a F-labeling agent using
conditions as described in Rotstein, et al., Spirocyclic hypervalent iodine(III)-mediated
radiofluorination of non-activated and hindered aromatics, Nature Communications, 2014, Vol. 5,
4365-4371 and Rotstein, et al., Mechanistic Studies and Radiofluorination of Structurally
Diverse Pharmaceuticals with Spirocyclic Iodonium(III) Ylides, Chemical Science, 2016, Vol. 7,
4407-4417, both of which are incorporated herein by reference in their entirety, to yield the F-
labeled intermediate methyl 2-((ethoxycarbonyl)amino)(4-(fluoro- F)phenyl)propanoate
(631) which is then transformed into the final α-ketoamide product represented by the general
structure XI (Scheme 3).
Scheme 3:
18 Scheme 1
steps
synthetic
O A H
Alternately, F-labeled compound XV is synthesized as shown in Scheme 4.
In one embodiment, iodanylidene intermediate XII is used to introduce the F label yielding
using conditons as described in Rotstein, et al., Spirocyclic hypervalent iodine(III)-mediated
radiofluorination of non-activated and hindered aromatics, Nature Communications, 2014, Vol. 5,
4365-4371 and Rotstein, et al., Mechanistic Studies and Radiofluorination of Structurally
Diverse Pharmaceuticals with Spirocyclic Iodonium(III) Ylides, Chemical Science, 2016, Vol. 7,
4407-4417 to yield the labeled α-ketoamide product XV. In another embodiment, iodanylidene
intermediate (XIV) is (Scheme 4) subjected to oxidation conditions with DMP oxidation (with
hypervalent iodine) or by an oxidizing agent such as PCC (pyridinium chlorochromate) to yield
17681897_1 (GHMatters) P110989.NZ
the α-ketoamide product (XV). In yet another embodiment, iodanylidene intermediate (XIII)
(Scheme 4) is subjected to F-labeling reaction conditions as described earlier followed by
hydrolysis of the ester under basic conditions to yield the carboxylic acid derivative which is then
subjected to amide-coupling conditions with an amino acid derivative wherein the carboxylic
acid group is functionalized with the R group to yield the labeled α-ketoamide product XV.
Scheme 4:
O 5 O A
NH N R
F XIV
O O 8
XIII
Administration and Pharmaceutical Compositions
The compounds are administered at a therapeutically effective dosage. While
human dosage levels have yet to be optimized for the compounds described herein, generally, a
daily dose may be from about 0.25 mg/kg to about 120 mg/kg or more of body weight, from
about 0.5 mg/kg or less to about 70 mg/kg, from about 1.0 mg/kg to about 50 mg/kg of body
weight, or from about 1.5 mg/kg to about 10 mg/kg of body weight. Thus, for administration to a
70 kg person, the dosage range would be from about 17 mg per day to about 8000 mg per day,
from about 35 mg per day or less to about 7000 mg per day or more, from about 70 mg per day to
about 6000 mg per day, from about 100 mg per day to about 5000 mg per day, or from about 200
mg to about 3000 mg per day. The amount of active compound administered will, of course, be
17681897_1 (GHMatters) P110989.NZ
dependent on the subject and disease state being treated, the severity of the affliction, the manner
and schedule of administration and the judgment of the prescribing physician.
Administration of the compounds disclosed herein or the pharmaceutically
acceptable salts thereof can be via any of the accepted modes of administration for agents that
serve similar utilities including, but not limited to, orally, subcutaneously, intravenously,
intranasally, topically, transdermally, intraperitoneally, intramuscularly, intrapulmonarilly,
vaginally, rectally, or intraocularly. Oral and parenteral administrations are customary in treating
the indications that are the subject of the preferred embodiments.
The compounds useful as described above can be formulated into
pharmaceutical compositions for use in treatment of these conditions. Standard pharmaceutical
formulation techniques are used, such as those disclosed in Remington's The Science and
Practice of Pharmacy, 21st Ed., Lippincott Williams & Wilkins (2005), incorporated by reference
in its entirety. Accordingly, some embodiments include pharmaceutical compositions
comprising: (a) a safe and therapeutically effective amount of a compound described herein
(including enantiomers, diastereoisomers, tautomers, polymorphs, and solvates thereof), or
pharmaceutically acceptable salts thereof; and (b) a pharmaceutically acceptable carrier, diluent,
excipient or combination thereof.
In addition to the selected compound useful as described above, come
embodiments include compositions containing a pharmaceutically-acceptable carrier. The term
“pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” includes any
and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and
absorption delaying agents and the like. The use of such media and agents for pharmaceutically
active substances is well known in the art. Except insofar as any conventional media or agent is
incompatible with the active ingredient, its use in the therapeutic compositions is contemplated.
In addition, various adjuvants such as are commonly used in the art may be included.
Considerations for the inclusion of various components in pharmaceutical compositions are
described, e.g., in Gilman et al. (Eds.) (1990); Goodman and Gilman’s: The Pharmacological
Basis of Therapeutics, 8th Ed., Pergamon Press, which is incorporated herein by reference in its
entirety.
17681897_1 (GHMatters) P110989.NZ
Some examples of substances, which can serve as pharmaceutically-acceptable
carriers or components thereof, are sugars, such as lactose, glucose and sucrose; starches, such as
corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl
cellulose, ethyl cellulose, and methyl cellulose; powdered tragacanth; malt; gelatin; talc; solid
lubricants, such as stearic acid and magnesium stearate; calcium sulfate; vegetable oils, such as
peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and oil of theobroma; polyols such as
propylene glycol, glycerine, sorbitol, mannitol, and polyethylene glycol; alginic acid; emulsifiers,
such as the TWEENS; wetting agents, such sodium lauryl sulfate; coloring agents; flavoring
agents; tableting agents, stabilizers; antioxidants; preservatives; pyrogen-free water; isotonic
saline; and phosphate buffer solutions.
The choice of a pharmaceutically-acceptable carrier to be used in conjunction
with the subject compound is basically determined by the way the compound is to be
administered.
The compositions described herein are preferably provided in unit dosage form.
As used herein, a "unit dosage form" is a composition containing an amount of a compound that
is suitable for administration to an animal, preferably mammal subject, in a single dose,
according to good medical practice. The preparation of a single or unit dosage form however,
does not imply that the dosage form is administered once per day or once per course of therapy.
Such dosage forms are contemplated to be administered once, twice, thrice or more per day and
may be administered as infusion over a period of time (e.g., from about 30 minutes to about 2-6
hours), or administered as a continuous infusion, and may be given more than once during a
course of therapy, though a single administration is not specifically excluded. The skilled artisan
will recognize that the formulation does not specifically contemplate the entire course of therapy
and such decisions are left for those skilled in the art of treatment rather than formulation.
The compositions useful as described above may be in any of a variety of
suitable forms for a variety of routes for administration, for example, for oral, nasal, rectal,
topical (including transdermal), ocular, intracerebral, intracranial, intrathecal, intra-arterial,
intravenous, intramuscular, or other parental routes of administration. The skilled artisan will
appreciate that oral and nasal compositions comprise compositions that are administered by
inhalation, and made using available methodologies. Depending upon the particular route of
17681897_1 (GHMatters) P110989.NZ
administration desired, a variety of pharmaceutically-acceptable carriers well-known in the art
may be used. Pharmaceutically-acceptable carriers include, for example, solid or liquid fillers,
diluents, hydrotropies, surface-active agents, and encapsulating substances. Optional
pharmaceutically-active materials may be included, which do not substantially interfere with the
inhibitory activity of the compound. The amount of carrier employed in conjunction with the
compound is sufficient to provide a practical quantity of material for administration per unit dose
of the compound. Techniques and compositions for making dosage forms useful in the methods
described herein are described in the following references, all incorporated by reference herein:
Modern Pharmaceutics, 4th Ed., Chapters 9 and 10 (Banker & Rhodes, editors, 2002); Lieberman
et al., Pharmaceutical Dosage Forms: Tablets (1989); and Ansel, Introduction to Pharmaceutical
Dosage Forms 8th Edition (2004).
Various oral dosage forms can be used, including such solid forms as tablets,
capsules, granules and bulk powders. Tablets can be compressed, tablet triturates, enteric-coated,
sugar-coated, film-coated, or multiple-compressed, containing suitable binders, lubricants,
diluents, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents, and
melting agents. Liquid oral dosage forms include aqueous solutions, emulsions, suspensions,
solutions and/or suspensions reconstituted from non-effervescent granules, and effervescent
preparations reconstituted from effervescent granules, containing suitable solvents, preservatives,
emulsifying agents, suspending agents, diluents, sweeteners, melting agents, coloring agents and
flavoring agents.
The pharmaceutically-acceptable carrier suitable for the preparation of unit
dosage forms for peroral administration is well-known in the art. Tablets typically comprise
conventional pharmaceutically-compatible adjuvants as inert diluents, such as calcium carbonate,
sodium carbonate, mannitol, lactose and cellulose; binders such as starch, gelatin and sucrose;
disintegrants such as starch, alginic acid and croscarmelose; lubricants such as magnesium
stearate, stearic acid and talc. Glidants such as silicon dioxide can be used to improve flow
characteristics of the powder mixture. Coloring agents, such as the FD&C dyes, can be added for
appearance. Sweeteners and flavoring agents, such as aspartame, saccharin, menthol,
peppermint, and fruit flavors, are useful adjuvants for chewable tablets. Capsules typically
comprise one or more solid diluents disclosed above. The selection of carrier components
17681897_1 (GHMatters) P110989.NZ
depends on secondary considerations like taste, cost, and shelf stability, which are not critical,
and can be readily made by a person skilled in the art.
Peroral compositions also include liquid solutions, emulsions, suspensions, and
the like. The pharmaceutically-acceptable carriers suitable for preparation of such compositions
are well known in the art. Typical components of carriers for syrups, elixirs, emulsions and
suspensions include ethanol, glycerol, propylene glycol, polyethylene glycol, liquid sucrose,
sorbitol and water. For a suspension, typical suspending agents include methyl cellulose, sodium
carboxymethyl cellulose, AVICEL RC-591, tragacanth and sodium alginate; typical wetting
agents include lecithin and polysorbate 80; and typical preservatives include methyl paraben and
sodium benzoate. Peroral liquid compositions may also contain one or more components such as
sweeteners, flavoring agents and colorants disclosed above.
Such compositions may also be coated by conventional methods, typically with
pH or time-dependent coatings, such that the subject compound is released in the gastrointestinal
tract in the vicinity of the desired topical application, or at various times to extend the desired
action. Such dosage forms typically include, but are not limited to, one or more of cellulose
acetate phthalate, polyvinylacetate phthalate, hydroxypropyl methyl cellulose phthalate, ethyl
cellulose, Eudragit coatings, waxes and shellac.
Compositions described herein may optionally include other drug actives.
Other compositions useful for attaining systemic delivery of the subject
compounds include sublingual, buccal and nasal dosage forms. Such compositions typically
comprise one or more of soluble filler substances such as sucrose, sorbitol and mannitol; and
binders such as acacia, microcrystalline cellulose, carboxymethyl cellulose and hydroxypropyl
methyl cellulose. Glidants, lubricants, sweeteners, colorants, antioxidants and flavoring agents
disclosed above may also be included.
A liquid composition, which is formulated for topical ophthalmic use, is
formulated such that it can be administered topically to the eye. The comfort should be
maximized as much as possible, although sometimes formulation considerations (e.g. drug
stability) may necessitate less than optimal comfort. In the case that comfort cannot be
maximized, the liquid should be formulated such that the liquid is tolerable to the patient for
17681897_1 (GHMatters) P110989.NZ
topical ophthalmic use. Additionally, an ophthalmically acceptable liquid should either be
packaged for single use, or contain a preservative to prevent contamination over multiple uses.
For ophthalmic application, solutions or medicaments are often prepared using
a physiological saline solution as a major vehicle. Ophthalmic solutions should preferably be
maintained at a comfortable pH with an appropriate buffer system. The formulations may also
contain conventional, pharmaceutically acceptable preservatives, stabilizers and surfactants.
Preservatives that may be used in the pharmaceutical compositions disclosed
herein include, but are not limited to, benzalkonium chloride, PHMB, chlorobutanol, thimerosal,
phenylmercuric, acetate and phenylmercuric nitrate. A useful surfactant is, for example, Tween
80. Likewise, various useful vehicles may be used in the ophthalmic preparations disclosed
herein. These vehicles include, but are not limited to, polyvinyl alcohol, povidone,
hydroxypropyl methyl cellulose, poloxamers, carboxymethyl cellulose, hydroxyethyl cellulose
and purified water.
Tonicity adjustors may be added as needed or convenient. They include, but
are not limited to, salts, particularly sodium chloride, potassium chloride, mannitol and glycerin,
or any other suitable ophthalmically acceptable tonicity adjustor.
Various buffers and means for adjusting pH may be used so long as the
resulting preparation is ophthalmically acceptable. For many compositions, the pH will be
between 4 and 9. Accordingly, buffers include acetate buffers, citrate buffers, phosphate buffers
and borate buffers. Acids or bases may be used to adjust the pH of these formulations as needed.
In a similar vein, an ophthalmically acceptable antioxidant includes, but is not
limited to, sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole
and butylated hydroxytoluene.
Other excipient components, which may be included in the ophthalmic
preparations, are chelating agents. A useful chelating agent is edetate disodium, although other
chelating agents may also be used in place or in conjunction with it.
For topical use, creams, ointments, gels, solutions or suspensions, etc.,
containing the compound disclosed herein are employed. Topical formulations may generally be
comprised of a pharmaceutical carrier, co-solvent, emulsifier, penetration enhancer, preservative
system, and emollient.
17681897_1 (GHMatters) P110989.NZ
For intravenous administration, the compounds and compositions described
herein may be dissolved or dispersed in a pharmaceutically acceptable diluent, such as a saline or
dextrose solution. Suitable excipients may be included to achieve the desired pH, including but
not limited to NaOH, sodium carbonate, sodium acetate, HCl, and citric acid. In various
embodiments, the pH of the final composition ranges from 2 to 8, or preferably from 4 to 7.
Antioxidant excipients may include sodium bisulfite, acetone sodium bisulfite, sodium
formaldehyde, sulfoxylate, thiourea, and EDTA. Other non-limiting examples of suitable
excipients found in the final intravenous composition may include sodium or potassium
phosphates, citric acid, tartaric acid, gelatin, and carbohydrates such as dextrose, mannitol, and
dextran. Further acceptable excipients are described in Powell, et al., Compendium of Excipients
for Parenteral Formulations, PDA J Pharm Sci and Tech 1998, 52 238-311 and Nema et al.,
Excipients and Their Role in Approved Injectable Products: Current Usage and Future Directions,
PDA J Pharm Sci and Tech 2011, 65 287-332, both of which are incorporated herein by
reference in their entirety. Antimicrobial agents may also be included to achieve a bacteriostatic
or fungistatic solution, including but not limited to phenylmercuric nitrate, thimerosal,
benzethonium chloride, benzalkonium chloride, phenol, cresol, and chlorobutanol.
The compositions for intravenous administration may be provided to caregivers
in the form of one more solids that are reconstituted with a suitable diluent such as sterile water,
saline or dextrose in water shortly prior to administration. In other embodiments, the
compositions are provided in solution ready to administer parenterally. In still other
embodiments, the compositions are provided in a solution that is further diluted prior to
administration. In embodiments that include administering a combination of a compound
described herein and another agent, the combination may be provided to caregivers as a mixture,
or the caregivers may mix the two agents prior to administration, or the two agents may be
administered separately.
The actual dose of the active compounds described herein depends on the
specific compound, and on the condition to be treated; the selection of the appropriate dose is
well within the knowledge of the skilled artisan.
The compounds and compositions described herein, if desired, may be
presented in a pack or dispenser device containing one or more unit dosage forms containing the
17681897_1 (GHMatters) P110989.NZ
active ingredient. Such a pack or device may, for example, comprise metal or plastic foil, such
as a blister pack, or glass, and rubber stoppers such as in vials. The pack or dispenser device may
be accompanied by instructions for administration. Compounds and compositions described
herein are formulated in a compatible pharmaceutical carrier may also be prepared, placed in an
appropriate container, and labeled for treatment of an indicated condition.
The amount of the compound in a formulation can vary within the full range
employed by those skilled in the art. Typically, the formulation will contain, on a weight percent
(wt %) basis, from about 0.01 99.99 wt % of a compound of the present technology based on the
total formulation, with the balance being one or more suitable pharmaceutical excipients.
Preferably, the compound is present at a level of about 1 80 wt %. Representative pharmaceutical
formulations are described below.
Formulation Examples
The following are representative pharmaceutical formulations containing a
compound of Formula I.
Formulation Example 1 -- Tablet formulation
The following ingredients are mixed intimately and pressed into single scored
tablets.
Quantity per
Ingredient tablet, mg
Compounds disclosed herein 400
cornstarch 50
croscarmellose sodium 25
lactose 120
magnesium stearate 5
Formulation Example 2 -- Capsule formulation
The following ingredients are mixed intimately and loaded into a hard-shell
gelatin capsule.
Quantity per
Ingredient capsule, mg
Compounds disclosed herein 200
lactose, spray-dried 148
17681897_1 (GHMatters) P110989.NZ
magnesium stearate 2
Formulation Example 3 -- Suspension formulation
The following ingredients are mixed to form a suspension for oral
administration.
Ingredient Amount
Compounds disclosed herein 1.0 g
fumaric acid 0.5 g
sodium chloride 2.0 g
methyl paraben 0.15 g
propyl paraben 0.05 g
granulated sugar 25.0 g
sorbitol (70% solution) 13.00 g
Veegum K (Vanderbilt Co.) 1.0 g
flavoring 0.035 mL
colorings 0.5 mg
distilled water q.s. to 100 mL
Formulation Example 4 -- Injectable formulation
The following ingredients are mixed to form an injectable formulation.
Ingredient Amount
Compounds disclosed herein 0.2 mg-20 mg
sodium acetate buffer solution, 0.4 M 2.0 mL
HCl (1N) or NaOH (1N) q.s. to suitable pH
water (distilled, sterile) q.s. to 20 mL
Formulation Example 5 -- Suppository Formulation
A suppository of total weight 2.5 g is prepared by mixing the compound of the
present technology with Witepsol® H-15 (triglycerides of saturated vegetable fatty acid;
Riches-Nelson, Inc., New York), and has the following composition:
Ingredient Amount
Compounds disclosed herein 500 mg
Witepsol® H-15 balance
Methods of Treatment
The compounds disclosed herein or their tautomers and/or pharmaceutically
acceptable salts thereof can effectively act as CAPN1, CAPN2, and/or CAPN9 inhibitors and
17681897_1 (GHMatters) P110989.NZ
treat conditions affected at least in part by CAPN1, CAPN2, and/or CAPN9. Some embodiments
provide pharmaceutical compositions comprising one or more compounds disclosed herein and a
pharmaceutically acceptable excipient. Some embodiments provide a method for treating a
fibrotic disease with an effective amount of one or more compounds as disclosed herein.
In some embodiments, the subject is a human.
Further embodiments include administering a combination of compounds to a
subject in need thereof. A combination can include a compound, composition, pharmaceutical
composition described herein with an additional medicament.
Some embodiments include co-administering a compound, composition, and/or
pharmaceutical composition described herein, with an additional medicament. By “co-
administration,” it is meant that the two or more agents may be found in the patient’s
bloodstream at the same time, regardless of when or how they are actually administered. In one
embodiment, the agents are administered simultaneously. In one such embodiment,
administration in combination is accomplished by combining the agents in a single dosage form.
In another embodiment, the agents are administered sequentially. In one embodiment the agents
are administered through the same route, such as orally. In another embodiment, the agents are
administered through different routes, such as one being administered orally and another being
administered i.v.
Some embodiments include combinations of a compound, composition or
pharmaceutical composition described herein with any other pharmaceutical compound approved
for treating fibrotic or myofibroblast differentiation associated diseases or disorders..
Some embodiments provide a method for inhibiting CAPN1, CAPN2, and/or
CAPN9 and/or a method for treating a disease affected at least in part by CAPN1, CAPN2,
and/or CAPN9 with an effective amount of one or more compounds as disclosed herein.
The compounds disclosed herein are useful in inhibiting CAPN1, CAPN2,
and/or CAPN9 enzymes and/or treating disorders relating to fibrosis or myofibroblast
differentiation.
Some embodiments provide a method for inhibiting CAPN1, CAPN2, and/or
CAPN9 which method comprises contacting cells (including neurons/microglia /invading
macrophages) with an effective amount of one or more compounds as disclosed herein.
17681897_1 (GHMatters) P110989.NZ
Some embodiments provide a method for treating a fibrotic disease, which
method comprises administering to a subject an effective amount of one or more compounds or a
pharmaceutical composition disclosed herein comprising a pharmaceutically acceptable
excipient.
Some embodiments provide a method for treating a disease affected at least in
part by CAPN1, CAPN2, and/or CAPN9, which method comprises administering to a subject an
effective amount of one or more compounds or a pharmaceutical composition disclosed herein
comprising a pharmaceutically acceptable excipient.
Some embodiments provide a method for inhibiting CAPN1, CAPN2, and/or
CAPN9 is provided wherein the method comprises contacting cells with an effective amount of
one or more compounds disclosed herein. In some embodiments a method for inhibiting
CAPN1, CAPN2, and/or CAPN9 is performed in-vitro or in-vivo.
Calpains are also expressed in cells other than neurons, microglia and invading
macrophages. In particular, they are important in skeletal muscle and herein inhibition of
calpains also refers to inhibition in these cells as well.
Selective inhibition
Some embodiments provide a method for competitive binding with calpastatin
(CAST), the method comprising contacting a compound disclosed herein with CAPN1, CAPN2,
and/or CAPN9 enzymes residing inside a subject. In such a method, the compound specifically
inhibits one or more of the enzymes selected from the group consisting of: CAPN1, CAPN2, and
CAPN9 by at least 2-fold, by at least 3-fold, by at least 4-fold, by at least 5-fold, by at least 10-
fold, by at least 15-fold, by at least 20-fold, by at least 50-fold, by at least 100-fold, by at least
150-fold, by at least 200-fold, by at least 400-fold, or by at least 500-fold.
Some embodiments provide a method for selectively inhibiting CAPN1 in the
presence of CAPN2 and CAPN9, which includes contacting cells (including neurons/microglia
/invading macrophages) with an effective amount of one or more compounds disclosed herein.
Some embodiments provide a method for selectively inhibiting CAPN2 in the
presence of CAPN1 and CAPN9, which includes contacting cells (including neurons/microglia
/invading macrophages) with an effective amount of one or more compounds disclosed herein.
17681897_1 (GHMatters) P110989.NZ
Some embodiments provide a method for selectively inhibiting CAPN9 in the
presence of CAPN2 and CAPN1, which includes contacting cells (including neurons/microglia
/invading macrophages) with an effective amount of one or more compounds disclosed herein.
Some embodiments provide a method for selectively inhibiting CAPN1 and
CAPN2 in the presence of CAPN9, which includes contacting cells (including neurons/microglia
/invading macrophages) with an effective amount of one or more compounds disclosed herein.
Some embodiments provide a method for selectively inhibiting CAPN1 and
CAPN9 in the presence of CAPN2, which includes contacting cells (including neurons/microglia
/invading macrophages) with an effective amount of one or more compounds disclosed herein.
Some embodiments provide a method for selectively inhibiting CAPN2 and
CAPN9 in the presence of CAPN1, which includes contacting cells (including neurons/microglia
/invading macrophages) with an effective amount of one or more compounds disclosed herein.
Some embodiments provide a method for treating a fibrotic disease, which
method comprises administering to a subject an effective amount of one or more compounds
which specifically inhibits CAPN1, CAPN2, and/or CAPN9, said compounds or a
pharmaceutical composition comprising one or more compounds disclosed herein and a
pharmaceutically acceptable excipient.
Some embodiments provide a method for treating a disease affected at least in
part by CAPN1, CAPN2, and/or CAPN9, which method comprises administering to a subject an
effective amount of one or more compounds which specifically inhibits CAPN1, CAPN2, and/or
CAPN9, said compounds being selected from compounds disclosed herein or a pharmaceutical
composition comprising one or more compounds disclosed herein and a pharmaceutically
acceptable excipient.
Some embodiments provide a method for treating a fibrotic disease, which
method comprises administering to a subject an effective amount of one or more compounds
which selectively inhibits CAPN1, CAPN2, and/or CAPN9, said compounds being selected from
compounds disclosed herein or a pharmaceutical composition comprising one or more
compounds disclosed herein and a pharmaceutically acceptable excipient..
Some embodiments provide a method for treating a disease affected at least in
part by CAPN1, CAPN2, and/or CAPN9, which method comprises administering to a subject an
17681897_1 (GHMatters) P110989.NZ
effective amount of one or more compounds which selectively inhibits CAPN1, CAPN2, and/or
CAPN9, said compounds being selected from compounds disclosed herein or a pharmaceutical
composition comprising one or more compounds disclosed herein and a pharmaceutically
acceptable excipient..
Some embodiments provide a method for treating a fibrotic disease, which
method comprises administering to a subject an effective amount of one or more compounds
which specifically inhibits two or more enzymes selected from the group consisting of CAPN1,
CAPN2, and CAPN9 in a ratio of at least 1:1:5.
Some embodiments provide a method for treating a fibrotic disease, which
method comprises administering to a subject an effective amount of one or more compounds
which specifically inhibits two or more enzymes selected from the group consisting of CAPN1,
CAPN2, and CAPN9 in a ratio of at least 1:1:10.
Some embodiments provide a method for treating a fibrotic disease, which
method comprises administering to a subject an effective amount of one or more compounds
which specifically inhibits two or more enzymes selected from the group consisting of CAPN1,
CAPN2, and CAPN9 in a ratio of at least 1:1:20.
Some embodiments provide a method for treating a fibrotic disease, which
method comprises administering to a subject an effective amount of one or more compounds
which specifically inhibits two or more enzymes selected from the group consisting of CAPN1,
CAPN2, and CAPN9 in a ratio of at least 1:1:50.
Some embodiments provide a method for treating a fibrotic disease, which
method comprises administering to a subject an effective amount of one or more compounds
which specifically inhibits two or more enzymes selected from the group consisting of CAPN1,
CAPN2, and CAPN9 in a ratio of at least 1:1:100.
Some embodiments provide a method for treating a fibrotic disease, which
method comprises administering to a subject an effective amount of one or more compounds
which specifically inhibits two or more enzymes selected from the group consisting of CAPN1,
CAPN2, and CAPN9 in a ratio of at least 1:1:200.
Some embodiments provide a method for treating a fibrotic disease, which
method comprises administering to a subject an effective amount of one or more compounds
17681897_1 (GHMatters) P110989.NZ
which specifically inhibits two or more enzymes selected from the group consisting of CAPN1,
CAPN2, and CAPN9 in a ratio of at least 1:1:250.
Some embodiments provide a method for treating a fibrotic disease, which
method comprises administering to a subject an effective amount of one or more compounds
which specifically inhibits two or more enzymes selected from the group consisting of CAPN1,
CAPN2, and CAPN9 in a ratio of at least 1:1:500.
Some embodiments provide a method for treating a fibrotic disease, which
method comprises administering to a subject an effective amount of one or more compounds
which selectively inhibits two or more enzymes selected from the group consisting of CAPN1,
CAPN2, and CAPN9 in a ratio of at least 1:1:5.
Some embodiments provide a method for treating a fibrotic disease, which
method comprises administering to a subject an effective amount of one or more compounds
which selectively inhibits two or more enzymes selected from the group consisting of CAPN1,
CAPN2, and CAPN9 in a ratio of at least 1:1:10.
Some embodiments provide a method for treating a fibrotic disease, which
method comprises administering to a subject an effective amount of one or more compounds
which selectively inhibits two or more enzymes selected from the group consisting of CAPN1,
CAPN2, and CAPN9 in a ratio of at least 1:1:20.
Some embodiments provide a method for treating a fibrotic disease, which
method comprises administering to a subject an effective amount of one or more compounds
which selectively inhibits two or more enzymes selected from the group consisting of CAPN1,
CAPN2, and CAPN9 in a ratio of at least 1:1:50.
Some embodiments provide a method for treating a fibrotic disease, which
method comprises administering to a subject an effective amount of one or more compounds
which selectively inhibits two or more enzymes selected from the group consisting of CAPN1,
CAPN2, and CAPN9 in a ratio of at least 1:1:100.
Some embodiments provide a method for treating a fibrotic disease, which
method comprises administering to a subject an effective amount of one or more compounds
which selectively inhibits two or more enzymes selected from the group consisting of CAPN1,
CAPN2, and CAPN9 in a ratio of at least 1:1:200.
17681897_1 (GHMatters) P110989.NZ
Some embodiments provide a method for treating a fibrotic disease, which
method comprises administering to a subject an effective amount of one or more compounds
which selectively inhibits two or more enzymes selected from the group consisting of CAPN1,
CAPN2, and CAPN9 in a ratio of at least 1:1:250.
Some embodiments provide a method for treating a fibrotic disease, which
method comprises administering to a subject an effective amount of one or more compounds
which selectively inhibits two or more enzymes selected from the group consisting of CAPN1,
CAPN2, and CAPN9 in a ratio of at least 1:1:500.
Some embodiments provide a method for treating a disease affected at least in
part by CAPN1, CAPN2, and/or CAPN9, which method comprises administering to a subject an
effective amount of one or more compounds which specifically inhibits two or more enzymes
selected from the group consisting of CAPN1, CAPN2, and CAPN9 in a ratio of at least 1:1:5.
Some embodiments provide a method for treating a disease affected at least in
part by CAPN1, CAPN2, and/or CAPN9, which method comprises administering to a subject an
effective amount of one or more compounds which specifically inhibits two or more enzymes
selected from the group consisting of CAPN1, CAPN2, and CAPN9 in a ratio of at least 1:1:10.
Some embodiments provide a method for treating a disease affected at least in
part by CAPN1, CAPN2, and/or CAPN9, which method comprises administering to a subject an
effective amount of one or more compounds which specifically inhibits two or more enzymes
selected from the group consisting of CAPN1, CAPN2, and CAPN9 in a ratio of at least 1:1:20.
Some embodiments provide a method for treating a disease affected at least in
part by CAPN1, CAPN2, and/or CAPN9, which method comprises administering to a subject an
effective amount of one or more compounds which specifically inhibits two or more enzymes
selected from the group consisting of CAPN1, CAPN2, and CAPN9 in a ratio of at least 1:1:50.
Some embodiments provide a method for treating a disease affected at least in
part by CAPN1, CAPN2, and/or CAPN9, which method comprises administering to a subject an
effective amount of one or more compounds which specifically inhibits two or more enzymes
selected from the group consisting of CAPN1, CAPN2, and CAPN9 in a ratio of at least 1:1:100.
Some embodiments provide a method for treating a disease affected at least in
part by CAPN1, CAPN2, and/or CAPN9, which method comprises administering to a subject an
17681897_1 (GHMatters) P110989.NZ
effective amount of one or more compounds which specifically inhibits two or more enzymes
selected from the group consisting of CAPN1, CAPN2, and CAPN9 in a ratio of at least 1:1:200.
Some embodiments provide a method for treating a disease affected at least in
part by CAPN1, CAPN2, and/or CAPN9, which method comprises administering to a subject an
effective amount of one or more compounds which specifically inhibits two or more enzymes
selected from the group consisting of CAPN1, CAPN2, and CAPN9 in a ratio of at least 1:1:250.
Some embodiments provide a method for treating a disease affected at least in
part by CAPN1, CAPN2, and/or CAPN9, which method comprises administering to a subject an
effective amount of one or more compounds which specifically inhibits two or more enzymes
selected from the group consisting of CAPN1, CAPN2, and CAPN9 in a ratio of at least 1:1:500.
Some embodiments provide a method for treating a disease affected at least in
part by CAPN1, CAPN2, and/or CAPN9, which method comprises administering to a subject an
effective amount of one or more compounds which selectively inhibits two or more enzymes
selected from the group consisting of CAPN1, CAPN2, and CAPN9 in a ratio of at least 1:1:5.
Some embodiments provide a method for treating a disease affected at least in
part by CAPN1, CAPN2, and/or CAPN9, which method comprises administering to a subject an
effective amount of one or more compounds which selectively inhibits two or more enzymes
selected from the group consisting of CAPN1, CAPN2, and CAPN9 in a ratio of at least 1:1:10.
Some embodiments provide a method for treating a disease affected at least in
part by CAPN1, CAPN2, and/or CAPN9, which method comprises administering to a subject an
effective amount of one or more compounds which selectively inhibits two or more enzymes
selected from the group consisting of CAPN1, CAPN2, and CAPN9 in a ratio of at least 1:1:20.
Some embodiments provide a method for treating a disease affected at least in
part by CAPN1, CAPN2, and/or CAPN9, which method comprises administering to a subject an
effective amount of one or more compounds which selectively inhibits two or more enzymes
selected from the group consisting of CAPN1, CAPN2, and CAPN9 in a ratio of at least 1:1:50.
Some embodiments provide a method for treating a disease affected at least in
part by CAPN1, CAPN2, and/or CAPN9, which method comprises administering to a subject an
effective amount of one or more compounds which selectively inhibits two or more enzymes
selected from the group consisting of CAPN1, CAPN2, and CAPN9 in a ratio of at least 1:1:100.
17681897_1 (GHMatters) P110989.NZ
Some embodiments provide a method for treating a disease affected at least in
part by CAPN1, CAPN2, and/or CAPN9, which method comprises administering to a subject an
effective amount of one or more compounds which selectively inhibits two or more enzymes
selected from the group consisting of CAPN1, CAPN2, and CAPN9 in a ratio of at least 1:1:200.
Some embodiments provide a method for treating a disease affected at least in
part by CAPN1, CAPN2, and/or CAPN9, which method comprises administering to a subject an
effective amount of one or more compounds which selectively inhibits two or more enzymes
selected from the group consisting of CAPN1, CAPN2, and CAPN9 in a ratio of at least 1:1:250.
Some embodiments provide a method for treating a disease affected at least in
part by CAPN1, CAPN2, and/or CAPN9, which method comprises administering to a subject an
effective amount of one or more compounds which selectively inhibits two or more enzymes
selected from the group consisting of CAPN1, CAPN2, and CAPN9 in a ratio of at least 1:1:500.
Some embodiments provide a method for prophylactic therapy or treatment of a
subject having a fibrotic disorder wherein said method comprising administering an effective
amount of one or more compounds disclosed herein to the subject in need thereof.
Some embodiments provide a method for prophylactic therapy or treatment of a
subject having a disorder affected by CAPN1, CAPN2, and/or CAPN9 wherein said method
comprising administering an effective amount of one or more compounds disclosed herein to the
subject in need thereof.
Some embodiments provide a method for inhibiting myofibroblast
differentiation (e.g., Epithelial/Endothelial-to-Mesenchymal Transition (EpMT/EnMT)) is
provided wherein the method comprises contacting cells with an effective amount of one or more
compounds disclosed herein. In one aspect, the method for inhibiting myofibroblast
differentiation (e.g., Epithelial/Endothelial-to-Mesenchymal Transition (EpMT/EnMT)) is
performed in-vitro or in-vivo.
Some embodiments provide a method for treating a disease or condition
selected from the group consisting of or that produces a symptom selected from the group
consisting of: liver fibrosis, renal fibrosis, lung fibrosis, hypersensitivity pneumonitis, interstitial
fibrosis, systemic scleroderma, macular degeneration, pancreatic fibrosis, fibrosis of the spleen,
cardiac fibrosis, mediastinal fibrosis, myelofibrosis, endomyocardial fibrosis, retroperitoneal
17681897_1 (GHMatters) P110989.NZ
fibrosis, progressive massive fibrosis, nephrogenic systemic fibrosis, fibrotic complications of
surgery, chronic allograft vasculopathy and/or chronic rejection in transplanted organs, ischemic-
reperfusion injury associated fibrosis, injection fibrosis, cirrhosis, diffuse parenchymal lung
disease, post-vasectomy pain syndrome, and rheumatoid arthritis diseases, wherein which
method comprises administering to a subject an effective amount of one or more compounds
disclosed herein to a subject in need thereof.
Some embodiments provide a method for treating liver fibrosis.
Some embodiments provide a method for treating cardiac fibrosis.
Some embodiments provide a method for treating fibrosis in rheumatoid
arthritis diseases.
Some embodiments provide a method for treating a condition affected by
CAPN1, CAPN2, and/or CAPN9, which is in both a therapeutic and prophylactic setting for
subjects. Both methods comprise administering of one or more compounds disclosed herein to a
subject in need thereof.
Some embodiments provide a method for treating stiff skin syndrome.
Preferred embodiments include combinations of a compound, composition or
pharmaceutical composition described herein with other CAPN1, CAPN2, and/or CAPN9
inhibitor agents, such as anti-CAPN1, CAPN2, AND/OR CAPN9 antibodies or antibody
fragments, CAPN1, CAPN2, and/or CAPN9 antisense, iRNA, or other small molecule CAPN1,
CAPN2, and/or CAPN9 inhibitors.
Some embodiments include combinations of a compound, composition or
pharmaceutical composition described herein to inhibit myofibroblast differentiation (e.g.,
Epithelial/Endothelial-to-Mesenchymal Transition (EpMT/EnMT)). Some embodiments include
combinations of one or more of these compounds which are inhibitors of one or more (or all
three) CAPN1, CAPN2, and/or CAPN9, alone or in combination with other TGFβ signaling
inhibitors, could be used to treat or protect against or reduce a symptom of a fibrotic, sclerotic or
post inflammatory disease or condition including: liver fibrosis, renal fibrosis, lung fibrosis,
hypersensitivity pneumonitis, interstitial fibrosis, systemic scleroderma, macular degeneration,
pancreatic fibrosis, fibrosis of the spleen, cardiac fibrosis, mediastinal fibrosis, myelofibrosis,
endomyocardial fibrosis, retroperitoneal fibrosis, progressive massive fibrosis, nephrogenic
17681897_1 (GHMatters) P110989.NZ
systemic fibrosis, fibrotic complications of surgery, chronic allograft vasculopathy and/or chronic
rejection in transplanted organs, ischemic-reperfusion injury associated fibrosis, injection
fibrosis, cirrhosis, diffuse parenchymal lung disease, postvasectomy pain syndrome, and
rheumatoid arthritis.
Some embodiments include a combination of the compounds, compositions
and/or pharmaceutical compositions described herein with an additional agent, such as anti-
inflammatories including glucocorticoids, analgesics (e.g. ibuprofen), aspirin, and agents that
modulate a Th2-immune response, immunosuppressants including methotrexate, mycophenolate,
cyclophosphamide, cyclosporine, thalidomide, pomalidomide, leflunomide, hydroxychloroquine,
azathioprine, soluble bovine cartilage, vasodilators including endothelin receptor antagonists,
prostacyclin analogues, nifedipine, and sildenafil, IL-6 receptor antagonists, selective and non-
selective tyrosine kinase inhibitors, Wnt-pathway modulators, PPAR activators, caspase-3
inhibitors, LPA receptor antagonists, B cell depleting agents, CCR2 antagonists, pirfenidone,
cannabinoid receptor agonists, ROCK inhibitors, miRNA-targeting agents, toll-like receptor
antagonists, CTGF-targeting agents, NADPH oxidase inhibitors, tryptase inhibitors, TGFD
inhibitors, relaxin receptor agonists, and autologous adipose derived regenerative cells.
Indications
In some embodiments, the compounds and compositions comprising the
compounds described herein can be used to treat a host of conditions arising from fibrosis or
inflammation, and specifically including those associated with myofibroblast differentiation.
Example conditions include liver fibrosis (alcoholic, viral, autoimmune, metabolic and hereditary
chronic disease), renal fibrosis (e.g., resulting from chronic inflammation, infections or type II
diabetes), lung fibrosis (idiopathic or resulting from environmental insults including toxic
particles, sarcoidosis, asbestosis, hypersensitivity pneumonitis, bacterial infections including
tuberculosis, medicines, etc.), interstitial fibrosis, systemic scleroderma (autoimmune disease in
which many organs become fibrotic), macular degeneration (fibrotic disease of the eye),
pancreatic fibrosis (resulting from, for example, alcohol abuse and chronic inflammatory disease
of the pancreas), fibrosis of the spleen (from sickle cell anemia, other blood disorders), cardiac
fibrosis (resulting from infection, inflammation and hypertrophy), mediastinal fibrosis,
myelofibrosis, endomyocardial fibrosis, retroperitoneal fibrosis, progressive massive fibrosis,
17681897_1 (GHMatters) P110989.NZ
nephrogenic systemic fibrosis, fibrotic complications of surgery, chronic allograft vasculopathy
and/or chronic rejection in transplanted organs, ischemic reperfusion injury associated fibrosis,
injection fibrosis, cirrhosis, diffuse parenchymal lung disease, post-vasectomy pain syndrome,
and rheumatoid arthritis diseases or disorders.
To further illustrate this invention, the following examples are included. The
examples should not, of course, be construed as specifically limiting the invention. Variations of
these examples within the scope of the claims are within the purview of one skilled in the art and
are considered to fall within the scope of the invention as described, and claimed herein. The
reader will recognize that the skilled artisan, armed with the present disclosure, and skill in the
art is able to prepare and use the invention without exhaustive examples. The following
examples will further describe the present invention, and are used for the purposes of illustration
only, and should not be considered as limiting.
EXAMPLES
General procedures
It will be apparent to the skilled artisan that methods for preparing precursors
and functionality related to the compounds claimed herein are generally described in the
literature. In these reactions, it is also possible to make use of variants which are themselves
known to those of ordinary skill in this art, but are not mentioned in greater detail. The skilled
artisan given the literature and this disclosure is well equipped to prepare any of the compounds.
It is recognized that the skilled artisan in the art of organic chemistry can
readily carry out manipulations without further direction, that is, it is well within the scope and
practice of the skilled artisan to carry out these manipulations. These include reduction of
carbonyl compounds to their corresponding alcohols, oxidations, acylations, aromatic
substitutions, both electrophilic and nucleophilic, etherifications, esterification and saponification
and the like. These manipulations are discussed in standard texts such as March Advanced
Organic Chemistry (Wiley), Carey and Sundberg, Advanced Organic Chemistry (incorporated
herein by reference in their entirety) and the like. All the intermediate compounds of the present
invention were used without further purification unless otherwise specified.
The skilled artisan will readily appreciate that certain reactions are best carried
out when other functionality is masked or protected in the molecule, thus avoiding any
17681897_1 (GHMatters) P110989.NZ
undesirable side reactions and/or increasing the yield of the reaction. Often the skilled artisan
utilizes protecting groups to accomplish such increased yields or to avoid the undesired reactions.
These reactions are found in the literature and are also well within the scope of the skilled
artisan. Examples of many of these manipulations can be found for example in T. Greene and P.
Wuts Protecting Groups in Organic Synthesis, 4th Ed., John Wiley & Sons (2007), incorporated
herein by reference in its entirety.
The following example schemes are provided for the guidance of the reader,
and represent preferred methods for making the compounds exemplified herein. These methods
are not limiting, and it will be apparent that other routes may be employed to prepare these
compounds. Such methods specifically include solid phase based chemistries, including
combinatorial chemistry. The skilled artisan is thoroughly equipped to prepare these compounds
by those methods given the literature and this disclosure. The compound numberings used in the
synthetic schemes depicted below are meant for those specific schemes only, and should not be
construed as or confused with same numberings in other sections of the application.
Trademarks used herein are examples only and reflect illustrative materials
used at the time of the invention. The skilled artisan will recognize that variations in lot,
manufacturing processes, and the like, are expected. Hence the examples, and the trademarks
used in them are non-limiting, and they are not intended to be limiting, but are merely an
illustration of how a skilled artisan may choose to perform one or more of the embodiments of
the invention.
The following abbreviations have the indicated meanings:
DCM = dichloromethane
DIEA = N,N-Diisopropylethylamine
DIPEA = N,N-Diisopropylethylamine
DMF = N,N-dimethylformamide
DMP = Dess Martin Periodinane
DNs = dinitrosulfonyl
ESBL = extended-spectrum β-lactamase
EtOAc = ethyl acetate
17681897_1 (GHMatters) P110989.NZ
EA = ethyl acetate
FCC = Flash Column Chromatography
HATU = 2-(7-aza-1H-benzotriazoleyl)-1,1,3,3-
tetramethyluronium hexafluorophosphate
MeCN = acetonitrile
NMR = nuclear magnetic resonance
PE = Petroleum Ether
Prep = preparatory
Py = pyridine
Sat. = saturated aqueous
TBDMSCl = tert-butyldimethylsilyl chloride
TBS = tert-butyldimethylsilyl
TFA = trifluoroacetic acid
THF = tetrahydrofuran
TLC = thin layer chromatography
The following example schemes are provided for the guidance of the reader,
and collectively represent an example method for making the compounds provided herein.
Furthermore, other methods for preparing compounds described herein will be readily apparent
to the person of ordinary skill in the art in light of the following reaction schemes and examples.
Unless otherwise indicated, all variables are as defined above.
EXAMPLE 1
COMPOUNDS 1-2, 5-6, 8, 91-92
(S)-N-(1-OXOPHENYLPROPANYL)PHENYL-1H-IMIDAZOLE
CARBOXAMIDE (1)
HBTU
H N N
OH 2
DIEA N
-50 C
1C 1
17681897_1 (GHMatters) P110989.NZ
A mixture of compound 1A (102 mg, 1.0 eq), compound 1B (160 mg, 1.2 eq)
and HBTU (250 mg, 1.25 eq) in DMF (8 mL) was stirred at room temperature for 5mins, and
then DIEA (0.3mL, 3.0eq) was added. After stirred at room temperature for 30mins, the
reaction mixture was diluted with 50 mL ethyl acetate and 20 mL Hexane, washed with water,
saturated NaHCO and brine and concentrated in vacuo to afford intermediate compound 1C
(190 mg, yield 92%).
A solution of compound 1C (190 mg, 1.0 eq) in dry THF (15 mL) was cooled
to -50 °C under N , and then was added a solution of 1N LAH in THF (0.55 mL, 1.1 eq)
dropwise at -50 °C. The reaction mixture was stirred at -30 °C to -10 °C for 2hrs, quenched with
saturated NaHCO at -20 °C, and then extracted with 3 x 30 mL ethyl acetate. The combined
organic phase was dried over Na SO to give the crude mixture, which was purified on silica gel
column. Compound 1 (105 mg, 65%): MS (ESI) m/z (M+H) : 320.3; H NMR (400 MHz,
CDCl ): δ 9.64 (s, 1H), 7.65 (s, 1H), 7.56 (s, 1H), 7.46 (m, 3H), 7.26-7.33 (m, 5H), 7.09 (m, 2H),
6.29 (d, 1H), 4.81(m, 1H), 3.19 (d, 2H) ppm
(S)-N-(1-OXOPHENYLPROPANYL)PHENYL-1H-PYRAZOLE
CARBOXAMIDE (2)
((S)METHYL-N-(1-OXOPHENYLPROPANYL)PHENYL-1H-PYRAZOLE
CARBOXAMIDE (5)
(S)-N-(1-OXOPHENYLPROPANYL)PHENYLTHIAZOLECARBOXAMIDE
(S)METHYL-N-(1-OXOPHENYLPROPANYL)PHENYL-1H-PYRAZOLE
CARBOXAMIDE (8)
Compounds 2, 5, 6 and 8 were prepared as in Example 1 using the
corresponding carboxylic acid, respectively. Compound 2: MS (ESI) m/z (M+H) : 320.2; H
NMR (400 MHz, DMSO): δ 9.6 (s, 1H), 9.15 (d, 1H), 7.73 (s, 1H), 7.4 - 7.2 (m, 10H), 6.8 (s,
1H), 4.53 (m, 1H), 3.25 (dd, 1H), 2.8 (dd, 1H) ppm.
Compound 5: MS (ESI) m/z (M+H) : 334.3; H NMR (400 MHz, CDCl ): δ
9.67 (s, 1H), 7.54 - 7.4 (m, 6H), 7.3 - 7.2 (m, 5H), 6.73 (s, 1H), 4.82 (m, 1H), 3.21 (d, 2H), 2.33
(s, 3H) ppm.
17681897_1 (GHMatters) P110989.NZ
Compound 6: MS (ESI) m/z (M+H) : 337.5; H NMR (400 MHz, CDCl ): δ
9.56 (s, 1H), 8.88 (s, 1H), 7.5 - 7.34 (m, 5H), 7.27 - 7.2 (m, 3H), 6.94 (m, 2H), 6.35 (d, 1H), 4.73
(m, 1H), 3.1 (dd, 1H), 3.08 (dd, 1H) ppm.
Compound 8: MS (ESI) m/z (M+H) : 334.3; H NMR (400 MHz, DMSO): δ
9.59 (s, 0.6H), 9.01 (d, 0.6 H), 8.35 (d, 0.4 H), 7.38 -7.06 (m, 10H), 6.58 (s, 0.6H), 6.48 (s, 0.4
H), 4.82 (m, 0.2 H), 4.54 (m, 0.6 H), 3.98 (m, 0.4 H), 3.25 (dd, 0.6 H), 2.98 (dd, 0.4 H), 2.78 (dd,
0.6 H), 2.7 (dd, 0.4 H), 2.48 (s, 1.8 H0, 2.21 (s, 1.2 H) ppm.
NH O
OH OH
(S)-N-(1-OXOPHENYLPROPANYL)THIAZOLECARBOXAMIDE (91)
Compound 91 was prepared as in Example 1 from the corresponding starting
materials, compounds 91A and 1B. Compound 91: H NMR (400 MHz, CDCl ): δ 9.69 (s, 1H),
8.85 (s, 1H), 8.21 (s, 1H), 7.06 (d, 1H), 7.32 -7.18 (m, 8H), 4.88 (m, 1H), 3.26 (m, 2H) ppm. MS
(ESI) m/z (M+H) 261.3.
(S)-N-(1-OXOPHENYLPROPANYL)PHENYL-1H-BENZO[d]IMIDAZOLE
CARBOXAMIDE (92)
Compound 92 was prepared as in Example 1 using the corresponding
carboxylic acid. H NMR (400 MHz, CDCl ): δ 12.07 (s, 1H), 11.92 (d, 1H), 9.84 (s, 1H), 8.1 -
8.0 (m, 3H), 7.5 - 7.46 (m, 10H), 7.32 -7.18 (m, 8H), 5.04 (m, 1H), 3.34 (d, 2H) ppm. MS (ESI)
m/z (M+H) 370.4.
17681897_1 (GHMatters) P110989.NZ
EXAMPLE 2
COMPOUNDS 3-4
(S)(BENZO[D]THIAZOLYL)-N-((S)OXOPHENYLPROPAN
YL)PYRROLIDINECARBOXAMIDE (3)
K CO
S 2 3
CO H
CO H
A mixture of compound 3A (500 mg, 1.0 eq), compound 3B (738 mg, 1.0 eq),
CuI (124 mg, 0.15 eq) and K CO (1.8 g, 3.0 eq) in DMA (15 mL) was heated at 100 °C for 18
hrs, and then the inorganic was removed by filtration. The mixture was diluted with water (50
mL), adjusted pH ~ 6, and then extracted with 3 x 50 mL acetate to afford intermediate
compound 3C. Compound 3 was prepared as in Example 1 using the corresponding carboxylic
acid, intermediate compound 3C. Compound 3: MS (ESI) m/z (M+H) : 380.2; H NMR (400
MHz, CDCl ): δ 9.66 (s, 1H), 8.32 (d, 1H), 7.63 (d, 1H), 7.52 (d, 1H), 7.30 (t, 1H), 7.10 (t, 1H),
6.92-7.01 (m, 5H), 4.69 (m, 2H), 3.45 (m, 1H), 3.36 (m, 1H), 3.17 (dd, 1H), 2.90 (dd, 1H), 2.55
(m, 1H), 2.03 (m, 3H) ppm.
(S)(BENZO[D]OXAZOLYL)-N-((S)OXOPHENYLPROPAN
YL)PYRROLIDINECARBOXAMIDE (4)
Compound 4 was prepared as in Example 2 using the corresponding starting
materials. MS (ESI) m/z (M+H) : 364.3; H NMR (400 MHz, CDCl ): δ 9.65 (s, 1H), 7.69 (br d,
1H), 7.37 (d, 1H), 7.33 (t, 1H), 7.18 (t, 1H), 6.98-7.10 (m, 6H), 4.71 (m, 2H), 4.59 (m, 1H), 3.61
(m, 2H), 3.19 (dd, 1H), 2.97 (dd, 1H), 2.41 (m, 1H), 1.91-2.12 (m, 3H) ppm.
17681897_1 (GHMatters) P110989.NZ
EXAMPLE 3
(S)-N-(1-OXOPHENYLPROPANYL)PHENYLISOTHIAZOLE
CARBOXAMIDE (9)
O NH
ClCOSCl EtOOC COOEt
Toluene
Toluene N
1,2-dichlorobenzene
NaOH
S 9E
To a suspension of compound 9A (1.2 g) in toluene (15 ml) was added
chlorocarbonylsulfenyl chloride (1.3 ml). The mixture was heated at 100° C for 2 hrs to obtain a
clear solution (gas evolution was observed). When TLC showed complete conversion, the
reaction mixture was concentrated and the solid residue was triturated with hexane, filtered and
dried to yield compound 9B.
To a solution of compound 9B (1.4 g) in α,α,α-trifluorotoluene (10 mL) was
added diethyl acetylenedicarboxylate (2.0 ml). After heated in the microwave at 170° C for 1 hr,
the reaction mixture was concentrated. and the oily residue was purified by flash column
chromatography. The product-containing fractions were combined, concentrated, and the residue
was triturated with hexane, filtered and dried to yield compound 9C.
A solution of compound 9C (2.1 g) and NaOH (1.4 g) in water (20 mL) was
refluxed for 2.5 hrs. The reaction mixture was cooled, diluted with water (150 mL) and acidified
with concentrated HCl (aqueous). A precipitate was formed. The water layer was extracted with
EtOAc (2 × 200 mL; the precipitate slowly dissolved). The combined organic layers were
washed with brine, dried (Na SO ) and concentrated to yield compound 9D.
A suspension of compound 9D (1.8 g) in 1,2-dichlorobenzene (20 mL) was
refluxed for 20 mins (gas formation is observed). The reaction mixture was cooled diluted with
hexane (50 mL) and filtered to precipitate the product. To a suspension of the crude product in
water (40 mL) was added 1N NaOH (10 ml). The water layer was extracted with ethyl acetate
(2×100 mL) and acidified with concentrated HCl to pH ~ 3. The product was extracted with
17681897_1 (GHMatters) P110989.NZ
EtOAc (2 × 100 mL). The combined organic layers were washed with brine, dried (Na SO ) and
concentrated to yield intermediate compound 9E.
Compound 9 was prepared as in Example 1 using the corresponding
carboxylic acid, intermediate compound 9E. MS (ESI) m/z (M+H) : 359.1; H NMR (400 MHz,
CDCl ): δ 9.59 (s, 1H), 9.16 (s, 1H), 7.56 - 7.5 (m, 2H), 7.48 - 7.4 (m, 3H), 7.27 - 7.22 (m, 3H),
6.94 (m, 2H), 6.15 (d, 1H), 4.79 (m, 1H), 3.1 (d, 2H) ppm.
EXAMPLE 4
COMPOUNDS 7, 10-11, 14, 18, 20
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)PHENYL-1H-IMIDAZOLE
CARBOXAMIDE (7)
O O O
HBTU / DIEA
NH N NH
OH H N N NH
7A 7
A mixture of compound 7A (50 mg, 1.0 eq), compound 7B (74 mg, 1.2 eq)
and HBTU (126 mg, 1.25 eq) in DMF (3mL) was stirred at room temperature for 5 mins, and
then DIEA (0.15 mL, 3.0 eq) was added. After stirred at room temperature for 30 mins, the
reaction mixture was diluted with ethyl acetate (30 mL) and hexane (10 mL), washed with 1N
HCl, water, saturated NaHCO and brine and concentrated in vacuo to afford intermediate
compound 7C (65 mg, yield 67%) as white solid.
To a solution of compound 7C (65 mg, 1.0 eq) in dry DCM (10ml) and DMSO
(2 mL) was added DMP (305 mg, 4.0 eq). After stirred at room temperature for 1 hr, the mixture
was diluted with DCM (30 mL), quenched by adding 10% aqueous Na S O /saturated aqueous
2 2 3
NaHCO (v/v = 1/1, ~ 10 mL). The organic layer was separated by extracting the aqueous layer
with DCM (30 mL x 5). The combined organic layer was washed with H O (10 mL), brine (10
mL), dried over Na SO , filtered and concentrated to afford white solid, which was then
triturated in CH Cl /Hexane to provide pure product compound 7 (29 mg, yield 45%). MS (ESI)
m/z (M+H) : 363.4; H NMR (400 MHz, CDCl ): δ 7.66 (s, 1H), 7.57 (s, 1H), 7.45 (m, 3H),
7.26-7.35 (m, 5H), 7.05 (m, 2H), 6.72 (s, 1H), 6.24 (d, 1H), 5.58 (m, 2H), 4.81(m, 1H), 3.38 (dd,
1H), 3.14 (dd, 1H) ppm.
17681897_1 (GHMatters) P110989.NZ
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)PHENYL-1H-PYRAZOLE
CARBOXAMIDE (10)
Prepared as in Example 4 using the corresponding carboxylic acid. MS (ESI)
m/z (M+H) : 363.3; H NMR (400 MHz, DMSO): δ 9.15 (d, 1H), 8.11 (s, 1H), 7.71 (s, 1H), 7.4 -
7.2 (m, 10H), 7.07 (d, 1H), 6.72 (s, 1H), 5.26 (m, 1H), 2.81 (dd, 1H), 2.64 (dd, 1H) ppm.
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)PHENYLISOTHIAZOLE
CARBOXAMIDE (11)
Prepared as in Example 4 using the corresponding carboxylic acid,
intermediate compound 9E. MS (ESI) m/z (M+H) 380.2; H NMR (400 MHz, DMSO): δ 9.15
(d, 1H), 9.05 (s, 1H), 8.14 (s, 1H), 7.89 (s, 1H), 7.5 -7.4 (m, 2H), 7.3 -7.2 (m, 8H), 5.34 (m, 1H),
3.2 (d, 2H) ppm.
(S)(BENZO[D]OXAZOLYL)-N-((S)OXOPHENYLPROPAN
YL)PYRROLIDINECARBOXAMIDE (14)
Intermediate compound 14E was prepared as in Example 3. Compound 14 was
then prepared as in Example 4 using the corresponding intermediate carboxylic acid, compound
14E. Compound 14: MS (ESI) m/z (M+H) : 431.5; H NMR (400 MHz, DMSO): δ 9.14 (s, 1H),
9.05 (d, 1H), 8.16 (d, 1H), 7.9 (s, 1H), 7.62 -7.56 (m, 2H), 7.3 -7.2 (m, 8H), 5.36 (m, 1H), 3.17
(dd, 1H), 2.78 (dd, 1H) ppm.
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)PHENYLTHIAZOLE
CARBOXAMIDE (18)
Prepared as in Example 4 using the corresponding carboxylic acid. MS (ESI)
m/z (M+H) : 380.1; H NMR (400 MHz, DMSO): δ 10.11(d, 1H), 9.33 (s, 1H), 8.49 (d, 1H),
8.13 (s, 1H), 8.07 (d, 1H), 8.03 (d, 1H), 7.85 (s, 1H), 7.74 (m, 2H), 7.65 (m, 1H), 7.12 - 7 (m,
5H), 5.51 (m, 1H), 3.18 (dd, 1H) 2.89 (dd, 1H) ppm.
17681897_1 (GHMatters) P110989.NZ
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)(BENZO[D][1,3]DIOXOL
YL)METHYLISOXAZOLECARBOXAMIDE (20)
Prepared as in Example 4 using the corresponding carboxylic acid. MS (ESI)
m/z (M+H) : 422.1; H NMR (400 MHz, DMSO-d6): δ 8.88 (d, 1H), 8.19 (s, 1H), 7.91 (s, 1H),
7.17-7.30 (m, 7H), 6.94 (d, 1H), 6.11 (s, 2H), 5.45 (m, 1H), 3.22 (dd, 1H), 2.72 (dd, 1H), 2.03 (s,
3H) ppm.
EXAMPLE 5
COMPOUNDS 12-13, 15-17, 19, 27, 44, 47, 54, 60, 94, 117-118, 128, 148, 207, 235, 303-305,
309-312, 23, 39, 456, 461, 492
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)METHYL(PYRIDINYL)-
1H-PYRAZOLECARBOXAMIDE (12)
NHNH
O O LiOH
NH HCl
4A° sieves
H 12E
CH CO
12A O
N . 2
ClH H N O O
12G DMP
N NH
OH H
N NH
HBTU / DIEA
To a solution of compound 12A (5.0 g, 1.0eq) and compound 12B (2.64 g,
1.0eq) in dry DMF (20 mL) was added 4A° molecular sieve (5.0 g, powder). The resulting
mixture was stirred room temperature under N for 20 hrs, filtrated to remove the molecular
sieves, diluted with hexane (80 mL) and ethyl acetate (80 mL), and then washed with 3 x 50 mL
water, 50 mL saturated NaHCO and brine. The crude mixture was purified on silica gel column
to provide compound 12C (3.2 g, yield 48%) as clear oil.
A mixture of compound 12C (350 mg, 1.0eq) and compound 12D (190 mg,
1.0 eq) in acetic acid (8 mL) was heated at 100 C for 1hr. The residue, upon in-vauo removal of
solvent, was suspended in ethyl acetate (80 mL), washed with saturated NaHCO and brine. The
crude mixture was purified on silica gel column to provide compound 12E (100 mg, yield 25%).
17681897_1 (GHMatters) P110989.NZ
Compound 12E (100 mg) was treated with LiOH in MeOH/water to afford compound 12F (87
mg, yield 100%).
A mixture of compound 12F (85 mg, 1.0 eq), compound 12G (116 mg, 1.2 eq)
and HBTU (190 mg, 1.2 eq) in DMF (5 mL) was stirred at room temperature for 5 mins, and then
DIEA (0.3 mL, 4.0 eq) was added. After stirred at room temperature for 30 mins, the mixture
was diluted with 50 mL ethyl acetate and 20 mL hexane, washed with 1N HCl, water, saturated
NaHCO and brine and concentrated in vacuo to afford intermediate compound 12H (150 mg,
yield 94%) as white solid.
To a solution of compound 12H (150 mg, 1.0 eq) in dry DCM (20ml) and
DMSO (2.5 mL) was added DMP (673 mg, 4.0 eq). After stirred at room temperature for 1 hr,
the mixture was diluted with DCM (80 mL), quenched by adding 10% Na S O /saturated
2 2 3
NaHCO (v/v = 1/1, ~ 20 mL). The organic layer was separated. The aqueous layer was
extracted with DCM (30 mL x 2). The combined organic layer was washed with H O (10 mL),
brine (10 mL), dried over Na SO , filtered and concentrated to afford white solid. The solid was
triturated in CH Cl /Hexane to provide pure compound 12 (95 mg, yield 64%). MS (ESI) m/z
(M+H) : 378.3; H NMR (400 MHz, DMSO-d6): δ 9.15 (d, 1H), 8.21 (d, 1H), 7.91 (t, 1H), 7.82
(s, 1H), 7.54 (d, 1H), 7.17-7.32 (m, 6H), 6.49 (s, 1H), 5.29 (m, 1H), 3.15 (dd, 1H), 2.84 (dd, 1H),
2.23 (s, 3H) ppm.
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)(BENZO[D]THIAZOLYL)-
3-METHYL-1H-PYRAZOLECARBOXAMIDE (13)
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)METHYL(QUINOLIN
YL)-1H-PYRAZOLECARBOXAMIDE (15)
(S)([1,1'-BIPHENYL]YL)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)
METHYL-1H-PYRAZOLECARBOXAMIDE (16)
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)METHYL(4-
(METHYLSULFONYL)PHENYL)-1H-PYRAZOLECARBOXAMIDE (17)
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)METHYL(4-
(TRIFLUOROMETHOXY)PHENYL)-1H-PYRAZOLECARBOXAMIDE (19)
Compounds 13, 15-17 and 19 were prepared, respectively, as in Example 5 by
utilizing the corresponding hydrazine derivative.
17681897_1 (GHMatters) P110989.NZ
Compound 13: MS (ESI) m/z (M+H) : 434.3; H NMR (400 MHz, DMSO-d6):
δ 10.09 (d, 1H), 8.10 (d, 1H), 7.99 (d, 1H), 7.83 (s, 1H), 7.62 (d, 1H), 7.40 (m, 2H), 7.04-7.24
(m, 5H), 6.68 (s, 1H), 5.51 (m, 1H), 3.16 (dd, 1H), 2.95 (dd, 1H), 2.24 (s, 3H) ppm.
Compound: 15: MS (ESI) m/z (M+H) : 428.4; 1H NMR (400 MHz,
DMSO): δ 9.28 (d, 0.5 H), 8.77 (d, 0.5 H), 8.45 (d, 1H), 8 (d, 1H), 7.9 - 7.5 (6 H), 7.2 - 7.1 (6 H),
.4 (m, 0.5 H4.44 (m, 0.5 H), 3.2 - 2.7 (m, 2H) ppm.
Compound 16: MS (ESI) m/z (M+H) : 453.3; H NMR (400 MHz,
DMSO-d6): δ 9.10 (d, 1H), 8.09 (s, 1H), 7.87 (s, 1H), 7.35-7.62 (m, 8H), 7.19-7.29 (m, 5H), 7.09
(d, 1H), 6.61 (s, 1H), 5.30 (m, 1H), 3.17 (dd, 1H), 2.81 (dd, 1H), 2.25 (s, 3H) ppm.
Compound 17: MS (ESI) m/z (M+H) : 455.3; H NMR (400 MHz, DMSO-d6):
δ 9.27 (d, 1H), 8.14 (s, 1H), 7.88 (m, 2H), 7.82 (d, 1H), 7.35-7.62 (m, 8H), 7.19-7.45 (m, 7H),
6.62 (s, 1H), 5.25 (m, 1H), 3.19 (m, 4H), 2.82 (dd, 1H), 2.25 (s, 3H) ppm.
Compound 19: MS (ESI) m/z (M+H) : 461.3; H NMR (400 MHz, DMSO-
d6): δ 9.15 (d, 1H), 8.11 (s, 1H), 7.87 (s, 1H), 7.82 (d, 1H), 7.21-7.35 (m, 9H), 6.61 (s, 1H), 5.23
(m, 1H), 3.20 (dd, 1H), 2.82 (dd, 1H), 2.24 (s, 3H) ppm.
S OH N
OH N
54A 94A
44A 60A 117A
O O N
OH .
O ClH H N
N OH
O OH OH
118A 148A
128A
235A
135A
(S)-
N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)METHYL
PHENYLISOXAZOLECARBOXAMIDE (27)
Compound 27 (30.0 mg, 43.0% yield, white solid) was prepared as in Example
12 from the corresponding carboxylic acid, compound 27A. Compound 27: H NMR (400MHz,
DMSO-d ) δ 8.94 (d, J = 7.6 Hz, 1H), 8.17 (s, 1H), 7.90 (s, 1H), 7.49 - 7.41 (m, 3H), 7.41 - 7.34
(m, 2H), 7.33 - 7.21 (m, 5H), 5.42 - 5.35 (m, 1H), 3.29 - 3.21 (m, 1H), 2.80 - 2.70 (m, 1H), 2.35 -
2.27 (m, 3H). MS (ESI) m/z (M+H) 378.1.
17681897_1 (GHMatters) P110989.NZ
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)PHENYL-1,2,3-
THIADIAZOLECARBOXAMIDE (44)
Compound 44 (42.4 mg, yield: 47.7%, white solid) was prepared as in Example
12 from the corresponding intermediate carboxylic acid, compound 44A. Compound 44: H
NMR (400 MHz, DMSO-d ) δ 9.60 (br d, J = 7.5 Hz, 1 H), 8.19 (s, 1 H), 7.93 (s, 1 H), 7.79 -
7.67 (m, 2 H), 7.52 - 7.39 (m, 3 H), 7.34 - 7.21 (m, 5 H), 5.52 - 5.39 (m, 1 H), 3.23 (dd, J = 14.0,
3.5 Hz, 1 H), 2.78 (dd, J = 13.6, 10.5 Hz, 1 H). MS (ESI) m/z (M+H) 381.0.
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)METHYL
PHENYLTHIAZOLECARBOXAMIDE (54)
Compound 54 (75 mg, yield: 75.4%, white solid) was prepared as in Example
12 from the corresponding intermediate carboxylic acid, compound 54A. H NMR (400 MHz,
DMSO-d ) δ 8.46 (br d, J = 7.7 Hz, 1 H) 8.05 (br s, 1 H) 7.81 (br s, 1 H) 7.43 - 7.29 (m, 1 H)
7.41 - 7.29 (m, 1 H) 7.29 - 7.29 (m, 1 H) 7.41 - 7.29 (m, 1 H) 7.30 - 7.28 (m, 1 H) 7.28 - 7.08 (m,
H) 5.37 (td, J = 8.1, 4.5 Hz, 1 H) 3.22 - 3.09 (m, 1 H) 3.17 (br dd, J = 14.0, 4.1 Hz, 1 H) 3.06 –
2.92 (m, 1 H) 2.72 - 2.60 (m, 3 H). MS (ESI) m/z (M+H) 394.0.
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)PHENYLISOXAZOLE
CARBOXAMIDE (60)
Compound 60 (40 mg, yield 36.20%, white solid) was prepared as in Example
from the corresponding carboxylic acid, compound 60A. Compound 60: H NMR (400MHz,
DMSO-d ) δ 9.02 (d, J=7.5 Hz, 1H), 8.83 (s, 1H), 8.16 (s, 1H),7.92 - 7.78 (m, 3H), 7.59 - 7.42
(m, 3H), 7.35 - 7.17 (m, 4H), 5.43 - 5.34 (m, 1H),3.27 - 3.17 (m, 1H), 2.90 - 2.79 (m, 1H). MS
(ESI) m/z (M +H) 364.1.
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)CHLOROMETHYL
PHENYL-1H-PYRAZOLECARBOXAMIDE (94)
Compound 94 was prepared as in Example 5 from the corresponding
intermediate carboxylic acid, compound 94A. Compound 94: H NMR (400 MHz, DMSO): δ 8.8
(d, 1H), 8.16 (s, 1H), 7.89 (s, 1H), 7.5 - 7.46 (m, 2H), 7.32 -7.18 (m, 8H), 5.41 (m, 1H), 3.82 (s,
3H), 3.17 (dd, 1H), 2.76 (dd, 1H) ppm. MS (ESI) m/z (M+H) 410.9.
17681897_1 (GHMatters) P110989.NZ
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)ISOPROPYLPHENYL-1H-
PYRAZOLECARBOXAMIDE (117)
Compound 117 (10 mg, yield 18.29%, white solid) was prepared as in Example
from the corresponding intermediate carboxylic acid, compound 117A. Compound 117: H
NMR (400MHz, DMSO-d ) δ 8.36 (d, J=7.8 Hz, 1H), 8.09 (s, 1H), 7.84 (s, 1H), 7.63 - 7.47 (m,
5H), 7.32 - 7.14 (m, 5H), 6.66 (s, 1H), 5.50 - 5.39 (m, 1H), 3.23 - 3.13 (m, 1H), 3.09 - 2.89 (m,
2H), 1.12 (d, J=6.8 Hz, 6H). MS (ESI) m/z (M + H) 405.2.
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)METHYL
PHENYLFURANCARBOXAMIDE (118)
Compound 118 (58 mg, yield: 55.4%, white solid) was prepared as in Example
from the corresponding intermediate carboxylic acid, compound 118A. Compound 118: H
NMR (400MHz, DMSO-d ) δ 8.54 (d, J = 7.5 Hz, 1H), 8.08 (s, 1H), 7.81 (s, 1H), 7.68 (d, J = 7.0
Hz, 2H), 7.35 - 7.26 (m, 7H), 7.23 - 7.17 (m, 1H), 6.39 (d, J = 0.9 Hz, 1H), 5.30 (br d, J = 0.7
Hz, 1H), 3.19 - 3.12 (m, 1H), 2.88 - 2.79 (m, 1H), 2.33 - 2.29 (m, 3H). MS (ESI) m/z (M+H)
377.1.
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)(TERT-BUTYL)PHENYL-
1H-PYRAZOLECARBOXAMIDE (128)
Compound 128 (101.7 mg, 68.04% yield, white solid) was prepared as in
Example 5 from the corresponding intermediate carboxylic acid, compound 128A. Compound
128: H NMR (400 MHz, CDCl ) δ 7.55 - 7.44 (m, 3H), 7.42 - 7.35 (m, 2H), 7.34 - 7.28 (m, 1H),
7.25 - 7.14 (m, 5H), 6.74 (br s, 1H), 6.70 (s, 1H), 5.73 - 5.64 (m, 1H), 5.53 (br s, 1H), 3.44 - 3.35
(m, 1H), 3.18 - 3.09 (m, 1H), 1.16 (s, 9H). MS (ESI) m/z (M+1) 419.3.
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)PHENYLOXAZOLE
CARBOXAMIDE (148)
Compound 148 (10 mg, yield: 30.8%, white solid) was prepared as in Example
from the corresponding intermediate carboxylic acid, compound 148A. Compound 148: H
NMR (400MHz, DMSO-d ) δ 8.57 (s, 1H), 8.44 (d, J=7.7 Hz, 1H), 8.14 - 8.03 (m, 3H), 7.85 (s,
1H), 7.49 - 7.42 (m, 3H), 7.30 - 7.15 (m, 5H), 5.49 - 5.40 (m, 1H), 3.26 - 3.17 (m, 1H), 3.12 -
3.02 (m, 1H). MS (ESI) m/z (M +H) 364.1.
17681897_1 (GHMatters) P110989.NZ
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)CYCLOPROPYL
PHENYLTHIAZOLECARBOXAMIDE (207)
Compound 207 (54.0 mg, 44.09% yield, white solid) was prepared as in
Example 5 from the corresponding intermediate carboxylic acid, compound 135A. Compound
207: H NMR (400 MHz, CDCl ) δ 7.52-7.45 (m, 2H), 7.43 - 7.38 (m, 3H), 7.21 - 7.17 (m, 3H),
6.79-6.77 (m, 2H), 6.70 (s, 1H), 6.19 – 6.17 (d, J = 6.0Hz, 1H), 5.53 (s, 1H), 5.50 – 5.45 (m, 1H),
3.25 - 3.21 (m, 1H), 2.90- 2.85 (m, 1H), 2.33-2.27 (m, 1H), 1.19 – 1.16 (m, 2H), 1.13 – 1.10 (m,
2H). MS (ESI) m/z (M+1) 420.1.
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)(2,6-DIMETHYLPYRIMIDIN-
4-YL)METHYL-1H-PYRAZOLECARBOXAMIDE (235)
Compound 235 (61.6 mg, 51.11% yield, white solid) was prepared as in
Example 5 from the corresponding intermediate carboxylic acid, compound 235A. Compound
235: H NMR (400 MHz, CDCl ) δ 9.83 (d, J = 7.2 Hz, 1H), 7.57 (s, 1H), 7.21 - 7.16 (m, 3H),
7.11 - 7.06 (m, 2H), 6.87 (s, 1H), 6.75 (br s, 1H), 5.84 - 5.76 (m, 1H), 5.56 (br s, 1H), 3.49 - 3.31
(m, 2H), 2.55 (s, 3H), 2.34 - 2.32 (m, 6H). MS (ESI) m/z (M+1) 407.1.
((S)-N-(1-AMINO-1,2-DIOXOPENTANYL)METHYLPHENYLISOXAZOLE
CARBOXAMIDE (47)
Compound 47 (90.00 mg, yield 60.4%, white solid) was prepared as in
Example 5 from the corresponding starting materials, 23A and 47A. Compound 47: H NMR
(400MHz, DMSO-d ) δ 8.98 (d, J = 6.6 Hz, 1H), 8.12 (br s, 1H), 7.88 - 7.79 (m, 3H),7.57 - 7.50
(m, 3H), 5.12 - 5.02 (m, 1H), 2.32 (s, 3H), 1.95 - 1.77 (m,1H), 1.65 - 1.48 (m, 1H), 0.93 (t, J=7.4
Hz, 3H). MS (ESI) m/z (M +H) 316.1.
17681897_1 (GHMatters) P110989.NZ
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)PHENYLOXAZOLE
CARBOXAMIDE (303)
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)PHENYLISOXAZOLE
CARBOXAMIDE (304)
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)PHENYL
(TRIFLUOROMETHYL)-1H-PYRAZOLECARBOXAMIDE (305)
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)-1,3-DIPHENYL-1H-
PYRAZOLECARBOXAMIDE (309)
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)(TERT-BUTYL)METHYL-
1H-PYRAZOLECARBOXAMIDE (310)
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)CHLOROETHYL-1H-
PYRAZOLECARBOXAMIDE (311)
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)CHLOROETHYL
METHYL-1H-PYRAZOLECARBOXAMIDE (312)
Compounds 303-305 and 309-312 were prepared as in Example 5 from the
corresponding carboxylic acid with compound 12G, respectively.
Compound 303: H NMR (400MHz, DMSO-d ) δ H NMR (400 MHz,
DMSO): δ 8.51 (s, 1H), 7.9 - 7.85 (m, 2H), 7.81 (d, 1H), 7.4 - 7.0 (m, 10H), 4.53 (m, 1H), 2.98
(dd, 1H), 2.57 (dd, 1H) ppm. MS (ESI) m/z (M+H) 364.3.
Compound 304: H NMR (400MHz, DMSO-d ) δ 9.2 - 8.9 (m, 1H), 8.11 (m,
1H), 7.7 - 7.1 (m, 12H), 5.3 (m, 0.5 H), 4.4 (m, 0.5H), 2.85 - 2.55 (m, 2H) ppm. MS (ESI) m/z
(M+H) 364.3.
Compound 305: H NMR (400MHz, DMSO-d ) δ 9.3 (d, 1H), 8.07 (s, 1H),
7.83 (s, 1H), 7.4 - 7.1 (m, 10H), 5.24 (m, 1H), 3.14 (dd, 1H), 2.74 (dd, 1H) ppm. MS (ESI) m/z
(M+H) 431.3.
Compound 309: H NMR (400MHz, DMSO-d ) δ 8.7 (m, 1H), 8.49 (d, 1H),
8.1 - 7.1 (m, 17H), 5.31 (m, 0.5 H), 4.6 - 4.4 (m, 0.5H), 3.1 - 2.7 (m, 2H) ppm. MS (ESI) m/z
(M+H) 439.3.
17681897_1 (GHMatters) P110989.NZ
Compound 310: H NMR (400MHz, DMSO-d ) δ 7.75 (d, 1H), 7.4 - 7.1 (m,
5H), 6.38 (s, 1H), 6.1 (d, 2H), 4.48 (m, 1H), 3.02 (dd, 1H), 2.52 (dd, 1H) 2.08 (s, 3H), 1.31 (s,
9H) ppm. MS (ESI) m/z (M+H) 379.3.
Compound 311: H NMR (400MHz, DMSO-d ) δ 8.89 (d, 1H), 8.13 (d, 1H),
7.86 (s, 1H), 7.33 (s, 1H), 7.3 - 7.1 (m, 5H), 6.8 (s, 1H), 5.38 (m, 1H), 3.99 (q, 2H), 3.21 (dd,
1H), 2.78 (dd, 1H) 1.11 (t, 3H) ppm. MS (ESI) m/z (M+H) 349.2.
Compound 312: H NMR (400MHz, DMSO-d ) δ 8.74 (d, 1H), 8.1 (s, 1H),
7.83 (s, 1H), 7.4 - 7.2 (m, 5H), 6.58 (s, 1H), 5.29 (m, 1H), 4.25 (q, 2H), 3.18 (dd, 1H), 2.87 (dd,
1H), 2.13 (s, 3H), 1.15 (t, 3H) ppm. MS (ESI) m/z (M+H) 329.1.
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)METHYL
PHENYLISOXAZOLECARBOXAMIDE (23)
O 23B
O EDCI,
THF,
To a solution of compound 23A (500 mg, 2.46 mmol) in THF (10 mL) was
added 23B (311 mg, 2.71 mmol) and EDCI (566 mg, 2.95 mmol) with DCM (10 mL). The
mixture was stirred at 25 °C for 3 hrs. The reaction mixture was concentrated and diluted with
EA (20 mL). Then the mixture was washed with HCl (1M, 20 mL), saturated aqueous NaHCO
(20 mL), dried over Na SO and concentrated. Compound 23C (800 mg, crude, yellow oil): H
NMR (400MHz, DMSO-d ) δ 7.93 - 7.88 (m, 2H), 7.69 - 7.63 (m, 1H), 7.62 - 7.56 (m, 2H), 2.87
(s, 4H), 2.54 - 2.51 (m, 3H).
Compound 23 (30.0 mg, yield 35.0%, white solid) was prepared as in Example
from the corresponding intermediate compounds 23C and 12G. Compound 23: H NMR
(400MHz, DMSO-d ) δ 9.08 (br d, J = 8.0 Hz, 1H), 8.22 (s, 1H), 7.94 (s, 1H), 7.64 (br d, J = 7.2
Hz, 2H), 7.55 - 7.41 (m, 3H), 7.35 - 7.21 (m, 5H), 5.54 - 5.45 (m, 1H), 3.29 - 3.23 (m, 1H), 2.81
- 2.71 (m, 1H), 2.09 (s, 3H). MS (ESI) m/z (M+H) 378.0.
17681897_1 (GHMatters) P110989.NZ
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)(4-PHENYL-1H-PYRAZOL
YL)THIAZOLECARBOXAMIDE (39)
Compound 39 (5.20 mg, 26.12% yield, white solid) was prepared as in
Example 5 from the corresponding starting materials, compounds 21F and 12G. Compound 39:
H NMR (CDCl 400 MHz): δ 11.75 (d, J = 4.8 Hz, 1H), 8.73 - 8.71 (m, 1H), 8.73 (s, 1H), 8.66
(s, 1H), 7.69 (s, 1H), 7.54 (d, J = 7.6 Hz, 2H), 7.45 - 7.41 (m, 2H), 7.35 - 7.31 (m, 1H), 7.29 -
7.27 (m, 1H), 7.25 - 7.21 (m, 4H), 6.78 (br s, 1H), 5.82 - 5.74 (m, 1H), 5.48 (br s, 1H), 3.46 -
3.41 (m, 1H), 3.27 - 3.20 (m, 1H). MS (ESI) m/z (M+H) 446.1.
N-(4-(CYCLOPROPYLAMINO)-3,4-DIOXOPHENYLBUTANYL)METHYL
(PYRIDINYL)-1H-PYRAZOLECARBOXAMIDE (456)
Compound 456 (240 mg, 86.0% yield, white solid) was prepared as in
compound 12 from the corresponding starting materials, compounds 12F and 3-amino-N-
cyclopropylhydroxyphenylbutanamide hydrochloride. Compound 456: H NMR (CDCl
400 MHz): δ 9.15 (d, J = 7.2 Hz, 1H), 8.80 (d, J = 5.2 Hz, 1H), 8.21 - 8.17 (m, 1H), 7.92 - 7.86
(m, 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.33 - 7.16 (m, 6H), 6.50 (s, 1H), 5.36 - 5.27 (m, 1H), 3.17 -
3.09 (m, 1H), 2.88 - 2.79 (m, 1H), 2.79 - 2.70 (m, 1H), 2.24 (s, 3H), 0.69 - 0.53 (m, 4H). MS
(ESI) m/z (M+H) 418.2.
N-(4-(CYCLOPROPYLAMINO)-3,4-DIOXOPHENYLBUTANYL)
PHENYLISOXAZOLECARBOXAMIDE (461)
Compound 461 (270 mg, 68.77% yield, white solid) was prepared as in
compound 12 from the corresponding starting materials, compounds 60A and 3-amino-N-
cyclopropylhydroxyphenylbutanamide hydrochloride. Compound 461: H NMR (CDCl
400 MHz): δ 9.04 (d, J = 7.5 Hz, 1H), 8.87 (d, J = 4.8 Hz, 1H), 8.82 (s, 1H), 7.85 (d, J = 7.3 Hz,
2H), 7.59 - 7.44 (m, 3H), 7.36 - 7.19 (m, 5H), 5.37 (br.s., 1H), 3.27 - 3.17 (m, 1H), 2.90 - 2.73
(m, 2H), 0.72 - 0.51 (m, 4H). MS (ESI) m/z (M+H) 404.1.
(S)-N-(4-AMINO(4-HYDROXYPHENYL)-3,4-DIOXOBUTANYL)METHYL
PHENYLISOXAZOLECARBOXAMIDE (492)
Compound 492 (35 mg, 60.9% yield, white solid) was prepared as in
compound 12 from the corresponding starting materials, compounds 23A and (3S)amino(4-
(tert-butoxy)phenyl)hydroxybutanamide followed by removal of the tert-butyl group to obtain
17681897_1 (GHMatters) P110989.NZ
the final compound 492. Compound 492: H NMR (DMSO-d 400 MHz): δ 9.29 (s, 1H), 9.01
(d, J = 7.5 Hz, 1H), 8.19 (s, 1H), 7.92 (s, 1H), 7.66 - 7.41 (m, 5H), 7.07 (d, J = 8.4 Hz, 2H), 6.68
(d, J = 8.6 Hz, 2H), 5.46 - 5.29 (m, 1H), 3.13 (br d, J = 10.8 Hz, 1H), 2.63 (br d, J = 2.9 Hz, 1H),
2.13 (s, 3H). MS (ESI) m/z (M+H) 394.1.
N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)METHYL(PYRIDINYL)-1H-
PYRAZOLECARBOXAMIDE (495)
Compound 495 (4.0 g, 44.68% yield, white solid) was prepared as in
compound 12 from the corresponding starting materials, compounds 12F and 3-amino
hydroxyphenylbutanamide hydrochloride to obtain the final compound 495. Compound 495:
H NMR (DMSO-d 400 MHz): δ 7.74 (br d, J = 9.0 Hz, 1H), 7.31 (d, J = 8.5 Hz, 2H), 7.20 -
7.08 (m, 5H), 7.04 (d, J = 9.0 Hz, 1H), 6.97 (d, J = 8.5 Hz, 2H), 5.40 (d, J = 6.3 Hz, 1H), 4.96 (s,
2H), 4.79 (d, J = 2.3 Hz, 2H), 4.48 - 4.15 (m, 2H), 3.97 - 3.86 (m, 1H), 3.68 (t, J = 8.2 Hz, 1H),
3.63 - 3.49 (m, 2H), 2.98 (dd, J = 3.4, 13.9 Hz, 1H), 2.70 - 2.59 (m, 1H), 1.78 (qd, J = 6.8, 13.6
Hz, 1H), 0.72 (d, J = 6.8 Hz, 3H), 0.69 - 0.62 (m, 1H), 0.67 (d, J = 6.8 Hz, 2H). MS (ESI) m/z
(M+Na) 493.1.
N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)PHENYLISOXAZOLE
CARBOXAMIDE (531)
Compound 531 (4.0 g, 44.68% yield, white solid) was prepared as in
compound 12 from the corresponding starting materials, compounds 60A and 3-amino
hydroxyphenylbutanamide hydrochloride to obtain the final compound 531. Compound 531:
H NMR (CD CN 400 MHz): δ 8.52 (s, 1H), 7.84 - 7.75 (m, 2H), 7.57 - 7.51 (m, 1H), 7.51 -
7.43 (m, 2H), 7.32 - 7.23 (m, 3H), 7.23 - 7.17 (m, 2H), 7.17 - 7.07 (m, 1H), 7.06 - 6.93 (m, 1H),
6.23 (s, 1H), 5.55 - 5.47 (m, 1H), 3.29 (dd, J = 4.9, 14.1 Hz, 1H), 2.92 (dd, J = 8.9, 14.0 Hz, 1H).
MS (ESI) m/z (M+H) 364.1.
EXAMPLE 6
Compounds 21-22, 322, 29, 31, 75, 90, 279
17681897_1 (GHMatters) P110989.NZ
(S)-N-(1-OXOPHENYLPROPANYL)(4-PHENYL-1H-PYRAZOL
YL)THIAZOLECARBOXAMIDE (21)
Br O
N 21E
LiOH•H O
N 2 O
, N O
Cs CO toluene
°C, MeOH:H O EDCI
S OH
110.6 16 hrs
2 hrs
O (2:1),
°C, DME, 6 hrs
OH N
21G DMP
DCM, 4 days
DME, 2 hrs
21F OH
A mixture consisting of compound 21A (500 mg, 2.12 mmol), compound 21B
(306 mg, 2.12 mmol) and Cs CO (2.07 g, 6.36 mmol) was stirred at 110.6 °C for 16 hrs. The
reaction mixture was cooled to room-temperature, filtered and concentrated under reduced
pressure to give a residue. The residue was purified by flash silica gel chromatography
(Petroleum ether: Ethyl acetate = 3:2 and then Acetic acid: Ethyl acetate = 1:100) to afford
compound 21C (80 mg, 12.61% yield) as a light yellow solid, and compound 21D (125 mg,
21.73% yield) as a yellow solid.
Compound 21C: H NMR (CDCl 400 MHz): δ 8.85 (s, 1H), 8.49 (s, 1H), 8.07
(s, 1H), 7.57 (d, J = 7.6 Hz, 2H), 7.40 (t, J = 7.6 Hz, 2H), 7.30 - 7.26 (m, 1H), 4.41 - 4.32 (m,
2H), 1.34 (t, J = 7.2 Hz, 3H).
Compound 21D: H NMR (CDCl 400 MHz): δ14.70 (br. s., 1H), 9.33 (s, 1H),
8.87 (d, J = 0.8 Hz, 1H), 8.41 (d, J = 0.8 Hz, 1H), 7.75 - 7.71 (m, 2H), 7.43 - 7.38 (m, 2H), 7.30 -
7.24 (m, 1H). MS (ESI) m/z (M+H) 271.8.
To a solution of compound 21C (80 mg, 267.25 umol) in MeOH (5 mL) and
H O (2.5 mL) was added LiOH (19.20 mg, 801.75 umol) in one portion at 25 °C under N . The
mixture was stirred at 25 °C for 2 hrs. The mixture was concentrated under reduced pressure to
give a residue. The residue was diluted with water (10 mL) and adjusted with 1N HCl to pH ~ 3,
extracted with ethyl acetate 90 mL (30 mL x 3). The combined organic layers were washed with
17681897_1 (GHMatters) P110989.NZ
brine 30 mL, dried over anhyrous Na SO , filtered and concentrated under reduced pressure to
afford intermediate compound 21D (71.1 mg, 98.07% yield) as white solid. H NMR (CDCl
400 MHz): δ 8.84 (s, 1H), 8.78 (d, J = 0.8 Hz, 1H), 8.13 (d, J = 0.8 Hz, 1H), 7.60 - 7.56 (m, 2H),
7.45 (t, J = 7.6 Hz, 2H), 7.39 - 7.34 (m, 1H). MS (ESI) m/z (M+H) 271.8.
To a solution of compound 21D (80 mg, 294.89 umol) and 1-
hydroxypyrrolidine-2,5-dione (21E) (35.6 mg, 309.63 umol) in DME (3.50 mL) was added EDCI
(84.8 mg, 442.34 umol) in one portion at 25 °C under N . The resultant mixture was stirred at 25
°C for 6 hrs. The mixture was concentrated under reduced pressure, diluted with EtOAc (100
mL), washed with 1N HCl (10 mL) and saturated aqueous NaHCO (10 mL x 3), and then
washed with brine (20 mL). The organic phase was dried with anhydrous Na SO , filtered and
concentrated in vacuum to afford intermediate compound 21F (100 mg, crude) as yellow oil. MS
(ESI) m/z (M+H) 368.9.
A mixture consisting of compound 21F (100 mg, 271.47 umol) and compound
21G (41.1 mg, 271.47 umol) in DME (3 mL) was stirred at 25 °C for 2 hrs. The mixture was
concentrated in vacuum, diluted with ethyl acetate (100 mL), washed with 1N HCl (10 mL) and
saturated aqueous NaHCO (10 mL x 3), and then washed with brine (20 mL). The organic
phase was dried with anhydrous Na SO , filtered and concentrated in vacuum to give a residue.
The residue was purified by flash silica gel chromatography (Petroleum ether: Ethyl acetate =
3:2) to afford compound 21H (65 mg, 59.20% yield). H NMR (CDCl 400 MHz): δ 10.54 (d, J
= 7.6 Hz, 1H), 9.21 (d, J=0.4 Hz, 1H), 8.93 (s, 1H), 8.40 (s, 1H), 7.78 (d, J=7.6 Hz, 2H), 7.45 –
7.38 (m, 2H), 7.31 - 7.26 (m, 1H), 7.24 - 7.18 (m, 4H), 7.15 – 7.10 (m, 1H), 4.96 – 4.89 (m, 1H),
4.13 – 4.02 (m, 1H), 3.52 - 3.43 (m, 2H), 2.97 – 2.91 (m, 1H), 2.82 – 2.74 (m, 1H). MS (ESI)
m/z (M+H) 405.0.
DMP (63 mg, 148.34 umol) was added to a solution of compound 21H (30
mg, 74.17 umol) in dichloromethane (6 mL). The mixture was stirred at 25 °C for 12 hrs.
Additional DMP (63 mg, 148.34 umol) was added and the mixture was stirred for additional 6
hrs at 25 °C. Additional DMP (157 mg, 0.37 mmol) was added. After stirred for additional 39
hrs, the mixture was diluted with dichloromethane (35 mL), quenched by the addition of 10 %
Na S O /saturated aqueous NaHCO (v/v = 1/1, ~35 mL). The organic layer was separated and
2 2 3 3
the aqueous layer was extracted with DCM (20 mL x 2). The combined organic layer was washed
17681897_1 (GHMatters) P110989.NZ
with H O (10 mL), brine (10 mL), dried over anhydrous MgSO , filtered and concentrated. The
residue was triturated with i-Pr O (3 mL). The insoluble substance was collected and dried in
vacuum. Compound 21 (20 mg, 67% yield, pale yellow solid): H NMR (CDCl 400 MHz): δ
11.71 (br. d, J = 6.0 Hz, 1H), 9.67 (s, 1H), 8.68 (s, 1H), 8.60 (s, 1H), 7.66 (s, 1H), 7.48 - 7.46 (m,
2H), 7.36 - 7.34 (m, 3H), 7.24 - 7.22 (m, 2H), 7.20 - 7.16 (m, 3H), 4.86 - 4.81(m, 1H), 3.21 -
3.18 (m, 2H). MS (ESI) m/z (M+H) 403.1.
(S)(1H-INDAZOLYL)-N-(1-OXOPHENYLPROPANYL)THIAZOLE
CARBOXAMIDE (22)
DME,
29 °C, 1 h
Compound 22 (4.70 mg, 16.87% yield, yellow solid) was prepared as in
Example 6 from the corresponding starting materials through intermediate compound 22E and
then compound 22G. Compound 22: H NMR (CD CN 400 MHz): δ 10.41 (br. s, 1H), 9.67 (s,
1H), 9.04 (s, 1H), 8.21 – 8.19 (m, 1H), 8.15 (s, 1H), 7.91 - 7.89 (m, 1H), 7.61 - 7.58 (m, 1H),
7.40 - 7.37 (m, 1H) 7.12 - 7.10 (m, 5H) 4.77 - 4.72 (m, 1H), 3.29 - 3.24 (m, 1H), 3.11 - 3.05 (m,
1H). MS (ESI) m/z (M+H) 377.0.
(S)METHYL-N-(1-OXOPHENYLPROPANYL)PHENYLOXAZOLE
CARBOXAMIDE (322)
Compound 322 (102.9 mg, 36.1% yield, off-white solid) was prepared as in
Example 6 from the corresponding intermediate compounds 107B and 21G ((S)amino
phenylpropanol). Compound 322: H NMR (400 MHz, CDCl ) δ 9.70 (s, 1H), 8.17 - 8.09 (m,
2H), 7.47 - 7.36 (m, 3H), 7.35 - 7.26 (m, 3H), 7.19 (d, J = 6.84 Hz, 2H), 6.82 (d, J = 6.00 Hz,
1H), 4.96 - 4.86 (m, 1H), 3.40 - 3.28 (m, 1H), 3.26 - 3.19 (m, 1H), 2.55 (s, 3H). MS (ESI) m/z
(M+1) 335.1.
17681897_1 (GHMatters) P110989.NZ
(S)(BENZO[D]THIAZOLYL)-N-(1-OXOPHENYLPROPANYL)-1H-
IMIDAZOLECARBOXAMIDE (29)
Tosmic, K CO
2 3 NaOH
THF,H O
TsOH, toluene
MeOH, 70 1hr
S N C,
OEt N
A mixture of compound 29A (20 g, 133 mmol), ethyl 2-oxoacetate (136 g, 665
mmol), TsOH.H O (2.5 g, 13.3 mmol) in toluene (200 mL) was stirred at 120 °C for 1 hour.
TLC (Petroleum ether: Ethyl acetate = 3: 1, R = 0.5) indicated reactant 29A was almost
consumed and one new spot formed. LCMS showed one peak with desired MS was detected.
The reaction mixture was concentrated under reduced pressure to give a residue. The residue
was purified by column chromatography (Petroleum ether: Ethyl acetate = 20: 1 to 5: 1) to give
compound 29B (30.0 g, crude) as a yellow oil. H NMR (400MHz, CDCl ) δ 9.40 (s, 1H), 7.98 -
7.78 (m, 1H), 7.77 - 7.57 (m, 1H), 7.55 - 7.31 (m, 1H), 7.30 - 7.07 (m, 1H), 5.38 - 5.26 (m, 1H),
4.33 - 4.21 (m, 3H). MS (ESI) m/z (M+H) 234.9.
A mixture of methyl 29B (10 g, 45.4 mmol), Tosmic (17.7 g, 90.8 mmol),
K CO (9.4 g, 68.1 mmol) in MeOH (200 mL) was stirred at 70 °C for 0.5 hour. TLC
(Petroleum ether: Ethyl acetate = 3: 1, Rf = 0.4) indicated 29B was consumed completely and
some new spots formed. The reaction mixture was filtered and concentrated under reduced
pressure to give a residue. The residue was purified by column chromatography (Petroleum
ether: Ethyl acetate = 20: 1 to 3: 1) to give compound 29C (1.2 g, yield: 10.2%) as a yellow solid.
H NMR (400MHz, CDCl ) δ 8.22 (d, J = 0.9 Hz, 1H), 8.06 (d, J = 7.9 Hz, 1H), 7.93 - 7.88 (m,
3H), 7.58 (dt, J = 1.3, 7.7 Hz, 1H), 7.52 - 7.49 (m, 1H), 7.49 - 7.43 (m, 1H), 4.58 (s, 1H), 3.87 (s,
3H), 2.51 (s, 1H). MS (ESI) m/z (M+H) 259.9.
To a solution of 29C (1.1 g, 4.24 mmol in THF (30 mL), H O (5 mL) was
added NaOH (339 mg, 8.48 mmol). The reaction mixture was stirred at 25 °C for 3hrs. LCMS
showed 29C was consumed completely and one main peak with desired MS was detected. The
reaction mixture was concentrated to give a residue. The residue was dissolved in water (10
mL), adjusted by aqueous HCl (2M) to pH ~ 5, filtered and the filtered cake was concentrated to
17681897_1 (GHMatters) P110989.NZ
give the product 29D (600 mg, yield: 57.7%) as a gray solid. H NMR (400MHz, DMSO-d ) δ
8.48 (d, J = 1.1 Hz, 1H), 8.22 - 8.18 (m, 1H), 8.06 (dd, J = 0.8, 8.0 Hz, 1H), 7.81 (d, J = 0.9 Hz,
1H), 7.64 - 7.53 (m, 2H). MS (ESI) m/z (M+H) 245.9.
Compound 29 (55.00 mg, yield: 76.12%, offwhite solid) was prepared as in
Example 21 from the corresponding intermediate compounds 29D and 21G. Compound 29: H
NMR (400MHz ,CDCl ) δ 9.75 (s, 1 H), 9.01 (d, J = 6.2 Hz, 1 H), 8.14 (s, 1 H), 7.90 - 7.75 (m, 3
H), 7.57 - 7.42 (m, 2 H), 7.19 - 7.00 (m, 5 H), 5.04 - 4.94 (m, 1 H), 3.37 - 3.21 (m, 2 H). MS
(ESI) m/z (M+H) 377.2.
(S)-N-(1-OXOPHENYLPROPANYL)(PYRIDINYL)-1H-IMIDAZOLE
CARBOXAMIDE (31)
Compound 31 (25 mg, yield: 57.86%, light yellow solid) was prepared as in
Example 6 from the corresponding intermediate compounds 24E and 21G. Compound 31: H
NMR (400MHz ,CDCl ) δ 9.70 (s, 1 H), 8.45 - 8.39 (m, 1 H), 7.94 (d, J = 1.1 Hz, 1 H), 7.89 -
7.82 (m, 1 H), 7.67 - 7.59 (m, 2 H), 7.39 - 7.32 (m, 2 H), 7.30 - 7.27 (m, 1 H), 7.26 - 7.21 (m, 2
H), 7.17 - 7.11 (m, 2 H), 4.87 (q, J = 6.6 Hz, 1 H), 3.25 (dd, J = 2.5, 6.5 Hz, 2 H). MS (ESI) m/z
(M+H) 321.1.
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)(5-PHENYLPYRIMIDIN
YL)-1H-IMIDAZOLECARBOXAMIDE (75)
Compound 75 (43.1 mg, yield: 66.6%, white solid) was prepared as in Example
6 from the corresponding intermediate compounds 74E and 21G. Compound 75:. H NMR
(CDCl 400 MHz) δ 9.79 (s, 1H), 9.61 (br d, J = 6.0 Hz, 1H), 8.75 (s, 2H), 8.65 (s, 1H), 7.84 (s,
1H), 7.58 - 7.53 (m, 5H), 7.25 - 7.14 (m, 5H), 5.06 - 5.01 (m, 1H), 3.43 - 3.38 (m, 1H), 3.33 -
3.28 (m, 1H). MS (ESI) m/z (M+H) 398.1.
(S)(1H-BENZO[d]IMIDAZOLYL)-N-(1-OXOPHENYLPROPANYL)-1H-
IMIDAZOLECARBOXAMIDE (90)
Compound 90 (20 mg, yield: 44.4%, white solid) was prepared as in Example 6
from the corresponding intermediate compounds 70D and 21G ((S)aminophenylpropan
ol). Compound 90: H NMR (400MHz,CDCl ) δ 12.77 (br s, 1H), 12.87 - 12.63 (m, 1H), 9.75 (s,
1H), 8.85 (s, 1H), 7.71 (br s, 1H), 7.57 (s, 1H), 7.50 (br s, 1H), 7.36 - 7.27 (m, 4H), 7.19 (br d, J
17681897_1 (GHMatters) P110989.NZ
= 6.8 Hz, 2H), 6.99 (br d, J = 5.3 Hz, 1H), 4.93 (q, J = 6.7 Hz, 1H), 3.32 (d, J = 6.4 Hz, 2H). MS
(ESI) m/z (M+H) 360.1.
(S)METHYL-N-(1-OXOPHENYLPROPANYL)(PYRIMIDINYL)-1H-
PYRAZOLECARBOXAMIDE (279)
Compound 279 (102.0 mg, 304.15 umol, 55.26% yield, white solid) was
prepared as in Example 6 from the corresponding intermediate compounds 245D and 21G ((S)
aminophenylpropanol). Compound 279: H NMR (400 MHz, CDCl ): δ 9.88(d, J = 5.6 Hz,
1H), 9.76 (s, 1H), 8.74 (d, J = 5.6 Hz, 1H), 8.61 (s, 1H), 7.91 – 7.87 (m, 1H), 7.27 – 7.23 (m, 3H),
7.19 – 7.17 (m, 2H), 8.89 (s, 1H), 5.02 – 4.97 (m, 1H), 3.40 – 3.35 (m, 1H), 3.30 – 3.25 (m, 1H),
2.34 (s, 1H). MS (ESI) m/z (M+1) 336.1.
EXAMPLE 7
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)(PYRIDINYL)-1H-
IMIDAZOLECARBOXAMIDE (24)
TosMIC O
LiOH.H O
N NH
OEt THF/H2O
MeOH
CO /EtOH
To a solution of compound 24B (16.2 g, 79.7 mmol) in MeOH (25 mL) was
added compound 24A (5 g, 53.1 mmol). The mixture was stirred at 80 °C for 6 hrs. TLC
(Petroleum ether: Ethyl acetate = 2:1, R = 0.24) indicated compound 24A was remained and one
major new spot with lower polarity was detected. Then the reaction mixture was concentrated
under reduced pressure to give a residue. Then the residue was purified by column
chromatography (SiO2, Petroleum ether: Ethyl acetate = 30:1 to 15:1) to give compound 24C (6
g, yield: 53.7%) as a yellow oil.
To a mixture of compound 24C (6 g, 28.5 mmol) in EtOH (15 mL) was added
TosMIC (8.3 g, 42.8 mmol), K CO (11.8 g, 85.6 mmol). The mixture was stirred at 80 °C for 12
hrs. TLC (Petroleum ether: Ethyl acetate = 1: 1, R = 0.70) indicated compound 24C remained
and one major new spot with higher polarity was detected. Then the reaction mixture was
filtered and concentrated under reduced pressure to give a residue. The residue was purified by
column chromatography (SiO , Petroleum ether: Ethyl acetate = 30: 1 to 3: 1) to give compound
17681897_1 (GHMatters) P110989.NZ
24D (1.60 g, yield: 25.8%) as a white solid. H NMR (400 MHz, CDCl ) δ 8.61 - 8.54 (m, 1H),
7.98 (s, 1H), 7.92 - 7.83 (m, 2H), 7.45 - 7.38 (m, 2H), 4.25 (q, J = 7.1 Hz, 2H), 1.28 (t, J = 7.2
Hz, 4H).
To a solution of compound 24D (1.6 g, 7.37 mmol) in THF (15 mL) and H O
(5 mL) was added LiOH.H O (618 mg, 14.7 mmol). The reaction mixture was stirred at 25 °C
for 12 hrs. LCMS showed compound 24D was consumed completely and one main peak with
desired MS was detected. Then the mixture was adjusted to pH ~ 5 by adding HCl (1M), and
then white solid was precipitate out. The white solid was filtered and dried over to give
compound 24E (1 g, yield: 71.7%) as a white solid. MS (ESI) m/z (M+H) 189.1.
Compound 24 (20 mg, yield: 33.5%, yellow solid) was prepared as in Example
from the corresponding intermediate carboxylic acid, compound 24E, and compound 12G.
Compound 24: H NMR (400 MHz, DMSO-d ) δ 8.95 (d, J = 7.6 Hz, 1H), 8.50 - 8.38 (m, 1H),
8.12 (s, 1H), 8.03 (br.s., 1H), 7.89 - 7.85 (m, 1H), 7.80 (br.s., 1H), 7.53 (s, 1H), 7.43 - 7.40 (m,
1H), 7.33 - 7.25 (m, 4H), 7.24 - 7.19 (m, 1H), 7.15 (d, J = 8.4 Hz, 1H), 5.25 - 5.20 (m, 1H), 3.17
(dd, J = 4.0, 14.4 Hz, 1H), 2.83 (dd, J = 10.0, 13.6 Hz, 1H). MS (ESI) m/z (M+H) 364.1.
EXAMPLE 8
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)METHYL
PHENYLTHIAZOLECARBOXAMIDE (25)
NaOH
O O O
SO Cl NH
MeOH
2 2 2
O OH
EtOH O
4 Cl
To a solution of compound 25A (20 g, 104 mmol) in CCl (200 ml) was added
SO Cl (14 g, 104 mmol) at 45-50 °C during a period of 0.3 h. Then the mixture was stirred at
45 – 50 °C for 1 h. The reaction mixture was diluted with ice-water (200 mL). The organic
O (200 mL x 2), brine (200 mL) dried over anhydrous
layer was separated, washed with H2
MgSO , filtered and concentrated under reduced pressure to afford compound 25B (25.g, crude)
as pale yellow oil, which was used for next step directly. H NMR (CDCl 400MHz,): δ 8.03 -
7.98 (m, 2H), 7.67 - 7.62 (m, 1H), 7.54 - 7.50 (m, 2H), 5.62 (s, 1H), 4.32 - 4.26 (q, J = 7.2 Hz,
2H), 1.25 (t, J = 7.2 Hz, 3H).
17681897_1 (GHMatters) P110989.NZ
A mixture of compound 25B (6.8 g, 30 mmol) and thioacetamide (2.25 g, 30.0
mmol) in EtOH (75 mL) was heated to 80 °C and stirred for 6 hrs. The solvent was distilled off
under reduced pressure. The residue was purified by a silica gel column chromatography (eluent:
Petroleum Ether/Ethyl Acetate = 50/1) to afford compound 25C (3.0 g, yield 40.4%) as yellow
oil. H NMR (CDCl , 400 MHz):δ 7.77 - 7.71 (m, 2H), 7.47 - 7.40 (m, 3H), 4.28 (q, J = 7.2 Hz,
2H), 2.77 (s, 3H), 1.29 (t, J = 7.2 Hz, 3H).
A solution of NaOH (2N, 12 mL, 24 mmol) was added to a solution of
compound 25C (1.24 g, 5.01 mmol) in MeOH/H O mixture (39 mL/13 mL). The mixture was
stirred at 25 °C for 3 hrs. The mixture was diluted with H O (5 mL). The volatile solvent was
removed by evaporation. The residue was treated with HCl (1N) until pH ~ 3. The precipitate
was collected by filtration, dried under reduced pressure to afford compound 25D (650 mg, yield
59.2%) as white solid, which was used directly in next step. H NMR (DMSO-d , 400 MHz):δ
7.72 - 7.65 (m, 2H), 7.43 - 7.36 (m, 3H), 2.68 (s, 3H).
Compound 25 (25 mg, yield 42%, white solid) was prepared as in Example 5
from the corresponding intermediate carboxylic acid, compound 25D. Compound 25: H NMR
(DMSO-d 400 MHz): δ 8.81 (d, J = 7.6 Hz, 1H), 8.12 (s, 1H), 7.86 (s, 1H), 7.55 - 7.53 (m, 2H),
7.31 - 7.19 (m, 8H), 5.35 - 5.31 (m, 1H), 3.15 (dd, J = 3.6, 13.8 Hz, 1H), 2.77 (dd, J = 9.9, 13.8
Hz, 1H), 2.67 (s, 3H). MS (ESI) m/z (M+H) 394.1.
EXAMPLE 9
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)METHYL
PHENYLOXAZOLECARBOXAMIDE (26)
HOAc
ammonium acetate
PhI(OAc)
reflux
O H N O
EtOH DCE,rt
O 26C
OH O
O NaOH
HO S NO
O OH
mCPBA 2
CH CONH H
CHCl
26E 3
Microwave
17681897_1 (GHMatters) P110989.NZ
To a mixture of compound 26A (7.2 g, 37.46 mmol, 6.5 mL) and ammonium
acetate (5.8 g, 74.92 mmol) were mixed in EtOH (70 mL) and refluxed at 80 °C for 16 hrs. After
removal of the solvent, the residue was dissolved in water (50 mL), extracted with EtOAc (100
mL x 2). This combined organic phase was washed with sat. NaHCO (50 mL x 2) and brine (50
mL), dried over Na SO , filtered and the solvent was removed in vacuo. The residue was
purified by column chromatography (SiO , Petroleum ether/Ethyl acetate = 20: 1 to 10: 1) to give
compound 26B (3.5 g, yield: 48.9%) as yellow oil. H NMR (CDCl 400 MHz): δ 7.57 - 7.53
(m, 2H), 7.48 - 7.37 (m, 3H), 5.07 - 4.89 (m, 1H), 4.22 - 4.11 (m, 2H), 1.33 - 1.25 (m, 3H).
To a mixture of compound 26B (2 g, 10.46 mmol) in DCE (4 mL) was added
PhI(OAc) (4.4 g, 13.60 mmol) in one portion at 25 °C under N . The mixture was stirred at 25
°C for 16 hrs. The reaction mixture was quenched with saturated aqueous NaHCO (50 mL) and
extracted with DCM (50 mL x 3). The organic layers were combined and dried over anhydrous
Na SO . The residue was purified by column chromatography (SiO , Petroleum ether/Ethyl
2 4 2
acetate = 20: 1 to 5: 1) to give compound 26C (400 mg, yield: 15.3%) as yellow oil. H NMR
(CDCl 400 MHz): δ 7.58 (dd, J = 1.1, 7.7 Hz, 1H), 7.44 - 7.39 (m, 4H), 4.28 - 4.21 (m, 2H),
1.94 (s, 3H), 1.66 - 1.60 (m, 1H), 1.62 (br s, 1H), 1.30 - 1.26 (m, 3H).
To a mixture of compound 26C (400 mg, 1.60 mmol) in DCE (5 mL) and
AcOH (10 mL) was stirred at 90 °C for 16 hrs. The solvent was removed. The residue was
purified by column chromatography (SiO , Petroleum ether/Ethyl acetate = 10: 1 to 5: 1) to give
compound 26D (220 mg, yield: 53.0%) as yellow oil. H NMR (CDCl 400 MHz): δ 8.11 - 7.89
(m, 2H), 7.56 - 7.32 (m, 3H), 4.40 (t, J = 7.3 Hz, 2H), 2.59 (s, 3H), 1.39 (q, J = 7.1 Hz, 3H). MS
(ESI) m/z (M+H) 231.8.
To a mixture of iodobenzene (2.5 g, 12.25 mmol, 1.4 mL) and compound 26E
(3.59 g, 13.48 mmol) in CHCl (25 mL), was added m-CPBA (2.33 g, 13.48 mmol). The mixture
was stirred for 2 hrs at 25 °C under an N atmosphere. After the reaction, MTBE (20 mL) was
added to the reaction mixture, and the resulting mixture was filtered and the solid was washed
with MTBE (30 mL) Compound 26F was obtained as a white solid
Ethyl 3-oxophenyl-propanoate 26A (500 mg, 2.60 mmol) and compound
26F (1.58 g, 3.38 mmol,) in CH CN (30 mL) were heated to reflux for 1 h at 80 °C, and
acetamide (461 mg, 7.80 mmol) was added to the mixture. The reaction mixture was heated at
17681897_1 (GHMatters) P110989.NZ
120 °C for 0.1 h under microwave irradiation. After being cooled to room temperature, the
suspension was diluted with saturated NaHCO solution (30 mL), extracted with EtOAc (10 mL
x 2), dried over Na SO , filtered, and concentrated in vacuo. The residue was purified by column
chromatography (SiO , Petroleum ether/Ethyl acetate = 10/1) and by preparatory-TLC (SiO ,
Petroleum ether/Ethyl acetate = 5/1). Compound 26G (50 mg, yield: 8.32%) was obtained as a
white solid. H NMR (CDCl 400 MHz): δ 8.06 - 7.93 (m, 2H), 7.48 - 7.39 (m, 3H), 4.38 (q, J =
7.1 Hz, 2H), 2.58 (s, 3H), 1.37 (t, J = 7.1 Hz, 3H). MS (ESI) m/z (M+H) 231.8.
To a mixture of compound 26G (60 mg, 259.46 umol) in THF (2 mL) and H O
(2 mL) was added NaOH (1 M, 778 uL) in one portion at 0 °C. The mixture was stirred at 25 °C
for 16 hrs. The mixture was extracted with MTBE (2 x 30 mL) and washed with water (3 x 30
mL). The water layers were acidified to pH ~ 4 with 1N HCl, then, the solution extracted with
EtOAc (3 x 30 mL). The organic layers were dried over Na SO and concentrated to give
compound 5 (50 mg, yield: 86.6%) as yellow oil, which was used directly for next step without
further purification. H NMR (CDCl 400 MHz): δ 8.05 - 8.01 (m, 2H), 7.48 - 7.43 (m, 3H),
2.62 (s, 3H). MS (ESI) m/z (M+H) 203.8.
Compound 26 (15 mg, yield: 23.0%, white solid) was prepared as in Example
from the corresponding intermediate carboxylic acid, compound 26H. Compound 26: H NMR
(CDCl3, 400 MHz): δ 8.08 (br d, J = 6.6 Hz, 2H), 7.41 (br d, J = 6.8 Hz, 2H), 7.32 - 7.24 (m,
4H), 7.13 (br d, J = 6.6 Hz, 2H), 6.77 (br s, 2H), 5.76 - 5.68 (m, 1H), 5.55 (br s, 1H), 3.45 (br dd,
J = 5.3, 14.3 Hz, 1H), 3.24 (br dd, J = 7.3, 14.1 Hz, 1H), 2.56 (s, 3H). MS (ESI) m/z (M+H)
378.1.
EXAMPLE 10
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)PHENYL-1,2,3-
THIADIAZOLECARBOXAMIDE (28)
O OH
N LiOH H2O N
PhB(OH)2
MeOH:H O
Na S 2 (2:1), S
CO ,
Pd(dppf)Cl
N Br 2 3 2
3 hrs
S °C
1,4-dioxane:H 28B
2 (5:1)
28A o
1 1.5 h
w,
A mixture consisting of compound 28A (200 mg, 843.63umol), phenyl boronic
acid (23 mg, 110.98 umol) and Na CO (22.4 mg, 2.11 mmol) was stirred at 110 °C for 1.5 hrs
17681897_1 (GHMatters) P110989.NZ
under microwave. The reaction mixture was cooled to room-temperature, filtered and
concentrated under reduced pressure to give a residue. The residue was purified by Pre-HPLC
(base condition) to afford compound 28B (23 mg, yield 11.64%) as a light yellow oil. H NMR
(CDCl 400 MHz): δ7.44 - 7.58 (m, 5 H), 4.44 (q, J = 7.20 Hz, 2 H), 1.32 (t, J = 7.17 Hz, 3 H).
To a mixture of compound 28B (50 mg, 213.43 umol) in MeOH (3 mL) and
H O (1.50 mL) was added LiOH•H O (26.9 mg, 640.29 umol) in one portion and the mixture
was stirred at 25 °C for 3 hrs. The reaction mixture was concentrated under reduced pressure to
remove MeOH. The residue was diluted with H O (8 mL), adjusted to pH ~ 3 with 1N HCl, and
then extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine
(20 mL), dried over anhydrous Na SO , filtered and concentrated under reduced pressure to give
intermediate compound 28C (38 mg, crude) as brown solid. H NMR (CDCl 400 MHz): δ 7.63
- 7.57 (m, 2H), 7.54 - 7.45 (m, 3H). MS (ESI) m/z (M+1) 206.7.
Compound 28 (18.9 mg, 38.00% yield, white solid) was prepared as in
Example 5 from the corresponding intermediate carboxylic acid, compound 28C. Compound 28:
H NMR (CDCl 400 MHz): δ 8.07 (d, J = 7.2 Hz, 1H), 7.59 - 7.53 (m, 2H), 7.49 - 7.41 (m,
3H), 7.33 - 7.27 (m, 3H), 7.23 - 7.19 (m, 2H), 6.77 (br s, 1H), 5.84 - 5.76 (m, 1H), 5.52 (br s,
1H), 3.51 - 3.45 (m, 1H), 3.25 - 3.18 (m, 1H). MS (ESI) m/z (M+1) 381.1.
EXAMPLE 11
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)PHENYL-1H-PYRAZOLE
CARBOXAMIDE (30)
Br O
O Br O
tert-butyl nitrite
SEM-Cl
CuBr
HN NaH, THF 30C
30A 30B
PhB(OH) HO
NaOH
Pd(dtbpf)Cl2
K PO
dioxane/H O
HCl/EtOAc
CONH CONH
N HN
17681897_1 (GHMatters) P110989.NZ
To a solution of t-BuONO (3.8 mL, 30.94 mmol) in CH CN (60 mL) was
added CuBr (6.91 g, 30.94 mmol). The mixture was stirred at 25 °C for 1 h under N . Then
compound 30A (4 g, 25.78 mmol) was added protionwise. The mixture was then heated to 70 °C
and stirred for 12 hrs. The reaction was washed with H O (100 mL), extracted with EtOAc (100
mL x 2). The organics were collected, dried with Na SO , filtered and concentrated to afford
intermediate compound 30B (6 g, crude) as black brown oil. MS (ESI) m/z (M+ H) 218.9,
220.9.
To a solution of NaH (1.64 g, 41.09 mmol, 60% purity) in THF (80 mL) at 0
°C was added a solution of compound 30B (6 g, 27.39 mmol) in THF (20 mL). After addition,
the mixture was warmed up to 25°C and stirred for 2 hrs. Then the solution was cooled to 0 °C
and a solution of SEM-Cl (5.34 mL, 30.13 mmol) in THF (100 mL) was added at 0 °C. The
mixture was then warmed up to 25 °C and stirred for 12 hrs. The reaction was quenched with
H O (100 mL) dropwise. The mixture was extracted with EtOAc (100 mL x 2). The organics
were collected and concentrated. The residue was purified by column (Petroleum Ether: Ethyl
Acetate = 10:1) to afford compound 30C (3 g, yield: 31.14%) as yellow oil.
To a solution of compound 30C (2.60 g, 7.44 mmol) and PhB(OH) (1.09 g,
8.93 mmol) in dioxane (36 mL) and H O (12 mL) was added Pd(dtbpf)Cl (485 mg, 0.74 mmol)
and K3PO4 (4.74 g, 22.32 mmol). The mixture was stirred at 70 °C under N2 for 2 hrs. The
reaction was diluted with H O (20 mL), extracted with EtOAc (20 mL x 2). The organics were
collected and concentrated. The residue was purified by column (Petroleum Ether: Ethyl Acetate
= 10:1) to afford compound 30D (2.40 g, yield: 93.1%) as colorless oil. MS (ESI) m/z (M+H)
347.1. H NMR (400MHz, DMSO-d ) δ 8.60 (s, 1H), 7.78 - 7.72 (m, 2H), 7.56 - 7.34 (m, 3H),
.52 (s, 2H), 4.25 - 4.16 (m, 2H), 3.70 - 3.62 (m, 2H), 1.26 (t, J=7.1 Hz, 3H), 0.94 - 0.85 (m,
2H), 0.03 - 0.02 (m, 9H).
A solution of compound 30D (200 mg, 577.20 umol) in MeOH (4 mL), and
then NaOH (230 mg, 5.77 mmol) in H O (4 mL) was added dropwise. The mixture was stirred
at 25 °C for 19 hrs. The reaction mixture was diluted by addition H O (10 mL), and then
extracted with MTBE (10 mL x 2). The water layers were neutralized by 1N HCl to pH ~ 3, and
extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (20
mL), dried over Na SO , filtered and concentrated under reduced pressure to give the compound
17681897_1 (GHMatters) P110989.NZ
30E (140 mg, yield: 76.17%) as a yellow oil. H-NMR (400MHz, DMSO-d ) δ 12.41 (br s, 1H),
8.54 (s, 1H), 7.81 - 7.74 (m, 2H), 7.53 - 7.36 (m, 3H), 5.50 (s, 2H), 3.66 (t, J = 8.0 Hz, 2H), 0.90
(t, J = 7.9 Hz, 2H), 0.01 - 0.04 (m, 9H).
Compound 30G (140 mg, yield: 93.72%, white solid) was prepared as in
Example 5 from the corresponding intermediate carboxylic acid, compound 30E. Compound
30G: H-NMR (400MHz, DMSO-d ) δ 8.54 (d, J = 7.3 Hz, 1H), 8.25 (s, 1H), 8.15 - 8.00 (m,
1H), 7.87 (s, 1H), 7.66 - 7.52 (m, 2H), 7.43 - 7.23 (m, 9H), 5.46 (br d, J = 6.8 Hz, 1H), 5.38 -
.30 (m, 1H), 3.76 - 3.57 (m, 2H), 3.27 - 3.12 (m, 1H), 2.96 - 2.76 (m, 1H), 0.94 - 0.89 (m, 2H),
0.03 - 0.00 (m, 9H).
To a solution of compound 30G (18.00 mg, 36.54 umol) in ethyl acetate (1.00
mL) was added 4M HCl/EtOAc (5.00 mL). Then the reaction was stirred at 30 °C for 4hrs. The
reaction mixture was added petroleum ether (50 mL), the mixture was stirred for 3 mins, filtered
and the desired solid was dried in vacuo to give compound 30 (6.00 mg, yield: 45.31%) as white
solid. H NMR (400MHz, DMSO-d6) δ 8.34 (d, J=7.5 Hz, 1H), 8.02 (s, 1H), 7.99 - 7.95 (m,
1H), 7.77 (s, 1H), 7.59 - 7.53 (m, 2H), 7.35 - 7.28 (m, 4H), 7.28 - 7.23 (m, 5H), 7.23 - 7.16 (m,
2H), 5.30 - 5.21(m, 1H), 3.19 - 3.10 (m, 1H), 2.83 (dd, J=9.8, 13.8 Hz, 1H). MS (ESI) m/z
(M+H) 363.1.
EXAMPLE 12
COMPOUNDS 32, 458, 476-479, 521
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)METHYLPHENYL-1H-
PYRAZOLECARBOXAMIDE (32)
Br Br
NH O Br O
MeI,Cs CO
2 3 N O
tert-butyl nitrite N O
CuBr
2 32D
HN 32C
32A 32B
PhB(OH)2
NaOH
N O N OH
N MeOH, THF
,K PO
Pd(dtbpf)Cl2 3 4
To a solution of t-BuONO (3.19 g, 30.94 mmol, 3.67 mL) in CH CN (60 mL)
was added CuBr (6.91 g, 30.94 mmol). The mixture was stirred at 25 °C for 1 hour under N .
Then compound 32A (4.00 g, 25.78 mmol) was added portionwise. After heated to 70 °C and
17681897_1 (GHMatters) P110989.NZ
stirred for 12 hrs, the mixture was concentrated and diluted with ethyl acetate (100 mL). The
mixture was then washed with HCl (1M, 100 mL), saturated NaHCO (100 mL), brine (100 mL),
dried over Na SO and concentrated to obtain intermediate compound 32B (5.6 g, crude) as
yellow oil. MS (ESI) m/z (M+H) 220.9.
To a solution of compound 32B (5.6 g, 25.57 mmol) in DMF (200 mL) was
added MeI (14.52 g, 102.28 mmol, 6.37 mL) and Cs CO (33.32 g, 102.28 mmol). The mixture
was stirred at 25 °C for 12 hrs. The mixture was diluted with H O (1000 mL) and extracted with
ethyl acetate (500 mL), then the organic layer was washed with brine (500 mL x 3), dried over
Na SO and concentrated. The residue (4 g) was purified by preparatory-HPLC (basic
condition). The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl
acetate=10/1 to 5:1). Compound 32C (1g, yield: 16.8%) was obtained as a white solid.
Compound 32D (2 g, yield: 33.6%) was obtained as a white solid.
Compound 32C : H NMR (400MHz, DMSO-d ) δ 7.93 (s, 1H), 4.24 - 4.18
(m, 2H), 3.85 (s, 3H), 1.28 - 1.23 (m, 3H).
Compound 32D : H NMR (400MHz, DMSO-d ) δ 8.33 (s, 1H), 4.22 - 4.16
(m, 2H), 3.83 (s, 3H), 1.26 - 1.22 (m, 3H).
A mixture of ethyl compound 32D (500.0 mg, 2.15 mmol), phenylboronic acid
(314.6 mg, 2.58 mmol), Pd(dtbpf)Cl2 (140.1 mg, 215.00 umol), K3PO4 (1.37 g, 6.45 mmol) in
dioxane (30 mL) and H O (10 mL) was degassed and purged with N for 3 times. After stirred at
70 °C for 1 hour under N atmosphere, the mixture was concentrated and diluted with ethyl
acetate (30 mL). The mixture was then washed with HCl (1M, 50 mL), saturated aqueous
NaHCO (50 mL), brine (50 mL), dried over Na SO and concentrated to obtain intermediate
3 2 4
compound 32E (480 mg, crude) as a brown oil. MS (ESI) m/z (M+H) 230.9.
To a solution of compound 32E (380.0 mg, 1.65 mmol) in MeOH (5 mL) and
THF (5 mL) was added NaOH (2 M, 16.5 mL). The mixture was stirred at 60 °C for 1 hour. The
mixture was concentrated and diluted with H O (10 mL), the mixture was extracted with ethyl
acetate (10 mL), the water phase was added HCl (1M) until pH ~ 3, then the mixture was
extracted with ethyl acetate (20 mL), the organic layer was washed with brine (10 mL), dried
over Na SO and concentrated. Compound 32F (320 mg, yield: 95.9%) was obtained as a brown
17681897_1 (GHMatters) P110989.NZ
solid. H NMR (400MHz, DMSO-d ) δ 12.03 - 11.85 (m, 1H), 8.27 (s, 1H), 7.74 - 7.68 (m, 2H),
7.40 - 7.30 (m, 3H), 3.87 (s, 3H).
Compound 32 (40.0 mg, yield: 64.7%, white solid) was prepared as in Example
from the corresponding intermediate carboxylic acid, compound 32F. Compound 32: H NMR
(400MHz, DMSO-d ) δ 8.33 (d, J = 7.2 Hz, 1H), 8.05 (s, 2H), 7.81 (br s, 1H), 7.63 - 7.53 (m,
2H), 7.39 - 7.20 (m, 8H), 5.33 - 5.26 (m, 1H), 3.93 - 3.86 (m, 3H), 3.21 - 3.13 (m, 1H), 2.88 -
2.79 (m, 1H). MS (ESI) m/z (M+H) 377.1.
N-(4-(CYCLOPROPYLAMINO)-3,4-DIOXOPHENYLBUTANYL)METHYL
PHENYL-1H-PYRAZOLECARBOXAMIDE (458)
Compound 458 (270 mg, yield: 67.4%, white solid) was prepared as in
compound 12 from the corresponding intermediate carboxylic acid, compound 32F and 3-amino-
N-cyclopropylhydroxyphenylbutanamide hydrochloride. Compound 458: H NMR
(400MHz, DMSO-d ) δ 8.80 (d, J = 4.4 Hz, 1H), 8.38 (d, J = 7.3 Hz, 1H), 8.05 (s, 1H), 7.56 (s,
2H), 7.36 - 7.17 (m, 8H), 5.28 (s, 1H), 3.89 (s, 3H), 3.16 (d, J = 11.2 Hz, 1H), 2.89 - 2.73 (m,
2H), 0.71 - 0.52 (m, 4H). MS (ESI) m/z (M+H) 417.1.
(S)-N-(4-FLUOROOXOPHENYLBUTANYL)METHYLPHENYL-1H-
PYRAZOLECARBOXAMIDE (476)
Compound 476 (36.8 mg, yield: 34.22%, white solid) was prepared as in
compound 12 from the corresponding intermediate carboxylic acid, compound 32F and (2S,3S)-
3-aminofluorophenylbutanol hydrochloride. Compound 476: H NMR (400MHz,
CDCl ) δ 7.91 (s, 1H), 7.52 - 7.47 (m, 2H), 7.46 - 7.37 (m, 3H), 7.25 - 7.19 (m, 3H), 6.94 - 6.84
(m, 2H), 6.06 (d, J = 6.4 Hz, 1H), 5.03 - 4.71 (m, 3H), 3.93 (s, 3H), 3.09 - 3.01 (m, 1H), 2.85 -
2.76 (m, 1H). MS (ESI) m/z (M+H) 366.1.
(S)-N-(4-FLUOROOXOPHENYLBUTANYL)METHYL(PYRAZINYL)-
1H-PYRAZOLECARBOXAMIDE (477)
Compound 477 (110 mg, yield: 90.33%, white solid) was prepared as in
compound 12 from the corresponding intermediate carboxylic acid, compound 85B and (2S,3S)-
3-aminofluorophenylbutanol hydrochloride. Compound 477: H NMR (400MHz,
CDCl ) δ 9.20 (s, 1H), 9.08 - 9.00 (m, 1H), 8.50 - 8.48 (m, 1H), 8.11 (s, 1H), 7.27 - 7.24 (m, 3H),
17681897_1 (GHMatters) P110989.NZ
7.17 - 7.12 (m, 2H), 6.79 (s, 1H), 5.33 - 5.24 (m, 1H), 5.11 - 4.79 (m, 2H), 3.45 - 3.33 (m, 1H),
3.15 - 3.11 (m, 1H), 2.38 (s, 3H). MS (ESI) m/z (M+H) 368.1.
(S)-N-(4-FLUOROOXOPHENYLBUTANYL)METHYL(PYRIDINYL)-
1H-PYRAZOLECARBOXAMIDE (478)
Compound 478 (82 mg, yield: 54.97%, white solid) was prepared as in
compound 12 from the corresponding intermediate carboxylic acid, compound 12F and (2S,3S)-
3-aminofluorophenylbutanol hydrochloride. Compound 478: H NMR (400MHz,
CDCl ) δ 10.70 (d, J = 6.40 Hz, 1H), 8.14 (d, J = 4.40 Hz, 1H), 7.92 - 7.83 (m, 2H), 7.26 - 7.14
(m, 6H), 6.88 (s, 1H), 5.24 - 5.20 (m, 1H), 5.05 – 4.74 (m, 2H), 3.29 - 3.18 (m, 2H), 2.35 (s, 3H).
MS (ESI) m/z (M+1) 367.2.
(S)-N-(4-FLUOROOXOPHENYLBUTANYL)METHYLPHENYL-1H-
PYRAZOLECARBOXAMIDE (479)
Compound 479 (100 mg, yield: 82.06%, white solid) was prepared as in
compound 12 from the corresponding intermediate carboxylic acid, 3-methylphenyl-1H-
pyrazolecarboxylic acid and (2S,3S)aminofluorophenylbutanol hydrochloride.
Compound 479: H NMR (400MHz, CDCl ) δ 7.46 - 7.28 (m, 8H), 7.08 - 7.03 (m, 2H), 6.51 (s,
1H), 6.28 (br d, J = 7.0 Hz, 1H), 5.20 - 5.13 (m, 1H), 5.03 - 4.73 (m, 2H), 3.22 - 3.15 (m, 1H),
3.02 - 2.95 (m, 1H), 2.35 (s, 3H). MS (ESI) m/z (M+H) 366.1.
(S)-N-(4-FLUOROOXOPHENYLBUTANYL)(2-FLUORO((PROPYN
YLOXY)METHYL)PHENYL)METHYL-1H-PYRAZOLECARBOXAMIDE (521)
Compound 521 (250 mg, yield: 78.40%, white solid) was prepared using
coupling conditions as in compound 476 from the corresponding intermediate ethyl 3-iodo
methyl-1H-pyrazolecarboxylate and (2-fluoro(hydroxymethyl)phenyl)boronic acid followed
by alkylation with 3-bromopropyne and then the intermediate obtained was subjected to
hydrolysis and coupling with (2S,3S)aminofluorophenylbutanol hydrochloride as in
compound 12 to yield compound 521. Compound 521: H NMR (400MHz, CDCl ) δ 7.89 (s,
1H), 7.40 (t, J=7.6 Hz, 1H), 7.24 - 7.13 (m, 5H), 6.94-6.92 (m, 2H), 5.97 (d, J=6.4 Hz, 1H), 5.09
- 5.01 (m, 1H), 4.96 - 4.83 (m, 1H), 4.83 - 4.70 (m, 1H), 4.66 (s, 2H), 4.19 (d, J=2.4 Hz, 2H),
3.95 (s, 3H), 3.03 (d, J=6.4 Hz, 1H), 2.95 - 2.88 (m, 1H), 2.49 (t, J=2.3 Hz, 1H). MS (ESI) m/z
(M+H) 452.2.
17681897_1 (GHMatters) P110989.NZ
EXAMPLE 13
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)ETHYLPHENYL-1H-
PYRAZOLECARBOXAMIDE (33)
MeONH HCl
4A molecular sieve
NaOEt,EtOH,
O 0 25 °C, 16 h 20 25 °C, 20 h
HOAc, 100 °C, 2 h
A mixture of compound 33A (46.73 mL, 342.14 mmol) and butanone
(30.46 mL, 342.14 mmol) was added dropwise to the solution of NaOEt (prepared by Na (9.5 g)
in EtOH (200 mL)) at 0 °C. Then the reaction was stirred at 20-25 °C for 16 hrs. The reaction
was adjusted to pH ~ 6-7 with HCl (2M) and then removed the solvent to give a residue, which
was diluted with ethyl acetate (500 mL), washed with brine (150 mL), dried over Na SO and
concentrated to give the crude product which was purified by flash column chromatography
(Petroleum Ether : Ethyl Acetate = 1:0 to 10:1) to give compound 33B (23.0 g, yield: 39.0 %) as
a yellow oil. H NMR (CDCl , 400 MHz) δ 14.34 (br s, 1H), 6.31 (s, 1H), 4.28 (q, J = 7.2 Hz,
2H), 2.47 (q, J = 7.3 Hz, 2H), 1.34 - 1.27 (m, 3H), 1.11 (t, J = 7.5 Hz, 3H).
The mixture of compound 33B (10 g, 58.08 mmol), O-methylhydroxylamine
(4.85 g, 58.08 mmol, HCl) and 4A° molecular sieve (10 g) in DMF (100 mL) was stirred at 20-
°C for 20 hrs. Filtered to remove the 4A° molecular sieve and the filtrate was diluted with
H2O (800 mL), extracted with ethyl acetate (300 mL x 3). The organic phase was combined and
washed with brine (300 mL x 3) and concentrated to give the crude product, which was purified
by flash column chromatography (Petroleum Ether : Ethyl Acetate = 1:0 to 5:1) to give
compound 33C (3.5 g, yield: 29.95%) as a yellow oil. H NMR (CDCl , 400 MHz) δ 4.41 - 4.29
(m, 2H), 4.06 (s, 3H), 3.71 (s, 2H), 2.60 - 2.46 (m, 2H), 1.42 - 1.32 (m, 3H), 1.08 (t, J = 7.3 Hz,
3H).
The mixture of compound 33C (3.5 g, 17.39 mmol) and phenylhydrazine (1.88
g, 17.39 mmol) in AcOH (20 mL) was stirred at 100 °C for 2 hrs. The solvent was removed and
17681897_1 (GHMatters) P110989.NZ
the residue was adjusted to pH ~ 7-8 with saturated NaHCO aqueous and extracted with ethyl
acetate (60 mL x 2). The organic phase were combined and washed with brine (50 mL),
concentrated to give a residue, which was purified by flash column chromatography (Petroleum
Ether : Ethyl Acetate = 1:0 to 5:1) to give compound 33D (0.3 g, 1.23 mmol, 7.05% yield) as a
yellow solid and compound 33E (3.0 g, 12.21 mmol, yield 70.19%) as a yellow oil.
Compound 33D : H NMR (CDCl , 400 MHz) δ 7.50 - 7.37 (m, 5H), 6.87 (s,
1H), 4.24 (q, J = 7.0 Hz, 2H), 2.76 (q, J = 7.5 Hz, 2H), 1.32 (t, J = 7.5 Hz, 3H), 1.25 (t, J = 7.2
Hz, 3H). MS (ESI) m/z (M+H) 245.0. Compound 33E : H NMR (CDCl , 400 MHz) δ 7.46 -
7.31 (m, 1H), 6.70 (s, 1H), 4.35 (q, J = 7.1 Hz, 1H), 2.58 (q, J = 7.4 Hz, 1H), 1.33 (t, J = 7.2 Hz,
1H), 1.16 (t, J = 7.5 Hz, 1H). MS (ESI) m/z (M+H) 245.0.
The mixture of compound 33D (3.0 g, 12.28 mmol) and LiOH.H O (3.09 g,
73.68 mmol) in MeOH (10 mL) and H O (3 mL) was stirred at 25 °C for 16 hrs. The reaction
was adjusted with HCl (2M) to pH ~ 3-4 and removed the solvent. The residue was extracted
with ethyl acetate (100 mL x 3) and combined, washed with brine (100 mL), dried over Na SO .
Filter and the filtrate were concentrated to give compound 33F (2.7 g, crude) as a yellow solid.
H NMR (CDCl , 400 MHz) δ 8.58 (br s, 1H), 7.46 - 7.34 (m, 5H), 6.89 (s, 1H), 2.73 (q, J = 7.6
Hz, 2H), 1.28 (t, J = 7.6 Hz, 3H). MS (ESI) m/z (M+H) 216.9.
The mixture of compound 33F (2.7 g, 12.49 mmol) and 1-hydroxypyrrolidine-
2,5-dione (1.44 g, 12.49 mmol) in THF (20 mL) was stirred at 0 °C for 15 min, then solution of
DCC (2.6 g, 12.61 mmol, 2.55 mL) in THF (10 mL) was added dropwise at 0 °C and stirred at
-30 °C for 16 hrs. After filtered and the filtrate was concentrated to give compound 33G (4.0
g, crude) as a yellow solid. The product was used directly in next step.
The mixture of compound 33G (0.2 g, 638.35 umol), compound 12G (147.3
mg, 638.35 umol, HCl) and DIEA (0.25 mL, 1.28 mmol) in DMF (10 mL) was stirred at 20-25
°C for 16 hrs. The reaction was diluted with H O (60 mL) and ethyl acetate (30 mL) and stirred
at 20-25 °C for 0.5 h. White solid precipitated out and was filtered, the filter cake was washed
with H O (10 mL x 2) and dried over under reduced pressure to give compound 33H (100.0 mg,
yield: 39.24%) as a white solid. H NMR (DMSO-d , 400 MHz) δ 8.53 - 8.11 (m, 1H), 7.40 -
7.20 (m, 10H), 7.16 - 7.01 (m, 2H), 6.59 (s, 1H), 5.96 - 5.69 (m, 1H), 4.49 - 4.36 (m, 1H), 4.03 -
17681897_1 (GHMatters) P110989.NZ
3.90 (m, 1H), 2.96 - 2.70 (m, 2H), 2.62 (q, J = 7.7 Hz, 2H), 1.22 (t, J = 7.5 Hz, 3H). MS (ESI)
m/z (M+H) 393.0.
The mixture of compound 33H (100 mg, 254.81 umol) and DMP (540.4 mg,
1.27 mmol, 394.44 uL) in DMSO (5.0 mL) was stirred at 25-30 °C for 16 hrs. The reaction was
diluted with DCM (20 mL) and quenched with a mixture of saturated NaHCO aqueous and
Na S O aqueous (10%) (80 mL, 1:1) and stirred at 20-25 °C for 0.5 hours. White solid
2 2 3
precipitated out and was filtered, the filter cake was washed with H O (3 mL x 2) and dried under
reduced pressure to give compopund 33 (20.0 mg, yield: 20%) as a white solid. H NMR
(DMSO-d 400 MHz) δ 9.10 (d, J = 7.9 Hz, 1H), 8.10 (s, 1H), 7.85 (s, 1H), 7.36 - 7.20 (m, 8H),
7.18 - 7.10 (m, 2H), 6.58 (s, 1H), 5.30 - 5.21 (m, 1H), 3.18 (dd, J = 3.5, 13.9 Hz, 1H), 2.80 (dd, J
= 10.6, 13.7 Hz, 1H), 2.60 (q, J =7.7 Hz, 2H), 1.20 (t, J = 7.6 Hz, 3H). MS (ESI) m/z (M+H)
391.1.
EXAMPLE 14
(S)-N-(1-OXOPHENYLPROPANYL)(1-PHENYL-1H-PYRAZOLYL)-1H-
IMIDAZOLECARBOXAMIDE (34)
N NaOH
THF/H
TOSMIC 2 N
N O O
O Cu(OAc)2
THF K CO
TEA/DCM
EtOH N
34A N
To a solution of 34A (15 g, 180.53 mmol) in THF (200 mL) was added ethyl 2-
oxoacetate (47.9 g, 234.69 mmol). The mixture was stirred at 25 °C for 0.5 h. The reaction
mixture was filtered and concentrated under reduced pressure to give intermediate compound
34B (55.3 g, crude) as brown solid. MS (ESI) m/z (M+H) 167.8.
To a solution of 34B (40 g, 239 mmol) in EtOH (400 mL) was added K CO
(50 g, 362 mol) and 1-(isocyanomethylsulfonyl)methyl-benzene (40 g, 204.88 mmol). The
mixture was stirred at 90 °C for 0.5 h. The reaction mixture was filtered and concentrated under
reduced pressure to give a residue. The residue was purified by column chromatography (SiO ,
Petroleum ether: Ethyl acetate = 1: 0 to 5: 2) to afford compound 34C (12 g, yield: 24.3%) as
brown solid. H NMR (400 MHz, CDCl ) δ 11.80 - 11.35 (m, 1H), 7.87 (d, J = 1.10 Hz, 1H),
17681897_1 (GHMatters) P110989.NZ
7.84 (d, J = 1.10 Hz, 1 H), 7.58 (d, J = 2.43 Hz, 1H), 6.45 (d, J = 2.43 Hz, 1H), 4.25 (q, J = 7.06
Hz, 2H), 1.29 (t, J = 7.17 Hz, 3H). MS (ESI) m/z (M+H) 207.0.
A mixture of 34C (5 g, 24.3mmol), phenylboronic acid (4.4 g, 36.4mmol),
Cu(OAc) (4.4 g, 24.3mmol), triethylamine (7.4 g, 72.8mmol) in DCM (200 mL) was degassed
and purged with O for 3 times, and then the mixture was stirred at 25 °C for 10 hrs under O
atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to give a
residue. The residue was purified by column chromatography (SiO , Petroleum ether: Ethyl
acetate= 1: 0 to 2: 1). Compound 34D (2.3 g, yield: 33.6%) was obtained as a white solid. H
NMR (400MHz, CDCl ) δ 8.04 - 7.94 (m, 2H), 7.87 (s, 1H), 7.71 (br d, J = 7.7 Hz, 2H), 7.49 (br
t, J = 7.1 Hz, 2H), 7.36 (br d, J = 7.1 Hz, 1H), 7.27 (d, J = 2.0 Hz, 2H), 6.70 - 6.61 (m, 1H), 4.29
(dd, J = 2.1, 7.2 Hz, 2H), 1.38 - 1.22 (m, 3H). MS (ESI) m/z (M+H) 282.9.
To a solution of 34D (2.5 g, 8.86 mmol) in THF (30 mL) and H O (6 mL) was
added NaOH (708 mg, 17.7 mmol). The mixture was stirred at 80 °C for 1.5 hrs. The reaction
mixture was concentrated under reduced pressure to remove THF, and then washed with EtOAc
(20 mL). The aqueous layer was acidized with 1M HCl (to pH ~ 5) and then extracted with
EtOAc (30 mL x 3). The combined organic layer was washed with H O (40 mL), brine (40 mL),
dried over Na SO , filtered and concentrated to afford intermediate compound 34E (1.90 g,
yield: 84.31%) as yellow solid. H NMR (400MHz, DMSO-d ) δ 8.62 (d, J = 2.6 Hz, 1H), 8.19
(s, 1H), 7.86 (d, J = 7.9 Hz, 2H), 7.76 (s, 1H), 7.53 (t, J = 7.9 Hz, 2H), 7.39 - 7.31 (m, 1H), 6.77
(d, J = 2.6 Hz, 1H). MS (ESI) m/z (M+H) 254.9.
Compound 34 (50 mg, yield: 62.8%, white solid) was prepared as in Example 6
from the corresponding intermediate compounds 34E and 21G. Compound 34: H NMR
(400MHz, CDCl ) δ 9.66 (s, 1H), 7.95 (d, J = 2.4 Hz, 1H), 7.89 (s, 1H), 7.67 (s, 1H), 7.58 (d, J =
8.2 Hz, 2H), 7.45 (t, J = 7.8 Hz, 2H), 7.36 - 7.31 (m, 1H), 7.26 - 7.19 (m, 4H), 7.08 (d, J = 6.4
Hz, 2H), 6.55 (d, J = 2.4 Hz, 1H), 4.84 (q, J = 6.4 Hz, 1H), 3.21 (d, J = 6.4 Hz, 2H). MS (ESI)
m/z (M + H O + H) 404.1.
17681897_1 (GHMatters) P110989.NZ
EXAMPLE 15
COMPOUNDS 35, 205
(S)-N-(1-AMINOMETHYL-1,2-DIOXOHEXANYL)METHYL
PHENYLISOXAZOLECARBOXAMIDE (35)
OH 35D
EDCI, DIEA LAH,THF H
HN HN
O Et N
DCM O
O O O O
HCl/dioxane
K H DMSO O
CO , O , HN NH
2 2 2
HN 3 2
ClHH N NH
To a solution of compound 35A (20 g, 86.47 mmol), N-methoxymethanamine
(12.65 g, 129.71 mmol, HCl), HOBt (11.68 g, 86.47 mmol) in DCM (400 mL) was added DIEA
(33.53 g, 259.41 mmol, 45.31 mL) at 0 °C. After that, the reaction mixture was stirred at 0 °C
for 0.1 h, and then EDCI (19.89 g, 103.76 mmol) was added, after addition, the reaction mixture
was stirred at 25 °C for 16 hrs. The reaction mixture was concentrated to give a residue and the
residue was dissloved in EtOAc (400 mL), washed with 1N HCl (400 mL x 2), sat.NaHCO (400
mL x 2) and brine (400 mL). The organic phase was dried over Na SO and concentrated. The
residue was purified by column chromatography (SiO , Petroleum Ether~Petroleum Ether:
EtOAc = 10: 1). Compound 35B (40.32 g, yield: 84.98%) was obtained as a colorless oil. H
NMR (400MHz, CDCl ) δ 5.04 (br d, J = 9.0 Hz, 1H), 4.71 (br s, 1H), 3.77 (s, 3H), 3.18 (s, 3H),
1.80 - 1.63 (m, 2H), 1.42 (s, 10H), 0.93 (dd, J = 6.5, 14.2 Hz, 6H).
To a mixture of LAH (1.53 g, 40.41 mmol) in THF (200 mL) was added
dropwise a solution of compound 35B (10.08 g, 36.74 mmol) in THF (100 mL) at 0 °C under N2
atmosphere. After addition, the reaction mixture was stirred at 0 °C for 2 hrs. EtOAc (150 mL)
was added dropwise into the reaction mixture at 0 °C and acidified to pH ~ 1~2 with 1N HCl,
then added saturated aqueous NaHCO (150 mL x 3) and brine (150 mL). The organic layer was
dried over Na SO and concentrated. The compound 35C (27.89 g, yield: 88.15%) was obtained
as a yellow oil, which was used for next step directly without purification. H NMR (400MHz,
17681897_1 (GHMatters) P110989.NZ
CDCl ): δ 9.71 - 9.32 (m, 1H), 4.99 (br s, 1H), 4.20 (br d, J = 2.9 Hz, 1H), 1.79 - 1.69 (m, 1H),
1.67 - 1.57 (m, 1H), 1.43 - 1.40 (m, 10H), 0.93 (dd, J = 1.4, 6.5 Hz, 6H).
To a solution of compound 35C (4 g, 18.58 mmol), compound 35D (3.16 g,
37.16 mmol, 3.40 mL) and Et N (2.26 g, 22.30 mmol, 3.09 mL) in dry DCM (40 mL) was stirred
at 25 °C for 16 hrs. The reaction mixture was diluted with 50 mL DCM, washed with 0.5 N HCl
(100 mL), water (100 mL) and brine (100 mL). The organic phase was dried over Na SO4,
concentrated. Then the residue was purified by column chromatography (SiO , Petroleum Ether:
EtOAc = 10: 1). Compound 35E (3.9 g, yield: 86.63%) was obtained as a yellow oil. H NMR
(400MHz, CDCl ): δ 4.80 (br s, 1H), 4.58 - 4.36 (m, 1H), 4.02 - 3.91 (m, 0.5H), 3.77 (br s,
0.5H), 1.75 - 1.60 (m, 2H), 1.51 - 1.33 (m, 10H), 1.03 - 0.89 (m, 6H)
To a solution of compound 35E (15 g, 61.90 mmol) and K CO (17.11 g,
123.80 mmol) in DMSO (300 mL) was added H O (70.17 g, 2.15 mol, 60 mL) under N at 0 °C.
2 2 2
After addition, the reaction mixture was stirred at 0 °C for 1 h. Then the reaction mixture was
diluted with water (150 mL) and quenched with saturated aqueous Na S O (300 mL) slowly at
2 2 3
ice water. The mixture was extracted with EtOAc (300 mL x 3) and the combined extracts were
washed with saturated aqueous Na S O (300 mL x 3). The organic layer was dried over Na SO
2 2 3 2 4
and concentrated. The residue was diluted with EtOAc (20 mL) and MTBE (200 mL), the solid
was collected and dried in vacuo. Compound 35F (15.15 g, yield: 47.01%) was obtained as a
white solid. H NMR (400MHz, DMSO-d ) δ 7.31 - 6.96 (m, 2H), 6.33 (br d, J = 9.0 Hz, 0.6H),
.95 (d, J = 9.5 Hz, 0.4H), 5.44 (br d, J = 5.1 Hz, 1H), 3.93 - 3.65 (m, 2H), 1.57 - 1.47 (m, 1H),
1.41 - 1.23 (m, 10H), 0.95 - 0.70 (m, 7H).
To a solution of compound 35F (5.42 g, 20.82 mmol) in dioxane (10 mL) was
added HCl/dioxane (4M, 55 mL) at 25 °C. After addition, the reaction mixture was stirred at 25
°C for 2 hrs. The reaction was concentrated, and 40 mL of MTBE was added into the reaction
mixture and the mixture was stirred for 5 min. Then the mixture was filtered to afford desired
compound. Compound 35G (3.8 g, yield: 92.80%) was obtained as a white solid. H NMR
(400MHz, DMSO-d ) δ 8.12 (br s, 1.5H), 7.87 (br s, 0.5H), 7.57 - 7.35 (m, 2H), 4.22 (d, J = 2.5
Hz, 0.7H), 4.02 (d, J = 3.8 Hz, 0.3H), 3.57 (s, 1H), 3.45 (br d, J = 3.5 Hz, 1H), 1.81 - 1.58 (m,
1H), 1.54 - 1.33 (m, 1.3H), 1.21 (ddd, J = 4.3, 9.5, 14.1 Hz, 0.7H), 0.93 - 0.67 (m, 6H).
17681897_1 (GHMatters) P110989.NZ
Compound 35 (48 mg, yield: 44.55%, white solid) was prepared as in Example
from the corresponding intermediate compounds 23A and 35G. Compound 35: H NMR
(400MHz, DMSO-d ) δ 8.99 (br d, J = 7.1 Hz, 1H), 8.13 (s, 1H), 7.89 - 7.77 (m, 3H), 7.54 - 7.48
(m, 3H), 5.20 (ddd, J = 3.3, 7.0, 10.6 Hz, 1H), 2.29 (s, 3H), 1.74 - 1.62 (m, 1H), 1.56 - 1.36 (m,
2H), 0.92 (d, J = 6.4 Hz, 3H), 0.89 - 0.84 (m, 3H).
(S)-N-(1-AMINO-1,2-DIOXOPHENYLPENTANYL)METHYL
PHENYLISOXAZOLECARBOXAMIDE (205)
HCl LiAlH THF
HN(Me)OMe (1.5 eq) (1.5 eq),
0 °C, 2 hr
EDCI HOBt
(1.2 eq), (1 eq),
DIEA DCM N
(3 eq),
205B
205A
N OH
K CO
2 3 (2 eq),
HCl/dioxane
H O , DMSO
Dioxane, 25 32 °C, 2 hr
0 1hr
Et N DCM O NH
3 (1.2 eq), 2
°C, 16 hr
2 ClHH N
H OH
H OH
205E
205C
205D
To a mixture of (S)((tert-butoxycarbonyl)amino)phenylbutanoic acid (5 g,
17.90 mmol) and N-methoxymethanamine (2.76 g, 28.26 mmol, HCl), HOBt (2.55 g, 18.84
mmol) in DCM (100.00 mL) was added dropwise DIEA (9.88 mL, 56.53 mmol) and EDCI (4.33
g, 22.61 mmol) in portion at 0°C under N . The mixture was stirred at 0 °C for 30 min, then the
mixture was stirred at 25°C for 16 hours. The reaction mixture was diluted with H O (200 mL).
The two layers were separated and the aqueous phase was extracted with Ethyl Acetate (2 x 150
mL). The combined organic layers were washed with 0.5 N HCl (2 x 150 mL) and NaHCO (2 x
150 mL), dried over Na SO4, filtered and concentrated under reduced pressure to give a residue.
The residue was purified by column chromatography (SiO , Petroleum ether/Ethyl acetate=10:1
to 3:1) to afford compound 205A (4.15 g, 68.32% yield) as a white solid. H NMR (400MHz,
DMSO-d ) δ 7.35 - 7.23 (m, 2H), 7.22 - 7.04 (m, 4H), 4.45 - 4.21 (m, 1H), 3.59 (s, 3H), 3.06 (s,
3H), 2.81 - 2.68 (m, 1H), 2.61 - 2.54 (m , 1H), 1.86 - 1.65 (m, 2H), 1.45 - 1.29 (s, 9H).
17681897_1 (GHMatters) P110989.NZ
To a solution of LiAlH (88.3 mg, 2.32 mmol) in THF (15 mL) was added
drop wise a solution of compound 205A (500 mg, 1.55 mmol) in THF (15 mL) at 0 °C under N
atmosphere. After addition, the reaction mixture was stirred at 0 °C for 2 hours. The mixture
was diluted with ethyl acetate (100 mL) and washed with 1N HCl (20 mL), saturated NaHCO (2
x 20 mL), brine (15 mL). The organic layer was dried over Na SO and concentrated to afford
compound 205B (400 mg, 1.52 mmol) a s a yellow oil. H NMR (400MHz, DMSO-d ) δ 9.4 (s,
1H), 7.33 - 7.05 (m, 5H), 3.82 - 3.72 (m, 1H), 2.71 - 2.51 (m, 2H), 1.97 - 1.9 (m, 1H), 1.81 - 1.66
(m, 1H), 1.51 - 1.25 (m, 10H).
A solution of compound 205B (1.86 g, 7.06 mmol), 2-hydroxy
methylpropanenitrile (1.29 mL, 14.12 mmol) and Et N (1.17 mL, 8.47 mmol) in dry DCM (60
mL) was stirred at 30 °C for 16 hours. The reaction mixture was diluted with DCM (50 mL),
washed with 0.5N HCl (20 mL), water (20 mL) and brine (20 mL). The organic phase was dried
over Na2SO4, concentrated. The residue was purified by column chromatography (SiO ,
Petroleum ether/Ethyl acetate=5/1 to 3:1) to afford compound 205C (900mg, 43.90% yield) as a
white solid. H NMR (400MHz, DMSO-d ) δ 7.44 - 7.21 (m, 5H), 6.75 - 6.58 (m, 1H), 4.70 -
4.29 (m, 1H), 3.80 - 3.51 (m, 1H), 2.86 - 2.68 (m, 1H), 2.62 - 2.59 (m, 1H), 2.04 - 1.64 (m, 2H),
1.53 - 1.43 (m, 9H).
To a solution of compound 205C (900 mg, 3.1 mmol) and K CO (856.9 mg,
6.2 mmol) in DMSO (18 mL) was added H2O2 (3.06 mL, 106.14 mmol) at 0 °C. After addition,
the reaction mixture was stirred at 0 °C for 1h. The reaction mixture was diulted with water (200
mL) and quenched with saturated aqueous Na S O (500 mL) slowly at ice water.The mixture
2 2 3
was extracted with EtOAc (3 x 500 mL) and the combined extracts were washed with saturated
aqueous Na S O (2 x 300 mL).The organic layer was dried over Na SO and concentrated. The
2 2 3 2 4
mixture was treated with MTBE and then it was filtered to afford Compound 205D (500 mg,
52.30% yield) as white solid. H NMR (CDCl 400 MHz): δ 7.34 - 7.11 (m, 1H), 6.81 - 6.67 (m,
1H), 5.54 - 5.35 (m, 1H), 5.19 - 5.05 (m, 2H), 4.28 - 4.12 (m, 1H), 3.85 - 3.72 (s, 1H), 2.81 - 2.54
(m, 2H), 2.24 - 1.99 (m, 2H), 2.98 - 2.78 (m, 1H), 1.65 - 1.41 (m, 9H).
To a solution of compound 205D (250 mg, 810.71 umol) in dioxane (2 mL)
was added HCl/dioxane (4M, 1.06 mL) at 25 °C. After addition, the reation was stirred at 32°C
for 2 hours and concentrated. The residue was purified by column chromatography (SiO ,
17681897_1 (GHMatters) P110989.NZ
Petroleum ether/Ethyl acetate = 10: 1 to 1: 2) to afford compound 205E (180 mg, 90.64% yield)
as white solid. H NMR (400MHz, DMSO-d ): δ 8.15 - 8.02 (m, 1H), 8.01 - 7.75 (m, 1H), 7.65 -
7.48 (m, 2H), 7.37 - 7.26 (m, 2H), 7.25 - 7.05 (m, 5H), 6.52 - 6.24 (s, 1H), 4.16 - 4.05 (m, 1H),
3.45 - 3.39 (m, 1H), 1.95 - 1.61 (m, 2H), 1.41 - 1.28 (m, 2H).
Compound 205 (23.5 mg, 31.69% yield, yellow solid) was prepared as in
Example 5 from the corresponding intermediate compounds 23A and 205E. Compound 205: H
NMR (400MHz, CDCl ) δ 7.84 - 7.72 (m, 2H), 7.60 - 7.50 (m, 3H), 7.26 - 7.12 (m, 4H), 7.07 -
7.00 (m, 2H), 6.66 (br s, 1H), 6.19 (br s, 1H), 5.51 - 5.34 (m, 2H), 2.66 - 2.54 (m, 2H), 2.47 (s,
3H), 2.38 - 2.25 (m, 1H), 1.99 - 1.85 (m, 1H). MS (ESI) m/z (M+H) 392.1.
EXAMPLE 16
COMPOUNDS 36, 49, 409, 455
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)METHYL(PYRIMIDIN
YL)-1H-PYRAZOLECARBOXAMIDE (36)
N NH
N N O
120 1 h
HOAc, °C,
36A O
LiOH
MeOH/H O
To a solution of compound 36B (1.31 g, 9.08 mmol) in AcOH (50 mL) was
added compound 36A (1 g, 9.08 mmol). The mixture was stirred at 120 °C for 1 h. The mixture
was in DCM (50 mL). The organic layer was washed with water (10 mL), NaHCO to pH ~ 8~9
and dried over Na SO and concentrated. The residue was purified by column chromatography
(SiO , Petroleum ether/Ethyl acetate = 10:1 to 5:1) to afford compounds 36C and 36D.
Compound 36C (500 mg, 2.29 mmol, 25.24% yield, white solid): H NMR (400MHz, DMSO-
d ) δ 9.03 - 8.79 (m, 2H), 7.67 - 7.45 (m, 1H), 6.87 (s, 1H), 3.73 (s, 3H), 2.29 (s, 3H). Compound
36D (1 g, 50.47% yield, white solid): H NMR (400MHz, DMSO-d ) δ 9.03 - 8.89 (m, J=4.9 Hz,
2H), 7.67 - 7.55 (m, 1H), 6.81 (s, 1H), 3.84 (s, 3H), 2.60 (s, 3H).
17681897_1 (GHMatters) P110989.NZ
Intermediate compound 36F (39.6 mg, 90% yield, white solid) was prepared as
in Example 85 from compound 36C. MS (ESI) m/z (M+1) 205. Compound 36 (15.5 mg,
43.77% yield, brown solid) was prepared as in Example 5 from the corresponding intermediate
compound 36F. Compound 36: H NMR (400MHz, DMSO-d ) δ 8.99 - 8.95 (m, 2H), 8.50 - 8.39
(m, 1H), 8.11 (s, 1H), 7.85 (s, 1H), 7.65 - 7.57 (m, 1H), 7.31 - 7.17 (m, 5H), 6.68 (s, 1H), 5.51 -
.45 (m, 1H), 3.26 - 3.18 (m, 1H), 3.13 - 3.03 (m, 1H), 2.58 (s, 3H).
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)METHYL(PYRIMIDIN
YL)-1H-PYRAZOLECARBOXAMIDE (49)
Following the procedure as used for compound 36, compound 49 (21 mg,
38.4% yield, white solid) was prepared from the corresponding intermediate compound 36D. H
NMR (400MHz, DMSO-d ) δ 9.08 - 8.98 (m, 1H), 8.76 - 8.70 (m, 2H), 8.05 (s, 1H), 7.82 (s,
1H), 7.49 - 7.44 (m, 1H), 7.35 - 7.26 (m, 4H), 7.26 - 7.19 (m, 1H), 6.58 (s, 1H), 5.31 - 5.25 (m,
1H), 3.19 - 3.09 (m, 1H), 2.90 - 2.78 (m, 1H), 2.27 (s, 3H). MS (ESI) m/z (M+Na) 379.
N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)METHYL(PYRIMIDINYL)-
1H-PYRAZOLECARBOXAMIDE (409)
Following the procedure as used for compound 36, compound 409 (4225.7 mg,
80.2% yield, white solid) was prepared from the corresponding starting materials, namely 4-
hydrazinylpyrimidine and intermediate compound 274D. H NMR (400MHz, DMSO-d6) δ 9.22
(d, J = 7.2 Hz, 1H), 8.84 (d, J = 5.6 Hz, 1H), 8.75 (s, 1H), 8.14 (s, 1H), 7.89 (s, 1H), 7.78 - 7.74
(m, 1H), 7.31 - 7.21 (m, 5H), 6.52 (s, 1H), 5.41 - 5.33 (m, 1H), 3.22 - 3.12 (m, 1H), 2.90 - 2.78
(m, 1H), 2.28 (s, 3H). MS (ESI) m/z (M+1) 379.0.
N-(4-(CYCLOPROPYLAMINO)-3,4-DIOXOPHENYLBUTANYL)METHYL
(PYRIMIDINYL)-1H-PYRAZOLECARBOXAMIDE (455)
Following the procedure as used for compound 36, compound 455 (180 mg,
71.6% yield, white solid) was prepared from the corresponding starting materials, namely 36F
and 3-amino-N-cyclopropylhydroxyphenylbutanamide. H NMR (400MHz, DMSO-d ) δ
9.05 - 9.00 (m, 1H), 9.03 (d, J = 7.3 Hz, 1H), 8.78 (d, J = 5.1 Hz, 1H), 8.69 (d, J = 4.9 Hz, 2H),
7.44 (t, J = 4.9 Hz, 1H), 7.29 - 7.18 (m, 5H), 6.56 (s, 1H), 5.31 - 5.24 (m, 1H), 3.12 (dd, J = 3.7,
13.9 Hz, 1H), 2.84 - 2.71 (m, 2H), 2.24 (s, 2H), 2.27 - 2.19 (m, 1H), 0.67 - 0.54 (m, 4H). MS
(ESI) m/z (M+H) 419.2.
17681897_1 (GHMatters) P110989.NZ
EXAMPLE 17
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)(2H-INDAZOL
YL)THIAZOLECARBOXAMIDE (37)
Br O
N LiOH
Cs CO , Toluene
MeOH/H O
120 °C, 12 h O N
A mixture of compound 37A (250 mg, 2.12 mmol), Cs CO (2.07 g, 6.36
mmol) in toluene (40 mL) was stirred at 110 °C for 13 hrs. The mixture was concentrated. The
residue was purified by column chromatography (SiO , Petroleum ether/Ethyl acetate = 10/1 to
:1) to afford compound 37B (43.75 mg, 7.55% yield) as white solid. MS (ESI) m/z (M+1) 274.
H NMR (400MHz, CDCl3) δ 8.93 (s, 1H), 8.68 (s, 1H), 7.85 - 7.65 (m, 2H), 7.39 - 7.30 (m,
1H), 7.17 - 7.05 (m, 1H), 4.44 - 4.24 (m, 2H), 1.28 (m, 3H).
A mixture of compound 37B (35 mg, 128.06 umol), LiOH (9.2 mg, 384.18
umol) in water (1 mL) and MeOH (5 mL) was stirred at 27 °C for 2 hrs. MeOH was evaporated.
To the residue was added water (10 mL). The mixture was extracted with MTBE (5 mL) and
separated. The aqueous layer was acidified to pH ~ 3 with 1N HCl and extracted with ethyl
acetate (3 x 20 mL). The combined organic layers were dried and concentrated to afford
compound 37D (25.3 mg, 80.55% yield) as brown solid.
Compound 37 (4 mg, 8.47 umol, yield 5.95%, yellow solid) was prepared as in
Example 5 from the corresponding intermediate carboxylic acid, compound 37D. Compound 37:
H NMR (400MHz, CDCl ) δ 12.72 - 12.49 (m, 1H), 8.97 (s, 1H), 8.80 (s, 1H), 7.80 - 7.64 (m,
1H), 7.46 - 7.29 (m, 2H), 7.20 - 6.98 (m, 6H), 6.83 - 6.72 (m, 1H), 5.97 - 5.84 (m, 1H), 5.52 -
.40 (m, 1H), 3.56 - 3.33 (m, 2H).
17681897_1 (GHMatters) P110989.NZ
EXAMPLE 18
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)METHYL(NAPHTHALEN-
1-YL)-1H-PYRAZOLECARBOXAMIDE (38)
ClH•H
LiOH H O
MeOH:H O
N 2 (2:1) N
HOAc, 120 °C,
O OH
°C, 3 hrs
1 hr
A mixture consisting of compound naphthalenyl hydrazine hydrochloride
(4.05 g, 20.81 mmol) and compound 38A (3.0 g, 20.81 mmol) in AcOH (30 mL) was stirred at
120 °C for 1 hour. The reaction mixture was cooled to 25 °C, concentrated under reduced
pressure and diluted with CH Cl (100 mL). The organic phase was washed with sat. NaHCO
2 2 3
(20 mL x 2), dried over anhydrous Na SO , filtered, and the filtration was concentrated under
reduced pressure to give a residue, which was purified by flash silica gel chromatography
(Petroleum ether: Ethyl acetate = 4:1) to afford compound 38B (154.3 mg, 2.79% yield) as a
brown solid. H NMR (CDCl , 400 MHz): δ 7.96 (d, J = 8.0 Hz, 1H), 7.91 (d, J = 8.4 Hz, 1H),
7.57 - 7.52 (m, 1H), 7.51 - 7.47 (m, 2H), 7.46 - 7.41 (m, 1H), 7.22 (d, J = 8.4 Hz, 1H), 6.90 (s,
1H), 3.62 (s, 3H), 2.43 (s, 3H). MS (ESI) m/z (M+1) 267.1.
To a mixture of compound 38B (160 mg, 570.78 umol) in MeOH (10 mL) and
H O (5 mL) was added LiOH.H O (71.9 mg, 1.71 mmol) in one portion and the mixture was
stirred at 25 °C for 3 hrs. The reaction mixture was concentrated under reduced pressure to
remove MeOH. The residue was diluted with H O (10 mL), adjusted to pH ~ 3 with 1N HCl,
and then extracted with EtOAc (40 mL x 3). The combined organic layers were washed with
brine (30 mL), dried over anhydrous Na SO , filtered and concentrated under reduced pressure to
give intermediate compound 38C (140 mg, yield 97.23%) as a white solid. H NMR (CDCl ,
400 MHz): δ 7.96 - 7.83 (m, 2H), 7.52 - 7.44 (m, 2H), 7.44 - 7.36 (m, 2H), 7.15 (d, J = 8.4 Hz,
1H), 6.87 (s, 1H), 2.37 (s, 3H). MS (ESI) m/z (M+1) 252.9.
Compound 38 (10.6 mg, yield 13.31%, white solid) was prepared as in
Example 5 from the corresponding intermediate carboxylic acid, compound 38C. Compound 38:
H NMR (400 MHz, CDCl ) δ 8.00 - 7.89 (m, 2H), 7.57 - 7.43 (m, 4H), 7.28 (d, J = 8.4 Hz, 1H),
7.22 - 7.10 (m, 3H), 6.82 - 6.72 (m, 2H), 6.69 (s, 1H), 6.54 (br s, 1H), 6.16 (d, J = 6.8 Hz, 1H),
17681897_1 (GHMatters) P110989.NZ
.48 - 5.33 (m, 2H), 3.19 - 3.09 (m, 1H), 2.94 - 2.84 (m, 1H), 2.40 (s, 3H). MS (ESI) m/z (M+1)
427.2.
EXAMPLE 19
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)(1H-INDAZOL
YL)THIAZOLECARBOXAMIDE (40)
LiOH
MeOH:H O
Cs CO toluene
, 2 (2:1)
S 25 °C, 3 hrs
40A 110.6 16 h 40B
EDCI, DME,
°C, 9
40C S
A mixture consisting of compound 40A (500 mg, 2.12 mmol), indazole (250.5
mg, 2.12 mmol), Cs CO (2.07 g, 6.36 mmol) in toluene (40 mL) was stirred at 110.6 °C for 16
hrs. The reaction mixture was cooled to 25 °C, filtered, concentrated under reduced pressure.
The obtained residue was purified by preparatory-HPLC (HCl condition) to afford compound
40B (56 mg, 9.67% yield) as a light yellow solid. H NMR (CDCl 400 MHz): δ 8.94 (s, 1H),
8.26 (s, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.62 (d, J = 8.4 Hz, 1H), 7.48 - 7.43 (m, 1H), 7.28 - 7.24
(m, 1H), 4.24 (q, J = 7.2 Hz, 2H), 1.17 - 1.12 (m, 1H), 1.14 (t, J = 7.2 Hz, 2H).
To a mixture of compound 40B (50 mg, 182.94 umol) in MeOH (2 mL) was
added LiOH (13.1 mg, 548.83 umol) in one portion and the mixture was stirred at 25 °C for 3
hrs. The reaction mixture was concentrated under reduced pressure to remove MeOH. The
residue was diluted with H O (8 mL), adjusted to pH ~ 3 with 1 N HCl, and then extracted with
EtOAc (30 mL x 3). The combined organic layers were washed with brine (20 mL), dried over
anhydrous Na SO , filtered and concentrated under reduced pressure to give intermediate
compound 40C (42 mg, 93.61% yield) as a white solid. H NMR (CDCl , 400 MHz): δ 8.95 (s,
1H), 8.73 (d, J = 8.4 Hz, 1H), 8.38 (s, 1H), 7.89 (d, J = 8.0 Hz, 1H), 7.67 (t, J = 7.6 Hz, 1H), 7.43
(t, J = 7.6 Hz, 1H).
To a solution consisting of compound 40C (42 mg, 171.25 umol) and 1-
hydroxypyrrolidine-2,5-dione (20.7 mg, 179.81 umol) in DME (5 mL) was added EDCI (49.24
17681897_1 (GHMatters) P110989.NZ
mg, 256.87 umol) in one portion at 25 °C under N . The mixture was stirred at 25 °C for 9 hrs.
The reaction mixture was concentrated under reduced pressure to remove DME. The residue was
diluted with EtOAc (60 mL), washed with 1N HCl (10 mL) and saturated aqueous NaHCO (10
mL x 3). The organic layers was washed with brine (20 mL), dried over anhydrous Na SO ,
filtered and concentrated under reduced pressure to afford intermediate compound 40D (60 mg,
crude) as a light yellow oil. MS (ESI) m/z (M+1) 342.8.
Compound 40 (15.10 mg, 50.57% yield, white solid) was prepared as in
Example 6 from the corresponding starting materials, compounds 40D and 12G. Compound 40:
H NMR (CDCl , 400 MHz): δ 11.07 (d, J = 6.0 Hz, 1H), 8.85 (s, 1H), 8.33 - 8.28 (m, 1H), 7.86
(d, J = 0.8 Hz, 1H), 7.77 (d, J = 8.0 Hz, 1H), 7.57 - 7.52 (m, 1H), 7.35 - 7.31 (m, 1H), 7.16 - 7.08
(m, 5H), 6.77 (br s, 1H), 5.81 - 5.75 (m, 1H), 5.55 (br s, 1H), 3.43 - 3.37 (m, 1H), 3.26 - 3.19 (m,
1H). MS (ESI) m/z (M+1) 420.1.
EXAMPLE 20
COMPOUNDS 41-43, 64-65, 67, 71, 76, 87, 100, 116, 132, 134-135, 137, 203-204
(S)-N-(4-(CYCLOPROPYLAMINO)-3,4-DIOXOPHENYLBUTANYL)(PYRIDIN-
2-YL)-1H-IMIDAZOLECARBOXAMIDE (41)
O N O
HBTU, DIEA, DMF
To a mixture of compound 24E (100 mg, 528 umol) and compound 41B (148
mg, 634 umol) in DMF (1.5 mL) was added HBTU (240 mg, 634 umol) in one portion at 25 °C
and stirred for 5 mins, and then DIEA (273 mg, 2.1 mmol) was added. The mixture was stirred
at 25 °C for 30 mins. LCMS showed compound 24E remained and desired MS was detected.
Then the residue was purified by preparatory-HPLC (TFA condition) to give compound 41A
(130 mg, yield: 60.6%) as a white solid. H NMR (400 MHz, Methanol-d ) δ 9.12 (br s, 1H),
8.49 (br d, J = 3.8 Hz, 1H), 7.95 - 7.74 (m, 2H), 7.50 (br s, 1H), 7.37 - 7.16 (m, 5H), 7.13 - 7.01
17681897_1 (GHMatters) P110989.NZ
(m, 1H), 4.69 - 4.52 (m, 1H), 4.22 - 4.03 (m, 1H), 3.29 (br s, 1H), 3.11 - 2.74 (m, 2H), 2.69 -
2.51 (m, 1H), 0.77 - 0.59 (m, 2H), 0.56 - 0.38 (m, 2H). MS (ESI) m/z (M+H) 405.2.
To a solution of compound 41A (130 mg, 320 umol) in DCM (10 mL) was
added DMP (543 mg, 1.3 mmol, 397 uL) in one portion at 0 °C. The mixture was stirred at 25
°C for 10 mins. LCMS showed compound 41A was consumed completely and one main peak
with desired MS was detected. Then the mixture was diluted with DCM (80 mL), quenched by
adding 10% Na S O /saturated aqueous NaHCO (v/v = 1/1, 20 mL). The organic layer was
2 2 3 3
separated, and the aqueous layer was extracted with DCM (30 mL x 2). The combined organic
layer was washed with H O (10 mL), brine (10 mL), dried over Na SO , filtered and
2 2 4
concentrated to afford white solid. Then the residue was purified by re-crystallization from
isopropyl ether (20 mL) to give compound 41 (20.6 mg, yield: 30.9%) as a white solid. H NMR
(400 MHz, DMSO-d ) δ 8.96 (d, J = 7.8 Hz, 1H), 8.79 (br d, J = 5.0 Hz, 1H), 8.45 (br d, J = 4.6
Hz, 1H), 8.14 (s, 1H), 7.88 (t, J = 7.8 Hz, 1H), 7.57 (s, 1H), 7.44 (dd, J = 7.0, 5.2 Hz, 1H), 7.34 -
7.28 (m, 4H), 7.24 (br d, J = 4.2 Hz, 1H), 7.18 (d, J = 8.2 Hz, 1H), 5.32 - 5.22 (m, 1H), 3.31 (s,
1H), 3.19 (dd, J = 13.8, 3.6 Hz, 1H), 2.89 - 2.71 (m, 2H), 0.70 - 0.64 (m, 2H), 0.60 - 0.55 (m,
2H). MS (ESI) m/z (M+H) 403.2.
(S)-N-(4-(CYCLOPROPYLAMINO)-3,4-DIOXOPHENYLBUTANYL)(1-
PHENYL-1H-PYRAZOLYL)-1H-IMIDAZOLECARBOXAMIDE (42)
Compound 42 (19.3 mg, yield: 55.2%, yellow solid) was prepared as in
Example 20 from the corresponding intermediate carboxylic acid, compound 34E. H NMR (400
MHz, DMSO-d ) δ 8.91 (d, J = 7.7 Hz, 1 H), 8.82 (d, J = 5.1 Hz, 1 H), 8.57 (d, J = 2.6 Hz, 1 H),
8.14 (s, 1 H), 7.83 (d, J = 7.9 Hz, 2 H), 7.63 (s, 1 H), 7.53 (t, J = 8.0 Hz, 2 H), 7.36 (t, J = 7.4 Hz,
1 H), 7.32 (d, J = 4.4 Hz, 4 H), 7.27 - 7.20 (m, 1 H), 6.48 (d, J = 2.6 Hz, 1 H), 5.34 - 5.26 (m, 1
H), 3.21 (dd, J = 13.8, 3.6 Hz, 1 H), 2.86 (dd, J = 13.8, 10.3 Hz, 1 H), 2.81 - 2.72 (m, 1 H), 0.71 -
0.63 (m, 2 H), 0.62 - 0.53 (m, 2 H). MS (ESI) m/z (M+H) 469.1.
(S)(BENZO[D]THIAZOLYL)-N-(4-(CYCLOPROPYLAMINO)-3,4-DIOXO
PHENYLBUTANYL)-1H-IMIDAZOLECARBOXAMIDE (43)
Compound 43 (24.4 mg, yield: 43%, white solid) was prepared as in Example
from the corresponding intermediate carboxylic acid, compound 29D. Compound 43: H
NMR (400 MHz, DMSO-d ) δ 9.13 (d, J = 7.7 Hz, 1 H), 8.77 (br d, J = 4.9 Hz, 1 H), 8.39 (s, 1
17681897_1 (GHMatters) P110989.NZ
H), 8.08 (d, J = 7.9 Hz, 1 H), 7.96 (d, J = 8.2 Hz, 1 H), 7.67 (s, 1 H), 7.59 - 7.43 (m, 2 H), 7.27
(d, J = 4.0 Hz, 4 H), 7.22 - 7.12 (m, 1 H), 5.34 - 5.16 (m, 1 H), 3.18 (dd, J = 13.9, 3.3 Hz, 1 H),
2.83 (dd, J = 13.7, 10.1 Hz, 1 H), 2.72 (br d, J = 4.2 Hz, 1 H), 0.69 - 0.58 (m, 2 H), 0.54 (br d, J
= 2.9 Hz, 2 H). MS (ESI) m/z (M+H) 460.1
(S)-N-(4-(CYCLOPROPYLAMINO)-3,4-DIOXOPHENYLBUTANYL)METHYL-
1-(PYRIMIDINYL)-1H-PYRAZOLECARBOXAMIDE (65)
LiOH.H O
(1.76
MeOH
A mixture of compound 65A (80 mg, 366.62 umol) in MeOH (5 mL) and H O
(1 mL) was added LiOH.H O (27.1 mg, 645.87 umol).The mixture was stirred at 31°C for 1h.
The mixture was evaporated to remove MeOH, then it was washed with water (3 x 50 mL) and
extracted with MTBE (2 x 50 mL). The water layers were acidized to pH ~ 4 with 1N HCl, then,
the solution extracted with ethyl acetate (3 x 100 mL). The organic layers were dried over
Na SO and concentrated to give compound 65B (50 mg, 66.79% yield) was obtained as white
solid.
Compound 65 (11.8 mg, 87.93% yield, white solid) was prepared as in
Example 20 from the corresponding intermediate compounds 65B and 41B. Compound 65: H
NMR (400MHz, DMSO-d ) δ 8.94 (s, 2H), 8.87 - 8.79(m, 1 H), 8.51 - 8.44 (m,1H), 7.62 - 7.55
(m,1H), 7.34 - 7.09 (m, 5H), 6.65 (s, 1H), 5.53 - 5.39 (m, 1H), 3.26 - 3.12 (m, 4H), 3.10 - 3.00
(m, 1H),2.81 - 2.71 (m,1H), 2.56 (s, 3H), 0.71 - 0.54 (m, 4H). MS (ESI) m/z (M+H) 419.2.
17681897_1 (GHMatters) P110989.NZ
OH N
64A 96D
OH N
OH HN
135A 136C
204A
(S)-N-(4-(CYCLOPROPYLAMINO)-3,4-DIOXOPHENYLBUTANYL)(2H-
INDAZOLYL)THIAZOLECARBOXAMIDE (64)
Compound 64 (48.2 mg 87.93% yield, white solid) was prepared as in Example
from the corresponding intermediate carboxylic acid, compound 64A. Compound 64: H
NMR (400MHz, DMSO-d ) δ 11.99 - 11.83 (m, 1H), 9.33 (s, 1H), 9.16 (s, 1H), 8.95 - 8.84 (m,
1H), 7.93 - 7.80 (m, 1H), 7.56 - 7.50 (m, 1H), 7.44 - 7.33 (m, 1H), 7.27 - 7.15 (m, 1H), 7.12 -
6.99 (m, 5H), 5.71 - 5.60 (m, 1H), 3.34 - 3.24 (m, 3H), 3.19 - 3.10 (m, 1H), 2.84 - 2.74 (m, 1H),
0.73 - 0.54 (m, 4H). MS (ESI) m/z (M+H) 460.1.
(S)-N-(4-(CYCLOPROPYLAMINO)-3,4-DIOXOPHENYLBUTANYL)METHYL-
1-(3-METHYLPYRIDINYL)-1H-PYRAZOLECARBOXAMIDE (67)
Compound 67 (30.8 mg, 38.6% yield, white solid) was prepared as in Example
from the corresponding intermediate carboxylic acid, compound 67A. Compound 67: H
NMR (CDCl 400 MHz) δ 8.24 (d, J = 4.4 Hz, 1H), 7.67 (d, J = 7.6 Hz, 1H), 7.2 (d, J = 7.2 Hz,
1H), 7.34 - 7.26 (m, 2H), 7.25 - 7.20 (m, 3H), 6.99 (d, J = 4.4 Hz, 2H), 6.86 (s, 1H), 6.56 (s, 1H),
.66 - 5.58 (m, 1H), 3.38 - 3.29 (m, 1H), 3.21 - 3.13 (m, 1H), 2.82 - 2.74 (m, 1H), 2.34 (s, 3H),
2.16 (s, 3H), 0.91 - 0.84 (m, 2H), 0.64 - 0.57 (m, 2H). MS (ESI) m/z (M+H) 432.1.
(S)(1H-BENZO[d]IMIDAZOLYL)-N-(4-(CYCLOPROPYLAMINO)-3,4-DIOXO
PHENYLBUTANYL)-1H-IMIDAZOLECARBOXAMIDE (71)
Compound 71 (75 mg, yield: 78.1%, white solid) was prepared as in Example
from the corresponding intermediate carboxylic acid, compound 70D. Compound 71: H
NMR (400MHz, DMSO-d ) δ 12.93 (br s, 1H), 9.25 (br s, 1H), 8.74 (d, J = 4.9 Hz, 1H), 8.29 (s,
1H), 7.83 (s, 1H), 7.52 (br s, 2H), 7.30 - 7.18 (m, 6H), 7.18 - 7.13 (m, 1H), 5.42 - 5.25 (m, 1H),
17681897_1 (GHMatters) P110989.NZ
3.17 (dd, J = 3.5, 13.7 Hz, 1H), 2.83 (dd, J = 10.0, 13.8 Hz, 1H), 2.74 - 2.64 (m, 1H), 0.70 - 0.42
(m, 4H). MS (ESI) m/z (M+H) 443.0.
(S)-N-(4-(CYCLOPROPYLAMINO)-3,4-DIOXOPHENYLBUTANYL)(5-
PHENYLPYRIMIDINYL)-1H-IMIDAZOLECARBOXAMIDE (76)
Compound 76 (24.7 mg, yield: 44.7%, white solid) was prepared as in
Example 20 from the corresponding intermediate compound 74E. Compound 76: H NMR
(CDCl 400 MHz) δ 9.46 (br d, J = 6.4 Hz, 1H), 8.66 (s, 2H), 8.62 (s, 1H), 7.80 (s, 1H), 7.57 -
7.49 (m, 5H), 7.22 - 7.16 (m, 2H), 7.16 - 7.07 (m, 3H), 6.93 (br s, 1H), 5.86 - 5.82 (m, 1H), 3.53
- 3.46 (m, 1H), 3.41 - 3.32 (m, 1H), 2.86 -2.82 (m, 1H), 0.92 - 0.86 (m, 2H), 0.64 -0.62 (m, 2H).
MS (ESI) m/z (M+H) 481.0.
(S)-N-(4-(CYCLOPROPYLAMINO)-3,4-DIOXOPHENYLBUTANYL)(4-
PHENYL-1H-PYRAZOLYL)THIAZOLECARBOXAMIDE (87)
Compound 87 (60.0 mg, 75.3% yield, white solid) was prepared as in Example
from the corresponding intermediate carboxylic acid, compound 21D. H NMR (400MHz,
CDCl ) δ 11.72 (br. d, J = 6.0 Hz, 1H), 8.73 (s, 1H), 8.68 - 8.64 (m, 1H), 7.76 - 7.72 (m, 1H),
7.58 - 7.52 (m, 2H), 7.48 - 7.40 (m, 2H), 7.37 - 7.30 (m, 1H), 7.29 - 7.21 (m, 5H), 6.97 - 6.91 (m,
1H), 5.86 - 5.74 (m, 1H), 3.53 - 3.41 (m, 1H), 3.29 - 3.17 (m, 1H), 2.88 - 2.75 (m, 1H), 0.93 -
0.82 (m, 2H), 0.68 - 0.58 (m, 2H). MS (ESI) m/z (M+1) 486.1.
(S)-N-(4-(CYCLOPROPYLAMINO)-3,4-DIOXOPHENYLBUTANYL)METHYL-
-PHENYLISOXAZOLECARBOXAMIDE (100)
Compound 100 (85 mg, yield: 83.27%, white solid) was prepared as in
Example 20 from the corresponding intermediate carboxylic acid, compound 23A. Compound
100: H NMR (400MHz, DMSO-d ) δ 9.09 (d, J = 7.5 Hz, 1H), 8.94 (br d, J = 5.1 Hz, 1H), 7.62
(d, J = 7.1 Hz, 2H), 7.53 - 7.46 (m, 1H), 7.44 - 7.39 (m, 2H), 7.32 - 7.20 (m, 5H), 5.48 (ddd, J =
3.3, 7.6, 10.7 Hz, 1H), 3.25 (br dd, J = 3.2, 14.0 Hz, 1H), 2.85 - 2.67 (m, 2H), 2.07 (s, 3H), 0.73 -
0.56 (m, 4H). MS (ESI) m/z (M+H) 418.1.
(S)-N-(4-(CYCLOPROPYLAMINO)-3,4-DIOXOPHENYLBUTANYL)METHYL-
-PHENYLISOTHIAZOLECARBOXAMIDE (116)
Compound 116 (88.00 mg, 87.41% yield, off-white solid) was prepared as in
Example 20 from the corresponding intermediate carboxylic acid, compound 96D. Compound
17681897_1 (GHMatters) P110989.NZ
116: H NMR (400MHz, CDCl ) δ 7.44 (s, 5H), 7.20 - 7.09 (m, 3H), 6.86 (br s, 1H), 6.77 - 6.68
(m, 2H), 5.93 (br d, J=6.6 Hz, 1H), 5.68 - 5.57 (m, 1H), 3.24 - 3.14 (m, 1H), 2.99 - 2.89 (m, 1H),
2.83 - 2.73 (m, 1H), 2.46 (s, 3H), 0.93 - 0.81 (m, 2H), 0.69 - 0.53 (m, 2H). MS (ESI) m/z
(M+H) 434.1.
(S)-N-(4-(CYCLOPROPYLAMINO)-3,4-DIOXOPHENYLBUTANYL)METHYL-
1-(PYRIDINYL)-1H-PYRAZOLECARBOXAMIDE (132)
Compound 132 (72.8 mg, 60.40% yield, white solid) was prepared as in
Example 20 from the corresponding intermediate carboxylic acid, compound 136C. Compound
132: H NMR (400 MHz, CDCl ): δ 8.61 (d, J = 2.4 Hz, 1H), 8.57 - 8.54 (m, 1H), 7.72 - 7.66 (m,
1H), 7.34 - 7.26 (m, 4H), 7.10 - 7.05 (m, 2H), 7.03 - 6.94 (m, 1H), 6.64 - 6.56 (m, 1H), 6.44 (s,
1H), 5.62 - 5.54 (m, 1H), 3.44 - 3.36 (m, 1H), 3.18 - 3.10 (m, 1H), 2.85 - 2.76 (m, 1H), 2.33 (s,
3H), 0.92 - 0.85 (m, 2H), 0.66 - 0.59 (m, 2H). MS (ESI) m/z (M+1) 418.1.
(S)-N-(4-(CYCLOPROPYLAMINO)-3,4-DIOXOPHENYLBUTANYL)
(ISOQUINOLINYL)METHYL-1H-PYRAZOLECARBOXAMIDE (134)
Compound 134 (57.4 mg, 62.9% yield, yellow solid) was prepared as in
Example 20 from the corresponding intermediate carboxylic acid, compound 133D. Compound
134: H NMR (400 MHz, CDCl ) δ 9.31 (br s, 1H), 8.47 (br s, 1H), 8.06 (d, J = 7.6 Hz, 1H), 7.74
- 7.61 (m, 2H), 7.43 (d, J = 8.0 Hz, 1H), 7.25 - 7.20 (m, 3H), 6.92 (br s, 2H), 6.84 (br s, 1H), 6.60
(s, 1H), 6.46 (d, J = 7.2 Hz, 1H), 5.50 - 5.41 (m, 1H), 3.30 - 3.22 (m, 1H), 3.14 - 3.04 (m, 1H),
2.79 - 2.70 (m, 1H), 2.40 (s, 3H), 0.87 - 0.82 (m, 2H), 0.63 - 0.53 (m, 2H). MS (ESI) m/z
(M+H) 468.1.
(S)CYCLOPROPYL-N-(4-(CYCLOPROPYLAMINO)-3,4-DIOXOPHENYLBUTAN-
2-YL)PHENYLTHIAZOLECARBOXAMIDE (135)
Compound 135 (52.8 mg, 53.03% yield, white solid) was prepared as in
Example 20 from the corresponding intermediate carboxylic acid, compound 135A. Compound
135: H NMR (CDCl 400 MHz) δ 1H NMR (400 MHz, CDCl3) δ 7.53 - 7.45 (m, 2H), 7.45 -
7.35 (m, 3H), 7.22 - 7.11 (m, 3H), 6.85 (br s, 1H), 6.80 - 6.70 (m, 2H), 6.17 (d, J = 6.4 Hz, 1H),
.54 - 5.45 (m, 1H), 3.27 - 3.22 (m, 1H), 2.89 - 2.84 (m, 1H),2.80 - 2.75 (m, 1H), 2.33 - 2.26 (m,
1H), 1.20 - 1.14 (m, 2H), 1.13 - 1.08 (m, 2H), 0.91 - 0.79 (m, 2H), 0.64 - 0.54 (m, 2H). MS
(ESI) m/z (M+H) 460.1.
17681897_1 (GHMatters) P110989.NZ
(S)(tert-BUTYL)-N-(4-(CYCLOPROPYLAMINO)-3,4-DIOXOPHENYLBUTAN
YL)PHENYL-1H-PYRAZOLECARBOXAMIDE (137)
Compound 137 (96.70 mg, 64.74% yield, white solid) was prepared as in
Example 20 from the corresponding intermediate carboxylic acid, compound 128A. Compound
137: H NMR (400 MHz, CDCl ) δ 7.54 - 7.45 (m, 3H), 7.41 - 7.36 (m, 2H), 7.31 - 7.27(m, 1H),
7.25 - 7.13 (m, 5H), 6.87 (br s, 1H), 6.69 (s, 1H), 5.77 - 5.68 (m, 1H), 3.44 - 3.36 (m, 1H), 3.17 -
3.09 (m, 1H), 2.82 - 2.74 (m, 1H), 1.16 (s, 9H), 0.89 - 0.81 (m, 2H), 0.64 - 0.54 (m, 2H). MS
(ESI) m/z (M+H) 459.2.
(S)-N-(4-(CYCLOPROPYLAMINO)-3,4-DIOXOPHENYLBUTANYL)METHYL-
1-(4-PHENYLTHIAZOLYL)-1H-PYRAZOLECARBOXAMIDE (203)
Compound 203 (30 mg, yield 60.18%, white solid) was prepared as in Example
from the corresponding intermediate carboxylic acid, compound 82D. Compound 203: H
NMR (CDCl 400MHz) δ 7.69 - 7.64 (m, 2H), 7.41 - 7.33 (m, 3H), 7.22 (s, 1H), 7.12 - 7.06 (m,
3H), 7.01 - 6.94 (m, 3H), 6.84 (br s, 1H), 5.65 - 5.58 (m, 1H), 3.41 - 3.34 (m, 1H), 2.97 - 2.89
(m, 1H), 2.79 - 2.71 (m, 1H), 2.32 (s, 3H), 0.86 - 0.80 (m, 2H), 0.61 - 0.53 (m, 2H). MS (ESI)
m/z (M+H) 500.1.
(S)-N-(4-(CYCLOPROPYLAMINO)-3,4-DIOXOPHENYLBUTANYL)PHENYL-
1H-1,2,3-TRIAZOLECARBOXAMIDE (204)
Compound 204 (4 mg, 8.9% yield, white solid) was prepared as in Example 20
from the corresponding intermediate carboxylic acid, compound 204A. Compound 204: H NMR
(CDCl 400 MHz) T = 80 : δ 8.55 (br s, 1H), 8.41 (d, J = 7.2 Hz, 1H), 7.82 - 7.78 (m, 2H), 7.50 -
7.35 (m, 4H), 7.32 - 7.20 (m, 5H), 5.51 - 5.45 (m, 1H), 3.30 - 3.22 (m, 1H), 3.05 (br s, 1H), 2.81
- 2.74 (m, 1H), 0.71 - 0.66 (m, 2H), 0.64 - 0.59 (m, 2H). MS (ESI) m/z (M+H) 404.1.
EXAMPLE 21
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)METHYLPHENYL-1H-
PYRAZOLECARBOXAMIDE (45)
NaOH
PhB(OH)2
,K PO MeOH,THF
Pd(dtbpf)Cl2 3 4 N
32C N 45A
17681897_1 (GHMatters) P110989.NZ
A mixture of ethyl compound 32C (500.0 mg, 2.15 mmol), phenylboronic acid
(262.1 mg, 2.15 mmol), Pd(dtbpf)Cl (140.1 mg, 215.00 umol), K PO (1.37 g, 6.45 mmol) in
2 3 4
dioxane (30 mL) and H O (10 mL) was degassed and purged with N for 3 times, and then the
mixture was stirred at 70 °C for 1 hour under N atmosphere. The mixture was concentrated and
diluted with ethyl acetate (30 mL), washed with HCl (1M, 50 mL), sarurated aqueous NaHCO
(50 mL), brine (50 mL), dried over Na SO and concentrated to afford intermediate compound
45A (490 mg, crude) as a brown oil. MS (ESI) m/z (M+H) 230.9.
To a solution of compound 45A (490.0 mg, 2.13 mmol) in MeOH (5 mL) and
THF (5 mL) was added NaOH (2M, 21.28 mL). The mixture was stirred at 60 °C for 1 hour.
The mixture was concentrated and diluted with H O (10 mL), the mixture was extracted with
ethyl acetate (10 mL), the water phase was added HCl (1M) until pH ~ 3, then the mixture was
extracted with ethyl acetate (20 mL), the organic layer was washed with brine (10 mL), dried
over Na SO and concentrated. Compound 45B (400 mg, yield: 93.0%) was obtained as a brown
solid. H NMR (400MHz, DMSO-d ) δ 12.09 (br s, 1H), 7.87 (s, 1H), 7.50 - 7.40 (m, 5H), 3.63
(s, 3H).
Compound 45 (50.0 mg, yield: 71.4%, white solid) was prepared as in
Example 5 from the corresponding intermediate carboxylic acid, compound 45B. Compound 45:
H NMR (400MHz, CDCl ) δ 7.97 (s, 1H), 7.55 - 7.43 (m, 3H), 7.32 - 7.27 (m, 2H), 7.23 - 7.15
(m, 3H), 6.85 - 6.65 (m, 3H), 5.80 - 5.71 (m, 1H), 5.55 - 5.40 (m, 2H), 3.71 - 3.60 (m, 3H), 3.29 -
3.19 (m, 1H), 2.94 - 2.84 (m, 1H), 2.94 - 2.84 (m, 1H). MS (ESI) m/z (M+H) 377.1.
17681897_1 (GHMatters) P110989.NZ
EXAMPLE 22
(S)-N-(4-AMINO(4-METHOXYPHENYL)-3,4-DIOXOBUTANYL)METHYL
PHENYLISOXAZOLECARBOXAMIDE (46)
K CO , MeI,
2 3 LiAlH , THF
4 DMP
HN O
HN O
HN O
O DCM
46A O
K CO
Et3N, DCM
OH OH
46D H O BocHN
dioxane
BocHN 2 2
DMSO
O NH
O NH
To a solution of compound 46A (13 g, 44.02 mmol, 1 eq) in DMF (150 mL)
was added K CO (12.17 g, 88.04 mmol, 2 eq) at 0 °C. After addition, the mixture was stirred at
this temperature for 0.2 h, and then CH I (8.97 g, 63.20 mmol, 3.93 mL) was added dropwise at 0
°C. The resulting mixture was stirred at 25 °C for 18.8 hours. The reaction mixture was diluted
with EtOAc (50 mL). The combined organic layers were washed with brine (100 mL x 2), dried
over Na SO , filtered and concentrated under reduced pressure to give the compound 46B (13.4
g, yield: 98.4%) as a colorless oil. H NMR (400MHz, CDCl ) δ 7.04 (d, J = 8.6 Hz, 2H), 6.84
(d, J = 7.7 Hz, 2H), 4.96 (br d, J = 7.3 Hz, 1H), 4.55 (br d, J = 7.1 Hz, 1H), 3.79 (s, 3H), 3.72 (s,
3H), 3.09 - 2.94 (m, 2H), 1.43 (s, 9H).
To a solution of LAH (490 mg, 12.92 mmol, 2 eq.) in THF (10 mL) was
degassed and purged with N for 3 times at 0 °C and the mixture of compound 46B (2 g, 6.46
mmol, 1 eq) in THF (30 mL) was added dropwise, and then the mixture was stirred at 0 °C for 2
hrs under N atmosphere. The reaction mixture was quenched by addition H O (0.5 mL), then
add NaOH (15% in H O, 0.5 mL), H O (1.5 mL), and then diluted with EtOAc (20 mL), dried
over Na SO , and stirred for 30 min, then filtered to give the organic layers. The combined
organic layers were washed with brine (20 mL x 2), dried over Na SO , filtered and concentrated
under reduced pressure to give the compound 46C (1.48 g, yield: 81.4%) was obtained as a
colorles oil. H NMR (400MHz, CDCl ) δ 7.12 (d, J = 8.4 Hz, 2H), 6.89 - 6.78 (m, 2H), 4.69 (br
17681897_1 (GHMatters) P110989.NZ
s, 1H), 3.88 - 3.80 (m, 1H), 3.79 (s, 3H), 3.69 - 3.48 (m, 2H), 2.77 (d, J = 7.1 Hz, 2H), 1.41 (s,
9H).
A solution of DMP (1.51 g, 3.56 mmol) in DCM (10 mL) was degassed and
purged with N for 3 times, and then compound 46C (500 mg, 1.78 mmol) in DCM (10 mL) was
added dropwise, and then the mixture was stirred at 25 °C for 20 hrs under N atmosphere. The
reaction mixture was quenched by addition of saturated aqueous Na S O (15 mL) and saturated
2 2 3
aqueous NaHCO (15 mL), and then diluted with DCM (10 mL) and extracted with H O (20 mL
x 3). The combined organic layers were washed with brine (20 mL), dried over Na SO , filtered
and concentrated under reduced pressure to give the compound 46D (430 mg, yield: 86.48%) was
obtained as a yellow solid. H NMR (400MHz, CDCl ) δ 9.62 (s, 1H), 7.13 - 7.02 (m, 2H), 6.84
(br d, J=8.6 Hz, 2H), 5.05 (br d, J=5.5 Hz, 1H), 4.46 - 4.32 (m, 1H), 3.78 (s, 3H), 3.06 (br d, J =
6.4 Hz, 2H), 1.43 (s, 9H).
To a solution of compound 46D (1.53 g, 5.48 mmol) in DCM (20 mL) was
added compound 2-hydroxymethylpropanenitrile (3.30 g, 38.78 mmol, 3.55 mL) and Et N
(832 mg, 8.22 mmol, 1.14 mL). The mixture was stirred at 25 °C for 2 hrs. The reaction mixture
was quenched by addition 1N HCl (20 mL), and then diluted with H O (20 mL) and extracted
with DCM (20 mL x 2). The combined organic layers were washed with brine (20 mL x 3),
dried over Na SO , filtered and concentrated under reduced pressure to give a residue. The
residue was purified by column chromatography (SiO , Petroleum ether/Ethyl acetate = 10/1 to
4:1) to give the compound 46E (980 mg, yield: 58.37%) was obtained as a white solid. H NMR
(400MHz, CDCl ) δ 7.16 - 6.97 (m, 2H), 6.90 - 6.71 (m, 2H), 4.96 - 4.72 (m, 1H), 4.52 - 4.37
(m, 1H), 3.74 - 3.72 (m, 3H), 3.07 - 2.66 (m, 2H), 1.37 (s, 9H).
To a solution of compound 46E (980 mg, 3.20 mmol) and K CO (885 mg,
6.40 mmol) in DMSO (15 mL) was added H O (9.3 mL, purity: 30%). The mixture was stirred
at 0 °C for 2 hrs. The reaction mixture was diluted with H O (100 mL) and extracted with
EtOAc (30 mL x 3). The combined organic layers were washed with brine (50 mL x 2), dried
over Na SO , filtered and concentrated under reduced pressure to give the compound 46F (560
mg, yield: 53.95%) was obtained as a white solid. H NMR (400MHz, CDCl ) δ 7.16 - 6.97 (m,
2H), 6.90 - 6.71 (m, 2H), 4.96 - 4.72 (m, 1H), 4.52 - 4.37 (m, 1H), 3.74 - 3.72 (m, 3H), 3.07 -
2.66 (m, 2H), 1.37 (s, 9H).
17681897_1 (GHMatters) P110989.NZ
To a solution of compound 46F (500 mg, 1.54 mmol) in EtOAc (5 mL) was
added HCl/EtOAc (4 M, 5 mL). The mixture was stirred at 25 °C for 1 h. The reaction mixture
was diluted with MTBE (20 mL), and filtered to give the compound 46G (300 mg, yield:
73.97%, HCl) was obtained as a white solid. H NMR (400MHz, DMSO-d ) δ 8.06 - 7.81 (m,
3H), 7.51 (br s, 2H), 7.26 - 7.07 (m, 2H), 6.95 - 6.79 (m, 2H), 6.65 - 6.35 (m, 1H), 4.21 - 3.78
(m, 1H), 3.71 (d, J = 1.5 Hz, 3H), 3.53 (br s, 1H), 2.87 - 2.62 (m, 2H).
Compound 46 (65 mg, yield: 65.3%, white solid) was prepared as in Example
from the corresponding intermediate compounds, 23A and 46G. Compouond 46: H NMR
(400MHz, DMSO-d ) δ 9.05 - 8.64 (m, 1H), 8.18 (s, 1H), 7.90 (s, 1H), 7.67 - 7.55 (m, 2H), 7.53
- 7.32 (m, 3H), 7.24 - 7.10 (m, 2H), 6.89 - 6.76 (m, 2H), 5.48 - 5.36 (m, 1H), 3.74 - 3.65 (m, 3H),
3.23 - 2.95 (m, 1H), 2.76 - 2.58 (m, 1H), 2.17 - 2.00 (m, 3H). MS (ESI) m/z (M +H) 408.1.
EXAMPLE 23
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)PHENYL-1H-IMIDAZOLE
CARBOXAMIDE (48)
O S O
NH CHO, water,
Cl o
O 180 3.5 h
Cl OH
CHCl3
To a solution of compound 48A (40 g) in CHCl (200 mL) cooled to 0 °C was
added dropwise sulfuryl dichloride (34 g). The mixture was warmed to 30 °C for 0.5 h and
heated at 70 °C for 5 hrs. After cooling to room temperature, the reaction mixture was diluted
with chloroform (40 mL), washed with aqueous NaHCO (40 mL x 2), water (20 mL) and then
brine (30 mL) successively. The organic phase was dried over Na SO and evaporated to afford
compound 48B (47 g, crude) was obtained as a yellow solid. H NMR (400MHz, CDCl ) δ 8.06
- 7.87 (m, 2H), 7.67 - 7.56 (m, 1H), 7.52 - 7.42 (m, 1H), 7.48 - 7.39 (m, 1H), 7.48 - 7.39 (m, 1H),
7.67 - 7.38 (m, 1H), 7.26 (s, 1H), 5.61 (s, 1H), 5.29 - 5.26 (m, 1H), 4.39 - 4.21 (m, 2H), 1.70 (s,
1H), 1.40 - 1.14 (m, 3H).
A solution of compound 48B (20 g) in NH CHO (40 g, 882.40 mmol, 35 mL)
and Water (3.2 g, 176.48 mmol) was heated at 180 °C for 3.5 hrs. The mixture was allowed to
cool to room temperature, then water (50 ml) was added and the mixture was extracted with
17681897_1 (GHMatters) P110989.NZ
DCM (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over
Na SO , filtered and concentrated under reduced pressure to give a residue. The residue was
purified by flash silica gel chromatography (Eluent of 0 ~ 100% Ethyl acetate/Petroleum ether
gradient @ 40 mL/min) to afford compound 48C (1.3 g) as yellow solid. H NMR (400MHz,
DMSO-d ) δ 8.09 (d, J=7.3 Hz, 7H), 4.28 - 4.08 (m, 2H), 1.24 (br t, J=6.8 Hz, 1H), 1.29 - 1.10
(m, 1H).
To a solution of ethyl compound 48C (800 mg, 3.70 mmol) in EtOH (20 mL)
was added a solution of KOH (2.1 g, 37.00 mmol) in H O (20 mL) at 0 °C. After addition, the
reaction mixture was stirred at 70 °C for 16 hrs 20 mL of water was added into the reaction
mixture and the mixture was extracted with MTBE (20 mL). The aqueous layer was acidified
with 1N HCl to pH ~ 4 and filtered to afford desired compound. The filtrate was extracted with
EtOAc (50 mL x 3). The combined extracts were washed with brine (50 mL) and dried over
Na SO , the mixture was concentrated in vacuum to afford desired compound 48D (500 mg,
yield 71.81%) as white solid. H NMR (400MHz, DMSO-d ) δ 13.42 - 12.33 (m, 1H), 7.97 -
7.67 (m, 3H), 7.48 - 7.21 (m, 3H).
Compound 48 (10 mg, yield 25.1%, light yellow solid) was prepared as in
Example 5 from the corresponding intermediate carboxylic acid, compound 48D. Compound 48:
H NMR (400MHz, DMSO-d ) δ 8.30 - 8.17(m, 1H), 8.00-7.53 (m, 5H), 7.46 - 7.13 (m, 8H),
.50 - 5.30 (m, 1H), 4.31 - 4.05 (m, 1H), 3.32 - 3.21(m, 1H), 2.71-2.61 (m, 1H). MS (ESI) m/z
(M +H) 363.2.
EXAMPLE 24
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)(BENZO[d]THIAZOLYL)-
1H-IMIDAZOLECARBOXAMIDE (50)
Tosmic, K CO NaOH
S N 2
THF,H O
O OH
MeOH, 70 0.5
50B TsOH, toluene, C,
(6 eq),
NH 25 °C, 3 h
120 1 h
50A 50C
A mixture of compound 50A (20 g, 133 mmol), compound 50B (136 g, 665
mmol), TsOH.H O (2.5 g, 13.3 mmol) in toluene (200 mL) was stirred at 120 °C for 1 hour.
TLC (Petroleum ether: Ethyl acetate = 3:1, R ~ 0.5) indicated 50A was almost consumed and
17681897_1 (GHMatters) P110989.NZ
one new spot formed. The reaction mixture was concentrated under reduced pressure to give a
residue. The residue was purified by column chromatography (Petroleum ether: Ethyl acetate =
:1 to 5:1) to give compound 50C (30 g, crude) as a yellow oil. H NMR (400MHz, CDCl ) δ
9.40 (s, 1H), 7.98 - 7.78 (m, 1H), 7.77 - 7.57 (m, 1H), 7.55 - 7.31 (m, 1H), 7.30 - 7.07 (m, 1H),
.38 - 5.26 (m, 1H), 4.33 - 4.21 (m, 3H). MS (ESI) m/z (M+H) 234.9.
A mixture of methyl 50C (10 g, 45.4 mmol), TosMIC (17.7 g, 90.8 mmol),
K CO (9.4 g, 68.1 mmol) in MeOH (200 mL) was stirred at 70 °C for 0.5 hour. TLC
(Petroleum ether: Ethyl acetate = 3:1, R = 0.4) indicated 50C was consumed completely and
some new spots formed. The reaction mixture was filtered and concentrated under reduced
pressure to give a residue. The residue was purified by column chromatography (Petroleum
ether: Ethyl acetate = 20:1 to 3:1) to give compound 50D (1.2 g, yield: 10.2%) as a yellow solid.
H NMR (400MHz, CDCl ) δ 8.22 (d, J = 0.9 Hz, 1H), 8.06 (d, J = 7.9 Hz, 1H), 7.93 - 7.88 (m,
3H), 7.58 (dt, J = 1.3, 7.7 Hz, 1H), 7.52 - 7.49 (m, 1H), 7.49 - 7.43 (m, 1H), 4.58 (s, 1H), 3.87 (s,
3H), 2.51 (s, 1H). MS (ESI) m/z (M+H) 259.9.
To a solution of 50D (1.1 g, 4.24 mmol in THF (30 mL), H O (5 mL) was
added NaOH (339 mg, 8.48 mmol). The reaction mixture was stirred at 25 °C for 3 hrs. LCMS
showed 50D was consumed completely and one main peak with desired MS was detected. The
reaction mixture was concentrated to give a residue. The residue was dissolved in water (10
mL), adjusted pH ~ 5 by aqueous HCl, filtered and the filtered cake was concentrated to give the
product 50E (0.6 g, yield: 57.7%) as a gray solid. H NMR (400MHz, DMSO-d ) δ 8.48 (d, J =
1.1 Hz, 1H), 8.22 - 8.18 (m, 1H), 8.06 (dd, J = 0.8, 8.0 Hz, 1H), 7.81 (d, J = 0.9 Hz, 1H), 7.64 -
7.53 (m, 2H). MS (ESI) m/z (M+H) 245.9.
Compound 50 (12.9 mg, yield: 18.8%, white solid) was prepared as in
Example 5 from the corresponding intermediate carboxylic acid, compound 50E. Compound 50:
H NMR (400 MHz, DMSO-d ) δ 9.11 (br d, J = 7.7 Hz, 1 H) 8.39 (s, 1 H) 8.12 - 8.03 (m, 2 H)
7.96 (d, J = 8.2 Hz, 1 H) 7.81 (s, 1 H) 7.66 (s, 1 H) 7.57 - 7.45 (m, 2 H) 7.26 (d, J = 4.2 Hz, 4 H)
7.20 - 7.16 (m, 1 H) 5.33 - 5.20 (m, 1 H) 3.18 (br dd, J = 13.9, 3.5 Hz, 1 H) 2.90 - 2.76 (m, 1 H).
MS (ESI) m/z (M+H) 420.0.
17681897_1 (GHMatters) P110989.NZ
EXAMPLE 25
(S)-N-(4-(CYCLOPROPYLAMINO)-3,4-DIOXOPHENYLBUTANYL)(1H-
INDAZOLYL)-1H-IMIDAZOLECARBOXAMIDE (51)
NH HN
TOSMIC
K CO /EtOH
CH OH, 25 °C, 2 h 2 3
H 90 °C, 0.5 h
NaOH
THF/DCM/DMF
THF/H
0 25 °C, 12 h O
°C, 10 h
51D N
To a solution of 51A (8.7 g, 65.3 mmol) in MeOH (90 mL) was added ethyl 2-
oxoacetate (20 g, 98.01 mmol). After stirred at 25 °C for 2 hours, the mixture was filtered and
concentrated to give crude product 51B (15 g, crude) as brown solid, which was used for the next
step without purification.
To a solution of 51B (15 g, 69.1 mmol) in EtOH (400 mL) was added K CO
(14.5 g, 104 mmol) and TosMIC (11.6 g 59.4 mmol). After stirred at 90 °C for 0.5 hour, the
reaction mixture was filtered and concentrated under reduced pressure to give a residue. The
residue was purified by column chromatography (SiO , Petroleum ether/Ethyl acetate = 1:0 to
1:1) to give compound 51C (2.9 g, yield: 16.4%) as a yellow solid. H NMR (400MHz, CDCl )
δ 11.04 (br s, 1H), 7.98 (d, J = 0.7 Hz, 1H), 7.91 (s, 1H), 7.48 - 7.41 (m, 3H), 7.25 - 7.19 (m,
1H), 4.24 - 4.14 (m, 2H), 1.14 (t, J = 7.1 Hz, 3H).
To a solution of 51C (2.9 g, 11.3 mmol) in THF (40 mL) and H O (8 mL) was
added NaOH (905 mg, 22.6 mmol). The mixture was stirred at 25 °C for 10 hours. The mixture
was concentrated under reduced pressure to remove the organic solvent, and extracted with
EtOAc (20 mL). The aqueous layer was acidized with 1M HCl to pH ~ 5 and then extracted with
EtOAc (30 mL x 3). The combined organic layer was washed with H O (40 mL), brine (40 mL),
dried over Na SO , filtered and concentrated to give 51D (1.5 g, yield: 58.1%) as yellow solid.
H NMR (400MHz, DMSO-d ) δ 13.35 (s, 1H), 8.16 (s, 1H), 7.83 (s, 1H), 7.61 (d, J = 8.3 Hz,
1H), 7.47 - 7.41 (m, 2H), 7.20 - 7.15 (m, 1H). MS (ESI) m/z (M+H) 228.9.
17681897_1 (GHMatters) P110989.NZ
To a solution of 51D (500 mg, 2.19 mmol,) and 1-hydroxypyrrolidine-2,5-
dione (252 mg, 2.19 mmol) in THF (10 mL), DCM (5 mL) and DMF (10 mL) was added EDCI
(420 mg, 2.19 mmol) at 0 °C. After addition, the mixture was stirred at 25°C for 12 h. The
solvent was removed under vacuum. The residue was diluted with EtOAc (50 mL), washed with
1N HCl (20 mL), saturated NaHCO (20 mL) and brine (20 mL). The organics were combined,
dried over Na SO , filtered, and concentrated to give crude 51E (476 mg, yield: 66.8%) as yellow
solid. H NMR (400MHz, DMSO-d ) δ 13.52 (s, 1H), 8.57 (s, 1H), 8.32 (s, 1H), 7.63 (d, J = 8.6
Hz, 1H), 7.49 - 7.43 (m, 2H), 7.24 - 7.17 (m, 1H), 2.77 (s, 5H).
Compound 51 (28.5 mg, yield: 29.1%, yellow solid) was prepared as in
Example 20 from the corresponding intermediate compounds 51E and 41B. Compound 51: H
NMR (400 MHz, CDCl ) δ 10.66 (br s, 1 H), 7.86 (s, 1 H), 7.73 (s, 1 H), 7.49 - 7.34 (m, 3 H),
7.34 - 7.28 (m, 1 H), 7.23 - 7.10 (m, 4 H), 7.09 - 6.90 (m, 3 H), 5.65 - 5.53 (m, 1 H), 3.33 (dd, J
= 14.1, 5.1 Hz, 1 H), 3.15 (dd, J = 14.1, 7.3 Hz, 1 H), 2.75 (td, J = 7.2, 3.6 Hz, 1 H), 0.76 - 0.86
(m, 2 H), 0.55 (br d, J = 2.6 Hz, 2 H). MS (ESI) m/z (M+H) 443.1.
EXAMPLE 26
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)(5-PHENYLTHIAZOLYL)-
1H-IMIDAZOLECARBOXAMIDE (52)
Ph N
Ph N
O LiOH H O O
TosMIC O
K CO , EtOH THF, H O
2 3 2 OH
MeOH
°C, 12 h
90 °C, 2 h
70 °C, 6 OMe
52A 52B 52C N
A mixture of compound 52A (4.2 g, 23.8 mmol) and ethyl 2-oxoacetate (14.6
g, 71.4 mmol) in MeOH (40 mL) was stirred at 70 °C for 6 hours. TLC (Petroleum ether: Ethyl
acetate = 2:1, R ~ 0.7) indicated compound 52A was consumed completely, and one major new
spot with lower polarity was detected. The reaction mixture was concentrated. The residue was
purified by column chromatography (SiO , Petroleum ether: Ethyl acetate = 20:1 to 10:1) to give
compound 52B (7 g, crude) as a yellow oil.
To a mixture of compound 52B (7 g, 23.9 mmol) and K2CO3 (6.6 g, 47.8
mmol) in EtOH (15 mL) was added TosMIC (6.9 g, 35.9 mmol). The mixture was stirred at 90
17681897_1 (GHMatters) P110989.NZ
°C for 2 hours. TLC (Petroleum ether: Ethyl acetate = 2:1, R ~ 0.55) indicated compound 52B
was consumed completely, and one major new spot with larger polarity was detected. The
reaction mixture was concentrated to give residue. The crude product was purified by silica gel
chromatography eluted with Petroleum ether: Ethyl acetate = 15:1 to 5:1 to give compound 52C
(6 g, crude) as a yellow solid. MS (ESI) m/z (M+H) 299.9.
To a solution of compound 52C (3.5 g, 11.69 mmol) in THF (20 mL) and H O
(6 mL) was added LiOH.H O (981 mg, 23.3 mmol) in one portion. The mixture was stirred at 25
°C for 12 hours. TLC (Petroleum ether: Ethyl acetate = 1:1, R ~ 0.25) indicated compound 52C
was consumed completely and one new spot formed. The mixture was adjusted to pH ~ 5 by
adding HCl (2M), and then white solid was precipitate out, filtered and dried under reduced
pressure to give compound 52D (1.5 g, yield: 47.3%) as a white solid. H NMR (400 MHz,
DMSO-d ) δ 8.37 (s, 1H), 8.19 (s, 1H), 7.76 - 7.70 (m, 3H), 7.53 - 7.46 (m, 2H), 7.45 - 7.38 (m,
1H).
Compound 52 (50.9 mg, yield: 43%, white solid) was prepared as in Example
from the corresponding intermediate carboxylic acid, compound 52D. Compound 52: H NMR
(400MHz, DMSO-d ) δ 9.05 (d, J = 7.5 Hz, 1H), 8.32 (s, 1H), 8.11 (s, 2H), 7.85 (s, 1H), 7.71 -
7.66 (m, 3H), 7.48 (t, J = 7.5 Hz, 2H), 7.44 - 7.39 (m, 1H), 7.30 (d, J = 4.4 Hz, 4H), 7.23 - 7.19
(m, 1H), 5.35 - 5.25 (m, 1H), 3.21 (dd, J = 3.7, 13.8 Hz, 1H), 2.85 (dd, J = 10.3, 13.8 Hz, 1H).
MS (ESI) m/z (M+H) 446.0.
EXAMPLE 27
(S)-N-(4-(CYCLOPROPYLAMINO)-3,4-DIOXOPHENYLBUTANYL)(5-
PHENYLTHIAZOLYL)-1H-IMIDAZOLECARBOXAMIDE (53)
N OH
N O O
N EDCI, THF, DCM
0 25 °C, 12 h
To a mixture of compound 53A (600 mg, 2.21 mmol) and compound 1-
hydroxypyrrolidine-2,5-dione (254 mg, 2.21 mmol) in THF (10 mL) at 0 °C was added a solution
of EDCI (423 mg, 2.21 mmol) in DCM (5 mL) dropwise. The mixture was stirred at 25 °C for
17681897_1 (GHMatters) P110989.NZ
12 hours. TLC (Petroleum ether: Ethyl acetate = 1:1, R ~ 0.4) indicated compound 53A was
consumed completely, and one major new spot with lower polarity was detected. The reaction
mixture was concentrated to remove solvent. The residue was diluted with EtOAc (50 mL),
washed with H O (20 mL), saturated NaHCO (20 mL), brine (20 mL). The organics were
collected, dried with Na SO , filtered, and concentrated to give desired intermediate compound
53B (700 mg, yield: 85.9%) as a yellow solid. H NMR (400 MHz, CDCl ) δ 8.29 (s, 1H), 8.20
(s, 1H), 7.86 (s, 1H), 7.57 (d, J = 6.5 Hz, 2H), 7.48 - 7.36 (m, 3H), 7.27 (s, 1H), 2.88 (s, 4H).
Compound 53 (41 mg, yield: 34.3%, white solid) was prepared as in Example
from the corresponding intermediate compound 53B. Compound 53: H NMR (400 MHz,
DMSO-d ) δ 9.08 (d, J = 7.7 Hz, 1H), 8.82 (d, J = 5.0 Hz, 1H), 8.32 (d, J = 0.8 Hz, 1H), 8.11 (s,
1H), 7.72 - 7.64 (m, 3H), 7.52 - 7.46 (m, 2H), 7.44 - 7.39 (m, 1H), 7.30 (d, J = 4.4 Hz, 4H), 7.24
- 7.18 (m, 1H), 5.31 - 5.22 (m, 1H), 3.21 (dd, J = 13.7, 3.6 Hz, 1H), 2.90 - 2.70 (m, 2H), 0.66 -
0.54 (m, 4H). MS (ESI) m/z (M+H) 486.1.
EXAMPLE 28
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)METHYLPHENYL-1H-
1,2,3-TRIAZOLECARBOXAMIDE (55)
t-BuONO
TMSN COOEt
NaOH N
MeCN MeOH
Toluene
COOEt
THF/H
A solution of compound 55A (2.5 g, 26.8 mmol) in MeCN (50 mL) was added
t-BuONO (4.15 g, 40.3 mmol) at 0 °C followed with TMSN (4.64 g, 40.3 mmol). The reaction
mixture was stirred at 20°C for 1hr. The solvent was evaporated to give intermediate compound
55B (4 g, crude) as yellow oil.
A mixture of compound 55B (4 g, crude) and compound ethyl butynoate (1
g, 8.92 mmol) in toluene (20 mL) was stirred at 110 °C for 5hrs. The solvent was evaporated.
The crude product was purified by silica gel column chromatography (Petroleum ether: Ethyl
acetate = 20: 1 ~ 5: 1) to give compound 55C (150 mg, yield: 7.27%) as yellow oil. H NMR
(400 MHz, CDCl ) δ 7.54 - 7.49 (m, 2H), 7.44 - 7.40 (m, 2H), 7.37 (d, J = 5.1 Hz, 1H), 4.25 (q, J
= 7.1 Hz, 2H), 1.21 (t, J = 7.1 Hz, 3H).
17681897_1 (GHMatters) P110989.NZ
A solution of compound 55C (150 mg, 649 umol) in THF (2 mL) and H O (2
mL) was added NaOH (51.9 mg). The reaction mixture was stirred at 20 °C for 30min. TLC
showed a new peak with higher polarity was generated. The solvent was evaporated and 1M HCl
was added until pH ~ 6. The mixture was filtered and the cake was dried to give compound 55D
(120 mg, yield: 91.0%) as a yellow solid.
Compound 55 (46 mg, 121 umol, yield: 42.0%, yellow solid) was prepared as
in Example 5 from the corresponding intermediate carboxylic acid, compound 55D. Compound
55: H NMR (400 MHz, DMSO-d ) δ 9.36 (br d, J = 7.9 Hz, 1H), 8.20 (s, 1H), 7.94 (s, 1H), 7.51
- 7.43 (m, 3H), 7.36 - 7.28 (m, 7H), 5.38 (br t, J = 7.7 Hz, 1H), 3.26 (br s, 1H), 2.82 - 2.73 (m,
1H), 2.21 (s, 3H). MS (ESI) m/z (M+H) 378.1.
EXAMPLE 29
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)METHYLPHENYL-1H-
1,2,3-TRIAZOLECARBOXAMIDE (56)
O O O
LiAlH , THF
OH O
N O N
O O N
EDCI, HOBt H
O N O
56B O
K CO , H O
CN 2 2 2
HCl / dioxane
O N H N NH
DMSO BocHN NH
Et DCM H 2
A mixture of compound 56A (1.0 g, 4.08 mmol), compound N,O-
dimethylhydroxylamine (478 mg, 4.90 mmol, HCl) , HOBt (552 mg, 4.08 mmol) and NMM
(1.24 g, 12.24 mmol, 1.35 mL) in CHCl (20 mL) was degassed and purged with N for 3 times
at 0 °C, then EDCI (1.17 g, 6.12 mmol) was added in portions. The mixture was stirred at 25 °C
for 20 hrs under N atmosphere. The reaction mixture was quenched by addition H O (20 mL),
and then diluted with DCM (10 mL). The combined organic layers were washed with 1N HCl
(15 mL x 2), saturated aqueous NaHCO (15 mL x 2) and brine (20 mL), dried over Na SO ,
3 2 4
filtered and concentrated under reduced pressure to give the compound 56B (1.15 g, yield:
97.7%) was obtained as a white solid. H NMR (400MHz, DMSO-d ) δ 6.97 (br d, J = 8.8 Hz,
1H), 4.47 (br t, J = 8.4 Hz, 1H), 3.73 - 3.64 (m, 3H), 3.06 (s, 3H), 1.51 - 1.27 (m, 11H), 0.87 (s,
9H).
17681897_1 (GHMatters) P110989.NZ
To a solution of LAH (303 mg, 7.98 mmol) in THF (10 mL) was degassed and
purged with N for 3 times at 0 °C , and the mixture of compound 56B (1.15 g, 3.99 mmol) in
THF (20 mL) was added dropwise, and then the mixture was stirred at 0 °C for 2 hrs under N
atmosphere. The reaction mixture was quenched by add EtOAc (10 mL), then add 1N HCl (50
mL), and then diluted with EtOAc (20 mL), dried over Na SO , and stirred for 30 min, then
filtered to give the organic layers. The combined organic layers were washed with brine (20 mL
x 2), dried over Na SO , filtered and concentrated under reduced pressure to give the compound
56C (900 mg, yield: 98.4%) was obtained as a white solid. H NMR (400MHz,CDCl ) δ 9.55 (s,
1H), 4.83 (br s, 1H), 4.24 (br s, 1H), 1.86 - 1.55 (m, 2H), 1.44 (s, 9H), 1.03 - 0.91 (m, 9H).
To a solution of compound 56C (900 mg, 3.92 mmol) in DCM (20 mL) was
added compound 2-hydroxymethylpropanenitrile (2.33 g, 27.32 mmol, 2.50 mL) and Et N
(595 mg, 5.88 mmol, 815 uL). The mixture was stirred at 25 °C for 2 hrs. The reaction mixture
was quenched by addition 1N HCl (20 mL), and then diluted with H O (20 mL) and extracted
with DCM (20 mL x 2). The combined organic layers were washed with brine (20 mL x 3),
dried over Na SO , filtered and concentrated under reduced pressure to give the compound 56D
(930 mg, yield: 92.55%) was obtained as a white solid. H NMR (400MHz, CDCl ) δ 5.06 - 4.66
(m, 1H), 4.55 - 4.35 (m, 1H), 4.05 - 3.73 (m, 1H), 1.80 - 1.65 (m, 2H), 1.45 (br d, J = 6.8 Hz,
9H), 1.10 - 0.80 (m, 9H).
To a solution of compound 56D (930 mg, 3.63 mmol) and K2CO3 (1.00 g, 7.26
mmol) in DMSO (15 mL) was added H O (4.12 g, 36.30 mmol, 3.49 mL, purity: 30%). The
mixture was stirred at 0 °C for 2 hrs. The reaction mixture was diluted with H O (50 mL) and
extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine (30
mL x 2), dried over Na SO , filtered and concentrated under reduced pressure to give a residue.
The residue was stirred in DCM (0.1 mL) and PE (5 mL) for 30 min and filtered to give the
compound 56E (480 mg, yield: 48.20%) was obtained as a white solid. H NMR
(400MHz,CDCl ) δ 6.83 (br s, 1H), 5.65 (br s, 1H), 5.27 - 5.06 (m, 1H), 4.99 - 4.82 (m, 1H),
4.23 - 4.00 (m, 1H), 3.88 (br t, J=8.6 Hz, 1H), 1.77 (br s, 1H), 1.60 - 1.51 (m, 1H), 1.42 (d, J =
9.3 Hz, 9H), 0.94 (d, J = 10.1 Hz, 9H).
To a solution of compound 56E (480 mg, 1.75 mmol) in EtOAc (5 mL) was
added HCl/EtOAc (4M, 5 mL). The mixture was stirred at 25 °C for 1 h. The reaction mixture
17681897_1 (GHMatters) P110989.NZ
was diluted with PE (20 mL), filtered and concentrated under reduced pressure to give the
compound 56F (360 mg, yield: 97.63%, HCl) was obtained as a white solid. H NMR (400MHz,
DMSO-d ) δ 8.00 (br s, 1H), 7.92 - 7.70 (m, 1H), 7.58 - 7.41 (m, 2H), 4.21 - 3.93 (m, 1H), 3.33
(br d, J=3.5 Hz, 2H), 1.76 - 1.24 (m, 2H), 0.86 (s, 9H).
Compound 56 (94.20 mg, yield: 85.26%, white solid) was prepared as in
Example 35 from the corresponding intermediate compounds, 23A and 56F. Compound 56: H
NMR (400MHz, DMSO-d ) δ 8.98 - 8.61 (m, 1H), 8.20 - 7.95 (m, 1H), 7.85 - 7.71 (m, 2H), 7.57
- 7.37 (m, 3H), 5.25 (br t, J = 6.8 Hz, 1H), 2.35 - 2.20 (m, 3H), 1.63 - 1.28 (m, 2H), 0.98 - 0.76
(m, 9H). MS (ESI) m/z (M+H) 358.2.
EXAMPLE 30
(S)-N-(4-AMINO(1H-INDOLYL)-3,4-DIOXOBUTANYL)METHYL
PHENYLISOXAZOLECARBOXAMIDE (57)
NH NH
NH O
LiAlH THF
OH EDCI, HOBt, NMM
57B 57C
NH NH
K CO , H O ,
2 3 2 2
HCl/dioxane
OH OH
DMSO
BocHN H N
57E 57F
A mixture of compound 57A (5.00 g, 16.43 mmol), compound N,O-
dimethylhydroxylamine (1.76 g, 18.07 mmol, HCl), HOBt (2.22 g, 16.43 mmol) and NMM (4.99
g, 49.29 mmol, 5.42 mL) in CHCl (150 mL) was degassed and purged with N for 3 times at 0
°C, then EDCI (4.72 g, 24.65 mmol) was added in portions, and then the mixture was stirred at
°C for 23 hrs under N atmosphere. The reaction mixture was quenched by addition H O (100
mL), and then diluted with 1N HCl (200 mL) and extracted with NaHCO (50 mL x 2). The
combined organic layers were washed with brine (200 mL), dried over Na SO , filtered and
concentrated under reduced pressure to give a residue. The residue was purified by column
chromatography (SiO , Petroleum ether/Ethyl acetate = 6/1 to 1/1) to give the compound 57B
(5.94 g) was obtained as a yellow solid. H NMR (400MHz, DMSO-d ) δ 10.79 (br s, 1H), 7.50
17681897_1 (GHMatters) P110989.NZ
(d, J = 7.7 Hz, 1H), 7.32 (d, J = 8.2 Hz, 1H), 7.19 - 7.11 (m, 1H), 7.07 - 6.96 (m, 3H), 4.59 (br s,
1H), 3.70 (br s, 3H), 3.10 (s, 3H), 3.03 - 2.94 (m, 1H), 2.89 - 2.77 (m, 1H), 1.29 (s, 9H).
To a solution of LAH (330 mg, 8.64 mmol) in THF (10 mL), and then
compound 57B (2.00 g, 5.76 mmol) in THF (20 mL) was added dropwise. The mixture was
stirred at 0 °C for 2 hrs. The reaction mixture was quenched by addition EtOAc (10 mL) at 0°C,
and then diluted with 1N HCl (40 mL) and extracted with EtOAc (20 mL x 2). The combined
organic layers were washed with 1N HCl (40 mL) and NaHCO (30 mL x 2) and brine (100 mL),
dried over Na SO , filtered and concentrated under reduced pressure to give the compound 57C
(1.55 g, yield: 93.33%) was obtained as a yellow solid. H NMR (400MHz, DMSO-d ) δ 11.02 -
.75 (m, 1H), 9.52 (s, 1H), 7.50 (br d, J = 7.7 Hz, 1H), 7.32 (d, J = 7.9 Hz, 1H), 7.25 (br d, J =
7.3 Hz, 1H), 7.14 (d, J = 1.8 Hz, 1H), 7.05 (t, J = 7.2 Hz, 1H), 7.00 - 6.92 (m, 1H), 4.14 - 4.05
(m, 1H), 3.19 - 3.10 (m, 1H), 2.95 - 2.85 (m, 1H), 2.52 - 2.45 (m, 4H), 1.39 - 1.23 (m, 9H).
To a solution of compound 57C (1.50 g, 5.20 mmol) in DCM (30.00 mL) was
added compound N,O-dimethylhydroxylamine (885 mg, 10.40 mmol, 960 uL) and Et N (790 mg,
7.80 mmol, 1.08 mL). After stirred at 25 °C for 20 hrs, the reaction mixture was quenched by
addition 0.5N HCl 30 mL, and then extracted with DCM (30 mL x 2). The combined organic
layers were washed with brine (30 mL x 2), dried over Na SO , filtered and concentrated under
reduced pressure. Compound 57D (1.74 g, yellow solid): H NMR (400MHz, CDCl ) δ 9.64 (s,
1H), 8.14 (br s, 1H), 7.60 (d, J = 7.7 Hz, 1H), 7.37 (d, J = 8.2 Hz, 1H), 7.24 - 7.18 (m, 1H), 7.17
- 7.11 (m, 1H), 7.03 (d, J = 2.2 Hz, 1H), 5.14 (br s, 1H), 4.51 (br d, J = 6.6 Hz, 1H), 3.41 - 3.16
(m, 2H), 1.44 (s, 9H).
To a solution of compound 57D (1.74 g, 5.52 mmol) and K CO (1.53 g, 11.04
mmol) in DMSO (25.00 mL) was added H O (6.43 g, 189.00 mmol, 5.45 mL) at 0 °C. The
mixture was stirred at 0 °C for 1 h. The reaction mixture was diluted with H O (50 mL), and
then quenched by addition Na S O (50 mL) and extracted with EtOAc (50 mL x 3) and
2 2 3
Na S O3 (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over
Na SO , filtered and concentrated under reduced pressure to give a residue. The residue was
purified by column chromatography (SiO , Petroleum ether/Ethyl acetate = 1/2 to 0:1) to give the
compound 57E (689.60 mg, yield: 37.47%) was obtained as a yellow solid. H NMR
(400MHz,CDCl ) δ 8.06 (br s, 1H), 7.70 (d, J = 8.3 Hz, 1H), 7.38 (d, J = 7.8 Hz, 1H), 7.25 - 7.06
17681897_1 (GHMatters) P110989.NZ
(m, 4H), 5.42 (br s, 1H), 5.19 - 5.04 (m, 1H), 4.21 - 4.08 (m, 3H), 3.30 - 3.12 (m, 2H), 1.41 (s,
9H).
To a solution of compound 57E (680.00 mg, 2.04 mmol) in EtOAc (5.00 mL)
was added HCl/EtOAc (5.00 mL). The mixture was stirred at 25 °C for 2.5 hrs. The reaction
mixture was concentrated under reduced pressure to remove solvent to give the compound 57F
(400.00 mg, yield: 72.69%, HCl) was obtained as a brown solid. H NMR (400MHz, DMSO-d )
δ 11.01 (br s, 1H), 7.92 (br s, 2H), 7.70 - 7.46 (m, 3H), 7.39 - 7.26 (m, 2H), 7.12 - 6.95 (m, 2H),
4.01 - 3.89 (m, 1H), 3.81 - 3.64 (m, 1H), 3.14 (s, 2H), 3.08 - 2.80 (m, 2H).
Compound 57 (11.20 mg, yield: 29.41%, white solid) was prepared as in
Example 15 from the corresponding intermediate compounds, 23A and 57F. Compound 57: H
NMR (400MHz, DMSO-d ) δ 10.89 (br s, 1H), 9.03 (d, J = 7.3 Hz, 1H), 8.23 (s, 1H), 7.95 (s,
1H), 7.70 (d, J = 7.8 Hz, 1H), 7.63 (d, J = 7.5 Hz, 2H), 7.48 (br d, J = 7.5 Hz, 1H), 7.39 (t, J =
7.4 Hz, 3H), 7.17 (d, J = 1.8 Hz, 1H), 7.13 - 6.96 (m, 2H), 5.56 (br s, 1H), 2.97 - 2.87 (m, 1H),
2.70 - 2.54 (m, 1H), 2.11 (s, 3H). MS (ESI) m/z (M+H) 417.1.
EXAMPLE 31
(S)-N-(4-AMINO(1H-INDOLYL)-3,4-DIOXOBUTANYL)METHYL
PHENYLISOXAZOLECARBOXAMIDE (58)
HCl HN O
HN(Me)OMe LiAlH THF
HN O
HN O
EDCI HOBT
O 58c
K CO , H O HCl/EtOAc
2 3 2 2
BocHN
TEA DCM
BocHN
DMSO
O NH
2 O NH
To a solution of N-methoxymethanamine (1.89 g 19.42 mmol), compound
58A (5.0 g, 17.65 mmol), HOBt (2.38 g, 17.65 mmol) and NMM (52.95 mmol, 5.8 mL) in
CHCl (100 mL) was degassed and purged with N for 3 times at 0 °C, then EDCI (5.1 g, 26.48
mmol) was added in portions. The mixture was stirred at 25 °C for 16 hrs under N atmosphere.
The reaction mixture was washed with H O (100 mL). The organic layers were washed with
17681897_1 (GHMatters) P110989.NZ
1mol/L HCl (100 mL x 2), saturated NaHCO (100 mL x 2) and saturated brine (100ml), dried
over Na SO , filtered and concentrated under reduced pressure to give a residue. The residue
was purified by flash silica gel chromatography (ISCO®;80 g SepaFlash® Silica Flash Column,
Eluent of 0 ~ 30% Ethyl acetate/Petroleum ether gradient @ 40mL/min) to afford compound 58B
(4.00 g, yield 69.4%) as white solid. H NMR (400MHz,CDCl ) δ 7.11 (dd, J=5.6, 8.3 Hz, 2H),
6.94 (t, J=8.7 Hz, 2H), 5.18 (br d, J=7.9 Hz, 1H), 4.98 - 4.80 (m, 1H), 4.13 - 4.07 (m, 2H), 3.72 -
3.64 (m, 4H), 3.14 (s, 3H), 3.08 - 2.94 (m, 1H), 2.91 - 2.70 (m, 1H), 2.02 (s, 2H), 1.78 (br s, 1H),
1.37 (s, 10H), 1.28 - 1.20 (m, 3H).
To LiAlH (128 mg 3.37 mmol) in 100 mL of dry flask was added dropwise
THF (15 mL) at 0 °C. After addition, the mixture was stirred at this temperature, and then a
solution of compound 58B (1.0 g 3.06 mmol) in THF (15 mL) was added dropwise to the above
mixture at 0 °C. The resulting mixture was stirred at 0 °C for 1.5 hrs. The reaction mixture was
quenched by slowly added EtOAc (20 mL) at 0 °C, and then added 1N HCl (20 mL) and
extracted with EtOAc (30 mL x 2). The combined organic layers were washed with NaHCO (30
mL x 2) and brine (20 mL), dried over Na SO , filtered and concentrated under reduced pressure
to give the compound 58C (810 mg, yield 99.0%) as white solid. H NMR (400MHz,CDCl ) δ
9.65 (br s, 1H), 9.63 (br s, 1H), 7.21 - 7.08 (m, 2H), 7.00 (br d, J=8.6 Hz, 2H), 5.05 (br s, 1H),
4.42 (br s, 1H), 3.09 - 3.02 (m, 1H), 3.11 (br d, J=6.2 Hz, 1H), 1.51 - 1.38 (m, 9H).
To a solution of compound 58C (3.2 g, 11.86 mmol) and 2-hydroxymethyl-
propanenitrile (2.2 mL, 23.72 mmol) in DCM (30 mL) was added TEA (2 mL, 14.23 mmol).
After addition, the reaction mixture was stirred at 28 °C for 14 hrs. The reaction mixture was
diluted with 30 mL of DCM and the mixture was quenched by addition 0.5N HCl 30 mL. The
organic layer were washed with H O (30 mL) and brine (50mL), dried over Na SO , filtered and
2 2 4
concentrated under reduced pressure to give compound 58D (3.4 g, yield 89.2%) as a white solid.
H NMR (400MHz, CDCl ) δ 7.15 - 7.07 (m, 2H), 7.01 - 6.90 (m, 2H), 4.94 - 4.70 (m, 1H), 4.52
- 4.36 (m, 1H), 4.16 - 3.67 (m, 1H), 3.11 - 2.78 (m, 2H), 1.57 - 1.47 (m, 2H).
To a solution of compound 58D (3.42 g 11.62 mmol) and K CO (3.21 g,
23.24 mmol) in DMSO (30 mL) was added H O (395.08 mmol, 12 mL,) at 0 °C. After addition,
the reaction mixture was stirred at 0 °C for 1.5 hrs. The reaction mixture was diluted with water
(100 mL) and quenched with saturated aqueous Na S O slowly into ice water. The mixture was
2 2 3
17681897_1 (GHMatters) P110989.NZ
extracted with EtOAc (200 mL x 3) and the combined extracts were washed with saturated
aqueous Na S O (100 mL x 3). The organic layer was dried over Na SO , concentrated and to
2 2 3 2 4
yield a residue. The residue was diluted with EtOAc (10 mL) and filtered to give the compound
58E (2.25 g, yield 61.99%) as a white solid. H NMR (400MHz, DMSO-d ) δ 7.25 (br s, 6H),
6.62 - 6.03 (m, 1H), 5.75 - 5.55 (m, 1H), 4.02 - 3.67 (m, 2H), 2.80 - 2.52 (m, 2H), 2.52 - 2.51 (m,
1H), 1.26 (d, J=3.7 Hz, 9H). MS (ESI) m/z (M +Na ) 334.9.
To a solution of compound 58E (1 g 3.20 mmol) in EtOAc (10 mL) was added
HCl/EtOAc (4 mmol, 20 mL). The mixture was stirred at 28 °C for 2 hrs. The reaction mixture
diluted with MTBE and filtered to give the compound 58F (750 mg, yield 94.25%) as white
solid. H NMR (400MHz, DMSO-d ) δ 8.25 - 7.94 (m, 3H), 7.58 - 7.43 (m, 2H), 7.41 - 7.33 (m,
1H), 7.30 - 7.23 (m, 1H), 7.41 - 7.23 (m, 1H), 7.20 - 7.05 (m, 2H), 6.90 - 6.37 (m, 1H), 6.80 -
6.25 (m, 1H), 4.24 (br s, 1H), 3.88 - 3.81 (m, 1H), 3.85 (br s, 1H), 3.68 - 3.50 (m, 1H), 2.96 -
2.76 (m, 2H). MS (ESI) m/z (M +H) 213.1.
Compound 58 (130 mg, yield 78.40%, light yellow solid) was prepared as in
Example 15 from the corresponding intermediate compounds, 23A and 58F. Compound 58: H
NMR (400MHz, DMSO-d ) δ 9.05 (d, J=7.7 Hz, 1H), 8.20 (br s, 1H), 7.93 (brs, 1H), 7.66 - 7.59
(m, 2H), 7.55 - 7.49 (m, 1H), 7.48 - 7.41 (m, 2H), 7.35 - 7.26(m, 2H), 7.17 - 7.06 (m, 2H), 5.51 -
.40 (m, 1H), 3.28 - 3.19 (m, 1H), 2.81 - 2.69 (m, 1H), 2.11 (s, 3H). MS (ESI) m/z (M +H)
396.1.
EXAMPLE 32
(S)-N-(4-AMINO(1H-INDOLYL)-3,4-DIOXOBUTANYL)METHYL
PHENYLISOXAZOLECARBOXAMIDE (59)
O N CF
LiOH
F C N Cl N
F C N NHNH N
3 2 O
THF/H O
NH NH H O
2 2 2
HOAc
EtOH, 80 C
reflux 1h
59A 59B
To a solution of compound 59A (10 g, 55.08 mmol) in EtOH (30 mL) was
added NH NH .H O (32 mL, 550.80 mmol). After addition, the reaction mixture was stirred at
2 2 2
80 °C for 14 hrs. The reaction mixture was concentrated and the residue was dissolved into 150
mL of EtOAc, the mixture was washed with water (50 mL) and brine (50 mL), then dried over
17681897_1 (GHMatters) P110989.NZ
Na SO and concentrated in vacuum to afford compound 59B (9.7 g, yield 99.4%) as white solid.
H NMR (400MHz, DMSO-d ) δ 8.02 (s, 1H), 7.71 - 7.53 (m, 1H), 7.03 - 6.79 (m, 2H), 4.23 (s,
2H).
To a solution of compound 59B (1 g, 5.65 mmol) in AcOH (10 mL) was added
ethyl 2-methoxyiminooxo-pentanoate (1.1 g, 5.65 mmol). After addition, the reaction mixture
was stirred at 120 °C for 14 hrs. The mixture was concentrated in vacuum and the residue was
dissolved into 80 mL of EtOAc, the mixture was washed with 30 mL of saturated aqueous
NaHCO and brine (30 mL). The mixture was dried over Na SO and concentrated in vacuum.
3 2 4
The residue was purified by column chromatography (SiO , Petroleum ether/Ethyl acetate = 20/1
to 10:1) to afford desired compound 59C (1.2 g, yield: 71%) as white solid. H NMR (400MHz,
DMSO-d ) δ 8.34 - 8.25 (m, 1H), 8.05 (d, J = 8.2 Hz, 1H), 7.93 (d, J = 7.5 Hz, 1H), 6.86 (s, 1H),
4.18 (q, J = 7.1 Hz, 2H), 2.29 (s, 3H), 1.11 (t, J = 7.1 Hz, 3H). MS (ESI) m/z (M +H) 299.9.
To a solution of compound 59C (700 mg, 2.34 mmol) in THF (10 mL) was
added a solution of LiOH.H O (393 mg, 9.36 mmol) in H O (10 mL) at 0 °C. After addition, the
reaction mixture was stirred at 28 °C for 16 hrs, 20 mL of MTBE was added into the reaction
mixture, then the mixture was separated and the aqueous layer was acidified by 1N HCl to pH ~
4, the mixture was filtered to afford white solid which was dried to afford compound 59D (330
mg, yield 51.95%) as white solid. H NMR (400MHz, DMSO-d ) δ 13.48 (br s, 1H), 8.31 - 8.22
(m, 1H), 8.02- 7.89 (m, 2H), 6.81 (s, 1H), 2.27 (s, 3H). MS (ESI) m/z (M +H) 271.8.
Compound 59 (50 mg, yield: 37.9%, white solid) was prepared as in Example 5
from the corresponding intermediate carboxylic acid, compound 59D. Compound 59: H NMR
(400MHz, DMSO-d ) δ 9.07 (d, J = 7.3 Hz, 1H), 8.27 - 8.16 (m, 1H),8.04 (s, 1H), 7.89 - 7.77 (m,
3H), 7.30 - 7.19 (m, 5H), 6.59 (s, 1H), 5.40 - 5.28 (m,1H), 3.15 (dd, J = 4.0, 13.8 Hz, 1H), 2.82
(dd, J = 9.5, 13.8 Hz, 1H), 2.30 (s, 3H). MS (ESI) m/z (M +H) 446.1.
17681897_1 (GHMatters) P110989.NZ
EXAMPLE 33
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)PHENYLISOXAZOLE
CARBOXAMIDE (61)
(0.9 eq) N
LiOH.H O
Sn(n-Bu)
MeOH/H O
Pd(PPh3)4 (0.05 eq),
32 °C, 0.5 hours
dioxane, 110 °C, 14 hours
A mixture of compound 61B (500 mg, 2.12 mmol), compound 61A (859 mg,
2.33 mmol), Pd(PPh ) (122 mg, 106 umol) was stirred at 105 °C for 14 hours. The mixture was
concentrated. The residue was purified by column chromatography (SiO , Petroleum ether/Ethyl
acetate = 3/1 to 1/1) to afford compound 61C (376 mg, 74.95% yield) as yellow oil. MS (ESI)
m/z (M+H) 234.9.
To a solution of compound 61C (320 mg, 1.37 mmol) in MeOH (20 mL) was
added LiOH.H O (144 mg, 3.43 mmol). The mixture was stirred at 32 °C for 0.5 h. MeOH was
evaporated. To the residue was added water (20 mL). The mixture was extracted with MTBE (5
mL) and separated. The aqueous layer was acidified to pH~ 3 with 1N HCl and extracted with
Ethyl Acetate (3 x 20 mL). The combined organic layers were dried over Na SO and
concentrated to afford compound 61D (220 mg, 77.9% yield) as white solid.
Compound 61 (21.8 mg, 21.78% yield, white solid) was prepared as in
Example 20 from the corresponding intermediate carboxylic acid, compound 61D. Compound
61: H NMR (400MHz, DMSO-d ) δ 13.06 - 12.79 (m, 1H), 9.27 (s, 1H), 8.95 - 8.84 (m, 1H),
8.42 - 8.32 (m, 1H), 8.32 - 8.24 (m, 1H), 8.13 - 8.00 (m, 1H), 7.55 - 7.45 (m, 1H), 7.21 - 7.10 (m,
3H), 7.22 - 7.03 (m, 2H), 5.70 - 5.59 (m, 1H), 3.32 - 3.25 (m, 1H), 3.20 - 3.12 (m, 1H), 2.85 -
421.1.
2.74 (m, 1H), 0.72 - 0.63 (m, 2H), 0.63 - 0.54 (m, 2H). MS (ESI) m/z (M+H)
EXAMPLE 34
(S)-N-(1-amino-1,2-dioxoheptanyl)methylphenylisoxazolecarboxamide (62)
17681897_1 (GHMatters) P110989.NZ
•HCl OH
(1.15
LiAlH
4 (1.2 eq)
EDCI , HOBt, CHCl
BocHN O
BocHN
Et N DCM
BocHN
3 (1.2 eq),
4-METHYLMORPHOLINE 0 °C, 2 hrs
°C 16 hr
0 - 25 °C, 16.5 hrs
K CO H O HCl/dioxane
eq) O eq)
2 3 (2 eq), 2 2 (34.1 (5.2
H N NH
•HCl
DMSO dioxane 2 2
BocHN
BocHN 2
0 °C, 1 hr -
32 °C, 2 hr
62D 62E
To a mixture of compound 62A (2 g, 8.65 mmol) and compound N,O-
dimethylhydroxylamine hydrochloride (970.3 mg, 9.95 mmol), HOBt (1.34g, 9.95 mmol) in
CHCl (40 mL) was added dropwise 4-methylmorpholine (2.62 g, 25.95 mmol) and EDCI (2.32
g, 12.11 mmol) in portion at 0 °C under N atmosphere. The mixture was stirred at 0 °C for 30
min, and then the mixture was stirred at 25 °C for 16 hours. The reaction mixture was diluted
with H O (5 mL). The two layers were separated and the aqueous phase was extracted with EA
(5 mL x 2). The combined organic layers were washed with 0.5 N HCl (5 mL x 2) and NaHCO
(5 mL x 2), dried over Na SO , filtered and concentrated under reduced pressure to give
compound 62B (1.7 g, yield 71.7%) as colorless oil. H NMR (CDCl 400 MHz): δ 5.19 - 5.06
(m, 1H), 4.66 (br s, 1H), 3.77 (s, 3H), 3.20 (s, 3H), 1.76 - 1.66 (m, 1H), 1.55 - 1.39 (m, 10H),
1.37 - 1.28 (m, 4H), 0.93 - 0.83 (m, 3H). MS (ESI) m/z (M – Boc + H) 175.0.
To a solution of LiAlH (258.7 mg, 6.82 mmol) in THF (36 mL) was added
drop wise a solution of compound 62B (1.7 g, 6.2 mmol) in THF (18 mL) at 0 °C under N
atmosphere. After addition, the reaction mixture was stirred at 0 °C for 2 hours. The mixture
was diluted with ethyl acetate (100 mL), washed with 1N HCl (20 mL), saturated NaHCO (20
mL x 2), brine (15 mL). The organic layer was dried over anhydrous Na SO and concentrated to
give compound 62C (1.5 g, crude) as yellow oil. H NMR (CDCl 400 MHz) δ 9.58 (s, 1H),
.03 (br s, 1H), 4.28 - 4.16 (m, 1H), 1.58 - 1.19 (m, 15H), 1.01 - 0.80 (m, 3H).
A solution of compound 62C (1.5 g, 6.97 mmol), compound 2-hydroxy
methylpropanenitrile (1.3 mL, 13.94 mmol) and Et N (1.16 mL, 8.36 mmol) in dry DCM (30
mL) was stirred at 30 °C for 16 hours. The reaction mixture was diluted with DCM (50 mL),
washed with 0.5 N HCl (20 mL), water (20 mL)and brine(20 mL). The
17681897_1 (GHMatters) P110989.NZ
organic phase was dried over Na SO , concentrated. The residue was purified by column
chromatography (SiO , Petroleum Ether/Ethyl Acetate = 5/1 to 3:1) to afford compound 62D
(1.12 g, 66.32% yield) as white solid. H NMR (400MHz, CDCl ) δ 5.44 - 4.34 (m, 3H), 3.94 -
3.83 (m, 1H), 3.74 - 3.61 (m, 1H), 3.98 - 3.55 (m, 1H), 1.66 - 1.28 (m, 14H), 0.99 - 0.90 (m, 3H).
The mixture of compound 62D (1.12 g, 4.62 mmol) and K CO (1.28 g, 9.24
mmol) in DMSO (18 mL) was added H O (4.6 mL, 158.19 mmol) at 0 °C. After addition, the
reaction mixture was stirred at 0 °C for 1h. After the reaction, MTBE (20 mL) was added to the
reaction mixture, and the resulting mixture was filtered and the solid was washed with MTBE
(30 mL) to afford compound 62E (1.1 g, 91.46% yield) as white solid. H NMR (400MHz,
DMSO-d ) δ 7.32 - 7.08 (m, 2H), 6.42 - 5.86 (m, 1H), 5.54 - 5.30 (m, 1H), 3.88 - 3.59 (m, 2H),
1.42 - 1.21 (m, 15H), 0.92 - 0.78 (m, 3H).
The solution of compound 62E (600 mg, 20.82 mmol) in dioxane (10 mL) was
added HCl/dioxane (3 mL ,4M) at 25 °C. The reaction mixture was stirred at 25 °C for 2 hours.
The mixture was filtered to afford compound 62F (320 mg, 70.7%, yield, HCl) was obtained as
white solid. H NMR (400 MHz, DMSO-d ) δ 7.90 (br s, 2H), 7.54 - 7.35 (m, 2H), 6.26 - 6.17
(m, 1H), 4.09 (br s, 1H), 1.66 - 1.37 (m, 2H), 1.37 - 1.12 (m, 5H), 0.93 - 0.72 (m, 3H)
Compound 62 (9.1 mg, yield: 38.6%, white solid) was prepared as in Example
from the corresponding intermediate compounds, 23A and 62F. Compound 62: H NMR
(CDCl 400 MHz): δ 7.84-7.67 (m, 2H), 7.57 - 7.43 (m, 3H), 6.73 (s, 1H), 6.17-6.03 (m, 1H),
.52 – 5.29 (m, 2H), 2.46 ( s, 3H), 1.99 - 1.84 (m, 1H), 1.41-1.04 (m, 5H), 0.90-0.78 (m, 3H).
MS (ESI) m/z (M+H)+ 344.1.
EXAMPLE 35
COMPOUNDS 63, 454
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)METHYL(PYRAZIN
YL)-1H-PYRAZOLECARBOXAMIDE (63)
LiOH.H O
eq) O
eq) 2 (4
N NH N
2 HOAc
MeOH/H O
2 OH
120 °C, 1 hr
31 °C 1 hr
17681897_1 (GHMatters) P110989.NZ
To a solution of compound methyl 2,4-dioxopentanoate (100 mg, 693.82
umol) in AcOH (20 mL) was added compound 63A (76.4 mg, 693.82 umol). The mixture was
stirred at 120 °C for 1 hour. The mixture was in DCM (5 mL). The organic layer was washed
with water (10 mL), NaHCO to pH ~ 8~9 and dried over Na SO and concentrated to afford
3 2 4
compound 63B (500 mg, 25.24% yield) as white solid.
To a solution of compound 63B (61 mg, 279.55 umol, ) in MeOH (6 mL) and
H O (1 mL) was added LiOH.H O (46.9 mg, 1.12 mmol). The mixture was stirred at 31 °C for
1h. MeOH was evaporated. To the residue was added water (10 mL) and the mixture was
extracted with MTBE (5 mL) and separated. The aqueous layer was acidified to pH ~ 3 with 1N
HCl and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were dried over
Na SO and concentrated to afford the product. (50 mg, 87.59% yield) as white solid.
Compound 63 (25.1 mg, 63.1% yield, white solid) was prepared as in Example
from the corresponding intermediate carboxylic acid, compound 63C. Compound 63: H NMR
(400MHz, CDCl ) δ 9.16 (s, 2 H), 9.08- 8.97 (m, 1H), 8.44 (s, 1H), 7.95 (s, 1H), 7.20 (s, 3 H),
7.08 (s, 2H), 5.78 (m, 1H), 5.54 (s, 1H), 3.45 (m, 1H), 3.38 - 3.24 (m, 1H), 2.36 (s, 3H). MS
(ESI) m/z (M+H) 379.1.
N-(4-(CYCLOPROPYLAMINO)-3,4-DIOXOPHENYLBUTANYL)METHYL
(PYRAZINYL)-1H-PYRAZOLECARBOXAMIDE (454)
Compound 454 (210 mg, 91.7% yield, white solid) was prepared as in
compound 12 from the corresponding intermediate carboxylic acid, compound 63C and 3-amino-
N-cyclopropylhydroxyphenylbutanamide hydrochloride. Compound 454: H NMR
(400MHz, DMSO-d ) δ 9.07 (d, J = 7.2 Hz, 1H), 8.84 - 8.77 (m, 2H), 8.57 (d, J = 2.8 Hz, 1H),
8.31 - 8.27 (m, 1H), 7.30 - 7.17 (m, 5H), 6.64 (s, 1H), 5.33 - 5.25 (m, 1H), 3.17 - 3.09 (m, 1H),
2.83 - 2.70 (m, 2H), 2.27 (s, 3H), 0.69 - 0.53 (m, 4H). MS (ESI) m/z (M+H) 419.2.
17681897_1 (GHMatters) P110989.NZ
EXAMPLE 36
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)METHYL(3-
METHYLPYRIDINYL)-1H-PYRAZOLECARBOXAMIDE (66)
NH •HCl
O LiOH H
O MeOH:H O
2 (2:1) OH
HOAc, 120 °C, 1.5 hr
°C, 1 hrs 66C
A mixture of compound 2-hydrazinylmethylpyridine hydrochloride (2 g,
12.53 mmol) and compound 66A (1.81 g, 12.53 mmol) in AcOH (30 mL) was degassed and
purged with N for 3 times, and then stirred at 120 °C for 1.5 hrs under N atmosphere. The
resultant mixture was concentrated under reduced pressure to remove AcOH and diluted with
DCM (10 mL), neutralized with saturated aqueous NaHCO . The mixture was extracted with
DCM (20 mL x 3) and the combined organic layers were dried over anhydrous Na SO , filtered
and concentrated under reduced pressure to give a residue, which was purified by flash silica gel
chromatography (Petroleum ether : Ethyl acetate = 1:0 to 0:1) to afford compound 66B (800.0
mg, 27.6% yield) as a white solid and compound 66B-1 (110.0 mg, 4.04% yield) as a white solid
and crude 66B-1 (~ 800.0 mg).
Compound 66B: Methyl 3-methyl(3-methylpyridinyl)-1H-pyrazole
carboxylate: H NMR (CDCl , 400 MHz) δ 8.42 - 8.37 (m, 1H), 7.70 (d, J = 7.6 Hz, 1H), 7.33 (d,
J = 7.6 Hz, 1H), 6.79 (s, 1H), 3.74 (s, 3H), 2.38 (s, 3H), 2.14 (s, 3H).
Compound 66B-1: Methyl 5-methyl(3-methylpyridinyl)-1H-pyrazole
carboxylate: H NMR (CDCl , 400 MHz) δ 8.42 (d, J =3.6 Hz, 1H), 7.72 (d, J=6.8 Hz, 1H), 7.34
(d, J = 7.6 Hz, 1H), 6.74 (s, 1H), 3.92 (s, 3H), 2.26 (s, 3H), 2.20 (s, 3H).
To a mixture of compound 66B (200.0 mg, 864.86 umol) in MeOH (10 mL)
and H O (5 mL) was added LiOH•H O (145.2 mg, 3.46 mmol) in one portion. After stirred at 25
°C for 1 hour, the reaction mixture was concentrated under reduced pressure to remove MeOH.
O (10 mL), adjusted to pH ~ 3 with 1N HCl, and then extracted
The residue was diluted with H2
with EtOAc (40 mL x 3). The combined organic layers were washed with brine (30 mL), dried
over anhydrous Na SO , filtered and concentrated under reduced pressure to give compound 66C
(150 mg, 79.84% yield, white solid). Compound 66C: H NMR (DMSO-d 400 MHz) δ 13.11
17681897_1 (GHMatters) P110989.NZ
(br s, 1H), 8.31 (d, J = 3.7 Hz, 1H), 7.84 (d, J = 7.3 Hz, 1H), 7.47 -7.40 (m, 1H), 6.78 (s, 1H),
2.25 (s, 3H), 2.03 (s, 3H). MS (ESI) m/z (M+1) 218.1.
Compound 66 (24.5 mg, 54.7% yield, white solid) was prepared as in Example
from the corresponding intermediate carboxylic acid, compound 66C. Compound 66: H NMR
(CDCl 400 MHz) δ 8.23 (d, J = 3.6 Hz, 1H), 7.67 (d, J = 7.2 Hz, 1H), 7.34 (d, J = 7.2 Hz, 1H),
7.27 (br s, 1H), 7.25 - 7.21 (m, 3H), 7.04 - 6.99 (m, 2H), 6.70 (br s, 1H), 6.57 (s, 1H), 5.65 - 5.6
(m, 1H), 5.57 ( br s, 1H), 3.37 - 3.29 (m, 1H), 3.2 - 3.14 (m, 1H), 2.34 (s, 3H), 2.17 (s, 3H). MS
(ESI) m/z (M+H) 392.2.
EXAMPLE 37
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)(1-PHENYL-1H-PYRAZOL
YL)-1H-IMIDAZOLECARBOXAMIDE (68)
NaOH
TOSMIC N
K CO N N
TEA / DCM THF H O
N 2 3
THF O
EtOH
68C H
To a solution of 68A (15 g, 181 mmol) in THF (200 mL) was added ethyl 2-
oxoacetate (47.9 g, 235 mmol). The mixture was stirred at 25 °C for 0.5 h. The reaction mixture
was filtered and concentrated under reduced pressure to give intermediate compound 68B (55.3
g, crude) as brown solid. MS (ESI) m/z (M+H) 167.8.
To a solution of 68B (40 g, 239 mmol) in EtOH (400 mL) was added K CO
(50 g, 362 mmol) and TosMIC (40 g, 204.88 mmol). The mixture was stirred at 90 °C for 0.5 h.
The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The
residue was purified by column chromatography (SiO , Petroleum ether: Ethyl acetate = 1: 0 to 5:
2) to afford compound 68C (12 g, yield: 24.3%) as brown solid. H NMR (400 MHz, CDCl ) δ
11.80 - 11.35 (m, 1H), 7.87 (d, J = 1.10 Hz, 1H), 7.84 (d, J = 1.10 Hz, 1 H), 7.58 (d, J = 2.43 Hz,
1H), 6.45 (d, J = 2.43 Hz, 1H), 4.25 (q, J = 7.06 Hz, 2H), 1.29 (t, J = 7.17 Hz, 3H). MS (ESI)
m/z (M+H) 207.0.
A mixture of 68C (5 g, 24.3 mmol), phenylboronic acid (4.4 g, 36.4 mmol),
Cu(OAc) (4.4 g, 24.3 mmol), TEA (7.4 g, 72.8 mmol) in DCM (200 mL) was degassed and
17681897_1 (GHMatters) P110989.NZ
purged with O for 3 times, and then the mixture was stirred at 25 °C for 10 hours under O
atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to give a
residue. The residue was purified by column chromatography (SiO , Petroleum ether: Ethyl
acetate = 1: 0 to 2: 1). Compound 68D (2.3 g, yield: 33.6%) was obtained as a white solid. H
NMR (400MHz, CDCl ) δ 8.04 - 7.94 (m, 2H), 7.87 (s, 1H), 7.71 (br d, J = 7.7 Hz, 2H), 7.49 (br
t, J = 7.1 Hz, 2H), 7.36 (br d, J = 7.1 Hz, 1H), 7.27 (d, J = 2.0 Hz, 2H), 6.70 - 6.61 (m, 1H), 4.29
(dd, J = 2.1, 7.2 Hz, 2H), 1.38 - 1.22 (m, 3H). MS (ESI) m/z (M+H) 282.9.
To a solution of 68D (2.5 g, 8.86 mmol) in THF (30 mL) and H O (6 mL) was
added NaOH (708 mg, 17.7mmol). The mixture was stirred at 80°C for 1.5 hour. The reaction
mixture was concentrated under reduced pressure to remove THF, and then washed with EtOAc
(20 mL). The aqueous layer was acidized with 1M HCl to pH ~ 5 and then extracted with EtOAc
(30 mL x 3). The combined organic layer was washed with H O (40 mL), brine (40 mL), dried
over Na SO , filtered and concentrated to afford crude intermediate compound 68E (1.90 g,
yield: 84.3%) as yellow solid. H NMR (400MHz, DMSO-d ) δ 8.62 (d, J = 2.6 Hz, 1H), 8.19 (s,
1H), 7.86 (d, J = 7.9 Hz, 2H), 7.76 (s, 1H), 7.53 (t, J = 7.9 Hz, 2H), 7.39 - 7.31 (m, 1H), 6.77 (d,
J = 2.6 Hz, 1H). MS (ESI) m/z (M+H) 254.9.
Compound 68 (33.5 mg, yield: 42.1%, white solid) was prepared as in
Example 5 from the corresponding intermediate carboxylic acid, compound 68E. Compound 68:
H NMR (400 MHz, DMSO-d ) δ 8.86 (d, J = 7.7 Hz, 1 H), 8.51 (d, J = 2.6 Hz, 1 H), 8.10 (d, J
= 0.9 Hz, 1 H), 8.06 (s, 1 H), 7.79 (dd, J = 8.7, 1.0 Hz, 3 H), 7.60 (d, J = 0.9 Hz, 1 H), 7.46 - 7.53
(m, 2 H), 7.30 - 7.36 (m, 1 H), 7.24 - 7.29 (m, 4 H), 7.16 - 7.23 (m, 1 H), 6.44 (d, J = 2.6 Hz, 1
H), 5.23 - 5.32 (m, 1 H), 3.17 (dd, J = 13.8, 3.9 Hz, 1 H), 2.83 (dd, J = 13.9, 10.4 Hz, 1 H). MS
(ESI) m/z (M+H) 429.1.
EXAMPLE 38
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)(1H-INDAZOLYL)-1H-
IMIDAZOLECARBOXAMIDE (69)
HN NaOH
TOSMIC O
K CO /EtOH O
N 80 C
17681897_1 (GHMatters) P110989.NZ
To a solution of 69A (8.7 g, 65.3 mmol) in MeOH (90 mL) was added ethyl 2-
oxoacetate (20 g, 98.01 mmol). The mixture was stirred at 25 °C for 2 hours. The mixture was
filtered and concentrated to give intermediate compound 69B (15 g, crude) as brown solid.
To a solution of 69B (15 g, 69.1 mmol) in EtOH (400 mL) was added K CO
(14.5 g, 104 mmol) and TosMIC (11.6 g 59.4 mmol). The mixture was stirred at 90 °C for 0.5
hour. The reaction mixture was filtered and concentrated under reduced pressure to give a
residue. The residue was purified by column chromatography (SiO , Petroleum ether: Ethyl
acetate = 1:0 to 1:1) to give compound 69C (2.9 g, yield: 16.4%) as a yellow solid. H NMR
(400MHz, CDCl ) δ 11.04 (br s, 1H), 7.98 (d, J = 0.7 Hz, 1H), 7.91 (s, 1H), 7.48 - 7.41 (m, 3H),
7.25 - 7.19 (m, 1H), 4.24 - 4.14 (m, 2H), 1.14 (t, J = 7.1 Hz, 3H).
To a solution of 69C (2.9 g, 11.3 mmol) in THF (40 mL) and H O (8 mL) was
added NaOH (905 mg, 22.6 mmol). The mixture was stirred at 25 °C for 10 hours. The mixture
was concentrated under reduced pressure to remove the organic solvent, and extracted with
EtOAc (20 mL). The aqueous layer was acidized with 1M HCl to pH ~ 5 and then extracted with
EtOAc (30 mL x 3). The combined organic layer was washed with H O (40 mL), brine (40 mL),
dried over Na SO , filtered and concentrated to give 69D (1.5 g, yield: 58.1%) as yellow solid.
HNMR (400MHz, DMSO-d ) δ 13.35 (s, 1H), 8.16 (s, 1H), 7.83 (s, 1H), 7.61 (d, J = 8.3 Hz,
1H), 7.47 - 7.41 (m, 2H), 7.20 - 7.15 (m, 1H). MS (ESI) m/z (M+H) 228.9.
Compound 69 (16.7 mg, yield: 20.9%, yellow solid) was prepared as in
Example 5 from the corresponding intermediate carboxylic acid, compound 69D. Compound 69:
H NMR (400MHz, DMSO-d ) δ 13.16 (br s, 1H), 8.84 (br d, J = 7.7 Hz, 1H), 8.08 - 7.95 (m,
2H), 7.80 - 7.70 (m, 2H), 7.52 (d, J = 8.4 Hz, 1H), 7.36 (br t, J = 7.5 Hz, 1H), 7.30 - 7.23 (m,
4H), 7.22 - 7.13 (m, 3H), 7.08 - 7.01 (m, 1H), 5.21 - 5.12 (m, 1H), 3.17 - 3.09 (m, 1H), 2.84 -
2.75 (m, 1H). MS (ESI) m/z (M+H) 403.1.
17681897_1 (GHMatters) P110989.NZ
EXAMPLE 39
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)(1H-BENZO[d]IMIDAZOL
YL)-1H-IMIDAZOLECARBOXAMIDE (70)
LiOH.H O O
O Tosmic,MeOH,reflux
HN N
HN N O
MeOH,reflux
THF, MeOH, H O OH
HN N
NH O
A mixture of 70A (10 g, 75.1 mmol), ethyl 2-oxoacetate (30.6 g, 150 mmol) in
MeOH (300 mL) was stirred at 70 °C for 12 hour under N atmosphere. LCMS showed 70A was
consumed completely and one peak with desired MS was detected. The reaction mixture was
concentrated under reduced pressure to give crude product 70B (15 g, crude) as yellow oil. MS
(ESI) m/z (M+H) 235.9.
A mixture of 70B (15 g, 63.7 mmol), K CO (13.2 g, 95.6 mmol), TosMIC
(24.9 g, 127 mmol) in MeOH (300 mL) was stirred at 70 °C for 1 hour. LCMS showed 70B was
consumed completely and one small peak with desired MS was detected. TLC (Petroleum ether :
Ethyl acetate = 1:1, R ~ 0.3) indicated 70B was consumed completely and one new spot formed.
The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The
residue was purified by column chromatography (Petroleum ether/Ethyl acetate = 10/1 to 1:1) to
give 70C (350 mg, yield: 2.3%) as a yellow oil. H NMR (400 MHz, CDCl ) δ 12.52 (br s, 1 H)
8.96 (s, 1 H) 7.98 (s, 1 H) 7.69 (br d, J = 4.4 Hz, 1 H) 7.48 (br s, 1 H) 7.28 (br dd, J = 5.8, 2.8
Hz, 2 H) 3.99 (s, 3 H). MS (ESI) m/z (M+H) 243.1.
A mixture of 70C (350 mg, 1.44 mmol), LiOH.H O (120 mg, 2.88 mmol) in
THF (5 mL), H O (2 mL) was stirred at 25 °C for 4 hours. LCMS showed 70C was consumed
completely and one peak with desired MS was detected. The reaction mixture was added aqueous
HCl (1M) to adjust the pH ~ 5, filtered and the filtered cake was concentrated under reduced
pressure. The filtered cake was washed with water. Compound 70D (230 mg, yield: 70.1%) was
obtained as a white solid. H NMR (400 MHz, DMSO-d ) δ 8.57 (d, J = 1.3 Hz, 1 H) 7.38 - 7.63
(m, 3 H) 7.03 - 7.22 (m, 1 H) 7.03 - 7.17 (m, 1 H). MS (ESI) m/z (M+H) 229.0.
17681897_1 (GHMatters) P110989.NZ
Compound 70 (40 mg, yield: 46.7%, white solid) was prepared as in Example 5
from the corresponding intermediate carboxylic acid, compound 70D. Compound 70: HNMR
(400MHz, DMSO-d ) δ 12.94 (br s, 1H), 9.31 (br s, 1H), 8.38 - 8.23 (m, 1H), 8.04 (br s, 1H),
7.87 - 7.74 (m, 2H), 7.60 - 7.43 (m, 2H), 7.29 - 7.10 (m, 6H), 5.33 (br t, J = 6.6 Hz, 1H), 3.17 (br
dd, J = 3.1, 13.9 Hz, 1H), 3.22 - 3.09 (m, 1H), 2.84 (br dd, J = 10.3, 13.8 Hz, 1H), 2.91 - 2.74
(m, 1H). MS (ESI) m/z (M+H) 403.1.
EXAMPLE 40
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)PHENYL-1,2,5-
THIADIAZOLECARBOXAMIDE (72)
N OH N
NaOH
, KF, toluene THF, H MeOH
Pd(PPh3)4 2
MeO MeO
72A 72B
A mixture of compound 72A (800 mg, 3.59 mmol) and phenylboronic acid
(1.31 g, 10.8 mmol) in toluene (10 mL) and H O (500 uL) was added KF (417 mg, 7.18 mmol)
and Pd(PPh ) (414 mg, 359 umol) under N . Then the reaction mixture was stirred at 100 °C
3 4 2
under N for 16hrs. The solvent was evaporated. The crude product was purified by silica gel
column (petroleum ether: ethyl acetate = 20: 1 to 5: 1) to give compound 72B (400 mg, crude) as
an oil. H NMR (400 MHz, CDCl ) δ 7.70 - 7.68 (m, 2H), 7.48 - 7.46 (m, 3H), 3.94 (s, 3H).
A solution of compound 72B (500 mg, 2.27 mmol) in THF (5 mL), H O (5
mL) and MeOH (5 mL) was added NaOH (182 mg, 4.54 mmol). The reaction mixture was stirred
at 20 °C for 1hr. 1M HCl was added to the reaction mixture until pH ~ 4. The solvent was
evaporated to give a crude product 72C (500 mg, crude) as a white solid. The crude product was
used in the next step without purification.
Compound 72 (50.5 mg, yield: 43.9%, white solid) was prepared as in
Example 5 from the corresponding intermediate carboxylic acid, compound 72C. Compound 72:
H NMR (400 MHz, DMSO-d ) δ 9.42 (d, J = 7.7 Hz, 1H), 8.18 (s, 1H), 7.91 (s, 1H), 7.60 - 7.55
(m, 2H), 7.48 - 7.43 (m, 1H), 7.42 - 7.36 (m, 2H), 7.31 - 7.22 (m, 5H), 5.51 (ddd, J = 3.6, 7.7,
17681897_1 (GHMatters) P110989.NZ
.0 Hz, 1H), 3.23 (dd, J = 3.6, 14.0 Hz, 1H), 2.87 (dd, J = 10.1, 14.1 Hz, 1H). MS (ESI) m/z
(M+H) 381.0.
EXAMPLE 41
N-((3S,4R)AMINOMETHYL-1,2-DIOXOHEXANYL)METHYL
PHENYLISOXAZOLECARBOXAMIDE (73)
HN(Me)OMe
EDCI, HOBt,NMM
LiAlH , THF O
BocHN O
BocHN CHCl
73A 73B
K H HCl/dioxane
CO , O ,
2 3 2 2
H N NH
DMSO
TEA 2 2
H BocHN NH
73D 73F
A mixture of N-methoxymethanamine (2.32 g, 23.78 mmol), compound 73A
(5.00 g, 21.62 mmol), HOBt (2.92 g, 21.62 mmol) and NMM (6.56 g, 64.86 mmol) in CHCl
(100 mL) was degassed and purged with N for 3 times at 0 °C, then EDCI (6.22 g, 32.43 mmol)
was added in portions. The mixture was stirred at 25 °C for 16 hrs under N atmosphere. The
reaction mixture was quenched by addition H O (100 mL). The organic layers were washed with
HCl (1N, 100 mL x 2), and saturated NaHCO (100 mL x 2), and saturated brine (50 mL), dried
over Na SO , filtered and concentrated under reduced pressure to give a residue. The residue
was purified by flash silica gel chromatography (Eluent of 0~10% Ethyl acetate/Petroleum ether
gradient) to give compound 73B (5.0 g, yield: 84.3%) as a colorless oil. H NMR (400MHz,
CDCl ) δ 5.10 (d, J=9.5 Hz, 1H), 4.67 - 4.53 (m, 1H), 3.76 (s, 3H), 3.20 (s, 3H), 1.70 (qt, J = 6.8,
9.9 Hz, 1H), 1.54 - 1.51 (m, 1H), 1.41 (s, 9H), 1.15 - 1.07 (m, 1H), 0.91 - 0.85 (m, 6H). MS
(ESI) m/z (M + Na ) 296.9.
To a solution of LiAlH (350 mg, 9.22 mmol) in THF (30 mL) was added a
solution of compound 73B (2.30 g, 8.38 mmol) in THF (30 mL) at 0 °C. After addition, the
reaction mixture was stirred for 1hr at 5 °C. The reaction mixture was quenched by addition of
ethyl acetate (10 mL) and HCl (1N, 10 mL), and extracted with EtOAc (100 mL x 2). The
combined organic layers were washed with HCl (1N, 30 mL x 2), sat. NaHCO (30 mL x 3), and
brines (30mL), dried over Na SO , filtered and concentrated under reduced pressure to give
17681897_1 (GHMatters) P110989.NZ
compound 73C (1.50 g, yield: 83.2%) as a colourless oil. H NMR (400MHz, DMSO-d ) δ 9.45
(d, J = 1.3 Hz, 1H), 7.22 (br d, J = 7.5 Hz, 1H), 3.79 (br t, J= 6.4 Hz, 1H), 1.89 - 1.75 (m, 1H),
1.42 - 1.32 (m, 10H), 1.25 - 1.10 (m, 1H), 0.86 (d, J=6.8 Hz, 3H), 0.81 (t, J=7.4 Hz, 3H). MS
(ESI) m/z (M+H) 216.0.
To a solution of compound 73C (1.5 g, 6.97 mmol) in DCM (10 mL) was
added 2-hydroxymethylpropanenitrile (1.28 mL, 13.93 mmol) and TEA (1.16 mL, 8.36
mmol), and then stirred at 25 °C for 14 hours. The reaction mixture was diluted with DCM (25
mL), washed with HCl (1N, 20 mL x 2), H O (30 mL), and brine (30mL), dried over Na SO ,
2 2 4
filtered and concentrated under reduced pressure to give compound 73D (1.5 g, yield: 88.8%) as
a colorless liquid. H NMR (400MHz, CDCl ) δ 5.24 - 5.08 (m, 1H), 4.92 - 4.56 (m, 1H), 3.90 -
3.25 (m, 1H), 2.04 - 1.80 (m, 1H), 1.66 - 1.52 (m, 1H), 1.50 - 1.40 (m, 9H), 1.33 - 1.09 (m, 2H),
1.02 - 0.75 (m, 6H).
To a solution of compound 73D (1.50 g, 6.19 mmol) and K CO (1.71 g, 12.38
mmol) in DMSO (15 mL) was added H O (7.21 g, 211.95 mmol) at 0 °C. After addition, the
reaction mixture was stirred at 0 °C for 1h. The reaction mixture was diulted with water (20 mL)
and quenched with saturated aqueous Na S O slowly at ice water. The mixture was extracted
2 2 3
with EtOAc (50 mL x 3) and the combined extracts were washed with saturated aqueous
Na S O (30 mL x 3). The organic layer was dried over Na SO , filtered and concentrated under
2 2 3 2 4
reduced pressure to give a residue. The residue was purified by flash silica gel chromatography
(eluent of 0 ~ 20% Ethyl acetate/Petroleum ethergradient) to give compound 73E (870 mg, yield:
54.0%) as a white solid. H NMR (400MHz, DMSO-d ) δ 7.31 - 6.97 (m, 2H), 6.29 - 5.87 (m,
1H), 5.44 - 5.12 (m, 1H), 3.99 - 3.80 (m, 1H), 3.71 - 3.50 (m, 1H), 1.67 - 1.41 (m, 2H), 1.39 -
1.30 (m, 9H), 1.11 - 0.92 (m, 1H), 0.89 - 0.75 (m, 6H). MS (ESI) m/z (M + Na) 282.9.
To a solution of compound 73E (870 mg, 3.34 mmol) in EtOAc (10 mL) was
added HCl/EtOAc (4M, 16.70 mL) at 0 °C. After addition, the reaction mixture was stirred at 25
°C for 2 hrs. The reaction mixture was concentrated under reduced pressure to remove solvent.
The residue was washed with MTBE (30 mL), filtered to give compound 73F (620 mg, yield:
94.4%) as a white solid. H NMR (400MHz, DMSO-d ) δ 8.14 - 7.71 (m, 3H), 7.64 - 7.37 (m,
2H), 6.57 - 6.28 (m, 1H), 4.32 - 3.99 (m, 1H), 3.21 (br s, 1H), 1.82 - 1.43 (m, 2H), 1.30 - 1.03
(m, 1H), 0.99 - 0.71 (m, 6H). MS (ESI) m/z (M +H) 161.1.
17681897_1 (GHMatters) P110989.NZ
Compound 73 (100 mg, yield: 63.6%, white solid) was prepared as in Example
from the corresponding intermediate compounds, 23A and 73F. Compound 73: H NMR
(400MHz, DMSO-d ) δ 8.92 (d, J = 7.0 Hz, 1H), 8.15 (s, 1H), 7.96 - 7.65 (m, 3H), 7.62 - 7.44
(m, 3H), 5.19 (t, J = 6.5 Hz, 1H), 3.33 (br s, 1H), 2.30 (s, 3H), 2.10 - 1.94 (m, 1H), 1.36 - 1.13
(m, 2H), 0.92 (d, J = 6.8 Hz, 3H), 0.81 (t, J = 7.4 Hz, 3H). MS (ESI) m/z (M +H) 344.1.
EXAMPLE 42
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)(5-PHENYLPYRIMIDIN
YL)-1H-IMIDAZOLECARBOXAMIDE (74)
Br O
PhB(OH)2
N N O
K PO , ,
N NH Pd(OAc) MeOH N N
3 4 2
N NH H
glycol
Tosmic
aq. KOH
K CO , MeOH THF/MeOH
The mixture of compound 74A (10.0 g, 57.47 mmol), phenylboronic acid (10.5
g, 86.21 mmol), K PO (24.4 g, 114.94 mmol), Pd(OAc) (1.3 g, 5.75 mmol) in ethylene glycol
3 4 2
(200 mL) was stirred at 80 °C for 12 hrs. The reaction mixture was added to H O (200 mL), the
insoluble substance was removed by filtration; the filtrate was extracted with ethyl acetate (200
mL x 3). The combined organic layer was washed with saturated aqueous NaHCO (150 mL x
3), saturated aqueous NaCl (150 mL x 3), dried over Na SO and concentrated in vacuum. The
resulting solid was treated with ethyl acetate (10 mL). The precipitate was filtered and dried in
vacuum to afford compound 74B (4.97 g, yield: 50.5%) as light yellow solid. H NMR (DMSO-
d 400 MHz) δ 8.55 (s, 2H), 7.62 - 7.58 (m, 2H), 7.43 - 7.40 (m, 2H), 7.33 - 7.27 (m, 1H), 6.76
(br.s., 2H).
The mixture of compound 74B (3.0 g, 17.35 mmol) and compound ethyl 2-
oxoacetate (2.3 g, 22.55 mmol) in MeOH (50 mL) was stirred at 80 °C for 12 hrs. The reaction
mixture was concentrated and the solid was filtered. The resulting solid was treated with MeOH
(10 mL), filtered and dried in vacuum to afford compound 74C (3.23 g, yield: 64.8%) as light
yellow solid. H NMR (DMSO-d 400 MHz) δ 8.71 (s, 2H), 8.24 (d, J = 8.8 Hz, 1H), 7.67 -
17681897_1 (GHMatters) P110989.NZ
7.63 (m, 2H), 7.47 - 7.41 (m, 2H), 7.37 - 7.31 (m, 1H), 5.64 (d, J = 8.8 Hz, 1H), 4.19 - 4.10 (m,
2H), 3.33 (s, 3H), 1.21 (t, J = 7.2 Hz, 3H).
The mixture of compound 74C (500 mg, 1.74 mmol), Tosmic (680 mg, 3.48
mmol), K CO (720 mg, 5.22 mmol) in absolute EtOH (50 mL) was stirred at 65 °C for 2 hrs.
The reaction mixture was concentrated under reduced pressure; the resulting residue was added
in water (30 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers
were dried over Na SO , filtered and concentrated. The residue was purified by column
chromatography (SiO2, petroleum ether/ethyl acetate = 15:1 to 8:1) to afford compound 4 (293
mg, yield: 52.2%) as white solid. H NMR (DMSO-d 400 MHz) δ 9.30 (s, 2H), 8.46 (s, 1H),
7.89 (t, J = 7.2 Hz, 2H), 7.76 (s, 1H), 7.59 - 7.49 (m, 3H), 4.23 - 4.13 (m, 2H), 1.17 (t, J = 7.2
Hz, 3H). MS (ESI) m/z (M+H) 295.1.
To the mixture of compound 74D (1.15 g, 3.91 mmol) in THF (10 mL) and
MeOH (10 mL) was added KOH (2M, 1.96 mL, 3.92 mmol) dropwise at 25 °C. The mixture
was stirred at 25 °C for 23 hrs, and then concentrated under reduced pressure to afford
intermediate compound 74E (2 g, crude).
Compound 74 (14.9 mg, yield 28.2%, white solid) was prepared as in Example
from the corresponding intermediate compounds 74E and 12G. H NMR (DMSO-d 400
MHz) δ 9.60 (br d, J = 6.4 Hz, 1H), 8.64 (br s, 3H), 7.82 (s, 1H), 7.59 - 7.50 (m, 6H), 7.22 - 7.11
(m, 5H), 5.83 (m, 1H), 5.61 (br s, 1H), 3.52 - 3.44 (m, 1H), 3.40 - 3.31 (m, 1H). MS (ESI) m/z
(M+H) 441.0.
17681897_1 (GHMatters) P110989.NZ
EXAMPLE 43
COMPOUNDS 77, 88
(S)-N-(4-(CYCLOPROPYLAMINO)-3,4-DIOXOPHENYLBUTANYL)(4-
(OXAZOLYL)PYRIDINYL)-1H-IMIDAZOLECARBOXAMIDE (77)
TOSMIC
N NH K CO /EtOH
2 2 3
Pin B N LiOH.H O
2 2 2
N N N
KOAc/Pd(dppf)Cl2
77D 77E
A mixture of 77A (20 g, 115.60 mmol) and ethyl 2-oxoacetate (30.7g, 150.28
mmol) in MeOH (300 mL) was heated to 80 °C for 3 hrs. LCMS showed desired MS. TLC
(Petroleum ether:Ethyl acetate = 3:1, R ~0.8) showed new point, the mixture was concentrated
and residue purified by silica gel column (Petroleum ether : Ethyl acetate = 20: 1). Compound
77B (28.9g, yield 86.5%, yellow solid): H NMR (400 MHz, CDCl ) δ 7.96 (d, J = 5.2 Hz, 1 H),
6.86 (dd, J = 5.2, 1.75 Hz, 1 H), 6.77 (d, J = 1.3 Hz, 1 H), 5.75 (br s, 1 H), 5.61 (d, J = 8.3 Hz, 1
H), 4.29 (q, J = 7.0 Hz, 2 H), 3.41 (s, 3 H), 1.37 - 1.31 (m, 3 H).
A mixture of 77B (15 g, 51.9 mmol) and K CO (21.5 g, 156 mmol) in EtOH
(300 mL) was stirred at 80 °C for 0.5 hr, then TosMIC (15.2 g, 77.82 mmol) was added, the
resulting mixture was stirred at 80 °C for another 2 hrs. LCMS showed desired MS, most of
ethanol was removed and a precipitate was formed, the solid was filtered and washed with water
(100 mL x 2), the solid was dried and concentrated to give 77C (6.4 g, yield: 41.7%), as yellow
solid. H NMR (400 MHz, CDCl ) δ 8.38 (d, J = 5.2 Hz, 1 H), 7.97 (s, 1 H), 7.85 (s, 1 H), 7.61
(s, 1 H), 7.56 (dd, J = 5.26 1.3 Hz, 1 H), 4.27 (q, J = 7.02Hz, 2 H), 1.29 (t, J = 7.02Hz, 3 H).
Compound 77C (3 g, 10.13 mmol), Pin B (2.57 g, 10.13 mmol), KOAc (2.98
g, 30.4 mmol) and Pd(dppf)Cl (741 mg, 1.01 mmol) in dioxane (100 mL) was de-gassed and
then heated at 70 °C for 4 hours under N . LCMS showed desired MS, TLC (Ethyl acetate:
17681897_1 (GHMatters) P110989.NZ
Methanol = 10: 1, Rf ~ 0), the mixture was filtered and the filtrate was concentrated, the residue
was purified by silica gel chromatography (DCM: Methanol = 5:1) to give 77D (1.70 g, crude) as
black solid.
Compound 77D (300 mg, 1.15 mmol), 2-iodooxazole (157 mg, 805.00 umol),
Pd(dppf)Cl (84.1 mg, 115.00 umol) and Na CO (244 mg, 2.30 mmol) in toluene (2 mL), EtOH
2 2 3
(2 mL), H O (1 mL) was de-gassed and then heated to 120 °C for 1h under microwave
condition. LCMS showed desired MS, the mixture was added water (5 mL) and extracted with
ethyl acetate (10 mL x 2), the organic phases were dried and concentrated, the residue was
purified by preparatory-TLC (Petroleum ether : Ethyl acetate = 1: 1) to give 77E (80 mg, yield:
24.5%) as yellow solid.
A mixture of 77E (80 mg, 281.42 umol) and LiOH.H O (17.7 mg, 422.13
umol) in THF (5 mL), H O (1 mL) was stirred at 25 °C for 12 hrs. LCMS showed desired MS,
THF was removed under vacuum, the water layer was extracted with ethyl acetate (10 mL x 2),
the water layer was adjusted to pH ~ 6 with 1N HCl and lyophilized, the residue was purified by
preparatory-HPLC (TFA) to give 77F (35 mg, yield: 48.5%), as white solid. H NMR (400MHz,
methanol-d ) δ 8.70 (d, J = 5.3 Hz, 1H), 8.25 (s, 1H), 8.16 (s, 1H), 8.11 (s, 1H), 8.08 (d, J = 5.1
Hz, 1H), 7.81 (s, 1H), 7.46 (s, 1H).
Compound 77 (38.4 mg, yield: 64.3%, white solid) was prepared as in
Example 41 from the corresponding intermediate carboxylic acid, compound 77F. Compound
77: H NMR (400MHz, DMSO-d ) δ 8.93 (d, J = 7.5 Hz, 1H), 8.74 (d, J = 5.1 Hz, 1H), 8.60 (d, J
= 5.7 Hz, 1H), 8.39 (d, J = 0.7 Hz, 1H), 8.22 (d, J = 0.7 Hz, 1H), 7.94 (dd, J = 1.4, 5.2 Hz, 1H),
7.82 (s, 1H), 7.65 (d, J = 0.7 Hz, 1H), 7.54 (d, J = 0.7 Hz, 1H), 7.28 (d, J = 4.4 Hz, 4H), 7.20 (qd,
J = 4.2, 8.5 Hz, 1H), 5.30 - 5.22 (m, 1H), 3.16 (dd, J = 3.9, 13.8 Hz, 1H), 2.85 (dd, J = 10.1, 13.9
Hz, 1H), 2.77 - 2.68 (m, 1H), 0.67 - 0.59 (m, 2H), 0.58 - 0.50 (m, 2H). MS (ESI) m/z (M+H)
471.1.
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)(4-(OXAZOLYL)PYRIDIN-
2-YL)-1H-IMIDAZOLECARBOXAMIDE (88)
Compound 88 (18.5 mg, yield: 46.5%, white solid) was prepared as in Example
from the corresponding intermediate carboxylic acid, compound 77F. H NMR (400MHz,
DMSO-d ) δ 8.93 (d, J = 7.5 Hz, 1H), 8.58 (d, J = 5.3 Hz, 1H), 8.37 (s, 1H), 8.21 (s, 1H), 8.01
17681897_1 (GHMatters) P110989.NZ
(br s, 1H), 7.91 (d, J = 5.1 Hz, 1H), 7.79 (s, 2H), 7.62 (s, 1H), 7.52 (s, 1H), 7.25 (d, J = 4.2 Hz,
4H), 7.18 (br dd, J = 4.5, 8.7 Hz, 1H), 5.25 - 5.17 (m, 1H), 3.14 (dd, J = 3.6, 14.0 Hz, 1H), 2.83
(dd, J = 10.5, 13.8 Hz, 1H). MS (ESI) m/z (M+H) 431.1.
EXAMPLE 44
(S)-N-(4-(CYCLOPROPYLAMINO)-3,4-DIOXOPHENYLBUTANYL)METHYL-
1-(QUINOLINYL)-1H-PYRAZOLECARBOXAMIDE (78)
NH NH O N
LiOH H O
SnCl 2H NaNO
2 2O, 2
N MeOH: H O
2 (2:1)
Conc.HCl,
AcOH 25 °C, 1 hr
110 2 hrs
° C,
to 5.5 hrs
0 25 C
78A 78D
A mixture consisting of compound 78A (1.0 g, 6.94 mmol) in conc. HCl (4.00
mL) at 0 °C was added NaNO (526.8 mg, 7.63 mmol) dropwise and the resultant mixture was
stirred at 0 °C for 0.5 hour. The reaction mixture was warmed to 25 °C over 0.5 hour, and then
cooled to 0 °C. The SnCl •2H O (3.13 g, 13.88 mmol, in 1.2 mL conc. HCl) was added
dropwise to the reaction mixture, and stirred at 0 °C for 0.5 hour. The resulting mixture was
allowed to warm to room temperature with vigorous stirring over 4 hours and then concentrated
under reduced pressure to remove solvent. The residue was filtered, and the cake was washed
with ethanol (30 mL x 3), and then dried under reduced pressure to afford compound 78B (700.0
mg, 51.55% yield) as a yellow solid. H NMR (DMSO-d 400 MHz) δ 9.95 (br s, 1H), 9.25 -
9.13 (m, 2H), 8.04 - 7.95 (m, 2H), 7.88 (d, J = 8.8 Hz, 1H), 7.26 (d, J = 7.6 Hz, 1H), 7.28 - 7.23
(m, 1H).
To a mixture of compound 78B (500 mg, 3.14 mmol) and compound ethyl 2-
(methoxyimino)oxopentanoate (588 mg, 3.14 mmol) in AcOH (1 mL) was degassed and
purged with N for 3 times, and then the mixture was stirred at 110 °C for 2 hrs under N
atmosphere. The reaction mixture was concentrated under reduced pressure to remove AcOH.
The residue was diluted with CH Cl (100 mL), adjusted to pH ~ 7 - 8 with saturated aqueous
NaHCO , and then extracted with CH Cl (40 mL x 2). The organic phase was dried over
3 2 2
anhydrous Na SO , filtered, and concentrated under reduced pressure to give a residue, which
was purified by column chromatography (SiO , Petroleum ether/Ethyl acetate = 1:0 to 1:0) to
give compound 78C (200 mg, 22.6% yield) as a yellow solid. H NMR (CDCl , 400 MHz) δ
17681897_1 (GHMatters) P110989.NZ
8.93 (d, J = 4.0 Hz, 1H), 8.23 (d, J = 8.4 Hz, 1H), 7.78 (t, J = 8.0 Hz, 1H), 7.64 (d, J = 8.4 Hz,
1H), 7.56 (d, J = 7.2 Hz, 1H), 7.38 (d, J = 8.8 Hz, 1H), 6.93 (s, 1H), 4.05 (q, J = 7.2 Hz, 2H),
2.41 (s, 3H), 1.00 (t, J = 7.2 Hz, 3H). MS (ESI) m/z (M+1) 282.0.
Intermediate compound 78D (135 mg, 74.98% yield, white solid) was prepared
as in Example 85 from compound 78C. Compound 78D: H NMR (DMSO-d 400 MHz) δ 8.97
(d, J = 4.0 Hz, 1H), 8.17 (d, J = 8.4 Hz, 1H), 7.89 - 7.82 (m, 1H), 7.67 - 7.52 (m, 3H), 6.97 (s,
1H), 2.32 (s, 3H). MS (ESI) m/z (M+1) 253.9.
Compound 78 (8.8 mg, 16.77% yield, yellow solid) was prepared as in
Example 20 from the corresponding intermediate carboxylic acid, compound 78D. Compound
78: H NMR (CDCl , 400 MHz): δ 8.95 (d, J = 4.0 Hz, 1H), 8.22 (d, J = 8.4 Hz, 1H), 7.76 - 7.66
(m, 2H), 7.49 (d, J = 6.4 Hz, 1H), 7.38 (d, J = 8.4 Hz, 1H), 7.24 - 7.16 (m, 3H), 6.87 (d, J = 7.6
Hz, 2H), 6.79 (br s, 1H), 6.64 (s, 1H), 6.33 (d, J = 7.2 Hz, 1H), 5.49 - 5.42 (m, 1H), 3.27 - 3.19
(m, 1H), 3.08 - 2.98 (m, 1H), 2.78 – 2.69 (m, 1H), 0.90 - 0.83 (m, 2H), 0.61 - 0.50 (m, 2H). MS
(ESI) m/z (M+H) 468.1.
EXAMPLE 45
COMPOUNDS 79, 146, 160, 264
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)METHYLPHENYL-1H-
IMIDAZOLECARBOXAMIDE (79)
O Br
SEM-Cl
HCl/MeOH SEM
NaH, THF N
HN DMF
79A 79C
LiOH
OH MeOH
Pd(dtbpf)Cl2 SEM THF
K PO
dioxane/H O
79E 79F
HCl/EtOAc
N NH
SEM 2
N HN
79H 79
The solution of compound 79A (500 mg, 3.96 mmol) in HCl/MeOH (4 M, 50
mL) was stirred at 80 °C for 12 hrs. The solvent was removed in vacuo. The residue was
17681897_1 (GHMatters) P110989.NZ
adjusted to pH ~ 8 with saturated aqueous NaHCO . The solution was extracted with EtOAc
(100 mL x 3). The organics were collected, dried with Na SO , filtered and concentrated.
Compound 79B (360 mg, yield: 64.87%, light yellow solid): H NMR (CDCl 400 MHz) δ 7.90
- 7.88 (m, 1H), 7.34 - 7.31 (m, 1H), 7.15 - 7.09 (m, 2H), 5.72 - 5.63 (m, 1H), 4.87 - 4.76 (m, 2H),
2.90 - 2.86 (m, 2H), 1.92 - 1.87 (m, 2H), 1.50 - 1.47 (m, 2H), 1.26 - 1.14 (m, 8H).
To a solution of compound 79B (360 mg, 2.57 mmol) in DMF (5 mL) at 0 °C
was added NBS (550 mg, 3.08 mmol). The mixture was then warmed up to 25 °C and stirred for
12 hrs. The reaction was washed with H O (10 mL), extracted with DCM (20 mL). The
organics were collected, dried with Na SO , filtered and concentrated to afford intermediate
compound 79C (550 mg, crude) as yellow solid. MS (ESI) m/z (M+2) 220.7.
To a solution of NaH (151 mg, 3.76 mmol, 60% purity) in THF (8 mL) at 0 °C
was added a solution of compound 79C (550 mg, 2.51 mmol) in THF (2 mL) dropwise. After
addition, the mixture was warmed up to 25 °C and stirred for 1h. Then SEM-Cl (0.5 mL, 2.76
mmol) was added. The mixture was stirred at 25 °C for 12 hrs. The reaction was quenched with
H O (10 mL), extracted with EtOAc (20 mL x 2). The organics were collected and concentrated.
The residue was purified by column (Petroleum Ether: Ethyl Acetate = 5:1) to afford compound
79D (180 mg, yield: 20.51%) as colorless oil. MS (ESI) m/z (M+2) 350.9.
To a solution of compound 79D (180 mg, 0.52 mmol) and phenylboronic acid
(76 mg, 0.62 mmol) in dioxane (12 mL) and H O (4 mL) was added Pd(dtbpf)Cl (34 mg, 0.052
mmol) and K PO (330 mg, 1.55 mmol). The mixture was stirred at 80 °C under N for 2 hrs.
3 4 2
The reaction was washed with H O (10 mL), extracted with EtOAc (15 mL x 2). The organics
were collected and concentrated. The residue was purified by column (Petroleum Ether: Ethyl
Acetate = 5:1) to afford compound 79E (150 mg, yield: 84.0%) as yellow oil. MS (ESI) m/z
(M+H) 347.0.
To a solution of compound 79E (180 mg, 0.52 mmol) in THF (5 mL), MeOH
(5 mL) and H O (5 mL) was added LiOH.H O (110 mg, 2.60 mmol). The mixture was stirred at
°C for 12 hrs. The reaction was acidified with 1N HCl to pH ~ 3. The mixture was extracted
with EtOAc (10 mL x 2). The organics were collected, dried with Na SO , filtered and
concentrated to afford compound 79F (130 mg, crude) as yellow oil. MS (ESI) m/z (M+H)
333.0. Intermediate compound 79H (65 mg, crude, yellow oil) was prepared as in Example 5
17681897_1 (GHMatters) P110989.NZ
from the corresponding carboxylic acid, compound 79F. Compound 79H: MS (ESI) m/z (M+H)
507.2.
To a solution of compound 79H (65 mg, 0.13 mmol) in EtOAc (5 mL) was
added HCl/EtOAc (4 M, 10 mL) dropwise. After addition, the mixture was stirred at 25 °C for 12
hrs. The solvent was removed in vacuo. The residue was purified by prep-HPLC (HCl) to afford
compound 79 (10.00 mg, yield: 18.7%) as white solid. H NMR (400MHz, D O) δ 7.45 - 7.28
(m, 3H), 7.23 - 6.97 (m, 7H), 4.46 - 4.38 (m, 1H), 3.02 - 2.93 (m, 1H), 2.48 - 2.41 (m, 3H), 2.39 -
2.29 (m, 1H). MS (ESI) m/z (M+H) 377.1.
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)(3-
((BENZYLAMINO)METHYL)PHENYL)METHYL-1H-PYRAZOLE
CARBOXAMIDE (146)
146A
140C
146B
O NH O
LiOH H O
NaH, DMF
MeOH, H O
To a mixture of compound 140C (250 mg, 0.72 mmol) and benzyl bromide
(310 mg, 1.8 mmol) in DMF (10 mL) was added NaH (87 mg, 2.2 mmol, 60% purity) in batches
at 0 °C under N . The mixture was stirred at 25 °C for 3h. The mixture was quenched with
NH Cl (10 mL), diluted with H O (30 mL), extracted with ethyl acetate (20 mL x 3). The
organic phase was combined and washed with brine (30 mL x 2), dried over Na SO , filtered and
concentrated to give a residue. The residue was purified by Flash Column Chromatography
(SiO2, Petroleum ether/Ethyl acetate=1/0 to 5/1) to afford compound 146A (182 mg, yield:
57.7%) as colorless clear liquid.
To a mixture of compound 146A (180 mg, 0.41 mmol) in MeOH (10 mL) and
H O (2 mL) was added LiOH.H O (52 mg, 1.24 mmol) in one portion at 25 °C. The mixture was
stirred at 25 °C for 3h. The reaction mixture was concentrated under reduced pressure to move
MeOH. Then the residue was diluted with water (15 mL) and extracted with MTBE (20 mL), the
aqueous phase was acidified with aqueous HCl (1M) till pH ~ 5~6 and extracted with ethyl
17681897_1 (GHMatters) P110989.NZ
acetate (20 mL x 2). The combined organic layers were washed with brine (40 mL) and dried
over Na SO , filtered and concentrated to afford compound 146B (158 mg, yield: 90. 8%) as
colorless liquid, which was used directly for next step without purification. H NMR (DMSO-d
400 MHz): δ 7.44 - 7.39 (m, 1H), 7.37 - 7.30 (m, 3H), 7.26 (q, J = 6.9 Hz, 5H), 6.81 (s, 1H), 4.48
- 4.26 (m, 4H), 2.25 (s, 3H), 1.39 (s, 9H).
Compound 146 was prepared as in Example 45 from the intermediate
compound 146B. Compound 146 (40.0 mg, yield 74.6%, white solid): H NMR (D O 400
MHz): δ 7.51 - 7.42 (m, 6H), 7.41 - 7.36 (m, 1H), 7.36 - 7.27 (m, 5H), 7.25 (s, 1H), 6.78 (d, J =
8.6 Hz, 1H), 6.60 (s, 1H), 4.52 - 4.43 (m, 1H), 4.30 - 4.18 (m, 4H), 3.24 - 3.15 (m, 1H), 2.82 -
2.71 (m, 1H), 2.29 (s, 3H). MS (ESI) m/z (M-HCl+H) 496.2.
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)(4-
((BENZYLAMINO)METHYL)PHENYL)METHYL-1H-PYRAZOLE
CARBOXAMIDE HYDROCHLORIDE (160)
Boc Boc Boc
N N N
LiOH
THF/H O
N N N
N N N
O OH H
160A 160B 160D
To a solution of compound 153E (350 mg, 1.01 mmol) and benzyl bromide
(432 mg, 2.53 mmol, 0.3 mL) in DMF (10 mL) was added NaH (121 mg, 3.03 mmol, 60%
purity) at 0 °C. The mixture was stirred at 25 °C for 1h. The mixture was quenched with NH Cl
(5 mL), diluted with H O (20 mL), extracted with ethyl acetate (20 mL x 3), the organic phase
was combined, and washed with NaCl (30 mL x 2), dried over Na SO , concentrated to give a
residue. The residue was purified by column chromatography (SiO , Petroleum ether/Ethyl
acetate = 20/1 to 5/1) to give compound 160A (400 mg, yield: 41.47%) as a yellow oil. H NMR
(400MHz, CDCl ) δ 8.02 (dd, J = 1.1 Hz, 1H), 7.37 - 7.25 (m, 9H), 6.88 - 6.75 (m, 1H), 4.49 -
4.28 (m, 4H), 2.98 - 2.88 (m, 4H), 2.46 - 2.30 (m, 3H), 1.57 - 1.41 (m, 8H). MS (ESI) m/z (M-
56) 380.0.
To a mixture of compound 160A (400 mg, 918.46 umol) in THF (10 mL) and
H O (10 mL) was added LiOH.H O (116 mg, 2.76 mmol) in portion at 25 °C and stirred for 2.5h.
17681897_1 (GHMatters) P110989.NZ
The mixture was diluted with H O (10 mL) and concentrated to remove THF, then the water was
extracted with MTBE (30 mL x 2). The water layers were acidified to pH ~ 2 with 1N HCl, then,
the solution extracted with ethyl acetate (30 mL x 3). The organic layers were dried over Na SO
and concentrated to give intermediate compound 160B (350 mg, yield: 86.82%) as white solid.
H NMR (400MHz, CDCl ) δ 7.40 - 7.20 (m, 9H), 6.85 (s, 1H), 4.43 (s, 2H), 4.33 (dd, J = 13.9
Hz, 2H), 2.34 (s, 3H), 1.47 (s, 8H). MS (ESI) m/z (M-56) 366.1.
Compound 160 was prepared as in Example 79 from the corresponding
carboxylic acid, compound 160B, and then through intermediate compound 160D. Compound
160 (30 mg, yield: 53.02%, light yellow solid): H NMR (400MHz, DMSO-d ) δ 9.62 - 9.57 (m,
1H), 9.15 (d, J = 7.9 Hz, 1H), 8.12 (s, 1H), 7.88 (s, 1H), 7.58 - 7.49 (m, 4H), 7.44 (dd, J = 6.8
Hz, 3H), 7.36 - 7.27 (m, 5H), 7.22 (d, J = 8.4 Hz, 2H), 6.61 (s, 1H), 5.35 - 5.28 (m, 1H), 4.18 (s,
4H), 3.25 - 3.18 (m, 1H), 2.83 (dd, J = 10.6, 13.9 Hz, 1H), 2.26 (s, 3H). MS (ESI) m/z
(M+H) 496.2.
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)(1H-BENZO[d]IMIDAZOL
YL)METHYL-1H-PYRAZOLECARBOXAMIDE (264)
264A
N N N
264B
N NH
264D
2-chloro-1H-benzo[d]imidazole (5 g, 32.8 mmol) was added to a solution of
NaH (1.31 g, 32.8 mmol, 60%) in DMF (50 mL) below 10 °C. After addition, the reaction
mixture was stirred at 20 °C for 2h. Then SEM-Cl (5.46 g, 32.8 mmol,) was added to the
reaction mixture. The reaction mixture was stirred at 20 °C for 16hrs. Water (150 mL) and
EtOAc (150 mL) were added. The organic layer was separated and washed by brine (100 mL),
concentrated to give a residue. The crude product was purified by silica gel column (petroleum
ether: ethyl acetate = 20: 1~ 4: 1) to give compound 264A (3.50 g, yield: 37.8%) as an oil. H
17681897_1 (GHMatters) P110989.NZ
NMR (400MHz, CDCl ) δ 7.78 - 7.71 (m, 1H), 7.54 - 7.48 (m, 1H), 7.41 - 7.32 (m, 2H), 5.62 (s,
2H), 3.66 - 3.59 (m, 2H), 0.99 - 0.93 (m, 2H), 0.07 (d, J = 2.0 Hz, 2H), 0.00 (s, 9H).
Compound 264 was prepared as in Example 79 from the corresponding
intermediate compound 264B, and then through intermediate compound 264D. Compound 264
(31.8 mg, yield: 28.0%, off-white solid): H NMR (400MHz, CDCl ) δ 13.04 (br s, 1H), 8.39 (d,
J = 7.6 Hz, 1H), 8.13 (br s, 1H), 7.88 (br s, 1H), 7.67 (br d, J = 7.2 Hz, 1H), 7.53 (br d, J = 7.5
Hz, 1H), 7.34 - 7.19 (m, 7H), 6.79 (s, 1H), 5.51 (dt, J = 4.0, 8.2 Hz, 1H), 3.27 (br d, J = 4.0 Hz,
1H), 3.02 (dd, J = 9.3, 13.9 Hz, 1H), 2.73 (s, 3H). MS (ESI) m/z (M+H) 417.2.
EXAMPLE 46
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)METHYL(4-
PHENYLTHIAZOLYL)-1H-PYRAZOLECARBOXAMIDE (80)
(S)-N-(4-(CYCLOPROPYLAMINO)-3,4-DIOXOPHENYLBUTANYL)METHYL-
1-(4-PHENYLTHIAZOLYL)-1H-PYRAZOLECARBOXAMIDE (125)
CO Et
NaOH
MeOH
Intermediate compound 80B (182.00 mg, 99.95% yield, white solid): H NMR
(DMSO-d 400 MHz) δ 8.02 (s, 1H), 7.96 (br d, J=7.5 Hz, 2H), 7.47 (br t, J=7.5 Hz, 2H), 7.41 -
7.32 (m, 1H), 6.80 (s, 1H), 2.78 (s, 3H).
Compound 80 (44 mg, 64.6% yield, white solid) was prepared as in Example 5
from the corresponding intermediate compounds 80B and 12G. Compound 80: H NMR
(DMSO-d 400 MHz) δ 8.53 (br d, J=7.3 Hz, 1H), 8.12 (br s, 1H), 8.04 - 7.94 (m, 3H), 7.86 (br
s, 1H), 7.52 - 7.44 (m, 2H), 7.39 (br d, J=6.4 Hz, 1H), 7.32 - 7.17 (m, 5H), 6.76 (s, 1H), 5.43 (br
s, 1H), 3.24 (br d, J=12.1 Hz, 1H), 3.12 - 3.03 (m, 1H), 2.78 (s, 3H). MS (ESI) m/z (M+H)
460.1.
Compound 125 (118 mg, yield 77.6%, white solid) was prepared as in Example
from the corresponding intermediate carboxylic compounds 80B and 41B. Compound 125: H
NMR (DMSO-d 400 MHz) δ 8.84 (br s, 1H), 8.60 - 8.53 (m, 1H), 8.06 - 7.94 (m, 3H), 7.52 -
7.44 (m, 2H), 7.42 - 7.35 (m, 1H), 7.29 (br s, 4H), 7.21 (br s, 1H), 6.76 (s, 1H), 5.44 (br s, 1H),
17681897_1 (GHMatters) P110989.NZ
3.27 - 3.19 (m, 1H), 3.11 - 3.02 (m, 1H), 2.78 (br s, 4H), 0.72 - 0.57 (m, 4H). MS (ESI) m/z
(M+H) 500.1.
EXAMPLE 47
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)METHYL(2'-METHYL-
[1,1'-BIPHENYL]YL)-1H-PYRAZOLECARBOXAMIDE (81)
O Br
CONH
NHNH
.HCl 12G
NaOH
aqueous OH
AcOH MeOH EDCI, HOBt, DIEA, DMF
Br N
N , Na CO ,
N Pd(PPh3)4 2 3
HO 2
THF/H O
To a mixture of compound 81A (25 g, 111.86 mmol) and compound ethyl 2-
(methoxyimino)oxopentanoate (22 g, 117.45 mmol) in AcOH (150 mL) was stirred at 110 °C
for 2 hrs. The reaction mixture was concentrated under reduced pressure to remove a large
amount of AcOH. The residue was acidified with saturated aqueous NaHCO till pH ~ 7-8. The
precipitate was collected by filtration and the cake was triturated with petroleum ether (20 mL),
filtered and dried in vacuum to afford compound 81B (26.41 g, yield: 74.0%) as gray solid. H
NMR (DMSO-d 400 MHz) δ 7.71 - 7.68 (m, 1H), 7.65 (td, J = 1.5, 7.7 Hz, 1H), 7.50 - 7.38 (m,
2H), 6.95 - 6.84 (m, 1H), 4.18 (q, J = 7.0 Hz, 2H), 2.27 (s, 3H), 1.17 (t, J = 7.0 Hz, 3H). MS
(ESI) m/z (M+H) 310.8.
To a mixture of compound 81B (5 g, 16.17 mmol) in MeOH (20.00 mL) was
added NaOH (2M, 40 mL) in one portion at 25 °C. The mixture was stirred at 25 °C for 2 hrs.
The reaction mixture was concentrated under reduced pressure to remove MeOH. The residue
was added H O (10 mL) and ethyl acetate (20 mL), and then the mixture was acidified with 1M
HCl till the aqueous phase pH ~ 5-6. The separated aqueous layer was extracted with ethyl
acetate (30 x 3 mL), the combined organic layers were washed with brine (60 mL), dried over
Na SO , filtered under reduced pressure to give crude product. The crude product was treated
17681897_1 (GHMatters) P110989.NZ
with isopropyl ether (15 mL), the precipitate was filtered and dried in vacuum to afford
compound 81C (4.21 g, yield: 80.67%) as white solid. H NMR (DMSO-d 400 MHz) δ 7.65 -
7.58 (m, 2H), 7.45 - 7.36 (m, 2H), 6.83 (s, 1H), 2.23 (s, 3H). MS (ESI) m/z (M+H) 282.8.
To a solution of compound 81C (1 g, 3.56 mmol) in DMF (50 mL) was added
HOBt (144 mg, 1.07 mmol), compound 12G (903 mg, 3.92 mmol, HCl) and DIEA (1.38 g, 10.68
mmol). After stirring for 5 min, EDCI (682 mg, 3.56 mmol,) was added at 0 °C. Then the
reaction mixture was stirred at 25 °C for 9 hrs. The reaction mixture was concentrated under
reduced pressure to move DMF, and to the residue was added ethyl acetate (100 mL) and
respectively washed with H O (80 mL), saturated aqueous NaHCO (80 mL x 2), brine (80 mL x
3). The organic phase was dried over Na SO and concentrated. The crude product was treated
with i-propyl ether. The solid was collected and dried in vacuum to afford compound 81D (1.3
g, yield: 79.85%) as white solid. H NMR (DMSO-d 400 MHz) δ 8.55 - 8.18 (m, 1H), 7.54 -
7.45 (m, 2H), 7.34 (br d, J=18.5 Hz, 1H), 7.30 - 7.14 (m, 7H), 7.00 - 6.89 (m, 1H), 6.58 (d, J=1.5
Hz, 1H), 5.98 - 5.73 (m, 1H), 4.44 - 4.33 (m, 1H), 4.00 - 3.89 (m, 1H), 2.93 - 2.87 (m, 0.5 H),
2.84 - 2.73 (m, 1H), 2.71 (br s, 0.6 H), 2.22 (s, 3H).
To a mixture of compound 81D (150 mg, 328.00 umol) and compound o-
tolylboronic acid (89.2 mg, 656.00 umol) in THF (50 mL) and H O (10 mL) was added Na CO
2 2 3
(70 mg, 656.00 umol,) and Pd(PPh ) (38 mg, 32.80 umol) in one portion at 25 °C under N . The
3 4 2
mixture was stirred at 80 °C for 12 hrs. Then to the reaction mixture was added H O (100 mL)
and extracted with ethyl acetate (100 mL x 3). The combined organic layer was washed with
saturated aqueous NaHCO (150 mL x 3), brine (150 mL x 3), dried over Na SO and
3 2 4
concentrated to afford compound 81E (110 mg, yield: 71.58%) was obtained as white solid. H
NMR (DMSO-d 400 MHz) δ 8.50 - 8.11 (m, 1H), 7.38 - 7.32 (m, 2H), 7.31 - 7.22 (m, 6H), 7.18
(br s, 5H), 7.10 (br d, J = 6.4 Hz, 1H), 7.00 (br.dd, J = 8.0, 16.4 Hz, 1H), 6.57 (s, 1H), 5.96 - 5.69
(m, 1H), 4.51 - 4.30 (m, 1H), 4.03 - 3.85 (m, 1H), 2.92 - 2.63 (m, 2H), 2.27 - 2.12 (m, 6H). MS
(ESI) m/z (M+H) 469.2.
The mixture of compound 81E (70 mg, 149.4 umol) in DCM (10 mL) and
DMSO (0.5 mL) was added DMP (190 mg, 448.2 umol) in one portion at 0 °C. The mixture was
stirred at 0 °C for 5 min, then heated to 25 °C and stirred for 1.5 hours. The reaction was
quenched by 20 mL of 10 % aqueous Na S O solution and 20 mL of saturated aqueous NaHCO
2 2 3 3
17681897_1 (GHMatters) P110989.NZ
solution and then extracted with DCM (30 mL x 3). The combined organic phase was washed
with brine (40 mL x 3), dried over anhydrous Na SO , filtered and concentrated in vacuum. The
residue was treated with i-propyl ether/CH3CN (v/v = 10/1, 10 mL). The solid was collected and
dried in vacuum to afford compound 81 (48.3 mg, yield: 66.3%) as white solid. H NMR
(DMSO-d 400 MHz) δ 9.11 (br d, J = 8.0 Hz, 1H), 8.18 - 7.79 (m, 2H), 7.49 - 7.37 (m, 1H),
7.29 - 7.26 (m, 8H), 7.21 - 7.12 (m, 4H), 6.60 (s, 1H), 5.32 (br.s., 1H), 3.21 - 3.18 (m, 1H), 2.86 -
2.76 (m, 1H), 2.25 (br.s., 3H), 2.18 (br.s., 3H). MS (ESI) m/z (M+H) 467.1.
EXAMPLE 48
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)METHYL(4-
PHENYLTHIAZOLYL)-1H-PYRAZOLECARBOXAMIDE (82)
2 N NaOH
O MeOH O
NHNH HOAc, 120 °C, 2 h
O OH
To a solution of compound 82A (2.0 g, 10.46 mmol) in CH COOH (30.0 mL)
was added compound ethyl 2,4-dioxopentanoate (1.65 g, 10.46 mmol, 1.48 mL) dropwise, then
the mixture was heated to 120 °C and stirred for 2 hrs and removed the solvent under reduced
pressure. The residue was dissolved in ethyl acetate (20 mL) and treated with NaHCO until pH
~ 8, and then the organic layer was collected and evaporated under reduced pressure. The residue
was purified by flash column chromatography (Petroleum Ether/Ethyl Acetate: 0 to 10/1).
Compound 82B (660.0 mg, 2.11 mmol, 20.14% yield) was obtained as white
solid. Compound 82B (low polarity): H NMR (CDCl , 400 MHz,) δ 7.88 - 7.83 (m, 2H), 7.43 -
7.38 (m, 3H), 7.36 - 7.31 (m, 1H), 6.71 (s, 1H), 4.33 (q, J = 7.2 Hz, 2H), 2.37 (s, 3H), 1.24 (t, J =
7.2 Hz, 3H).
To a solution of compound 82B (650.0 mg, 2.07 mmol) in MeOH (10.00 mL)
was added NaOH (2M, 6.00 mL) drop wise and the mixture was stirred at 25 °C for 2 hrs. The
reaction was diluted with H O (10 mL) and extracted with MBTE(10 mL x 2). The water phase
was treated with HCl (1M) until pH ~ 4, then the precipitate was filtered and dried under reduced
pressure. Compound 82D (540.0 mg, 91.3% yield) was obtained as white solid. H NMR
17681897_1 (GHMatters) P110989.NZ
(DMSO-d 400 MHz) δ 8.04 (s, 1H), 7.88 (d, J =7.1 Hz, 2H), 7.47 - 7.41 (m, 2H), 7.38 - 7.33
(m, 1H), 6.83 (s, 1H), 2.27 (s, 3H)
Compound 82 (20.0 mg, 42.74% yield, white solid) was prepared as in
Example 5 from the corresponding intermediate carboxylic acid, compound 82D. Compound 82:
H NMR (DMSO-d 400MHz) δ 9.49 (d, J = 7.6 Hz, 1H), 8.12 (s, 1H), 7.94 (s, 1H), 7.88 (br s,
1H), 7.78 (br d, J = 7.2 Hz, 2H), 7.42 - 7.37 (m, 2H), 7.35 - 7.29 (m, 1H), 7.22 - 7.12 (m, 5H),
6.55 (s, 1H), 5.55 - 5.47 (m, 1H), 3.16 (m, 1H), 2.80 (m, 1H), 2.27 (s, 3H). MS (ESI) m/z
(M+H) 403.1.
EXAMPLE 49
COMPOUNDS 83, 126, 130
(S)([1,1'-BIPHENYL]YL)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)
METHYL-1H-PYRAZOLECARBOXAMIDE (83)
MeOH, 25°C, 3
°C , 2h N
HOAc,120 NaOH
NHNH
CONH
O PhB(OH)2
, Na CO ,
Pd(PPh )
EDCI, HOBt, DIEA N 3 4 2 3
80°C, 12 h H
h HO
°C,12
To a solution of compound 83A (20.0 g, 89.49 mmol, HCl) in CH COOH
(150.0 mL) was added compound ethyl 2-(methoxyimino)oxopentanoate (14.0 g, 89.49
mmol), then the mixture was heated to 120 °C and stirred for 2 hrs and removed the solvent
under reduced pressure. The residue was dissolved in ethyl acetate (150 mL), treated with
NaHCO until pH ~ 7 and filtered. The solid was treated with petroleum ether. Compound 83B
(22.0g, 71.16 mmol, 79.52% yield) was obtained as yellow solid. H NMR (CDCl , 400MHz) δ
7.56 (d, J = 8.4 Hz, 2H), 7.31 - 7.24 (m, 2H), 6.81 (s, 1H), 4.23 (q, J = 7.2 Hz, 2H), 2.34 (s, 3H),
1.26 (t, J = 7.2 Hz, 3H).
17681897_1 (GHMatters) P110989.NZ
To a solution of compound 83B (5.0 g, 16.17 mmol) in MeOH (40.0 mL) was
added NaOH (2M, 45.0 mL) dropwise and the mixture was stirred at 25 °C for 3 hrs and
removed the solvent under reduced pressure, then the mixture was diluted with H O (30 mL) and
extracted with MTBE (60 mL x 2). Water phase was treated with HCl (1M) until pH ~ 4, and
then the precipitate was filtered and dried under reduced pressure. The water phase was
extracted with ethyl acetate (50 mL x 2), the organic layer (extracted with ethyl acetate) was
evaporated under reduced pressure. The solid collected was compound 83C (3.75 g, 82.5%
yield) obtained as white solid. H NMR (DMSO-d 400MHz) δ 7.62 (d, J = 8.8 Hz, 2H), 7.36
(d, J = 8.8 Hz, 2H), 6.81 (s, 1H), 2.23 (s, 3H).
Compound 83 (25.0 mg, 61.24% yield, white solid) was prepared as in
Example 47 from the corresponding intermediate compounds 83C, 12G and phenylboronic acid.
Compound 83: H NMR (CDCl 400 MHz) δ 9.49 (d, J = 7.3 Hz, 1H), 8.12 (s, 1H), 7.94 (s, 1H),
7.88 (br s, 1H), 7.78 (br d, J = 7.3 Hz, 2H), 7.48 - 7.27 (m, 4H), 7.26 - 6.96 (m, 7H), 6.55 (s, 1H),
.55 - 5.47 (m, 1H), 3.16 (br dd, J = 4.2, 14.1 Hz, 1H), 2.80 (br dd, J = 9.7, 13.9 Hz, 1H), 2.27 (s,
3H), 2.06 (s, 1H). MS (ESI) m/z (M+H) 453.1.
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)(4'-FLUORO-[1,1'-
BIPHENYL]YL)METHYL-1H-PYRAZOLECARBOXAMIDE (126)
Compound 126 (32 mg, yield 25.5%, light yellow solid) was prepared as in
Example 63 from the corresponding starting materials, compound 83D and (4-
fluorophenyl)boronic acid. Compound 126: H NMR (CD CN, 400MHz ) δ 7.73 - 7.67 (m, 2H),
7.63 - 7.59 (m, 2H), 7.37 - 7.22 (m, 10H), 7.02 (br s, 1H), 6.54 (s, 1H), 6.27 (br s, 1H), 5.42
(ddd, J = 4.5, 7.8, 9.5 Hz, 1H), 3.32 (dd, J=4.5, 13.8 Hz, 1H), 2.93 (dd, J = 9.6, 14.0 Hz, 1H),
2.31 (s, 3H). MS (ESI) m/z (M+H) 471.1.
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)(4'-FLUORO-[1,1'-
BIPHENYL]YL)METHYL-1H-PYRAZOLECARBOXAMIDE (130)
Compound 130 (30 mg, yield 34.7%, light yellow solid) was prepared as in
Example 105 from the corresponding starting materials, compound 83D and p-tolylboronic acid.
Compound 130: H NMR (DMSO-d 400MHz) δ 9.14 (br d, J = 7.7 Hz, 1H), 8.11 (br s, 1H),
7.87 (br s, 1H), 7.60 - 7.55 (m, 3H), 7.33 - 7.22 (m, 10H), 6.56 - 6.50 (m, 1H), 5.24 (br s, 1H),
17681897_1 (GHMatters) P110989.NZ
3.20 (br d, J = 13.5 Hz, 1H), 2.87 - 2.78 (m, 1H), 2.33 (s, 3H), 2.24 (s, 3H). MS (ESI) m/z
(M+H) 467.1.
EXAMPLE 50
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)METHYL(6-
METHYLPYRIDINYL)-1H-PYRAZOLECARBOXAMIDE (84)
N Cl N
N NHNH
LiOH
NH NH •H
2 2 2
THF/H O
reflux HOAc, reflux
84A OH
A mixture of compound 84A (5 g, 39.19 mmol) and NH NH .H O (20 g,
2 2 2
391.94 mmol) was heated under reflux (119 °C) for 36 hours. The reaction mixture was
concentrated under reduced pressure to remove the unreacted hydrazine hydrate. The residue
was diluted with H O (30 mL) and extracted with DCM (30 mL x 3). The combined organic
layers were washed with brines (30 mL), dried over Na SO , filtered and concentrated under
reduced pressure to give a residue. The residue was purified by re-crystallization from Petroleum
Ether (15 mL) at -10 °C to give compound 84B (2.40 g, yield: 49.35%) as a black brown solid.
H NMR (400MHz, DMSO-d ) δ 7.39 - 7.29 (m, 1H), 7.25 (s, 1H), 6.51 (d, J = 8.4 Hz, 1H), 6.39
(d, J = 7.3 Hz, 1H), 4.06 (s, 2H), 2.26 (s, 3H). MS (ESI) m/z (M+H) 127.8.
To a solution of compound 84B (970 mg, 7.88 mmol) in AcOH (20 mL) was
added compound ethyl 2-(methoxyimino)oxopentanoate (1.36 g, 7.88 mmol). The mixture
was stirred at 120 °C for 20 hrs. The reaction mixture was concentrated under reduced pressure
to remove solvent. The residue was diluted with H O (30 mL) and extracted with ethyl acetate
(10 mL x 3). The combined organic layers were washed with saturated aqueous NaHCO (15 mL
x 3), dried over Na SO filtered and concentrated under reduced pressure to give a residue. The
2 4,
residue was purified by flash silica gel chromatography, and then by preparatory-HPLC (HCl
condition) to give compound 84C (160 mg, yield: 8.22%) was obtained as a white solid. H
NMR (400MHz, DMSO-d ) δ 7.88 (t, J = 7.8 Hz, 1H), 7.50 (d, J = 8.0 Hz,1H), 7.28 (d, J = 7.5
Hz, 1H), 6.76 (s, 1H), 4.20 (d, J = 7.3 Hz, 2H), 2.43 (s, 3H), 2.28 (s, 3H), 1.14 (t, J = 7.0 Hz,
3H). MS (ESI) m/z (M+H) 246.0.
17681897_1 (GHMatters) P110989.NZ
To a solution of compound 84C (100 mg, 432.43 umol) in THF (5 mL) was
added a solution of LiOH.H O (91 mg, 2.16 mmol) in H O (5 mL) at 0 °C. After addition, the
reaction mixture was stirred for 14 hrs at 25 °C. The reaction mixture was diluted with H O (10
mL) and extracted with MTBE (30 mL). The aqueous phase was neutralized by 1N HCl to the
pH ~ 4 and then was extracted with EtOAc (30 mL x 3). The combined organic layers were
washed with brine (30 mL), dried over Na SO , filtered and concentrated under reduced pressure
to give compound 84D (50 mg, yield: 53.2%) as a red solid. H NMR (400MHz, CDCl ) δ 8.06
(d, J = 8.4 Hz, 1H), 7.89 (t, J = 8.0 Hz, 1H), 7.20 - 7.14 (m, 2H), 2.64 (s, 3H), 2.36 (s, 3H). MS
(ESI) m/z (M +H) 217.9.
Compound 84 (70 mg, yield: 54.12%, white solid) was prepared as in Example
from the corresponding intermediate carboxylic acid, compound 84D. Compound 84: H NMR
(400MHz, DMSO-d ) δ 9.09 (d, J = 7.3 Hz, 1H), 8.04 (s, 1H), 7.81 (s, 1H), 7.76 (t, J = 7.7 Hz,
1H), 7.32 (d, J = 7.9 Hz, 1H), 7.29 - 7.17 (m, 5H), 7.15 (d, J = 7.5 Hz, 1H), 6.44 (s, 1H), 5.37 -
.25 (m, 1H), 3.13 (dd, J = 4.0, 13.9 Hz, 1H), 2.82 (dd, J = 9.7, 13.9 Hz, 1H), 2.24 (s, 6H). MS
(ESI) m/z (M +H) 392.1.
EXAMPLE 51
(S)-N-(4-(CYCLOPROPYLAMINO)-3,4-DIOXOPHENYLBUTANYL)METHYL-
1-(PYRAZINYL)-1H-PYRAZOLECARBOXAMIDE (85)
LiOH H O
MeOH: H O
2 (2:1)
O OH
°C, 1 hr
63B 85B
To a mixture of compound 63B (200 mg, 916.55 umol) in MeOH (10 mL) and
H O (5 mL) was added LiOH•H O (153.8 mg, 3.67 mmol) in one portion and the mixture was
stirred at 25 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to
remove MeOH. The residue was diluted with H O (10 mL), adjusted to pH ~ 3 with 1N HCl, and
then extracted with EtOAc (40 mL x 3). The combined organic layers were washed with brine
(30 mL), dried over anhydrous Na SO4, filtered and concentrated under reduced pressure to
afford intermediate compound 85B (160 mg, 85.49% yield) as a white solid. H NMR (400
17681897_1 (GHMatters) P110989.NZ
MHz, CDCl ) δ 9.60 (br s, 1H), 8.67 (br s, 1H), 8.32 (br s, 1H), 7.25 (br s, 1H), 2.41 (br s, 3H).
MS (ESI) m/z (M+1) 205.0.
Compound 85 (30.7 mg, 59.7% yield, white solid) was prepared as in Example
from the corresponding intermediate carboxylic acid, compound 85B. Compound 85: H
NMR (400 MHz, CDCl ) δ 8.95 (d, J = 4.0 Hz, 1H), 8.22 (d, J = 8.4 Hz, 1H), 7.76 - 7.66 (m,
2H), 7.49 (d, J = 6.4 Hz, 1H), 7.38 (d, J = 8.4 Hz, 1H), 7.24 - 7.16 (m, 3H), 6.87 (d, J =7.6 Hz,
2H), 6.79 (br s, 1H), 6.64 (s, 1H), 6.33 (d, J = 7.2 Hz, 1H), 5.49 - 5.42 (m, 1H), 3.27 - 3.19 (m,
1H), 3.08 - 2.98 (m, 1H), 2.78 - 2.69 (m, 1H), 0.90 - 0.83 (m, 2H), 0.61 - 0.50 (m, 2H). MS
(ESI) m/z (M+H) 419.1.
EXAMPLE 52
(S)-N-(4-(CYCLOPROPYLAMINO)-3,4-DIOXOPHENYLBUTANYL)(1H-
INDAZOLYL)THIAZOLECARBOXAMIDE (86)
N N N
Br O •
O LiOH H2O O
O OH
N MeOH: H O
Cs CO toluene 2 (5:1)
N o N
C, 1 hr
110 32 hrs
C, S S
86B 86C
A mixture consisting of compound 86A (250 mg, 1.06 mmol), 1H-indazole
(125.2 mg, 1.06 mmol) and Cs CO (1.04 g, 3.18 mmol) in toluene (15 mL) was stirred at 110 °C
for 32 hours. The reaction mixture was cooled to room-temperature, filtered, and concentrated
under reduced pressure to give a residue, which was purified by preparatory-HPLC (HCl
condition) to afford compound 86B (20 mg, 6.90% yield) as a white solid. H NMR (CDCl 400
MHz) δ 8.87 (s, 1H), 8.19 (d, J = 0.8 Hz, 1H), 7.75 - 7.70 (m, 1H), 7.54 (d, J = 8.4 Hz, 1H), 7.41
- 7.35 (m, 1H), 7.22 - 7.17 (m, 2H), 4.17 (q, J = 7.2 Hz, 2H), 1.07 (t, J = 7.2 Hz, 3H).
To a mixture of 86B (40 mg, 146.35 umol) in MeOH (5 mL) and H O (1 mL)
was added LiOH•H O (24.6 mg, 585.40 umol) in one portion and the mixture was stirred at 25
°C for 1 hour. The reaction mixture was concentrated under reduced pressure to remove MeOH
and the residue was diluted with H O (10 mL), adjusted to pH ~ 3 with 1N HCl, and then
extracted with EtOAc (40 mL x 3). The combined organic layers were washed with brine (30
mL), dried over anhydrous Na SO , filtered and concentrated under reduced pressure to afford
intermediate compound 86C (30 mg, 83.58% yield) as a white solid. MS (ESI) m/z (M+1)
245.8.
17681897_1 (GHMatters) P110989.NZ
Compound 86 (5.4 mg, 10.0% yield, white solid) was prepared as in Example
from the corresponding intermediate carboxylic acid, compound 86C. Compound 86: H
NMR (400 MHz, CDCl ) δ 10.97 (d, J = 5.2 Hz, 1H), 8.78 (s, 1H), 8.23 (d, J =6.4 Hz, 1H), 7.82
(s, 1H), 7.71 (d, J =3.2 Hz, 1H), 7.54 - 7.44 (m, 1H), 7.32 - 7.23 (m, 1H), 7.11 - 6.96 (m, 5H),
6.85 (br s, 1H), 5.79 - 5.66 (m, 1H), 3.40 - 3.29 (m, 1H), 3.21 - 3.09 (m, 1H), 2.78 - 2.69 (m,
1H), 0.80 (d, J = 6.2 Hz, 2H), 0.55 (br s, 2H). MS (ESI) m/z (M+H) 460.1.
EXAMPLE 53
(S)-N-(4-(CYCLOPROPYLAMINO)-3,4-DIOXOPHENYLBUTANYL)(5-
(OXAZOLYL)PYRIDINYL)-1H-IMIDAZOLECARBOXAMIDE (89)
EtO O
HN O
TosMic, K CO
O 2 3
N OEt
(HO)2 O
O LiOH
O OH
To a solution of compound 89A (40 g, 231 mmol) in MeOH (500 mL) was
added ethyl 2-oxoacetate (188 g, 924 mmol) at 25 °C. The reaction mixture was stirred at 70 °C
for 1hr. The reaction mixture was concentrated to give a residue. The residue was purified by
column chromatography (SiO , Petroleum ether: Ethyl acetate = 50 : 1 to 30 : 1). Compound
89B (70 g, crude) was obtained as yellow oil. MS (ESI) m/z (M+H) 258.8.
To a solution of compound 89B (35 g, 136 mmol) in EtOH (300 mL) was
added TosMIC (66.4 g, 340 mmol) and K CO (28.2 g, 204 mmol) at 25 °C. The reaction
mixture was stirred at 70 °C for 1hr. The reaction mixture was filtered and the filtrate was
concentrated to give a residue. The residue was purified by column chromatography (SiO ,
Petroleumether: Ethylacetate = 20 : 1 to 3 : 1). Compound 89C (17 g) was obtained as a yellow
solid. H NMR (400MHz, CDCl3) δ 8.62 (d, J = 2.4 Hz, 1H), 8.00 - 7.96 (m, 2H), 7.86 (d, J =
17681897_1 (GHMatters) P110989.NZ
0.9 Hz, 1H), 7.36 - 7.32 (m, 1H), 4.27 (q, J = 7.1 Hz, 2H), 1.31 (t, J = 7.2 Hz, 3H). MS (ESI) m/z
(M+H) 297.0.
To a solution of compound 89C (5g, 16.8 mmol) in dioxane (100 mL) was
added bis(pinacolato)diboron (8.58 g, 33.7mmol), KOAc (16.5 g, 168 mmol) at 25 °C. The
mixture was degassed and purged with N for 3 times, followed by addition of Pd(dppf)Cl (617
mg, 844 umol). The reaction mixture was degassed and purged with N for 3 times and stirred at
75 °C for 4hrs. The reaction mixture was concentrated to give a residue. The residue was
purified by column chromatography (SiO , Petroleum ether : Ethyl acetate = 20 : 1 to
Dichloromethane: Methanol = 5 : 1). Compound 89D (2.7 g, yield: 61.2%) was obtained as a
white solid. H NMR (400MHz, methanol-d ) δ 8.63 (br s, 1H), 8.06 (s, 2H), 7.76 (s, 1H), 7.36
(br d, J = 7.1 Hz, 1H), 4.14 (q, J = 7.1 Hz, 2H), 1.14 (t, J = 7.2 Hz, 3H). MS (ESI) m/z (M+H)
261.9.
To a solution of compound 89D (500mg, 1.92 mmol) in dioxane (4 mL) was
added 2-iodooxazole (561.48 mg, 2.88 mmol) K CO (796.09 mg, 5.76 mmol) H O (1 mL) at 25
2 3 2
°C. The reaction mixture was degassed and purged with N . Then Pd(dppf)Cl (140 mg, 192
umol) was added. The mixture was degassed and purged with N and stirred at 150 °C for 1hr
under microwave conditions. The reaction mixture was concentrated to give a residue. The
residue was purified by column chromatography (SiO , Petroleum ether: Ethyl acetate = 10: 1 ~
1.5: 1). Compound 89E (300 mg, crude) was obtained as a grey solid. MS (ESI) m/z (M+H)
285.0.
To a solution of compound 89E (200 mg, 703 umol) in THF (2 mL) H O (500
uL) was added LiOH.H O (59 mg, 1.41 mmol) and stirred at 25 °C for 12 hrs. The reaction
mixture was acidified by HCl (1N) to pH ~ 5, and the precipitation was filtered to give a crude
product. Compound 89F (60 mg, crude) was obtained as a grey solid. MS (ESI) m/z (M+H)
257.0.
Compound 89 (35 mg, yield: 65.4%, white solid) was prepared as in Example
from the corresponding intermediate carboxylic acid, compound 89F. Compound 89: H
NMR (400MHz, DMSO-d ) δ 9.04 - 8.93 (m, 2H), 8.77 (br d, J = 5.1 Hz, 1H), 8.38 - 8.28 (m,
2H), 8.20 (s, 1H), 7.56 (s, 1H), 7.46 (s, 1H), 7.34 (d, J = 8.6 Hz, 1H), 7.29 - 7.22 (m, 4H), 5.32 -
17681897_1 (GHMatters) P110989.NZ
.14 (m, 1H), 3.28 (br s, 1H), 3.20 - 3.10 (m, 1H), 2.81 (br dd, J = 10.1, 13.7 Hz, 1H), 2.77 - 2.69
(m, 1H), 0.73 - 0.42 (m, 4H). MS (ESI) m/z (M+H) 471.1.
EXAMPLE 54
(S)-N-(1-(4-(ALLYLOXY)PHENYL)OXOPROPANYL)METHYL(PYRIDIN
YL)-1H-PYRAZOLECARBOXAMIDE (93)
4M HCl
HN O O
O Dioxane
HBTU
HBTU/ DIEA
OH N N
N H N O
N N O
O N O
93A 93C
Compound 93A (1 g, 1.0 eq), N,O-dimethylhydroxylamine (607 mg, 2 eq) and
HBTU (1.36 g, 1.15 eq) were combined in 10 mL DMF, the mixture was stirred at room
temperature for 5 mins, and then TEA (1.3 mL, 3.0 eq) was added. The resulting mixture was
stirred at room temperature for 1h. The mixture was diluted with 100 mL ethyl acetate and 20
mL Hexane, washed with 0.25N HCl, water, saturated aqueous NaHCO , and brine and
concentrated in vacuo to afford intermediate compound 93B (1 g, yield 88%) as white solid.
To a solution of compound 93B (1 g, 1.0 eq) in 6 mLdry DCM was added 3
mL of 4M HCl in Dioxane. Resulting mixture was stirred at room temperature for 2 hrs. DCM
and Dioxane were removed under vacuo, residue was diluted with EtOAc, washed with saturated
aqueous NaHCO and brine and concentrated in vacuo to afford intermediate compound 93C
(650mg, yield 90%) as white solid.
Compound 93C (125 mg, 1.0 eq), compound 12F (115 mg, 1.2 eq) and HBTU
(226 mg, 1.25 eq) were combined in 5 mL DMF, the mixture was stirred at room temperature for
mins, and then DIEA (0.23 mL, 3.0 eq) was added. The resulting mixture was stirred at room
temperature for 30 mins. The mixture was diluted with 50 mL ethyl acetate and 20 mL Hexane,
washed with water, saturated aqueous NaHCO and brine and concentrated in vacuo to afford
intermediate compound 93D (180 mg, yield 85%).
Compound 6 (90 mg, 1.0 eq) was dissolved in 8 mL dry THF, cooled to -50 C
under N . A solution of 1N LAH in THF (0.22 mL, 1.1 eq) was added dropwise at -50 C. The
17681897_1 (GHMatters) P110989.NZ
resulting mixture was stirred at -30 to -10 C for 2 hrs. The reaction was quenched with
saturated aqueous NaHCO at -20 C, and then extracted with 3 x 15 mL acetate. The combined
organic phase was dried over Na SO . The crude mixture was purified on silica gel column to
provide compound 93 (40 mg, 51%).
EXAMPLE 55
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)METHYL
PHENYLISOTHIAZOLECARBOXAMIDE (96)
NC CN
AlMe ,
Cl S
N conc.
H SO
S Cl ,
Pd(PPh ) 1) 2 4
S dioxane NaNO S
2) 2
Pyridine
96A Cl
96C 96D
To a solution of benzaldehyde (10.00 g, 94.23 mmol) and malononitrile (6.54
g, 98.94 mmol) in EtOH (75.00 mL) was added catalytic piperidine (80.24 mg, 942.30 umol).
Then the reaction was stirred at 90°C for 2h. Yellow solid was precipitated out when the
reaction mixture was cooled to room temperature, the mixture was filtered, the desired yellow
solid was washed with EtOH (20 mL) and dried in vacuo to give intermediate compound 96A
(23.00 g, 79.2% yield) as yellow solid. H NMR (400MHz, CHLOROFORM-d) δ 7.91 (d, J =
7.7 Hz, 2H), 7.79 (s, 1H), 7.67 - 7.60 (m, 1H), 7.58 - 7.50 (m, 2H).
To a mixture of compound 96A (17.50 g, 113.51 mmol) and chlorosulfanyl
thiohypochlorite (70.00 g, 518.36 mmol, 41.42 mL) was added pyridine (900.00 mg, 11.38
mmol). Then the reaction was stirred at 140°C for 16h. The reaction mixture was cooled to
room temperature and quenched with ice/H O (200 mL) and EtOAc (500 mL), yellow solid was
was precipitate out, filtered and the filtrate was extracted with EtOAc(100 mL x 2), the combined
organic was washed with brine (100 mL), dried over Na SO , filtered and the filtrate was
concentrated in vacuo. The residue was purified by flash silica gel chromatography (ISCO®; 120
g SepaFlash® Silica Flash Column, eluent of 0 ~ 10% Ethyl acetate/Petroleum ether gradient @
50 mL/min) to give compound 96B (21.00 g, 70.4% yield) as light yellow solid. H NMR
(400MHz, CHLOROFORM-d) δ 7.77 (br d, J=7.1 Hz, 2H), 7.65 - 7.53 (m, 3H).
To a mixture of compound 96B (2.00 g, 9.06 mmol) in dioxane (150.00 mL)
was added AlMe (2M, 20.00 mL) and Pd(PPh ) (1.05 g, 906.00 umol) under N , Then the
3 3 4 2
17681897_1 (GHMatters) P110989.NZ
reaction was stirred at 110 °C for 3h. The reaction mixture was cooled to room temperature and
quenched with ice/H O(100 mL) and EtOAc(150 mL), yellow solid was precipitate out, filtered
and the filtrate was extracted with EtOAc(60 mL x 2), the combined organic was washed with
brine (70 mL), dried over Na SO , filtered and the filtrate was concentrated in vacuo. The
residue was purified by flash silica gel chromatography (ISCO®;40 g SepaFlash® Silica Flash
Column, eluent of 0 ~ 10% Ethyl acetate/Petroleum ether gradient @ 40 mL/min) to give
compound 96C (700.00 mg, 16.59% yield, 43% purity) as light yellow solid. H NMR
(400MHz, CHLOROFORM-d) δ 7.79 - 7.75 (m, 2H), 7.56 - 7.51 (m, 3H), 2.67 (s, 3H). MS
(ESI) m/z (M+H) 200.9.
To compound 96C (490.00 mg, 2.45 mmol) was added H SO (9.20 g, 93.81
mmol, 5.00 mL), and the reaction was stirred at 135 °C for 1.5h. Then the reaction was cooled to
0 °C and a solution of NaNO (339.79 mg, 4.92 mmol) in H O (2.00 mL) was added to the above
mixture and the reaction mixture was stirred at 70 °C for 1h. The reaction mixture was cooled to
room temperature and poured into ice/H O(40 mL) and EtOAc(40 mL), extracted with EtOAc(50
mL x 2), the combined organic was extracted with 0.1N NaOH (40 mL x 2), the desired basic
water phase was then added 1N HCl to pH<4, then extracted with EtOAc(40 mL x 3) and washed
with brine (40 mL), dried over Na SO , filtered and the filtrate was concentrated in vacuo to give
compound 96D (410.00 mg, 76.25% yield) as light yellow solid. H NMR (400MHz, DMSO-d )
δ 7.49 (s, 5H), 2.57 (s, 3H). MS (ESI) m/z (M+H) 219.9.
Compound 96 (35 mg, yield: 65.86%, white solid) was prepared as in Example
from the corresponding intermediate carboxylic acid, compound 96D. Compound 96: H NMR
(400MHz, CD CN) δ 7.48 - 7.33 (m, 5H), 7.29 - 7.17 (m, 3H), 7.15 - 7.06 (m, 3H), 7.01 (br s,
1H), 6.26 (br s, 1H), 5.56 (ddd, J=4.4, 7.5, 9.5 Hz, 1H), 3.23 (dd, J=4.3, 14.2 Hz, 1H), 2.77 (dd,
J=9.5, 14.3 Hz, 1H), 2.28 (s, 3H). MS (ESI) m/z (M+H) 394.1.
17681897_1 (GHMatters) P110989.NZ
EXAMPLE 56
(S)-N-(4-AMINO(3,5-DIMETHYLPHENYL)-3,4-DIOXOBUTANYL)METHYL
PHENYLISOXAZOLECARBOXAMIDE (97)
H LiAlH , THF
O O O
EDCI, HOBt
OH O
O N O NH O N
K H O
CN CO , O ,
2 3 2 2 HCl/dioxane
H N NH
DMSO 2 2
BocHN NH
Et DCM 2
O N OH
H 97E
OH O O
CONH
N NH
A mixture of compound 97A (1.0 g, 3.41 mmol), compound N,O-
dimethylhydroxylamine (400 mg, 4.09 mmol, HCl) , HOBt (460 mg, 3.41 mmol) and NMM
(1.03 g, 10.23 mmol, 1.12 mL) in CHCl (20 mL) was degassed and purged with N for 3 times
at 0 °C, then EDCI (980 mg, 5.12 mmol) was added in portions. The mixture was stirred at 25
°C for 20 h under N atmosphere. The reaction mixture was quenched by addition H O (20 mL),
and then diluted with DCM (10 mL). The combined organic layers were washed with 1N HCl
(15 mL x 2), saturated aqueous NaHCO (15 mL x 2) and brine (20 mL), dried over Na2SO4,
filtered and concentrated under reduced pressure to give the compound 97B (1.13 g, yield:
98.5%) was obtained as a white solid. H NMR (400MHz, DMSO-d ) δ 7.08 (br d, J = 8.2 Hz,
1H), 6.82 (s, 3H), 4.55 (br s, 1H), 3.71 (br s, 3H), 3.09 (s, 3H), 2.82 - 2.72 (m, 1H), 2.68 - 2.58
(m, 1H), 2.22 (s, 6H), 1.32 (s, 9H).
To a solution of LAH (255 mg, 6.72 mmol) in THF (10 mL) was degassed and
purged with N for 3 times at 0 °C , and the mixture of compound 97B (1.13 g, 3.36 mmol) in
THF (20 mL) was added dropwise, and then the mixture was stirred at 0 °C for 2 h under N
atmosphere. The reaction mixture was quenched by addition EtOAc (10 mL), then added 1N
17681897_1 (GHMatters) P110989.NZ
HCl (50 mL), and then diluted with EtOAc (20 mL), dried over Na SO , and stirred for 30 min,
then filtered to give the organic layers. The combined organic layers were washed with brine (20
mL x 2), dried over Na SO , filtered and concentrated under reduced pressure to give the
compound 97C (860 mg, yield: 92.3%) was obtained as a white solid. H NMR (400MHz,
DMSO-d ) δ 9.48 (s, 1H), 7.24 (br d, J = 7.7 Hz, 1H), 6.85 - 6.73 (m, 3H), 4.08 - 3.94 (m, 1H),
3.04 - 2.91 (m, 1H), 2.70 - 2.57 (m, 1H), 2.20 (s, 6H), 1.39 - 1.19 (m, 9H).
To a solution of compound 97C (860 mg, 3.10 mmol) in DCM (10 mL) was
added compound 2-hydroxymethylpropanenitrile (530 mg, 6.20 mmol, 570 µL) and Et N (470
mg, 4.65 mmol, 650 µL). The mixture was stirred at 25 °C for 22 h. The reaction mixture was
quenched by addition 1N HCl (20 mL), and then diluted with H O (20 mL) and extracted with
DCM (20 mL x 2). The combined organic layers were washed with brine (20 mL x 3), dried over
Na SO , filtered and concentrated under reduced pressure to give the compound 97D (930.00
mg, yield: 98.6%) was obtained as a yellow solid. H NMR (400MHz, DMSO-d ) δ 7.19 - 6.99
(m, 1H), 6.91 - 6.78 (m, 3H), 6.77 - 6.51 (m, 1H), 4.66 - 4.34 (m, 1H), 3.84 (br s, 1H), 2.99 -
2.81 (m, 1H), 2.75 - 2.60 (m, 1H), 2.27 (br s, 6H), 1.40 - 1.20 (m, 9H).
To a solution of compound 97D (930 mg, 3.63 mmol) and K CO (850 mg,
6.11 mmol) in DMSO (10 mL) was added H O (3.46 g, 30.55 mmol, 2.94 mL, purity: 30%).
The mixture was stirred at 0 °C for 2 h. The reaction mixture was diluted with H O (100 mL)
and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine
(50 mL x 2), dried over Na SO , filtered and concentrated under reduced pressure to give a
residue. The residue was stirred in DCM (3 mL) and PE (25 mL) for 30 min and filtered to give
the compound 5 (970 mg, yield: 98.32%) was obtained as a white solid. H NMR (400MHz,
DMSO-d ) δ 7.42 - 7.08 (m, 1H), 6.86 - 6.45 (m, 3H), 6.21 - 5.49 (m, 1H), 4.06 - 3.82 (m, 1H),
3.31 (s, 1H), 2.72 - 2.52 (m, 2H), 2.26 - 2.13 (m, 6H), 1.40 - 1.18 (m, 9H).
To a solution of compound 97E (970 mg, 3.01 mmol) in EtOAc (5 mL) was
added HCl/EtOAc (4M, 5 mL). The mixture was stirred at 25 °C for 3 h. The reaction mixture
was diluted with PE (20 mL), filtered and concentrated under reduced pressure to give the
compound 97F (370 mg, yield: 43.7%, HCl) was obtained as a white solid. H NMR (400MHz,
DMSO-d ) δ 8.09 - 7.89 (m, 3H), 7.58 (br s, 2H), 6.96 (br s, 2H), 6.89 (s, 1H), 4.26 (br s, 1H),
17681897_1 (GHMatters) P110989.NZ
3.89 (br s, 1H), 3.69 - 3.57 (m, 1H), 2.91 - 2.73 (m, 2H), 2.30 (br s, 6H). MS (ESI) m/z (M+H)
223.1.
A mixture of compound 97F (310 mg, 1.18 mmol, HCl), compound 6A (200
mg, 984.30 umol), HOBT (133 mg, 984.30 umol) and DIEA (520 uL, 2.95 mmol) in DCM (15
mL) was added EDCI (285 mg, 1.48 mmol), and then the mixture was stirred at 25°C for 18 h.
The reaction mixture was washed with H O (20 mL x 2). The combined organic layers were
washed with HCl (1N, 30 mL), saturated aqueous NaHCO (30mL) and brine (50 mL), dried
over Na SO , filtered and concentrated under reduced pressure to give a residue. The residue was
stirred in Petroleum Ether (5 mL) and DCM (1 mL) for 30 min and filtered to give the compound
97G (270 mg, yield: 61.9%) was obtained as a white solid. H NMR (400MHz, DMSO-d ) δ
8.59 - 8.24 (m, 1H), 7.64 - 7.51 (m, 2H), 7.49 - 7.28 (m, 5H), 6.89 - 6.77 (m, 3H), 5.98 - 5.63 (m,
1H), 4.61 - 4.49 (m, 1H), 4.11 - 3.86 (m, 1H), 2.86 - 2.59 (m, 2H), 2.21 - 2.03 (m, 9H). MS
(ESI) m/z (M+H) 408.1.
To a solution of compound 97G (100 mg, 245.42 umol) in DCM (10 mL) was
added DMP (320 mg, 736.26 umol) at 0 °C. The mixture was stirred at 25°C for 7 h. The
reaction mixture was quenched by addition saturated aqueous Na S O (15 mL) and saturated
2 2 3
aqueous NaHCO (15mL), the mixture was stirred for 0.2 h, and then diluted with DCM (10 mL)
and extracted with H O (20 mL x 3). The combined organic layers were washed with brine (20
mL), dried over Na SO , filtered and concentrated under reduced pressure to give a residue. The
residue was stirred in Petroleum Ether (15 mL) and EtOAc (1 mL) for 30 min and filtered to give
the compound 97 (60 mg, yield: 60.3%) was obtained as a white solid. H NMR (400MHz,
DMSO-d ) δ 9.01 (br d, J = 7.5 Hz, 1H), 8.18 (br s, 1H), 7.90 (br s, 1H), 7.64 (br d, J=7.3 Hz,
2H), 7.53 - 7.46 (m, 1H), 7.45 - 7.38 (m, 2H), 6.92 - 6.81 (m, 3H), 5.40 (br t, J = 7.3 Hz, 1H),
3.15 (br d, J=10.6 Hz, 1H), 2.72 - 2.58 (m, 1H), 2.18 (s, 6H), 2.11 (s, 3H). MS (ESI) m/z
406.1.
(M+H)
17681897_1 (GHMatters) P110989.NZ
EXAMPLE 57
(S)-N-(4-AMINO(3,5-DIMETHYLPHENYL)-3,4-DIOXOBUTANYL)METHYL
PHENYLISOXAZOLECARBOXAMIDE (98)
Cl Cl
NaHSO , MeOH/H O
LiAlH , THF 1) 3 2
HN(Me)OMe
EDCI, HOBt Cl
NaCN, EtOAc Cl
BocHN
BocHN BocHN
BocHN
Cl Cl
K H 7
CO , O
2 3 2 2 O O
HCl/dioxane
DMSO
EDCI, HOBt,
OH O
OH 2
BocHN
N HO
DIPEA, DCM/DMF
O NH NH
2 2 98G
To a solution of compound 98A (1.0 g, 2.99 mmol) and N-
methoxymethanamine (321 mg, 3.29 mmol, HCl) in CHCl (30 mL) was added HOBt (404 mg,
2.99 mmol,) and EDCI (803 mg, 4.19 mmol). Then NMM (1.3 mL, 11.96 mmol) was added into
the reaction mixture. After addition, the reaction mixture was stirred at 28 °C for 14 h. The
reaction mixture was concentrated in vacuum and the residue was dissolved into 80 mL of
EtOAc. The mixture was washed with 1N HCl (30 mL x 2) and saturated aqueous NaHCO (30
mL x 2), then brine (30 mL). The mixture was dried over Na SO and concentrated in vacuum to
afford compound 98B (1.1 g, yield 82.9%) as white solid. H NMR (400MHz, DMSO-d6) δ 7.44
(s, 1H), 7.34 - 7.19 (m, 3H), 4.55 (br s, 1H), 3.71 (br s, 3H), 3.17 - 3.00 (m, 3H), 2.90 - 2.80 (m,
1H), 2.76 - 2.67 (m, 1H), 1.29 (s, 8H). MS (ESI) m/z (M-56) 320.9.
To a solution of LiAlH (122 mg, 3.21 mmol) in THF (10 mL) was added a
solution of compound 98B (1.1 g, 2.92 mmol) in THF (20 mL) at 0 °C under N atmosphere.
After addition, the reaction mixture was stirred at 0 °C for 1h. 2 mL of EtOAc was added into
the reaction mixture at 0 °C and the mixture was stirred for 10 min. Then 2 mL of 1N HCl was
added into the reaction mixture slowly. After addition, the mixture was diluted with 80 mL of
EtOAc and the mixture was washed with 1 N HCl (30 mL x 2), brine (30 mL). Then the mixture
was dried over Na SO and concentrated in vacuum to afford compound 98C (800 mg, yield
17681897_1 (GHMatters) P110989.NZ
80.9%) as white solid. H NMR (400MHz, DMSO-d ) δ 9.52 (s, 1H), 7.53 - 7.17 (m, 4H), 4.20 -
4.08(m, 1H), 3.19 -3.08 (m, 1H), 2.72 - 2.63 (m, 1H), 1.37 - 1.27 (m, 9H).
To a solution of compound 98C (800 mg, 2.51 mmol) in MeOH (10 mL) was
added dropwise a solution of NaHSO (261 mg, 2.51 mmol) in H O (15 mL) at 0-5 °C. After
that, the reaction mixture was stirred at 25 °C for 5h. NaCN (129 mg, 2.64 mmol) in H O (20
mL) was added into the reaction mixture followed by EtOAc (40 mL). After that, the reaction
mixture was stirred at 25 °C for 14h. The organic layer was separated and washed with brine (30
mL), then dried over Na SO .The mixture was concentrated to afford compound 98D (800 mg,
yield 92.33%) as light yellow gum. H NMR (400MHz, DMSO-d ) δ 7.46 - 7.22 (m, 3H), 7.16 -
7.02 (m, 1H), 6.89 - 6.70 (m, 1H), 4.65 - 4.30 (m, 1H), 3.95 - 3.76 (m, 1H), 3.07 - 2.87 (m, 1H),
2.76 -2.55 (m, 1H), 1.32 - 1.20 (m, 8H).
To a solution of compound 98D (800 mg, 2.32 mmol) and K CO (641 mg,
4.64 mmol) in DMSO (8 mL) was added H O (2 mL, 22.25 mmol, 30% purity) at 0 °C. After
addition, the reaction mixture was stirred at 0 °C for 1h. The reaction mixture was diluted with
ice water (20 mL) and 50 mL of saturated aqueous Na SO . The mixture was extracted with
EtOAc (50 mL x 3) and the combined extracts were washed with saturated aqueous Na SO (50
mL x 2). The organic layer was dried over Na SO and concentrated to afford crude compound.
The crude compound was diluted with MTBE (5 mL) and filtered to afford compound 98E (800
mg, yield 94.9%) as white solid. H NMR (400MHz, DMSO-d ) δ 7.48 - 7.12 (m, 5H), 6.73 -
6.20 (m, 1H), 5.86 - 5.63 (m, 1H), 4.04 - 3.71 (m, 2H), 2.86 - 2.54 (m, 1H), 1.34 - 1.19 (m, 9H).
MS (ESI) m/z (M +23) 384.9.
To a solution of compound 98E (800 mg, 2.20 mmol) in EtOAc (10 mL) was
added HCl/EtOAc (4M, 55 mL). After addition, the reaction mixture was stirred at 26 °C for 1h.
mL of Petroleum ether was added into the reaction mixture and the mixture was filtered to
afford compound 98F (400 mg, yield 58.87%, HCl) as white solid. H NMR (400MHz, DMSO-
d ) δ 8.35 (br s, 1H), 8.14 (br s, 1H), 7.62 - 7.41 (m, 3H), 7.33 (d, J=1.8 Hz, 1H), 6.90 - 6.50 (m,
1H), 4.28 (br s, 1H), 3.94 - 3.84 (m, 1H), 3.77 - 3.56 (m, 1H), 3.03 - 2.80 (m, 2H).
To a solution of compound 7 (100 mg, 492.15 umol) and compound 98F (162
mg, 541.37 umol, HCl) in DMF (10 mL) was added HOBT (67 mg, 492.15 umol) and DIEA
(340 uL, 1.97 mmol), then EDCI (133 mg, 689.01 umol) was added. After addition, the reaction
17681897_1 (GHMatters) P110989.NZ
mixture was stirred at 26 °C for 14h. The mixture was diluted with 30 mL of EtOAc. The
mixture was washed with 1N HCl (15 mL x 2) and saturated aqueous NaHCO (15 mL x 3), then
brine (20 mL). The residue was dried over Na SO and concentrated in vacuum. The residue
was diluted with 4 mL of EtOAc and filtered to afford compound 98G (110 mg, yield 45.87%) as
white solid. H NMR (400MHz, DMSO-d ) δ 8.65 - 8.26 (m, 1H), 7.60 - 7.30 (m, 9H), 7.28 -
7.17 (m, 1H), 6.04 - 5.65 (m, 1H), 4.73 - 4.56 (m, 1H), 4.11 - 4.06 (m, 0.5H), 4.01 - 3.95 (m,
0.5H), 3.01 - 2.70 (m, 2H), 2.18 - 2.09 (m, 3H). MS (ESI) m/z (M +H) 448.1.
To a solution of compound 98G (110 mg, 245.37 umol) in DCM (30 mL) and
DMSO (4 mL) was added DMP (416 mg, 981.48 umol). After addition, the reaction mixture was
stirred at 26 °C for 2h. 10 mL of saturated aqueous Na S O and 10 mL of saturated aqueous
2 2 3
NaHCO was added into the reaction mixture, and the mixture was stirred for 20 min. Then the
mixture was separated, the organic layer was washed with 10 mL of saturated aqueous Na S O
2 2 3
and 10 mL of saturated aqueous NaHCO , then water (20 mL) and brine (20 mL). The mixture
was dried over Na SO and concentrated in vacuum to afford compound 98 (30 mg, yield
24.66%) as light yellow solid. H NMR (400MHz, DMSO-d ) δ 9.08 (d, J=7.5 Hz, 1H), 8.21 (s,
1H), 7.94 (s,1H), 7.68 - 7.58 (m, 2H), 7.54 - 7.42 (m, 4H), 7.34 (d, J=1.8 Hz, 2H), 5.45 - 5.33
(m, 1H), 3.28 - 3.19 (m, 1H), 2.83 - 2.73 (m, 1H), 2.12 (s, 3H). MS (ESI) m/z (M +H) 446.0.
EXAMPLE 58
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)(6-METHOXYPYRIDIN
YL)METHYL-1H-PYRAZOLECARBOXAMIDE (99)
N NHNH
O LiOH
THF/H O OH
HOAc, reflux O
A mixture of compound 2-chloromethoxypyridine (5.0 g, 34.83 mmol) in
NH NH H O (17.44 g, 348.30 mmol, 16.93 mL) was stirred at 120 °C for 16h. The reaction
2 2 2
mixture was concentrated under reduced pressure to give a residue .then diluted with H O (30
mL) and extracted with ethyl acetate (40 mL). The combined organic layers were washed with
brine (50 mL), dried over Na SO , filtered and concentrated under reduced pressure to give a
residue. The residue was purified by column chromatography (SiO , Petroleum ether/Ethyl
17681897_1 (GHMatters) P110989.NZ
acetate = 5:1 to 1:1) to give compound 99B (1.06 g, 21.87% yield) as a yellow oil. H NMR
(400MHz, CDCl ) δ 7.41 (t, J=7.8 Hz, 1H), 6.24 - 6.08 (m, 2H), 5.73 (br s, 1H), 3.86 (s, 3H),
3.83 - 2.75 (m, 2H). MS (ESI) m/z (M+H) 140.1.
A mixture of compound 99B (1.00 g, 7.19 mmol) and ethyl 2-(methoxyimino)-
4-oxopentanoate (1.35 g, 7.19 mmol) in HOAc (20.00 mL) was stirred at 120 °C for 16h. The
reaction mixture was concentrated under reduced pressure to remove HOAc. The residue was
diluted with H O (20 mL) and extracted with ethyl acetate (20 mL). The combined organic
layers were washed with brine (20 mL), dried over Na SO , concentrated under reduced pressure
to give a residue. The residue was purified by column chromatography (SiO , Petroleum
ether/Ethyl acetate = 1:0 to 5:1) and further purified by preparatory-HPLC (TFA condition) to
give compound 99C (487.00 mg, 25.87% yield) was obtained as a yellow oil. H NMR
(400MHz, CDCl ) δ 7.70 (t, J=7.9 Hz, 1H), 7.21 (d, J=7.5 Hz, 1H), 6.71 (d, J=8.2 Hz, 1H), 6.66
(s, 1H), 4.27 (q, J=7.2 Hz, 2H), 3.85 (s, 3H), 2.36 (s, 3H), 1.25 (t, J=7.2 Hz, 3H). MS (ESI) m/z
(M+H) 261.9.
To a solution of compound 99C (487.00 mg, 1.99 mmol) in THF (15.00 mL)
was added LiOH H O (417.50 mg, 9.95 mmol) in H O (5.00 mL). The mixture was stirred at 28
°C for 16h. The reaction mixture was diluted with H O (10 mL) and extracted with MTBE (15
mL x 2), the water phase was added 1N HCl to pH = 3~4, extracted with EA (15 mL x 2). The
combined organic layers were washed with brine (15 mL), dried over Na SO , filtered and
concentrated under reduced pressure to give intermediate compound 99D (396 mg, 91.61% yield)
as a white solid. Compound 99D: H NMR (400MHz, DMSO-d ) δ 7.86 (t, J=7.8 Hz, 1H), 7.26
(d, J=7.5 Hz, 1H), 6.80 (d, J=8.2 Hz, 1H), 6.67 (s, 1H), 3.80 (s, 3H), 2.26 (s, 3H). MS (ESI) m/z
(M+H) 234.1.
Compound 99 (10.00 mg, 13.78% yield, white solid) was prepared as in
Example 5 from the corresponding intermediate carboxylic acid, compound 99D. Compound 99:
H NMR (400MHz, CDCl ) δ 7.68 (br t, J=7.9 Hz, 1H), 7.26 - 7.18 (m, 4H), 7.12 - 7.01 (m, 3H),
6.73 (br s, 1H), 6.68 - 6.60 (m, 1H), 6.65 (br d, J=8.2 Hz, 1H), 6.50 (s, 1H), 5.73 - 5.64 (m, 1H),
.50 (br s, 1H), 3.67 (s, 3H), 3.45 - 3.35 (m, 1H), 3.25 - 3.11 (m, 1H), 2.33 (s, 3H). MS (ESI)
m/z (M+H) 408.1.
17681897_1 (GHMatters) P110989.NZ
EXAMPLE 59
COMPOUNDS 101, 493
(S)-N-(4-((3,4-DICHLOROBENZYL)AMINO)-3,4-DIOXOPHENYLBUTANYL)
METHYLPHENYLISOXAZOLECARBOXAMIDE (101)
OH EDCI O O
ethyl acetate
N N O
101B
101A
DMP TMSCN O
N CN
DCM TEA,
N O H
OSi(CH
101C
101D
conc.HCl
N OH
O EDCI,DIEA, H H
H Cl
N OH
N HOBT
101F
101E
To a solution of compound 23A (20.00 g, 98.43 mmol) in THF (300 mL) was
added 1-hydroxypyrrolidine-2,5-dione (12.46 g, 108.27 mmol) and EDCI (22.64 g, 118.12
mmol) with DCM (200 mL). The mixture was stirred at 25 °C for 12 hours. The reaction
mixture was concentrated and diluted with ethyl acetate (200 mL). Then the mixture was washed
with HCl (1M, 200 mL), saturated aqueous NaHCO (200 mL), dried over Na2SO4 and
concentrated. Compound 101A (28.00 g, crude) was obtained as a yellow oil. H NMR
(400MHz, DMSO-d ) δ 7.94 - 7.88 (m, 2H), 7.69 - 7.63 (m, 1H), 7.62 - 7.56 (m, 2H), 2.87 (br s,
4H), 2.50 - 2.48 (m, 3H).
To a solution of compound 101A (28.00 g, 93.25 mmol) in DMF (200 mL)
was added (2S)aminophenyl-propanol (15.51 g, 102.57 mmol). The mixture was stirred
at 25 °C for 12 hour. The mixture was diluted with H O (1000 mL), extracted with ethyl acetate
(1000 mL), the organic layer was washed with HCl (aqueous 1000 mL), NaHCO (aqueous 1000
mL), dried over Na SO and concentrated. Compound 3 (20.00 g, yield 63.8%) was obtained as a
white solid. H NMR (400MHz, DMSO-d ) δ 8.45 (br d, J = 8.8 Hz, 1H), 7.66 - 7.61 (m, 2H),
17681897_1 (GHMatters) P110989.NZ
7.53 - 7.40 (m, 3H), 7.32 - 7.18 (m, 5H), 4.97 - 4.92 (m, 1H), 4.33 - 4.23 (m, 1H), 3.54 - 3.41 (m,
2H), 3.01 - 2.97 (m, 1H), 2.69 - 2.57 (m, 1H), 2.06 (s, 3H).
To a solution of compound 101B (3.00 g, 8.92 mmol) in DCM (100 mL) was
added DMP (5.67 g, 13.38 mmol). The mixture was stirred at 25 °C for 3 hour. The mixture
quenched with 10% Na S O (aqueous): saturated NaHCO (aqueous) (1:1, 200 mL), extracted
2 2 3 3
with DCM (200 mL) and washed with brine (200 mL x 3). The combined organic layers were
dried over Na SO and concentrated. Compound 101C (2.70 g, yield 90.5%) was obtained as a
white solid. H NMR (400MHz, DMSO-d ) δ 9.66 (s, 1H), 8.91 (d, J = 8.4 Hz, 1H), 7.67 - 7.63
(m, 2H), 7.53 - 7.47 (m, 1H), 7.46 - 7.40 (m, 2H), 7.29 - 7.19 (m, 5H), 4.79 - 4.72 (m, 1H), 3.37 -
3.32 (m, 1H), 2.81 - 2.72 (m, 1H), 2.09 (s, 3H).
To a solution of compound 101C (500.0 mg, 1.50 mmol) in DCM (20 mL)
was added TMSCN (223.2 mg, 2.25 mmol, 280 uL) and TEA (15.2 mg, 150.00 umol, 20 uL).
The mixture was stirred at 0 °C for 3 hours. The mixture was concentrated, diluted with ethyl
acetate (20 mL), washed with water (20 mL), brine (20 mL), dried over Na SO and concentrated
to obtain compound 101D (600.0 mg, crude) as colorless oil.
To a solution of compound 101D (600.0 mg, 1.41 mmol) in THF (10 mL) was
added HCl (10 mL). The mixture was stirred at 60 °C for 12 hours. The mixture was diluted
with H O (200 mL), extracted with ethyl acetate (100 mL), the organic layer was washed with
NaHCO (aqueous 100 mL), the water phase was added HCl (1M) until pH ~ 1, then extracted
with ethyl acetate (100 mL), the organic layer was washed with brine (100 mL), dried over
Na SO and concentrated. Compound 101E (240.0 mg, crude) was obtained as a colorless oil
and used in next step directly.
To a solution of compound 101E (200.0 mg, 526 umol) in THF (10.00 mL)
was added (3,4-dichlorophenyl)methanamine (92.6 mg, 525.78 umol, 70 uL), DIEA (203.85 mg,
1.58 mmol, 275.48 uL), HOBt (71.04 mg, 525.78 umol) and EDCI (120.95 mg, 630.93 umol).
The mixture was stirred at 25 °C for 4 hours. The mixture was concentrated and diluted with
ethyl acetate (50 mL), washed with HCl (1M, 50 mL), saturated NaHCO (aqueous 50 mL), brine
(50 mL x 3), dried over Na SO and concentrated. The mixture was triturated with CH CN (5
2 4 3
mL) and filtered. Compound 101F (70.0 mg, yield 24.7%) obtained as a white solid. H NMR
(400MHz, DMSO-d ) δ 8.63 - 8.53 (m, 1H), 8.30 (d, J = 9.2 Hz, 1H), 7.58 - 7.10 (m, 13H), 6.20
17681897_1 (GHMatters) P110989.NZ
- 5.94 (m, 1H), 4.68 - 4.57 (m, 1H), 4.32 - 4.16 (m, 2H), 4.08 - 3.99 (m, 1H), 2.97 - 2.67 (m, 2H),
2.07 - 1.96 (m, 1H), 2.07 - 1.96 (m, 2H).
To a solution of compound 101F (60.0 mg, 111.44 umol,) in DCM (10 mL)
and DMSO (1.00 mL) was added DMP (141.8 mg, 334.32 umol). The mixture was stirred at 25
°C for 3 hours. The mixture quenched with 10% Na S O (aqueous): saturated NaHCO
2 2 3 3
(aqueous) (1:1, 20 mL), extracted with DCM (10 mL) and washed with brine (20 mL x 3). The
combined organic layers were dried over Na SO and concentrated. Compound 101 (33.2 mg,
yield 55.5%) was obtained as a white solid. H NMR (400MHz, DMSO-d ) δ 9.52 - 9.43 (m,
1H), 9.12 (d, J = 7.6 Hz, 1H), 7.69 - 7.38 (m, 7H), 7.35 - 7.20 (m, 6H), 5.53 - 5.42 (m, 1H), 4.40
- 4.32 (m, 2H), 3.31 - 3.19 (m, 1H), 2.93 - 2.71 (m, 1H), 2.12 - 2.00 (m, 3H). MS (ESI) m/z
(M+H) 536.1.
(S)-N-(4-(((1H-BENZO[d]IMIDAZOLYL)METHYL)AMINO)-3,4-DIOXO
PHENYLBUTANYL)METHYLPHENYLISOXAZOLECARBOXAMIDE (493)
Compound 493 (20 mg, 23.4% yield, yellow solid) was prepared as in
compound 101 from the corresponding intermediate carboxylic acid, compound 101E and (1-((2-
(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazolyl)methanamine followed by removal of
the 2-(trimethylsilyl)ethoxy)methyl group to obtain compound 493. Compound 493: H NMR
(400MHz, DMSO-d ) δ 8.07 (s, 1H), 7.67 - 7.59 (m, 3H), 7.56 (br s, 1H), 7.52 - 7.38 (m, 4H),
7.30 (br s, 1H), 7.25 - 7.14 (m, 4H), 6.89 (br d, J = 6.2 Hz, 2H), 6.12 (br d, J = 6.8 Hz, 1H), 5.72
- 5.63 (m, 1H), 4.62 (br d, J = 5.5 Hz, 2H), 3.37 (br dd, J = 4.7, 14.0 Hz, 1H), 2.99 (br dd, J =
7.9, 14.3 Hz, 1H), 2.33 (s, 3H). MS (ESI) m/z (M+H) 378.1.
EXAMPLE 60
(S)(1H-INDAZOLYL)-N-(1-OXOPHENYLPROPANYL)-1H-IMIDAZOLE
CARBOXAMIDE (102)
2 O N
NaOH
TOSMIC
N OH
K CO /EtOH 80 C
N 2 3
102C
102B
102A
To a solution of 1H-indazolamine (8.7 g, 65.3 mmol) in MeOH (90 mL)
was added ethyl 2-oxoacetate (20 g, 98.01 mmol). The mixture was stirred at 25°C for 2 hours.
17681897_1 (GHMatters) P110989.NZ
The mixture was filtered and concentrated to give crude product 102A (15 g, crude) as brown
solid, which was used for the next step without purification.
To a solution of 102A (15 g, 69.1 mmol) in EtOH (400 mL) was added K CO
(14.5 g, 104 mmol) and TosMIC (11.6 g 59.4 mmol). The mixture was stirred at 90 °C for 0.5
hour. The reaction mixture was filtered and concentrated under reduced pressure to give a
residue. The residue was purified by column chromatography (SiO , Petroleum ether/Ethyl
acetate = 1:0 to 1:1) to give compound 102B (2.9 g, yield: 16.4%) as yellow solid. H NMR
(400MHz, CDCl ) δ 11.04 (br s, 1H), 7.98 (d, J = 0.7 Hz, 1H), 7.91 (s, 1H), 7.48 - 7.41 (m, 3H),
7.25 - 7.19 (m, 1H), 4.24 - 4.14 (m, 2H), 1.14 (t, J = 7.1 Hz, 3H).
To a solution of 102B (2.9 g, 11.3 mmol) in THF (40 mL) and H O (8 mL)
was added NaOH (905 mg, 22.6 mmol). The mixture was stirred at 25 °C for 10 hours. The
mixture was concentrated under reduced pressure to remove the organic solvent, and extracted
with EtOAc (20 mL). The aqueous layer was acidified with 1M HCl to pH ~ 5 and then
extracted with EtOAc (30 mL x 3). The combined organic layer was washed with H O (40 mL),
brine (40 mL), dried over Na SO , filtered and concentrated to give 102C (1.5 g, yield: 58.1%) as
yellow solid. H NMR (400MHz, DMSO-d ) δ 13.35 (s, 1H), 8.16 (s, 1H), 7.83 (s, 1H), 7.61 (d,
J = 8.3 Hz, 1H), 7.47 - 7.41 (m, 2H), 7.20 - 7.15 (m, 1H). MS (ESI) m/z (M+H) 228.9.
Compound 102 (20 mg, yield 52.9%, pale yellow solid) was prepared as in
Example 6 from the corresponding intermediate compounds 102C and 21G ((S)amino
phenylpropanol). Compound 102: H NMR (DMSO-d 400 MHz) δ 13.22 (s, 1H), 9.48 (s,
1H), 8.95 (d, J = 8.0 Hz, 1H), 8.07 (s, 1H), 7.72 (s, 1H), 7.59 - 7.51 (m, 1H), 7.42 - 7.40 (m, 1H),
7.31 - 7.24 (m, 2H), 7.24 - 7.18 (m, 4H), 7.12 - 7.06 (m, 1H), 7.06 - 7.06 (m, 1H), 4.34 - 4.23 (m,
1H), 3.19- 3.15 (m, 1H), 2.77 - 2.74(m, 1H). MS (ESI) m/z (M+H) 360.1.
EXAMPLE 61
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)METHYL(3'-METHYL-
[1,1'-BIPHENYL]YL)-1H-PYRAZOLECARBOXAMIDE (105)
DMSO/DCM
N NH
105A
17681897_1 (GHMatters) P110989.NZ
To a mixture of compound 103A (150 mg, 0.33 mmol) and m-tolylboronic
acid (89 mg, 0.66 mmol) in THF (50 mL) was added H O (10 mL), Na CO (70 mg, 0.66 mmol)
2 2 3
and Pd(PPh ) (38 mg, 0.033 mmol) in one portion at 25 °C under N . The mixture was stirred at
3 4 2
80 °C for 12h. The reaction mixture was added H O (100 mL) and extracted with EA (100 mL x
3). The combined organic layer was washed with saturated aqueous NaHCO (150 mL x 3),
brine (150 mL x 3), dried over Na SO and concentrated. The crude product was treated with i-
propyl ether/CH CN (10/1, 10 mL). The solid was collected and dried in vacuo to afford
compound 2A (72.7 mg, yield 42.70%) as gray solid. Compound 105A: H NMR (DMSO-d
400 MHz) δ 8.51 - 8.10 (m, 1H), 7.60 - 7.52 (m, 2H), 7.47 - 7.38 (m, 2H), 7.36 - 7.28 (m, 3H),
7.26 - 7.12 (m, 7H), 7.03 - 6.93 (m, 1H), 6.57 (d, J = 3.3 Hz, 1H), 5.93 - 5.73 (m, 1H), 4.49 -
4.29 (m, 1H), 4.04 - 3.86 (m, 1H), 2.90 - 2.81 (m, 1H), 2.81 - 2.72 (m, 1H), 2.35 (s, 3H), 2.24 (s,
3H). MS (ESI) m/z (M+H) 469.2.
To a mixture of compound 105A (65 mg, 0.14 mmol) in DCM (10 mL) and
DMSO (1 mL) was added DMP (177 mg, 0.42 mmol) in one portion at 0 °C. The mixture was
stirred at 0 °C for 10 min, then temperature to 25 °C and stirred for 2 hours. The reaction was
quenched by 20 mL of 10 % Na S O aquoeus solution and 20 mL of saturated aqueous NaHCO
2 2 3 3
solution and then extracted with DCM (30 mL x 3). The combined organic phase was washed
with brine (40 mL x 3), dried over anhydrous Na SO , filtered and concentrated in vacuo. The
residue was purified by preparatory-HPLC (basic condition) to afford compound 105 (35.0 mg,
yield 53.6%) as white solid. H NMR (DMSO-d 400 MHz) δ 9.08 (d, J = 7.7 Hz, 1H), 8.08 -
8.00 (m, 1H), 7.84 (br s, 1H), 7.60 - 7.52 (m, 2H), 7.45 - 7.37 (m, 3H), 7.36 -7.30 (m, 1H), 7.28 -
7.25 (m, 3H), 7.23 - 7.16 (m, 3H), 7.12 - 7.06 (m, 1H), 6.60 (br s, 1H), 5.29 (br s, 1H), 3.22 -
3.14 (m, 1H), 2.86 - 2.76 (m, 1H), 2.35 (s, 3H), 2.28 - 2.22 (m, 3H). MS (ESI) m/z (M+H)
467.2.
17681897_1 (GHMatters) P110989.NZ
EXAMPLE 62
COMPOUNDS 103, 106, 216-218, 214
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)(4'-FLUORO-[1,1'-
BIPHENYL]YL)METHYL-1H-PYRAZOLECARBOXAMIDE (103)
, Na CO ,
Pd(PPh )
3 4 2 3
NH N
THF/H O NH
103A
103B
Compound 103B (110 mg, yield 70.98%, off-white solid) was prepared as in
Example 49 from the corresponding intermediate compounds 103A and (4-fluorophenyl)boronic
acid. Compound 103B: H NMR (DMSO-d 400 MHz) δ 8.45 (d, J = 9.0 Hz, 0.5H), 8.15 (d, J =
9.0 Hz, 0.5H), 7.68 - 7.52 (m, 4H), 7.40 - 7.13 (m, 10H), 7.02 (br d, J = 8.4 Hz, 0.5H), 6.94 (br d,
J = 7.9 Hz, 0.5H), 6.59 (d, J = 2.4 Hz, 1H), 5.93 - 5.74 (m, 1H), 4.49 - 4.32 (m, 1H), 4.02 - 3.88
(m, 1H), 2.95 - 2.66 (m, 2H), 2.26 - 2.19 (m, 3H).
Compound 103 (78 mg, yield 68.93%, pale yellow solid) was prepared as in
Example 61 from the corresponding intermediate compounds 103B. Compound 103: H NMR
(DMSO-d 400 MHz) δ 9.09 (d, J = 7.7 Hz, 1H), 8.09 (s, 1H), 7.86 (s, 1H), 7.65 (dd, J = 5.4, 8.7
Hz, 2H), 7.58 (br d, J = 7.7 Hz, 1H), 7.52 (s, 1H), 7.41 (t, J = 7.8 Hz, 1H), 7.32 - 7.25 (m, 6H),
7.23 - 7.19 (m, 1H), 7.11 (br d, J=7.9 Hz, 1H), 6.60 (s, 1H), 5.35 - 5.25 (m, 1H), 3.18 (dd, J =
3.5, 13.7 Hz, 1H), 2.81 (dd, J = 10.4, 13.7 Hz, 1H), 2.25 (s, 3H). MS (ESI) m/z (M+H) 471.1.
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)(3'-FLUORO-[1,1'-
BIPHENYL]YL)METHYL-1H-PYRAZOLECARBOXAMIDE (106)
Compound 106 (18.7 mg, yield 46.2%, light yellow solid) was prepared as in
Example 61 from the corresponding starting materials, compound 103A and (3-
fluorophenyl)boronic acid. Compound 106: H NMR (DMSO-d 400 MHz) δ 9.08 (br d, J = 7.7
Hz, 1H), 8.05 (br s, 1H), 7.85 (br s, 1H), 7.69 - 7.62 (m, 1H), 7.60 - 7.56 (m, 1H), 7.52 - 7.43 (m,
3H), 7.43 - 7.37 (m, 1H), 7.33 - 7.24 (m, 4H), 7.24 - 7.15 (m, 2H), 7.13- 7.05 (m, 1H), 6.62 (s,
1H), 5.35 - 5.25 (m, 1H), 3.20 - 3.15 (m, 1H), 2.86 - 2.76 (m, 1H), 2.28 - 2.21 (m, 3H). MS
(ESI) m/z (M+H) 471.1.
17681897_1 (GHMatters) P110989.NZ
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)(3'-FLUORO-[1,1'-
BIPHENYL]YL)METHYL-1H-PYRAZOLECARBOXAMIDE (216)
N , Cs CO , THF/H O
Pd(PPh )
3 4 2 3 2
H 80 °C, 12 h NH
216A
Compound 216 (26 mg, yield 16.7%, yellow solid) was prepared as in Example
62 from the corresponding starting materials, compound 83D and (3-fluorophenyl)boronic acid.
Compound 216: H NMR (CDCl 400MHz) δ 7.59 (br d, J = 7.7 Hz, 2H), 7.47 - 7.35 (m, 4H),
7.33 - 7.27 (m, 4H), 7.05 (br d, J = 6.4 Hz, 3H), 6.75 (br s, 1H), 6.49 (s, 1H), 6.42 - 6.33 (m, 1H),
.66 - 5.50 (m, 2H), 3.39 (br dd, J = 5.0, 13.8 Hz, 1H), 3.16 (br dd, J = 7.4, 14.0 Hz, 1H), 2.40 -
2.29 (m, 3H). MS (ESI) m/z (M+H) 471.1.
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)(2'-FLUORO-[1,1'-
BIPHENYL]YL)METHYL-1H-PYRAZOLECARBOXAMIDE (217)
Compound 217 was prepared as in Example 62 from the corresponding starting
materials, compound 83D and (2-fluorophenyl)boronic acid. Compound 217 (13 mg, yield
14.49%, yellow solid): H NMR (CDCl 400MHz) δ 7.59 (d, J = 7.3 Hz, 2H), 7.49 - 7.39 (m,
3H), 7.37 - 7.26 (m, 3H), 7.24 - 7.13 (m, 3H), 7.02 (br d, J = 6.0 Hz, 2H), 6.72 (br s, 1H), 6.49 (s,
1H), 6.37 - 6.29 (m, 1H), 5.62 - 5.49 (m, 2H), 3.36 (dd, J = 5.3, 14.1 Hz, 1H), 3.11 (dd, J = 7.4,
14.0 Hz, 1H), 2.38 - 2.29 (m, 3H). MS (ESI) m/z (M+H) 471.2.
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)METHYL(3'-METHYL-
[1,1'-BIPHENYL]YL)-1H-PYRAZOLECARBOXAMIDE (218)
Compound 218 was prepared as in Example 62 from the corresponding starting
materials, compound 83D and m-tolylboronic acid. Compound 218 (yield 36.1%, yellow solid):
H NMR (CDCl 400MHz) δ 9.16 (d, J = 7.7 Hz, 1H), 8.11 (s, 1H), 7.87 (s, 1H), 7.60 (d, J = 8.6
Hz, 2H), 7.50 - 7.43 (m, 2H), 7.38 - 7.28 (m, 5H), 7.26 - 7.21 (m, 3H), 7.18 (br d, J = 7.5 Hz,
1H), 6.54 (s, 1H), 5.28 - 5.18 (m, 1H), 3.20 (br dd, J = 3.6, 13.8 Hz, 1H), 2.83 (dd, J = 10.6, 13.7
Hz, 1H), 2.37 (s, 3H), 2.24 (s, 3H).
17681897_1 (GHMatters) P110989.NZ
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)(2'-FLUORO-[1,1'-
BIPHENYL]YL)METHYL-1H-PYRAZOLECARBOXAMIDE (214)
Br OH
Na CO THF/H O
N , ,
Pd(PPh3)4 2 3 2
H NH
HO H
103A
214A
Compound 214 was prepared as in Example 62 from the corresponding starting
materials, compound 103A and (2-fluorophenyl)boronic acid. Compound 214 (20 mg, yield
29.5%, white solid): H NMR (CDCl 400 MHz) δ 7.62 - 7.55 (m, 2H), 7.52 - 7.43 (m, 2H), 7.41
- 7.30 (m, 2H), 7.26 - 7.22 (m, 3H), 7.21 - 7.13 (m, 2H), 7.03 - 6.94 (m, 2H), 6.65 (br s, 1H),
6.49 (s, 1H), 6.33 - 6.26 (m, 1H), 5.56 - 5.52 (m, 1H), 5.37 (br s, 1H), 3.38 - 3.31 (m, 1H), 3.17 -
3.09 (m, 1H), 2.36 - 2.30 (m, 3H). MS (ESI) m/z (M+H) 471.1.
EXAMPLE 63
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)PHENYLFURAN
CARBOXAMIDE (104)
O O O
MeI, Cs CO O
NaOH.H O OH
PhB(OH) 2
Cs CO
, MeOH
Pd(PPh3)4 2 3
104A
104B
104D
104C
To a solution of i-Pr NH (3 mL ,18.71 mmol) in anhydrous THF ( 13 mL) was
added n-BuLi (7 mL,18.71 mmol) dropwise at -78 °C and stirred at 0 °C for 30 min. Then a
solution of 3-bromofuran (2.5 g, 17.01 mmol) in THF (13 mL) was added to the mixture drop
wise at -78 °C and the mixture was stirred at -78 °C for 30 minutes. Anhydrous CO was poured
into the solution at -78 °C for 30 minutes. The reaction was quenched with H2O (20 mL) and
extracted with ethyl acetate (20 mL), then water phase was treated with HCl until pH ~ 3. The
precipitation was filtered and dried under reduced pressure. Compound 104A (1.8g, crude) was
obtained as yellow solid. H NMR (DMSO-d 400MHz) δ 7.96 (d, J = 1.8 Hz, 1H), 6.89 (d, J =
1.8 Hz, 1H).
17681897_1 (GHMatters) P110989.NZ
Cs CO (2.13 g, 6.55 mmol) was added to a solution of compound 104A (500
mg, 2.62 mmol) in DMF (10 mL). Then MeI (652.43 uL, 10.48 mmol) was added to the mixture.
The mixture was stirred at 25 °C for 13h. The mixture was diluted with ethyl acetate (35 mL)
and H O (30 mL). The organic layer was separated and the aqueous layer was washed extracted
with ethyl acetate (20 mL x 2). The combined organic layer was washed brine (30 mL), dried
over MgSO4, filtered and concentrated. The residue was purified by Flash column
chromatography (Petroleum Ether/Ethyl Acetate = 15/1). Compound 104B (250 mg, yield
46.54%) was obtained as white solid. H NMR (CDCl , 400MHz) δ 7.50 (d, J = 2.0 Hz, 1H),
6.61 (d, J = 2.0 Hz, 1H), 3.94 - 3.92 (m, 3H)
To a solution of Compound 104B (221 mg, 1.08 mmol) in THF (4 mL) and
H O (2 mL) was added phenylboronic acid (263 mg, 2.16 mmol) and Cs CO (553 mg, 1.70
2 2 3
mmol), followed by Pd(PPh ) (125 mg, 108.00 umol), then the mixture was heated to 80 °C and
stirred for 12h. The reaction mixture was cooled to the room temperature and H O (6 mL) was
added to quenched the reaction. The mixture was extracted with ethyl acetate (10mL x 2). The
combined organic layer was washed with H O (10 mL), brine (10 mL), dried over Na SO ,
2 2 4
filtered, evaporated under reduced pressure. The residue was purified by FCC (PE/EA: 0 to
/1). Compound 104C (180 mg, yield 82.42%) was obtained as yellow oil. H NMR (CDCl ,
400MHz) δ 7.61 - 7.55 (m, 3H), 7.45 - 7.35 (m, 3H), 6.64 (d, J = 1.8 Hz, 1H), 3.86 (s, 3H)
To a solution Compound 104C (170 mg, 840.71 umol) in MeOH (5 mL) was
added NaOH (2 M, 2 mL) dropwise, then the mixture was stirred at 25 °C for 2h. The reaction
was diluted with H O (5 mL) and removed solvent under reduced pressure, then the mixture was
extracted with MTBE (5 mL). The water phase was treated with HCl (1 M) until pH ~ 3, then
water phase was extracted with ethyl acetate (5 mL x 3). The organic layer was washed with
brine, dried over anhydrous Na SO , evaporated under reduced pressure. Compound 104D (120
mg, yield 75.85%) was obtained as white solid which was used directly in next step. H NMR
(DMSO-d 400MHz) δ 7.90 (d, J = 1.8 Hz, 1H), 7.59 - 7.53 (m, 2H), 7.39 - 7.28 (m, 3H), 6.80
(d, J = 1.8 Hz, 1H)
Compound 104 (35 mg, yield 44.0%, yellow solid) was prepared as in
Example 5 from the corresponding intermediate carboxylic acid, compound 104D. Compound
104: H NMR (DMSO-d 400MHz) δ 8.56 (d, J = 7.5 Hz, 1H), 8.07 (s, 1H), 7.88 (d, J = 1.8 Hz,
17681897_1 (GHMatters) P110989.NZ
1H), 7.81 (s, 1H), 7.61 - 7.54 (m, 2H), 7.36 - 7.29 (m, 3H), 7.29 - 7.25 (m, 4H), 7.21 - 7.17 (m,
1H), 6.90 - 6.83 (m, 1H), 5.39 - 5.29 (m, 1H), 3.21 - 3.12 (m, 1H), 3.01 - 2.92 (m, 1H). MS (ESI)
m/z (M+H) 363.1
EXAMPLE 64
COMPOUNDS 107, 243, 253, 265, 168, 459, 460, 475
(S)-N-(4-AMINO(4-FLUOROPHENYL)-3,4-DIOXOBUTANYL)METHYL
PHENYLOXAZOLECARBOXAMIDE (107)
(S)-N-(1-AMINO-1,2-DIOXOPENTANYL)METHYLPHENYLOXAZOLE
CARBOXAMIDE (243)
(S)-N-(1-AMINOMETHYL-1,2-DIOXOHEXANYL)METHYL
PHENYLOXAZOLECARBOXAMIDE (253)
(S)-N-(1-AMINO-1,2-DIOXOHEPTANYL)METHYLPHENYLOXAZOLE
CARBOXAMIDE (265)
OH CONH
H N H N
•HCl
N OH
O NH
107B 47A
107B 58F
H N NH
2 (S) 2
BocHN (S)
•HCl N
253A
107B
107B
Compounds 107, 243, 253 and 265 were prepared as in Example 5 from the
corresponding starting materials, respectively—compound 107B and compound 58F, 47A, 253A
or 62E.
Compound 107 (77.3 mg, 51.80% yield, white solid): H NMR (400 MHz,
CDCl ) δ 8.12 - 8.05 (m, 2H), 7.46 - 7.36 (m, 3H), 7.12 - 7.05(m, 2H), 7.00 - 6.94 (m, 2H), 6.79
- 6.70 (m, 2H), 5.72 - 5.64 (m, 1H), 5.53 (br s,1H), 5.57 - 5.47 (m, 1H), 3.46 - 3.38 (m, 1H), 3.24
- 3.16 (m,, 1H), 2.56 (s, 3H). MS (ESI) m/z (M+H) 396.1.
Compound 243 (52.8 mg, 42.87% yield, yellow solid): H NMR (400 MHz,
CDCl ): δ 8.13 (d, J = 6.8 Hz, 2H), 7.47 - 7.33 (m, 3H), 6.91 -6.81 (m, 1H), 6.75 (br s, 1H), 5.53
17681897_1 (GHMatters) P110989.NZ
- 5.36 (m, 2H), 2.58 (s, 3H), 2.20 - 2.08 (m, 1H),1.88 - 1.76 (m, 1H), 0.99 (t, J = 7.2 Hz, 3H).
MS (ESI) m/z (M+H) 316.1.
Compound 253 (6.5 mg, 6.42% yield, white solid): H NMR (CDCl 400
MHz): δ 8.19 - 8.09 (m, 2H), 7.50 - 7.34 (m, 3H), 6.84 - 6.68 (m, 2H), 5.55 - 5.38 (m, 2H), 2.60
(s, 3H), 1.87 - 1.74 (m, 2H), 1.63 - 1.58 (m, 1H), 1.04 (d, J = 6.4 Hz, 3H), 0.98 (d, J = 6.4 Hz,
3H). MS (ESI) m/z (M+H) 344.1.
Compound 265 (79.7 mg, 94.04% purity, white solid): H NMR (400MHz,
DMSO-d ) δ 8.73 (d, J=6.8 Hz, 1H), 8.13 - 8.03 (m, 3H), 7.79 (s, 1H), 7.45 - 7.35 (m, 3H), 5.17 -
.10 (m, 1H), 2.56 (s, 3H), 1.87 - 1.76 (m, 1H), 1.73 - 1.60 (m, 1H), 1.45 - 1.26 (m, 4H), 0.93 -
0.83 (m, 3H). MS (ESI) m/z (M+H) 344.1.
(S)-N-(4-AMINO(4-FLUOROPHENYL)-3,4-DIOXOBUTANYL)METHYL
PHENYL-1H-PYRAZOLECARBOXAMIDE (168)
Prepared as in Example 64 from the corresponding starting materials,
compounds 32F and 58F. Compound 168 (21.3 mg, yield: 45.1%, light yellow solid): H NMR
(400MHz, DMSO-d ) δ 8.38 (br d, J = 7.7 Hz, 1H), 8.12 - 7.99 (m, 2H), 7.81 (s, 1H), 7.54 (br d,
J = 3.7 Hz, 2H), 7.36 - 7.24 (m, 5H), 7.12 (br t, J = 8.7 Hz, 2H), 5.30 - 5.20 (m, 1H), 3.89 (s,
3H), 3.19 - 3.09 (m, 1H), 2.87 - 2.74 (m, 1H). MS (ESI) m/z (M+H) 395.1.
N-(4-(CYCLOPROPYLAMINO)-3,4-DIOXOPHENYLBUTANYL)METHYL
PHENYLOXAZOLECARBOXAMIDE (459)
Prepared as in compound 107 from the corresponding starting materials,
compounds 107B and 3-amino-N-cyclopropylhydroxyphenylbutanamide hydrochloride.
Compound 459 (210 mg, yield: 65.2%, white solid): H NMR (400MHz, DMSO-d ) δ 8.88 -
8.79 (m, 2H), 8.06 - 7.99 (m, 2H), 7.43 - 7.34 (m, 3H), 7.33 - 7.26 (m, 4H), 7.25 - 7.18 (m, 1H),
.48 - 5.35 (m, 1H), 3.26 - 3.17 (m, 1H), 3.05 - 2.94 (m, 1H), 2.82 - 2.71 (m, 1H), 2.55 (s, 3H),
0.70 - 0.52 (m, 4H). MS (ESI) m/z (M+H) 418.2.
N-(1-(CYCLOPROPYLAMINO)-1,2-DIOXOHEPTANYL)METHYL
PHENYLOXAZOLECARBOXAMIDE (460)
Prepared as in compound 107 from the corresponding starting materials,
compounds 107B and 3-amino-N-cyclopropylhydroxyheptanamide hydrochloride. Compound
460 (180 mg, yield: 53.3%, white solid): H NMR (400MHz, DMSO-d ) δ 8.76 (br s, 2H), 8.10
17681897_1 (GHMatters) P110989.NZ
(br s, 2H), 7.40 (br s, 3H), 5.12 (br s, 1H), 2.77 (br s, 1H), 2.56 (br s, 3H), 1.81 (br s, 1H), 1.68
(br s, 1H), 1.32 (br s, 4H), 0.88 (br s, 3H), 0.70 - 0.52 (m, 4H). MS (ESI) m/z (M+H) 384.2.
(S)-N-(4-FLUOROOXOPHENYLBUTANYL)METHYL
PHENYLOXAZOLECARBOXAMIDE (475)
Prepared as in compound 107 from the corresponding starting materials,
compounds 107B and (2S,3S)aminofluorophenylbutanol hydrochloride. Compound
475 (75 mg, yield: 50.28%, white solid): H NMR (400MHz, CDCl ) δ 8.13 - 8.08 (m, 2H), 7.47
- 7.38 (m, 3H), 7.36 - 7.28 (m, 3H), 7.18 (d, J=6.6 Hz, 2H), 6.81 - 6.76 (m, 1H), 5.31 - 5.22 (m,
1H), 5.05 - 4.89 (m, 1H), 4.88 - 4.72 (m, 1H), 3.29 - 3.22 (m, 1H), 3.17 - 3.10 (m, 1H), 2.57 (s,
3H). MS (ESI) m/z (M+H) 367.1.
EXAMPLE 65
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)METHYL(QUINOLIN
YL)-1H-PYRAZOLECARBOXAMIDE (108)
HCl H N
LiOH H O
AcOH, 110 °C MeOH: H O
2 (2:1)
°C, 1 h
108A
108B
108D
A mixture consisting of quinolinamine (5 g, 34.68 mmol) in conc. HCl (20
mL) at 0 °C was added NaNO (2.63 g, 38.15 mmol) dropwise and the resultant mixture was
stirred at 0 °C for 0.5 hour. The reaction mixture was warmed to 25 °C over 0.5 hour, and then
cooled to 0 °C. The SnCl •2H O (15.65 g, 68.36 mmol, in 20 mL conc. HCl) was added
dropwise to the reaction mixture, and stirred at 0 °C for 0.5 hour. The resulting mixture was
allowed to warm to 25 °C with vigorous stirring over 4 hours. The reaction mixture was
concentrated under reduced pressure to remove solvent. The residue was diluted with ethanol 90
mL (30 mL x 3), filtered and concentrated under reduced pressure to afford compound 108A (5.2
g, 76.64% yield, HCl) as a yellow solid. H NMR (DMSO-d 400 MHz): δ 9.98 (br s, 1H), 9.26
- 9.15 (m, 2H), 8.07 - 7.97 (m, 2H), 7.89 (d, J = 8.8 Hz, 1H), 7.27 (d, J = 7.8 Hz, 1H).
To a mixture of compound 108A (2 g, 12.56 mmol, HCl) and ethyl 2-
(methoxyimino)oxopentanoate (1.91 g, 10.22 mmol) in AcOH (20 mL) was degassed and
17681897_1 (GHMatters) P110989.NZ
purged with N for 3 times, and then the mixture was stirred at 110 °C for 2h under N
atmosphere. The reaction mixture was concentrated under reduced pressure to remove AcOH.
The residue was diluted with CH Cl (100 mL), adjusted to pH ~ 7 - 8 with saturated aqueous
NaHCO and then extracted with CH Cl (40 mL x 2). The organic phase was dried over
3, 2 2
anhydrous Na SO , filtered, and concentrated under reduced pressure to give a residue, which
was purified by column chromatography (SiO , Petroleum ether/Ethyl acetate = 1:0 to 0:1) to
give compound 108B (1.2 g, 41.78% yield) as a yellow solid and compound 108C (150 mg,
.22% yield) as a yellow solid. Compound 108B: H NMR (CDCl , 400 MHz): δ 8.93 (d, J = 4.0
Hz, 1H), 8.23 (d, J = 8.4 Hz, 1H), 7.78 (t, J = 8.0 Hz, 1H), 7.64 (d, J = 8.4 Hz, 1H), 7.56 (d, J =
7.2 Hz, 1H), 7.38 (d, J = 8.8 Hz, 1H), 6.93 (s, 1H), 4.05 (q, J = 7.2 Hz, 2H), 2.41 (s, 3H), 1.00 (t,
J = 7.2 Hz, 3H).
Compound 108C: H NMR (CDCl , 400 MHz): δ H NMR (400MHz, DMSO-
d ) δ 8.98 - 8.87 (m, 1H), 8.27 (d, J = 8.8 Hz, 1H), 7.83 - 8.77(m, 1H), 7.68 - 7.56 (m, 2H), 7.45 -
7.40 (m, 1H), 6.85 (s, 1H), 4.42 (q, J = 7.2 Hz, 2H), 2.13 (s, 3H), 1.40 (t, J = 7.2 Hz, 3H).
To a mixture of 108B (250 mg, 888.7 umol) in MeOH (10 mL) and H O (5
mL) was added LiOH•H O (149.2 mg, 3.55 mmol) in one portion and the mixture was stirred at
°C for 1 hour. The reaction mixture was concentrated under reduced pressure to remove
MeOH. The residue was diluted with H O (10 mL), adjusted to pH ~ 3 with 1N HCl, and then
extracted with DCM (40 mL x 3). The combined organic layers were washed with brine (30
mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford
intermediate compound 108D (200 mg, 88.03% yield) as a white solid. H NMR (DMSO-d 400
MHz): δ 8.97 (d, J = 4.0 Hz, 1H), 8.17 (d, J = 8.8 Hz, 1H), 7.89 - 7.79 (m, 1H), 7.67 - 7.62 (m,
1H), 7.61 - 7.52 (m, 2H), 6.96 (s, 1H), 5.76 (s, 1H), 2.32 (s, 3H). MS (ESI) m/z (M+1) 253.9.
Compound 108 (21.2 mg, 23.11 % yield, white solid) was prepared as in
Example 107 from the corresponding intermediate compounds 108D and 12G. Compound 108:
H NMR (CDCl , 400 MHz): δ 8.95 (d, J = 2.8 Hz, 1H), 8.22 (d, J = 8.8 Hz, 1H), 7.77 - 7.66 (m,
2H), 7.50 (d, J = 7.2 Hz, 1H), 7.39 (d, J = 8.4 Hz, 1H), 7.24 - 7.18 (m, 3H), 6.89 (d, J = 5.6 Hz,
2H), 6.63 (s, 2H), 6.28 (d, J = 7.2 Hz, 1H), 5.53 - 5.39 (m, 2H), 3.24 (d, J = 14.4 Hz, 1H), 3.03
(d, J = 14.4 Hz, 1H), 2.39 (s, 3H). MS (ESI) m/z (M+H) 428.1.
17681897_1 (GHMatters) P110989.NZ
EXAMPLE 66
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)(PYRIDINYL)THIAZOLE-
-CARBOXAMIDE (109)
Br O N N
Sn(n-Bu)3 LiOH.H O
(1.1 eq)
(2.5
S dioxane, 105 °C MeOH/H O
Pd(PPh3)4 2
32 °C, 0.5 hr
109A
eq) 109B
(0.05
A mixture of ethyl 4-bromothiazolecarboxylate (500 mg, 2.12 mmol), 2-
(tributylstannyl)pyridine (858.5 mg, 2.33 mmol), Pd(PPh ) (122.5 mg, 106 umol) in dioxane (15
mL) was stirred at 105 °C for 14h. The mixture was concentrated. The residue was purified by
column chromatography (SiO , Petroleum ether/Ethyl acetate=3:1 to 1:1) to afford compound
109A (221 mg, 44.05% yield) as yellow oil. MS (ESI) m/z (M+H) 235.0.
To a solution of compound 109A (221 mg, 943.36 umol) in MeOH (10 mL)
and water (2 mL) was added LiOH.H O (99 mg, 2.36 mmol, 2.5 eq). The mixture was stirred at
32 °C for 0.5 hr. MeOH was evaporated. To the residue was added water (20 mL). The mixture
was extracted with MTBE (5 mL) and separated. The aqueous layer was acidified to pH ~ 3 with
1N HCl and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were dried
over Na SO and concentrated to afford compound 109B (155 mg, 79.68% yield) as white solid.
H NMR (400MHz, DMSO-d6) δ 9.37 (s, 1H), 8.84 (br d, J = 4.8 Hz, 1H), 8.57 (d, J = 8.0 Hz,
1H), 8.34 (br t, J = 7.4 Hz, 1H), 7.78 (t, J = 6.2 Hz, 1H).
Compound 109 (5.7 mg, 13.91% yield, yellow solid) was prepared as in
Example 5 from the corresponding intermediate carboxylic acid, compound 109B. Compound
109: MS (ESI) m/z (M+H) 381.0. H NMR (400MHz, CDCl ) δ 13.47 - 13.34 (m, 1H), 8.85 (s,
1H), 8.43 (d, J = 8.0 Hz, 1H), 8.03 (d, J = 5.2 Hz, 1H), 7.96 - 7.79 (m, 1H), 7.26 - 7.22 (m, 1H),
7.20 - 7.06 (m, 5H), 6.81 (br s, 1H), 5.94 - 5.86 (m, 1H), 5.68 (br s, 1H), 3.49 - 3.33 (m, 2H).
17681897_1 (GHMatters) P110989.NZ
EXAMPLE 67
(S)(4-(OXAZOLYL)PYRIDINYL)-N-(1-OXOPHENYLPROPANYL)-1H-
IMIDAZOLECARBOXAMIDE (110)
TOSMIC
K CO /EtOH
N NH
110A N
110B
Pin B N I LiOH.H O
2 2 O N
KOAc/Pd(dppf)Cl
2 OH
110E
110C
110D
A mixture of 4-bromopyridinamine (20 g, 115.60 mmol) and ethyl 2-
oxoacetate (30.7 g, 150.28 mmol) in MeOH (300 mL) was heated to 80 °C for 3 h. The mixture
was concentrated, the residue was purified by silica gel column (Petroleum ether : Ethyl acetate =
: 1). Compound 110A (28.9 g, yield: 86.5%, yellow solid): H NMR (400 MHz, CDCl ) δ 7.96
(d, J = 5.2 Hz, 1 H), 6.86 (dd, J = 5.2, 1.75 Hz, 1 H), 6.77 (d, J = 1.3 Hz, 1 H), 5.75 (br s, 1 H),
.61 (d, J = 8.3 Hz, 1 H), 4.29 (q, J = 7.0 Hz, 2 H), 3.41 (s, 3 H), 1.37 - 1.31 (m, 3 H).
A mixture of 110A (15 g, 51.9 mmol) and K CO (21.5 g, 156 mmol) in EtOH
(300 mL) was stirred at 80 °C for 0.5 hr, then 1-(isocyanomethylsulfonyl)methyl-benzene
(15.2 g, 77.82 mmol) was added, the resulting mixture was stirred at 80 °C for another 2 h. Most
of ethanol was removed and a precipitate was formed, the solid was filtered and washed with
water (100 mL x 2), the solid was dried and concentrated to give 110B (6.4 g, yield: 41.7%), as
yellow solid. H NMR (400 MHz, CDCl ) δ 8.38 (d, J = 5.2 Hz, 1 H), 7.97 (s, 1 H), 7.85 (s, 1
H), 7.61 (s, 1 H), 7.56 (dd, J = 5.26, 1.3 Hz, 1 H), 4.27 (q, J = 7.02 Hz, 2 H), 1.29 (t, J = 7.02 Hz,
3 H).
110B (3 g, 10.13 mmol), Pin B (2.57 g, 10.13 mmol), KOAc (2.98 g, 30.4
mmol) and Pd(dppf)Cl (741 mg, 1.01 mmol) in dioxane (100 mL) was de-gassed and then
heated at 70 °C for 4 hours under N . The mixture was filtered and the filtrate was concentrated,
the residue was purified by silica gel chromatography (DCM: Methanol = 5:1) to give 110C
(1.70 g, crude) as black solid.
17681897_1 (GHMatters) P110989.NZ
110C (300 mg, 1.15 mmol), 2-iodooxazole (157 mg, 805.00 umol),
Pd(dppf)Cl (84.1 mg, 115.00 umol) and Na CO (244 mg, 2.30 mmol) in toluene (2 mL), EtOH
2 2 3
(2 mL), H O (1 mL) was degassed and then heated to 120 °C for 1 hour under microwave
condition. LCMS showed desired MS, the mixture was added water (5 mL) and extracted with
ethyl acetate (10 mL x 2), the organic phases were dried and concentrated, the residue was
purified by preparatory-TLC (Petroleum ether : Ethyl acetate = 1: 1) to give 110D (80 mg, yield:
24.5%), as yellow solid.
A mixture of 110D (80 mg, 281.42 umol) and LiOH.H O (17.7 mg, 422.13
umol) in THF (5 mL), H O (1 mL) was stirred at 25 °C for 12 h. LCMS showed desired MS,
THF was removed under vacuum, the water layer was extracted with ethyl acetate (10 mL x 2),
the water layer was adjusted to pH ~ 6 with 1N HCl and lyophilized, the residue was purified by
prep-HPLC (FA) to give 110E (35 mg, yield: 48.5%), as white solid. H NMR (400MHz,
methanol-d ) δ 8.70 (d, J = 5.3 Hz, 1H), 8.25 (s, 1H), 8.16 (s, 1H), 8.11 (s, 1H), 8.08 (d, J = 5.1
Hz, 1H), 7.81 (s, 1H), 7.46 (s, 1H).
Compound 110 (38 mg, yield: 58.8%, white solid) was prepared as in Example
6 from the corresponding intermediate compounds 110E and 21G ((S)aminophenylpropan-
1-ol). Compound 110: H NMR (400MHz, CDCl ) δ 9.69 (s, 1H), 8.52 (d, J = 5.1 Hz, 1H), 7.98
(br d, J = 9.9 Hz, 2H), 7.92 (br d, J = 5.1 Hz, 1H), 7.81 (s, 1H), 7.59 (s, 1H), 7.52 (br d, J = 5.3
Hz, 1H), 7.34 (s, 1H), 7.31 - 7.17 (m, 4H), 7.13 (br d, J = 7.1 Hz, 2H), 4.84 (q, J = 6.5 Hz, 1H),
3.33 - 3.18 (m, 2H). MS (ESI) m/z (M+H) 388.1.
17681897_1 (GHMatters) P110989.NZ
EXAMPLE 68
COMPOUNDS 111-112
(S)(5-(OXAZOLYL)PYRIDINYL)-N-(1-OXOPHENYLPROPANYL)-1H-
IMIDAZOLECARBOXAMIDE (111)
TosMic, K O
N CO
O NH OEt
NH N
O OEt
111B
111A
(HO)2
LiOH
Pin B
111D
111C 111E
Compound 111E (60 mg, crude, grey solid) was prepared as in Example 110
from the corresponding starting materials, 5-bromopyridinamine. Compound 111E: MS (ESI)
m/z (M+H) 257.0. Compound 111 (55 mg, yield: 76.9%, white solid) was prepared as in
Example 21 from the corresponding intermediate compounds 111E and 21G ((S)amino
phenylpropanol). Compound 111: H NMR (400MHz, CDCl ) δ 9.71 (s, 1H), 9.05 (d, J = 1.5
Hz, 1H), 8.42 (dd, J = 2.2, 8.4 Hz, 1H), 8.02 (s, 1H), 7.79 (s, 1H), 7.57 (s, 1H), 7.39 (d, J = 8.4
Hz, 1H), 7.34 (br d, J = 6.4 Hz, 1H), 7.31 (s, 1H), 7.28 - 7.24 (m, 2H), 7.22 - 7.17 (m, 1H), 7.14
(br d, J = 7.1 Hz, 2H), 4.87 (q, J = 6.5 Hz, 1H), 3.24 (d, J = 6.4 Hz, 2H). MS (ESI) m/z (M+H)
388.1.
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)(5-(OXAZOLYL)PYRIDIN-
2-YL)-1H-IMIDAZOLECARBOXAMIDE (112)
Compound 112 (20 mg, yield: 48.2%, white solid) was prepared as in Example
from the corresponding starting materials, compounds 111E and 12G. H NMR (400MHz,
DMSO-d ) δ 9.06 (d, J = 7.5 Hz, 1H), 8.99 (d, J = 1.8 Hz, 1H), 8.39 (dd, J = 2.4, 8.4 Hz, 1H),
8.34 (s, 1H), 8.26 - 8.21 (m, 1H), 8.08 (s, 1H), 7.84 (s, 1H), 7.57 (s, 1H), 7.48 (s, 1H), 7.34 (d, J
= 8.4 Hz, 1H), 7.31 - 7.25 (m, 4H), 7.24 - 7.16 (m, 1H), 7.24 - 7.16 (m, 1H), 5.28 - 5.13 (m, 1H),
3.18 (dd, J = 3.7, 13.9 Hz, 1H), 2.85 (dd, J = 10.3, 13.8 Hz, 1H). MS (ESI) m/z (M+H) 431.1.
17681897_1 (GHMatters) P110989.NZ
LiOH
EXAMPLE 69
COMPOUNDS 113, 115
S N N
N HOAc O
NHNH
113B
113C
113A
115A
113D
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)METHYL(5-
PHENYLTHIAZOLYL)-1H-PYRAZOLECARBOXAMIDE (113)
5-phenylthiazolamine (850 mg, 4.82 mmol) was added to concentrated
hydrochloric acid (5 mL). While being stirred at 0 °C, the aqueous solution of NaNO (998 mg,
14.5 mmol) in H O (3 mL) was dropped slowly into the mixture, and the mixture was stirred for
1hr. Then hydrochloric acid solution of SnCl .2H O (3.26 g, 14.4 mmol) was added drop-wise
slowly, and the mixture was stirred at 25 °C for 3h. LCMS showed 5-phenylthiazolamine was
consumed completely and one peak with desired MS was detected. The reaction mixture was
filtered. The filtered cake was wash with water (20 mL), and concentrated under reduced
pressure to give the product 113A (1 g, crude) as a yellow solid. MS (ESI) m/z (M+H) 191.9.
A mixture of compound 113A (1 g, 5.23 mmol), methyl 2,4-dioxopentanoate
(754 mg, 5.23 mmol) in HOAc (15 mL) was stirred at 120 °C for 1hr. The reaction mixture was
filtered, the filtrate was concentrated under reduced pressure to remove the solvent, and adjusted
the pH to 8 ~ 9 with the saturated aqueous NaHCO . Then the mixture was extracted with Ethyl
acetate (60 mL x 3). The combined organic layers were dried over Na SO , filtered and
concentrated under reduced pressure to give a residue. Firstly, the residue was purified by
column chromatography (Petroleum ether : Ethyl acetate = 50:1 to 10:1) to give the pure
compound 113C (300 mg) and the mixture of 113B & 113C (300 mg). And then the mixture of
17681897_1 (GHMatters) P110989.NZ
LiOH
113B & 113C (300 mg) was purified by preparatory-HPLC (TFA condition) to give 113B (30
mg) and 113C (120 mg) both as a yellow solid.
Compound 113B: H NMR (400MHz, CDCl ) δ 7.79 (br s, 1H), 7.60 - 7.51 (m,
2H), 7.46 - 7.38 (m, 2H), 7.38 - 7.29 (m, 1H), 6.75 (br s, 1H), 4.05 - 3.71 (m, 3H), 2.54 - 2.16
(m, 3H). MS (ESI) m/z (M+H) 300.0.
Compound 113C: H NMR (400MHz, CDCl ) δ 7.74 (s, 1H), 7.58 - 7.53 (m,
2H), 7.46 - 7.40 (m, 2H), 7.38 - 7.32 (m, 1H), 7.26 (s, 1H), 6.72 (d, J = 0.7 Hz, 1H), 3.96 (s, 3H),
2.75 (s, 3H). MS (ESI) m/z (M+H) 300.0.
To a solution of 113B (30 mg, 100 umol) in THF (5 mL), H O (1 mL) was
added LiOH.H O (6.31 mg, 150 umol). The mixture was stirred at 25 °C for 12 hours. The
reaction mixture was added aqueous HCl to adjust the pH ~ 5. Then the mixture was freezed.
Compound 113D (35 mg, crude) was obtained as a white solid. H NMR (400MHz, DMSO-d )
δ 8.07 (s, 1H), 7.68 (d, J = 7.3 Hz, 2H), 7.49 - 7.41 (m, 2H), 7.40 - 7.32 (m, 1H), 6.79 (s, 1H),
2.25 (s, 3H).
Compound 113 (20 mg, yield: 66.4%, white solid) was prepared as in Example
from the corresponding intermediate compounds 113D and 12G. Compound 113: H NMR
(400MHz, CDCl3) δ 11.73 (br d, J = 5.5 Hz, 1H), 7.55 - 7.45 (m, 2H), 7.42 (br t, J = 7.3 Hz, 2H),
7.38 - 7.31 (m, 1H), 7.23 (br dd, J = 3.9, 8.0 Hz, 6H), 7.03 (s, 1H), 6.80 (br s, 1H), 5.87 - 5.70
(m, 1H), 5.58 (br s, 1H), 3.43 (br dd, J = 4.5, 14.2 Hz, 1H), 3.22 (br dd, J = 8.2, 14.3 Hz, 1H),
2.31 (s, 3H). MS (ESI) m/z (M+H) 460.1.
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)METHYL(5-
PHENYLTHIAZOLYL)-1H-PYRAZOLECARBOXAMIDE (115)
Following the procedure as used for compound 113, compound 115 (62.0 mg,
yield: 68.3%, white solid) was prepared from the corresponding intermediate carboxylic acid,
compound 115A. Compound 115: H NMR (400MHz, CDCl ) δ 7.71 (s, 1H), 7.56 (d, J = 7.3
Hz, 2H), 7.48 - 7.40 (m, 2H), 7.39 - 7.33 (m, 2H), 7.33 - 7.27 (m, 2H), 7.26 (s, 1H), 7.19 (br d, J
= 6.8 Hz, 2H), 6.76 (br s, 1H), 6.65 (s, 1H), 5.77 - 5.62 (m, 1H), 5.52 (br s, 1H), 3.43 (dd, J =
.5, 13.9 Hz, 1H), 3.26 (dd, J = 7.1, 13.9 Hz, 1H), 2.71 (s, 3H). MS (ESI) m/z (M+23) 460.1.
17681897_1 (GHMatters) P110989.NZ
EXAMPLE 70
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)METHYL(5-
PHENYLOXAZOLYL)-1H-PYRAZOLECARBOXAMIDE (114)
LiOH.H O
O O 2
K CO CN, MW N
,CH OH
2 3 3 N
114C
114A
114B
To a solution of 5-phenyloxazole (800 mg, 5.51 mmol) in THF (10 mL) was
added n-BuLi (2.5 M, 2.76 mL) drop-wise at -78 °C and stirred for 30 min, then
hexachloroethane (1.96 g, 8.27 mmol) in THF (2 mL) was added, the reaction mixture was
slowly warmed to 25 °C and stirred for 12 h. The mixture was poured into ice-water (20 mL)
and extracted ethyl acetate (10 mL x 2), the organic phases were washed with brine (10 mL),
dried over Na SO , filtered and concentrated, the residue was purified by silica gel column
(Petroleum ether: Ethyl acetate = 10:1) to give 114A (900 mg, yield: 90.9%) as yellow oil. H
NMR (400MHz, CDCl -d) δ 7.58 (d, J = 7.3 Hz, 2H), 7.45 - 7.38 (m, 2H), 7.38 - 7.31 (m, 1H),
7.27 (s, 1H).
A mixture of 114A (90 mg, 501 umol), ethyl 3-methyl-1H-pyrazole
carboxylate (92.7 mg, 601 umol) and K CO (103 mg, 752 umol) in CH CN (3 mL) was stirred
2 3 3
at 120 °C for 2 hr under microwave condition. The mixture was diluted with ethyl acetate (20
mL) and water (20 mL), the organic phase was dried over Na SO , filtered and concentrated, the
residue was purified by preparatory-TLC (Petroleum ether: Ethyl acetate = 5: 1) to give 114B
(0.14 g, yield: 60.4%) as yellow oil, H NMR (400MHz, CDCl ) δ 7.76 - 7.67 (m, 2H), 7.47 -
7.41 (m, 2H), 7.39 - 7.32 (m, 2H), 6.75 (d, J = 0.9 Hz, 1H), 4.44 (q, J = 7.2 Hz, 2H), 2.67 (d, J =
0.7 Hz, 3H), 1.43 (t, J = 7.2 Hz, 3H).
A mixture of 114B (140 mg, 471 umol) and LiOH.H O (39.5 mg, 942 umol) in
THF (5 mL), H O (1 mL) was stirred at 25 °C for 2 h. The organic solvent was removed under
vacuum, the water layer was adjusted to pH ~ 5 with 1N HCl and filtered, the water layer was
extracted with DCM (10 mL x 3), the organic phases were washed with brine (10 mL), dried over
Na SO , filtered and concentrated, the residue combined the filtrate cake to give 114C (120 mg,
17681897_1 (GHMatters) P110989.NZ
crude), as white solid. H NMR (400MHz, DMSO-d ) δ 7.88 (s, 1H), 7.81 - 7.71 (m, 2H), 7.52
(t, J = 7.7 Hz, 2H), 7.46 - 7.40 (m, 1H), 6.81 (d, J = 0.7 Hz, 1H), 2.62 (s, 3H).
Compound 114 (53 mg, yield: 66.5%, white solid) was prepared as in Example
from the corresponding carboxylic acid, compound 114C. Compound 114: H NMR (400MHz,
DMSO-d ) δ 8.59 (d, J = 7.7 Hz, 1H), 8.10 (s, 1H), 7.87 (s, 1H), 7.84 (s, 1H), 7.76 (d, J = 7.3 Hz,
2H), 7.52 (t, J = 7.7 Hz, 2H), 7.45 - 7.38 (m, 1H), 7.31 - 7.22 (m, 4H), 7.19 (qd, J = 4.3, 8.8 Hz,
1H), 6.72 (d, J = 0.7 Hz, 1H), 5.49 - 5.40 (m, 1H), 3.25 - 3.17 (m, 1H), 3.06 (dd, J = 9.4, 14.0
Hz, 1H), 2.57 (s, 3H). MS (ESI) m/z (M+H) 444.1.
EXAMPLE 71
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)(ISOQUINOLINYL)
METHYL-1H-PYRAZOLECARBOXAMIDE (119)
N NHNH
LiOH
HOAc, reflux THF/H O
119C
119A
119B
To a mixture of 1-chloroisoquinoline (5.0 g, 30.56 mmol) in dioxane (10.00
mL) was added NH NH H O (305.62 mmol, 15 mL). The mixture was stirred at 80 °C for 16h.
2 2 2
The reaction mixture was washed with H O (100 mL). The reaction mixture diluted with MTBE
and filtered to give compound 119A (4.27 g, 87.77% yield) as a yellow solid. H NMR
(400MHz, DMSO-d ) δ 8.16 (d, J=8.3 Hz, 1H), 7.87 (d, J=5.8 Hz, 1H), 7.72 - 7.65 (m, 1H), 7.64
- 7.56 (m, 1H), 7.48 - 7.41 (m, 1H), 6.90 (d, J=5.8 Hz, 1H). MS (ESI) m/z (M+H) 160.1.
A mixture of compound 119A (4.20 g, 26.38 mmol ) and ethyl 2-
(methoxyimino)oxopentanoate (4.94 g, 26.38 mmol) in HOAc (40.00 mL) was stirred at 120
°C for 48h. The reaction mixture was concentrated under reduced pressure to remove HOAc.
The residue was diluted with H O (20 mL) and extracted with ethyl acetate (40 mL). The
combined organic layers were washed with brine (40 mL), dried over Na SO , concentrated
under reduced pressure to give a residue. The residue was purified by column chromatography
(SiO , Petroleum ether/Ethyl acetate=10/1 to 0:1) to give compound 119B (238.00 mg, 3.08%
yield) was obtained as a yellow oil. H NMR (400MHz, CDCl ) δ 8.46 (br d, J=5.5 Hz, 1H),
17681897_1 (GHMatters) P110989.NZ
7.92 (d, J=8.2 Hz, 1H), 7.79 (d, J=5.5 Hz, 1H), 7.72 (t, J=7.4 Hz, 1H), 7.67 - 7.53 (m, 2H), 6.92
(s, 1H), 4.06 (q, J=7.1 Hz, 2H), 2.43 (s, 3H), 0.99 (t, J=7.2 Hz, 3H). MS (ESI) m/z (M+H) 282.
To a solution of compound 119B (238.00 mg, 846.04 umol) in THF (6.00 mL)
was added LiOH H O (177.50 mg, 4.23 mmol) in H O (2.00 mL). The mixture was stirred at 28
°C for 16h. The reaction mixture was diluted with H O (10 mL) and extracted with MTBE (15
mL x 2), the water phase was added 1N HCl to pH ~ 3~4, extracted with ethyl acetate (15 mL x
2). The combined organic layers were washed with brine (15 mL), dried over Na SO , filtered
and concentrated under reduced pressure to give intermediate compound 119C (201.00 mg,
92.87% yield) as a yellow solid. Compound 119C: H NMR (400MHz, DMSO-d ) δ 8.42 (d,
J=5.5 Hz, 1H), 8.12 (d, J=8.2 Hz, 1H), 8.01 (d, J=5.7 Hz, 1H), 7.85 (t, J=7.2 Hz, 1H), 7.69 (t,
J=7.4 Hz, 1H), 7.56 (d, J=8.4 Hz, 1H), 6.92 (s, 1H), 2.32 (s, 3H). MS (ESI) m/z (M+H) 254.1.
Compound 119 (20.00 mg, 35.64% yield, light yellow solid) was prepared as
in Example 5 from the corresponding intermediate carboxylic acid, compound 119C. Compound
119: H NMR (400MHz, CDCl ) δ 8.23 (br d, J=6.2 Hz, 1H), 7.94 - 7.85 (m, 3H), 7.75 (br t,
J=7.8 Hz, 1H), 7.69 (br d, J=5.3 Hz, 1H), 7.62 (br t, J=7.7 Hz, 1H), 7.12 (br d, J=7.1 Hz, 1H),
7.09 - 7.03 (m, 2H), 6.92 (br d, J=7.1 Hz, 2H), 6.73 (s, 1H), 6.67 (br s, 1H), 5.65 - 5.59 (m, 1H),
.51 (br s, 1H), 3.36 - 3.28 (m, 1H), 3.21 - 3.14 (m, 1H), 2.41 (s, 3H). MS (ESI) m/z (M+H)
428.1.
EXAMPLE 72
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)METHYL(5-
METHYLPYRIDINYL)-1H-PYRAZOLECARBOXAMIDE (120)
N NHNH
LiOH
MeOH/H O
HOAc, reflux
120A
120B 120D
A mixture of 2-fluoromethylpyridine (10.00 g, 89.99 mmol, 9.35 mL) in
NH NH .H O (53.00 g, 899.93 mmol, 51.5 mL) was degassed and purged with N 3 times, and
2 2 2 2
then the mixture was stirred at 120 °C for 15 h under N atmosphere. The reaction mixture was
concentrated under reduced pressure to remove solvent. The residue was diluted with H O (30
17681897_1 (GHMatters) P110989.NZ
mL) and extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed
with brine (20 mL x 2), dried over Na SO , filtered and concentrated under reduced pressure to
give the compound 120A (6.09 g, yield: 54.9%) was obtained as a light pink solid. H NMR
(400MHz, CDCl ) δ 7.95 (s, 1H), 7.32 (dd, J = 2.0, 8.4 Hz, 1H), 6.63 (d, J = 8.4 Hz, 1H), 5.68
(br s, 1H), 2.20 (s, 3H).
A mixture of compound 120A (2 g, 16.24 mmol), ethyl 2-(methoxyimino)
oxopentanoate (3.04 g, 16.24 mmol) in HOAc (20 mL) was stirred at 120 °C for 20 h. The
reaction mixture was concentrated under reduced pressure to remove solvent. The residue was
diluted with H O (15 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic
layers were washed with NaHCO (20 mL x 3), and then washed with brine (20 mL x 2), dried
over Na SO , filtered and concentrated under reduced pressure to give a residue. The residue
was purified by preparatory-HPLC (HCl condition) to give the compound 120B (340 mg, yield:
8.5%) was obtained as a white solid. Compound 120B: H NMR (400MHz, DMSO-d ) δ 8.27 (s,
1H), 7.82 (dd, J = 1.8, 8.3 Hz, 1H), 7.58 (d, J = 8.3 Hz, 1H), 6.77 (s, 1H), 4.19 (q, J = 7.0 Hz,
2H), 2.35 (s, 3H), 2.28 (s, 3H), 1.14 (t, J = 7.0 Hz, 3H).
To a solution of compound 120B (340 mg, 1.39 mmol) in THF (10 mL) was
added LiOH.H O (291 mg, 6.95 mmol) in H O (3 mL). The mixture was stirred at 25 °C for 30
h. The reaction mixture was diluted with H O (15 mL) and extracted with MTBE (10 mL). The
combined water layers were adjusted to pH ~ 6 by adding 1N HCl, and then extracted with ethyl
acetate (20 mL x 2). The combined organic layers were washed with brine (20 mL), dried over
Na SO , filtered and concentrated under reduced pressure to give the compound 120D (300 mg,
yield: 99.4%) was obtained as a white solid. H NMR (400MHz, DMSO-d ) δ 13.50 (br s, 1H),
8.26 (s, 1H), 7.79 (dd, J = 1.8, 8.2 Hz, 1H), 7.54 (d, J = 8.2 Hz, 1H), 6.73 (s, 1H), 2.33 (s, 3H),
2.24 (s, 3H).
Compound 120 (15 mg, yield: 54.1% light yellow solid) was prepared as in
Example 5 from the corresponding intermediate carboxylic acid, compound 120D. Compound
120: H NMR (400MHz, DMSO-d ) δ 9.21 (d, J = 7.3 Hz, 1H), 8.09 (s, 1H), 8.04 (s, 1H), 7.85
(s, 1H), 7.73 (dd, J = 1.6, 8.2 Hz, 1H), 7.44 (d, J = 8.3 Hz, 1H), 7.31 - 7.23 (m, 5H), 6.53 (s, 1H),
.35 - 5.26 (m, 1H), 3.16 (dd, J = 4.0, 14.1 Hz, 1H), 2.87 (dd, J = 9.8, 14.1 Hz, 1H), 2.31 (s, 3H),
2.26 (s, 3H).
17681897_1 (GHMatters) P110989.NZ
EXAMPLE 73
COMPOUNDS 121-122, 445
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)METHYL(5-
METHYLPYRIDINYL)-1H-PYRAZOLECARBOXAMIDE (121)
CF 3
O N 3
N NHNH
LiOH
MeOH/H O
HOAc, reflux
121A
121B
121D
Intermediate compound 121D (650 mg, yield: 89.8%, white solid) was
prepared as in Example 120 from the corresponding starting materials, compound 121A and 2-
chloro(trifluoromethyl)pyridine. Compound 121A: H NMR (400MHz, DMSO-d ) δ 13.55 (br
s, 1H), 8.86 (s, 1H), 8.39 (dd, J = 2.3, 8.5 Hz, 1H), 7.91 (d, J = 8.4 Hz, 1H), 6.81 (s, 1H), 2.27 (s,
3H).
Compound 121 (35.9 mg, yield: 55.2%, white solid) was prepared as in
Example 12 from the corresponding intermediate carboxylic acid, compound 121D. Compound
121: H NMR (400MHz, DMSO-d ) δ 9.15 (d, J = 7.3 Hz, 1H), 8.45 (s, 1H), 8.29 (dd, J = 2.1,
8.7 Hz, 1H), 8.11 (s, 1H), 7.88 - 7.80 (m, 2H), 7.28 - 7.24 (m, 4H), 7.22 - 7.17 (m, 1H), 6.51 (s,
1H), 5.36 - 5.28 (m, 1H), 3.14 (dd, J = 3.6, 14.0 Hz, 1H), 2.81 (dd, J = 9.9, 14.1 Hz, 1H), 2.27 (s,
3H).
(S)-N-(4-(CYCLOPROPYLAMINO)-3,4-DIOXOPHENYLBUTANYL)METHYL-
1-(5-(TRIFLUOROMETHYL)PYRIDINYL)-1H-PYRAZOLECARBOXAMIDE
(122)
Compound 122 (54.1 mg, yield: 87.9%, white solid) was prepared as in
Example 20 from the corresponding intermediate carboxylic acid, compound 121D. Compound
122: H NMR (400MHz, DMSO-d ) δ 9.16 (d, J = 7.3 Hz, 1H), 8.85 (d, J = 5.1 Hz, 1H), 8.42 (s,
1H), 8.30 (dd, J = 2.1, 8.7 Hz, 1H), 7.83 (d, J = 8.6 Hz, 1H), 7.29 - 7.23 (m, 4H), 7.22 - 7.16 (m,
1H), 6.51 (s, 1H), 5.38 - 5.30 (m, 1H), 3.14 (dd, J = 3.7, 14.1 Hz, 1H), 2.86 - 2.72 (m, 2H), 2.27
(s, 3H), 0.68 - 0.55 (m, 4H).
17681897_1 (GHMatters) P110989.NZ
N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)METHYL(5-
(TRIFLUOROMETHYL)PYRIDINYL)-1H-PYRAZOLECARBOXAMIDE (445)
Compound 445 (140 mg, yield: 47.4%, white solid) was prepared as in
compound 121 from the corresponding intermediates 121D and 274D. Compound 445: H NMR
(400MHz, DMSO-d ) δ 9.16 (d, J = 7.5 Hz, 1H), 8.50 - 8.43 (m, 1H), 8.31 (dd, J = 2.2, 8.8 Hz,
1H), 8.12 (s, 1H), 7.90 - 7.81 (m, 2H), 7.29 - 7.18 (m, 4H), 6.53 (s, 1H), 5.38 - 5.29 (m, 1H),
3.16 (dd, J = 4.0, 14.1 Hz, 1H), 2.83 (dd, J = 9.9, 14.1 Hz, 1H), 2.28 (s, 3H). MS (ESI) m/z
(M+H) 446.1.
EXAMPLE 74
COMPOUNDS 123-124
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)(4,6-DIMETHYLPYRIDIN
YL)METHYL-1H-PYRAZOLECARBOXAMIDE (123)
N NHNH
LiOH
HOAc, reflux, 16 h N
THF/H O
123A
123B
123C
Intermediate compound 123C (210 mg, yield: 78.29%, white solid) was
prepared as in Example 120 from the corresponding starting materials, compound 123A and 2-
chloro(trifluoromethyl)pyridine. H NMR (400MHz, DMSO-d6) δ 7.38 (s, 1H), 7.14 (s, 1H),
6.77 (s, 1H), 2.40 (s, 3H), 2.37 (s, 3H), 2.26 (s, 3H). MS (ESI) m/z (M +H) 232.0.
Compound 123 (40 mg, yield: 38.78%, light yellow solid) was prepared as in
Example 5 from the corresponding intermediate carboxylic acid, compound 123C. Compound
123: H NMR (400MHz, DMSO-d ) δ 9.13 (d, J = 7.3 Hz, 1H), 8.04 (s, 1H), 7.81 (s,1H), 7.28 -
7.18 (m, 6H), 6.99 (s, 1H), 6.44 (s, 1H), 5.41 - 5.21 (m, 1H), 3.12 (dd, J = 4.0, 13.9 Hz, 1H), 2.82
(dd, J = 9.7, 13.9 Hz, 1H), 2.31 (s, 3H), 2.23 (s, 3H), 2.19 (s, 3H). MS (ESI) m/z (M +H) 406.1.
(S)-N-(4-(CYCLOPROPYLAMINO)-3,4-DIOXOPHENYLBUTANYL)METHYL-
4-PHENYLTHIAZOLECARBOXAMIDE (124)
Compound 124 (40 mg, yield: 57.35%, white solid) was prepared as in
Example 41 from the corresponding carboxylic acid, 2-methylphenylthiazolecarboxylic
17681897_1 (GHMatters) P110989.NZ
acid. H NMR (400MHz, CDCl ) δ 7.58 - 7.50 (m, 2H), 7.49 - 7.36 (m, 3H), 7.22 - 7.13 (m, 3H),
6.84 (br s, 1H), 6.80 - 6.69 (m, 2H), 6.22 (br d, J = 6.3 Hz, 1H), 5.58 - 5.46 (m, 1H), 3.26 (dd, J
= 4.9, 14.2 Hz, 1H), 2.89 (dd, J = 7.5, 14.1 Hz, 1H), 2.79 (qt, J = 3.8, 7.4 Hz, 1H), 2.71 (s, 3H),
0.94 - 0.82 (m, 2H), 0.66 - 0.55 (m, 2H). MS (ESI) m/z (M +H) 434.1.
EXAMPLE 75
(S)-N-(4-(CYCLOPROPYLAMINO)-3,4-DIOXOPHENYLBUTANYL)METHYL-
1-(4-PHENYLTHIAZOLYL)-1H-PYRAZOLECARBOXAMIDE (127)
LiOH H2O
N MeOH: H N
2 (2:1)
°C, 3
O OH
127A
127B
Intermediate compound 127B (150 mg, 94.78% yield, white solid) was
prepared as in Example 85 from compound 127A. Compound 127B: H NMR (400 MHz,
DMSO-d ): δ 9.20 (s, 1H), 8.99 (s, 2H), 6.94 (s, 1H), 2.27 (s, 3H).
Compound 127 (55.3 mg, 45.18% yield, white solid) was prepared as in
Example 20 from the corresponding intermediate carboxylic acid, compound 127B. Compound
127: H NMR (400 MHz, CDCl ): δ 9.15 (s, 1H), 8.76 (s, 2H), 7.35 - 7.28 (m, 3H), 7.13 - 7.09
(m, 2H), 6.95 (br s, 1H), 6.66 - 6.60 (m, 1H), 6.47 (s, 1H), 5.60 - 5.54 (m, 1H), 3.46 - 3.38 (m,
1H), 3.20 - 3.13 (m, 1H), 2.87 - 2.77 (m, 1H), 2.35 (s, 3H), 0.92 - 0.87 (m, 2H), 0.66 - 0.61 (m,
2H). MS (ESI) m/z (M+1) 419.1.
17681897_1 (GHMatters) P110989.NZ
EXAMPLE 76
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)PHENYL-1H-PYRAZOLE
CARBOXAMIDE (129)
PhB(OH)2
NaOH
Pd(dtbpf)Cl2
K PO MeOH,THF
3 4 OH
129A
SEM 129B 129C
CONH
2 EtOAc
N NH
129E
NH O
To a solution of NaH (1.46 g, 36.59 mmol, 60% purity) in THF (80 mL) was
added methyl 4-bromo-1H-pyrazolecarboxylate (5.00 g, 24.39 mmol) ith THF (20 mL) at 0°C.
After addition, the mixture was warmed to 25°C and stirred for 2h. Then the mixture was cooled
to 0°C and a solution of SEM-Cl (4.47 g, 26.83 mmol, 4.8 mL) in THF (100 mL). The mixture
was stirred at 25°C for 12h. The mixture was diluted with H O (200 mL), the organic layer was
washed with HCl (1M, 100 mL), saturated NaHCO (100 mL), brine (100 mL), dried over
Na SO and concentrated. The residue was purified by column chromatography (SiO ,
2 4 2
Petroleum ether/Ethyl acetate = 10/1 to 3:1). Compound 129A (3.40 g, yield 41.6%) was
obtained as a colorless oil. H NMR (400MHz, DMSO-d ) δ 8.39 (s, 1H), 5.51 (s, 2H), 3.87 (s,
3H), 3.62 - 3.56 (m, 2H), 0.95 - 0.81 (m, 2H), 0.07 - -0.07 (m, 9H).
A mixture of compound 2 (3.40 g, 10.14 mmol), phenylboronic acid (1.48 g,
12.17 mmol), ditert-butyl(cyclopentyl)phosphane;dichloropalladium;iron (660.9 mg, 1.01 mmol),
K PO (6.46 g, 30.42 mmol) in dioxane (30 mL) and H O (10 mL) was degassed and purged
3 4 2
with N 3 times, and then the mixture was stirred at 70 °C for 1 hour under N atmosphere. The
mixture was concentrated under reduced pressure. The residue was purified by column
chromatography (SiO , Petroleum ether/Ethyl acetate=10/1 to 3:1). Compound 129B (3.00 g,
crude) was obtained as a brown oil. H NMR (400MHz, DMSO-d6) δ 8.26 (s, 1H), 7.51 - 7.32
(m, 5H), 5.53 (s, 2H), 3.78 (s, 3H), 3.67 - 3.59 (m, 2H), 0.94 - 0.82 (m, 2H), 0.06 - -0.07 (m, 9H).
17681897_1 (GHMatters) P110989.NZ
To a solution of compound 129B (3.00 g, 9.02 mmol) in MeOH (100 mL) and
THF (100 mL) was added NaOH (2M, 90 mL). The mixture was stirred at 60 °C for 1 hour. The
mixture was concentrated and diluted with H O (200 mL), the mixture was extracted with ethyl
acetate (200 mL), the water phase was added HCl (1M) until pH ~ 3, then the mixture was
extracted with ethyl acetate (200 mL), the organic layer was washed with brine (200 mL), dried
over Na SO and concentrated. Compound 129C (300.0 mg, yield 10.4%) was obtained as a
brown oil. H NMR (400MHz, DMSO-d ) δ 8.20 (s, 1H), 7.51 - 7.47 (m, 2H), 7.43 - 7.37 (m,
2H), 7.35 - 7.30 (m, 1H), 5.50 (s, 2H), 3.67 - 3.61 (m, 2H), 0.92 - 0.87 (m, 2H), 0.03 - -0.03 (m,
9H).
Intermediate compound 129E (70.0 mg, crude, colorless oil) was prepared as in
Example 5 from the corresponding carboxylic acid, compound 129C. Compound 129E: H NMR
(400MHz, DMSO-d ) δ 8.45 (d, J = 7.6 Hz, 1H), 8.25 - 8.21 (m, 1H), 8.20 - 8.13 (m, 1H), 7.90
(s, 1H), 7.44 - 7.38 (m, 2H), 7.36 - 7.19 (m, 8H), 5.51 - 5.43 (m, 3H), 3.68 - 3.60 (m, 2H), 3.26 -
3.18 (m, 1H), 3.08 - 2.99 (m, 1H), 0.95 - 0.87 (m, 2H), 0.06 - -0.05 (m, 9H).
To a solution of compound 129E (70.0 mg, 142.09 umol) in ethyl acetate (10
mL) was added HCl/EtOAc (4M, 710 uL). The mixture was stirred at 25 °C for 3 hours. The
mixture was concentrated. The residue was purified by prep-HPLC (HCl condition). Compound
129 (20.0 mg, HCl, yield 34.4%) was obtained as a white solid. H NMR (400MHz, D O) δ 7.74
- 7.61 (m, 1H), 7.41 - 7.33 (m, 2H), 7.30 - 7.09 (m, 10H), 4.54 - 4.53 (m, 1H), 3.00 - 2.92 (m,
2H). MS (ESI) m/z (M+H) 363.1.
EXAMPLE 77
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)METHYL(4-
(PHENOXYMETHYL)PHENYL)-1H-PYRAZOLECARBOXAMIDE (131)
LiOH
Cu(OAc)2
MS, O , DCM
N OH
131C
131A
17681897_1 (GHMatters) P110989.NZ
To a mixture of ethyl 3-methyl-1H-pyrazolecarboxylate (250 mg, 1.62
mmol), [4-(phenoxymethyl)phenyl]boronic acid (554.7 mg, 2.43 mmol), 4A° MS (8 g) and
pyridine (141 mg, 1.78 mmol, 0.15 mL) in DCM (50 mL) was added Cu(OAc) (383 mg, 2.11
mmol), the mixture was stirred at 25 °C for 16h under O balloon (15 psi). The reaction mixture
was filtered to get rid of 4A° MS and catalyst, and then the filtrate was concentrated. The residue
was purified by column chromatography (SiO , Petroleum ether/Ethyl acetate = 5/1) and by
preparatory-TLC (SiO , Petroleum ether/Ethyl acetate = 5/1).
Compound 131A (69.3 mg, yield: 13.03%) was obtained as a yellow oil. H
NMR (400MHz, CDCl ) δ 7.99 - 7.93 (m, 2H), 7.91 - 7.82 (m, 2H), 7.80 - 7.68 (m, 2H), 7.46 -
7.40 (m, 3H), 5.59 (s, 2H), 4.68 (q, J = 7.1 Hz, 2H), 2.81 (s, 3H), 2.05 (s, 1H), 1.69 (t, J = 7.2
Hz, 3H). MS (ESI) m/z (M+H) 337.1.
To a solution of compound 131A (69.3 mg, 206.02 umol), in THF (5 mL) and
H O (3 mL) was added LiOH.H O (26 mg, 618.06 umol).After stirred at 25 °C for 3h, the
reaction mixture was added H O (10 mL) and extracted with MTBE (20 mL).The organic layer
was washed with H O (10 mL). The combined aqueous layer was acidified to pH ~ 1~2 with 1N
HCl, extracted with ethyl acetate (20 mL x 3), dried over Na SO , filtered and concentrated.
Compound 131C (70 mg, crude, white solid): H NMR (400MHz, DMSO-d ) δ 13.23 (br s, 1H),
7.57 - 7.51 (m, 2H), 7.43 (d, J = 8.3 Hz, 2H), 7.35 - 7.27 (m, 2H), 7.05 (d, J = 7.8 Hz, 2H), 6.96
(t, J = 7.3 Hz, 1H), 6.83 (s, 1H), 5.17 (s, 2H), 2.26 (s, 3H).
Compound 131 (37.2 mg, yield: 45.9%, white solid) was prepared as in
Example 5 from the corresponding intermediate carboxylic acid, compound 131C. Compound
131: H NMR (400MHz, DMSO-d ) δ 9.12 (br d, J = 7.5 Hz, 1H), 8.11 (br s, 1H), 7.86 (s, 1H),
7.39 (br d, J = 8.2 Hz, 2H), 7.33 - 7.26 (m, 6H), 7.23 (br d, J = 6.4 Hz, 1H), 7.17 (br d, J = 8.2
Hz, 2H), 7.01 (br d, J = 8.2 Hz, 2H), 6.93 (t, J = 7.4 Hz, 1H), 6.56 (s, 1H), 5.31 - 5.22 (m, 1H),
.09 (s, 2H), 3.19 (br dd, J = 3.2, 13.8 Hz, 1H), 2.82 (br dd, J = 10.9, 13.6 Hz, 1H), 2.23 (s, 3H).
MS (ESI) m/z (M+H) 483.1.
17681897_1 (GHMatters) P110989.NZ
EXAMPLE 78
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)(ISOQUINOLINYL)
METHYL-1H-PYRAZOLECARBOXAMIDE (133)
H N N
O O N
LiOH H O
N MeOH: H O
o (2:1)
AcOH,120 C,
°C, 1 h
133A
133D
133B
To a solution of isoquinolinamine (1.4 g, 9.71 mmol ) in 5N aqueous
hydrochloric acid (12 mL) at 0 °C was added a solution of NaNO (670 mg, 9.71 mmol) in
deionized water (1 mL). The reaction mixture was stirred at 0 °C for 0.5h and a solution of
SnCl •2H O (5.48 g, 24.28 mmol) dissolved in concentrated hydrochloric acid (5 mL) was added
dropwise. The mixture was stirred at 25 °C for 2h. The mixture was adjusted to pH ~ 12 - 14
with 20 % aqueous NaOH. The mixture was extracted with 2:1 CHCl /iPrOH (200 mL). The
organic layer was dried (Na SO ), filtered, and concentrated in vacuo. The residue was purified
by column chromatography (SiO , Petroleum ether/Ethyl acetate = 1/0 to 0:1) and then dried
under reduced pressure to afford compound 133A (720 mg, 46.55 % yield) as a brown solid. H
NMR (DMSO-d 400 MHz): δ 9.95 (br s, 1H), 9.25 - 9.13 (m, 2H), 8.04 - 7.95 (m, 2H), 7.88 (d, J = 8.8 Hz,
1H), 7.26 (d, J = 7.6 Hz, 1H), 7.28 - 7.23 (m, 1H).
To a mixture of compound 133A (620 mg, 3.89 mmol) and ethyl 2,4-
dioxopentanoate (615.9 mg, 3.89 mmol) in AcOH (5 mL) was degassed and purged with N for 3
times, and then the mixture was stirred at 120 °C for 2 hours under N atmosphere. The reaction
mixture was concentrated under reduced pressure to remove AcOH. The residue was diluted
with EtOAc 10 mL and adjusted with saturated NaHCO and then finally extracted with EtOAc
(30 mL x 3). The combined organic layers were dried by Na SO , filtered and concentrated
under reduced pressure to give a crude product. The reaction solution was purified by column
chromatography (SiO , Petroleum ether/Ethyl acetate=1/0 to 0/1) to give compound 133B (600.00
mg, 45.16% yield) as a yellow oil. Compound 133B: H NMR (CDCl , 400 MHz): δ 9.34 (s, 1H),
8.54 (s, 1H), 8.07 (d, J = 7.6 Hz, 1H), 7.72 - 7.61 (m, 2H), 7.37 (d, J = 8.0 Hz, 1H), 6.96 (s, 1H), 4.05 (q, J = 7.2
Hz, 2H), 2.42 (s, 3H), 0.98 (t, J = 7.2 Hz, 3H). MS (ESI) m/z (M+1) 282.1.
17681897_1 (GHMatters) P110989.NZ
To a mixture of 133B (200 mg, 711 umol) in MeOH (10 mL) and H O (5 mL)
was added LiOH•H O (119.3 mg, 2.84 mmol) in one portion and the mixture was stirred at 25°C
for 1 hour. The reaction mixture was concentrated under reduced pressure to remove MeOH.
The residue was diluted with H O (5 mL), adjusted to pH ~ 3 with 1N HCl, and then extracted
with EtOAc (40 mL x 3). The combined organic layers were dried over anhydrous Na SO ,
filtered and concentrated under reduced pressure to afford intermediate compound 133D (150
mg, 75.43% yield) as a yellow solid. H NMR (DMSO-d 400 MHz): δ 9.45 (s, 1H), 8.54 (s, 1H),
8.28 (d, J = 7.6 Hz, 1H), 7.86 - 7.73 (m, 2H), 7.27 (d, J = 8.4 Hz, 1H), 6.99 (s, 1H), 2.33 (s, 3H). MS (ESI) m/z
(M+1) 254.0.
Compound 133 (22.2 mg, 31.49% yield, white solid) was prepared as in
Example 5 from the corresponding intermediate carboxylic acid, compound 133D. Compound
133: H NMR (CDCl , 400 MHz): δ 9.30 (s, 1H), 8.46 (s, 1H), 8.06 (d, J = 8.0 Hz, 1H), 7.73 -
7.63 (m, 2H), 7.47 (d, J = 8.4 Hz, 1H), 7.26 - 7.24 (m, 3H), 6.97 - 6.95 (m, 2H), 6.66 (br s, 1H),
6.59 (s, 1H), 6.48 (d, J = 7.2 Hz, 1H), 5.65 (br s, 1H), 5.41 - 5.36 (m, 1H), 3.28 - 3.24 (m, 1H),
3.11 - 3.06 (m, 1H), 2.40 (s, 3H). MS (ESI) m/z (M+H) 428.1.
EXAMPLE 79
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)METHYL(PYRIDINYL)-
1H-PYRAZOLECARBOXAMIDE (136)
LiOH.H O
O 55 O
°C,MeOH:H
(2:1)
136C
136A
To a solution of ethyl 3-methyl(pyridinyl)-1H-pyrazolecarboxylate
(2.0 g, 12.97 mmol) and pyridinylboronic acid (1.59 g, 12.97 mmol) in pyridine (30 mL) was
added Cu(OAc) (1.18 g, 6.49 mmol) .The mixture was stirred at 55 °C for 18 hrs. The mixture
filtered and concentrated in vacuum. The residue was purified by flash silica gel chromatography
(ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 0~50% Ethyl acetate/Petroleum
ethergradient @ 40 mL/min). Compound 136A (850 mg, 28.34% yield, white solid): H NMR
(400MHz, CDCl ): δ 8.69 (d, J = 2.0 Hz, 1H), 8.65 - 8.62 (m, 1H), 7.80 - 7.77 (m, 1H), 7.42 -
7.38 (m, 1H), 6.86 (s, 1H), 4.27 - 4.21 (m, 2H), 2.37 (s, 3H), 1.27 - 1.23 (m, 3H).
17681897_1 (GHMatters) P110989.NZ
Compound 136C (160 mg, 60.57% yield, white solid) was prepared as in
Example 85. Compound 136C: H NMR (400 MHz, DMSO-d ): δ 8.65 - 8.55 (m, 2H), 7.91 -
7.85 (m, 1H), 7.53 - 7.47 (m, 1H), 6.88 (s, 1H), 2.26 (s, 3H).
Compound 136 (46.2 mg, 54.66% yield, yellow solid) was prepared as in
Example 5 from the corresponding intermediate compounds 136C and 12G. Compound 136: H
NMR (400 MHz, CDCl ) δ 8.61 (d, J = 2.4 Hz, 1H), 8.58 - 8.55 ( m, 1H), 7.74 - 7.69 (m, 1H),
7.36 - 7.28 (m, 4H), 7.12 - 7.07 (m, 2H), 6.79 (br s, 1H), 6.55 - 6.48(m, 1H), 6.43 (s, 1H), 5.69
(br s, 1H), 5.56 - 5.49 (m, 1H), 3.43 - 3.36 (m, 1H), 3.20 - 3.13 (m, 1H), 2.33 (s, 3H). MS (ESI)
m/z (M+H) 378.1.
EXAMPLE 80
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)METHYL(PYRIMIDIN
YL)-1H-PYRAZOLECARBOXAMIDE (138)
O N N
N H N
, DBAD in Dioxane 2
Cu(OAc)2 (4 M)
(HO)2
NH N
138B
138A
O TMSOK, THF
hrs N
°C, 0.5
(1.0
120 °C, 2 hrs
CH COOH N
138D
138C
To a solution of pyrimidinylboronic acid (5.00 g, 40.35 mmol) in MeOH
(32 mL) was added Cu(OAc) (732.8 mg, 4.04 mmol) and DBAD (9.29 g, 40.35 mmol). The
resulting mixture was stirred at 60 °C for 1 hour. The reaction mixture was cooled to 25°C,
concentrated under reduced pressure, diluted with water (50 mL), and extracted with ethyl acetate
(80 mL x 3). The extract was dried over anhydrous Na SO and concentrated under reduced
pressure to give the title compound as yellow oil, which was used in the next step without
purification. Compound 138A (9.00 g, 71.87% yield) was obtained as a yellow oil. H NMR
(400 MHz, CDCl ) δ 8.96 (s, 1H), 8.89 (br s, 1H), 1.53 – 1.50 (m, 18H).
To a solution of compound 138A (9.00 g, 25.00 mmol) in 1,4-dioxane (60 mL)
was added 4M HCl 1,4-dioxane (60 mL) and the mixture was stirred at room-temperature for 30
hours. The suspension was filtered, and the residue was washed with ethyl acetate (100 mL x 2)
17681897_1 (GHMatters) P110989.NZ
and dried under reduced pressure to afford the title compound (3.45 g, crude), which was used in
the next step without purification. Compound 138B (3.45 g, 81.17% yield, HCl) was obtained as
a white solid. H NMR (400 MHz, DMSO-d ) δ 8.80(s, 1H), 8.61(s, 2H).
To a solution of compound 138B (800.0 mg, 5.46 mmol, HCl) in CH COOH
(12 mL) was added ethyl 2-(methoxyimino)oxopentanoate (1.02 g, 5.46 mmo), then the
mixture was stirred at 120 °C for 2 hours. The mixture was diluted with CH Cl (70 mL) and
washed by saturated sodium bicarbonate (20 mL x 2) and saturated brine (20 mL x 2), the
organic layer was dried over anhydrous Na SO , filtered and concentrated in vacuum. The
residue was purified by flash column chromatography (SiO , petroleum ether : ethyl acetate =
/1 to 3/1). Compound 138C (250.0 mg, 19.72% yield) was obtained as a white solid.
To a solution of compound 138C (50.0 mg, 215.29 umol) in THF (3.00 mL)
was added TMSOK (55.2 mg, 430.58 umol), then the mixture was stirred at 25 °C for 0.5 hour.
The mixture was diluted with petroleum ethyl (20 mL) and the precipitate was filtered to give
intermediate compound 138D (45.0 mg, 86.27% yield) as a white solid. MS (ESI) m/z (M+1)
204.9.
Compound 138 (10.0 mg, 14.63% yield) was prepared as in Example 5from
the corresponding intermediate carboxylic acid, compound 138D. Compound 138: H NMR (400
MHz, CDCl3): δ 9.15(s, 1H), 8.78(s, 2H), 7.35-7.31(m, 3H), 7.13(d, J = 6.4 Hz, 2 H), 6.82(s,
1H), 6.58(d, J = 7.2 Hz, 1H), 6.47(s, 1H), 5.57-5.52(m, 1H), 5.46-5.58(m, 1H), 3.45-3.40(m,
1H), 3.21-3.15(m, 1H), 2.35(s, 3H). MS (ESI) m/z (M+1) 379.1.
EXAMPLE 81
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)(2H-INDAZOLYL)
METHYLISOXAZOLECARBOXAMIDE (139)
NH OH•HCl O
POCl Cl
Na CO
O O 2 3
O OEt
EtOH
O O N
139B
139A
LiOH O
N 2 N
THF/H O
K CO DMF
2 3 O
139D
139C
17681897_1 (GHMatters) P110989.NZ
To a solution of diethyl 2-acetylmalonate (5 g, 24.7 mmol) in EtOH (50 mL)
was added NH OH.HCl (1.9 g, 27.2 mmol) and Na CO (1.3 g, 12.4 mmol) in one portion, the
2 2 3
mixture was stirred at 90 °C for 2 hours. Then the contents were poured into ice-cold water (6
mL), and then filtered to give intermediate compound 139A (3.2 g, yield: 75.6%) as a pale
yellow solid. H NMR (400MHz, CDCl ) δ 4.37 (q, J = 7.0 Hz, 2H), 2.43 - 2.37 (m, 3H), 1.38 (t,
J = 7.2 Hz, 3H). MS (ESI) m/z (M+H) 126.2.
To compound 139A (3 g, 17.5 mmol) was added POCl (21.5 g, 140.2 mmol,
13 mL) in one portion. Then TEA (1.8 g, 17.5 mmol) were added. The mixture was stirred at
110 °C for 24 hours under N . Then ice water (15 mL) was added in to the mixture, and the
aqueous phase was extracted with EtOAc (25 mL x 3), the combined organic layer was washed
with brine, dried over Na SO , and concentrated to give intermediate compound 139B (2.6 g,
13.7 mmol, yield: 78.2%) as brown oil. H NMR (400MHz, CDCl ) δ 4.36 (q, J = 7.1 Hz, 2H),
2.48 (s, 3H), 1.38 (t, J = 7.2 Hz, 5H).
To a mixture of compound 139B (400 mg, 2.1 mmol) and 2H-indazole (299
mg, 2.5 mmol) in DMF (3 mL) was added K CO (1.2 g, 8.4 mmol) in one portion. The mixture
was stirred at 80 °C for 12 hours. Then H O (9mL) was added into the mixture, and the aqueous
phase was extracted with EtOAc (15 mL x 3), and the combined organic layer was concentrated
to give a residue. The residue was purified by column chromatography (SiO , Petroleum ether:
Ethyl acetate = 300:1 to 40:1) to give compound 139C (340 mg, yield: 59.4%) as a pale yellow
solid. H NMR (400MHz, CDCl ) δ 8.33 (s, 1H), 7.82 (d, J = 7.9 Hz, 1H), 7.68 (d, J = 8.8 Hz,
1H), 7.57 - 7.51 (m, 1H), 7.35 (t, J = 7.7 Hz, 1H), 4.24 (q, J = 7.0 Hz, 2H), 2.56 (s, 3H), 1.13 (t, J
= 7.2 Hz, 3H).
To a solution of compound 139C (100 mg, 368.6 umol) in THF (2 mL) and
H O (500 uL) was added LiOH.H O (15.5 mg, 368.6 umol) in one portion. The mixture was
stirred at 25 °C for 12 hours. Then the pH of the aqueous phase was adjusted to about 5 by
adding HCl (1M), and the residue concentrated on a rotary evaporator to give intermediate
compound 139D (83 mg, yield: 92.6%) as a white solid. H NMR (400MHz, DMSO-d6) δ 8.62
(s, 1H), 7.94 (d, J = 7.9 Hz, 1H), 7.59 (d, J = 3.5 Hz, 2H), 7.41 - 7.35 (m, 1H), 3.30 (br s, 3H).
MS (ESI) m/z (M+H) 243.9.
17681897_1 (GHMatters) P110989.NZ
Compound 139 (18 mg, yield: 24.8%, white solid) was prepared as in Example
from the corresponding intermediate carboxylic acid, compound 139D. Compound 139: H
NMR (400MHz, CDCl ) δ 10.32 (br d, J = 5.7 Hz, 1H), 8.17 (d, J = 8.6 Hz, 1H), 7.93 (s, 1H),
7.81 (d, J = 7.9 Hz, 1H), 7.65 (t, J = 7.4 Hz, 1H), 7.43 (t, J = 7.5 Hz, 1H), 7.19 - 7.12 (m, 5H),
6.77 (br s, 1H), 5.77 - 5.69 (m, 1H), 5.49 (br s, 1H), 3.42 (dd, J = 5.1, 14.3 Hz, 1H), 3.20 (dd, J =
7.9, 14.3 Hz, 1H), 2.57 (s, 3H). MS (ESI) m/z (M+H) 418.0.
EXAMPLE 82
METHYL (S)-(3-(5-((4-AMINO-3,4-DIOXOPHENYLBUTANYL)CARBAMOYL)
METHYL-1H-PYRAZOLYL)BENZYL)CARBAMATE (140)
NHBoc
Raney Ni, H
TEA HCl, EtOAc
(Boc)2
EtOH DCM
140C
140A
140B
NH •HCl N O
LiOH
Cl O
MeOH/H O
N TEA, DCM N
140E
140D 140F
To a solution of 3-hydrazinylbenzonitrile (30.0 g, 176.9 mmol , HCl salt) in
HOAc (500 mL) was added ethyl 2-methoxyiminooxo-pentanoate (33.1 g, 176.9 mmol). The
mixture was stirred at 100 °C for 12 hours. The mixture was concentrated, diluted with ethyl
acetate (200 mL), washed with NaHCO (aqueous, 200 mL), brine (200 mL), dried over Na SO
3 2 4
and concentrated. The residue was purified by column chromatography (SiO2, Petroleum
ether/Ethyl acetate = 1:0 to 5:1). The product obtained was triturated with Petroleum ether/Ethyl
acetate = 10:1 (100 mL) and filtered. Compound 140A (20.0 g, yield 44.3%) was obtained as a
white solid. H NMR (400MHz, DMSO-d ) δ 8.05 - 8.02 (m, 1H), 7.93 - 7.88 (m, 1H), 7.83 -
7.78 (m, 1H), 7.70 - 7.63 (m, 1H), 6.94 (s, 1H), 4.21 - 4.13 (m, 2H), 2.26 (s, 3H), 1.19 - 1.11 (m,
3H).
To a solution of compound 140A (9.00 g, 35.26 mmol) in MeOH (500 mL)
was added Raney-Ni (1.51 g) and NH .H O (4 mL). The mixture was stirred at 25 °C under H
3 2 2
at 40 psi for 12 hours. The mixture was concentrated, diluted with ethyl acetate (500 mL),
17681897_1 (GHMatters) P110989.NZ
washed with HCl (500 mL), the water phase was added NaHCO (aqueous) until pH ~ 11. Then
the mixture was extracted with ethyl acetate (500 mL), washed with brine (500 mL), dried over
Na SO and concentrated to afford intermediate compound 140B (15 g, crude) as a yellow oil.
To a solution of compound 140B (9.6 g, 37.06 mmol) in DCM (100 mL) was
added TEA (7 mL, 55.6 mmol), then Boc O (9 mL, 40.77 mmol) was added to the mixture and
the mixture was stirred at 25°C for 12h. The reaction was washed with citric acid (10%, 100
mL), extracted with DCM (100 mL x 2), washed with H O (100 mL), dried over anhydrous
Na SO , filtered, evaporated under reduced pressure. The crude product was purified by Flash
Column Chromatography (Petroleum Ether/Ethyl Acetate =5/1) to afford compound 140C (8.5 g,
yield 63.8%) as yellow oil. H NMR (DMSO-d 400MHz) δ 7.50 - 7.44 (m, 1H), 7.43 - 7.37 (m,
1H), 7.32 - 7.24 (m, 3H), 6.88 (s, 1H), 4.20 - 4.13 (m, 4H), 2.27 (s, 3H), 1.37 (s, 9H), 1.20 - 1.14
(m, 3H).
To a suspension of compound 140C (4.5 g, 13.03 mmol) in EA (350 mL) was
added HCl/EtOAc (4 M, 35 mL) and the mixture was stirred at 25 °C for 2 h. The reaction was
evaporated under reduced pressure to afford compound 140D (3.3 g, yield 89.9%, HCl) as white
solid, which was used directly in next step.
To a solution of compound 140D (1 g, 3.4 mmol, HCl) in DCM (20 mL) was
added TEA (1.4 mL, 10.1 mmol), followed by compound methylchloroformate (1.6 mL, 20.1
mmol), then the mixture was stirred at 25°C for 1h. The reaction was diluted with H2O (10 mL),
the mixture was extracted DCM (20 mL x 2). The organic layer was collected, washed with
brine (20 mL x 3), dried over anhydrous Na SO , filtered, and concentrated under reduced
pressure. The product was purified by Flash Column Chromatography (Petroleum Ether/Ethyl
Acetate, 0 to 10/1) to afford compound 140E (400 mg, yield 37.3%) was obtained as white solid.
H NMR (DMSO-d 400MHz) δ 7.77 (br t, J = 6.2 Hz, 1H), 7.43 - 7.38 (m, 1H), 7.33 - 7.25 (m,
3H), 6.88 (s, 1H), 4.23 (d, J = 6.2 Hz, 2H), 4.16 (q, J = 7.1 Hz, 2H), 3.55 (s, 3H), 2.26 (s, 3H),
1.14 (t, J = 7.1 Hz, 3H).
Compound 140F (230 mg, yield 64.6%, white solid) was prepared as in
Example 85 from the intermediate compound 140E. H NMR (DMSO-d 400MHz) δ 7.76 (br t,
J = 6.1 Hz, 1H), 7.42 - 7.35 (m, 1H), 7.31 - 7.22 (m, 3H), 6.82 (s, 1H), 4.23 (br d, J = 6.2 Hz,
2H), 3.55 (s, 3H), 2.25 (s, 3H)
17681897_1 (GHMatters) P110989.NZ
Compound 140 (35 mg, yield 21.1%, white solid) was prepared as in Example
from the corresponding intermediate carboxylic acid, compound 140F. Compound 140: H
NMR (CD CN 400MHz) δ 7.40 - 7.17 (m, 10H), 7.07 (br d, J = 18.3 Hz, 2H), 6.47 (br s, 1H),
6.26 (br s, 1H), 6.09 (br s, 1H), 5.34 (br s, 1H), 4.29 (br s, 2H), 3.60 (br s, 3H), 3.27 (br d, J = 9.5
Hz, 1H), 2.99 - 2.85 (m, 1H), 2.27 (br s, 3H). MS (ESI) m/z (M+H) 464.2.
EXAMPLE 83
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)(3-
(BENZAMIDOMETHYL)PHENYL)METHYL-1H-PYRAZOLECARBOXAMIDE
(141)
2 OH N
LiOH
DIEA
N EDCI, HOBt, O
THF/H O
140D
141A
141B
To a solution of compound 140D (300 mg, 1.22 mmol) and benzoic acid (150
mg, 1.22 mmol) in DCM (10 mL) was added HOBt (330 mg, 2.44 mmol), DIEA (0.5 mL, 3.05
mmol) and EDCI (470 mg, 2.44 mmol). The mixture was stirred at 25°C for 12h. The solvent
was removed in vacuo. The residue was dissolved in EtOAc (20 mL), washed with 1N HCl (20
mL). The organics were collected, washed with saturated NaHCO (20 mL). The organics were
collected, washed with brine (20 mL), dried with Na SO , filtered and concentrated to afford
compound 141A (400 mg, crude) as yellow oil. MS (ESI) m/z (M+H) 364.0.
To a solution of compound 141A (400 mg, 1.14 mmol) in THF (5 mL) and
H O (5 mL) was added LiOH.H O (241 mg, 5.72 mmol). The mixture was stirred at 25°C for
12h. The reaction was acidified with 1N HCl to pH ~ 4, extracted with EtOAc (15 mL x 2). The
organics were collected and concentrated. The residue was purified by preparatory-HPLC
(Neutral conditions) to afford compound 141B (100 mg, yield: 26.16%) as white solid. MS
(ESI) m/z (M+Na) 358.0.
Compound 141 (4.4 mg, yield: 14.40%, white solid) was prepared as in
Example 5 from the corresponding intermediate carboxylic acid, compound 141B. Compound
141: MS (ESI) m/z (M+H) 510.0. H NMR (400MHz, DMSO-d ) δ 8.86 - 8.68 (m, 2H), 7.94 -
17681897_1 (GHMatters) P110989.NZ
7.88 (m, 2H), 7.84 - 7.57 (m, 2H), 7.54 - 7.20 (m, 11H), 7.11 - 6.99 (m, 1H), 6.55 (s, 1H), 5.33 -
.24 (m, 1H), 4.56 - 4.48 (m, 2H), 3.26 - 3.18 (m, 1H), 2.95 - 2.86 (m, 1H), 2.25 (s, 3H).
EXAMPLE 84
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)METHYL(3-((3-
PHENYLPROPANAMIDO)METHYL)PHENYL)-1H-PYRAZOLECARBOXAMIDE
(142)
LiOH
EDCI, HOBt, DIEA
THF/H O
O DCM
140D
142A
142B
To a solution of compound 140D (500 mg, 2.04 mmol) and 3-phenylpropanoic
acid (310 mg, 2.04 mmol) in DCM (20 mL) was added DIEA (0.9 mL, 5.10 mmol), HOBt (552
mg, 4.08 mmol) and EDCI (783 mg, 4.08 mmol). The mixture was stirred at 25°C for 12h. The
solvent was removed in vacuo. The residue was dissolved in EtOAc (30 mL), washed with 1N
HCl (30 mL). The organics were collected, washed with saturated (30 mL), brine (30 mL), dried
with Na SO , filtered, collected and dried in vacuo to afford intermediate compound 22 (700 mg,
crude) as yellow oil. MS (ESI) m/z (M+Na) 414.0.
To a solution of compound 142A (700 mg, 1.85 mmol) in THF (10 mL) and
H O (10 mL) was added LiOH.H O (390 mg, 9.27 mmol). The mixture was stirred at 25°C for
12h. The residue was acidified with 1N HCl to pH ~ 4. The solution was extracted with EtOAc
(20 mL x 2). The organics were collected and concentrated. The residue was purified by
preparatory-HPLC (Neutral) to afford compound 142B (210 mg, yield: 31.24%) as white solid.
MS (ESI) m/z (M+Na) 386.0.
Compound 142 (49.5 mg, yield: 37.88%, white solid) was prepared as in
Example 5 from the corresponding intermediate carboxylic acid, compound 142B. Compound
142: MS (ESI) m/z (M+H) 538.2. H NMR (400MHz, DMSO-d ) δ 8.80 - 8.68 (m, 1H), 8.18 -
8.08 (m, 1H), 7.88 - 7.54 (m, 2H), 7.33 - 7.02 (m, 15H), 6.59 - 6.49 (m, 1H), 5.33 - 5.26 (m, 1H),
4.32 - 4.25 (m, 2H), 3.26 - 3.20 (m, 1H), 2.95 - 2.90 (m, 1H), 2.90 - 2.85 (m, 2H), 2.49 - 2.45 (m,
2H), 2.28 - 2.22 (m, 3H).
17681897_1 (GHMatters) P110989.NZ
EXAMPLE 85
(S)(3-(ACETAMIDOMETHYL)PHENYL)-N-(4-AMINO-3,4-DIOXO
PHENYLBUTANYL)METHYL-1H-PYRAZOLECARBOXAMIDE (143)
LiOH
THF/H O N
N DCM
140D
143A 143B
To a solution of compound 140D (500 mg, 2.04 mmol) and acetyl chloride
(160 mg, 2.04 mmol) in DCM (20 mL) was added TEA (0.7 mL, 5.10 mmol). The mixture was
stirred at 25°C for 12 h. The reaction was washed with 1N HCl (10 mL). The organics were
collected, dried with Na SO , filtered and concentrated to afford intermediate compound 143A
(580 mg, crude) as yellow oil. MS (ESI) m/z (M+Na) 323.9.
To a solution of compound 143A (580 mg, 2.02 mmol) in THF (10 mL) and
H O (10 mL) was added LiOH.H O (424 mg, 10.09 mmol). The mixture was stirred at 25 °C for
12h. The reaction was acidified with 1N HCl to pH ~ 4. The solution was extracted with EtOAc
(20 mL x 2). The organics were collected and concentrated. The residue was purified by
preparatory-HPLC (Neutral) to afford compound 26 (100 mg, yield: 18.11%) as white solid. MS
(ESI) m/z (M+Na) 295.9.
Compound 143 (6.2 mg, yield: 12.26%, white solid) was prepared as in
Example 5 from the corresponding intermediate carboxylic acid, compound 143B. Compound
143: MS (ESI) m/z (M+H) 448.1. H NMR (400MHz, DMSO-d ) δ 8.78 - 8.67 (m, 0.6H), 8.19
- 8.05 (m, 1H), 7.85 - 7.72 (m, 1H), 7.67 - 7.53 (m, 0.6H), 7.36 - 6.87 (m, 10H), 6.59 - 6.46 (m,
1H), 6.30 - 5.89 (m, 1H), 5.33 - 5.23 (m, 0.6H), 4.52 - 4.40 (m, 0.6H), 4.32 - 4.22 (m, 2H), 3.27 -
3.19 (m, 0.5H), 2.96 - 2.85 (m,0.6H), 2.77 - 2.66 (m, 1H), 2.29 - 2.19 (m, 3H), 1.89 (s, 3H).
17681897_1 (GHMatters) P110989.NZ
EXAMPLE 86
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)METHYL(3-((2-
PHENYLACETAMIDO)METHYL)PHENYL)-1H-PYRAZOLECARBOXAMIDE (144)
NH O
LiOH
EDCI, HOBt, DIEA
DCM THF/H O
O OH
220B 144A
144B
To a solution of compound 140D (500 mg, 2.04 mmol) and 2-phenylacetic
acid (278 mg, 2.04 mmol) in DCM (20 mL) was added DIEA (0.9 mL, 5.10 mmol), HOBt (552
mg, 4.08 mmol) and EDCI (783 mg, 4.08 mmol). The mixture was stirred at 25 °C for 12h. The
solvent was removed in vacuo. The residue was dissolved in EtOAc (30 mL), washed with 1N
HCl (30 mL). The organics were collected, washed with saturated NaHCO (30 mL). The
organics were collected, washed with brine (30 mL). The organics were collected, dried with
Na SO , filtered and concentrated to afford intermediate compound 144A (700.00 mg, crude) as
yellow oil. MS (ESI) m/z (M+H) 378.0.
To a solution of compound 144A (700 mg, 1.93 mmol) in THF (10 mL) and
H2O (10 mL) was added LiOH.H2O (405 mg, 9.63 mmol). The mixture was stirred at 25 °C for
12h. The reaction was acidified with 1N HCl to pH ~ 4. The solution was extracted with EtOAc
(15 mL x 2). The organics were collected and concentrated. The residue was purified by
preparatory-HPLC (Neutral) to give compound 144B (260 mg, yield: 38.56%) as yellow oil. MS
(ESI) m/z (M+H) 349.9.
Compound 144 (36 mg, yield: 45.17%, white solid) was prepared as in
Example 5 from the corresponding starting materials, compounds 144B and 12G. Compound
144: MS (ESI) m/z (M+H) 524.2. H NMR (400MHz, DMSO-d ) δ 9.07 (d, J = 7.6 Hz, 1H),
8.66 - 8.49 (m, 1H), 8.08 (br. s, 1H), 7.84 (br. s, 1H), 7.34 - 7.10 (m, 13H), 6.94 - 6.86 (m, 1H),
6.53 (s, 1H), 5.27 - 5.16 (m, 1H), 4.32 - 4.16 (m, 2H), 3.44 (s, 2H), 3.22 - 3.10 (m, 1H), 2.85 -
2.73 (m, 1H), 2.22 (s, 3H).
17681897_1 (GHMatters) P110989.NZ
EXAMPLE 87
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)METHYL(3-
(PHENYLSULFONAMIDOMETHYL)PHENYL)-1H-PYRAZOLECARBOXAMIDE
(145)
HN O
NH O
.HCl O
O LiOH H O
TEA, MeOH, H O
140D
145B
145A
To a mixture of compound 140D (300 mg, 1.1 mmol, HCl salt) in DCM (20
mL) was added TEA (0.44 mL, 3.2 mmol) in one portion. Benzenesulfonyl chloride (0.15 mL,
1.2 mmol) was added dropwise to the mixture at 0 °C for 30 min and then stirred at 25 °C for 1h.
The reaction mixture was washed with 0.5 N HCl (10 mL), saturated aqueous NaHCO (10 mL)
and brine (10 mL). The separated organic layer was dried over Na SO , filtered and concentrated
under reduced pressure to give a residue. The residue was triturated with CH CN (2 mL). The
solid was collected and dried in vacuum to afford compound 145A (330 mg, yield 79.2%) as
white solid. MS (ESI) m/z (M+H) 386.0.
To a mixture of compound 145A (150 mg, 0.39 mmol) in MeOH (10 mL) and
H O (0.5 mL) was added LiOH.H O (81.6 mg, 1.9 mmol) in one portion. The mixture was
stirred at 25 °C for 12h. The reaction mixture was concentrated under reduced pressure to move
MeOH. Then the residue was diluted with water (15 mL) and extracted with ethyl acetate (10
mL), the aqueous phase was acidified with aqueous HCl (1M) till pH ~ 6~7 and extracted with
ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (40 mL) and
dried over Na SO , filtered and concentrated to afford intermediate compound 145B (140 mg,
crude) as white solid. H NMR (DMSO-d 400 MHz): δ 8.29 - 8.22 (m, 1H), 7.85 - 7.78 (m,
2H), 7.65 - 7.54 (m, 3H), 7.38 - 7.23 (m, 4H), 6.82 (s, 1H), 4.04 (d, J = 6.0 Hz, 2H), 2.26 (s, 3H).
Compound 145 (30 mg, yield 46.8%, white solid) was prepared as in Example
12 from the corresponding intermediate carboxylic acid, compound 145B. Compound 145: H
NMR (CDCl 400 MHz): δ 7.86 - 7.81 (m, 2H), 7.58 - 7.46 (m, 3H), 7.37 - 7.26 (m, 5H), 7.15 -
17681897_1 (GHMatters) P110989.NZ
7.06 (m, 5H), 6.41 (s, 1H), 6.24 - 6.18 (m, 1H), 6.16 - 6.10 (m, 2H), 5.38 - 5.31 (m, 1H), 4.20 -
4.08 (m, 2H), 3.34 - 3.27 (m, 1H), 3.10 - 3.03 (m, 1H), 2.30 (s, 3H). MS (ESI) m/z (M+H)
546.1.
EXAMPLE 88
ETHYL (S)-(3-(5-((4-AMINO-3,4-DIOXOPHENYLBUTANYL)CARBAMOYL)
METHYL-1H-PYRAZOLYL)BENZYL)CARBAMATE (147)
•HCl
2 N O
Cl O LiOH
TEA,
DCM N MeOH/H O
140D
147B
147A
To a solution of compound 140D (1 g, 3.38 mmol, HCl salt) in DCM (20 mL)
was added TEA (1.4 mL, 10.14 mmol), ethylchloroformate (1.9 mL, 20.27 mmol,) dropwise,
then the mixture was stirred at 25 °C for 1h. The reaction was diluted with H O (10 mL), the
mixture was extracted DCM (20 mL x 2). The combined organic layer was washed with brine
(20 mL x 3), dried over anhydrous Na SO , filtered, concentrated under reduced pressure. The
product was purified by Flash Column Chromatography (Petroleum Ether/Ethyl Acetate: 0 to
/1) to afford compound 147A (570 mg, yield 50. 9%) as white solid. H NMR (DMSO-d
400MHz) δ 7.72 (br t, J = 6.1 Hz, 1H), 7.43 - 7.37 (m, 1H), 7.32 - 7.25 (m, 3H), 6.88 (s, 1H),
4.23 (br d, J = 6.2 Hz, 2H), 4.15 (q, J = 7.1 Hz, 2H), 4.03 - 3.97 (m, 2H), 2.26 (s, 3H), 1.16 -
1.12 (m, 6H).
To a solution of compound 147A (560 mg, 1.69 mmol) in MeOH (15 mL) was
added LiOH (2 M, 5mL) dropwise and then the mixture was stirred at 25°C for 1h. The reaction
was diluted with H O (10 mL) and concentrated under reduced pressure. The mixture was
extracted with TBME (10 mL) and the water phase was treated with HCl (1M) until pH ~ 5. The
mixture was extracted with ethyl acetate (15 mL x 3), the combined organic layer was washed
with brine (20 mL), dried over anhydrous Na SO , filtered, concentrated under reduced pressure
to afford compound 147B (420 mg, yield 81.9%) was obtained as white solid, which was used
directly in next step. H NMR (DMSO-d 400MHz) δ 7.69 (br t, J = 6.2 Hz, 1H), 7.38 - 7.33 (m,
1H), 7.27 - 7.20 (m, 3H), 6.78 (s, 1H), 4.19 (br d, J = 6.2 Hz, 2H), 3.97 (q, J = 7.1 Hz, 2H), 2.22
(s, 3H), 1.16 - 1.10 (m, 3H).
17681897_1 (GHMatters) P110989.NZ
Compound 147 (45mg, yield 27.4%, white solid) was prepared as in Example
from the corresponding intermediate carboxylic acid, compound 147B. Compound 147: H
NMR (CD CN 400MHz) δ 7.37 - 7.22 (m, 9H), 7.10 (br d, J = 7.7 Hz, 2H), 6.49 (s, 1H), 6.33 (br
s, 1H), 6.10 (br s, 1H), 5.40 - 5.31 (m, 1H), 4.31 (br d, J = 6.2 Hz, 2H), 4.08 (q, J = 7.1 Hz, 2H),
3.29 (dd, J = 4.5, 14.0 Hz, 1H), 2.93 (dd, J = 9.4, 14.0 Hz, 1H), 2.29 (s, 3H), 1.21 (t, J = 7.2 Hz,
3H). MS (ESI) m/z (M+H) 478.2.
EXAMPLE 89
(S)-N-(4-((3,4-DICHLOROBENZYL)AMINO)-3,4-DIOXOPHENYLBUTANYL)
METHYLPHENYL-1H-PYRAZOLECARBOXAMIDE (149)
NHNH
HOAc, reflux, 36 h
149A
149B
149E
NaOH OH
O DMP
MeOH/THF N N O
TMSCN
N DIEA, DMF N
N HOBT,EDCI, DCM N
OH N
DCM.TEA
149A 149C HO
149D
O N Cl
EDCI,DIEA,HOBT
CN N N
OSi(CH
149F
3)3 OH 149H
149G
To a solution of phenylhydrazine (1.00 g, 9.25 mmol, 910 uL) in HOAc (20
mL) was added ethyl 2,4-dioxopentanoate (1.46 g, 9.25 mmol, 1.3 mL). The mixture was stirred
at 100 °C for 12 hours. The mixture was concentrated and diluted with ethyl acetate (50 mL),
washed with NaHCO (aqueous, 50 mLx3), brine (50 mL), dried over Na SO and concentrated.
3 2 4
The residue was purified by preparatory-HPLC (TFA condition). Compound 149A (700.0 mg,
yield 32.9%) was obtained as a yellow oil. Compound 149B (1.00 g, yield 46.9%) was obtained
as a yellow oil.
Compound 149A: H NMR (400MHz, DMSO-d ) δ 7.48 - 7.36 (m, 5H), 6.87
(s, 1H), 4.18 - 4.10 (m, 2H), 2.25 (s, 3H), 1.16 - 1.11 (m, 3H). [0893] Compound 149B: H
NMR (400MHz, DMSO-d ) δ 7.61 - 7.44 (m, 5H), 6.75 (s, 1H), 4.31 - 4.23 (m, 2H), 2.31 (s,
3H), 1.30 - 1.24 (m, 3H).
17681897_1 (GHMatters) P110989.NZ
To a solution of compound 149A (700.0 mg, 3.04 mmol) in THF (20 mL) and
MeOH (20mL) was added NaOH (2M, 30) .The mixture was stirred at 25 °C for 12 hours. The
mixture was concentrated, diluted with H O (20 mL), extracted with ethyl acetate (20 mL), the
water phase was added HCl (1M) until pH ~ 1, then the mixture was extracted with ethyl acetate
(20 mL), the organic layer was washed with brine (20 mL), dried over Na SO and concentrated.
Compound 149C (600.0 mg, yield 97.6%) was obtained as a colorless oil. H NMR (400MHz,
DMSO-d ) δ 13.21 (br s, 1H), 7.49 - 7.31 (m, 5H), 6.81 (s, 1H), 2.24 (s, 3H).
To a solution of compound 149C (600.0 mg, 2.97 mmol) in THF (20 mL) was
added DIEA (1.54 g, 11.88 mmol, 2 mL), (2S)aminophenyl-propanol (448.7 mg, 2.97
mmol), HOBt (401.3 mg, 2.97 mmol) and EDCI (683.2 mg, 3.56 mmol). The mixture was
stirred at 25 °C for 12 hours. The mixture was concentrated and diluted with ethyl acetate (50
mL), washed with HCl (1M, 50 mL), saturated NaHCO (aqueous, 50 mL), brine (50 mLx3),
dried over Na SO and concentrated. Compound 149D (600.0 mg, yield 60.2%) was obtained as
a white solid. H NMR (400MHz, DMSO-d ) δ 8.38 (d, J = 8.8 Hz, 1H), 7.32 - 7.17 (m, 8H),
7.12 - 7.07 (m, 2H), 6.50 (s, 1H), 4.89 - 4.83 (m, 1H), 4.10 - 3.99 (m, 1H), 3.48 - 3.35 (m, 2H),
2.95 - 2.87 (m, 1H), 2.68 - 2.59 (m, 1H), 2.21 (s, 3H).
To a solution of compound 149D (600.0 mg, 1.79 mmol) in DCM (200 mL)
was added DMP (1.14 g, 2.69 mmol). The mixture was stirred at 25 °C for 2 hours. The mixture
quenched with 10% Na S O (aqueous): saturated NaHCO3 (aqueous) (1:1, 200 mL), extracted
2 2 3
with DCM (100 mL) and washed with brine (20 mL x 3). The combined organic layers were
dried over Na SO and concentrated. Compound 149E (500.0 mg, yield 83.8%) was obtained as
a white solid. H NMR (400MHz, DMSO-d ) δ 9.58 (s, 1H), 9.03 (d, J = 8.0Hz, 1H), 7.36 - 7.13
(m, 10H), 6.57 (s, 1H), 4.56 - 4.49 (m, 1H), 3.28 - 3.21 (m, 1H), 2.81 - 2.72 (m, 1H), 2.25 - 2.17
(m, 3H).
To a solution of compound 149E (500.0 mg, 1.50 mmol) in DCM (10 mL) was
added TEA (15.2 mg, 150.00 umol, 20 uL) and TMSCN (223.2 mg, 2.25 mmol, 280 uL). The
mixture was stirred at 0 °C for 3 hours. The mixture was washed with H O (100 mL), brine (100
mL), dried over Na SO and concentrated to obtain intermediate compound 149F (600.0 mg,
crude) as a colorless oil.
17681897_1 (GHMatters) P110989.NZ
To a solution of compound 149F (600.0 mg, 1.39 mmol) in THF (30 mL) was
added HCl (10 mL). After stirred at 60 °C for 12 hours, the mixture was diluted with H O (100
mL), extracted with ethyl acetate (50 mL). The organic layer was washed with NaHCO (aq, 50
mL). The water phase was added HCl (1M) until pH ~ 1, and then extracted with ethyl acetate
(500 mL). The organic layer was washed with brine (50 mL), dried over Na SO and
concentrated to obtain intermediate compound 149G (500.0 mg, crude) as colorless oil.
To a solution of compound 149G (500.0 mg, 1.32 mmol) in THF (10 mL) was
added (3, 4-dichlorophenyl)methanamine (255.6 mg, 1.45 mmol, 190 uL), HOBt (178.4 mg, 1.32
mmol), DIEA (682.4 mg, 5.28 mmol, 920 uL) and EDCI (303.7 mg, 1.58 mmol) with DCM (10
mL). The mixture was stirred at 25 °C for 12 hours. The mixture was concentrated and diluted
with ethyl acetate (30 mL), washed with HCl (1M, 30 mL), saturated NaHCO (aqueous, 30 mL),
brine (30 mL), dried over Na SO and concentrated. The crude product was purified by
preparatory-HPLC (TFA condition). The product obtained (70 mg) was triturated with CH CN
(5 mL) and filtered. Compound 149H (30.0 mg, 4.23%) was obtained as a white solid. H NMR
(400MHz, DMSO-d ) δ 8.67 - 8.50 (m, 1H), 8.11 (d, J = 9.6 Hz, 1H), 7.50 - 7.41 (m, 1H), 7.39 -
7.34 (m, 1H), 7.32 - 7.14 (m, 9H), 7.07 - 6.96 (m, 2H), 6.47 - 6.36 (m, 1H), 4.46 - 4.36 (m, 1H),
4.34 - 4.10 (m, 2H), 4.06 - 3.99 (m, 1H), 2.95 - 2.71 (m, 2H), 2.26 - 2.13 (m, 2H), 2.26 - 2.13 (m,
1H).
To a solution of compound 149H (30.0 mg, 55.82 umol) in DCM (10 mL) and
DMSO (1 mL) was added DMP (47.4 mg, 111.64 umol). The mixture was stirred at 25 °C for 48
hours. The mixture was quenched with 10% Na S O (aqueous): saturated NaHCO (aqueous)
2 2 3 3
(1:1, 20 mL), extracted with DCM (10 mL) and washed with brine (20 mL x 3). The combined
organic layers were dried over Na SO and concentrated. The crude product was triturated with
CH CN (3 mL) and filtered. Compound 149 (15.0 mg, yield 40.0%) was obtained as a white
solid. H NMR (400MHz, DMSO-d ) δ 9.36 - 9.30 (m, 1H), 9.11 (br d, J = 7.6 Hz, 1H), 7.54 -
7.48 (m, 2H), 7.33 - 7.19 (m, 9H), 7.13 (br d, J=6.6 Hz, 2H), 6.52 (s, 1H), 5.29 - 5.22 (m, 1H),
4.34 - 4.28 (m, 2H), 3.22 - 3.15 (m, 1H), 2.89 - 2.80 (m, 1H), 2.26 - 2.18 (m, 3H). MS (ESI) m/z
(M+H) 535.1.
17681897_1 (GHMatters) P110989.NZ
EXAMPLE 90
COMPOUNDS 150-152
(S)-N-(3,4-DIOXOPHENYL((3-
(TRIFLUOROMETHOXY)BENZYL)AMINO)BUTANYL)METHYL
PHENYLISOXAZOLECARBOXAMIDE (150)
150A
To a solution of compound 101E (500.0 mg, 1.31 mmol) in THF (10 mL) was
added [3-(trifluoromethoxy)phenyl]methanamine (251.3 mg, 1.31 mmol), DIEA (509.6 mg, 3.94
mmol, 690 uL), HOBt (177.6 mg, 1.31 mmol) and EDCI (302.4 mg, 1.58 mmol) with DCM (5
mL). After stirred at 25 °C for 12 hours, the mixture was concentrated and diluted with ethyl
acetate (50 mL), washed with HCl (1M, 50 mL), saturated aqueous NaHCO (50 mL), brine (50
mL x 3), dried over Na SO and concentrated. The crude product (0.30 g) was triturated with
CH CN (5 mL) and filtered. Compound 150A (140.0 mg, yield 19.3%, white solid): H NMR
(400MHz, DMSO-d ) δ 8.75 - 8.53 (m, 1H), 8.31 (d, J = 9.6 Hz, 1H), 7.59 - 7.08 (m, 14H), 6.21
- 5.91 (m, 1H), 4.71 - 4.56 (m, 1H), 4.40 - 4.24 (m, 2H), 4.22 - 4.01 (m, 1H), 2.98 - 2.67 (m, 2H),
2.09 - 1.96 (m, 3H).
To a solution of compound 150A (60.0 mg, 108.40 umol) in DCM (10 mL) and
DMSO (1 mL) was added DMP (137.9 mg, 325.20 umol). After stirred at 25 °C for 4 hour, the
mixture was quenched with 10% Na S O (aqueous): saturated aq. NaHCO (1:1, 20 mL),
2 2 3 3
extracted with DCM (10 mL) and washed with brine (20 mLx3). The combined organic layers
were dried over Na SO and concentrated. The crude product was triturated with CH CN (3 mL)
2 4 3
and filtered. Compound 150 (50.0 mg, yield 82.8%, white solid): H NMR (400MHz, DMSO-
d6) δ 9.54 - 9.45 (m, 1H), 9.11 (d, J = 7.6 Hz, 1H), 7.67 - 7.57 (m, 2H), 7.54 - 7.36 (m, 4H), 7.34
- 7.18 (m, 8H), 5.52 - 5.43 (m, 1H), 4.40 (br d, J = 6.0 Hz, 2H), 3.27 - 3.18 (m, 1H), 2.84 - 2.72
(m, 1H), 2.04 (s, 3H). MS (ESI) m/z (M+H) 552.1.
17681897_1 (GHMatters) P110989.NZ
(S)METHYL-N-(4-((4-(METHYLSULFONYL)BENZYL)AMINO)-3,4-DIOXO
PHENYLBUTANYL)PHENYLISOXAZOLECARBOXAMIDE (151)
(S)METHYL-N-(4-((3-(METHYLSULFONYL)BENZYL)AMINO)-3,4-DIOXO
PHENYLBUTANYL)PHENYLISOXAZOLECARBOXAMIDE (152)
Compounds 151 and 152 were prepared as in Example 150 from compound
101E and the corresponding amine, respectively. Compound 151 (40.0 mg, 63.6% yield, white
solid): H NMR (400MHz, DMSO-d ) δ 9.58 - 9.51 (m, 1H), 9.12 (d, J = 7.2 Hz, 1H), 7.86 (d, J
= 8.4 Hz, 2H), 7.65 - 7.59 (m, 2H), 7.56 - 7.38 (m, 5H), 7.31 - 7.19 (m, 5H), 5.53 - 5.44 (m, 1H),
4.48 - 4.42 (m, 2H), 3.29 - 3.21 (m, 1H), 3.20 - 3.10 (m, 3H), 2.83 - 2.73 (m, 1H), 2.08 - 1.96 (m,
3H). MS (ESI) m/z (M+H) 546.1.
Compound 152 (42.0 mg, 68.8% yield, white solid): H NMR (400MHz,
DMSO-d ) δ 9.59 - 9.51 (m, 1H), 9.11 (d, J = 7.6 Hz, 1H), 7.91 - 7.78 (m, 2H), 7.67 - 7.57 (m,
4H), 7.53 - 7.37 (m, 3H), 7.34 - 7.17 (m, 5H), 5.53 - 5.45 (m, 1H), 4.46 (br d, J = 6.4 Hz, 2H),
3.29 - 3.21 (m, 1H), 3.20 - 3.10 (m, 3H), 2.83 - 2.72 (m, 1H), 2.09 - 1.98 (s, 3H). MS (ESI) m/z
(M+H) 546.1
EXAMPLE 91
BENZYL (S)-(4-(5-((4-AMINO-3,4-DIOXOPHENYLBUTANYL)CARBAMOYL)
METHYL-1H-PYRAZOLYL)BENZYL)CARBAMATE (153)
BocHN
2 ClHH N
Boc O
HCl/EtOAc
Ni, H
Raney
MeOH O
153D
153B 153E
153F
HN HN
Cl O
LiOH
THF/H
TEA, DCM
153H
153G
To a solution of 4-hydrazinylbenzonitrile (20 g, 117.92 mmol, HCl) in HOAc
(200 mL) was added ethyl 2-methoxyiminooxo-pentanoate (23.18 g, 123.82 mmol), then the
17681897_1 (GHMatters) P110989.NZ
mixture was heated to 110 °C and stirred for 12h and then removed the solvent under reduced
pressure. The residue was dissolved in ethyl acetate (200 mL) and treated with NaHCO until pH
~ 8 and then the organic layer was collected and evaporated under reduced pressure. The residue
was purified by column chromatography (SiO , Petroleum ether/Ethyl acetate = 15/1 to 3/1) to
give compound 153B (5 g, yield: 16.61%) as a white solid. Compound 153B: H NMR
(400MHz, CDCl ) δ 7.71 (dd, J = 7.9 Hz, 2H), 7.53 (br d, J = 7.5 Hz, 2H), 6.84 (s, 1H), 4.23 (q,
J = 7.0 Hz, 2H), 2.33 (s, 3H), 1.25 (t, J = 7.1 Hz, 3H). MS (ESI) m/z (M+H) 255.9.
To a solution of compound 153B (6.5 g, 25.46 mmol) in MeOH (70 mL) was
added Raney-Ni (1.09 g, 12.73 mmol) and NH .H O (2.68 g, 76.38 mmol, 3 mL) under argon.
The suspension was degassed under vacuum and purged with H 3 times. The mixture was
stirred at 30 °C for 16h under H (40 psi). The reaction mixture was filtered and the filtrate was
concentrated under reduced pressure to give intermediate compound 153D (6.6 g, crude) as a
yellow oil. H NMR (400MHz, DMSO-d ) δ 7.46 - 7.36 (m, 2H), 7.35 - 7.29 (m, 2H), 6.87 (s,
1H), 3.77 (s, 2H), 3.71 (s, 3H), 2.26 (s, 3H).
To a mixture of compound 153D (3.3 g, 13.45 mmol) in DCM (40 mL) was
added Et N (2.04 g, 20.17 mmol, 2.8 mL) and Boc O (3.52 g, 16.14 mmol, 3.7 mL) in portion at
°C under N . The mixture was stirred at 25 °C for 1.5h. The reaction mixture was diluted
with DCM (20 mL), and washed with H O (50 mL). The organic layer was separated and the
aqueous layer was extracted with DCM (20 mL x 2). The combined organic layers was washed
with brine (30 mL x 2), dried over anhydrous Na SO , filtered and concentrated. The residue
was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate = 5/1 to 2/1) to
give compound 153E (3.3 g, yield: 64.86%) as yellow oil. H NMR (400MHz, CDCl ) δ 7.37 (s,
4H), 6.80 (s, 1H), 4.38 (dd, J = 5.1 Hz, 2H), 3.78 (s, 3H), 2.36 (s, 3H), 1.47 (s, 9H). MS (ESI)
m/z (M+H) 346.1.
To a mixture of compound 153E (3.3 g, 9.55 mmol) in ethyl acetate (20 mL)
was added HCl/EtOAc (4M, 20 mL) dropwise at 0 °C. The reaction mixture was stirred at 25 °C
for 2h. The mixture was concentrated to give intermediate compound 153F (2.7 g, crude, HCl)
as white solid. H NMR (400MHz, CDCl ) δ 8.62 (s, 1H), 7.63 (dd, J = 7.9 Hz, 2H), 7.40 (dd, J
= 7.5 Hz, 2H), 6.80 (s, 1H), 4.16 (s, 2H), 3.74 (s, 3H), 2.34 (s, 3H).
17681897_1 (GHMatters) P110989.NZ
To a mixture of compound 153F (300 mg, 1.06 mmol, HCl) in DCM (20 mL)
was added Et N (268.15 mg, 2.65 mmol, 0.4 mL) and benzyl carbonochloridate (181 mg, 1.06
mmol, 0.2 mL) in portion at 25 °C and stirred for 1.5h. The reaction mixture was treated with
DCM (20 mL), added with H O (30 mL). The organic layer was separated and washed with
brine (30 mL), dried over anhydrous Na SO , filtered and concentrated. The residue was purified
by column chromatography (SiO , Petroleum ether/Ethyl acetate = 5/1 to 1/1) to give compound
153G (350 mg, yield: 87.03%) as off-white solid. H NMR (400MHz, CDCl ) δ 7.42 - 7.29 (m,
9H), 6.82 - 6.78 (m, 1H), 5.16 (s, 2H), 4.45 (dd, J = 6.2 Hz, 2H), 3.80 - 3.77 (m, 3H), 2.39 - 2.34
(m, 3H). MS (ESI) m/z (M+H) 380.0.
To a mixture of compound 153G (350 mg, 922.48 umol) in THF (10 mL) and
H O (10 mL) was added LiOH.H O (116 mg, 2.77 mmol) in portion at 25 °C and stirred for 1.5h.
The mixture was diluted with H O (10 mL) and concentrated to remove THF, then, the water was
extracted with MTBE (30 mL x 2). The water layers were acidified to pH ~ 2 with 1N HCl, then,
the solution extracted with ethyl acetate (30 mL x 3). The organic layers were dried over Na SO
and concentrated to give intermediate compound 153H (300 mg, yield: 89.04%) as white solid.
H NMR (400MHz, CDCl ) δ 7.35 (dd, J = 5.3, 8.2 Hz, 6H), 7.30 - 7.16 (m, 2H), 7.14 - 6.98 (m,
1H), 6.90 - 6.82 (m, 1H), 5.15 (s, 2H), 4.47 - 4.30 (m, 2H), 2.46 - 2.28 (m, 3H). MS (ESI) m/z
(M+H) 366.1.
Compound 153 (35 mg, yield: 50.19%, white solid) was prepared as in
Example 5 from the corresponding intermediate carboxylic acid, compound 153H. Compound
153: H NMR (400MHz, DMSO-d ) δ 9.04 (d, J = 7.7 Hz, 1H), 8.09 (s, 1H), 7.84 (br s, 2H),
7.38 - 7.17 (m, 12H), 7.09 (d, J = 8.2 Hz, 2H), 6.53 (s, 1H), 5.27 (t, J = 7.5 Hz, 1H), 5.04 (s, 2H),
4.20 (d, J = 6.0 Hz, 2H), 3.19 (dd, J = 3.3, 14.1 Hz, 1H), 2.86 - 2.75 (m, 1H), 2.22 (s, 3H). MS
(ESI) m/z (M+H) 540.2.
EXAMPLE 92
COMPOUNDS 154-159, 496
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)(4-
(BENZAMIDOMETHYL)PHENYL)METHYL-1H-PYRAZOLECARBOXAMIDE
(154)
17681897_1 (GHMatters) P110989.NZ
ClHH N
OH HN
NaOH
O MeOH, O
O N N
153F
154A
154B
To a mixture of compound 153F (300 mg, 1.06 mmol, HCl), benzoic acid (155
mg, 1.27 mmol, 0.2 mL), HOBt (286 mg, 2.12 mmol) and DIEA (343 mg, 2.65 mmol, 0.5 mL) in
DCM (20 mL) was added EDCI (406 mg, 2.12 mmol) in portion at 25 °C and stirred for 4h. The
reaction mixture was treated with DCM (10 mL), washed with H O (20 mL). The organic layer
was separated and the aqueous layer was extracted with DCM (10 mL x 2). The combined
organic layer was washed with 0.5N HCl (20 mL x 2), NaHCO (20 mL x 2) and brine (30 mL),
dried over Na SO , filtered and the solvent was removed in vacuo. The residue was purified by
column chromatography (SiO , Petroleum ether/Ethyl acetate = 5/1 to 1/1) to give compound
154A (280 mg, yield: 75.61%) as offwhite solid. H NMR (400MHz, CDCl ) δ 7.81 (dd, J = 6.4
Hz, 2H), 7.58 - 7.40 (m, 7H), 6.85 - 6.78 (m, 1H), 6.48 (br s, 1H), 4.72 (br d, J = 5.1 Hz, 2H),
3.84 - 3.77 (m, 3H), 2.41 - 2.34 (m, 4H). MS (ESI) m/z (M+Na) 372.0.
To a mixture of compound 154A (280 mg, 801.42 umol) in MeOH (10 mL)
and H O (10 mL) was added NaOH (2M, 2 mL) in portion at 25 °C and stirred for 3h. The
mixture was concentrated to remove MeOH and then the water was extracted with MTBE (30
mL x 2). The water layer were acidized to pH ~ 2 with 1N HCl, then the solution extracted with
ethyl acetate (20 mL x 2). The organic layers were dried over Na SO and concentrated to give
intermediate compound 154B (200 mg, yield: 74.41%) as white solid. H NMR (400MHz,
CDCl ) δ 7.79 (dd, J = 8.2 Hz, 2H), 7.50 - 7.31 (m, 7H), 6.78 (s, 1H), 4.62 (s, 2H), 2.31 (s, 3H).
MS (ESI) m/z (M+H) 336.0.
Compound 154 (20 mg, yield: 29.53%, white solid) was prepared as in
Example 5 from the corresponding intermediate carboxylic acid, compound 154B. Compound
154: H NMR (400MHz, DMSO-d ) δ 9.11 - 9.04 (m, 2H), 8.11 (s, 1H), 7.96 - 7.91 (m, 2H),
7.86 (s, 1H), 7.56 - 7.47 (m, 3H), 7.30 (d, J = 4.4 Hz, 3H), 7.27 (d, J = 8.6 Hz, 2H), 7.23 - 7.19
17681897_1 (GHMatters) P110989.NZ
(m, 1H), 7.12 (d, J = 8.4 Hz, 2H), 6.55 (s, 1H), 5.32 - 5.26 (m, 1H), 4.51 (br d, J = 5.7 Hz, 2H),
3.21 (dd, J = 3.5, 13.9 Hz, 1H), 2.86 - 2.78 (m, 1H), 2.25 (s, 3H). MS (ESI) m/z (M+H) 510.1.
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)METHYL(4-((3-
PHENYLPROPANAMIDO)METHYL)PHENYL)-1H-PYRAZOLECARBOXAMIDE
(155)
ClHH N
HN HN
COOH
NaOH
MeOH, H O
O OH
153F
155A 155B
Following the procedure as used for compound 154B, intermediate compound
155B (200 mg, yield: 74.41%, white solid) was prepared from compound 153F through 155A.
Compound 155B: H NMR (400MHz, CDCl ) δ 7.28 - 7.12 (m, 8H), 6.94 (s, 1H), 6.78 (s, 1H),
4.42 - 4.31 (m, 2H), 2.94 (t, J = 7.5 Hz, 2H), 2.50 (t, J = 7.2 Hz, 2H), 2.31 (s, 3H). MS (ESI) m/z
(M+H) 364.1.
Compound 155 (20 mg, yield: 27.16%, light yellow solid) was prepared as in
Example 12 from the corresponding intermediate carboxylic acid, compound 155B. Compound
155: H NMR (400MHz, DMSO-d ) δ 9.06 (d, J = 7.7 Hz, 1H), 8.38 (t, J = 5.8 Hz, 1H), 8.11 (s,
1H), 7.87 (s, 1H), 7.33 - 7.29 (m, 4H), 7.27 (d, J = 7.5 Hz, 2H), 7.24 - 7.18 (m, 3H), 7.13 - 7.07
(m, 4H), 6.56 (s, 1H), 5.30 (dd, J = 2.6 Hz, 1H), 4.27 (d, J = 5.7 Hz, 2H), 3.25 - 3.19 (m, 1H),
2.87 - 2.83 (m, 2H), 2.53 (d, J = 2.0 Hz, 1H), 2.49 - 2.44 (m, 2H), 2.25 (s, 3H). MS (ESI) m/z
(M+H) 538.2.
17681897_1 (GHMatters) P110989.NZ
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)METHYL(4-
(PHENYLSULFONAMIDOMETHYL)PHENYL)-1H-PYRAZOLECARBOXAMIDE
(156)
ClHH N
SO Cl
NaOH
MeOH/H O
153F
156A 156B
Following the procedure as used for compound 154B, intermediate compound
156B (250 mg, yield: 86.48%, white solid) was prepared from compound 153F through 156A.
Compound 156B: H NMR (400MHz, CDCl ) δ 7.85 (dd, J = 7.7 Hz, 2H), 7.61 - 7.43 (m, 3H),
7.29 - 7.20 (m, 4H), 6.78 (s, 1H), 4.09 (s, 2H), 2.30 (s, 3H). MS (ESI) m/z (M+H) 372.0.
Compound 156 (45 mg, yield: 78.05%, white solid) was prepared as in
Example 12 from the corresponding intermediate carboxylic acid, compound 156B. Compound
156: H NMR (400MHz, DMSO-d ) δ 9.10 - 9.01 (m, 1H), 8.19 (br s, 1H), 8.09 (s, 1H), 7.86 -
7.79 (m, 3H), 7.63 - 7.56 (m, 3H), 7.32 - 7.25 (m, 5H), 7.19 (d, J = 8.4 Hz, 2H), 7.07 (d, J = 8.4
Hz, 2H), 6.52 (s, 1H), 5.26 (br s, 1H), 3.97 (d, J = 5.3 Hz, 2H), 3.23 - 3.13 (m, 1H), 2.87 - 2.75
(m, 1H), 2.22 (s, 3H). MS (ESI) m/z (M+H) 546.1.
(S)(4-(ACETAMIDOMETHYL)PHENYL)-N-(4-AMINO-3,4-DIOXO
PHENYLBUTANYL)METHYL-1H-PYRAZOLECARBOXAMIDE (157)
ClHH N
NaOH
TEA,
DCM MeOH/H O
153F
157A 157B
Following the procedure as used for compound 154B, intermediate compound
157B (162 mg, yield: 94.62%, white solid) was prepared from compound 153F through 157A.
Compound 157B: H NMR (400MHz, DMSO-d ) δ 13.20 (br s, 1H), 8.43 (br t, J = 5.8 Hz, 1H),
7.37 - 7.25 (m, 4H), 6.79 (s, 1H), 4.29 (d, J = 6.0 Hz, 2H), 2.23 (s, 3H), 1.88 (s, 3H).
17681897_1 (GHMatters) P110989.NZ
Compound 157 (17 mg, yield: 33.13%, gray solid) was prepared as in Example
from the corresponding intermediate carboxylic acid, compound 157B. Compound 157: H
NMR (400MHz, DMSO-d ) δ 8.71 (br d, J = 7.5 Hz, 1H), 8.12 (br s, 1H), 7.83 - 7.54 (m, 2H),
7.31 - 7.18 (m, 9H), 6.55 (s, 1H), 5.35 - 5.27 (m, 1H), 4.28 (d, J = 6.0 Hz, 2H), 3.25 (d, J = 4.3
Hz, 0.5H), 3.21 (d, J = 4.0 Hz, 0.5H), 2.94 (s, 0.5H), 2.91 (d, J=4.3 Hz, 0.5H), 2.25 (s, 3H), 1.91
(s, 3H). MS (ESI) m/z (M+H) 448.1.
METHYL (S)-(4-(5-((4-AMINO-3,4-DIOXOPHENYLBUTANYL)CARBAMOYL)
METHYL-1H-PYRAZOLYL)BENZYL)CARBAMATE (158)
ClHH N
Cl O
LiOH
THF/H
TEA, DCM 2
153F
158A 158B
Following the procedure as used for compound 154B, intermediate compound
158B (150 mg, yield: 62.91%, white solid) was prepared from compound 153F through 158A.
Compound 158B: H NMR (400MHz, CDCl ) δ 7.36 - 7.28 (m, 4H), 6.78 (s, 1H), 4.36 (s, 2H),
3.67 (s, 3H), 2.34 - 2.30 (m, 3H). MS (ESI) m/z (M+H) 289.9.
Compound 158 (12 mg, yield: 22.68%, light yellow solid) was prepared as in
Example 5 from the corresponding intermediate carboxylic acid, compound 158B. Compound
158: H NMR (400MHz, DMSO-d ) δ 9.08 (dd, J = 7.5 Hz, 1H), 8.13 (s, 1H), 7.87 (br s, 1H),
7.74 (s, 1H), 7.35 - 7.17 (m, 7H), 7.16 - 7.07 (m, 2H), 6.54 (s, 1H), 5.34 - 5.24 (m, 1H), 4.19 (dd,
J = 6.0 Hz, 2H), 3.57 (s, 3H), 3.28 - 3.18 (m, 1H), 2.82 (dd, J = 10.9, 13.3 Hz, 1H), 2.24 (s, 3H).
MS (ESI) m/z (M+H) 464.1.
17681897_1 (GHMatters) P110989.NZ
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)METHYL(4-((2-
PHENYLACETAMIDO)METHYL)PHENYL)-1H-PYRAZOLECARBOXAMIDE (159)
ClHH N
NaOH
MeOH/H O
HBTU, DIEA
O N N
153F
159A 159B
To a mixture of compound 153F (300 mg, 1.06 mmol, HCl) and 2-
phenylacetic acid (173 mg, 1.27 mmol, 0.16 mL) in DMF (10 mL) was added DIEA (548 mg,
4.24 mmol, 0.75 mL) and HBTU (603 mg, 1.59 mmol) in one portion at 25 °C. The mixture was
stirred at 25 °C for 1.5h. The mixture was diluted with 30 mL ethyl acetate and 20 mL H O, the
organic layer was separated and washed with 1N HCl (20 mL x 2), saturated NaHCO (20 mL
x2) and brine (20 mL), the organic layer was dried with over Na SO , and filtered and organic
layer was concentrated in vacuum. The residue was purified by column chromatography (SiO ,
Petroleum ether/Ethyl acetate = 4/1). Compound 159A (190 mg, yield: 49.32%) was obtained as
a yellow oil. H NMR (400MHz, DMSO-d ) δ 8.62 (br t, J = 5.8 Hz, 1H), 7.36 - 7.14 (m, 9H),
6.91 - 6.78 (m, 1H), 4.31 (d, J = 6.0 Hz, 2H), 3.69 (s, 3H), 3.48 (s, 2H), 2.24 (s, 3H).
To a solution of compound 159A (190 mg, 522.83 umol) in MeOH (8 mL) and
H O (5 mL) was added NaOH (84 mg, 2.09 mmol). The mixture was stirred at 25 °C for 2h.
The reaction mixture was concentrated and added 10 mL of water and the mixture was extracted
with MTBE (10 mL x 2), the aqueous layer was acidified by 1N HCl to pH ~ 2~3 at 0 °C, and
extracted with EtOAc (10 mL x 2), the organic phase was dried over Na SO , and concentrated
to give a residue. Compound 159B (143 mg, yield: 78.28%) was obtained as a white solid,
which was used for next step directly. H NMR (400MHz, DMSO-d ) δ 8.62 (br t, J = 5.7 Hz,
1H), 7.34 - 7.24 (m, 8H), 7.24 - 7.19 (m, 1H), 6.76 (s, 1H), 4.30 (d, J = 5.7 Hz, 2H), 3.48 (s, 2H),
2.22 (s, 3H).
Compound 159 (25 mg, yield: 33.34%, white solid) was prepared as in
Example 5 from the corresponding intermediate carboxylic acid, compound 159B. Compound
17681897_1 (GHMatters) P110989.NZ
159: H NMR (400MHz, DMSO-d ) δ 8.31 (br s, 1H), 7.40 - 7.05 (m, 17H), 6.56 (s, 1H), 5.31
(dd, J = 4.3, 9.8 Hz, 1H), 4.31 (d, J = 4.3 Hz, 2H), 3.52 (s, 2H), 3.23 (dd, J = 4.3, 14.1 Hz, 1H),
2.91 (dd, J = 10.0, 13.8 Hz, 1H), 2.25 (s, 3H). MS (ESI) m/z (M+H) 524.2.
N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)(4-((4-
FLUOROBENZAMIDO)METHYL)PHENYL)METHYL-1H-PYRAZOLE
CARBOXAMIDE (496)
Compound 496 (246.9 mg, yield: 80.2%, white solid) was prepared as in
compound 154 using intermediate 153F and 4-fluorobenzoyl chloride and the resulting product
was subjected to reactions as in compound 12 to obtain compound 496. Compound 496: H
NMR (400MHz, DMSO-d ) δ 99.20 - 9.05 (m, 2H), 8.13 (s, 1H), 8.05 - 7.96 (m, 2H), 7.87 (s,
1H), 7.40 - 7.16 (m, 9H), 7.16 - 7.08 (m, 2H), 6.54 (s, 1H), 5.32 - 5.22 (m, 1H), 4.55 - 4.45 (m,
2H), 3.22 - 3.14 (m, 1H), 2.83 -2.73 (m, 1H), 2.24 (s, 3H). MS (ESI) m/z (M+H) 526.2.
EXAMPLE 93
METHYL (S)-(4-(5-((4-AMINO-3,4-DIOXOPHENYLBUTANYL)CARBAMOYL)
METHYL-1H-PYRAZOLYL)BENZYL)CARBAMATE (161)
ClHH
Cl O
LiOH
THF/H O
TEA, DCM 2
153F
161A 161B
To a mixture of compound 153F (450 mg, 1.60 mmol, HCl) in DCM (15.00
mL) was added TEA (485 mg, 4.79 mmol, 0.7mL) and ethyl carbonochloridate (452 mg, 4.17
mmol, 0.4 mL) in portion at 25 °C and stirred for 2h. The reaction mixture was treated with
DCM (20 mL), washed with H O (30 mL). The organic layer was separated and washed with
brine (30 mL), dried over anhydrous NaSO , filtered and concentrated. The residue was purified
by column chromatography (SiO , Petroleum ether/Ethyl acetate = 5/1 to 1/1) to give compound
161A (400 mg, yield: 52.81%) as offwhite solid. H NMR (400MHz, CDCl ) δ 7.37 (br s, 4H),
6.80 (dd, J = 3.5 Hz, 1H), 4.43 (s, 2H), 4.20 - 4.09 (m, 2H), 3.79 (d, J = 3.7 Hz, 3H), 2.36 (dd, J
= 3.5 Hz, 3H), 1.27 (td, J = 3.5, 7.1 Hz, 3H). MS (ESI) m/z (M+H) 318.0.
17681897_1 (GHMatters) P110989.NZ
To a mixture of compound 161A (400 mg, 1.26 mmol) in THF (10 mL) and
H O (10 mL) was added LiOH.H O (159 mg, 3.78 mmol) in portion at 25 °C and stirred for 0.5h.
The mixture was diluted with H O (10 mL) and concentrated to remove THF, then, the water was
extracted with MTBE (30 mL x 2). The water layers were acidified to pH ~ 2 with 1N HCl, then,
the solution extracted with ethyl acetate (30 mL x 3). The organic layers were dried over Na SO
and concentrated to give intermediate compound 161B (300 mg, yield: 78.50%) as white solid.
H NMR (400MHz, CDCl ) δ 7.33 (s, 4H), 6.79 (s, 1H), 4.35 (s, 2H), 4.23 - 4.03 (m, 2H), 2.38 -
2.27 (m, 3H), 1.41 - 1.19 (m, 4H). MS (ESI) m/z (M+H) 304.0.
Compound 161 (25 mg, yield: 22.8%, white solid) was prepared as in Example
from the corresponding intermediate carboxylic acid, compound 161B. Compound 161: H
NMR (400MHz, DMSO-d ) δ 9.07 (dd, J = 8.2 Hz, 1H), 8.12 (s, 1H), 7.87 (s, 1H), 7.69 (s, 1H),
7.42 - 7.27 (m, 5H), 7.20 (dd, J = 7.9 Hz, 2H), 7.16 - 7.06 (m, 2H), 6.54 (s, 1H), 5.34 - 5.24 (m,
1H), 4.18 (dd, J = 5.5 Hz, 2H), 4.02 (q, J = 7.1 Hz, 2H), 3.21 (dd, J = 2.9, 13.2 Hz, 1H), 2.92 -
2.77 (m, 1H), 2.24 (s, 3H), 1.18 (br t, J = 7.1 Hz, 3H). MS (ESI) m/z (M+H) 478.1.
EXAMPLE 94
PHENYL (S)-(4-(5-((4-AMINO-3,4-DIOXOPHENYLBUTANYL)CARBAMOYL)
METHYL-1H-PYRAZOLYL)BENZYL)CARBAMATE (162)
CONH
HBTU, DIEA O
162B
162A
Cl O
HCl/EtOAc
Et N
EtOAc
162C HO
162D
To a mixture of compound 153E (300 mg, 868.58 umol) in THF (10 mL) and
H O (10 mL) was added LiOH.H O (109 mg, 2.61 mmol) in portion at 25 °C and stirred for 12h.
17681897_1 (GHMatters) P110989.NZ
The mixture was diluted with H O (10 mL) and concentrated to remove THF, then, the water was
extracted with MTBE (30 mL x 2). The water layers were acidified to pH ~ 2 with 1N HCl, then,
the solution extracted with ethyl acetate (30 mL x 3). The organic layers were dried over Na SO
and concentrated to give intermediate compound 162A (250 mg, yield: 86.86%) as white solid.
H NMR (400MHz, CDCl ) δ 7.41 - 7.30 (m, 2H), 7.27 - 7.04 (m, 2H), 6.86 (s, 1H), 4.43 - 4.26
(m, 2H), 2.46 - 2.32 (m, 3H), 1.60 - 1.40 (m, 9H). MS (ESI) m/z (M+H) 332.0.
To a mixture of compound 12G (209 mg, 905.33 umol, HCl) and compound
162A (250 mg, 754.44 umol) in DMF (10 mL) was added DIEA (244 mg, 1.89 mmol, 0.3 mL)
and HBTU (343 mg, 905.33 umol) in portion at 25 °C and stirred for 1.5h. The reaction mixture
was treated with ethyl acetate (40 mL), washed with H O (50 mL x 2). The organic layer was
washed with brine (30 mL), dried over Na SO , filtered and the solvent was removed in vacuo.
The residue was triturated in DCM (2 mL) and petroleum ether (10 mL), the solid was collected
and was dried in vacuo to give compound 162B (300 mg, yield: 75.76%) as white solid. H
NMR (400MHz, DMSO-d ) δ 8.72 - 8.41 (m, 1H), 7.95 (s, 1H), 7.45 - 7.20 (m, 7H), 7.12 (dd, J
= 8.4 Hz, 2H), 7.02 - 6.91 (m, 2H), 6.70 - 6.48 (m, 1H), 6.08 (d, J = 5.5 Hz, 1H), 4.45 (s, 1H),
4.12 - 3.98 (m, 2H), 2.89 (s, 1H), 2.87 - 2.80 (m, 1H), 2.73 (s, 1H), 2.28 - 2.14 (m, 3H), 1.52 -
1.33 (m, 9H). MS (ESI) m/z (M-56) 452.1.
To a mixture of compound 162B (300 mg, 591.04 umol) in EA (10 mL) was
added HCl/EtOAc (4M, 10 mL) dropwise at 0 °C. The reaction mixture was stirred at 25 °C for
2h. The mixture was concentrated to give intermediate compound 162C (250 mg, yield: 95.28%,
HCl) as white solid. H NMR (400MHz, DMSO-d ) δ 8.71 - 8.64 (m, 2H), 7.53 - 7.35 (m, 3H),
7.34 - 7.17 (m, 7H), 7.03 (dd, J = 8.4 Hz, 2H), 6.65 (s, 1H), 4.59 - 4.30 (m, 1H), 4.15 (s, 2H),
2.88 (s, 1H), 2.83 (dd, J = 11.9 Hz, 1H), 2.72 (s, 1H), 2.22 (s, 3H).
To a mixture of compound 162C (120 mg, 270.31 umol, HCl) in DCM (10
mL) was added Et N (68 mg, 675.78 umol, 0.1 mL) and phenyl carbonochloridate (51 mg,
324.38 umol, 0.1 mL) in portion at 25 °C and stirred for 1h. The reaction mixture was treated
with DCM (20 mL), added with H O (30 mL). The organic layer was separated and washed with
brine (30 mL), dried over anhydrous NaSO , filtered and concentrated. The residue was purified
by preparatory-HPLC (HCl condition) to give compound 162D (70 mg, yield: 47.71%) as off-
white solid. H NMR (400MHz, DMSO-d ) δ 9.36 (s, 1H), 8.50 (dd, J = 9.0 Hz, 1H), 7.41 - 7.11
17681897_1 (GHMatters) P110989.NZ
(m, 14H), 7.08 (s, 1H), 7.02 (dd, J = 8.4 Hz, 1H), 6.99 (dd, J = 8.4 Hz, 1H), 6.78 - 6.72 (m, 2H),
6.57 - 6.50 (m, 1H), 4.43 (s, 1H), 4.31 - 4.22 (m, 2H), 3.99 (s, 1H), 2.87 - 2.75 (m, 2H), 2.74 -
2.65 (m, 2H), 2.27 - 2.20 (m, 3H). MS (ESI) m/z (M+H) 528.1.
To a mixture of compound 162D (40 mg, 75.82 umol) in DMSO (3 mL) and
DCM (15 mL) was added DMP (96 mg, 227.46 umol) in one portion at 25 °C under N . The
mixture was stirred at 25 °C for 1.5h. The reaction mixture was diluted with DCM (10 mL),
NaHCO (5 mL) and Na S O (10 mL), then stirred for 10 min and layers were separated. The
3 2 2 3
organic layers were washed with water (50 mL x 2), dried over Na SO , filtered and concentrated
under reduced pressure to give a residue. The residue was triturated in DCM (2 mL) and
petroleum ether (10 mL), the solid was collected and was dried in vacuo to give compound 162
(25 mg, yield: 51.13%) as a white solid. H NMR (400MHz, DMSO-d ) δ 9.15 (d, J = 8.0 Hz,
1H), 8.39 (t, J = 6.0 Hz, 1H), 8.14 (s, 1H), 7.88 (s, 1H), 7.41 - 7.19 (m, 11H), 7.14 (dd, J = 8.0
Hz, 3H), 6.68 - 6.51 (m, 1H), 5.41 - 5.22 (m, 1H), 4.29 (dd, J = 6.0 Hz, 2H), 3.21 (dd, J = 3.5,
13.6 Hz, 1H), 2.85 (dd, J = 10.8, 13.8 Hz, 1H), 2.25 (s, 3H). MS (ESI) m/z (M+H) 526.1.
EXAMPLE 95
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)METHYL(m-TOLYL)-1H-
PYRAZOLECARBOXAMIDE (163)
O Br
2 Br O O
Br O
tert-butyl nitrite CH
OEt +
N OEt
N OEt N
CuBr
Cs CO
2 2 3
163C
163B
163A
Br O O
Br O
ClH • H N NH
Br O 2 2
NaOH OH
12G N NH
N OH
EDCI,HOBt,DIEA,
163E
163B N
163D
Br O O
ClH • H N NH
Br Br O 2 2
12G OH
NaOH
N NH
EDCI,HOBt,DIEA,
163C
163G
163F
HO OH
Pd(dppf)Cl DCM
2 N NH
N NH N 2
N 2 N NH
K H N 2
H 2 3
OH N
dioxane
163J
163H
H O 163
17681897_1 (GHMatters) P110989.NZ
To a solution of t-BuONO (3.8 mL, 30.94 mmol) in CH CN (60 mL) was
added CuBr (6.91 g, 30.94 mmol). The mixture was stirred at 25 °C for 1h under N . Then
ethyl 3-amino-1H-pyrazolecarboxylate (4 g, 25.78 mmol) was added in portions. The mixture
was then heated to 70 °C and stirred for 12h. The reaction was washed with H O (100 mL),
extracted with EtOAc (100 mL x 2). The organics were collected, dried with Na SO , filtered
and concentrated to afford intermediate compound 163A (6 g, crude) as black oil. MS (ESI) m/z
(M+2) 220.9.
To a solution of compound 163A (10 g, 45.65 mmol) and Cs CO (29.75 g,
91.30 mmol) in DMF (250 mL) was added MeI (19.44 g, 136.95 mmol, 8.53 mL). The mixture
was stirred at 25 °C for 16h. The mixture was filtered, the filtrate was diluted with H O (500
mL), and extracted with ethyl acetate (100 mL x 3), dried over Na SO , concentrated to give a
residue. The residue was purified by column chromatography (SiO , Petroleum ether/Ethyl
acetate = 5/1). Compound 163B (2.5 g, yield: 23.50%) was obtained as a yellow oil, and
Compound 163C (5.5 g, yield: 51.70%) was obtained as a white solid.
Compound 163B: H NMR (400MHz, CDCl ) δ 7.93 (s, 1H), 4.31 (q, J = 7.1
Hz, 2H), 3.95 - 3.87 (m, 3H), 1.36 (t, J = 7.1 Hz, 3H).
Compound 163C: H NMR (400MHz, CDCl3) δ 7.82 (s, 1H), 4.30 (q, J = 7.1
Hz, 2H), 3.99 - 3.77 (m, 3H), 1.35 (t, J = 7.2 Hz, 3H).
To a solution of compound 163B (600 mg, 2.57 mmol) in MeOH (10 mL) and
H O (10 mL) was added NaOH (514 mg, 12.85 mmol). The mixture was stirred at 25 °C for 3h.
The reaction mixture was concentrated and added 20 mL of water, the mixture was extracted
with MTBE (10 mL x 2), the aqueous layer was acidified by 1N HCl to pH ~ 2~3 at 0 °C, and
extracted with EtOAc (20 mL x 2), the organic phase was dried over Na SO , concentrated to
give a residue. Compound 163D (480 mg, yield: 91.05%) was obtained as a white solid. H
NMR (400MHz, DMSO-d ) δ 12.65 (s, 1H), 8.13 (s, 1H), 3.82 (s, 3H).
To a solution of Compound 163D (450 mg, 2.20 mmol), (3S)amino
hydroxyphenyl-butanamide 12G (761 mg, 3.30 mmol, HCl) and HOBT (445 mg, 3.30 mmol)
in DCM (20 mL) was added DIEA (1.14 g, 8.80 mmol, 1.54 mL) and EDCI (843 mg, 4.40
mmol). The mixture was stirred at 25 °C for 16h. The mixture was diluted with CHCl : iPrOH
= 3: 1 (50 mL), washed with 1N HCl (30 mL), saturated aqueous NaHCO (30 mL) and brine (30
17681897_1 (GHMatters) P110989.NZ
mL). The organic layer was dried over anhydrous Na SO and concentrated in vacuo. The solid
was triturated in ethyl acetate (30 mL), filtered. Compound 163E (550 mg, yield: 61.64%) was
obtained as a yellow solid. H NMR (400MHz, DMSO-d ) δ 8.09 - 7.95 (m, 1H), 7.78 (d, J = 8.8
Hz, 0.6H), 7.46 (d, J = 9.0 Hz, 0.4H), 7.38 - 7.07 (m, 6H), 6.01 - 5.86 (m, 1H), 4.54 - 4.33 (m,
1H), 4.00 (dd, J = 3.4, 5.2 Hz, 1H), 3.85 - 3.74 (m, 4H), 2.93 - 2.67 (m, 1H), 2.62 (dd, J = 2.3,
13.8 Hz, 1H). MS (ESI) m/z (M+H) 381.0.
To a solution of compound 163C (2.6 g, 11.16 mmol) in MeOH (10 mL) and
H O (10 mL) was added LiOH.H O (2.34 g, 55.80 mmol). The mixture was stirred at 25 °C for
12h. The reaction mixture was concentrated and added 20 mL of water and the mixture was
extracted with MTBE (20 mL x 2), the aqueous layer was acidified by 1N HCl to pH ~ 2~3 at 0
°C, and extracted with EtOAc (30 mL x 2), the organic phase was dried over Na SO and
concentrated to give a residue. Compound 163F (2.2 g, yield: 96.16%) was obtained as a gray
solid, which was used for next step directly. H NMR (400MHz, DMSO-d ) δ 12.55 (br s, 1H),
8.24 (s, 1H), 3.81 (s, 3H).
To a mixture of compound 163F (2.2 g, 10.73 mmol) and compound 12G (2.97
g, 12.88 mmol HCl) in DMF (20 mL) and HOBt (2.17 g, 16.10 mmol) and DIEA (4.16 g, 32.19
mmol, 5.62 mL) and EDCI (4.11 g, 21.46 mmol) in one portion at 25 °C. The mixture was
stirred at 25 °C for 12h. The reaction mixture was diluted with H O (40 mL) and extracted with
CHCl : isopropanol (v: v = 3: 1; 30 x 3 mL), then the organic phase was washed with 1N HCl
(20 mL x 2) and saturated aqueous NaHCO (20 mL x 2). The mixture was dried over Na SO
3 2 4
and concentrated. The residue was diluted with EtOAc (15 mL) the solid was collected and dried
in vacuo. Compound 163G (2.9 g, yield: 68.06%) was obtained as a white solid. H NMR
(400MHz, DMSO-d ) δ 8.18 (s, 1H), 7.61 (br d, J = 8.8 Hz, 1H), 7.31 (br d, J = 2.4 Hz, 2H),
7.24 - 7.13 (m, 5H), 5.89 (d, J = 5.7 Hz, 1H), 4.51 - 4.40 (m, 1H), 4.00 - 3.97 (m, 1H), 3.79 (s,
3H), 2.80 - 2.76 (m, 1H), 2.65 - 2.58 (m, 1H). MS (ESI) m/z (M+H) 381.0.
Compound 163G (200 mg, 525 umol), m-tolylboronic acid (85.6 mg, 629
umol), Pd(dppf)Cl (38.4 mg, 52.5 umol) and K CO (145 mg, 1.05 mmol) in dioxane (5 mL)
2 2 3
was de-gassed and then heated to 100 °C for 12 hours under N . The mixture was filtered and
concentrated, the residue was purified by prep-TLC (Dichloromethane: Methanol = 10: 1) to give
compound 163H (100 mg, yield: 48.6%), as white solid. H NMR (400MHz, DMSO-d ) δ 7.99
17681897_1 (GHMatters) P110989.NZ
(d, J = 19.4 Hz, 1H), 7.37 (br s, 1H), 7.31 - 7.06 (m, 11H), 5.76 (br s, 1H), 4.52 - 4.31 (m, 1H),
3.98 (br s, 1H), 3.83 (s, 3H), 3.80 (br s, 1H), 2.87 - 2.72 (m, 1H), 2.71 - 2.56 (m, 1H), 2.26 (d, J
= 6.8 Hz, 3H).
A mixture of compound 163H (100 mg, 255 umol) and DMP (432 mg, 1.02
mmol) in DCM (10 mL), DMSO (2 mL) was stirred at 25°C for 1 hr. The mixture was diluted
DCM (20 mL), quenched with saturated aqueous NaHCO (20 mL), saturated aqueous Na S O
3 2 2 3
(20 mL) and stirred for 20 min, the mixture was extracted with DCM (20 mL x 2), the combined
organic phase was washed with water (20 mL), brine (20 mL), dried over Na SO , filtered and
concentrated, the residue was stirred in DCM and n-hexane for 20 min, the solid was filtered and
dried to give 163 (43.5 mg, yield: 43.7%) as white solid. H NMR (400MHz, DMSO-d ) δ 8.23
(br d, J = 7.3 Hz, 1H), 8.08 - 7.97 (m, 2H), 7.78 (s, 1H), 7.38 (s, 1H), 7.31 (br d, J = 7.5 Hz, 1H),
7.28 - 7.13 (m, 6H), 7.11 - 7.05 (m, 1H), 5.31 - 5.21 (m, 1H), 3.85 (s, 3H), 3.12 (dd, J = 3.7, 13.9
Hz, 1H), 2.79 (dd, J = 9.7, 13.9 Hz, 1H), 2.25 (s, 3H). MS (ESI) m/z (M+H) 391.1.
EXAMPLE 96
COMPOUNDS 164, 169, 480-488, 498-518, 530, 548, 567-573, 585, 587, 591, 593, 597, 601-
605, 607, 611, 613-617, 620-621, 624-629
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)METHYL(PYRIDINYL)-
1H-PYRAZOLECARBOXAMIDE (164)
Sn(Bu) N
O O O O
Pd(PPh3)4
N NH
NH NH N NH
toluene 2
N OH N
OH O
163E 164A
To the mixture of 163E (200 mg, 527 umol) and tributyl(2-pyridyl)stannane
(388 mg, 1.05 mmol) in toluene (5 mL) was added Pd(PPh ) (60.9 mg, 52.7 umol) under N (15
3 4 2
psi). After stirred at 110 °C for 10 h, the mixture was concentrated in vacuum to get residue.
The residue was purified by preparatory-HPLC (acid) to get compound 164A (85 mg, yield:
42.5%) as light yellow solid. H NMR (400 MHz, CDCl -d) δ 8.97 (br d, J = 7.06 Hz, 1H), 8.72
(br d, J = 7.28 Hz, 1H), 8.55 (dd, J = 17.64, 4.85 Hz, 1H), 8.03 – 7.95 (m, 1H), 7.88 - 7.79 (m,
1H), 7.43 - 7.31 (m, 2H), 7.13 - 6.99 (m, 6H), 5.49 (br d, J = 10.14 Hz, 1H), 4.27 - 4.17 (m, 2H),
3.89 (d, J = 3.53 Hz, 3H), 3.26 - 2.91 (m, 2H).
17681897_1 (GHMatters) P110989.NZ
Compound 164 (31 mg, yield: 41.6%, white solid) was prepared as in Example
105 from the intermediate compound 164A. Compound 164: H NMR (400MHz, CDCl -d) δ
8.51 (br d, J = 6.4 Hz, 1H), 8.43 (d, J = 5.1 Hz, 1H), 8.01 (s, 1H), 7.84 (br t, J = 7.8 Hz, 1H),
7.49 (d, J=7.9 Hz, 1H), 7.32 (dd, J = 5.3, 7.1 Hz, 1H), 7.21 - 7.09 (m, 3H), 6.96 (br d, J = 5.7 Hz,
2H), 6.75 (br s, 1H), 5.70 - 5.60 (m, 2H), 3.89 (s, 3H), 3.33 (dd, J = 5.1, 14.3 Hz, 1H), 3.15 (dd, J
= 7.1, 14.1 Hz, 1H). MS (ESI) m/z (M+H) 378.1.
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)METHYL(PYRIDINYL)-
1H-PYRAZOLECARBOXAMIDE (169)
Compound 169 (20 mg, yield: 48.2%, white solid) was prepared as in
compound 163 from the corresponding starting materials, compound 163G and tributyl(2-
pyridyl)stannane. H NMR (400MHz, DMSO-d ) δ 11.88 (br d, J = 7.9 Hz, 1H), 8.32 (br d, J =
.3 Hz, 1H), 8.20 (s, 1H), 8.08 (d, J = 8.3 Hz, 1H), 7.91 (t, J = 7.7 Hz, 1H), 7.74 (br s, 1H), 7.52
(br s, 1H), 7.40 - 7.32 (m, 1H), 7.20 - 7.05 (m, 5H), 5.64 - 5.47 (m, 1H), 3.91 (s, 3H), 3.27 (dd, J
= 4.8, 14.5 Hz, 1H), 3.12 - 3.07 (m, 1H). MS (ESI) m/z (M+H) 378.1.
N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)(2,3-DIFLUOROPHENYL)
METHYL-1H-PYRAZOLECARBOXAMIDE (480)
Compound 480 (60 mg, yield: 48.13%, white solid) was prepared as in
compound 163 from the corresponding starting materials, compound 163G and (2,3-
difluorophenyl)boronic acid. H NMR (400MHz, DMSO-d6) δ 8.39 (d, J = 7.3 Hz, 1H), 8.30 (s,
1H), 8.03 (s, 1H), 7.78 (s, 1H), 7.45 - 7.34 (m, 1H), 7.33 - 7.13 (m, 7H), 5.28 - 5.22 (m, 1H),
3.92 (s, 3H), 3.13 (dd, J = 3.6, 13.8 Hz, 1H), 2.83 (dd, J = 10.1, 13.9 Hz, 1H). MS (ESI) m/z
(M+H) 413.1.
N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)(6-CYANOPYRIDINYL)
METHYL-1H-PYRAZOLECARBOXAMIDE (481)
Compound 481 (15 mg, yield: 37.47%, white solid) was prepared as in
compound 163 from the corresponding starting materials, compound 163G and (6-cyanopyridin-
3-yl)boronic acid. H NMR (400MHz, DMSO-d ) δ 8.91 (d, J = 1.8 Hz, 1H), 8.67 (d, J = 7.3 Hz,
1H), 8.25 (s, 1H), 8.15 (dd, J = 2.0, 8.2 Hz, 1H), 8.08 (s, 1H), 7.97 (d, J = 8.2 Hz, 1H), 7.81 (s,
1H), 7.27 (d, J = 4.4 Hz, 4H), 7.24 - 7.17 (m, 1H), 5.27 (t, J = 3.0 Hz, 1H), 3.94 (s, 3H), 3.15
(dd, J = 3.7, 13.9 Hz, 1H), 2.86 - 2.74 (m, 1H). MS (ESI) m/z (M+H) 403.2.
17681897_1 (GHMatters) P110989.NZ
N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)(1H-INDAZOLYL)
METHYL-1H-PYRAZOLECARBOXAMIDE (482)
Compound 482 (18 mg, yield: 14.77%, white solid) was prepared as in
compound 163 from the corresponding starting materials, compound 163C and 3-(4,4,5,5-
tetramethyl-1,3,2-dioxaborolanyl)((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole and the
final compound 482 was obtained by removal of the 2-(trimethylsilyl)ethoxy)methyl group. H
NMR (400MHz, DMSO-d ) δ 11.10 (br s, 1H), 9.57 (br s, 1H), 8.44 (d, J = 8.0 Hz, 1H), 8.08 (s,
1H), 7.46 - 7.38 (m, 2H), 7.24 (s, 6H), 6.84 (br s, 1H), 5.70 (br s, 1H), 5.50 (br s, 1H), 3.97 (s,
3H), 3.42 - 3.32 (m, 1H), 3.26 - 3.20 (m, 1H). MS (ESI) m/z (M+H) 417.0.
N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)BENZYLMETHYL-1H-
PYRAZOLECARBOXAMIDE (483)
Compound 483 (65 mg, yield: 66.57%, white solid) was prepared using the
procedures similar to compound 163 from the corresponding starting materials, compound ethyl
3-iodomethyl-1H-pyrazolecarboxylate and 2-benzyl-4,4,5,5-tetramethyl-1,3,2-
dioxaborolane and the final compound 483 was obtained by removal of the 2-
(trimethylsilyl)ethoxy)methyl group. H NMR (400MHz, DMSO-d ) δ 8.33 (d, J = 7.1 Hz, 1H),
8.19 (s, 1H), 8.05 (s, 1H), 7.79 (s, 1H), 7.31 - 7.23 (m, 4H), 7.20 - 7.07 (m, 6H), 5.31 - 5.23 (m,
1H), 4.05 (s, 2H), 3.77 (s, 3H), 3.20 - 3.09 (m, 1H), 2.91 - 2.80 (m, 1H). MS (ESI) m/z (M+H)
391.1.
N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)(2-FLUOROPHENYL)
METHYL-1H-PYRAZOLECARBOXAMIDE (484)
Compound 484 (3.35 g, white solid) was prepared using the procedures similar
to compound 163 from the corresponding starting materials, compound 163C and (2-
fluorophenyl)boronic acid and the final compound 484 was obtained. H NMR (400MHz,
DMSO-d ) δ 8.30 (d, J = 7.3 Hz, 1H), 8.26 (s, 1H), 8.04 (s, 1H), 7.79 (s, 1H), 7.41 - 7.11 (m,
9H), 5.30 - 5.18 (m, 1H), 3.90 (s, 3H), 3.12 (dd, J = 3.6, 14.0 Hz, 1H), 2.83 (dd, J = 9.8, 13.8 Hz,
1H). MS (ESI) m/z (M +H) 395.0.
17681897_1 (GHMatters) P110989.NZ
N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)(3-FLUOROPHENYL)
METHYL-1H-PYRAZOLECARBOXAMIDE HYDROCHLORIDE (485)
N NH
HCl/EA N NH
N N 2
•HCl 485
Compound 485 was synthesized from intermediate 590 which was synthesized
using 163H. Compound 485 (3.1 g, yield: 79.85% white solid) was prepared from intermediate
590 using the procedures similar to compound 163 from the corresponding starting materials and
the final compound 485 was obtained. H NMR (400MHz, DMSO-d ) δ 8.51 (d, J = 7.3 Hz,
1H), 8.12 (s, 2H), 7.85 (br s, 1H), 7.46 (d, J = 8.3 Hz, 2H), 7.39 - 7.28 (m, 5H), 7.25 - 7.20 (m,
1H), 7.14 (t, J = 8.0 Hz, 1H), 5.43 - 5.25 (m, 1H), 3.18 (dd, J = 3.4, 13.7 Hz, 1H), 2.84 (dd, J =
.3, 13.8 Hz, 1H). MS (ESI) m/z (M+H) 395.1..
N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)(2,6-DIFLUOROPHENYL)
METHYL-1H-PYRAZOLECARBOXAMIDE (486)
Compound 486 (60 mg, yield: 43.0% light yellow solid) was prepared using the
procedures similar to compound 163 from the corresponding starting materials, compound 163C
and (2,6-difluorophenyl)boronic acid and the final compound 486 was obtained. H NMR
(400MHz, CDCl ) δ 7.94 (s, 1H), 7.41 - 7.33 (m, 1H), 7.22 - 7.17 (m, 3H), 6.99 - 6.93 (m, 2H),
6.88 (dd, J = 3.0, 6.3 Hz, 2H), 6.67 (br s, 1H), 6.01 (br d, J = 7.1 Hz, 1H), 5.63 - 5.57 (m, 1H),
.53 (br s, 1H), 3.97 (s, 3H), 3.27 (dd, J = 5.3, 14.1 Hz, 1H), 3.09 (dd, J = 6.6, 14.1 Hz, 1H). MS
(ESI) m/z (M+H) 413.1
N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)(6-METHOXYPYRIDINYL)
METHYL-1H-PYRAZOLECARBOXAMIDE (487)
Compound 487 (10 mg, yield: 20.06% white solid) was prepared using the
procedures similar to compound 163 from the corresponding starting materials, compound 163C
and 2-methoxy(tributylstannyl)pyridine and the final compound 487 was obtained. H NMR
(400MHz, CD CN) δ 11.02 (d, J = 5.5 Hz, 1H), 8.01 (s, 1H), 7.81 (t, J = 7.9 Hz, 1H), 7.60 (d, J
= 7.5 Hz, 1H), 7.14 - 7.06 (m, 5H), 7.00 - 6.88 (m, 1H), 6.81 (d, J = 8.2 Hz, 1H), 6.23 - 6.01 (m,
17681897_1 (GHMatters) P110989.NZ
1H), 5.21 - 5.15 (m, 1H), 3.85 (s, 3H), 3.73 (s, 3H), 3.27 (dd, J = 4.4, 13.9 Hz, 1H), 2.97 (dd, J =
9.9, 13.9 Hz, 1H). MS (ESI) m/z (M+H) 408.1.
N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)BENZYLMETHYL-1H-
PYRAZOLECARBOXAMIDE (488)
Compound 488 (35.6 mg, yield: 35.57%, white solid) was prepared using the
procedures similar to compound 163 from the corresponding starting materials, compound ethyl
-iodomethyl-1H-pyrazolecarboxylate and 2-benzyl-4,4,5,5-tetramethyl-1,3,2-
dioxaborolane and the final compound 488 was obtained. H NMR (400MHz, DMSO-d ) δ 8.40
(d, J = 7.8 Hz, 1H), 8.03 (br. s, 1H), 7.92 (s, 1H), 7.77 (br. s, 1H), 7.31 - 7.03 (m, 10H), 5.32 -
.23 (m, 1H), 4.36 - 4.24 (m, 2H), 3.58 (s, 3H), 3.19 - 3.10 (m, 1H), 2.89 - 2.79 (m, 1H). MS
(ESI) m/z (M+H) 391.1.
N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)METHYL(5-METHYLFURAN-
2-YL)-1H-PYRAZOLECARBOXAMIDE (498)
Compound 498 (70 mg, yield: 54.1%, light yellow solid) was prepared using
the procedures similar to compound 163 from the corresponding starting materials, compound
ethyl 3-iodomethyl-1H-pyrazolecarboxylate and (5-methylfuranyl)boronic acid and the
final compound 498 was obtained. H NMR (400MHz, DMSO-d ) δ 8.38 - 8.22 (m, 1H), 8.20 -
8.01 (m, 2H), 7.91 - 7.71 (m, 1H), 7.31 - 7.17 (m, 5H), 6.90 (d, J = 3.1 Hz, 1H), 6.08 (d, J = 2.2
Hz, 1H), 5.47 - 5.20 (m, 1H), 3.87 (s, 3H), 3.17 (dd, J = 3.9, 13.8 Hz, 1H), 2.88 (dd, J = 9.7, 14.1
Hz, 1H), 2.29 - 2.19 (m, 3H). MS (ESI) m/z (M+H) 381.1.
N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)(2,5-DIMETHYLTHIOPHEN
YL)METHYL-1H-PYRAZOLECARBOXAMIDE (499)
Compound 499 (110 mg, yield: 64.9%, white solid) was prepared using the
procedures similar to compound 163 from the corresponding starting materials, compound ethyl
3-iodomethyl-1H-pyrazolecarboxylate and (2,5-dimethylthienyl)boronic acid and the
final compound 499 was obtained. H NMR (400MHz, DMSO-d ) δ 8.14 - 8.00 (m, 2H), 7.87 -
7.73 (m, 2H), 7.34 - 7.12 (m, 5H), 6.58 (d, J = 1.1 Hz, 1H), 5.28 (ddd, J = 4.0, 7.3, 9.5 Hz, 1H),
3.91 - 3.79 (m, 3H), 3.14 (dd, J = 4.0, 13.9 Hz, 1H), 2.77 (dd, J = 9.4, 14.0 Hz, 1H), 2.33 (s, 3H),
2.22 - 2.12 (m, 3H). MS (ESI) m/z (M+H) 411.1.
17681897_1 (GHMatters) P110989.NZ
N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)(FURANYL)METHYL-1H-
PYRAZOLECARBOXAMIDE (500)
Compound 500 (55 mg, yield: 91.2%, white solid) was prepared using the
procedures similar to compound 163 from the corresponding starting materials, compound ethyl
3-iodomethyl-1H-pyrazolecarboxylate and 2-furylboronic acid and the final compound 500
was obtained. H NMR (400MHz, DMSO-d ) δ 8.37 (d, J = 7.1 Hz, 1H), 8.14 (s, 1H), 8.07 (br s,
1H), 7.81 (br s, 1H), 7.61 (s, 1H), 7.28 (s, 4H), 7.20 (br s, 1H), 6.99 (d, J = 2.9 Hz, 1H), 6.48 (br
s, 1H), 5.37 - 5.28 (m, 1H), 3.88 (s, 3H), 3.18 (dd, J = 3.5, 13.7 Hz, 1H), 2.86 (dd, J = 9.7, 13.9
Hz, 1H). MS (ESI) m/z (M+H) 367.1
N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)(2-CHLOROTHIOPHENYL)
METHYL-1H-PYRAZOLECARBOXAMIDE (501)
Compound 501 (110 mg, yield: 68.3%, white solid) was prepared using the
procedures similar to compound 163 from the corresponding starting materials, compound ethyl
3-iodomethyl-1H-pyrazolecarboxylate and (2-chlorothiophenyl)boronic acid and the
final compound 501 was obtained. H NMR (400MHz, DMSO-d ) δ 8.13 (s, 1H), 7.80 - 7.46
(m, 3H), 7.35 (d, J = 5.8 Hz, 1H), 7.30 - 7.24 (m, 2H), 7.23 - 7.16 (m, 3H), 6.98 (d, J = 5.8 Hz,
1H), 5.31 (m, 1H), 3.89 (s, 3H), 3.17 (dd, J = 4.4, 13.9 Hz, 1H), 2.88 (dd, J = 8.9, 13.9 Hz, 1H).
MS (ESI) m/z (M+H) 417.1.
N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)(FURANYL)METHYL-1H-
PYRAZOLECARBOXAMIDE (502)
Compound 502 (160 mg, yield: 63.78%, white solid) was prepared using the
procedures similar to compound 163 from the corresponding starting materials, compound ethyl
3-iodomethyl-1H-pyrazolecarboxylate and furanylboronic acid and the final compound
502 was obtained. H NMR (400MHz, DMSO-d ) δ 8.35 (d, J = 7.6 Hz, 1H), 8.22 - 8.18 (m,
1H), 8.13 (s, 1H), 8.04 (br. s, 1H), 7.76 (br. s, 1H), 7.61 - 7.57 (m, 1H), 7.31 - 7.14 (m, 5H), 6.80
- 6.75 (m, 1H), 5.32 - 5.23 (m, 1H), 3.85 (s, 3H), 3.19 - 3.11 (m, 1H), 2.88 - 2.78 (m, 1H). MS
(ESI) m/z (M+H) 367.1.
17681897_1 (GHMatters) P110989.NZ
N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)METHYL(THIOPHENYL)-
1H-PYRAZOLECARBOXAMIDE (503)
Compound 503 (65 mg, yield: 47.7%, light yellow solid) was prepared using
the procedures similar to compound 163 from the corresponding starting materials, compound
ethyl 3-iodomethyl-1H-pyrazolecarboxylate and thiophenylboronic acid and the final
compound 503 was obtained. H NMR (400MHz, DMSO-d ) δ 8.37 (d, J = 7.3 Hz, 1H), 8.04 (s,
2H), 7.92 (s, 1H), 7.77 (br s, 1H), 7.50 - 7.34 (m, 2H), 7.30 - 7.22 (m, 4H), 7.18 (dd, J = 4.4, 8.6
Hz, 1H), 5.38 - 5.18 (m, 1H), 3.84 (s, 3H), 3.22 - 3.08 (m, 1H), 2.81 (dd, J = 9.9, 13.9 Hz, 1H).
MS (ESI) m/z (M+H) 383.1.
N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)METHYL(4-
METHYLTHIOPHENYL)-1H-PYRAZOLECARBOXAMIDE (504)
Compound 504 (100 mg, yield: 65.93%, light yellow solid) was prepared using
the procedures similar to compound 163 from the corresponding starting materials, compound
ethyl 3-iodomethyl-1H-pyrazolecarboxylate and (4-methylthiophenyl)boronic acid and
the final compound 504 was obtained. H NMR (400MHz, DMSO-d ) δ 8.37 (d, J = 7.2 Hz,
1H), 8.09 (s, 1H), 8.06 (br. s, 1H), 7.78 (br. s, 1H), 7.57 - 7.54 (m, 1H), 7.29 - 7.23 (m, 4H), 7.22
- 7.15 (m, 1H), 6.99 - 6.95 (m, 1H), 5.34 - 5.27 (m, 1H), 3.83 (s, 3H), 3.19 - 3.10 (m, 1H), 2.88 -
2.77 (m, 1H), 2.14 (s, 3H). MS (ESI) m/z (M+H) 397.1.
N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)METHYL(5-
METHYLTHIOPHENYL)-1H-PYRAZOLECARBOXAMIDE (505)
Compound 505 (130 mg, yield: 61%, light yellow solid) was prepared using the
procedures similar to compound 163 from the corresponding starting materials, compound ethyl
3-iodomethyl-1H-pyrazolecarboxylate and (5-methylthiophenyl)boronic acid and the
final compound 505 was obtained. H NMR (400MHz, DMSO-d ) δ 8.68 (s, 1H), 8.57 (d, J =
7.5 Hz, 1H), 8.53 - 8.48 (m, 1H), 8.23 (s, 1H), 8.08 (s, 1H), 7.92 - 7.86 (m, 1H), 7.81 (s, 1H),
7.34 - 7.25 (m, 4H), 7.23 - 7.18 (m, 1H), 5.36 - 5.28 (m, 1H), 3.94 (s, 3H), 3.17 (dd, J = 3.9, 14.0
Hz, 1H), 2.83 (dd, J = 10.0, 14.0 Hz, 1H). MS (ESI) m/z (M+H) 396.1.
17681897_1 (GHMatters) P110989.NZ
N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)(5-FLUOROPYRIDINYL)
METHYL-1H-PYRAZOLECARBOXAMIDE (506)
Compound 506 (35 mg, yield: 20.4%, white solid) was prepared using the
procedures similar to compound 163 from the corresponding starting materials, compound ethyl
3-iodomethyl-1H-pyrazolecarboxylate and (5-fluoropyridinyl)boronic acid and the final
compound 506 was obtained. H NMR (400MHz, DMSO-d ) δ 8.40 (d, J = 7.3 Hz, 1H), 8.16 -
8.03 (m, 2H), 7.81 (s, 1H), 7.54 (d, J = 3.5 Hz, 1H), 7.29 (d, J = 4.2 Hz, 4H), 7.24-7.19 (m, 1H),
6.66 (dd, J = 1.0, 3.6 Hz, 1H), 5.34-5.29 (m, 1H), 3.85 (s, 3H), 3.17 (dd, J = 3.7, 13.9 Hz, 1H),
2.84 (dd, J = 9.9, 13.9 Hz, 1H), 2.40 (s, 3H). MS (ESI) m/z (M+H) 397.1.
N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)(2-FLUORO
METHOXYPHENYL)METHYL-1H-PYRAZOLECARBOXAMIDE (507)
Compound 507 (34 mg, yield: 15.75%, white solid) was prepared using the
procedures similar to compound 163 from the corresponding starting materials, compound ethyl
3-iodomethyl-1H-pyrazolecarboxylate and (2-fluoromethoxyphenyl)boronic acid and the
final compound 507 was obtained. H NMR (400MHz, DMSO-d ) δ 8.14 (s, 1H), 7.68 (br d, J =
7.0 Hz, 2H), 7.51 (br s, 1H), 7.30 - 7.15 (m, 5H), 7.10 - 7.01 (m, 1H), 6.98 - 6.87 (m, 2H), 5.28
(ddd, J = 4.6, 7.3, 8.8 Hz, 1H), 3.90 (s, 3H), 3.75 (s, 3H), 3.15 (dd, J = 4.5, 14.1 Hz, 1H), 2.87
(dd, J = 8.9, 14.2 Hz, 1H). F NMR (376 MHz, DMSO-d6) δ -124.53 (br d, J = 88.69 Hz, 1 F).
MS (ESI) m/z (M+Na) 447.2.
N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)(3-
(DIFLUOROMETHYL)PHENYL)METHYL-1H-PYRAZOLECARBOXAMIDE
(508)
Compound 508 (140 mg, yield: 69.98%, white solid) was prepared using the
procedures similar to compound 163 from the corresponding starting materials, compound ethyl
3-iodomethyl-1H-pyrazolecarboxylate and (3-(difluoromethyl)phenyl)boronic acid and the
final compound 508 was obtained. H NMR (400MHz, DMSO-d ) δ 8.43 (d, J = 7.6 Hz, 1H),
8.09 (s, 1H), 8.02 (br. s, 1H), 7.85 - 7.81 (m, 1H), 7.78 (br. s, 1H), 7.73 - 7.67 (m, 1H), 7.51 -
7.46 (m, 1H), 7.44 - 7.39 (m, 1H), 7.30 - 7.16 (m, 5H), 7.15 - 6.84 (m, 1H), 5.32 - 5.23 (m, 1H),
3.89 (s, 3H), 3.19 - 3.11 (m, 1H), 2.87 - 2.76 (m, 1H). MS (ESI) m/z (M+H) 427.1.
17681897_1 (GHMatters) P110989.NZ
N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)(2-FLUORO
METHOXYPHENYL)METHYL-1H-PYRAZOLECARBOXAMIDE (509)
Compound 509 (190 mg, yield: 66.92%, white solid) was prepared using the
procedures similar to compound 163 from the corresponding starting materials, compound ethyl
3-iodomethyl-1H-pyrazolecarboxylate and (2-fluoromethoxyphenyl)boronic acid and the
final compound 509 was obtained. H NMR (400MHz, DMSO-d ) δ 8.18 (s, 1H), 8.13 (d, J =
7.6 Hz, 1H), 7.96 (br. s, 1H), 7.73 (br. s, 1H), 7.30 - 7.16 (m, 5H), 7.14 - 7.01 (m, 2H), 6.87 -
6.79 (m, 1H), 5.27 - 5.16 (m, 1H), 3.88 (s, 3H), 3.80 (s, 3H), 3.14 - 3.06 (m, 1H), 2.84 - 2.74 (m,
1H). MS (ESI) m/z (M+H) 425.1.
N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)(2,2-
DIFLUOROBENZO[d][1,3]DIOXOLYL)METHYL-1H-PYRAZOLE
CARBOXAMIDE (510)
Compound 510 (70 mg, yield: 34%, white solid) was prepared using the
procedures similar to compound 163 from the corresponding starting materials, compound ethyl
3-iodomethyl-1H-pyrazolecarboxylate and (2,2-difluorobenzo[d][1,3]dioxolyl)boronic
acid and the final compound 510 was obtained. H NMR (400MHz, DMSO-d ) δ 8.44 (d, J =
7.5 Hz, 1H), 8.19 (s, 1H), 7.98 (s, 1H), 7.76 (s, 1H), 7.35 (d, J = 7.8 Hz, 1H), 7.31 - 7.12 (m,
7H), 5.34 - 5.21 (m, 1H), 3.93 (s, 3H), 3.14 (dd, J = 3.6, 13.9 Hz, 1H), 2.82 (dd, J = 9.9, 14.2 Hz,
1H). MS (ESI) m/z (M+H) 457.1.
N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)(2-METHOXYPHENYL)
METHYL-1H-PYRAZOLECARBOXAMIDE (511)
Compound 511 (23 mg, yield: 8.04%, white solid) was prepared using the
procedures similar to compound 163 from the corresponding starting materials, compound ethyl
3-iodomethyl-1H-pyrazolecarboxylate and (2-methoxyphenyl)boronic acid and the final
compound 511 was obtained. H NMR (400MHz, DMSO-d ) δ 8.04 (s, 1H), 7.72 (br s, 1H),
7.55 (br s, 1H), 7.37 (br t, J = 7.9 Hz, 1H), 7.28 - 7.10 (m, 5H), 7.08 - 6.90 (m, 4H), 5.30 (br d, J
= 4.3 Hz, 1H), 3.91 - 3.81 (m, 3H), 3.66 - 3.54 (m, 3H), 3.12 (br d, J = 4.3 Hz, 1H), 2.76 (dd, J =
8.8, 14.1 Hz, 1H). MS (ESI) m/z (M+Na) 407.2.
17681897_1 (GHMatters) P110989.NZ
N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)(3-FLUORO
(TRIFLUOROMETHYL)PHENYL)METHYL-1H-PYRAZOLECARBOXAMIDE
(512)
Compound 512 (60 mg, yield: 21.65%, white solid) was prepared using the
procedures similar to compound 163 from the corresponding starting materials, compound ethyl
3-iodomethyl-1H-pyrazolecarboxylate and 2-(3-fluoro(trifluoromethyl)phenyl)-4,4,5,5-
tetramethyl-1,3,2-dioxaborolane and the final compound 512 was obtained. H NMR (400MHz,
DMSO-d ) δ 8.28 (s, 1H), 8.21 (d, J = 7.5 Hz, 1H), 7.99 (s, 1H), 7.76 (s, 1H), 7.67 - 7.59 (m,
1H), 7.52 - 7.43 (m, 1H), 7.31 - 7.17 (m, 5H), 7.05 (d, J = 7.7 Hz, 1H), 5.25 - 5.16 (m, 1H), 3.90
(s, 3H), 3.11 (dd, J = 3.6, 14.0 Hz, 1H), 2.79 (dd, J = 10.0, 14.0 Hz, 1H). F NMR (376MHz,
DMSO- d ) δ -55.03 (d, J = 18.3 Hz, 3F), -114.43 (tdd, J = 6.1, 12.3, 18.7 Hz, 1F). MS (ESI)
m/z (M+Na) 463.2.
N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)METHYL(2-
(TRIFLUOROMETHYL)PHENYL)-1H-PYRAZOLECARBOXAMIDE (513)
Compound 513 (45 mg, yield: 54.58%, white solid) was prepared using the
procedures similar to compound 163 from the corresponding starting materials, compound ethyl
3-iodomethyl-1H-pyrazolecarboxylate and (2-(trifluoromethyl)phenyl)boronic acid and the
final compound 513 was obtained. H NMR (400MHz, DMSO-d ) δ 8.25 (s, 1H), 7.99 (br d, J =
7.1 Hz, 2H), 7.80 - 7.69 (m, 2H), 7.62 - 7.52 (m, 2H), 7.30 - 7.17 (m, 6H), 5.20 (ddd, J = 3.9,
7.4, 9.7 Hz, 1H), 3.89 (s, 3H), 3.17 - 3.03 (m, 1H), 2.78 (dd, J = 9.7, 13.9 Hz, 1H). F NMR
(376MHz, DMSO- d ) δ -57.15 (s, 3F). MS (ESI) m/z (M+H) 445.2.
N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)(BENZO[d][1,3]DIOXOLYL)
METHYL-1H-PYRAZOLECARBOXAMIDE (514)
Compound 514 (92 mg, yield: 34.71%, light yellow solid) was prepared using
the procedures similar to compound 163 from the corresponding starting materials, compound
ethyl 3-iodomethyl-1H-pyrazolecarboxylate and benzo[d][1,3]dioxolylboronic acid and
the final compound 514 was obtained. H NMR (400MHz, DMSO-d ) δ 2.82 (dd, J = 13.89,
9.48 Hz, 1 H) 3.12 (dd, J = 14.00, 4.08 Hz, 1 H) 3.88 (s, 3 H) 5.16 - 5.34 (m, 1 H) 5.77 (s, 1 H)
.87 (s, 1 H) 6.76 - 6.90 (m, 3 H) 7.18 - 7.31 (m, 5 H) 7.77 (s, 1 H) 8.00 (s, 1 H) 8.07 (s, 1 H)
8.11 (d, J = 7.28 Hz, 1 H). MS (ESI) m/z (M+H)+ 421.1.
17681897_1 (GHMatters) P110989.NZ
N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)(5-METHOXYPYRIDINYL)
METHYL-1H-PYRAZOLECARBOXAMIDE (515)
Compound 515 (60 mg, yield: 20.6%, yellow solid) was prepared using the
procedures similar to compound 163 from the corresponding starting materials, compound ethyl
3-iodomethyl-1H-pyrazolecarboxylate and (5-methoxypyridinyl)boronic acid and the
final compound 515 was obtained. H NMR (400MHz, DMSO-d ) δ 8.50 (d, J = 7.5 Hz, 1H),
8.39 (d, J = 1.5 Hz, 1H), 8.22 (d, J = 2.6 Hz, 1H), 8.17 (s, 1H), 8.06 (s, 1H), 7.80 (s, 1H), 7.59
(dd, J = 1.8, 2.9 Hz, 1H), 7.29 (d, J = 4.4 Hz, 4H), 7.24 - 7.18 (m, 1H), 5.35 - 5.26 (m, 1H), 3.93
(s, 3H), 3.79 (s, 3H), 3.16 (dd, J = 3.6, 13.8 Hz, 1H), 2.83 (dd, J = 9.9, 13.9 Hz, 1H). MS (ESI)
m/z (M+H) 408.2.
N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)(2-FLUORO
(TRIFLUOROMETHYL)PHENYL)METHYL-1H-PYRAZOLECARBOXAMIDE
(516)
Compound 516 (85 mg, yield: 78.65%, light yellow solid) was prepared using
the procedures similar to compound 163 from the corresponding starting materials, compound
ethyl 3-iodomethyl-1H-pyrazolecarboxylate and (2-fluoro
(trifluoromethyl)phenyl)boronic acid and the final compound 516 was obtained. H NMR
(400MHz, DMSO-d ) δ 8.42 (d, J = 7.5 Hz, 1H), 8.29 (s, 1H), 8.00 (s, 1H), 7.79 - 7.72 (m, 2H),
7.63 (br t, J = 7.1 Hz, 1H), 7.37 (t, J = 7.7 Hz, 1H), 7.31 - 7.18 (m, 5H), 5.29 - 5.19 (m, 1H), 3.93
(s, 3H), 3.13 (dd, J = 3.5, 14.1 Hz, 1H), 2.82 (dd, J = 10.1, 13.9 Hz, 1H). F NMR (376MHz,
DMSO-d ) δ -59.92 (s, 1F), -59.96 (s, 1F), -116.72 -116.79 (m, 1F), -116.80 - 116.86 (m, 1F).
MS (ESI) m/z (M+H)+ 463.1.
N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)(2-FLUORO
METHYLPHENYL)METHYL-1H-PYRAZOLECARBOXAMIDE (517)
Compound 517 (170 mg, yield: 53.97%, light yellow solid) was prepared using
the procedures similar to compound 163 from the corresponding starting materials, compound
ethyl 3-iodomethyl-1H-pyrazolecarboxylate and (2-fluoromethylphenyl)boronic acid and
the final compound 517 was obtained. H NMR (400MHz, DMSO-d ) δ 8.20 (s, 1H), 8.13 (d, J
= 7.5 Hz, 1H), 8.02 (s, 1H), 7.78 (s, 1H), 7.31 - 7.20 (m, 6H), 7.15 - 7.10 (m, 1H), 7.07 – 7.02
(m, 1H), 5.25 (ddd, J = 3.9, 7.3, 9.5 Hz, 1H), 3.91 (s, 3H), 3.75 (s, 3H), 3.13 (dd, J = 4.0, 13.9
17681897_1 (GHMatters) P110989.NZ
Hz, 1H), 2.82 (dd, J = 9.7, 13.9 Hz, 1H). 2.21 (d, J = 1.5 Hz, 3H). F NMR (376 MHz, DMSO-
d ) δ -116.59 - 120.74 (m, 1F). MS (ESI) m/z (M+H) 409.2.
N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)(2,5-DIFLUOROPHENYL)
METHYL-1H-PYRAZOLECARBOXAMIDE (518)
Compound 518 (35.9 mg, yield: 24.08%, light yellow solid) was prepared using
the procedures similar to compound 163 from the corresponding starting materials, compound
ethyl 3-iodomethyl-1H-pyrazolecarboxylate and (2,5-difluorophenyl)boronic acid and the
final compound 518 was obtained. H NMR (400MHz, DMSO-d ) δ 8.33 (d, J = 7.3 Hz, 1H),
8.23 (s, 1H), 8.02 (s, 1H), 7.78 (s, 1H), 7.31 - 7.17 (m, 8H), 5.29 - 5.21 (m, 1H), 3.92 (s, 3H),
3.13 (dd, J = 3.6, 14.0 Hz, 1H), 2.82 (dd, J = 9.8, 13.8 Hz, 1H). F NMR (376 MHz, DMSO-d )
δ -119.41(tdd, J = 4.8, 8.7, 17.7 Hz, 1F), -119.69 -120.11 (m, 1F). MS (ESI) m/z (M+H) 413.1.
N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)(1H-INDAZOLYL)
METHYL-1H-PYRAZOLECARBOXAMIDE (530)
Compound 530 (85 mg, yield: 39.2%, light yellow solid) was prepared using
the corresponding starting materials, compound ethyl 3-iodomethyl-1H-pyrazole
carboxylate and 1H-indazole and alkylated using K PO , CuI, and (1R,2R)-N1,N2-
dimethylcyclohexane-1,2-diamine, followed by subjecting the nresulting intermediate to
procedures such as in compound 12 to obtain compound 530. H NMR (400MHz, DMSO-d ) δ
9.41 (d, J = 5.8 Hz, 1H), 8.28 (d, J = 2.3 Hz, 2H), 8.00 (d, J = 8.5 Hz, 1H), 7.91 (d, J = 8.0 Hz,
1H), 7.79 (br s, 1H), 7.68 - 7.48 (m, 2H), 7.33 (t, J = 7.4 Hz, 1H), 7.19 - 7.04 (m, 5H), 5.47 (dt,
J=4.8, 7.7 Hz, 1H), 3.95 (s, 3H), 3.23 (dd, J = 4.6, 14.2 Hz, 1H), 2.94 (dd, J = 8.4, 14.2 Hz, 1H).
MS (ESI) m/z (M+H) 417.1.
N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)(2,2-
DIFLUOROBENZO[d][1,3]DIOXOLYL)METHYL-1H-PYRAZOLE
CARBOXAMIDE (548)
Compound 548 (130 mg, yield: 53.1%, white solid) was prepared using the
corresponding starting materials, compound ethyl 3-iodomethyl-1H-pyrazolecarboxylate
(198A) and (2,2-difluorobenzo[d][1,3]dioxolyl)boronic acid, followed by subjecting the
resulting intermediate to procedures such as in compound 12 to obtain compound 548. H NMR
(400MHz, DMSO-d ) δ 8.48 (d, J = 7.5 Hz, 1H), 8.14 - 8.04 (m, 2H), 7.82 (s, 1H), 7.57 (d, J =
17681897_1 (GHMatters) P110989.NZ
1.5 Hz, 1H), 7.46 (dd, J = 1.8, 8.4 Hz, 1H), 7.36 - 7.17 (m, 5H), 5.38 - 5.19 (m, 1H), 3.90 (s,
3H), 3.17 (dd, J = 4.0, 13.9 Hz, 1H), 2.83 (dd, J = 9.9, 13.9 Hz, 1H). MS (ESI) m/z
(M+H) 457.1.
N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)(BENZO[d][1,3]DIOXOLYL)
METHYL-1H-PYRAZOLECARBOXAMIDE (567)
Compound 567 (125 mg, yield: 72.7%, yellow solid) was prepared using the
corresponding starting materials, compound ethyl 3-iodomethyl-1H-pyrazolecarboxylate
(198A) and benzo[d][1,3]dioxolylboronic acid, followed by subjecting the resulting
intermediate to procedures such as in compound 12 to obtain compound 567. H NMR
(400MHz, DMSO-d ) δ 8.29 (d, J = 7.5 Hz, 1H), 8.08 - 7.99 (m, 2H), 7.80 (s, 1H), 7.32 - 7.19
(m, 5H), 7.16 - 7.08 (m, 2H), 6.83 (d, J = 8.2 Hz, 1H), 6.01 (s, 2H), 5.33 - 5.24 (m, 1H), 3.86 (s,
3H), 3.16 (dd, J = 4.1, 13.8 Hz, 1H), 2.82 (dd, J = 9.9, 14.1 Hz, 1H). MS (ESI) m/z
(M+H) 421.1.
N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)-1,2'-DIMETHYL-1H,2'H-[3,3'-
BIPYRAZOLE]CARBOXAMIDE (568)
Compound 568 (24 mg, yield: 12.0%, white solid) was prepared using the
corresponding starting materials, compound ethyl 3-iodomethyl-1H-pyrazolecarboxylate
(198A) and (1-methyl-1H-pyrazolyl)boronic acid, followed by subjecting the nresulting
intermediate to procedures such as in compound 12 to obtain compound 568. H NMR
(400MHz, DMSO-d ) δ 8.28 - 8.10 (m, 1H), 7.99 - 7.69 (m, 2H), 7.59 (br s, 1H), 7.40 - 7.10 (m,
6H), 6.42 - 6.29 (m, 1H), 5.31 (br s, 1H), 3.98 - 3.85 (m, 3H), 3.77 - 3.57 (m, 3H), 3.19 (br d, J =
13.6 Hz, 1H), 2.92 - 2.81 (m, 1H). MS (ESI) m/z (M+H) 381.1.
N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)METHYL(NAPHTHALEN
YL)-1H-PYRAZOLECARBOXAMIDE (569)
Compound 569 (125 mg, yield: 72.0%, off-white solid) was prepared using the
corresponding starting materials, compound ethyl 3-iodomethyl-1H-pyrazolecarboxylate
(198A) and naphthalenylboronic acid, followed by subjecting the resulting intermediate to
procedures such as in compound 12 to obtain compound 569. H NMR (400MHz, DMSO-d ) δ
8.32 (s, 1H), 8.02 (s, 1H) 8.03 - 7.89 (m, 3H), 7.82 (d, J = 7.3 Hz,1H), 7.76 (s, 1H), 7.68 (d, J =
8.4 Hz,1H), 7.53 - 7.44 (m, 2H), 7.40 (dt, J = 1.1, 7.6 Hz ,1H), 7.35 (dd, J = 1.1, 7.1 Hz ,1H),
17681897_1 (GHMatters) P110989.NZ
7.28 - 7.15 (m, 3H), 7.08 - 7.00 (m, 2H), 5.15 (ddd, J = 4.0, 7.4, 9.4 Hz ,1H), 3.96 (s, 3H), 3.04
(dd, J = 3.5, 13.9 Hz ,1H), 2.67 (dd, J = 9.7, 13.7 Hz ,1H). MS (ESI) m/z (M+H) 427.2..
N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)(2,3-
DIHYDROBENZO[b][1,4]DIOXINYL)METHYL-1H-PYRAZOLE
CARBOXAMIDE (570)
Compound 570 (41.8 mg, yield: 45.3%, off-white solid) was prepared using the
corresponding starting materials, compound ethyl 3-iodomethyl-1H-pyrazolecarboxylate
(198A) and (2,3-dihydrobenzo[b][1,4]dioxinyl)boronic acid, followed by subjecting the
resulting intermediate to procedures such as in compound 12 to obtain compound 570. H NMR
(400MHz, DMSO-d ) δ 8.09 - 7.93 (m, 2H), 7.83 - 7.69 (m, 2H), 7.31 - 7.10 (m, 5H), 6.88 - 6.73
(m, 3H), 5.34 - 5.22 (m, 1H), 4.15 - 4.06 (m, 2H), 4.02 - 3.93 (m, 1H), 3.91 - 3.82 (m, 4H), 3.11
(dd, J = 4.0, 13.9 Hz, 1H), 2.79 (dd, J = 9.3, 13.9 Hz, 1H). MS (ESI) m/z (M+H) 435.1.
N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)METHYL(NAPHTHALEN
YL)-1H-PYRAZOLECARBOXAMIDE (571)
Compound 571 (41.8 mg, yield: 45.3%, off-white solid) was prepared using the
corresponding starting materials, compound ethyl 3-iodomethyl-1H-pyrazolecarboxylate
(198A) and naphthalenylboronic acid, followed by subjecting the nresulting intermediate to
procedures such as in compound 12 to obtain compound 571. H NMR (400MHz, DMSO-d ) δ
8.45 (d, J = 7.3 Hz, 1H), 8.18 - 8.06 (m, 3H), 7.92 - 7.81 (m, 4H), 7.72 (dd, J = 1.4, 8.5 Hz, 1H),
7.55 - 7.45 (m, 2H), 7.33 - 7.19 (m, 5H), 5.36 - 5.27 (m, 1H), 3.94 (s, 3H), 3.17 (dd, J = 3.9, 14.0
Hz, 1H), 2.84 (dd, J = 10.0, 13.8 Hz, 1H). MS (ESI) m/z (M+H) 427.1.
N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)(2-
(DIFLUOROMETHYL)PHENYL)METHYL-1H-PYRAZOLECARBOXAMIDE
(572)
Compound 572 (110 mg, yield: 40.9%, light yellow solid) was prepared using
the corresponding starting materials, compound ethyl 3-iodomethyl-1H-pyrazole
carboxylate (198A) and 1-bromo(difluoromethyl)benzene and 4,4,4',4',5,5,5',5'-octamethyl-
2,2'-bi(1,3,2-dioxaborolane) in presence of palladium catalyst, followed by subjecting the
resulting intermediate to procedures such as in compound 12 to obtain compound 572. H NMR
(400MHz, DMSO-d ) δ 8.31 - 8.21 (m, 2H), 8.03 (s, 1H), 7.79 (s, 1H), 7.64 (d, J = 7.5 Hz, 1H),
17681897_1 (GHMatters) P110989.NZ
7.55 - 7.42 (m, 2H), 7.33 - 7.17 (m, 6H), 7.00 - 6.66 (m, 1H), 5.30 - 5.18 (m, 1H), 3.92 (s, 3H),
3.13 (dd, J = 3.6, 13.7 Hz, 1H), 2.79 (dd, J = 10.0, 13.8 Hz, 1H). F NMR (376MHz, DMSO-d )
δ -107.64 - 110.93 (m, 2F). MS (ESI) m/z (M+H) 396.
N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)CYCLOHEXYLMETHYL-1H-
PYRAZOLECARBOXAMIDE (573)
Compound 573 (172 mg, yield: 81.1%, white solid) was prepared using the
corresponding starting materials, compound ethyl 3-iodomethyl-1H-pyrazolecarboxylate
(198A) and 2-(cyclohexenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane followed by
hydrogenolysis of the resulting product which then followed by subjecting the resulting
intermediate to procedures such as in compound 12 to obtain compound 573. H NMR
(400MHz, DMSO-d ) δ 8.11 (d, J = 7.3 Hz, 1H), 8.02 (s, 2H), 7.76 (s, 1H), 7.28 - 7.21 (m, 4H),
7.20 - 7.11 (m, 1H), 5.24 (ddd, J = 3.6, 7.1, 10.3 Hz, 1H), 3.74 (s, 3H), 3.11 (dd, J = 3.7, 13.9
Hz, 1H), 3.05 - 2.96 (m, 1H), 2.79 (dd, J = 10.0, 13.8 Hz, 1H), 1.76 - 1.55 (m, 5H), 1.39 - 1.05
(m, 5H). MS (ESI) m/z (M+ H) 383.3.
N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)(ISOQUINOLINYL)
METHYL-1H-PYRAZOLECARBOXAMIDE (585)
Compound 585 (120 mg, yield: 60.0%, light yellow solid) was prepared using
the corresponding starting materials, compound ethyl 3-iodomethyl-1H-pyrazole
carboxylate (198A) and isoquinolinylboronic acid followed by subjecting the resulting
intermediate to procedures such as in compound 12 to obtain compound 585. H NMR
(400MHz, DMSO-d ) δ 9.28 (s, 1H), 8.56 (d, J = 7.3 Hz, 1H), 8.48 (d, J = 5.8 Hz, 1H), 8.20 (s,
1H), 8.16 - 8.08 (m, 2H), 8.04 (d, J = 8.8 Hz, 1H), 7.90 - 7.77 (m, 3H), 7.29 (d, J = 4.3 Hz, 4H),
7.25 - 7.18 (m, 1H), 5.38 - 5.25 (m, 1H), 3.95 (s, 3H), 3.18 (dd, J = 3.8, 14.1 Hz, 1H), 2.85 (dd, J
= 10.0, 13.8 Hz, 1H). MS (ESI) m/z (M+ H) 428.1.
N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)METHYL(QUINOLINYL)-
1H-PYRAZOLECARBOXAMIDE (587)
Compound 587 (70 mg, yield: 49.7%, light pink solid) was prepared using the
corresponding starting materials, compound ethyl 3-iodomethyl-1H-pyrazolecarboxylate
(198A) and 2-bromoquinoline and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) in
presence of palladium catalyst, followed by subjecting the resulting intermediate to procedures
17681897_1 (GHMatters) P110989.NZ
such as in compound 12 to obtain compound 587. H NMR (400MHz, DMSO-d ) δ 12.08 (br d,
J = 8.0 Hz, 1H), 8.50 (br d, J = 8.8 Hz, 1H), 8.36 (s, 1H), 8.26 (br d, J = 8.8 Hz, 1H), 8.14 (br s,
1H), 8.02 (br d, J = 7.5 Hz, 1H), 7.84 (br s, 1H), 7.74 - 7.59 (m, 3H), 7.07 - 6.90 (m, 5H), 5.75 -
.66 (m, 1H), 3.98 (s, 3H), 3.31 - 3.26 (m, 1H), 3.18 - 3.08 (m, 1H). MS (ESI) m/z (M+H)
428.1.
N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)(ISOQUINOLINYL)
METHYL-1H-PYRAZOLECARBOXAMIDE (591)
Compound 591 (35 mg, yield: 56.3%, white solid) was prepared using the
corresponding starting materials, compound ethyl 3-iodomethyl-1H-pyrazolecarboxylate
(198A) and 4-isoquinolylboronic acid followed by subjecting the resulting intermediate to
procedures such as in compound 12 to obtain compound 591. H NMR (400MHz, DMSO-d ) δ
9.26 (s, 1H), 8.36 - 8.30 (m, 2H), 8.25 - 8.21 (m, 1H), 8.14 - 8.09 (m, 1H), 7.93 (s, 1H), 7.71 (br
s, 1H), 7.68 - 7.60 (m, 3H), 7.27 - 7.20 (m, 2H), 7.19 - 7.13 (m, 3H), 5.17 - 5.09 (m, 1H), 3.95 (s,
3H), 3.09 - 3.02 (m, 1H), 2.77 - 2.69 (m, 1H). MS (ESI) m/z (M+H) 428.1.
N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)METHYL(QUINOLINYL)-
1H-PYRAZOLECARBOXAMIDE (593)
Compound 593 (30 mg, 29.9% yield; pale yellow solid) was prepared using the
corresponding starting materials, compound ethyl 3-iodomethyl-1H-pyrazolecarboxylate
(198A) and quinolinylboronic acid followed by subjecting the resulting intermediate to
procedures such as in compound 12 to obtain compound 593. H NMR (400MHz, DMSO-d ) δ
8.86 (br s, 1H), 8.50 (br.d, J = 6.6 Hz, 1H), 8.31 (br.d, J = 7.9 Hz, 1H), 8.20 (br.s, 1H), 8.09
(br.d, J = 9.5 Hz, 2H), 7.93(br.s, 2H), 7.81 (br s, 1H), 7.53 - 7.47 (m, 1H), 7.30 - 7.15 (m, 5H),
.29 (br.s, 1H), 3.92 (s, 3H), 3.16 (br.d, J = 11.5 Hz, 1H), 2.88 - 2.78 (m, 1H). MS (ESI) m/z
(M+H) 428.1
N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)METHYL(QUINOLINYL)-
1H-PYRAZOLECARBOXAMIDE (597)
Compound 597 (20 mg, yield: 25.1%, yellow solid) was prepared using the
corresponding starting materials, compound ethyl 3-iodomethyl-1H-pyrazolecarboxylate
(198A) and quinolinylboronic acid followed by subjecting the resulting intermediate to
procedures such as in compound 12 to obtain compound 597. H NMR (400MHz, DMSO-d ) δ
17681897_1 (GHMatters) P110989.NZ
8.88 (dd, J = 1.8, 4.0 Hz, 1H), 8.34 - 8.19 (m, 1H), 8.17 - 7.97 (m, 2H), 7.81 - 7.35 (m, 6H), 7.27
- 7.03 (m, 5H), 5.29 - 5.11 (m, 1H), 4.02 - 3.90 (m, 3H), 3.07 - 3.0 (m, 1H), 2.80 - 2.74 (m, 1H).
MS (ESI) m/z (M+ H) 428.1.
N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)(ISOQUINOLINYL)
METHYL-1H-PYRAZOLECARBOXAMIDE (602)
Compound 602 (55 mg, yield: 36.3%, white solid) was prepared using the
corresponding starting materials, compound ethyl 3-iodomethyl-1H-pyrazolecarboxylate
(198A) and 3-bromoisoquinoline and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) in
presence of palladium catalyst, followed by subjecting the resulting intermediate to procedures
such as in compound 12 to obtain compound 602. H NMR (400MHz, DMSO-d ) δ 12.07 (d, J
= 7.1 Hz, 1H), 8.98 (s, 1H), 8.51 (s, 1H), 8.28 (s, 1H), 8.10 (d, J = 7.5 Hz, 3H), 7.89 - 7.79 (m,
2H), 7.75 - 7.67 (m, 1H), 7.15 - 7.06 (m, 4H), 7.04 - 6.97 (m, 1H), 5.64 - 5.53 (m, 1H), 4.03 -
3.84 (m, 3H), 3.27 (dd, J = 5.0, 14.0 Hz, 1H), 3.10 (dd, J = 7.7, 14.1 Hz, 1H). MS (ESI) m/z
(M+ H) 428.2.
N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)(2-CHLOROPHENYL)
METHYL-1H-PYRAZOLECARBOXAMIDE (604)
Compound 604 (120 mg, yield: 58.6%, pale yellow solid) was prepared using
the corresponding starting materials, compound ethyl 3-iodomethyl-1H-pyrazole
carboxylate (198A) and (2-chlorophenyl)boronic acid followed by subjecting the resulting
intermediate to procedures such as in compound 12 to obtain compound 604. H NMR
(400MHz, DMSO-d ) δ 8.19 (s, 1H), 8.03 (d, J = 7.3 Hz, 1H), 7.97 (s, 1H), 7.73 (s, 1H), 7.39 -
7.15 (m, 9H), 5.24 - 5.19 (m, 1H), 3.87 (s, 3H), 3.08 (dd, J = 3.6, 14.0 Hz, 1H), 2.76 (dd, J = 9.8,
14.0 Hz, 1H). MS (ESI) m/z (M+ H) 411.1.
N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)METHYL(QUINOLINYL)-
1H-PYRAZOLECARBOXAMIDE (605)
Compound 605 (140 mg, yield: 55.6%, white solid) was prepared using the
corresponding starting materials, compound ethyl 3-iodomethyl-1H-pyrazolecarboxylate
(198A) and quinolinylboronic acid followed by subjecting the resulting intermediate to
procedures such as in compound 12 to obtain compound 605. H NMR (400MHz, DMSO-d ) δ
9.08 (s, 1H), 8.65 - 8.45 (m, 2H), 8.23 (s, 1H), 8.08 (br s, 1H),7.99 (dd, J = 8.3, 12.7 Hz, 2H),
17681897_1 (GHMatters) P110989.NZ
7.85 - 7.70 (m, 2H), 7.60 (t, J = 7.4 Hz, 1H), 7.34 - 7.13 (m, 5H), 5.36 - 5.20 (m, 1H), 4.05 - 3.89
(m, 3H), 3.18 - 2.78 (m, 2H). MS (ESI) m/z (M+ H) 428.2.
N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)(ISOQUINOLINYL)
METHYL-1H-PYRAZOLECARBOXAMIDE (607)
Compound 607 (50 mg, yield: 34.6%, white solid) was prepared using the
corresponding starting materials, compound ethyl 3-iodomethyl-1H-pyrazolecarboxylate
(198A) and isoquinolinylboronic acid followed by subjecting the resulting intermediate to
procedures such as in compound 12 to obtain compound 607. H NMR (400MHz, DMSO-d ) δ
9.41 - 9.21 (m, 1H), 8.52 - 8.27 (m, 2H), 8.23 - 7.93 (m, 3H), 7.81 - 7.48 (m, 4H), 7.32 - 7.09 (m,
5H), 5.22 - 5.10 (m, 1H), 4.06 - 3.90 (m, 3H), 3.09 (dd, J = 3.2, 13.8 Hz, 1H), 2.76 (dd, J = 9.8,
13.8 Hz, 1H). MS (ESI) m/z (M+ H) 428.1.
N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)METHYL(QUINOLINYL)-
1H-PYRAZOLECARBOXAMIDE (611)
Compound 611 (55 mg, yield: 78.2%, light yellow solid) was prepared using
the corresponding starting materials, compound ethyl 3-iodomethyl-1H-pyrazole
carboxylate (198A) and quinolinylboronic acid followed by subjecting the resulting
intermediate to procedures such as in compound 12 to obtain compound 611. H NMR
(400MHz, DMSO-d ) δ 8.86 - 8.76 (m, 1H), 8.41 - 8.34 (m, 1H), 8.07 - 7.88 (m, 2H), 7.85 - 7.58
(m, 3H), 7.49 (t, J = 7.8 Hz, 1H), 7.33 - 7.11 (m, 7H), 5.21 - 5.11 (m, 1H), 4.30 (br s, 1H), 4.04 -
3.93 (m, 3H), 3.10 (dd, J = 3.5, 14.1 Hz, 1H), 2.78 (dd, J = 10.1, 13.9 Hz, 1H). MS (ESI) m/z
(M+ H) 428.1.
N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)METHYL(THIOPHENYL)-
1H-PYRAZOLECARBOXAMIDE (615)
Compound 615 (122 mg, yield: 73.0%, white solid) was prepared using the
corresponding starting materials, compound 1-methyl(thiophenyl)-1H-pyrazole
carboxylic acid and 3-aminohydroxyphenylbutanamide hydrochloride using the procedures
such as in compound 12 to obtain compound 615. H NMR (400MHz, DMSO-d ) δ 8.42 (d, J =
7.3 Hz, 1H), 8.10 (s, 1H), 8.06 (s, 1H), 7.79 (s, 1H), 7.73 (d, J = 3.5 Hz, 1H), 7.41 (dd, J = 1.1,
.1 Hz, 1H), 7.28 (d, J = 4.2 Hz, 4H), 7.24 - 7.18 (m, 1H), 6.97 (dd, J = 3.6, 5.0 Hz, 1H), 5.49 -
17681897_1 (GHMatters) P110989.NZ
.20 (m, 1H), 3.85 (s, 3H), 3.16 (dd, J = 3.5, 13.9 Hz, 1H), 2.83 (dd, J = 10.1, 13.9 Hz, 1H). MS
(ESI) m/z (M+ H) 383.1.
N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)CYCLOPROPYLMETHYL-
1H-PYRAZOLECARBOXAMIDE (616)
Compound 616 (120 mg, yield: 71.5%, white solid) was prepared using the
corresponding starting materials, compound 3-cyclopropylmethyl-1H-pyrazolecarboxylic
acid and 3-aminohydroxyphenylbutanamide hydrochloride using the procedures such as in
compound 12 to obtain compound 616. H NMR (400MHz, DMSO-d ) δ 8.08 (d, J = 7.5 Hz,
1H), 8.04 (s, 1H), 8.03 (br s, 1H), 7.77 (s, 1H), 7.27 (d, J = 4.4 Hz, 4H), 7.20 - 7.16 (m, 1H), 5.31
- 5.26 (m, 1H), 3.71 (s, 3H), 3.15 (dd, J = 3.9, 13.8 Hz, 1H), 2.84 (dd, J = 9.9, 13.9 Hz, 1H), 2.41
- 2.35 (m, 1H), 0.77 - 0.70 (m, 2H), 0.69 - 0.65 (m, 2H). MS (ESI) m/z (M+H) 341.2.
N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)METHYL(TETRAHYDRO-2H-
PYRANYL)-1H-PYRAZOLECARBOXAMIDE (617)
Compound 617 (55 mg, yield: 34.4%, white solid) was prepared using the
corresponding starting materials, compound 1-methyl(tetrahydro-2H-pyranyl)-1H-pyrazole-
4-carboxylic acid and 3-aminohydroxyphenylbutanamide hydrochloride using the
procedures such as in compound 12 to obtain compound 617. H NMR (400MHz, DMSO-d ) δ
8.20 (d, J = 7.5 Hz, 1H), 8.07 (s, 1H), 8.01 (s, 1H), 7.75 (s, 1H), 7.30 - 7.21 (m, 4H), 7.19 - 7.14
(m, 1H), 5.31 - 5.15 (m, 1H), 3.80 (d, J = 9.5 Hz, 2H), 3.76 (s, 3H), 3.29 - 3.20 (m, 3H), 3.11
(dd, J = 3.5, 13.9 Hz, 1H), 2.79 (dd, J = 10.0, 13.8 Hz, 1H), 1.65 - 1.52 (m, 4H). MS (ESI) m/z
(M+H) 385.1.
N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)CYCLOPENTYLMETHYL-
1H-PYRAZOLECARBOXAMIDE (620)
Compound 620 (70 mg, yield: 53.1%, white solid) was prepared using the
corresponding starting materials, compound 3-cyclopentylmethyl-1H-pyrazolecarboxylic
acid and 3-aminohydroxyphenylbutanamide hydrochloride using the procedures such as in
compound 12 to obtain compound 620. H NMR (400MHz, DMSO-d ) δ 8.14 (br d, J = 7.3 Hz,
1H), 8.06 - 8.02 (m, 2H), 7.77 (br.s, 1H), 7.29 (d, J = 4.3 Hz, 4H), 7.24 - 7.17 (m, 1H), 5.29 -
.21(m, 1H), 3.77 (s, 3H), 3.42 (br.t, J = 8.0 Hz, 1H), 3.14 (br.dd, J = 3.5, 13.8 Hz, 1H), 2.83
17681897_1 (GHMatters) P110989.NZ
(br.dd, J = 10.2, 13.4 Hz, 1H), 1.80 (br.d, J = 7.8 Hz, 2H), 1.69 - 1.45 (m, 6H). MS (ESI) m/z
(M+H) 369.2.
N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)(5-CHLOROTHIOPHENYL)
METHYL-1H-PYRAZOLECARBOXAMIDE (621)
Compound 621 (25 mg, yield: 25.1%, pale-yellow solid) was prepared using
the corresponding starting materials, compound 3-(5-chlorothiophenyl)methyl-1H-
pyrazolecarboxylic acid and 3-aminohydroxyphenylbutanamide hydrochloride using the
procedures such as in compound 12 to obtain compound 621. H NMR (400MHz, DMSO-d ) δ
8.53 (br d, J = 6.8 Hz, 1H), 8.22 - 8.04 (m, 2H), 7.87 - 7.61 (m, 2H), 7.35 - 6.97 (m, 6H), 5.33
(br s, 1H), 3.88 (br s, 3H), 3.19 (br d, J = 14.1 Hz, 1H), 2.92 - 2.79 (m, 1H). MS (ESI) m/z
(M+H) 417.0.
TERT-BUTYL 3-(4-((4-AMINO-3,4-DIOXOPHENYLBUTANYL)CARBAMOYL)
METHYL-1H-PYRAZOLYL)PIPERIDINECARBOXYLATE (624)
Compound 624 (100 mg, yield: 33.04%, white solid) was prepared using the
corresponding starting materials, compound 3-(1-(tert-butoxycarbonyl)piperidinyl)methyl-
1H-pyrazolecarboxylic acid and 3-aminohydroxyphenylbutanamide hydrochloride using
the procedures such as in compound 12 to obtain compound 624. H NMR (400MHz, DMSO-
d ) δ 8.27 - 8.18 (m, 1H), 8.12 (s, 1H), 8.02 (d, J = 2.9 Hz, 1H), 7.78 (s, 1H), 7.32 - 7.13 (m, 5H),
.29 (s, 1H), 4.02 - 3.85 (m, 2H), 3.82 - 3.75 (m, 3H), 3.20 - 3.09 (m, 2H), 3.19 - 2.99 (m, 1H),
2.99 - 2.78 (m, 2H), 2.73 - 2.64 (m, 1H), 1.84 (s, 1H), 1.62 (s, 1H), 1.48 (d, J = 11.9 Hz, 1H),
1.39 - 1.27 (m, 10H). MS (ESI) m/z (M+H) 484.2.
N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)(3,4-DIHYDRO-2H-
BENZO[b][1,4]DIOXEPINYL)METHYL-1H-PYRAZOLECARBOXAMIDE (625)
Compound 625 (70 mg, yield: 58.6%, yellow solid) was prepared using the
corresponding starting materials, compound 3-(3,4-dihydro-2H-benzo[b][1,4]dioxepinyl)
methyl-1H-pyrazolecarboxylic acid and 3-aminohydroxyphenylbutanamide
hydrochloride using the procedures such as in compound 12 to obtain compound 625. H NMR
(400MHz, DMSO-d ) δ 8.29 (d, J = 7.3 Hz, 1H), 8.09 - 7.94 (m, 2H), 7.80 (s, 1H), 7.32 - 7.14
(m, 7H), 6.90 - 6.83 (m, 1H), 5.39 - 5.22 (m, 1H), 4.16 - 4.07 (m, 4H), 3.88 - 3.82 (m, 3H), 3.16
17681897_1 (GHMatters) P110989.NZ
(dd, J = 4.0, 13.7 Hz, 1H), 2.82 (dd, J = 9.8, 13.8 Hz, 1H), 2.13 - 2.06 (m, 2H). MS (ESI) m/z
(M+H) 449.1.
N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)-1,1'-DIMETHYL-1H,1'H-[3,4'-
BIPYRAZOLE]CARBOXAMIDE (626)
Compound 626 (55 mg, yield: 34.4%, white solid) was prepared using the
corresponding starting materials, compound 1,1'-dimethyl-1H,1'H-[3,4'-bipyrazole]carboxylic
acid and 3-aminohydroxyphenylbutanamide hydrochloride using the procedures such as in
compound 12 to obtain compound 626. H NMR (400MHz, DMSO-d ) δ 8.06 (d, J = 17.6 Hz,
2H), 7.94 (s, 1H), 7.76 - 7.45 (m, 3H), 7.31 - 7.23 (m, 4H), 7.23 - 7.15 (m, 1H), 5.37 - 5.28 (m,
1H), 3.83 (d, J = 8.3 Hz, 6H), 3.22 (dd, J = 4.1, 13.7 Hz, 1H), 2.95 (dd, J = 8.9, 14.4 Hz, 1H).
MS (ESI) m/z (M+H) 381.2.
N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)METHYL
(TETRAHYDROFURANYL)-1H-PYRAZOLECARBOXAMIDE (627)
Compound 627 (40 mg, yield: 25.1%, pale yellow solid) was prepared using
the corresponding starting materials, compound 1-methyl(tetrahydrofuranyl)-1H-pyrazole-
4-carboxylic acid and 3-aminohydroxyphenylbutanamide hydrochloride using the
procedures such as in compound 12 to obtain compound 627. H NMR (400MHz, DMSO-d ) δ
8.06 (s, 1H), 8.00 - 7.87 (m, 1H), 7.69 (s, 0.5H), 7.57 - 7.44 (m, 0.7H), 7.30 - 7.03 (m, 6H), 5.33
- 5.23 (m, 1H), 3.92 (dt, J = 2.6, 7.7 Hz, 1H), 3.86 - 3.81 (m, 1H), 3.79 (s, 3H), 3.77 - 3.73 (m,
1H), 3.71 (d, J = 7.8 Hz, 1H), 3.62 - 3.54 (m, 1H), 3.20 (dd, J = 4.3, 14.1 Hz, 1H), 2.96 - 2.88
(m, 1H), 2.09 (q, J = 7.3 Hz, 2H). MS (ESI) m/z (M+H) 371.2.
N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)(BENZOFURANYL)
METHYL-1H-PYRAZOLECARBOXAMIDE (628)
Compound 628 (143 mg, yield: 98.6%, white solid) was prepared using the
corresponding starting materials, compound 3-(benzofuranyl)methyl-1H-pyrazole
carboxylic acid and 3-aminohydroxyphenylbutanamide hydrochloride using the procedures
such as in compound 12 to obtain compound 628. H NMR (400MHz, DMSO-d ) δ 8.56 (d, J =
7.3 Hz, 1H), 8.24 (s, 1H), 8.10 (s, 1H), 7.82 (s, 1H), 7.63 (d, J = 6.8 Hz, 1H), 7.56 - 7.50 (m,
2H), 7.33 - 7.15 (m, 7H), 5.36 (ddd, J = 3.9, 7.3, 9.8 Hz, 1H), 3.94 (s, 3H), 3.24 - 3.14 (m, 1H),
2.87 (dd, J = 10.0, 14.0 Hz, 1H). MS (ESI) m/z (M+H) 417.1.
17681897_1 (GHMatters) P110989.NZ
N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)(ISOQUINOLINYL)
METHYL-1H-PYRAZOLECARBOXAMIDE (629)
Compound 629 (25 mg, yield: 50.14%, pale yellow solid) was prepared using
the corresponding starting materials, compound ethyl 3-iodomethyl-1H-pyrazole
carboxylate (198A) and 7-bromoisoquinoline and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-
dioxaborolane) in presence of palladium catalyst, followed by subjecting the resulting
intermediate to procedures such as in compound 12 to obtain compound 629. H NMR
(400MHz, DMSO-d ) δ 9.27 (s, 1H), 8.54 (d, J = 7.5 Hz, 1H), 8.49 (d, J = 5.7 Hz, 1H), 8.35 (s,
1H), 8.15 (s, 1H), 8.11 (s, 1H), 8.00 - 7.94 (m, 1H), 7.92 - 7.87 (m, 1H), 7.85 - 7.78 (m, 2H),
7.30 - 7.17 (m, 5H), 5.36 - 5.26 (m, 1H), 3.95 (s, 3H), 3.18 (dd, J = 4.0, 13.9 Hz, 1H), 2.85 (dd, J
= 9.9, 13.9 Hz, 1H). MS (ESI) m/z (M+ H) 428.2.
BENZYL 4-(4-((4-AMINO-3,4-DIOXOPHENYLBUTANYL)CARBAMOYL)
METHYL-1H-PYRAZOLYL)PIPERAZINECARBOXYLATE (601)
O O O O
I O N
N O O
, , Cs CO
Pd(OAc) Sphos
2 2 3
198A
N N NH
100 C
1,4-dioxane, N 2
601A
To the solution of compound 198A (500 mg, 1.79 mmol) and benzyl
piperazinecarboxylate (590 mg, 2.68 mmol) in 1,4-dioxane (20 mL) was added Pd(OAc) (40
mg, 0.18 mmol), Cs CO (116 mg, 3.57 mmol) and Sphos (147 mg, 0.36 mmol) under N
2 3 2
atmosphere. The reaction was stirred at 100 °C for 16 h. The reaction mixture was filtered and
washed with EtOAc (10 mL). The organic phase was concentrated under reduced pressure to
give a residue. The residue was purified on Combi flash (eluent: PE ~ 10% ~ 30% EtOAc/PE) to
afford the compound 601A (183 mg, yield 25.7%) as a yellow oil.
Compound 601 (55 mg, yield: 78.8%, pink solid) was prepared using the
corresponding starting materials, compound benzyl 4-(4-(ethoxycarbonyl)methyl-1H-pyrazol-
3-yl)piperazinecarboxylate (601A) and 3-aminohydroxyphenylbutanamide
hydrochloride using the procedures such as in compound 12 to obtain compound 601. H NMR
17681897_1 (GHMatters) P110989.NZ
(400MHz, DMSO-d ) δ 8.28 - 8.15 (m, 2H), 8.03 (s, 1H), 7.92 (s, 1H), 7.43 - 7.33 (m, 5H), 7.28
- 7.21 (m, 2H), 7.19 - 7.13 (m, 1H), 7.06 (d, J = 7.0 Hz, 2H), 5.53 (q, J = 6.3 Hz, 1H), 5.13 - 5.04
(m, 2H), 3.79 - 3.68 (m, 3H), 3.33 - 3.18 (m, 5H), 3.17 - 3.08 (m, 1H), 2.86 (br s, 2H), 2.81 -
2.75 (m, 2H). MS (ESI) m/z (M+H) 519.2.
TERT-BUTYL 4-(4-((4-AMINO-3,4-DIOXOPHENYLBUTANYL)CARBAMOYL)
METHYL-1H-PYRAZOLYL)PIPERAZINECARBOXYLATE (603)
Intermediate 603A was prepared using the same procedure as for intermediate
601A using tert-butyl piperazinecarboxylate.
Compound 603 (18 mg, yield: 41.6%, white solid) was prepared using the
corresponding starting materials, compound tert-butyl 4-(4-(ethoxycarbonyl)methyl-1H-
pyrazolyl)piperazinecarboxylate (603A) and 3-aminohydroxyphenylbutanamide
hydrochloride using the procedures such as in compound 12 to obtain compound 603. H NMR
(400MHz, DMSO-d ) δ 8.07 (d, J = 7.5 Hz, 1H), 7.98 - 7.81 (m, 2H), 7.80 - 7.61 (m, 1H), 7.30 -
7.24 (m, 2H), 7.22 - 7.19 (m, 1H), 7.13 (d, J = 7.5 Hz, 2H), 5.56 - 5.45 (m, 1H), 3.76 - 3.67 (m,
3H), 3.42 (br s, 1H), 3.35 - 3.28 (m, 2H), 3.27 - 3.21 (m, 2H), 3.15 - 3.13 (m, 1H), 2.88 (d, J =
6.3 Hz, 2H), 2.84 - 2.77 (m, 2H), 1.44 (s, 9H). MS (ESI) m/z (M+H) 485.2.
N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)(1,1-
DIOXIDOTHIOMORPHOLINO)METHYL-1H-PYRAZOLECARBOXAMIDE
(613)
Intermediate 613A was prepared using the same procedure as for intermediate
601A using thiomorpholine 1,1-dioxide.
Compound 613 (70 mg, yield: 33.7%, light yellow solid) was prepared using
the corresponding starting materials, compound ethyl 3-(1,1-dioxidothiomorpholino)methyl-
1H-pyrazolecarboxylate (613A) and 3-aminohydroxyphenylbutanamide hydrochloride
using the procedures such as in compound 12 to obtain compound 613. H NMR (400MHz,
DMSO-d ) δ 8.15 (d, J = 7.0 Hz, 2H), 8.05 (s, 1H), 7.87 (s, 1H), 7.31 - 7.26 (m, 2H), 7.23 (br d,
J = 7.0 Hz, 1H), 7.16 (d, J = 6.8 Hz, 2H), 5.48 - 5.31 (m, 1H), 3.75 (s, 3H), 3.42 (m, 4H), 3.25 -
3.20 (m, 1H), 3.14 - 3.07 (m, 2H), 3.06 - 2.98 (m, 3H). MS (ESI) m/z (M+H) 434.1.
17681897_1 (GHMatters) P110989.NZ
N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)METHYLMORPHOLINO-1H-
PYRAZOLECARBOXAMIDE (614)
Intermediate 614A was prepared using the same procedure as for intermediate
601A using morpholine.
Compound 614 (45 mg, yield: 86.3%, yellow solid) was prepared using the
corresponding starting materials, compound ethyl 1-methylmorpholino-1H-pyrazole
carboxylate (614A) and 3-aminohydroxyphenylbutanamide hydrochloride using the
procedures such as in compound 12 to obtain compound 614. H NMR (400MHz, DMSO-d ) δ
8.21 - 8.11 (m, 2H), 7.98 (s, 1H), 7.91 - 7.84 (m, 1H), 7.26 - 7.21 (m, 2H), 7.18 (s, 1H), 7.07 (d,
J = 6.8 Hz, 2H), 5.52 - 5.44 (m, 1H), 3.71 (s, 3H), 3.55 - 3.47 (m, 2H), 3.46 - 3.39 (m, 2H), 3.23
(dd, J = 5.3, 14.1 Hz, 1H), 3.06 (dd, J = 7.1, 14.1 Hz, 1H), 2.89 - 2.82 (m, 2H), 2.80 - 2.75 (m,
2H). MS (ESI) m/z (M+H) 386.2.
EXAMPLE 97
COMPOUNDS 165-167, 170-173, 176-190, 315, 407, 408, 446, 447
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)METHYL(PYRIDINYL)-
1H-PYRAZOLECARBOXAMIDE (165)
Br O O
N NH
N NH
N 2 N 2
, K CO , dioxane, H O
Pd(dppf)Cl
2 2 3 2 OH
N OH N
165A
163E
To a mixture of compound 163E (200 mg, 525 umol), 4-pyridylboronic acid
(129 mg, 1.05 mmol) and K CO (218 mg, 1.57 mmol) in dioxane (9 mL) and H O (1 mL) was
2 3 2
added Pd(dppf)Cl (76.8 mg, 105 umol) under N . The mixture was stirred at 130 °C under
microwave conditions for 2h. The solvent was removed under vacuum. The residue was purified
by prep-TLC (Dichloromethane: Methanol = 10: 1, R = 0.5) to give 165A (90 mg, yield: 45.2%)
as a white solid. Compound 165A: H NMR (400 MHz, DMSO-d ) δ 8.55 - 8.70 (m, 2H), 7.96
(br dd, J = 15.55, 5.40 Hz, 1H), 7.79 (br d, J = 7.94 Hz, 1H), 7.03 - 7.44 (m, 10H), 5.74 - 5.87
(m, 1H), 4.25 - 4.45 (m, 1H), 3.75 - 4.02 (m, 1H), 3.68 (br t, J = 5.40 Hz, 3H), 2.57 - 2.91 (m,
3H).
17681897_1 (GHMatters) P110989.NZ
Compound 165 was prepared as in Example 61 from the corresponding
intermediate compound 165A. Compound 165: H NMR (400 MHz, DMSO-d ) δ 8.60 - 8.65 (m,
2H), 8.40 (d, J = 7.50 Hz, 1H), 8.00 (s, 2H), 7.77 (s, 1H), 7.32 - 7.36 (m, 2H), 7.18 - 7.31 (m,
5H), 5.14 - 5.25 (m, 1H), 3.68 (s, 3H), 3.14 (dd, J = 13.89, 3.75 Hz, 1H), 2.83 (dd, J = 13.67,
.14 Hz, 1H). MS (ESI) m/z (M+H) 378.1.
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)METHYL(p-TOLYL)-1H-
PYRAZOLECARBOXAMIDE (166)
Compound 166 (17.5 mg, yield: 27.9%, off-white solid) was prepared as in
Example 97 from the corresponding starting materials, compound 163G and p-tolylboronic acid.
Compound 166: H NMR (400MHz, DMSO-d ) δ 8.28 (d, J = 7.3 Hz, 1H), 8.09 - 7.99 (m, 2H),
7.81 (br s, 1H), 7.46 (d, J = 8.2 Hz, 2H), 7.33 - 7.19 (m, 5H), 7.11 (d, J = 7.9 Hz, 2H), 5.33 -
.23 (m, 1H), 3.93 - 3.81 (m, 3H), 3.15 (dd, J = 3.6, 13.8 Hz, 1H), 2.82 (dd, J = 10.0, 13.8 Hz,
1H), 2.30 (s, 3H). MS (ESI) m/z (M+H) 391.1.
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)METHYL(p-TOLYL)-1H-
PYRAZOLECARBOXAMIDE (167)
Compound 167 (40.0 mg, yield: 66.9%, white solid) was prepared as in
Example 97 from the corresponding starting materials, compound 163E and p-tolylboronic acid.
Compound 167: H NMR (400MHz, DMSO-d ) δ 7.98 - 7.91 (m, 2H), 7.89 (s, 1H), 7.73 (s, 1H),
7.30 - 7.08 (m, 9H), 5.24 - 5.11 (m, 1H), 3.58 (s, 3H), 3.08 (dd, J = 3.6, 14.0 Hz, 1H), 2.77 (dd, J
= 9.8, 13.6 Hz, 1H), 2.32 (s, 3H). MS (ESI) m/z (M+H) 391.1.
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)METHYL(PYRIDIN
YL)-1H-PYRAZOLECARBOXAMIDE (170)
Compound 170 (15.6 mg, yield: 17.3%, off-white solid) was prepared as in
Example 97 from the corresponding starting materials, compound 163G and 4-pyridylboronic
acid. Compound 170: H NMR (400 MHz, DMSO-d ) δ 8.61 (br d, J = 7.50 Hz, 1H), 8.49 (d, J =
4.85 Hz, 2H), 8.03 - 8.15 (m, 2H), 7.82 (br s, 1H), 7.56 (d, J = 4.85 Hz, 2H), 7.19 - 7.34 (m, 5H),
.22 - 5.36 (m, 1H), 3.87 - 3.96 (m, 3H), 3.18 (br dd, J = 14.00, 3.42 Hz, 1H), 3.12 - 3.22 (m,
1H), 2.83 (br dd, J = 13.56, 10.25 Hz, 1H). MS (ESI) m/z (M+H O+H) 396.1.
17681897_1 (GHMatters) P110989.NZ
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)METHYL(o-TOLYL)-1H-
PYRAZOLECARBOXAMIDE (171)
Compound 171 (16 mg, 41 umol, yield: 14.6%, purity: 100.0%, white solid)
was prepared as in Example 97 from the corresponding starting materials, compound 163G and
o-tolylboronic acid. Compound 171: H NMR (400MHz, CDCl ) δ 7.95 (s, 1H), 7.38 - 7.33 (m,
1H), 7.30 - 7.26 (m, 1H), 7.25 - 7.21 (m, 2H), 7.19 - 7.12 (m, 3H), 6.75 - 6.71 (m, 2H), 6.68 (br
s, 1H), 5.81 (br d, J = 5.7 Hz, 1H), 5.57 (br s, 1H), 5.47 - 5.39 (m, 1H), 3.94 - 3.87 (m, 3H), 3.15
(dd, J = 4.4, 14.1 Hz, 1H), 2.62 (dd, J = 8.5, 14.2 Hz, 1H), 2.11 (s, 3H). MS (ESI) m/z (M+H)
391.1.
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)METHYL(m-TOLYL)-1H-
PYRAZOLECARBOXAMIDE (172)
Compound 172 (25.3 mg, yield: 21.2%, yellow solid) was prepared as in
Example 97 from the corresponding starting materials, compound 163E and m-tolylboronic acid.
Compound 172: H NMR (400MHz, DMSO-d ) δ 7.98 (br s, 1H), 7.91 (s, 1H), 7.88 (br d, J =
7.3 Hz, 1H), 7.75 (br s, 1H), 7.33 - 7.21 (m, 4H), 7.20 - 7.10 (m, 4H), 7.07 (br d, J = 7.3 Hz, 1H),
.19 (br s, 1H), 3.58 (s, 3H), 3.09 (br dd, J = 3.3, 13.7 Hz, 1H), 2.77 (br dd, J = 9.7, 13.7 Hz,
1H), 2.29 (s, 3H). MS (ESI) m/z (M+H) 391.1.
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)METHYL(PYRIMIDIN
YL)-1H-PYRAZOLECARBOXAMIDE (173)
Compound 173 (6.9 mg, yield: 18.6%, light yellow solid) was prepared as in
Example 97 from the corresponding starting materials, compound 163G and pyrimidin
ylboronic acid. Compound 173: H NMR (400MHz, DMSO-d ) δ 9.15 - 9.06 (m, 1H), 8.97 -
8.77 (m, 1H), 8.62 (d, J = 7.5 Hz, 1H), 8.34 - 8.22 (m, 1H), 8.09 (s, 1H), 7.86 - 7.62 (m, 1H),
7.40 - 7.07 (m, 6H), 5.36 - 5.25 (m, 1H), 3.98 - 3.90 (m, 3H), 3.17 (dd, J = 4.0, 13.7 Hz, 1H),
2.83 (br dd, J = 10.3, 13.8 Hz, 1H). MS (ESI) m/z (M+H) 379.1.
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)METHYL(PYRIMIDIN
YL)-1H-PYRAZOLECARBOXAMIDE (176)
Compound 176 (15 mg, yield: 12.19%, white solid) was prepared as in
Example 97 from the corresponding starting materials, compound 163E and pyrimidin
ylboronic acid. H NMR (400MHz, CD CN) δ 9.24 - 9.17 (m, 1H), 8.77 - 8.68 (m, 1H), 7.87 (s,
17681897_1 (GHMatters) P110989.NZ
1H), 7.61 (s, 1H), 7.34 - 7.18 (m, 5H), 6.97 (br s, 2H), 6.24 - 6.09 (m, 1H), 5.38 - 5.33 (m, 1H),
3.73 (s, 3H), 3.25 (dd, J = 5.0, 14.0 Hz, 1H), 2.92 (dd, J = 9.0, 13.9 Hz, 1H). MS (ESI) m/z
(M+H) 379.1.
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)(3-METHOXYPHENYL)
METHYL-1H-PYRAZOLECARBOXAMIDE (177)
Compound 177 (46 mg, yield: 74.2%, white solid) was prepared as in Example
97 from the corresponding starting materials, compound 163G and (3-methoxyphenyl) boronic
acid. Compound 177: H NMR (400MHz, DMSO-d ) δ 8.02 (s, 1H), 7.85 (br d, J = 7.3 Hz, 1H),
7.78 - 7.65 (m, 1H), 7.54 (br s, 1H), 7.30 - 7.25 (m, 3H), 7.24 - 7.18 (m, 5H), 6.92 - 6.87 (m,
1H), 5.38 -5.31 (m, 1H), 3.89 (s, 3H), 3.78 - 3.74 (m, 3H), 3.20 (dd, J=4.5, 14.1 Hz, 1H), 2.90
(dd, J=9.0, 14.1 Hz, 1H).
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)(3-FLUOROPHENYL)
METHYL-1H-PYRAZOLECARBOXAMIDE (178)
Compound 178 (26 mg, yield: 49.4% white solid) was prepared as in Example
97 from the corresponding starting materials. H NMR (400MHz, DMSO-d ) δ 8.46 (br d, J =
7.3 Hz, 1H), 8.07 (s, 2H), 7.80 (br s, 1H), 7.42 (d, J = 8.2 Hz, 2H), 7.36 - 7.31 (m, 1H), 7.30 -
7.25 (m, 4H), 7.22 - 7.18 (m, 1H), 7.11 (br t, J = 8.3 Hz, 1H), 5.33 - 5.25 (m, 1H), 3.88 (s, 3H),
3.15 (br dd, J = 3.5, 13.7 Hz, 1H), 2.80 (dd, J = 10.1, 13.9 Hz, 1H). MS (ESI) m/z (M+H)
395.1.
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)(4-FLUOROPHENYL)
METHYL-1H-PYRAZOLECARBOXAMIDE (179)
Compound 179 (15 mg, yield: 36.7%, light yellow solid) was prepared as in
Example 97 from the corresponding starting materials. H NMR (400MHz, DMSO-d ) δ 8.42 (d,
J = 7.5 Hz, 1H), 8.07 (s, 2H), 7.81 (s, 1H), 7.61 (dd, J = 5.7, 8.8 Hz, 2H), 7.34 - 7.19 (m, 5H),
7.12 (br t, J = 8.9 Hz, 2H), 5.37 - 5.22 (m, 1H), 3.89 (s, 3H), 3.16 (br dd, J = 3.5, 14.1 Hz, 1H),
2.82 (br dd, J = 10.1, 13.7 Hz, 1H). MS (ESI) m/z (M+H) 395.1.
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)(3-ISOPROPYLPHENYL)
METHYL-1H-PYRAZOLECARBOXAMIDE (180)
Compound 180 (58 mg, yield: 60.95%, white solid) was prepared as in
Example 97 from the corresponding starting materials. H NMR (400MHz, DMSO-d ) δ 8.29 (d,
17681897_1 (GHMatters) P110989.NZ
J = 7.5 Hz, 1H), 8.11 - 7.98 (m, 2H), 7.81 (s, 1H), 7.48 (s, 1H), 7.37 - 7.16 (m, 9H), 5.38 - 5.23
(m, 1H), 3.89 (s, 3H), 3.15 (dd, J = 3.6, 14.0 Hz, 1H), 2.91 - 2.77 (m, 3H), 1.18 (d, J = 6.8 Hz,
6H). MS (ESI) m/z (M+H) 419.2..
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)(2-FLUOROPHENYL)
METHYL-1H-PYRAZOLECARBOXAMIDE (181)
Compound 181 (46 mg, yield: 70.7%, white solid) was prepared as in Example
97 from the corresponding starting materials. H NMR (400MHz, DMSO-d ) δ 8.26 - 8.16 (m,
2H), 8.01 (s, 1H), 7.77 (s, 1H), 7.43 - 7.07 (m, 9H), 5.28 - 5.18 (m, 1H), 3.96 - 3.85 (m, 3H),
3.12 (dd, J = 3.6, 14.0 Hz, 1H), 2.81 (dd, J = 9.7, 13.9 Hz, 1H). MS (ESI) m/z (M+H) 395.1.
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)(3-ETHYLPHENYL)
METHYL-1H-PYRAZOLECARBOXAMIDE (182)
Compound 182 (24 mg, yield: 65.4%, white solid) was prepared as in Example
97 from the corresponding starting materials. H NMR (400MHz, DMSO-d ) δ 8.13 (s, 1H),
7.94 (br d, J = 7.0 Hz, 1H), 7.60 (s, 1H), 7.52 (d, J = 7.8 Hz, 1H), 7.40 - 7.36 (m, 2H), 7.35 -
7.26 (m, 6H), 5.48 - 5.43 (m, , 1H), 4.01 (s, 3H), 3.30 (dd, J = 4.5, 14.1 Hz, 1H), 3.00 (dd, J =
9.0, 14.1 Hz, 1H), 2.74 (q, J = 7.5 Hz, 3H), 1.32 (t, J = 7.7 Hz, 4H).
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)METHYL(3-
(TRIFLUOROMETHYL)PHENYL)-1H-PYRAZOLECARBOXAMIDE (183)
Compound 183 (38 mg, yield: 61.9%, white solid) was prepared as in Example
97 from the corresponding starting materials. H NMR (400MHz, DMSO-d ) δ 8.51 (d, J = 7.5
Hz, 1H), 8.12 (s, 1H), 8.03 (s, 1H), 7.97 (s, 1H), 7.84 (br d, J = 7.9 Hz, 1H), 7.80 (s, 1H), 7.63
(br d, J = 7.7 Hz, 1H), 7.55 - 7.48 (m, 1H), 7.26 (d, J = 4.2 Hz, 4H), 7.21 - 7.16 (m, 1H), 5.32 -
.25 (m, 1H), 3.89 (s, 3H), 3.17 - 3.11 (m, 1H), 2.83 - 2.76 (m, 1H). MS (ESI) m/z (M+H)
445.1.
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)METHYL(3-
(TRIFLUOROMETHOXY)PHENYL)-1H-PYRAZOLECARBOXAMIDE (184)
Compound 184 (18 mg, yield: 53.5%, white solid) was prepared as in Example
97 from the corresponding starting materials. H NMR (400MHz, DMSO-d ) δ 8.48 (d, J = 7.7
Hz, 1H), 8.10 (s, 1H), 8.03 (s, 1H), 7.79 (s, 1H), 7.64 - 7.56 (m, 2H), 7.41 (t, J = 8.2 Hz, 1H),
17681897_1 (GHMatters) P110989.NZ
7.30 - 7.24 (m, 5H), 7.12 - 7.16 (m, 1H), 5.33 - 5.27 (m, 1H), 3.89 (s, 3H), 3.15 (dd, J = 3.9, 13.8
Hz, 1H), 2.81 (dd, J = 10.1, 13.9 Hz, 1H). MS (ESI) m/z (M+H) 461.1.
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)(3-CYANOPHENYL)
METHYL-1H-PYRAZOLECARBOXAMIDE (185)
Compound 185 (20 mg, yield: 43.2%, white solid) was prepared as in Example
97 from the corresponding starting materials. H NMR (400MHz, DMSO-d ) δ 8.65 (dd, J = 7.3
Hz, 1H), 8.28 (s, 1H), 8.07 (s, 1H), 8.00 (s, 1H), 7.89 (dd, J = 7.5 Hz, 1H), 7.82 (s, 1H), 7.77 (dd,
J = 8.2 Hz, 1H), 7.52 (t, J = 7.9 Hz, 1H), 7.31 - 7.19 (m, 5H), 5.31 (dd, J = 6.8 Hz, 1H), 3.91 (s,
3H), 3.16 (dd, J = 9.9 Hz, 1H), 2.91 - 2.81 (m, 1H). MS (ESI) m/z (M+H) 402.1.
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)(3-
CYCLOPROPYLPHENYL)METHYL-1H-PYRAZOLECARBOXAMIDE (186)
Compound 186 (30 mg, yield: 53.72%, yellow solid) was prepared as in
Example 97 from the corresponding starting materials. H NMR (400MHz, DMSO-d ) δ 8.36
(dd, J = 6.8 Hz, 1H), 8.14 - 8.01 (m, 2H), 7.82 (s, 1H), 7.30 - 7.14 (m, 8H), 6.99 (dd, J = 7.5 Hz,
1H), 5.28 (s, 1H), 3.88 (s, 3H), 3.14 (dd, J = 11.0 Hz, 1H), 2.87 - 2.80 (m, 1H), 1.89 (s, 1H), 0.92
(dd, J = 6.6 Hz, 2H), 0.62 (s, 2H). MS (ESI) m/z (M+H) 417.1.
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)(3-CHLOROPHENYL)
METHYL-1H-PYRAZOLECARBOXAMIDE (187)
Compound 187 (35 mg, yield: 53.0%, white solid) was prepared as in Example
97 from the corresponding starting materials. H NMR (400MHz, DMSO-d ) δ 8.52 - 8.44 (m,
1H), 8.11 (s, 1H), 8.06 (s, 1H), 7.81 (s, 1H), 7.74 - 7.65 (m, 1H), 7.60 - 7.50 (m, 1H), 7.39 - 7.33
(m, 2H), 7.30 - 7.28 (m, 3H), 7.25 - 7.18 (m, 2H), 5.38 - 5.25 (m, 1H), 3.90 (s, 3H), 3.17 (dd, J =
3.6, 14.0 Hz, 1H), 2.89 - 2.80 (m, 1H). MS (ESI) m/z (M+H) 411.1..
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)METHYL(PYRIDIN
YL)-1H-PYRAZOLECARBOXAMIDE (188)
Compound 188 (15.8 mg, yield: 26.5%, white solid) was prepared as in
Example 97 from the corresponding starting materials, compound 163G and pyridinylboronic
acid. Compound 188: H NMR (400MHz, DMSO-d ) δ 8.77 (d, J = 1.6 Hz, 1H), 8.53 - 8.47 (m,
2H), 8.19 (s, 1H), 8.06 (br s, 1H), 7.92 (td, J = 1.9, 7.9 Hz, 1H), 7.80 (br s, 1H), 7.34 (dd, J = 5.1,
17681897_1 (GHMatters) P110989.NZ
7.6 Hz, 1H), 7.32 - 7.28 (m, 4H), 7.26 - 7.18 (m, 1H), 5.35 - 5.26 (m, 1H), 3.93 (s, 3H), 3.18 (dd,
J = 3.8, 13.8 Hz, 1H), 2.84 (dd, J = 10.1, 13.9 Hz, 1H). MS (ESI) m/z (M+H) 378.1.
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)METHYL(PYRIDINYL)-
1H-PYRAZOLECARBOXAMIDE (189)
Compound 189 (16 mg, 42.4 umol, yield: 30.9%, white solid) was prepared as
in Example 97 from the corresponding starting materials, compound 163E and pyridin
ylboronic acid. Compound 189: H NMR (400MHz, CDCl ) δ 8.74 (br d, J = 4.2 Hz, 1H), 8.60
(s, 1H), 7.86 (s, 1H), 7.69 (br d, J = 7.9 Hz, 1H), 7.42 - 7.36 (m, 1H), 7.25 (br d, J = 3.3 Hz, 2H),
6.94 (br d, J = 3.5 Hz, 2H), 6.74 (br s, 1H), 5.93 (br d, J = 6.6 Hz, 1H), 5.63 (br s, 1H), 5.52 (q, J
= 6.5 Hz, 1H), 3.73 (s, 3H), 3.32 (dd, J = 5.3, 13.9 Hz, 1H), 3.08 (dd, J = 6.8, 13.9 Hz, 1H). MS
(ESI) m/z (M+H) 378.1.
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)METHYL(o-TOLYL)-1H-
PYRAZOLECARBOXAMIDE(190)
Compound 190 (28.4 mg, yield: 30.7%, white solid) was prepared as in
Example 97 from the corresponding starting materials, compound 163E and o-tolylboronic acid.
Compound 190: H NMR (400MHz, DMSO-d ) δ 7.94 (d, J = 4.8 Hz, 1H), 7.43 - 7.31 (m, 3H),
7.30 - 7.15 (m, 5H), 7.15 - 7.05 (m, 4H), 5.30 - 5.19 (m, 1H), 3.48 (s, 3H), 3.12 (dd, J = 4.4, 14.0
Hz, 1H), 2.76 (ddd, J = 4.8, 9.0, 13.8 Hz, 1H), 1.96 (d, J = 10.1 Hz, 3H). MS (ESI) m/z (M+H)
391.1.
N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)METHYL(6-
(TRIFLUOROMETHYL)PYRIDINYL)-1H-PYRAZOLECARBOXAMIDE (315)
N CF
HO OH
Br O O
Pd(dppf)Cl
N NH
N NH
K CO 2
dioxane/H O N
315B
315A
To a mixture of 3-aminohydroxyphenylbutanamide hydrochloride (1.35
g, 5.86 mmol, HCl) and compound 163F (1 g, 4.88 mmol), HOBt (659 mg, 4.88 mmol) in DMF
(20 mL) was added DIEA (1.58 g, 12.20 mmol, 2 mL) and EDCI (1.4 g, 7.32 mmol) in portion at
17681897_1 (GHMatters) P110989.NZ
°C and stirred for 16h. The reaction mixture was treated with EA (40 mL), washed with H O
(50 mL x 2). The organic layer was washed with 0.5N HCl (40 mL), saturated aqueous NaHCO
(40 mL) and brine (30 mL), dried over Na SO , filtered and the solvent was removed in vacuo.
The residue was triturated with DCM (2 mL) and PE (10 mL), the precipitate was formed, the
solid was collected and was dried in vacuo to give compound 315A (900 mg, yield: 45.38%) as
yellow solid. H NMR (400MHz, DMSO-d ) δ 8.25 (s, 1H), 7.85 - 7.42 (m, 1H), 7.35 (dd, J =
7.3 Hz, 1H), 7.28 - 7.18 (m, 5H), 6.15 (d, J = 6.2 Hz, 1H), 5.95 (d, J = 5.5 Hz, 1H), 4.56 - 4.32
(m, 1H), 3.86 - 3.78 (m, 4H), 2.95 - 2.84 (m, 1H), 2.82 - 2.73 (m, 1H), 2.69 - 2.58 (m, 1H). MS
(ESI) m/z (M+H) 381.0.
Compound 315 (30 mg, yield: 28.27%, white solid) was prepared as in
Example 97 from the corresponding intermediate compounds, 315A and (6-
(trifluoromethyl)pyridinyl)boronic acid and through intermediate compound 315B. Compound
315: H NMR (400MHz, DMSO-d ) δ 8.92 (s, 1H), 8.65 (dd, J = 7.3 Hz, 1H), 8.26 (s, 1H), 8.20
(dd, J = 8.4 Hz, 1H), 8.05 (s, 1H), 7.88 - 7.76 (m, 2H), 7.28 (d, J = 3.7 Hz, 4H), 7.24 - 7.16 (m,
1H), 5.27 (t, J = 3.1 Hz, 1H), 3.94 (s, 3H), 3.16 (dd, J = 3.7, 14.1 Hz, 1H), 2.83 (dd, J = 10.4,
13.7 Hz, 1H). MS (ESI) m/z (M+H) 446.1.
N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)(3-METHOXYPHENYL)
METHYL-1H-PYRAZOLECARBOXAMIDE (407)
Compound 407 (3.9 g, yield: 94.15%, white solid) was prepared as in Example
97 from the corresponding starting materials, compound 163C, (3-methoxyphenyl) boronic acid,
and 274D. Compound 407: H NMR (400MHz, DMSO-d ) δ 8.44 - 8.25 (m, 1H), 8.15 - 7.97 (m,
2H), 7.84 (br s, 1H), 7.37 - 7.11 (m, 8H), 6.96 - 6.80 (m, 1H), 5.44 - 5.19 (m, 1H), 3.90 (br s,
3H), 3.73 (br s, 3H), 3.26 - 3.07 (m, 1H), 2.92 - 2.72 (m, 1H). MS (ESI) m/z (M+H) 407.1.
17681897_1 (GHMatters) P110989.NZ
3-((1H-PYRAZOLO[4,3-c]PYRIDINYL)METHYL)-N-(4-AMINO-3,4-DIOXO
PHENYLBUTANYL)METHYL-1H-PYRAZOLECARBOXAMIDE (408)
Br O O
MeB(OH)
NBS,AIBN,
K CO
Pd(PPh3)4 2 3 CCl
4,reflux
reflux
163C
408A 408B
KOH, DMF, 0 C N
NH NH
408C
A mixture of compound 163C (2 g, 8.58 mmol), MeB(OH) (2.05 g, 34.3
mmol), Pd(PPh ) (793 mg, 687 umol), K CO (2.37 g, 17.2 mmol) in dioxane (50 mL) and H O
3 4 2 3 2
(10 mL) was degassed and purged with N for 3 times, and then the mixture was stirred at 120 °C
for 12 hour under N2 atmosphere. The reaction mixture was extracted with Ethyl acetate 50 mL
(50 mL x 2). The combined organic layers were dried over Na SO , filtered and concentrated
under reduced pressure to give a residue. The residue was purified by column chromatography
(SiO , Petroleum ether: Ethyl acetate = 100:1 to 80:1). Compound 408A (1.4 g, yield: 97.0%)
was obtained as a yellow solid. H NMR (400MHz, CDCl ) δ 7.87 - 7.73 (m, 1H), 4.27 (q, J =
7.1 Hz, 2H), 3.91 - 3.75 (m, 3H), 2.51 - 2.40 (m, 3H), 1.33 (t, J = 7.1 Hz, 3H).
A mixture of compound 408A (1.2 g, 7.13 mmol), NBS (1.9 g, 10.7 mmol),
AIBN (586 mg, 3.57 mmol) in CCl (30 mL) was stirred at 80 °C for 12 hours. The reaction
mixture was filtered and concentrated under reduced pressure to give a residue. The residue was
purified by column chromatography (SiO , Petroleum ether: Ethyl acetate = 98:1 to 90:1).
Compound 408B (600 mg, yield: 34.1%) was obtained as a yellow oil. H NMR (400MHz,
CDCl ) δ 7.76 (s, 1H), 4.66 (s, 2H), 4.30 - 4.21 (m, 2H), 3.90 - 3.79 (m, 3H), 1.38 - 1.22 (m, 3H).
To a mixture of 1H-pyrazolo [4,3-c]pyridine (797 mg, 6.69 mmol) in DMF (20
mL) was added KOH (501 mg, 8.92 mmol). The mixture was stirred at 15 °C for 30min. And
then to the mixture was added compound 408B (550 mg, 2.23 mmol) in DMF (10 mL) drop-wise
at 0 °C over 10 min, and the mixture was stirred at 0 °C for 2hr. The desired product was
confirmed by NOE. The reaction mixture was concentrated under reduced pressure to give a
17681897_1 (GHMatters) P110989.NZ
residue. The residue was purified by preparatory-HPLC (basic condition). Compound 408C (300
mg, yield: 47.2%) was obtained as a yellow oil. H NMR (400MHz, CDCl ) δ 9.14 - 8.99 (m,
1H), 8.40 (d, J = 6.2 Hz, 1H), 8.15 (s, 1H), 7.92 - 7.75 (m, 1H), 7.51 (d, J = 6.0 Hz, 1H), 5.85 (s,
2H), 4.26 (q, J = 7.2 Hz, 2H), 3.93 - 3.75 (m, 3H), 1.29 (t, J = 7.1 Hz, 3H).
Compound 408 (24.1 mg, yield: 40.4%, white solid) was prepared as in
Example 95 from the corresponding starting materials, compound 408C and 274D.
Compound 408: H NMR (400MHz, DMSO-d ) δ 9.07 (s, 1H), 8.91 (br d, J =
.5 Hz, 1H), 8.46 (br d, J = 5.5 Hz, 1H), 7.93 (s, 1H), 7.69 (s, 1H), 7.59 (br d, J = 5.5 Hz, 1H),
7.24 - 7.17 (m, 1H), 7.23 (br s, 2H), 7.25 - 7.15 (m, 1H), 6.79 (br s, 1H), 5.69 - 5.51 (m, 1H),
.73 - 5.38 (m, 1H), 5.49 - 5.37 (m, 1H), 5.50 - 5.37 (m, 1H), 5.74 - 5.33 (m, 1H), 3.79 (s, 3H),
3.56 - 3.42 (m, 1H), 3.17 (br dd, J = 9.5, 14.1 Hz, 1H). MS (ESI) m/z (M+H) 432.3.
N-(4-AMINOHYDROXYOXOPHENYLBUTANYL)(4-FLUOROPHENYL)-
1-METHYL-1H-PYRAZOLECARBOXAMIDE (446) and
N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)(4-FLUOROPHENYL)
METHYL-1H-PYRAZOLECARBOXAMIDE (447)
1. acid,
(4-fluorophenyl)boronic
274D
Pd(dppf)Cl
HBTU, DIEA
2. NaOH
446A
446A
O O DMP O O
N NH N NH
N 2 N 2
OH O
Compound 446A was treated with (4-fluorophenyl)boronic acid using
procedure as in compound 163E followed by subjecting the resulting product to ester hydrolysis
using sodium hydroxide and coupling with intermediate 274D using the procedures as in
compound 12 to yield compounds 446 and compound 447. Compound 446 (550 mg, yield:
75.9%) was obtained as a white solid. H NMR (400MHz, DMSO-d ) δ 8.08 - 8.00 (m, 1H),
7.75 (d, J = 9.0 Hz, 1H), 7.56 (dd, J = 5.6, 8.7 Hz, 2H), 7.33 - 7.08 (m, 8H), 5.83 (d, J = 5.7 Hz,
1H), 4.59 - 4.37 (m, 1H), 4.00 (d, J = 1.8 Hz, 1H), 3.86 (s, 3H), 2.80 - 2.73 (m, 1H), 2.68 (s, 1H),
17681897_1 (GHMatters) P110989.NZ
2.66 (d, J = 5.1 Hz, 1H). MS (ESI) m/z (M+H) 397.1. Compound 447 (80 mg, yield: 39.9%)
was obtained as a white solid. H NMR (400MHz, DMSO-d ) δ 8.42 (d, J = 7.3 Hz, 1H), 8.11 -
8.03 (m, 2H), 7.81 (s, 1H), 7.65 - 7.57 (m, 2H), 7.32 - 7.18 (m, 5H), 7.12 (t, J = 8.8 Hz, 2H), 5.27
(d, J = 3.1 Hz, 1H), 3.89 (s, 3H), 3.30 - 3.12 (m, 1H), 2.83 (dd, J = 9.9, 13.7 Hz, 1H). MS (ESI)
m/z (M+H) 395.1.
EXAMPLE 98
COMPOUNDS 174-175, 191-193, 313, 293
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)METHYL(PYRIMIDIN
YL)-1H-PYRAZOLECARBOXAMIDE (174)
SnBu
Br O O
N NH N NH
N 2 N 2
N OH
163E
174A
To a solution of Compound 163E (150 mg, 393.47 umol) and tributyl(pyrazin-
2-yl)stannane (217 mg, 590.21 umol) in dioxane (15 mL) was added palladium;tritert-
butylphosphane (100 mg, 196.74 umol). The mixture was stirred at 90 °C for 16h. The mixture
was quenched with aqueous KF (20 mL), filtered, washed with ethyl acetate (20 mL), the filtrate
was extracted with ethyl acetate (20 mL x 2). The organic phase was dried over Na SO ,
concentrated to give a residue. The residue was purified by preparatory-HPLC (basic condition)
and by preparatory-TLC (SiO , DCM: MeOH = 10: 1). Compound 174A (70 mg, yield: 45.6%)
was obtained as a white solid. H NMR (400MHz, MeOD) δ 8.77 - 8.69 (m, 1H), 8.66 - 8.54 (m,
2H), 7.94 - 7.78 (m, 1H), 7.25 - 7.12 (m, 5H), 4.63 - 4.58 (m, 1H), 4.26 - 4.02 (m, 1H), 3.91 -
3.84 (m, 3H), 3.01 - 2.83 (m, 2H). MS (ESI) m/z (M+H) 381.1.
Compound 174 (25 mg, yield: 34.93%, white solid) was prepared as in
Example 61 from the intermediate compound 174A. Compound 174A: H NMR (400MHz,
DMSO-d ) δ 8.75 (d, J = 1.5 Hz, 1H), 8.71 (dd, J = 1.6, 2.6 Hz, 1H), 8.66 - 8.64 (m, 1H), 8.31
(d, J = 7.5 Hz, 1H), 7.99 (s, 1H), 7.70 (br s, 1H), 7.51 (br s, 1H), 7.28 - 7.23 (m, 4H), 7.22 - 7.17
(m, 1H), 5.33 - 5.28 (m, 1H), 3.83 (s, 3H), 3.20 (dd, J = 4.5, 14.1 Hz, 1H), 2.93 (dd, J = 9.3, 14.1
Hz, 1H). MS (ESI) m/z (M+H) 379.1.
17681897_1 (GHMatters) P110989.NZ
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)METHYL(PYRIMIDIN
YL)-1H-PYRAZOLECARBOXAMIDE (175)
Compound 175 (35 mg, yield: 47.75%, white solid) was prepared as in
Example 98 from the corresponding starting materials, compound 163E and tributyl(pyrimidin
yl)stannane. Compound 175: H NMR (400MHz, DMSO-d ) δ 9.24 (d, J = 1.1 Hz, 1H), 8.82 (d,
J = 5.3 Hz, 1H), 8.71 (d, J = 7.5 Hz, 1H), 8.03 (s, 1H), 7.93 (s, 1H), 7.78 (s, 1H), 7.54 (dd, J =
1.3, 5.3 Hz, 1H), 7.27 - 7.17 (m, 6H), 5.28 - 5.19 (m, 1H), 3.85 (s, 3H), 3.15 (dd, J = 4.0, 13.9
Hz, 1H), 2.83 (dd, J = 10.1, 13.9 Hz, 1H). MS (ESI) m/z (M+H) 379.1.
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)METHYL(PYRIMIDIN
YL)-1H-PYRAZOLECARBOXAMIDE (191)
Compound 191 (20 mg, yield: 38.77%, white solid) was prepared as in
Example 98 from the corresponding starting materials, compound 163E and tributyl(pyrimidin
yl)stannane. Compound 191: H NMR (400MHz, DMSO-d ) δ 9.63 (d, J = 6.3 Hz, 1H), 8.86 (d,
J = 5.0 Hz, 2H), 7.90 (s, 1H), 7.81 - 7.56 (m, 2H), 7.55 (t, J = 4.9 Hz, 1H), 7.21 - 7.14 (m, 3H),
7.12 - 7.06 (m, 2H), 5.47 (t, J = 5.1, 7.5 Hz, 1H), 4.05 (s, 3H), 3.24 (dd, J = 5.1, 14.2 Hz, 1H),
3.05 - 3.00 (m, 1H). MS (ESI) m/z (M+H) 379.1.
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)METHYL(PYRIMIDIN
YL)-1H-PYRAZOLECARBOXAMIDE (192)
Compound 192 (15 mg, yield: 29.82%, white solid) was prepared as in
Example 98 from the corresponding starting materials, compound 163G and 4-
(tributylstannyl)pyrimidine. Compound 192: H NMR (400MHz, CD CN) δ 11.76 - 11.65 (m,
1H), 8.81 - 8.73 (m, 2H), 8.14 (s, 1H), 8.07 (dd, J = 1.1, 5.3 Hz, 1H), 7.59 (s, 1H), 7.15 (s, 4H),
7.04 (s, 1H), 6.24 (s, 1H), 5.65 - 5.59 (m, 1H), 3.93 (s, 3H), 3.33 (dd, J = 5.1, 14.1 Hz, 1H), 3.14
(dd, J = 7.7, 14.1 Hz, 1H). MS (ESI) m/z (M+H) 379.1.
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)METHYL(PYRIMIDIN
YL)-1H-PYRAZOLECARBOXAMIDE (193)
Compound 193 (25 mg, yield: 54.29%, white solid) was prepared as in
Example 98 from the corresponding starting materials, compound 163G and tributyl(pyrimidin-
2-yl)stannane. Compound 193: H NMR (400MHz, DMSO-d ) δ 11.24 (d, J = 7.3 Hz, 1H), 8.69
(d, J = 4.9 Hz, 2H), 8.29 (s, 1H), 8.08 (s, 1H), 7.82 (s, 1H), 7.47 (t, J = 4.9 Hz, 1H), 7.16 - 7.09
17681897_1 (GHMatters) P110989.NZ
(m, 3H), 7.07 - 7.03 (m, 2H), 5.61 - 5.49 (m, 1H), 3.92 (s, 3H), 3.23 (dd, J = 5.1, 14.1 Hz, 1H),
3.07 (dd, J = 7.3, 14.1 Hz, 1H). MS (ESI) m/z (M+H) 379.0.
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)METHYL(PYRAZIN
YL)-1H-PYRAZOLECARBOXAMIDE (313)
Br O O O O
SnBu
Pd(PtBu3)2
N NH N NH
OH OH
163G
313A
Compound 313 was prepared as in Example 98 from the corresponding starting
materials, compound 163G and 2-(tributylstannyl)pyrazine, through intermediate compound
313A. Compound 313 (70 mg, yield: 69.7%, white solid): H NMR (400MHz, CD CN) δ 11.26
(d, J = 6.0 Hz, 1H), 9.34 (d, J = 1.3 Hz, 1H), 8.54 (d, J = 2.6 Hz, 1H), 8.23 - 8.10 (m, 2H), 7.17 -
7.11 (m, 5H), 7.01 (br s, 1H), 6.19 (br s, 1H), 5.67 - 5.55 (m, 1H), 3.94 (s, 3H), 3.33 (dd, J = 5.3,
14.1 Hz, 1H), 3.13 (dd, J = 7.7, 14.1 Hz, 1H). MS (ESI) m/z (M+H) 379.1.
N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)METHYL(6-
METHYLPYRIDINYL)-1H-PYRAZOLECARBOXAMIDE (316)
Sn(n-Bu)3
Br O O
palladium;tritert-butylphosphane
N NH N NH
dioxane H
OH N
315A
316A
Compound 316 was prepared as in Example 98 from the corresponding starting
materials, compound 315A and 2-methyl(tributylstannyl)pyridine, through intermediate
compound 316A. Compound 316 (20 mg, yield: 21.64%, white solid): H NMR (400MHz,
DMSO-d ) δ 11.79 (d, J = 7.7 Hz, 1H), 8.24 (s, 1H), 8.02 (s, 1H), 7.92 - 7.86 (m, 1H), 7.84 -
7.78 (m, 1H), 7.75 (s, 1H), 7.24 (d, J = 7.7 Hz, 1H), 7.15 - 7.08 (m, 3H), 7.08 - 7.02 (m, 2H),
.52 (t, J = 5.2, 8.1 Hz, 1H), 3.89 (s, 3H), 3.22 (dd, J = 4.7, 13.8 Hz, 1H), 2.99 (dd, J = 8.4, 13.7
Hz, 1H), 2.28 (s, 3H). MS (ESI) m/z (M+H) 392.2.
17681897_1 (GHMatters) P110989.NZ
EXAMPLE 99
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)METHYL(6-
(TRIFLUOROMETHYL)PYRIDINYL)-1H-PYRAZOLECARBOXAMIDE (194)
SnSn
1,4-dioxane
Pd(PPh3)4
SnMe
100 °C, 6 hrs
194A
To a mixture of 2-bromo(trifluoromethyl)pyridine (3 g, 13.27 mmol) and
1,1,1,2,2,2-hexamethyldistannane (5.7 g, 17.40 mmol) in 1,4-dioxane (96 mL) was added
Pd(PPh ) (3.07 g, 2.65 mmol) at 25 °C under nitrogen atmosphere and the resultant mixture was
stirred at 100 °C for 6 hours. The reaction mixture was cooled to room temperature, and filtered
through a thin layer of celite. The filter cake was washed with DCM. The filtrate was
concentrated in vacuum to give a dark solid, which was purified by column chromatography
(SiO , Petroleum ether/Ethyl acetate = 100:1 to 10:1) to afford crude compound 194A (3.2 g,
26.46% purity by LCMS) as a white solid. MS (ESI) m/z (M+H) 311.8.
Compound 194 (32.1 mg, 62.15% yield, white solid) was prepared as in
Example 98 from the corresponding starting materials, intermediate compounds 163E and 194A.
Compound 194: H NMR (400MHz, CDCl ): δ 7.98 - 7.91 (m, 1H), 7.85 (d, J = 7.6 Hz, 1H),
7.75 (s, 1H), 7.72 (d, J = 7.6 Hz, 1H), 7.26 - 7.21 (m, 3H), 7.07 - 7.02 (m, 2H), 6.74 (br s, 1H),
6.63 - 6.56 (m, 1H), 5.60 - 5.54 (m, 1H), 5.51 (br s, 1H), 3.94 (s, 3H), 3.41 - 3.31 (m, 1H), 3.14 -
3.06 (m, 1H). MS (ESI) m/z (M+H) 446.0.
17681897_1 (GHMatters) P110989.NZ
EXAMPLE 100
N-(1-AMINO-1,2-DIOXOHEXENYL)METHYLPHENYL-1H-PYRAZOLE
CARBOXAMIDE (195)
HO OH
LiOH
O OH
, K PO THF
Pd(dtbpf)Cl2 3 4 N N
163B dioxane/H O
195A
195B
N LiAlH4
ClHH O
EDCI, HOBt, DIEA
DCM N 195D
195C
O O O
K CO , H O
2 3 2 2
DMSO
TEA N N NH
OH OH
195E
195F
To a solution of compound 163B (2 g, 8.58 mmol) and phenylboronic acid
(1.26 g, 10.30 mmol) in dioxane (30 mL) and H O (10 mL) was added Pd(dtbpf)Cl (280 mg,
0.43 mmol) and K PO (5.46 g, 25.74 mmol). The mixture was stirred at 70 °C under N for 3h.
3 4 2
The reaction was washed with H O (20 mL), extracted with EtOAc (15 mL x 2). The organics
were collected and concentrated. The residue was purified by column (Petroleum Ether: Ethyl
Acetate = 10:1) to afford compound 195A (1.9 g, yield: 96.17%) as yellow oil.
To a solution of compound 195A (1.9 g, 8.25 mmol) in THF (20 mL) and H O
(20 mL) was added LiOH.H O (1.73 g, 41.25 mmol). The mixture was stirred at 25°C for 24h.
The reaction was acidified with 1N HCl to pH ~ 4. The mixture was extracted with EtOAc (25
mL x 2). The organics were collected, washed with brine (30 mL), dried with Na SO , filtered
and concentrated to afford compound 195B (1.3 g, yield: 77.93%) as light yellow solid. MS
(ESI) m/z (M+1) 202.9.
To a solution of compound 195B (800 mg, 3.96 mmol) and (S)amino-N-
methoxy-N-methylpentenamide hydrochloride (926 mg, 4.75 mmol) in DCM (20 mL) was
added DIEA (1.73 mL, 9.90 mmol), HOBt (1.07 g, 7.92 mmol) and EDCI (1.52 g, 7.92 mmol).
The mixture was stirred at 25°C for 12h. The solvent was removed in vacuo. The reaction was
17681897_1 (GHMatters) P110989.NZ
diluted with EtOAc (30 mL), washed with 1N HCl (20 mL). The organics were collected and
concentrated. The residue was purified by column chromatography (Petroleum Ether: Ethyl
Acetate = 1:1) to afford compound 195C (1.2 g, yield: 88.50%) as colorless oil. MS (ESI) m/z
(M+1) 343.1.
To a solution of compound 195C (1 g, 2.92 mmol) in THF (10 mL) at -40°C
was added LiAlH (1M, 3.1 mL) dropwise. After addition, the mixture was stirred at 0°C for 1h.
The reaction was quenched with 1N HCl (30 mL) dropwise, extracted with EtOAc (20 mL x 3).
The organics were collected, washed with brine (30 mL), dried with Na SO , filtered and
concentrated to afford intermediate compound 195D (800 mg, crude) as white solid. MS (ESI)
m/z (M+1) 284.0.
To a solution of compound 195D (280 mg, 0.99 mmol) and 2-hydroxy
methylpropanenitrile (0.54 mL, 5.88 mmol) in DCM (20 mL) was added TEA (0.17 mL, 1.19
mmol). The mixture was stirred at 25°C for 12h. The solvent was removed in vacuo. The
residue was purified by column (Petroleum Ether: Ethyl Acetate = 1:1) to give compound 195E
(200 mg, yield: 65.21%) as yellow oil. MS (ESI) m/z (M+1) 311.0.
To a solution of compound 195E (736 mg, 2.37 mmol) in DMSO (5 mL) at 0
°C was added K CO (656 mg, 4.74 mmol). Then H O (2.28 mL, 23.72 mmol, 30% purity) was
2 3 2 2
added dropwise. The mixture was stirred at 25°C for 1h. The reaction was quenched with 10%
aq. Na2S2O3 (30 mL) dropwise. The mixture was extracted with EtOAc (20 mL x 3). The
organics were collected, washed with brine (30 mL), dried with Na SO, filtered and
concentrated. The residue was washed with CH CN (5 mL). The solid was filtered, collected
and dried in vacuo to afford compound 195F (200 mg, yield: 25.60%) as white solid. H NMR
(DMSO-d 400 MHz): δ 8.09 (s, 1H), 7.72 - 7.61 (m, 2H), 7.48 - 7.42 (m, 1H), 7.40 - 7.26 (m,
3H), 7.25 - 7.12 (m, 2H), 5.81 - 5.60 (m, 2H), 5.12 - 4.93 (m, 2H), 4.33 - 4.17 (m, 1H), 3.96 -
3.93 (m, 1H), 3.86 (s, 3H), 2.34 - 2.05 (m, 2H). MS (ESI) m/z (M+1) 329.0.
To a solution of compound 195F (200 mg, 609.07 umol) in DCM (15 mL) and
DMSO (5 mL) was added DMP (775 mg, 1.83 mmol). The mixture was stirred at 25°C for 30
min. The reaction was diluted with DCM (20 mL), quenched with a solution of 10% aqueous
Na S O and saturated NaHCO (v/v = 1/1) (40 mL). The organics were collected, washed with
2 2 3 3
brine (30 mL x 3). The organics were collected, dried with Na SO , filtered and concentrated.
17681897_1 (GHMatters) P110989.NZ
The residue was washed with CH CN (5 mL). The solid was filtered, collected and dried in
vacuo to afford 195 (38 mg, yield: 18.72%) as white solid. H NMR (DMSO-d 400 MHz): δ
8.23 (d, J = 6.8 Hz, 1H), 8.13 (s, 1H), 7.98 (br. s, 1H), 7.73 (br. s, 1H), 7.68 - 7.61 (m, 2H), 7.38
- 7.25 (m, 3H), 5.89 - 5.71 (m, 1H), 5.11 - 4.98 (m, 3H), 3.88 (s, 3H), 2.57 - 2.50 (m, 1H), 2.40 -
2.31 (m, 1H). MS (ESI) m/z (M+1) 327.1.
EXAMPLE 101
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)BROMOMETHYL-1H-
PYRAZOLECARBOXAMIDE (196)
Compound 196 (54 mg, yield: 50.44%, white solid) was prepared as in
Example 61 from the corresponding intermediate compound 163G. Compound 196: H NMR
(400MHz, DMSO-d ) δ 8.21 - 8.15 (m, 2H), 8.06 (br s, 1H), 7.80 (br s, 1H), 7.28 - 7.23 (m, 4H),
7.20 - 7.16 (m, 1H), 5.33 - 5.26 (m, 1H), 3.82 (s, 3H), 3.15 (br dd, J = 3.7, 13.9 Hz, 1H), 2.83 (br
dd, J = 9.8, 13.8 Hz, 1H). MS (ESI) m/z (M+H) 379.0 & 381.0.
EXAMPLE 102
N-(1-AMINO-1,2-DIOXOHEXENYL)METHYLPHENYL-1H-PYRAZOLE
CARBOXAMIDE (197)
SEM O O
SEM-Cl
KOAc,
, 1,4-dioxane O O
NaH, DMF Pd(dppf)Cl2
~25 6.2 h
80 °C, 12 h
197A
197B
O O N
Br O O
N NH , K CO , dioxane, H O
Pd(dtbpf)Cl
N 2 2 2 3 2
N NH
H N 2
OH , 2 h H
N 70 °C
N OH
163E
197D
HCl/EtOAc
DMP, DCM (4M)
N NH
°C, 1 h N 2
°C, 78 hrs
N NH
197E
17681897_1 (GHMatters) P110989.NZ
To a cold (0 °C), stirred solution of 3-bromo-1H-indazole (5 g, 25.38 mmol) in
DMF (130 mL) was added NaH (1.22 g, 50.76 mmol) in portions. After 0.2h, SEM-Cl (5.08 g,
.46 mmol) was added and then the mixture was stirred at 25 °C for 6 hours under N
atmosphere. The reaction was quenched with a saturated aqueous solution of NH CI and the
resulting layer was extracted with EtOAc (100 mL x 2). The combined organic layers were
dried, filtered and concentrated under reduced pressure to leave a residue. The residue which
was purified by flash chromatography on silica (elution with 100: 1 to 10: 1 Petroleum Ether :
EtOAc ) to give compound compound 197A (5.5 g, 66.21% yield) as an oil. H NMR (CDCl
400 MHz): δ 7.71 - 7.69 (m, 1H), 7.65 - 7.60 (m, 1H), 7.57 - 7.51 (m, 1H), 7.37 - 7.29 (m, 1H),
.76 (d, J = 3.2 Hz, 2H), 3.70 - 3.55 (m, 2H), 1.02 - 0.87 (m, 2H), 0.00 (d, J = 3.2 Hz, 9H). MS
(ESI) m/z (M+H) 338.3.
To a mixture of compound 197A (2 g, 6.11 mmol), compound
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (1.86 g, 7.33 mmol), KOAc (2.4 g,
24.44 mmol), Pd (dppf) Cl (894.3 mg, 1.22 mmol) in dioxane (80 mL) was heated at 80 °C for
12 hours under N atmosphere. Compound 197B (crude) was obtained as a solution (15.8 mg/mL
in dioxane).
To a mixture of compound 197B (461.6 mg, 1.23 mmol, 30 mL in dioxane),
compound 163E (100 mg, 262.3 umol), Pd(dtbpf)Cl (34.19 mg, 52.46 umol) and K PO (111.4
2 3 4
mg, 524.6 umol) in H2O (2 mL) was degassed and purged with N2 for 3 times, and then the
mixture was stirred at 70 °C for 2 hours under N atmosphere. The reaction solution was
purified by preparatory-HPLC (basic condition) to give compound 197D (50 mg, 16.54%
yield)as a brown solid. H NMR (CDCl 400 MHz): δ 8.14 - 8.02 (m, 1H), 8.01 - 7.82 (m, 1H),
7.70 - 7.63 (m, 1H), 7.58 (t, J = 7.6 Hz, 1H), 7.51 (d, J = 8.4 Hz, 1H), 7.39 - 7.32 (m, 1H), 7.02 -
6.89 (m, 1H), 6.88 - 6.69 (m, 5H), 6.42 (br s, 1H), 5.70 - 5.48 (m, 2H), 5.34 (br s, 1H), 4.39 -
4.27 (m, 1H), 4.24 - 4.08 (m, 1H), 3.84 (s, 3H), 3.58 (t, J = 8.0 Hz, 2H), 3.04 - 2.74 (m, 2H), 0.92
- 0.87 (m, 2H), -0.07 (s, 9H). MS (ESI) m/z (M+H) 549.2.
A mixture of compound 197D (50 mg, 91.12 umol) in DCM (10 mL) was
added DMP (116 mg, 273.4 umol) in one portion at 0 °C under N , and then the mixture was
stirred at 0 °C for 1 hour under N atmosphere. The mixture was quenched with saturated
aqueous NaHCO (15 mL) and saturated aqueous Na S O (15 mL), and stirred for 20 min, then
3 2 2 3
17681897_1 (GHMatters) P110989.NZ
diluted with dichloromethane (100 mL). The mixture was stirred for 20 mins and washed with
water (2 x 20 mL). The combined organic layers were dried over Na SO and concentrated under
reduced pressure to give the crude product. The residue was purified by preparatory-HPLC
(basic condition) to give compound 197E (30 mg, 55.67% yield) as white solid. H NMR
(CDCl 400 MHz): δ 8.23 (s, 1H), 7.98 (d, J = 6.8 Hz, 1H), 7.74 (d, J = 8.8 Hz, 1H), 7.70 - 7.60
(m, 2H), 7.48 - 7.38 (m, 1H), 7.03 (t, J = 7.2 Hz, 1H), 6.89 - 6.75 (m, 3H), 6.74 - 6.67 (m, 2H),
.84 - 5.75 (m, 1H), 5.63 (d, J = 11.6 Hz, 2H), 5.45 (d, J = 11.2 Hz, 1H), 4.01 - 3.87 (m, 3H),
3.78 - 3.57 (m, 2H), 3.39 - 3.12 (m, 2H), 1.02 - 0.92 (m, 2H), 0.16 - 0.07 (m, 9H). MS (ESI) m/z
(M+ H) 547.2.
A mixture of compound 197E (30 mg, 54.88 umol) in HCl/EtOAc (4 M, 1.50
mL) was stirred at 25 °C for 78 hours. The reaction mixture was concentrated under reduced
pressure to give a residue, which was purified by preparatory-HPLC (basic condition) to afford
compound 197 (1.6 mg, 6.68% yield) as a white solid. H NMR (400 MHz, CDCl ): δ 10.35 (br
s, 1H), 8.12 (s, 1H), 7.77 (br s, 1H), 7.61 - 7.50 (m, 3H), 7.34 - 7.28 (m, 1H), 7.10 - 7.04 (m,
1H), 6.98 - 6.90 (m, 2H), 6.84 - 6.68 (m, 3H), 5.62 - 5.42 (m, 2H), 3.83 (s, 3H), 3.29 - 3.19 (m,
1H), 3.08 - 2.97 (m, 1H). MS (ESI) m/z (M+H) 417.2.
EXAMPLE 103
N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)METHYL(6-
(TRIFLUOROMETHYL)PYRIDINYL)-1H-PYRAZOLECARBOXAMIDE (198)
LiOH H
F C N SnMe
CH OH-H O
194A
°C 0.5 hr OH
P) ,
Pd(t-Bu 2 1,4-dioxane N
198A
90 48 hrs 198B
°C, N
198C
A mixture of compound ethyl 3-iodomethyl-1H-pyrazolecarboxylate
(200 mg, 714.13 umol) and compound 194A (1.91 g, 856.96 umol) in dioxane (3 mL) was added
Pd(t-Bu P) (110 mg, 214.24 umol) under nitrogen atmosphere. The mixture was stirred at 90 °C
for 48 hours. The mixture was diluted with CH Cl (30 mL), filtered to remove the precipitate
and the filtrate was concentrated under reduced pressure to give a residue. The residue was
purified by flash column chromatography (Petroleum Ether: Ethyl Acetate = 10/1 to 5/1) to
17681897_1 (GHMatters) P110989.NZ
afford compound (175.00 mg, 77.93% yield) as brown solid. H NMR (400 MHz, CDCl ) δ 8.01
– 7.91 (m, 3H), 7.72 – 7.67 (m, 1H), 4.26 – 4.20 (m, 2H), 4.00 (s, 3H), 1.25 – 1.19 (s, 3H).
To a mixture of compound 198B (170 mg, 568.09 umol) in MeOH (8 mL) and
H O (4 mL) was added LiOH H O (191 mg, 4.54 mmol) in one portion and the mixture was
stirred at 25°C for 12 hours. The reaction mixture was concentrated under reduced pressure to
remove MeOH. The residue was diluted with H O (20 mL), adjusted to pH ~ 3 with 1N HCl,
and then extracted with EtOAc (20 mL x 3). The combined organic layers were washed with
brine (30 mL), dried over anhydrous Na SO , filtered and concentrated under reduced pressure to
give intermediate compound 198C (150 mg, 97.36% yield) as a brown solid. H NMR (400
MHz, DMSO-d ) δ 8.44 (s 1H), 8.25 (d, J = 4 Hz, 1H), 8.00 – 7.98 (m, 2H), 3.95 (s, 3H).
Compound 198 (94.2 mg, 63.09% yield, white solid) was prepared as in
Example 5 from the corresponding intermediate carboxylic acid, compound 198C. Compound
198: H NMR (400 MHz, CDCl ) δ 10.92 (d, J = 6.80 Hz, 1H), 8.39 (d, J = 8.40 Hz, 1H), 8.08
(s, 1 H) 7.92 - 8.02 (m, 1 H), 7.65 (d, J=8.00 Hz, 1 H), 7.06 - 7.23 (m, 5 H), 6.72 (s, 1 H), 5.51
(br s, 1 H), 5.31 - 5.43 (m, 1 H), 3.93 (s, 3 H), 3.38 - 3.49 (m, 1 H), 2.96 - 3.11 (m, 1 H). MS
(ESI) m/z (M+1) 446.1.
EXAMPLE 104
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)METHYL(3'-METHYL-
[1,1'-BIPHENYL]YL)-1H-PYRAZOLECARBOXAMIDE (199)
Compound 199 (35.0 mg, yield 53.6%, white solid) was prepared as in
Example 61 from the corresponding starting materials, compound 103A and m-tolylboronic acid.
Compound 199: H NMR (DMSO-d 400 MHz) δ 9.08 (d, J = 7.7 Hz, 1H), 8.08 - 8.00 (m, 1H),
7.84 (br s, 1H), 7.60 - 7.52 (m, 2H), 7.45 - 7.37 (m, 3H), 7.36 -7.30 (m, 1H), 7.28 - 7.25 (m, 3H),
7.23 - 7.16 (m, 3H), 7.12 - 7.06 (m, 1H), 6.60 (br s, 1H), 5.29 (br s, 1H), 3.22 - 3.14 (m, 1H),
2.86 - 2.76 (m, 1H), 2.35 (s, 3H), 2.28 - 2.22 (m, 3H). MS (ESI) m/z (M+H) 467.2.
17681897_1 (GHMatters) P110989.NZ
EXAMPLE 105
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)(6-PHENYLPYRIDAZIN
YL)-1H-IMIDAZOLECARBOXAMIDE (200)
O Tosmic, K
MeOH
MeOH
N NH
200B
200A
LiOH.H O
200C
200D
To a mixture of 6-bromopyridazinamine (10 g, 57 mmol) and
phenylboronic acid (10.5 g, 86 mmol) in toluene (150 mL) and EtOH (150 mL) was added LiCl
(7.3 g, 172.4 mmol). Then Na CO (1M, 155 mL) was added, followed by Pd(PPh ) Cl (403
2 3 3 2 2
mg, 0.57 mmol). The mixture was heated to reflux for 16h. The mixture was filtered through
Celite. The filtrate was diluted with H O (15 mL), extracted with ethyl acetate (15 mL x 3). The
combined organic layer was washed with brine (15 mL), dried over MgSO , filtered and
concentrated. The residue was triturated with TBME/ethyl acetate (v/v = 1/1, 50 mL). The cake
was dried in vaccum to afford compound 2 (4.4 g, yield 44.7%) as off-white solid. H NMR
(DMSO-d 400 MHz) δ 7.94 (d, J = 7.2 Hz, 2H), 7.79 (d, J = 9.2 Hz, 1H), 7.46 -7.42 (m, 2H),
7.38 - 7.36 (m, 1H), 6.86 (d, J = 9.2 Hz, 2H), 6.52 (s, 2H). MS (ESI) m/z (M+H) 172.0.
Ethyl 2-oxoacetate (26 mL, 128.50 mmol) was added to a solution of
compound 200A (4.4 g, 25.7 mmol) in MeOH (100 mL). The mixture was heated to 65 °C and
stirred for 15h. The mixture was concentrated. The residue was purified by Flash Column
Chromatography (Petroleum Ether/Ethyl Acetate = 3/1) to afford compound 200B (5.5 g, yield
52%, 69.8% purity) as brown oil. MS (ESI) m/z (M+H) 288.1.
K CO (6.61 g, 47.85 mmol) was added to a solution of compound 200B (5.5
g, 19.14 mmol) and tosylmethyl isocyanide (5.04 g, 25.84 mmol) in EtOH (190 mL). The
mixture was heated to 65 °C and stirred for 3h. The mixture was concentrated in vacum and the
residue was treated with Ethyl Acetate (100 mL) and H O (75 mL). The organic layer was
separated and the aqueous layer was extracted with Ethyl Acetate (50 mL x2). The combined
organic layer was washed with brine (100 mL), dried over MgSO , filtered and concentrated.
17681897_1 (GHMatters) P110989.NZ
The residue was purified by Flash Column Chromatography (Petroleum Ether/Ethyl Acetate =
/1 to 1/1) to afford (1.80 g, yield 30%) as yellow solid. H NMR (CDCl 400 MHz) δ 8.22 (s,
1H), 8.12 -8.10 (m, 2H), 8.01 (d, J = 7.2 Hz, 1H), 7.94 , (s, 1H), 7.76 - 7.74 (m, 1H), 7.56 -7.54
(m, 3H), 4.29 (q, J = 6.8 Hz, 2H), 1.33 (t, J = 6.8 Hz, 3H). MS (ESI) m/z (M+H) 295.0.
LiOH.H O (114 mg, 2.72 mmol) was added to a solution of compound 200C
(100 mg, 0.34 mmol,) in MeOH (5 mL). Then H O (0.5 mL) was added. The mixture was
stirred at 25 °C for 3h. The mixture was diluted with H O (25 mL) and the volatile solvent was
evaporated in vacuum. The residue was acidified to pH ~ 3 with 1N HCl. The mixture was
extracted with Ethyl Acetate (25 mL x 3). The combined organic layer was washed with brine
(20 mL), dried over MgSO , filtered and concentrated to afford compound 200D (90 mg, yield
99.5%) as yellow solid, which was used for next step directly. H NMR (DMSO-d 400 MHz) δ
8.50 (d, J=9.3 Hz, 1H), 8.38 (d, J=1.0 Hz, 1H), 8.24 (dd, J=1.9, 7.7 Hz, 2H), 8.13 (d, J=9.0 Hz,
1H), 7.85 (d, J=1.0 Hz, 1H), 7.66 - 7.55 (m, 3H).
Compound 200 (35 mg, yield 35.2%, white solid) was prepared as in Example
from the corresponding intermediate carboxylic acid, compound 200D. Hydrate was observed
in H NMR. Compound 200: H NMR (DMSO-d 400 MHz) δ 8.83 (br s, 1H), 8.34 - 8.25 (m,
2H), 8.19 (dd, J = 1.8, 7.8 Hz, 2H), 7.81 (br s, 1H), 7.75 (s, 1H), 7.66 - 7.48 (m, 5H), 7.34 - 7.20
(m, 5H), 5.32 - 5.23 (m, 1H), 3.24 (dd, J = 4.3, 14.1 Hz, 1H), 2.94 (dd, J = 9.7, 13.9 Hz, 1H).
MS (ESI) m/z (M+H) 441.1.
EXAMPLE 106
(S)-N-(4-(CYCLOPROPYLAMINO)-3,4-DIOXOPHENYLBUTANYL)(6-
PHENYLPYRIDAZINYL)-1H-IMIDAZOLECARBOXAMIDE (201)
Compound 201 (89 mg, yield 54.5%, yellow solid) was prepared as in Example
from the corresponding intermediate carboxylic acid, compound 200D. Hydrate was observed
on H NMR. Compound 201: H NMR (DMSO-d 400 MHz) δ 8.82 (br s, 0.8H), 8.51 (br s,
0.9H), 8.31 - 8.22 (m, 2.7H), 8.20 - 8.14 (m, 2.3H), 7.93 (s, 0.9H), 7.79 - 7.70 (m, 1.7H), 7.69 -
7.64 (m, 1.7H), 7.63 - 7.54 (m, 5.7H), 7.37 (br d, J=8.5 Hz, 0.9H), 7.31 (d, J=4.5 Hz, 3.6H), 7.28
- 7.17 (m, 5.2H), 5.35 - 5.28 (m, 1H), 4.42 - 4.35 (m, 0.9H), 3.23 (dd, J=4.0, 14.1 Hz, 0.7H),
3.07 (br s, 1.7H), 2.97 - 2.89 (m, 1.1H), 2.80 - 2.74 (m, 1.7H), 2.68 - 2.64 (m, 1.0H), 0.71 - 0.63
(m, 2.0H), 0.62 - 0.55 (m, 3.2H), 0.48 (br s, 1.6H). MS (ESI) m/z (M+H) 481.1.
17681897_1 (GHMatters) P110989.NZ
EXAMPLE 107
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)METHYL(2'-METHYL-
[1,1'-BIPHENYL]YL)-1H-PYRAZOLECARBOXAMIDE (202)
, Cs CO
Pd(PPh3)4 2 3 N
NH N
THF/H 80 °C, 12h
202A
To a solution of compound 83D (150 mg, 0.33 mmol) in THF (6 mL) and H O
(3 mL) was added Cs CO (168mg, 0.51 mmol,) and o-tolylboronic acid (89 mg, 0.66 mmol),
followed by Pd(PPh ) (38 mg, 0.033 mmol). Then the mixture was heated to 80 °C and stirred
for 12h. The reaction mixture was cooled to the room temperature and H O (10 mL) was added
to quenched the reaction and then the mixture was evaporated under reduced pressure. The water
phase was extracted with ethyl acetate (10 mL x 3). The combined organic layer was washed
with NaHCO (10 ml), H O (10 mL), brine (10 mL), dried over Na SO , filtered, evaporated
3 2 2 4
under reduced pressure. The crude product was triturated with isopropyl ether/acetonitrile(10/1,
mL) to afford compound 202A (50 mg, yield 32.5%) as yellow solid. H NMR (DMSO-d
400MHz) δ 8.54 (br d, J = 9.3 Hz, 1H), 8.20 (br d, J = 9.7 Hz, 1H), 7.66 - 7.46 (m, 1H), 7.38 (br
s, 1H), 7.35 - 7.19 (m, 12H), 7.14 (br d, J = 8.4 Hz, 1H), 6.61 - 6.51 (m, 1H), 6.01 - 5.66 (m,
1H), 4.45 (br s, 1H), 4.04 - 3.90 (m, 1H), 3.00 - 2.62 (m, 2H), 2.37 - 2.17 (m, 6H).
To a solution of compound 202A (46 mg, 98.2 umol) in DCM (10 mL) was
added DMP (125 mg, 294.5 umol) and the mixture was at 25 °C for 2h. The reaction mixture
was diluted with DCM (10 mL) and quenched with NaHCO /Na S O (1/1, 20 mL), then the
3 2 2 3
mixture was stirred for 0.25h. The mixture was extracted with DCM(10 mL x 2), the combined
organic layer was washed with NaHCO (10 mL x 3) and brine (10 mL x 3), dried over
anhydrous Na SO , filtered, evaporated under reduced pressure. The crude product was purified
by preparatory-HPLC (base) to afford 202 (30 mg, yield 60.65%) was obtained as white solid.
H NMR (CDCl , 400MHz) δ 7.43 - 7.39 (m, 2H), 7.39 - 7.35 (m, 2H), 7.30 - 7.28 (m, 3H), 7.26
- 7.21 (m, 4H), 7.03 (dd, J = 1.9, 7.6 Hz, 2H), 6.72 (br s, 1H), 6.52 (s, 1H), 6.37 (br d, J = 7.5 Hz,
17681897_1 (GHMatters) P110989.NZ
1H), 5.66 - 5.60 (m, 1H), 5.55 (br s, 1H), 3.38 (dd, J = 5.4, 14.2 Hz, 1H), 3.16 (dd, J = 7.3, 14.3
Hz, 1H), 2.36 (s, 3H), 2.29 - 2.27 (m, 3H). MS (ESI) m/z (M+H) 467.1.
EXAMPLE 108
(S)-N-(4-(CYCLOPROPYLAMINO)-3,4-DIOXOPHENYLBUTANYL)METHYL-
1-(6-METHYL(TRIFLUOROMETHYL)PYRIDINYL)-1H-PYRAZOLE
CARBOXAMIDE (206)
H NHN
LiOH•H O
N CF
CH OH-H O
206A
206B
To a solution of 2-hydrazinylmethyl(trifluoromethyl)pyridine (500 mg,
2.62 mmol) in CH COOH (10 mL) was added ethyl 2-(methoxyimino)oxopentanoate (490.4
mg, 2.62 mmol), then the mixture was stirred at 120 °C for 2 hours. The mixture was diluted
with CH Cl (100 mL) and washed by saturated sodium bicarbonate (30 mL x 2 ) and saturated
brine (30 mL x 2 ), dried with anhydrous Na SO , filtered and concentrated in vacuum. The
residue was purified by flash column chromatography (SiO , Petroleum Ether : Ethyl Acetate =
/1 to 3/1). Compound 206A (200.0 mg, 24.37% yield) was obtained as white solid. H NMR
(400 MHz, CDCl ) δ 7.72 (s, 1H), 7.33(s, 1H), 6.68(s, 1H), 4.33 - 4.28(m. 2H), 2.60(s, 3H),
3.23(s, 3H), 1.31 - 1.20(m, 3H).
To a mixture of compound 206A (180.0 mg, 574.58 umol) in MeOH (6 mL)
and H2O (3 mL) was added LiOH•H2O (96.4 mg, 2.30 mmol) in one portion and the mixture was
stirred at 25 °C for 6 hours. The reaction mixture was concentrated under reduced pressure to
remove MeOH. Then the mixture was diluted with H O (10 mL) and the pH was adjusted to ~ 3
with 1N HCl and then extracted with EtOAc (40 mL x 3). The combined organic layers were
SO , filtered and concentrated under
washed with brine (30 mL), dried over anhydrous Na2 4
reduced pressure to give intermediate compound 206B (145.0 mg, 88.48% yield) as white solid.
H NMR (400 MHz, DMSO-d ) δ 7.80 (s, 1H), 7.73(s, 1H), 6.79(d, J = 4 Hz, 1H), 2.56(s, 3H),
2.29(s, 3H).
Compound 206 (52.0 mg, 52.16% yield, pale yellow solid) was prepared as in
Example 41 from the corresponding intermediate carboxylic acid, compound 206B. Compound
17681897_1 (GHMatters) P110989.NZ
206: H NMR (400 MHz, CDCl ) δ 8.65 (J = 7.6 Hz, 1H), 7.86 (s, 1H), 7.22 (s, 1H), 7.18 - 7.16
(m, 3H), 7.04 – 7.03 (m, 2H), 6.88 (s, 1H), 6.70 (s, 1H), 5.77 - 5.72 (m, 1H), 3.46-3.41 (m, 1H),
3.35-3.30 (m, 1H), 2.83 - 2.79 (m, 1H), 2.34 (s, 3H), 2.32 (s, 3H), 0.91 - 0.86 (m, 2H), 0.63-0.60
(m, 2H). MS (ESI) m/z (M+1) 500.2.
EXAMPLE 109
(S)-N-(4-(CYCLOPROPYLAMINO)-3,4-DIOXOPHENYLBUTANYL)METHYL-
1-(6-METHYL(TRIFLUOROMETHYL)PYRIDINYL)-1H-PYRAZOLE
CARBOXAMIDE (208)
KOTMS
HOAc, 118 °C, 5 hrs THF, 25 °C
NHNH
208A 208B
A mixture of ethyl 2-(methoxyimino)oxopentanoate (558.2 mg, 2.98 mmol)
and 6-hydrazinylnicotinonitrile (400 mg, 2.98 mmol) in AcOH (5 mL) was stirred at 118 °C for 5
hours. The reaction mixture was cooled to 25 °C and concentrated under reduced pressure to
give a residue, which was diluted with CH Cl (100 mL). The organic phase was washed with
saturated aqueous NaHCO (20 mL), dried over anhydrous Na SO , filtered and concentrated
3 2 4
under reduced pressure to give a residue, which was purified by column chromatography (SiO2,
Petroleum ether/Ethyl acetate = 1:0 to 5:1) to afford compound 208A (160 mg, 19.09% yield) as
a white solid, but structure (proposed structure) could not be confirmed by N-H HMBC. H
NMR (400 MHz, CDCl ): δ 8.66 (dd, J = 0.8, 2.4 Hz, 1H), 8.07 (dd, J = 2.4, 8.4 Hz, 1H), 7.88
(dd, J = 0.8, 8.4 Hz, 1H), 6.67 (s, 1H), 4.35 (q, J = 6.8 Hz, 2H), 2.37 (s, 3H), 1.32 (t, J = 7.2 Hz,
3H). MS (ESI) m/z (M+1) 257.1.
To a solution of compound 208A (100 mg, 390.23 umol) in THF (4 mL) was
added KOTMS (100 mg, 780.46 umol), then the mixture was stirred at 25 °C for 0.3 hour. The
mixture was diluted by petroleum ether (20 mL), the precipitate was filtered to afford the residue.
The mixture was diluted by petroleum ether (20 mL), the precipitate was filtered to afford
intermediate compound 208B (80 mg, 76.98% yield) as white solid.
17681897_1 (GHMatters) P110989.NZ
Compound 208 (13.5 mg, 27.13% yield, white solid) was prepared as in
Example 5 from the corresponding starting materials, compounds 208B and 12G. Compound
208: H NMR (400 MHz, DMSO-d ): δ 9.09 (d, J = 7.2 Hz, 1H), 8.49 (d, J = 1.6 Hz, 1H), 8.40 -
8.36 (m, 1H), 8.10 (br s, 1H), 7.86 (br s, 1H), 7.82 (d, J = 8.4 Hz, 1H), 7.31 - 7.23 (m, 5H), 6.51
(s, 1H), 5.35 - 5.29 (m, 1H), 3.19 - 3.13 (m, 1H), 2.84 - 2.76 (m, 1H). MS (ESI) m/z (M+1)
403.1.
EXAMPLE 110
COMPOUNDS 209, 439-441, 443-444
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)METHYL(PYRIDINYL)-
1H-PYRAZOLECARBOXAMIDE (209)
Cu(OAc)2 Pyridine
55 hrs
°C,18
209B
209A
NaOH
(1M)
EtOH, 25 °C, 1 hr
O OH
209A
209C
To a solution of ethyl 3-methyl-1H-pyrazolecarboxylate (3.0 g, 19.46
mmol), pyridinylboronic acid (5.98 g, 48.65 mmol) in Pyridine (40 mL) was added Cu(OAc)
(1.8 g, 9.73 mmol). The mixture was stirred at 55 °C for 18 hrs. The mixture was filtered and
concentrated in vacuum. The residue was purified by flash silica gel chromatography (ISCO®;
120 g SepaFlash® Silica Flash Column, Eluent of 0~50% Ethyl acetate/Petroleum ether gradient
@ 40 mL/min). Compound 209A (850 mg, 18.91% yield) was obtained as white solid.
Compound 209B (850 mg, 18.91% yield) was obtained as white solid. Compound 209A (850
mg, 18.91% yield, white solid): H NMR (400MHz, CDCl ) δ 8.75 - 8.65 (m, 2H), 7.42 (d, J =
6.0 Hz, 2H), 6.87 (s, 1H), 4.33 - 4.25 (m, 2H), 2.36 (s, 3H), 1.32 - 1.28 (m, 3H).
To a mixture of compound 209A (600 mg, 2.59 mmol) in EtOH (5 mL) was
added aq. NaOH (1 M, 2.59 mL) in one portion and the mixture was stirred at 25°C for 1 hour.
The reaction mixture was concentrated under reduced pressure to remove EtOH. The residue
17681897_1 (GHMatters) P110989.NZ
was adjusted to pH ~ 3 with 1N HCl, and then extracted with EtOAc (200 mL x 4). The
combined organic layers were washed with brine (80 mL), dried over anhydrous Na SO , filtered
and concentrated under reduced pressure to afford intermediate compound 209C (390 mg,
74.10% yield) as a white solid. H NMR (400 MHz, DMSO-d ): δ 8.63 (br s, 2H), 7.50 (br d, J =
.2 Hz, 2H), 6.90 (s, 1H), 2.26 (s, 3H).
Compound 209 (27.1 mg, 25.46% yield, white solid) was prepared as in
Example 5 from the corresponding intermediate carboxylic acid, compound 209C. Compound
209: H NMR (400MHz, DMSO-d ) δ 9.33 (d, J = 7.8 Hz, 1H), 8.55 - 8.49 (m, 2H), 8.17 (s, 1H),
7.92 (s, 1H), 7.37 - 7.27 (m, 5H), 7.22 - 7.18 (m, 2H), 6.60 (s, 1H), 5.33 (s, 1H), 3.28 - 3.21 (m,
1H), 2.88 - 2.79 (m, 1H), 2.28 (s, 3H). MS (ESI) m/z (M+H) 378.1.
N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)METHYL(4-
PHENOXYPHENYL)-1H-PYRAZOLECARBOXAMIDE (439)
Compound 439 (65 mg, yield: 61.4%, yellow solid) was prepared from ethyl 3-
methyl-1H-pyrazolecarboxylate which was subjected to coupling with (4-
phenoxyphenyl)boronic acid as in compound 209 followed by ester hydrolysis and coupling with
intermediate 274D using procedures as in compound 12 to obtain compound 439. Compound
439: H NMR (400MHz, DMSO-d ) δ 9.08 (br d, J = 7.3 Hz, 1H), 8.12 (br s, 1H), 7.87 (br s,
1H), 7.44 (br t, J = 7.4 Hz, 2H), 7.31 - 7.13 (m, 8H), 7.06 (br d, J = 7.9 Hz, 2H), 6.93 (br d, J =
8.4 Hz, 2H), 6.57 (s, 1H), 5.26 (br s, 1H), 3.20 (br d, J = 14.6 Hz, 1H), 2.81 (br t, J = 12.3 Hz,
1H), 2.24 (s, 3H). MS (ESI) m/z (M+H) 469.2.
N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)METHYL(4-((TETRAHYDRO-
2H-PYRANYL)OXY)PHENYL)-1H-PYRAZOLECARBOXAMIDE (440)
Compound 440 (90 mg, yield: 58%, white solid) was prepared from ethyl 1-(4-
hydroxyphenyl)methyl-1H-pyrazolecarboxylate which was subjected to mitsunobu
coupling with tetrahydro-2H-pyranol followed by ester hydrolysis and coupling with
intermediate 274D using procedures as in compound 12 to obtain compound 440. Compound
440: H NMR (400MHz, DMSO-d ) δ 9.03 (d, J = 7.8 Hz, 1H), 8.11 (s, 1H), 7.87 (s, 1H), 7.35 -
7.23 (m, 5H), 7.07 (d, J = 8.8 Hz, 2H), 6.92 (d, J = 9.0 Hz, 2H), 6.53 (s, 1H), 5.27 - 5.14 (m,
1H), 4.59 - 4.54 (m, 1H), 3.89 - 3.82 (m, 2H), 3.49 (t, J = 9.3 Hz, 2H), 3.19 (dd, J = 3.1, 13.9 Hz,
17681897_1 (GHMatters) P110989.NZ
1H), 2.81 (dd, J = 10.8, 13.8 Hz, 1H), 2.23 (s, 3H), 1.97 (d, J = 12.0 Hz, 2H), 1.58 (d, J = 7.8 Hz,
2H). MS (ESI) m/z (M+H) 477.2.
N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)(4-(4-
((DIETHYLAMINO)METHYL)PHENOXY)PHENYL)METHYL-1H-PYRAZOLE
CARBOXAMIDE HYDROCHLORIDE (441)
Compound 441 (14 mg, yield: 26.21%, white solid) was prepared from ethyl 1-
(4-hydroxyphenyl)methyl-1H-pyrazolecarboxylate which was subjected to coupling with
(4-((diethylamino)methyl)phenyl)boronic acid as in compound 209 followed by ester hydrolysis
and coupling with intermediate 274D using procedures as in compound 12 to obtain compound
441. Compound 441: H NMR (400MHz, DMSO-d ) δ 11.55 (br. s, 1H), 7.77 - 7.71 (m, 2H),
7.37 - 7.15 (m, 8H), 7.12 - 7.06 (m, 2H), 6.99 (d, J = 9.0 Hz, 2H), 6.57 (s, 2H), 6.13 - 5.96 (m,
1H), 4.72 - 4.63 (m, 1H), 4.23 - 4.13 (m, 2H), 3.27 - 3.18 (m, 1H), 3.13 - 2.92 (m, 5H), 2.28 (s,
3H), 1.34 (t, J = 3.5, 7.3 Hz, 6H). MS (ESI) m/z (M+H) 554.3.
N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)(4-(2-(2-
METHOXYETHOXY)ETHOXY)PHENYL)METHYL-1H-PYRAZOLE
CARBOXAMIDE (443)
Compound 443 (75 mg, yield: 61.3%, white solid) was prepared from ethyl 3-
methyl-1H-pyrazolecarboxylate which was subjected to coupling with (4-
(benzyloxy)phenyl)boronic acid as in compound 209 followed by hydrogenolysis to yield the
phenolic derivative which was subjected to mitsunobu coupling with 2-(2-methoxyethoxy)ethan-
1-ol followed by ester hydrolysis and coupling with intermediate 274D using procedures as in
compound 12 to obtain compound 443. Compound 443: H NMR (400MHz, DMSO-d ) δ 9.02
(br d, J = 7.8 Hz, 1H), 8.10 (s, 1H), 7.86 (s, 1H), 7.37 - 7.20 (m, 5H), 7.08 (br d, J = 8.8 Hz, 2H),
6.89 (br d, J = 9.0 Hz, 2H), 6.53 (s, 1H), 5.28 - 5.17 (m, 1H), 4.16 - 4.06 (m, 2H), 3.80 - 3.71 (m,
2H), 3.65 - 3.56 (m, 2H), 3.51 - 3.44 (m, 2H), 3.25 (s, 3H), 3.21 - 3.14 (m, 1H), 2.81 (br dd, J =
.7, 13.7 Hz, 1H), 2.23 (s, 3H). MS (ESI) m/z (M+H) 495.2.
N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)(3-(2-(2-
METHOXYETHOXY)ETHOXY)PHENYL)METHYL-1H-PYRAZOLE
CARBOXAMIDE (444)
17681897_1 (GHMatters) P110989.NZ
Compound 444 (60 mg, yield: 39.58%, white solid) was prepared from ethyl 3-
methyl-1H-pyrazolecarboxylate which was subjected to coupling with (3-
(benzyloxy)phenyl)boronic acid as in compound 209 followed by hydrogenolysis to yield the
phenolic derivative which was subjected to mitsunobu coupling with 2-(2-methoxyethoxy)ethan-
1-ol followed by ester hydrolysis and coupling with intermediate 274D using procedures as in
compound 12 to obtain compound 444. Compound 444: H NMR (400MHz, DMSO-d ) δ 9.07
(d, J = 7.3 Hz, 1H), 8.09 (s, 1H), 7.85 (s, 1H), 7.35 - 7.18 (m, 6H), 6.93 - 6.81 (m, 2H), 6.71 (d, J
= 8.2 Hz, 1H), 6.54 (s, 1H), 5.28 (s, 1H), 4.05 (s, 2H), 3.72 (s, 2H), 3.57 (d, J = 4.2 Hz, 2H), 3.46
(d, J = 4.2 Hz, 2H), 3.24 (s, 3H), 3.18 (s, 1H), 2.88 - 2.77 (m, 1H), 2.24 (s, 3H). MS (ESI) m/z
(M+H) 495.2.
EXAMPLE 111
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)METHYL(3-PHENYL-1H-
PYRAZOLYL)ISOXAZOLECARBOXAMIDE (211)
LiOH.H O
N K DMF
CO , THF, H O
O OH
211A
211B
To a mixture of ethyl 5-chloromethylisoxazolecarboxylate (400 mg, 2.1
mmol) and 3-phenyl-1H-pyrazole (365 mg, 2.5 mmol) in DMF (3 mL) was added K CO (1.2 g,
8.4 mmol) in one portion. Then the mixture was stirred at 80 °C for 12 hours. Then H O (9 mL)
was added into the mixture, and the aqueous phase was extracted with EtOAc (15 mL x 3), and
the combined organic layer was concentrated to give a residue. The residue was purified by
column chromatography (SiO , Petroleum ether: Ethyl acetate = 300: 1 to 30: 1). Compound
211A (256 mg, yield: 40.8%, pale yellow solid): H NMR (400MHz, CDCl ) δ 8.62 (d, J = 2.6
Hz, 1H), 7.93 (d, J = 6.8 Hz, 2H), 7.49 - 7.37 (m, 3H), 6.86 (d, J = 2.6 Hz, 1H), 4.37 (q, J = 7.1
Hz, 2H), 2.53 (s, 3H), 1.40 - 1.34 (m, 2H), 1.41 - 1.33 (m, 1H).
To a solution of compound 211A (150 mg, 504.5 umol) in THF (2 mL) and
H O (500 uL) was added LiOH.H O (31.8 mg, 756.8 umol) in one portion. Then the mixture was
stirred at 25 °C for 3 hours. TLC (Petroleum ether: Ethyl acetate = 1: 1, R ~ 0.45) indicated
17681897_1 (GHMatters) P110989.NZ
compound 211A was consumed completely and one new main spot formed. The pH of the
aqueous phase was adjusted to around 5 by adding HCl (1M), and then the residue was
concentrated on a rotary evaporator to give intermediate compound 211B (92 mg, yield: 67.7%)
as a white solid. H NMR (400MHz, DMSO-d ) δ 9.39 (br s, 1H), 7.92 (d, J = 7.0 Hz, 2H), 7.50
- 7.43 (m, 2H), 7.42 - 7.36 (m, 1H), 7.02 (s, 1H), 2.51 - 2.51 (m, 3H). MS (ESI) m/z (M+H)
269.9.
Compound 211 (20 mg, yield: 44.7%, white solid) was prepared as in Example
from the corresponding intermediate carboxylic acid, compound 211B. Compound 211: H
NMR (400MHz, CDCl ) δ 10.59 (br d, J = 6.8 Hz, 1H), 8.19 (d, J = 2.6 Hz, 1H), 7.74 - 7.65 (m,
2H), 7.45 - 7.38 (m, 3H), 7.12 - 7.05 (m, 3H), 7.03 - 6.98 (m, 2H), 6.89 (d, J = 2.4 Hz, 1H), 6.72
(br s, 1H), 5.73 - 5.64 (m, 1H), 5.47 (br s, 1H), 3.38 (dd, J = 5.3, 14.1 Hz, 1H), 3.06 (dd, J = 8.4,
13.9 Hz, 1H), 2.56 (s, 3H). MS (ESI) m/z (M+H) 444.1.
EXAMPLE 112
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)METHYL(5-
PHENYLOXAZOLYL)-1H-PYRAZOLECARBOXAMIDE (212)
N O N
O N O
NHNH
LiOH.H O
O 212A
HOAc
212D
212C
212B
A solution of 2-chlorophenyloxazole (compound 114A) (560 mg, 3.12
mmol) and NH NH .H O (468 mg, 9.35 mmol) in dioxane (10 mL) was heated to reflux for 3hr.
2 2 2
The mixture was concentrated to give compound 212A (610 mg, crude) as yellow solid. H
NMR (400MHz, DMSO-d ) δ 8.27 (br s, 1H), 7.48 (br d, J = 7.9 Hz, 1H), 7.36 (br t, J = 7.7 Hz,
2H), 7.29 (s, 1H), 7.19 (br t, J = 7.4 Hz, 2H), 4.53 - 4.12 (m, 1H), 4.35 (br s, 1H).
A solution of O-methylhydroxylamine (1.74 g, 20.8 mmol) in H O (20 mL)
was added dropwise to a solution of methyl 2,4-dioxopentanoate (5 g, 34.7 mmol) in ethanol (45
mL), H O (25 mL), the mixture was stirred at 25 °C for 12 hrs. The organic solvent was
removed under vacuum, the water layer was extracted with ethyl acetate (20 mL x 2), the
combined organic layer was washed with brine (20 mL), dried over Na2SO4, filtered and
17681897_1 (GHMatters) P110989.NZ
concentrated, the residue was purified by silica gel chromatography to give compound 212B (3.3
g, yield: 54.9%), as yellow oil. H NMR (400MHz, CDCl -d) δ 4.06 (s, 3H), 3.87 (s, 3H), 3.72
(s, 2H), 2.21 (s, 2H).
A mixture of compound 212B (360 mg, 2.05 mmol) and compound 212A (355
mg, 2.05 mmol) in dioxane (5 mL) was heated to 110 °C for 12 hrs. The mixture was
concentrated, the residue was purified by TLC (Petroleum ether: Ethyl acetate = 5: 1) to give
compound 212C (140 mg, yield: 24.1%) as yellow oil.
A mixture of compound 212C (140 mg, 494 umol) and LiOH.H O (31.1 mg,
741 umol) in THF (5 mL), H O (1 mL) was stirred at 25°C for 2 hrs. TLC (Petroleum ether:
Ethyl acetate = 1: 1, R ~ 0) showed the reaction was complete, the organic solvent was removed
under reduced pressure, the water layer extracted with ethyl acetate (3 mL), then the water layer
was adjusted to pH ~ 3 with 1N HCl to give a precipitate, the solid was filtered and dried to give
compound 212D (100 mg, yield: 75.2%) as yellow solid. H NMR (400MHz, DMSO-d ) δ 7.85
(s, 1H), 7.74 - 7.69 (m, 2H), 7.48 (t, J = 7.7 Hz, 2H), 7.44 - 7.37 (m, 1H), 6.91 (s, 1H), 2.28 (s,
3H).
Compound 212 (34 mg, yield: 52.6%, white solid) was prepared as in Example
from the corresponding intermediate carboxylic acid, compound 212D. Compound 212: H
NMR (400MHz, DMSO-d6) δ 9.17 (br d, J = 7.5 Hz, 1H), 8.08 (br s, 1H), 7.83 (br s, 1H), 7.73
(s, 1H), 7.62 (br d, J = 7.5 Hz, 2H), 7.48 - 7.41 (m, 2H), 7.40 - 7.34 (m, 1H), 7.25 (s, 4H), 7.19
(br d, J = 4.0 Hz, 1H), 6.92 (s, 1H), 5.28 (br d, J = 7.7 Hz, 1H), 3.16 (br dd, J = 3.0, 14.0 Hz,
1H), 2.81 (br dd, J = 10.6, 13.7 Hz, 1H), 2.27 (s, 3H). MS (ESI) m/z (M+H) 444.1.
17681897_1 (GHMatters) P110989.NZ
EXAMPLE 113
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)CHLORO
PHENYLISOTHIAZOLECARBOXAMIDE (213)
NaHSO
,NaCN
LAH,THF
H CN
HN HN
MeOH/H O/EtOAc
0 °C, 1h
O OH
0-25 °C, 20 h
O O O O O O
213C
213A
213B
HCl/dioxane
OH H N
K CO , H O ,
2 3 2 2
DMSO
O NH
213D
conc. H SO
1) 2 4
NaNO
213F
A mixture of (tert-butoxycarbonyl)-L-phenylalanine (50 g, 188.47 mmol), N-
methoxymethanamine (20 g, 207.32 mmol, HCl), NMM (57 g, 565.41 mmol) and HOBT (25 g,
188.47 mmol) in CHCl (700 mL) was degassed and purged with N for 3 times at 0 °C, then
EDCI (54 g, 282.71 mmol) was added in portions. The mixture was stirred at 25 °C for 16h
under N atmosphere. The reaction mixture was quenched by addition H O (500 mL). The
organic layer was separated, washed with 1N HCl (300 mL x 2), saturated aqueous NaHCO (300
mL x 3), and brine (300 mL), dried over Na SO , filtered and concentrated under reduced
pressure to give a residue. The residue was dissolved with petroleum ether (300 mL) and stirred
for 2h, filtered and concentrated under reduced pressure to give compound 213A (46 g, yield:
79.15%) as a colorless oil. H NMR (400MHz, CDCl3) δ 7.27 - 7.13 (m, 5H), 5.26 - 4.85 (m,
2H), 3.64 (s, 3H), 3.15 (br s, 3H), 3.04 (br dd, J=5.8, 13.6 Hz, 1H), 2.91 - 2.81 (m, 1H), 1.37 (s,
9H). MS (ESI) m/z (M +23) 331.0.
To a solution of LiAlH (5.32 g, 140.09 mmol) in THF (1L) was added a
solution of compound 213A (36 g, 116.74 mmol) in THF (500 mL) at 0 °C. After addition, the
reaction mixture was stirred for 1h at 0 °C. The reaction mixture was quenched by addition ethyl
17681897_1 (GHMatters) P110989.NZ
acetate (200 mL) and 1N HCl (200 mL), and then extracted with EtOAc (300 mL x 3). The
combined organic layers were washed with 1N HCl (300mL x 2), saturated aqueous NaHCO
(300mLx 3), and brine (300 mL), dried over Na SO , filtered and concentrated under reduced
pressure to give compound 213B (25.3 g, yield: 86.93%) as a white solid. H NMR (400MHz,
CDCl ) δ 9.61 (s, 1H), 7.33 - 7.24 (m, 3H), 7.16 (br d, J = 7.1 Hz, 2H), 5.16 - 5.03 (m, 1H), 4.40
(q, J = 6.6 Hz, 1H), 3.10 (br d, J = 5.3 Hz, 2H), 1.42 (s, 9H).
To a solution of compound 213B (32 g, 128.36 mmol) in MeOH (250 mL) was
added dropwise a solution of NaHSO (13.5 g) in H O (400 mL) at 0-5 °C. After that, the
reaction mixture was stirred at 28 °C for 5h. NaCN (6.6 g, 134.78 mmol) in H O (600 mL) was
added into the reaction mixture followed by EtOAc (1.2 L). After that, the reaction mixture was
stirred at 28 °C for 14h. The mixture was separated and the organic layer was washed with brine
(500 mL). The mixture was dried over Na SO and concentrated to afford compound 213C (35
g, yield: 98.68%) as a light yellow gum. H NMR (400MHz, DMSO-d ) δ 7.26 - 7.14 (m, 6H),
6.82 - 6.70 (m, 1H), 4.57 - 4.28 (m, 1H), 3.88 - 3.72 (m, 1H), 3.01 - 2.58 (m, 2H), 1.31 - 1.22 (m,
9H). MS (ESI) m/z (M -55) 220.9.
To a solution of compound 213C (35 g, 126.66 mmol) and K CO (35 g,
253.32 mmol,) in DMSO (400 mL) was added H O (148 g, 4.35 mol) at 0 °C. After addition,
the reaction mixture was stirred at 25 °C for 2h. The reaction mixture was filtered to give a
residue. The residue was washed with saturated aqueous Na S O (100 mL x 2) and H O (100
2 2 3 2
mL), dissolved with toluene (200 mL), concentrated under reduced pressure to remove H O. The
filtrate was quenched with saturated aqueous Na2SO3 slowly at 0 °C. The mixture was extracted
with EtOAc (200 mL x 3) and the combined extracts were washed with saturated aqueous
Na SO (300 mL x 3), brine (200 mL). The organic layer was dried over Na SO , filtered and
2 3 2 4
concentrated under reduced pressure to give compound 213D (37.5 g, yield: 88.51%) as a white
solid. H NMR (400MHz, DMSO-d ) δ 7.29 - 7.16 (m, 7H), 6.64 - 6.09 (m, 1H), 5.74 - 5.61 (m,
1H), 4.09 - 3.67 (m, 2H), 2.86 - 2.56 (m, 2H), 1.36 - 1.22 (m, 9H). MS (ESI) m/z (M -100+H)
194.9.
To a solution of compound 213D (41 g, 139.29 mmol) in EtOAc (300 mL) was
added HCl/EtOAc (4M, 696.45 mL) at 0 °C. After addition, the reaction mixture was stirred at
°C for 2h. The reaction mixture was filtered to give a residue. The residue was washed with
17681897_1 (GHMatters) P110989.NZ
ethyl acetate (30 mL), concentrated under reduced pressure to give compound 12G (26 g, yield:
66.35%, HCl) as a brown solid. H NMR (400MHz, DMSO-d ) δ 8.42 - 7.95 (m, 3H), 7.60 -
7.43 (m, 2H), 7.37 - 7.12 (m, 6H), 4.38 - 3.79 (m, 2H), 3.73 - 3.62 (m, 1H), 3.03 - 2.73 (m, 2H).
MS (ESI) m/z (M + H) 195.1.
To a 100 mL round-bottom placed compound 96B (2.00 g, 9.06 mmol) was
added H SO (27.60 g, 281.40 mmol) dropwise, and stirred at 135 °C for 1h. Then, the mixture
was added NaNO (907 mg, 13.14 mmol) in H O (10 mL) dropwise at 0 °C. The resulting
solution was stirred at 50 °C for 0.5h. The reaction mixture was diluted with H O (50 mL) and
extracted with ethyl acetate (50 mL x 3). The combined organic layers were extracted with 10%
NaOH (50 mL x 2). The aqueous phase was adjusted to 3 with 1N HCl, extracted with ethyl
acetate (50 mL x 3). The combined organic layers were washed with brines (50 mL), dried
Na SO , filtered and concentrated under reduced pressure to give a compound 213F (1.17 g,
yield: 49.13%) as a yellow solid. H NMR (400MHz, DMSO-d ) δ 7.55 (d, J=1.3 Hz, 5H). MS
(ESI) m/z (M +H) 239.9.
Compound 213 (65 mg, yield: 40.23%, gray solid) was prepared as in Example
from the corresponding starting materials, compounds 12G and 213F. H NMR (400MHz,
DMSO-d ) δ 9.35 (d, J=7.3 Hz, 1H), 8.19 (br s, 1H), 7.91 (br s, 1H), 7.51 - 7.32 (m, 5H), 7.27 -
7.17 (m, 5H), 5.71 - 5.21 (m, 1H), 3.17 (dd, J = 3.4, 14.2 Hz, 1H), 2.72 (dd, J = 10.4, 14.1 Hz,
1H). MS (ESI) m/z (M +H) 414.0.
EXAMPLE 114
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)METHYL(THIAZOL
YL)-1H-PYRAZOLECARBOXAMIDE (215)
NHNH N
•HCl
NaOH
aq. N
MeOH
HOAc, reflux
215A
215B
A mixture of 2-hydrazinylthiazole hydrochloride (600 mg, 3.9 mmol, HCl salt)
and ethyl 2-(methoxyimino)oxopentanoate (815 mg, 4.35 mmol) in AcOH (15 mL) was stirred
at 110 °C for 2h. The reaction mixture was concentrated under reduced pressure to remove
AcOH. The residue was treated with H O (50 mL) and ethyl acetate (50 mL), and then the
mixture was acidified with saturated aqueous NaHCO till the aqueous phase pH ~ 7 - 8. The
17681897_1 (GHMatters) P110989.NZ
separated aqueous layer was extracted with ethyl acetate (80 mL x 3), the combined organic
layers were washed with saturated aqueous. NaCl (100 mL), dried over Na SO , filtered under
reduced pressure to give crude product, which was purified by Flash Column Chromatography
(petroleum ether:ethyl acetate = 1~9) to afford compound 215A (138 mg, yield 12.6%) as white
solid. Compound 215A: H NMR (DMSO-d 400 MHz) δ 7.71 - 7.69 (m, 1H), 7.66 (d, J=3.5
Hz, 1H), 6.87 (s, 1H), 4.23 (q, J=7.1 Hz, 2H), 2.26 (s, 3H), 1.20 - 1.15 (m, 3H). MS (ESI) m/z
(M+H) 237.9.
To a mixture of compound 215A (130 mg, 0.55 mmol) in MeOH (10 mL) was
added NaOH (2M, 1.4 mL) in one portion at 25 °C. After stirred at 25 °C for 1.5h, the reaction
mixture was concentrated under reduced pressure to remove MeOH. The residue was added H O
(10 mL) and extracted with ethyl acetate (10 mL), the separated aqueous phase was acidified
with 1M HCl till pH ~ 5 - 6. The solid was separated and filtered under reduced pressure to
afford compound 215B (70 mg, crude) as white solid. Compound 215B: H NMR (CDCl 400
MHz) δ 7.56 (d, J = 3.7 Hz, 1H), 7.21 - 7.17 (m, 2H), 2.37 (s, 3H).
Compound 215 (10 mg, yield 53.7%, white solid) was prepared as in Example
from the corresponding intermediate carboxylic acid, compound 215B. Compound 215: H
NMR (CDCl 400 MHz) δ 11.76 (s, 1H), 7.27 - 7.18 (m, 5H), 7.17 - 7.12 (m, 1H), 7.10 - 7.00
(m, 2H), 6.78 (s, 1H), 5.83 - 5.74 (m, 1H), 5.50 (s, 1H), 3.48 - 3.40 (m, 1H), 3.28 - 3.18 (m, 1H),
2.32 (s, 3H). MS (ESI) m/z (M+H) 384.0.
EXAMPLE 115
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)METHYL(THIAZOL
YL)-1H-PYRAZOLECARBOXAMIDE (219)
NaOH
NHNH N
S HOAc, reflux
•HCl
MeOH
219B
219A
To a solution of 2-hydrazinylthiazole hydrochloride (700 mg, 4.39 mmol, HCl
salt) in CH COOH (15 mL) was added ethyl 2,4-dioxopentanoate (632 uL, 4.48 mmol) drop wise
, then the mixture was heated to 120 °C and stirred for 2h. Remove the solvent under reduced
pressure, the residue was dissolve in ethyl acetate (5 mL) and treated with NaHCO until pH ~ 8.
The organic layer was collected and evaporated under reduced pressure. The residue was purified
17681897_1 (GHMatters) P110989.NZ
by Flash Column Chromatography (Petroleum Ether/Ethyl Acetate = 1/ 0 to 10/1) to afford
compound 219A (160 mg, yield 15.4%) as white solid. Compound 219A: H NMR (CDCl ,
400MHz) δ 7.60 (d, J=3.5 Hz, 1H), 7.18 (d, J = 3.5 Hz, 1H), 6.70 (d, J = 0.9 Hz, 1H), 4.42 (q, J =
7.1 Hz, 2H), 2.74 (d, J = 0.9 Hz, 3H), 1.42 (t, J = 7.1 Hz, 3H).
To a solution of compound 219A (160 mg, 674.31 umol) in MeOH (10 mL)
was added NaOH (2M, 2.00 mL) dropwise and then the mixture was stirred at 25°C for 2h. The
reaction mixture was diluted with H O (5 mL), evaporated under reduced pressure and then the
water phase was extracted with MBTE (5 mL). The water phase (acidified with HCl, pH ~ 3)
was extracted with Ethyl Acetate (10 mL x 3), then the organic (Ethyl Acetate) was collected,
washed with saturate brine, dried over anhydrous Na SO and filtered ,concentrated under
reduced pressure. Compound 219B (110 mg, yield 78%, white solid): H NMR (DMSO-d
400MHz) δ 7.72 (d, J=3.5 Hz, 1H), 7.64 (d, J=3.5 Hz, 1H), 6.77 (d, J=0.7 Hz, 1H), 2.67 (s, 3H).
Compound 219 (15 mg, yield 31.8%, white solid) was prepared as in Example
from the corresponding intermediate carboxylic acid, compound 219B. Compound 219: H
NMR (DMSO-d 400MHz) δ 7.58 (d, J = 3.5 Hz, 1H), 7.37 - 7.26 (m, 3H), 7.26 - 7.24 (m, 1H),
7.22 - 7.15 (m, 3H), 6.78 (br s, 1H), 6.65 (s, 1H), 5.73 - 5.64 (m, 1H), 5.58 (br s, 1H), 3.43 (dd, J
= 5.4, 14.0 Hz, 1H), 3.26 (dd, J = 6.9, 14.2 Hz, 1H), 2.71 (s, 3H). MS (ESI) m/z (M+H) 384.1.
EXAMPLE 116
(2S,4R)-N-((S)AMINO-3,4-DIOXOPHENYLBUTANYL)(BENZYLOXY)
PHENYLPYRROLIDINECARBOXAMIDE (220)
O B(OH)
HCl/MeOH
LiOH.H O O
THF N
Cu(OAc) ,Py,4 OH
MS,DCE
220B
BnO 220C
220A
A mixture of (2S,4R)(benzyloxy)(tert-butoxycarbonyl)pyrrolidine
carboxylic acid (500 mg, 1.56 mmol) in MeOH (3 mL), HCl/MeOH (15 mL) was stirred at 20 °C
for 12 hours. LCMS showed starting material was consumed completely and one main peak with
, adjusted the
desired MS was detected. The reaction mixture was diluted with aqueous NaHCO3
pH ~ 7, and extracted with DCM (30 mL x 2). The combined organic layers were dried over
Na SO , filtered and concentrated under reduced pressure to give a residue. Compound 220A
17681897_1 (GHMatters) P110989.NZ
(340 mg, crude, yellow oil): H NMR (400MHz, CDCl ) δ 7.37 - 7.20 (m, 5H), 4.52 - 4.41 (m,
2H), 4.12 (br s, 1H), 4.00 (br t, J = 7.6 Hz, 1H), 3.77 - 3.62 (m, 3H), 3.11 (br s, 2H), 2.66 (br s,
1H), 2.29 (br dd, J = 7.8, 13.1 Hz, 1H), 1.98 (td, J = 6.6, 13.4 Hz, 1H). MS (ESI) m/z (M+H)
236.1.
A mixture of compound 220A (240 mg, 1.02 mmol), phenylboronic acid (249
mg, 2.04 mmol), Cu(OAc) (278 mg, 1.53 mmol), pyridine (161 mg, 2.04 mmol) and 4A° MS
(400 mg) in DCE (20 mL) was degassed and purged with O for 3 times, and then the mixture
was stirred at 60 °C for 12 hours under O atmosphere. The reaction mixture was filtered and
concentrated under reduced pressure to give a residue. The residue was purified by column
chromatography (SiO , Petroleum ether: Ethyl acetate = 50: 1 to 10: 1). Compound 220B (130
mg, yellow oil): H NMR (400MHz, CDCl ) δ 7.36 - 7.16 (m, 5H), 7.16 - 7.06 (m, 2H), 6.68 -
6.57 (m, 1H), 6.42 (d, J = 8.1 Hz, 2H), 4.45 (s, 2H), 4.39 - 4.25 (m, 2H), 3.77 - 3.67 (m, 1H),
3.66 - 3.56 (m, 3H), 3.34 (dd, J = 4.4, 9.5 Hz, 1H), 2.42 - 2.28 (m, 1H), 2.28 - 2.15 (m, 1H). MS
(ESI) m/z (M+H) 312.0.
A mixture of compound 220B (130 mg, 418 umol), LiOH.H O (26.3 mg, 626
umol) in THF (5 mL), H O (2 mL) was stirred at 20 °C for 12 hours. The reaction mixture was
added aqueous HCl to adjust the pH ~ 5. And then the mixture was filtered, and the filter cake
was dried by freeze dryer. Compound 220C (130 mg, crude, white solid: H NMR (400MHz,
DMSO-d ) δ 7.36 - 7.15 (m, 6H), 7.13 - 6.98 (m, 2H), 6.57 - 6.47 (m, 1H), 6.40 (br d, J = 7.9 Hz,
2H), 4.48 - 4.40 (m, 2H), 4.28 (br s, 1H), 4.15 - 4.05 (m, 1H), 3.29 - 3.26 (m, 1H), 3.27 - 3.17 (m,
1H), 2.33 - 2.22 (m, 1H), 2.21 - 2.09 (m, 1H). MS (ESI) m/z (M+H) 298.2.
Compound 220 (18.6 mg, yield: 70.3%, brown solid) was prepared as in
Example 12 from the corresponding intermediate carboxylic acid, compound 220C. Compound
220: H NMR (400MHz, CDCl ) δ 7.33 - 7.07 (m, 11H), 6.93 (br s, 2H), 6.84 - 6.70 (m, 2H),
6.59 (br s, 1H), 6.49 (br d, J = 8.4 Hz, 2H), 5.35 (br s, 1H), 5.30 - 5.13 (m, 1H), 4.50 - 4.29 (m,
2H), 4.01 (br dd, J = 4.2, 9.0 Hz, 1H), 3.95 - 3.85 (m, 1H), 3.62 (dd, J = 5.8, 8.9 Hz, 1H), 3.30
(br dd, J = 5.0, 14.0 Hz, 1H), 3.17 (dd, J = 6.4, 9.0 Hz, 1H), 2.80 (dd, J = 9.0, 13.9 Hz, 1H), 2.31
- 2.17 (m, 1H), 2.16 - 2.03 (m, 1H). MS (ESI) m/z (M+H) 472.2.
17681897_1 (GHMatters) P110989.NZ
EXAMPLE 117
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)PHENYL-1H-IMIDAZOLE
CARBOXAMIDE (221)
B(OH)
N O H
LiOH O
N THF, H
Pyridine, O OH
Cu(OAc)2
4A° N
MS, O , DCE N
221A 221B
To a mixture of ethyl 1H-imidazolecarboxylate (5 g, 35.7 mmol) and
phenylboronic acid (8.7 g, 71.4 mmol) in DCE (150 mL) was added Cu(OAc) (7.13 g, 39.25
mmol), pyridine (5.64 g, 71.36 mmol, 5.76 mL), 4A° MS (3 g). The mixture was stirred at 60 °C
for 16 hours under O . The reaction mixture was filtered and the filtrate was concentrated. The
crude product was purified by silica gel chromatography eluted with Petroleum ether: Ethyl
acetate = 10:1, 4:1 to give compound 221A (3 g, 13.9 mmol, yield: 38.9%) as a yellow solid.
Compound 221A: H NMR (400MHz, CDCl -d) δ 7.43 - 7.39 (m, 3H), 7.27 - 7.23 (m, 2H), 7.22
- 7.19 (m, 1H), 7.11 (d, J = 1.0 Hz, 1H), 4.22 (q, J = 7.2 Hz, 2H), 1.24 (t, J = 7.2 Hz, 3H).
To a mixture of compound 221A (300 mg, 1.39 mmol) in THF (3 mL) and H O
(1 mL) was added LiOH.H O (52 mg, 1.25 mmol). The mixture was stirred at 25 °C for 12
hours. The residue was extracted with ethyl acetate (5 mL x 2). The mixture was adjusted to pH
~ 5 with aqueous HCl (1M) and concentrated by lyophilization to give intermediate compound
221B (550 mg, crude) as a white solid.
Compound 221 (17.1 mg, yield: 30.9%, yellow solid) was prepared as in
Example 5 from the corresponding intermediate carboxylic acid, compound 221B.
Compound 221: H NMR (400MHz, CDCl ) δ 7.76 (br d, J = 7.9 Hz, 1H),
7.35 (br d, J = 2.6 Hz, 3H), 7.24 - 7.16 (m, 5H), 7.12 (br d, J = 7.1 Hz, 2H), 7.08 (s, 1H), 7.04 (s,
1H), 6.67 (br s, 1H), 5.60 - 5.47 (m, 2H), 3.32 (dd, J = 4.9, 13.9 Hz, 1H), 3.08 (dd, J = 7.4, 14.0
Hz, 1H). MS (ESI) m/z (M+H) 363.1.
17681897_1 (GHMatters) P110989.NZ
EXAMPLE 118
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)METHYL
PHENYLTHIOPHENECARBOXAMIDE (222)
N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)(2H-INDAZOLYL)
METHYLTHIOPHENECARBOXAMIDE (428), and N-(4-AMINO-3,4-DIOXO
PHENYLBUTANYL)(1H-BENZO[d]IMIDAZOLYL)METHYLTHIOPHENE-
3-CARBOXAMIDE (429)
Br O
O NaOH
, Cs CO ,
EtOH, H O OH
Pd(dppf)Cl2 2 3
O 2 S
222A
dioxane
222B 222C
A mixture of ethyl 2-aminomethylthiophenecarboxylate (9 g, 48.6 mmol)
and CuBr (13 g, 58.3 mmol) in MeCN (150 mL) was stirred at 0 °C – 5 °C. t-BuONO (5.5 g,
53.5 mmol) was added dropwise. The reaction mixture was stirred for 0.5 hour at 0-5 °C and 2
hours at 20 °C. The reaction mixture was diluted with EtOAc (400 mL), washed with water (100
mL) and brine (100 mL), dried over MgSO , filtered, and concentrated in vacuo. The residue
was purified by column chromatography (SiO , Petroleum ether: Ethyl acetate = 100:1) to give
compound 222A (2 g, yield: 16.5%) as yellow oil. Compound 222A: H NMR (400MHz, CDCl -
d) δ 7.01 (s, 1H), 4.30 (q, J = 7.1 Hz, 2H), 2.38 (s, 3H), 1.40 - 1.29 (m, 3H).
To a mixture of compound 222A (400 mg, 1.61 mmol) and phenylboronic acid
(393 mg, 3.22 mmol), Cs CO (1.05 g, 3.22 mmol) in dioxane (20 mL) and H O (2 mL) was
2 3 2
added Pd(dppf)Cl (118 mg, 161 umol) under N . T he mixture was stirred at 110 °C for 12 hours
under N . The reaction mixture was filtered and the filter was concentrated. The residue was
purified by preparatory-TLC (SiO , Petroleum ether: Ethyl acetate = 5:1) to give compound 222B
(350 mg, yield: 88.3%) as a white solid. Compound 222B: H NMR (400MHz, CDCl ) δ 7.48 (br
s, 2H), 7.38 (br s, 3H), 7.19 (br s, 1H), 4.19 (q, J=6.9 Hz, 2H), 2.50 (br s, 3H), 1.23 - 1.15 (m,
3H).
To a mixture of compound 222B (350 mg, 1.42 mmol) in EtOH (10 mL) and
H O (5 mL) was added NaOH (142 mg, 3.55 mmol). The mixture was stirred at 80 °C for 3
hours. The mixture was concentrated to remove solvent and adjusted to pH ~ 5 with aqueous HCl
17681897_1 (GHMatters) P110989.NZ
(1M). The mixture was filtered and the solid was washed with H O (3 mL) to give intermediate
compound 222C (250 mg, yield: 81.0%) as a white solid. Compound 222C: H NMR (400MHz,
DMSO-d ) δ 12.47 (br s, 1H), 7.43 - 7.38 (m, 2H), 7.37 - 7.32 (m, 3H), 7.10 (d, J = 0.9 Hz, 1H),
2.41 (s, 3H).
Compound 222 (15.7 mg, yield: 29.6%, white solid) was prepared as in
Example 12 from the corresponding intermediate carboxylic acid, compound 222C. Compound
222: H NMR (400MHz, CDCl ) δ 7.36 - 7.30 (m, 4H), 7.19 (s, 1H), 7.13 - 7.07 (m, 3H), 6.97 (s,
1H), 6.71 - 6.60 (m, 3H), 5.89 (br d, J = 5.3 Hz, 1H), 5.49 - 5.34 (m, 2H), 3.10 (dd, J = 5.0, 14.0
Hz, 1H), 2.81 (dd, J = 7.9, 13.9 Hz, 1H), 2.37 (s, 3H). MS (ESI) m/z (M+H) 393.1.
Compound 428 (44.7 mg, yield: 40.5%, white solid) was prepared using
intermediate 222A to synthesize the intermediate carboxylic acid, 2-(2H-indazolyl)
methylthiophenecarboxylic acid which was converted to compound 428 using the procedures
as for compound 12. Compound 428: H NMR (400MHz, CDCl ) δ 9.17 (br d, J = 5.6 Hz, 1H),
8.25 (s, 1H), 7.70 (br d, J = 8.3 Hz, 1H), 7.61 (br d, J = 8.7 Hz, 1H), 7.34 (br t, J = 7.5 Hz, 1H),
7.21 - 7.13 (m, 2H), 7.00 (br s, 3H), 6.85 (br s, 2H), 6.69 (br s, 1H), 5.69 - 5.58 (m, 1H), 5.43 (br
s, 1H), 3.27 (br dd, J = 4.8, 14.0 Hz, 1H), 2.95 (br dd, J = 7.3, 14.1 Hz, 1H), 2.48 (s, 3H). MS
(ESI) m/z (M+H) 433.1.
Compound 429 (31.6 mg, yield: 35.7%, yellow solid) was prepared using
intermediate 222A to synthesize the intermediate carboxylic acid, 5-methyl(1-((2-
(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazolyl)thiophenecarboxylic acid which was
converted to compound 429 using the procedures as for compound 12. Compound 429: H
NMR (400MHz, CDCl ) δ 12.80 (br s, 1H), 10.05 (br d, J = 6.8 Hz, 1H), 8.18 (br s, 1H), 7.85 (br
s, 1H), 7.66 - 7.57 (m, 2H), 7.32 - 7.19 (m, 7H), 7.17 - 7.11 (m, 1H), 5.44 (br s, 1H), 3.27 (br s,
1H), 3.03 - 2.93 (m, 1H). MS (ESI) m/z (M+H) 433.1.
17681897_1 (GHMatters) P110989.NZ
EXAMPLE 119
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)METHYLPHENYL-1H-
PYRAZOLECARBOXAMIDE (223)
LiOH,
THF/H
223A 223C
To a mixture of ethyl 4-methyl-1H-pyrazolecarboxylate (2.00 g, 12.97
mmol), phenylboronic acid (2.37 g, 19.45 mmol), Py (1.13 g, 14.27 mmol, 1.2 mL) in DCM
(40.00 mL) was added 4A° MS (10.00 g)(activated 4A° MS) and Cu(OAc) (2.59 g, 14.27
mmol), the mixture was stirred at 40 °C for 63h. The reaction mixture was filtered, the filtrate
was concentrated in vacuo. The residue was purified by flash silica gel chromatography (PE:
EA=1:0 to 5:1) to give the compound 223A (725 mg, yield: 24.3%) was obtained as a colorless
oil. Compound 223A: H NMR (400MHz, DMSO-d ) δ 8.44 (s, 1H), 7.83 (d, J = 7.7 Hz, 2H),
7.52 (t, J = 7.9 Hz, 2H), 7.43 - 7.32 (m, 1H), 4.31 (q, J = 7.1 Hz, 2H), 2.27 (s, 3H), 1.32 (t, J =
7.1 Hz, 3H).
To a solution of compound 223A (720 mg, 3.13 mmol) in THF (20.00 mL) was
added LiOH.H O (700 mg, 16.68 mmol) in H O (6.00 mL). The reaction was stirred at 25 °C for
27h and then a solution of NaOH (626 mg, 15.65 mmol) in H O (5.00 mL) and MeOH (4.00 mL)
was added in the mixture. The mixture was stirred at 25 °C for 3.5h. The reaction mixture was
diluted with H O (25 mL) and extracted with MTBE (15 mL). The aqueous layers were adjusted
pH ~ 3 by addtion 1N HCl, and then the aqueous layer was extracted with EA (20 mL x 3). The
combine organic layer was washed with brine (20 mL), dried over Na SO , filtered and
concentrated under reduced pressure to give the compound 223C (526 mg, yield: 83.1%) was
obtained as a white solid. Compound 223C: H NMR (400MHz, DMSO-d ) δ 7.63 (s, 1H), 7.51
- 7.28 (m, 5H), 2.25 (s, 3H).
Compound 223 (34 mg, yield: 68.3%, white solid) was prepared as in Example
12 from the corresponding intermediate carboxylic acid, compound 223C. Compound 223: H
NMR (400MHz, DMSO-d ) δ 9.18 (d, J = 7.8 Hz, 1H), 8.21 (s, 1H), 7.94 (s, 1H), 7.54 (s, 1H),
17681897_1 (GHMatters) P110989.NZ
7.37 - 7.22 (m, 10H), 5.46 - 5.36 (m, 1H), 3.26 (br dd, J = 3.0, 13.8 Hz, 1H), 2.78 (dd, J = 11.2,
13.9 Hz, 1H), 2.00 - 1.93 (m, 3H).
EXAMPLE 120
COMPOUNDS 224-225
N N N O
225A
224A
(S)-N-(3,4-DIOXOPHENYL((PYRIDINYLMETHYL)AMINO)BUTANYL)
METHYLPHENYLISOXAZOLECARBOXAMIDE (224)
(S)-N-(4-((BENZO[D][1,3]DIOXOLYLMETHYL)AMINO)-3,4-DIOXO
PHENYLBUTANYL)METHYLPHENYLISOXAZOLECARBOXAMIDE (225)
To a solution of compound 101E (350.0 mg, 920.11 umol) in DMF
(10 mL) was added 3-pyridylmethanamine (119.4 mg, 1.10 mmol, 110 uL), DIEA (0.5 mL),
HOBt (124.33 mg, 920.11 umol) and EDCI (211.66 mg, 1.10 mmol). After stirred at 25 °C for
48h, the mixture was added HBTU (418.7 mg, 1.10 mmol) and DIEA (0.5 mL), and then stirred
at 25°C for 12h. The mixture was diluted with H O (100 mL), extracted with EA (30 mL),
washed with HCl (1M, 30 mL), saturated NaHCO (aq, 30mL), brine (30 mL), dried over
Na SO and concentrated. The residue was purified by column chromatography (SiO ,
2 4 2
Petroleum ether/Ethyl acetate=5/1 to 0:1) to give compound 224A.
Compound 224A (60.0 mg, yield 13.9%, white solid): H NMR (400MHz,
DMSO-d ) δ 8.67 - 8.50 (m, 1H), 8.48 - 8.45 (m, 1H), 8.42 - 8.37 (m, 1H), 8.30 - 8.24 (m, 1H),
7.73 - 7.33 (m, 6H), 7.31 - 7.09 (m, 6H), 6.14 - 5.86 (m, 1H), 4.69 - 4.55 (m, 1H), 4.36 - 4.14 (m,
2H), 4.08 - 4.01 (m, 1H), 2.97 - 2.87 (m, 1H), 2.77 - 2.66 (m, 1H), 2.08 - 1.96 (m, 3H). MS (ESI)
m/z (M+H) 471.2.
Compound 225A (130.0 mg, 27.5% yield, white solid) was synthesiszed as
shown above for 224A from the corresponding amine. Compound 225A: H NMR (400MHz,
DMSO-d ) δ 8.35 - 8.28 (m, 1H), 8.26 - 8.21 (m, 1H), 7.57 - 7.51 (m, 2H), 7.48 - 7.42 (m, 1H),
7.41 - 7.35 (m, 2H), 7.29 - 7.12 (m, 5H), 6.89 - 6.79 (m, 1H), 6.79 - 6.68 (m, 2H), 5.94 - 5.88 (m,
17681897_1 (GHMatters) P110989.NZ
2H), 5.87 - 5.81 (m, 1H), 4.66 - 4.57 (m, 1H), 4.23 - 4.09 (m, 2H), 4.04 - 3.99 (m, 1H), 4.04 -
3.99 (m, 1H), 2.95 - 2.86 (m, 1H), 2.78 - 2.66 (m, 1H), 2.07 - 1.98 (m, 3H). MS (ESI) m/z
(M+H) 514.2.
To a solution of compound 225A (120.0 mg, 233.67 umol) in DMSO (10 mL)
and DCM (1 mL) was added DMP (297.3 mg, 701.01 umol). After stirred at 25 °C for 1 hour,
the mixture was quenched with 10% Na S O (aqueous): saturated aqueous NaHCO (1:1, 50
2 2 3 3
mL), the organic layer was washed with brine (50 mLx3). The combined organic layers were
dried over Na SO and concentrated. The crude product was triturated with CH CN (5 mL) and
2 4 3
filtered to obtain compound 225 (62.0 mg, yield 51.9%) as yellow solid. Compound 225: H
NMR (400MHz, DMSO-d ) δ 9.41 - 9.32 (m, 1H), 9.10 (d, J = 7.6 Hz, 1H), 7.66 - 7.62 (m, 2H),
7.53 - 7.48 (m, 1H), 7.46 - 7.40 (m, 2H), 7.33 - 7.23 (m, 5H), 6.89 - 6.83 (m, 2H), 6.79 - 6.76 (m,
1H), 5.98 (s, 2H), 5.54 - 5.47 (m, 1H), 4.27 (d, J = 6.4 Hz, 2H), 3.30 - 3.23 (m, 1H), 2.83 - 2.74
(m, 1H), 2.09 - 2.06 (m, 3H). MS(ESI) m/z (M+H) 512.2.
Compound 224 was synthesiszed from the corresponding intermediate
compound 224A as shown above for compound 225. Compound 224 (25.0 mg, 50.2% yield) has
been obtained as white solid. H NMR (400MHz, DMSO-d ) δ 9.53 - 9.45 (m, 1H), 9.11 (d, J =
7.6 Hz, 1H), 8.54 (s, 1H), 8.49 - 8.46 (m, 1H), 7.72 - 7.67 (m, 1H), 7.67 - 7.62 (m, 2H), 7.54 -
7.48 (m, 1H), 7.46 - 7.40 (m, 2H), 7.38 - 7.33 (m, 1H), 7.32 - 7.23 (m, 5H), 5.54 - 5.47 (m, 1H),
4.40 (d, J=6.3 Hz, 2H), 3.30 - 3.23 (m, 1H), 2.83 - 2.75 (m, 1H), 2.09 - 2.05 (m, 3H). MS(ESI)
m/z (M+H) 469.1.
EXAMPLE 121
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)ETHYL
PHENYLOXAZOLECARBOXAMIDE (226)
LiOH H O
O O 2
propanamide, O
MeOH:H O
N (2:1) OH
microwave, 120 °C
°C, 1.5 h
- 1.2 h
226A
226B
226C
To a mixture of iodobenzene (5 g, 24.51 mmol) and 2,4-dinitrobenzenesulfonic
acid (7.83 g, 29.41 mmol, H O) in CHCl (20 mL), was added m-CPBA (4.23 g, 24.51 mmol).
The mixture was stirred for 2 hours at 25 °C under an N atmosphere. After the reaction, MTBE
17681897_1 (GHMatters) P110989.NZ
(20 mL) was added to the reaction mixture, and the resulting mixture was filtered and the solid
was washed with MTBE (30 mL) and compound 226A ( 8.9 g, 77.6% yield ) was obtained as a
white solid. Compound 226A: H NMR (CDCl 400 MHz): δ 9.76 (br s, 1H), 8.57 (d, J = 2.4 Hz,
1H), 8.43 - 8.40 (m, 1H), 8.23 (d, J = 7.6 Hz, 2H), 8.10 (d, J = 8.4 Hz, 1H), 7.75 - 7.69 (m, 1H),
7.66 - 7.59 (m, 2H).
Ethyl 3-oxophenylpropanoate (1.3 g, 6.76 mmol) and compound 226A (4.12
g, 8.79 mmol) in CH CN (50 mL) were stirred at 80 °C for 1h, and propanamide (5.93 g, 81.1
mmol) was added to the mixture, then the mixture was stirred at 120 °C for 0.2 hour under
microwave irradiation. After being cooled to 25 °C, the suspension was diluted with saturated
NaHCO solution (30 mL), extracted with EtOAc (100 mL x 2), dried over Na SO , filtered, and
3 2 4
concentrated in vacuo. The residue was purified by column chromatography (SiO , Petroleum
ether/Ethyl acetate = 10/1) to obtain compound 226B (200 mg, 11.22% yield) as white solid.
Compound 226B: H NMR (CDCl 400 MHz): δ 8.03 - 7.96 (m, 2H), 7.46 - 7.35 (m, 3H), 4.36
(q, J = 7.2 Hz, 2H), 2.88 (q, J = 7.6 Hz, 2H), 1.40 (t, J = 7.6 Hz, 3H), 1.35 (t, J = 7.2 Hz, 3H).
Compound 226C (170 mg, 93.71% yield, yellow solid) was prepared as in
Example 51 from the corresponding intermediate compound 226B. Compound 226C: H NMR
(CDCl 400 MHz): δ 7.99 - 7.97 (m, 2H), 7.47 - 7.35 (m, 3H), 2.83 (q, J = 7.6 Hz, 2H), 1.27 (t, J
= 7.6 Hz, 3H). MS (ESI) m/z (M+H) 217.9.
Compound 226 (59.7 mg, 58.17% yield, white solid) was prepared as in
Example 5 from the corresponding carboxylic acid, compound 226C. Compound 226: H NMR
(CDCl 400 MHz): δ 8.12 - 8.04 (m, 2H), 7.45 - 7.35 (m, 3H), 7.32 - 7.23 (m, 3H), 7.13 (d, J =
6.4 Hz, 2H), 6.81 - 6.68 (m, 2H), 5.74 - 5.59 (m, 2H), 3.46 - 3.41 (m, 1H), 3.26 - 3.21 (m, 1H),
2.91 - 2.80 (m, 2H), 1.40 (t, J = 7.6 Hz, 3H). MS (ESI) m/z (M+ H) 392.1.
17681897_1 (GHMatters) P110989.NZ
EXAMPLE 122
COMPOUNDS 268-269
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)METHYLPHENYL-1H-
IMIDAZOLECARBOXAMIDE (268)
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)METHYLPHENYL-1H-
IMIDAZOLECARBOXAMIDE (269)
O O O
H NH O
O O MeI
NH N
268C
268B 268D
268A
NaOH
NaOH
OH OH
268E
269A
Sulfuryl chloride (33.7 g, 250 mmol) was added drop wise to ethyl 3-oxo
phenylpropanoate (40 g, 208 mmol,) in CHCl (200 mL) at 0 °C. The mixture was warmed to
°C for 30 min, and then heated to 80 °C for 3.5h. TLC (Petroleum ether: Ethyl acetate = 10:1,
R ~ 0.45) showed the reaction was complete. LCMS showed desired MS after cooling to room
temperature, the reaction mixture was diluted with chloroform (40 mL), washed with NaHCO
(aqueous; 40 mL x 2), water (40 mL) and then brine (30 mL) successively. The organic phase
was dried over Na SO , filtered and evaporated to give the crude product compound 268A (48 g,
crude), as yellow oil. Compound 268A: H NMR (400MHz, CDCl -d) δ 8.10 - 7.96 (m, 2H),
7.73 - 7.58 (m, 1H), 7.57 - 7.39 (m, 2H), 5.62 (s, 1H), 4.39 - 4.25 (m, 2H), 1.32 - 1.13 (m, 3H).
A solution of compound 268A (20 g, 88.2 mmol), formamide (39.7 g, 882
mmol) and H O (3.18 g, 176 mmol) was heated to 180 °C for 3.5h. After cooling, the mixture
was added water (100 mL) and extracted with DCM (50 mL x 3), the organic phase give a
precipitate, the solid was filtered and dried to give compound 268B (1.45 g, yield: 7.6%), as off
white solid. Compound 268B: H NMR (400MHz, DMSO-d ) δ 13.26 - 12.66 (m, 1H), 7.96 -
17681897_1 (GHMatters) P110989.NZ
7.78 (m, 1H), 7.81 (s, 1H), 7.63 (br d, J = 7.2 Hz, 1H), 7.53 - 7.26 (m, 3H), 4.33 - 4.09 (m, 2H),
1.33 - 1.13 (m, 3H).
To a solution of NaH (277 mg, 6.94 mmol, 60% purity) in DMF (5 mL) was
added compound 268B (1.25 g, 5.78 mmol) in portions and stirred for 30 min, then CH I (903
mg, 6.36 mmol) was added, the mixture was stirred at 15 °C for 2h. The mixture was quenched
with water (15 mL) and extracted with ethyl acetate (20 mL x 3), the organic phases were dried
over Na SO , filtered and concentrated, the residue was purified by prep-HPLC (neutral) to give
compounds 268Cand 268D. Compound 268C (430 mg, yield: 64.7%, yellow solid): H NMR
(400MHz, CDCl -d) δ 7.67 (br d, J = 7.1 Hz, 2H), 7.57 (s, 1H), 7.43 - 7.30 (m, 3H), 4.25 (q, J =
7.1 Hz, 2H), 3.93 (s, 3H), 1.22 (t, J = 7.2 Hz, 3H).
Compound 268D (380 mg, yield: 57.1%, yellow solid): H NMR (400MHz,
CDCl -d) δ 7.54 (s, 1H), 7.52 - 7.44 (m, 3H), 7.41 - 7.34 (m, 2H), 4.24 (q, J = 7.1 Hz, 2H), 3.50
(s, 3H), 1.25 (t, J = 7.2 Hz, 3H).
A mixture of compound 268C (200 mg, 869 umol) and NaOH (69.5 mg, 1.74
mmol) in THF (5 mL), H O (1 mL) was stirred at 15 °C for 12 h. TLC (ethyl acetate, R ~ 0)
showed the reaction was complete, the organic solvent was removed under vacuum, the water
layer was adjusted to pH ~ 5 with 1NHCl to give a precipitate, the solid was filtered and dried to
give compound 268E (120 mg, yield: 68.3%) as white solid. Compound 268E: H NMR
(400MHz, DMSO-d6) δ 12.90 (br s, 1H), 7.86 (s, 1H), 7.62 (br d, J = 7.1 Hz, 2H), 7.38 - 7.21 (m,
3H), 3.80 (s, 3H).
Compound 268 (40.2 mg, yield: 27.2%, white solid) was prepared as in
Example 5 from the corresponding intermediate carboxylic acid, compound 268E. Compound
268: H NMR (400MHz, DMSO-d ) δ 8.96 (d, J = 7.5 Hz, 1H), 8.19 (s, 1H), 7.92 (s, 1H), 7.66
(s, 1H), 7.55 (d, J = 6.8 Hz, 2H), 7.31 - 7.18 (m, 8H), 5.52 (ddd, J = 3.5, 7.4, 10.5 Hz, 1H), 3.40
(s, 3H), 3.21 (dd, J = 3.5, 14.1 Hz, 1H), 2.75 (dd, J = 10.6, 14.1 Hz, 1H). MS (ESI) m/z (M+H)
377.1.
Following the procedure used for intermediate compound 268E and compound
268, intermediate compound 269A and compound 269 were prepared. Compound 269A (130
mg, yield: 74%, white solid): H NMR (400MHz, DMSO-d ) δ 7.76 (s, 1H), 7.47 - 7.30 (m, 5H),
3.40 (s, 3H). Compound 269 (32.4 mg, yield: 37.5%, white solid): H NMR (400MHz, CDCl -d)
17681897_1 (GHMatters) P110989.NZ
δ 7.67 (br d, J = 7.2 Hz, 1H), 7.51 - 7.43 (m, 4H), 7.42 - 7.35 (m, 2H), 7.32 - 7.29 (m, 1H), 7.28
(s, 1H), 7.26 - 7.23 (m, 1H), 7.22 - 7.18 (m, 2H), 6.72 (br s, 1H), 5.64 (dt, J = 5.3, 7.5 Hz, 1H),
.44 (br s, 1H), 3.51 (s, 3H), 3.41 (dd, J = 5.3, 14.1 Hz, 1H), 3.20 (dd, J = 7.4, 14.0 Hz, 1H). MS
(ESI) m/z (M+H) 377.1.
EXAMPLE 123
COMPOUNDS 227-228
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)(4-
(ETHOXYMETHYL)PHENYL)METHYL-1H-PYRAZOLECARBOXAMIDE (227)
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)(4-
((BENZYLOXY)METHYL)PHENYL)METHYL-1H-PYRAZOLECARBOXAMIDE
(228)
OH O
NaOH
227A
227B: R Et
227C: R Et
228B: R CH Ph
228C: R CH Ph
To a solution of ethyl 3-methyl-1H-pyrazolecarboxylate (2 g, 12.97 mmol),
[4-(hydroxymethyl)phenyl]boronic acid (3.94 g, 25.94 mmol) in NMP (200 mL) was added
pyridine (2.05 g, 25.94 mmol, 2.09 mL), Cu(OAc) (3.53 g, 19.45 mmol), 4A° MS (20 g, 12.97
mmol). After stirred at 25 °C for 24h, the mixture was filtered. The filtrate was washed with
H O (500 mL), extracted with ethyl acetate (50 mL x 3). The organic phase was washed brine
(500 mL), dried over Na SO , concentrated to give a residue. The residue was purified by
column chromatography (SiO , Petroleum ether/Ethyl acetate = 5/1 to 3/1) to obtain intermediate
Compound 227A (1 g, yield: 29.62%) as white solid. Compound 227A: H NMR (400MHz,
CDCl ) δ 7.41 - 7.34 (m, 4H), 6.80 (s, 1H), 4.71 (s, 2H), 4.22 (q, J = 7.1 Hz, 2H), 2.35 (s, 3H),
1.24 (t, J = 7.2 Hz, 3H). MS (ESI) m/z (M+H) 261.0.
To a solution of compound 227A (350 mg, 1.34 mmol) and benzyl bromide
(458 mg, 2.68 mmol, 318 uL) in DMF (10 mL) was added NaH (160 mg, 4.02 mmol, 60%
purity) at 0 °C. The mixture was stirred at 25 °C for 1h. The mixture was quenched with NH Cl
17681897_1 (GHMatters) P110989.NZ
(1 mL), diluted with H O (30 mL), extracted with ethyl acetate (20 mL x 3), the organic phase
was combined, washed with NaCl (50 mL x 2), dried over Na SO , and concentrated to give a
residue. The residue was purified by column chromatography (SiO , Petroleum ether/Ethyl
acetate = 10/1 to 5:1) to obtain compound 228B (350 mg, yield: 64.85%, yellow oil). Compound
228B: H NMR (400MHz, CDCl ) δ 7.47 - 7.28 (m, 9H), 6.87 - 6.78 (m, 1H), 4.66 - 4.60 (m,
2H), 4.56 (s, 2H), 4.23 (q, J = 7.1 Hz, 2H), 2.36 (s, 3H), 1.24 (t, J = 7.2 Hz, 3H). MS (ESI) m/z
(M+H) 351.0.
To a solution of compound 228B (350 mg, 998.83 umol) in MeOH (10 mL)
and H O (10 mL) was added NaOH (119 mg, 3.00 mmol). The mixture was stirred at 25 °C for
3h. The reaction mixture was concentrated and added 20 mL of water, the mixture was extracted
with MTBE (10 mL x 2), the aqueous layer was acidified by 1N HCl to pH ~ 2~3 at 0 °C, and
extracted with EtOAc (20 mL x 2), the organic phase was dried over Na SO , concnetrated to
give a residue. Compound 228C (270 mg, yield: 83.86%, white solid): H NMR (400MHz,
DMSO-d ) δ 13.58 - 12.95 (m, 1H), 7.45 - 7.24 (m, 9H), 6.79 (s, 1H), 4.57 (d, J = 6.8 Hz, 4H),
2.23 (s, 3H). MS (ESI) m/z (M+H) 323.0.
Compound 228 (37.6 mg, yield: 51.78%, white solid) was prepared as in
Example 5 from the corresponding intermediate carboxylic acid, compound 228C. Compound
228: H NMR (400MHz, DMSO-d6) δ 9.09 (d, J = 7.9 Hz, 1H), 8.11 (s, 1H), 7.86 (s, 1H), 7.39 -
7.21 (m, 12H), 7.14 (d, J = 8.2 Hz, 2H), 6.58 - 6.50 (m, 1H), 5.33 - 5.17 (m, 1H), 4.53 (d, J = 6.0
Hz, 4H), 3.18 (dd, J = 3.2, 13.6 Hz, 1H), 2.80 (dd, J = 10.8, 13.7 Hz, 1H), 2.23 (s, 3H). MS
(ESI) m/z (M+H) 497.2.
Intermediate compound 227C (300 mg, yield: 95.04%) was obtained as a white
solid using the same procedure as for compound 228C. Compound 227C: H NMR (400MHz,
DMSO-d ) δ 13.20 (br s, 1H), 7.47 - 7.24 (m, 4H), 6.79 (s, 1H), 4.49 (s, 2H), 3.50 (q, J = 7.0 Hz,
2H), 2.23 (s, 3H), 1.16 (t, J = 7.1 Hz, 3H). MS (ESI) m/z (M+H) 261.0.
Compound 227 (31 mg, yield: 54.75%, light yellow solid) was prepared as in
Example 5 from the corresponding intermediate carboxylic acid, compound 227C. Compound
227: H NMR (400MHz, DMSO-d ) δ 9.07 (d, J = 7.7 Hz, 1H), 8.11 (d, J = 3.1 Hz, 1H), 7.87 -
7.84 (m, 1H), 7.31 - 7.24 (m, 7H), 7.13 (br d, J = 8.2 Hz, 2H), 6.53 (s, 1H), 5.25 (t, J = 7.4 Hz,
17681897_1 (GHMatters) P110989.NZ
1H), 4.44 (s, 2H), 3.52 - 3.44 (m, 2H), 3.19 (dd, J = 3.0, 13.6 Hz, 1H), 2.84 - 2.76 (m, 1H), 2.23
(s, 3H), 1.15 (t, J = 6.9 Hz, 3H). MS (ESI) m/z (M+H) 435.1.
EXAMPLE 124
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)(3-
(ETHOXYMETHYL)PHENYL)METHYL-1H-PYRAZOLECARBOXAMIDE (229)
OH O
O OH
NaOH
CH CH I
Cu(OAc)2 N
, O O
Pyridine
4A° MS, O
2 229A 229B
229C
To ethyl 3-methyl-1H-pyrazolecarboxylate (3 g, 19.46 mmol), [3-
(hydroxymethyl)phenyl]boronic acid (4.44 g, 29.19 mmol), 4A° MS (8 g) and Pyridine (1.69 g,
21.41 mmol, 1.8 mL) in DCM (70 mL) was added Cu(OAc) (4.59 g, 25.30 mmol), the mixture
was stirred at 25 °C for 16h under O balloon (15 psi). The reaction mixture was filtered to get
rid of 4A° MS and catalyst, and then the filtrate was concentrated. The residue was purified by
preparatory-HPLC (TFA condition). Compound 229A (1.8 g, yield: 35.54%) was obtained as a
colorless oil. H NMR (400MHz, CDCl ) δ 7.48 - 7.35 (m, 3H), 7.32 - 7.28 (m, 1H), 6.81 (s,
1H), 4.71 (s, 2H), 4.22 (q, J = 7.0 Hz, 2H), 2.35 (s, 3H), 1.24 (t, J = 7.0 Hz, 3H).
To a solution of compound 229A (465 mg, 1.79 mmol) and iodoethane (1.4 g,
8.95 mmol, 0.75 mL) in dry DMF (10 mL) was added NaH (214.8 mg, 5.37 mmol, 60% purity)
at 0 °C, then the mixture was reaction at 25 °C for 2h. The reaction mixture was quenched with
50 mL saturated NH Cl at 0 C, extracted with ethyl acetate (30 mL x 2), the organic phase was
dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The
residue was purified by column chromatography (SiO , Petroleum ether/Ethyl acetate = 5/1).
Compound 229B (443 mg, yield: 85.83%) was obtained as a colorless oil. H NMR (400MHz,
CDCl ) δ 7.43 - 7.36 (m, 3H), 7.33 - 7.28 (m, 1H), 6.80 (s, 1H), 4.56 (s, 2H), 4.21 (q, J = 7.3 Hz,
2H), 3.54 (q, J = 7.0 Hz, 2H), 2.35 (s, 3H), 1.23 (t, J = 2.4, 7.1 Hz, 6H).
To a solution of compound 229B (443 mg, 1.54 mmol) in MeOH (10 mL) and
H O (6 mL) was added NaOH (184.8 mg, 4.62 mmol). The mixture was stirred at 25 °C for 2h.
17681897_1 (GHMatters) P110989.NZ
The reaction mixture was concentrated and added 20 mL of water and the mixture was extracted
with MTBE (10 mL x 2), the aqueous layer was acidified by 1N HCl to pH ~ 2 to 3 at 0 °C, and
extracted with EtOAc (10 mL x 2), the organic phase was dried over Na SO , filtered and
concentrated to give a residue. Compound 229C (400 mg, yield: 99.79%) was obtained as a
white solid, which was used for next step directly. H NMR (400MHz, DMSO-d ) δ 7.43 - 7.37
(m, 1H), 7.35 - 7.26 (m, 3H), 6.79 (s, 1H), 4.48 (s, 2H), 3.48 (q, J = 6.9 Hz, 2H), 2.23 (s, 3H),
1.16 - 1.12 (m, 3H).
Compound 229 (30.1 mg, yield: 47.21%, white solid) was prepared as in
Example 5 from the corresponding intermediate carboxylic acid, compound 229C. Compound
229: H NMR (400MHz, DMSO-d ) δ 9.07 (br d, J = 7.7 Hz, 1H), 8.08 (s, 1H), 7.84 (s, 1H),
7.32 - 7.22 (m, 8H), 6.99 (br d, J = 7.5 Hz, 1H), 6.54 (s, 1H), 5.31 - 5.20 (m, 1H), 4.42 (s, 2H),
3.47 - 3.43 (m, 2H), 3.17 (br dd, J = 3.4, 13.8 Hz, 1H), 2.80 (br dd, J = 10.6, 13.7 Hz, 1H), 2.23
(s, 3H), 1.11 (t, J=6.9 Hz, 3H). MS (ESI) m/z (M+H) 435.1.
EXAMPLE 125
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)(3-
((BENZYLOXY)METHYL)PHENYL)METHYL-1H-PYRAZOLECARBOXAMIDE
(230)
OH O Ph
NaOH
O OH
229A
230A
230B
To a solution of compound 229A (472 mg, 1.81 mmol) and
bromomethylbenzene (1.55 g, 9.05 mmol, 1.1 mL) in dry DMF (15 mL) was added NaH (218
mg, 5.43 mmol, 60% purity) at 0 °C and then the mixture was reaction at 25 °C for 2h. The
reaction mixture was quenched with 50 mL saturated NH Cl at 0 C, extracted with ethyl acetate
(30 mL x 2), dried over Na SO , filtered and concentrated under reduced pressure to give a
residue. The residue was purified by column chromatography (SiO , Petroleum ether/Ethyl
acetate = 5/1). Compound 230A (623 mg, yield: 98.23%) was obtained as a colorless oil. H
17681897_1 (GHMatters) P110989.NZ
NMR (400MHz, CDCl ) δ 7.43 - 7.41 (m, 3H), 7.37 - 7.34 (m, 5H), 7.31 (d, J = 2.0 Hz, 1H),
6.81 (s, 1H), 4.62 (s, 2H), 4.57 (s, 2H), 4.23 - 4.18 (m, 2H), 2.36 (s, 3H), 1.22 (t, J = 7.1 Hz, 3H).
To a solution of compound 230A (623 mg, 1.78 mmol) in MeOH (15 mL) and
H O (8 mL) was added NaOH (214 mg, 5.34 mmol). The mixture was stirred at 25 °C for 2h.
The reaction mixture was concentrated and added 20 mL of water, the mixture was extracted
with MTBE (10 mL x 2), the aqueous layer was acidified by 1N HCl to pH ~ 2~3 at 0 °C, and
extracted with EtOAc (10 mL x 2), the organic phase was dried over Na SO , concentrated to
give a residue. Compound 230B (569 mg, yield: 99.16%) was obtained as a white solid, which
was used for next step directly. H NMR (400MHz, DMSO-d ) δ 7.45 - 7.23 (m, 10H), 6.80 (s,
1H), 4.57 (s, 2H), 4.54 (s, 2H), 2.24 (s, 3H).
Compound 230 (33.3 mg, yield: 54.97%, white solid) was prepared as in
Example 5 from the corresponding intermediate carboxylic acid, compound 230B. Compound
230: H NMR (400MHz, DMSO-d ) δ 9.08 (d, J = 7.7 Hz, 1H), 8.08 (s, 1H), 7.85 (s, 1H), 7.35 -
7.25 (m, 12H), 7.23 - 7.20 (m, 1H), 7.03 - 6.98 (m, 1H), 6.55 (s, 1H), 5.30 - 5.21 (m, 1H), 4.51
(d, J = 2.9 Hz, 4H), 3.17 (dd, J = 3.4, 13.8 Hz, 1H), 2.80 (dd, J = 10.6, 13.7 Hz, 1H), 2.23 (s,
3H). MS (ESI) m/z (M+H) 497.1.
EXAMPLE 126
COMPOUNDS 231, 438, 442
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)METHYL(3-
(PHENOXYMETHYL)PHENYL)-1H-PYRAZOLECARBOXAMIDE (231)
OH O
DIAD, PPh
NaOH
O N OH
229A
231A
231B
To a suspended solution of compound 229A (400 mg, 1.54 mmol) and phenol
(174 mg, 1.85 mmol) in dry THF (10 mL) was added PPh (605 mg, 2.31 mmol) and then slowly
added DIAD (467 mg, 2.31 mmol, 449 uL) under N2. The mixture was reaction at 25 °C for 12h
under N . The reaction mixture dissolved in DCM (30 mL) and H O (20 mL), then extracted
17681897_1 (GHMatters) P110989.NZ
with DCM (20 mL x 2), the organic layer was combined and the mixture was dried over Na SO ,
filtered and concentrated. The residue was purified by column chromatography (SiO , Petroleum
ether/Ethyl acetate = 4/1). Compound 231A (489.7 mg, yield: 94.53%) was obtained as a
colorless oil. H NMR (400MHz, DMSO-d ) δ 7.51 - 7.43 (m, 3H), 7.36 (d, J = 7.7 Hz, 1H),
7.31 - 7.24 (m, 2H), 7.13 (t, J = 7.8 Hz, 1H), 7.00 (d, J = 7.7 Hz, 2H), 6.87 (s, 1H), 5.14 (s, 2H),
4.13 (q, J = 7.1 Hz, 2H), 2.25 (s, 3H), 1.11 (t, J = 7.1 Hz, 3H).
To a solution of compound 231A (551 mg, 1.64 mmol) in MeOH (5 mL) and
H O (5 mL) was added NaOH (262 mg, 6.56 mmol). The mixture was stirred at 25 °C for 1h.
The reaction mixture was concentrated and added 10 mL of water and the mixture was extracted
with MTBE (10 mL x 2), the aqueous layer was acidified by 1N HCl to pH ~ 2~3 at 0 °C, and
extracted with EtOAc (10 mL x 2), the organic phase was dried over Na SO , filtered and
concentrated to give a residue. Compound 231B (490 mg, yield: 96.90%) was obtained as a
white solid, which was used for next step directly. H NMR (400MHz, DMSO-d ) δ 7.50 - 7.42
(m, 3H), 7.36 - 7.32 (m, 1H), 7.31 - 7.25 (m, 2H), 7.01 (dd, J = 1.0, 8.7 Hz, 2H), 6.95 - 6.90 (m,
1H), 6.81 (s, 1H), 5.13 (s, 2H), 2.24 (s, 3H).
Compound 231 (68 mg, yield: 65.87%, white solid) was prepared as in
Example 5 from the corresponding intermediate carboxylic acid, compound 231B. Compound
231: H NMR (400MHz, DMSO-d ) δ 9.08 (d, J = 7.7 Hz, 1H), 8.07 (s, 1H), 7.84 (s, 1H), 7.40 -
7.23 (m, 10H), 7.21 - 7.17 (m, 1H), 7.04 - 6.95 (m, 3H), 6.91 (br t, J = 7.3 Hz, 1H), 6.55 (s, 1H),
.28 - 5.20 (m, 1H), 5.08 (s, 2H), 3.17 (dd, J = 3.3, 13.9 Hz, 1H), 2.80 (br dd, J = 10.5, 13.8 Hz,
1H), 2.22 (s, 3H).
N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)(3-
((BENZYLOXY)METHYL)PHENYL)METHYL-1H-PYRAZOLECARBOXAMIDE
(438)
Compound 438 (2.9 g, yield: 86.54%, white solid) was prepared from the
corresponding intermediate compound 229A by alkylating with benzyl bromide followed by ester
hydrolysis and coupling with intermediate 274D as in compound 12. Compound 438: H NMR
(400MHz, DMSO-d ) δ 9.10 (d, J = 7.7 Hz, 1H), 8.11 (s, 1H), 7.87 (s, 1H), 7.39 - 7.23 (m, 13H),
7.10 - 6.99 (m, 1H), 6.58 (s, 1H), 5.28 (s, 1H), 4.53 (d, J=3.1 Hz, 4H), 3.32 - 3.16 (m, 1H), 2.83
(dd, J = 10.6, 13.7 Hz, 1H), 2.25 (s, 3H). MS (ESI) m/z (M+H) 497.2.
17681897_1 (GHMatters) P110989.NZ
N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)METHYL(4-
(MORPHOLINOMETHYL)PHENYL)-1H-PYRAZOLECARBOXAMIDE (442)
Compound 442 (50 mg, yield: 50.01%, yellow solid) was prepared from the
corresponding intermediate compound 229A by converting it to the morpholino derivative via
the mesylate. The morpholino derivative was subjected to ester hydrolysis and coupling with
intermediate 274D as in compound 12. Compound 442: H NMR (400MHz, CD CN) δ 7.34 -
7.15 (m, 11H), 7.07 - 6.96 (m, 1H), 6.50 (s, 1H), 6.24 (s, 1H), 5.39 (dd, J = 4.6, 8.0, 9.4 Hz, 1H),
3.64 - 3.60 (m, 4H), 3.50 (s, 2H), 3.30 - 3.25 (m, 1H), 2.89 (dd, J = 9.4, 14.0 Hz, 1H), 2.40 (s,
4H), 2.26 (s, 3H). MS (ESI) m/z (M+H) 476.2.
EXAMPLE 127
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)(2,6-DIMETHYLPYRIMIDIN-
4-YL)METHYL-1H-PYRAZOLECARBOXAMIDE (232)
O LiOH•H O N
N OH
HOAc,100°C,2 MeOH:H
N O(2:1)
H NHN 25°C,3 hrs
232D
232C
232A
To a solution of 4-chloro-2,6-dimethylpyrimidine (3.0 g, 21.04 mmol) and
NH NH .H O (10.5 g, 210.40 mmol) in EtOH (40 mL). The mixture was stirred at 70 °C for 2
2 2 2
hours. The mixture was cooled to room-temperature and concentrated under reduced pressure to
afford intermediate compound 232A (2.30 g, 62.60% yield) as a yellow solid. H NMR (400
MHz, DMSO-d ): δ 6.33 (br s, 1H), 2.24 (s, 3H), 2.15 (s, 3H).
To a solution of compound 232A (2.30 g, 13.17 mmol, HCl) and ethyl 2,4-
dioxopentanoate (2.08 g, 13.17 mmol,) in AcOH (30 mL). The mixture was stirred at 100 °C for
2 hrs. The reaction mixture was concentrated under reduced pressure to remove AcOH, then
diluted with H O, the pH was adjusted to around 9 by progressively adding NaHCO , then
partitioned between EtOAc (20 mL x 3), dried over Na SO . The residue was purified by flash
silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0~50%
Ethyl acetate/Petroleum ethergradient @ 30 mL/min), then the residue was purified by
preparatory-HPLC (basic condition). Compound 232C (50 mg, 1.46% yield) was obtained as a
white solid. Compound 232C: H NMR (400MHz, CDCl ) δ 7.76 - 7.71 (m, 1H), 6.72 - 6.66 (m,
17681897_1 (GHMatters) P110989.NZ
1H), 4.48 - 4.37 (m, 2H), 2.82 - 2.74 (m, 3H), 2.73 - 2.66 (m, 3H), 2.58 - 2.52 (m, 3H), 1.47 -
1.38 (m, 3H)[1169] . Compound 232D (38 mg, 85.18% yield, white solid) was prepared as in
Example 85 from the corresponding intermediate compound 232C. H NMR (400MHz, DMSO-
d ) δ 7.63 (s, 1H), 6.74 (s, 1H), 2.68 (s, 3H), 2.60 (s, 3H), 2.50 (s, 3H).
Compound 232 (48.4 mg, 57.40% yield, white solid) was prepared as in
Example 5 from the corresponding intermediate carboxylic acid, compound 232D. Compound
232: H NMR (400MHz, CDCl ) δ 7.53 (s, 1H), 7.40 (br d, J = 7.2 Hz, 1H), 7.33 - 7.23 (m, 3H),
7.21 - 7.15 (m, 2H), 6.80 (br s, 1H), 6.66 (s, 1H), 5.77 - 5.69 (m, 2H), 3.49 - 3.40 (m, 1H), 3.34 -
3.24 (m, 1H), 2.75 (s, 3H), 2.69 (s, 3H), 2.58 (s, 3H). MS (ESI) m/z (M+H) 407.1.
EXAMPLE 128
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)METHYL(6-
PHENYLPYRIDAZINYL)-1H-PYRAZOLECARBOXAMIDE (233)
N LiOH.H O
NH NH H O O N
N 2 2 2
CH OH-H O
3 2 O
CH COOH
N EtOH, 78 °C O
HN N
233A
233B
233D
To a solution of 3-chlorophenylpyridazine (1.00 g, 5.25 mmol) in EtOH (20
mL) was added N H .H O (2.63 g, 52.46 mmol, 2.55 mL). After stirred at 78 °C for 10 hours, the
2 4 2
reaction mixture was concentrated under reduced pressure to remove the solvent. The residue
was diluted with petroleum ether 30 mL, stirred for 30 min, and then filtered to give crude
intermediate product 233A as grey residue. H NMR (400 MHz, DMSO-d ): δ 7.96 (d, J = 7.2
Hz, 1H), 7.85 (d, J = 9.6 Hz, 1H), 7.47 – 7.43 (m, 2H), 7.39 – 7.35 (m, 1H), 7.09 (d, J = 9.2 Hz,
1H).
To a solution of compound 233A (1.30 g, 6.98 mmol) in CH COOH (12 mL)
was added ethyl 2,4-dioxopentanoate (1.10 g, 6.98 mmol, 985.61 uL), then the mixture was
stirred at 120 °C for 2 hours. The reaction mixture was concentrated under reduced pressure to
remove solvent. The residue was diluted with solvent ethyl acetate (70 mL) and washed with
solvent saturated aqueous NaHCO solution (20 mL x 3), dried over anhydrous Na SO , filtered
3 2 4
and concentrated under reduced pressure to give a residue. The residue was purified by column
17681897_1 (GHMatters) P110989.NZ
chromatography (Petroleum Ether: Ethyl Acetate = 30/1 to 10/1) to afford a residue. The crude
was further separated by preparatory-HPLC (Acid condition). Compound 233B was obtained as a
white solid (270.00 mg, 875.69 umol, 12.55% yield).
To a mixture of compound 233B (180.0 mg, 583.79 umol) in MeOH (6 mL)
and H O (3.00 mL) was added LiOH.H O (73.5 mg, 1.75 mmol) in one portion and the mixture
was stirred at 25 °C for 6 hours. The reaction mixture was concentrated under reduced pressure
to remove MeOH. The residue was diluted with H O (20 mL), adjusted to pH ~ 3 with 1N HCl,
and then extracted with EtOAc (60 mL x 3). The combined organic layers were washed with
brine (30 mL), dried over anhydrous Na SO , filtered and concentrated under reduced pressure to
give intermediate compound 233D (160.00 mg, 97.78% yield) as a white solid. H NMR (400
MHz, DMSO-d ) δ 8.52 (d, J = 9.2 Hz, 1H), 8.27 – 8.22 (m, 2H), 7.63 – 7.56 (m, 2H), 6.85 (s,
1H), 2.73 (s, 3H).
Compound 233 (67.0 mg, 63.93% yield white solid) was prepared as in
Example 5 from the corresponding intermediate carboxylic acid, compound 233D. Compound
233: H NMR (400 MHz, CDCl ) δ 8.16 (d, J = 9.2 Hz, 1H), 8.13 – 8.11 (m, 2H), 8.03 (d, J =
9.2 Hz, 1H), 7.59 – 7.54 (m, 3H), 7.42 (d, J = 7.2 Hz, 1H), 7.32 - 7.27 (m, 3H), 7.20 – 7.18 (m,
1H), 6.77 (s, 1H), 6.75 (d, J = 0.4 Hz, 1H), 5.76 – 5.71 (m, 1H), 5.55 (s, 1H), 3.49 – 3.44 (m,
1H), 3.32 – 3.27 (m, 1H), 2.85 (s, 3H). MS (ESI) m/z (M+1) 455.1.
EXAMPLE 129
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)METHYL(6-METHYL
(TRIFLUOROMETHYL)PYRIDINYL)-1H-PYRAZOLECARBOXAMIDE (234)
F C F C
F C O
LiOH•H O
CH OH: H O
CH COOH, 120 °C, 2 hrs 3 2 (2:1)
O 4hrs OH
234B
234A
To a solution of 2-hydrazineylmethyl(trifluoromethyl)pyridine (400 mg,
2.09 mmol) in CH COOH (4 mL) was added ethyl 2-(methoxyimino)oxopentanoate (391 mg,
2.09 mmol), then he mixture was stirred at 120 °C for 2 hours. The mixture was diluted with
CH Cl (70 mL) and washed by saturated sodium bicarbonate (20 mL x 2) and saturated brine
(20 mL x 2), dried with anhydrous Na SO , filtered and concentrated in vacuum. The residue
17681897_1 (GHMatters) P110989.NZ
was purified by flash column chromatography (SiO , Petroleum Ether: Ethyl Acetate = 10:1 to
3:1) to afford proposed compound 3 (150 mg, 22.91% yield) as white solid. H NMR (400 MHz,
CDCl ): δ 8.08 (s, 1H), 7.32 (s, 1H), 6.72 (s, 1H), 4.46 – 4.36 (m, 2H), 2.72 (s, 3H), 2.65 (s,
3H), 1.44 – 1.41 (m, 3H).
To a solution of compound 234A (100 mg, 319.21 umol) in MeOH (4 mL) and
H O (2 mL) was added LiOH•H O (53 mg, 1.28 mmol), then the mixture was stirred at 25 °C for
4 hours. The reaction mixture was concentrated under reduced pressure to remove MeOH. The
residue was diluted with H O (10 mL), adjusted to pH ~ 3 with 1N HCl, and extracted with
EtOAc (40 mL x 3). The combined organic layers were washed with brine (30 mL), dried over
anhydrous Na SO4, filtered and concentrated under reduced pressure to afford intermediate
compound 234B (80 mg, 87.87% yield) as a white solid. H NMR (400 MHz, DMSO-d ): δ 7.79
(s, 1H), 7.72 (s, 1H), 6.79 (s, 1H), 2.56 (s, 3H), 2.28 (s, 3H).
Compound 234 (24.1 mg, 34.58% yield, white solid) was prepared as in
Example 5 from the corresponding carboxylic acid, compound 234B. Compound 234: H NMR
(400 MHz, DMSO-d , t = 80 °C) δ 8.81 (d, J = 6.4 Hz, 1H), 7.75 (br s, 1H), 7.67 (s, 1H), 7.59
(br, s, 1H), 7.52 (s, 1H), 7.27 - 7.19 (m, 5H), 6.53 (s, 1H), 5.43 - 5.35 (m, 1H), 3.23 - 3.16 (m,
1H), 2.96 - 2.87 (m, 1H), 2.39 (s, 3H), 2.30 (s, 3H). MS (ESI) m/z (M+1) 460.1.
EXAMPLE 130
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)(BENZO[D]OXAZOLYL)-
3-METHYL-1H-PYRAZOLECARBOXAMIDE (238)
TMSOK
O N HOAc N
NHNH O
238C
238A 238B
A solution of 2-chlorobenzo[d]oxazole (2.5 g, 16.3 mmol) in dioxane (4 mL)
was added to a solution of N H .H O (4.07 g, 81.4 mmol) in dioxane (20 mL) dropwise keeping
2 4 2
the reaction temperature below 30 °C. The reaction mixture was stirred at 20 °C for 1hr. The
solvent was evaporated. Water (50 mL) was added and the mixture was stirred for 10min. The
solid was collected by filtration and the cake was washed by water (50mL). The cake was dried
17681897_1 (GHMatters) P110989.NZ
to give pure product 238A (2g, yield: 82.4%) as a white solid. H NMR (400MHz, DMSO-d ) δ
8.76 (br s, 1H), 7.31 (d, J = 7.7 Hz, 1H), 7.22 (d, J = 7.3 Hz, 1H), 7.09 (dt, J = 1.0, 7.7 Hz, 1H),
6.95 (dt, J = 1.1, 7.7 Hz, 1H), 4.47 (br s, 2H).
A mixture of compound 238A (1 g, 6.70 mmol) and methyl 2, 4-
dioxopentanoate (966 mg, 6.70 mmol) in AcOH (5 mL) was stirred at 120 °C for 16hrs. The
solvent was evaporated. The crude product was purified by silica gel column chromatography
(petroleum ether: ethyl acetate= 20:1~3:1) to give compound 238B (900 mg, crude) as off-white
solid.
A solution of compound 238B (200 mg, 777 umol) in toluene (5 mL) was
added TMSOK (199 mg, 1.55 mmol). The reaction mixture was stirred at 80 °C for 5hrs. The
reaction mixture was poured into saturated NH Cl (5mL). The product was extracted with EtOAc
(10 mL x 3). The combined organic layer was purified by preparatory-HPLC (HCOOH) to give
compound 238C (30 mg, yield: 15.9%) as a white solid. H NMR (400MHz, DMSO-d ) δ 13.30
(br s, 1H), 7.80 (td, J = 4.2, 8.4 Hz, 2H), 7.52 - 7.37 (m, 2H), 6.83 (s, 1H), 5.72 (s, 1H), 2.69 (s,
3H).
Compound 238 (21 mg, yield: 70%, white solid) was prepared as in Example 5
from the corresponding carboxylic acid, compound 238C. Possible isomer could not confirmed
by 2DNMR. Compound 238: H NMR (400MHz, CDCl ) δ 7.78 - 7.69 (m, 1H), 7.61 (dd, J =
3.2, 5.8 Hz, 1H), 7.51 (br d, J = 7.1 Hz, 1H), 7.43 - 7.35 (m, 2H), 7.32 - 7.16 (m, 6H), 6.80 - 6.70
(m, 2H), 5.81 - 5.71 (m, 1H), 5.55 (br s, 1H), 3.45 (dd, J = 5.4, 14.0 Hz, 1H), 3.22 (dd, J = 7.3,
14.1 Hz, 1H), 2.75 (s, 3H). MS (ESI) m/z (M+H) 418.1.
EXAMPLE 131
COMPOUNDS 239-242, 469-474
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)ETHYLPHENYL-1H-
PYRAZOLECARBOXAMIDE (239)
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)ISOPROPYLPHENYL-1H-
PYRAZOLECARBOXAMIDE (242)
A solution of p-TsOH.H O (61.3 g, 322.27 mmol) in H O (20 mL) was added
to a suspension of compound 1 (20.0 g, 128.91 mmol) in CH CN (400 mL) at 0 °C. The mixture
turned clear. The mixture was stirred at 0 °C for 30 min. Then a solution of NaNO (13.3 g,
17681897_1 (GHMatters) P110989.NZ
1) i-PrI, Cs CO , DMF
separation
193.4 mmol) and KI (32.1 g, 193.4 mmol) in H2O (20 mL) was added dropwise to the mixture at
0 °C. After addition, the mixture was stirred at 20 °C for 1h. The mixture was quenched by the
addition of saturated Na SO (~100 mL) at 0 °C. The black mixture turned yellow. The mixture
was concentrated to 200 mL and then extracted with DCM (75 mL x 3). The combined organic
layer was washed with brine (75 mL x 2), dried over MgSO , filtered and concentrated. The
residue was treated with 100 mL ethyl acetate. The insoluble substance was removed off by
filter. The filtrate was concentrated and purified by FCC (PE/EA = 1/1) to afford compound
239A (17.50 g, yield 48.4%) as white solid. H NMR (DMSO-d 400 MHz): δ 13.01 - 12.65 (m,
1H), 8.13 -8.11 (m, 1H), 4.38 – 4.32 (m, 2H), 1.41 – 1.37 (m, 3H). MS (ESI) m/z (M+H) 266.8.
Cs CO (7.35 g, 22.56 mmol) was added to a solution of compound 239A (2.0
g, 7.52 mmol) in DMF (15 mL). Then EtI (1.50 mL, 18.8 mmol,) was added. The mixture was
stirred at 25 °C for 2.5h. The mixture was treated with EA (50 mL) and H O (50 mL). The
organic layer was separated and the aqueous layer was extracted with EA (25 mL x 2). The
combined organic layer was washed brine (30 mL x 3), dried over MgSO , filtered and
concentrated. The residue was purified by FCC (PE/EA = 8/1) to afford compound 239B (1.31 g,
yield 59.2%) as colorless oil. Compound 239B (R = 0.24, PE/EA = 8/1): H NMR (DMSO-d
f 6,
400 MHz): δ 8.28 (s, 1H), 4.21 - 4.12 (m, 4H), 1.34 (t, J=7.3 Hz, 3H), 1.25 (t, J=7.1 Hz, 3H).
I Cs CO , EtI, DMF PhB(OH)
1) 2 3
2) separation O MeOH OH
HN N PddppfCl N
Na CO
2 3 N
239B
239E
239A 239D
PhB(OH)2
Na CO , MeOH, H O
Pd(dppf)Cl
2 3 2 2
dioxane, H O
242D
242C
242A
Na CO (360 mg, 3.4 mmol) was added to a solution of compound 239B (500
mg, 1.7 mmol) and phenylboronic acid (311 mg, 2.6 mmol) in dioxane (10 mL). Then H O (2
mL) was added, followed by Pd(dppf)Cl2 (124 mg, 0.17 mmol). The mixture was de-gassed 3
times and heated to 80 °C and stirred for 22h at 80 °C. The mixture was filtered through a pad of
Celite, the solid was washed with EA (25 mL x 3). The organic layer was separated from the
17681897_1 (GHMatters) P110989.NZ
filtrate, and then washed with brine (30 mL x 2), dried over MgSO , filtered and concentrated.
The residue was purified by FCC (PE/EA = 10/1) to afford compound 239D (380 mg, yield
91.5%) as pale yellow oil. H NMR (CDCl 400 MHz): δ 7.99 (s, 1H), 7.76 (dd, J = 1.5, 7.9 Hz,
2H), 7.44 - 7.32 (m, 3H), 4.28 - 4.17 (m, 4H), 1.55 (t, J = 7.3 Hz, 3H), 1.27 (t, J = 7.2 Hz, 3H).
To a solution of compound 239D (380 mg, 1.56 mmol) in MeOH (15 mL) was
added a solution of KOH (875 mg, 15.6 mmol) in H O (3 mL). The mixture was stirred at 70 °C
for 2h. The mixture was diluted with H O (15 mL), and then the volatile solvent was removed
by evaporation. The residue was acidified to pH ~ 2 with 1N HCl. The precipitate was collected
by filter and dried in vacuum to afford compound 239E (250 mg, yield 74.1%) was obtained as
white solid, which was used for next step directly. H NMR (DMSO-d 400 MHz): δ 12.19
(br.s., 1H), 8.32 (s, 1H), 7.72 (dd, J = 1.4, 7.8 Hz, 2H), 7.41 - 7.24 (m, 3H), 4.17 (q, J = 7.3 Hz,
2H), 1.39 (t, J = 7.3 Hz, 3H).
Compound 239 (80 mg, yield 51.3%, white solid) was prepared as in Example
from the corresponding intermediate carboxylic acid, compound 239E. Compound 239: H
NMR (CDCl 400 MHz): δ 8.32 (d, J = 7.2 Hz, 1H), 8.07 (s, 1H), 8.05 (br.s., 1H), 7.79 (br.s.,
1H), 7.62 - 7.51 (m, 2H), 7.32 - 7.17 (m, 8H), 5.32 - 5.22 (m, 1H), 4.16 (q, J = 7.2 Hz, 2H), 3.14
(dd, J = 4.0, 14.0 Hz, 1H), 2.81 (dd, J = 10.0, 14.0 Hz, 1H), 1.40 (t, J =7.2 Hz, 3H). MS (ESI)
m/z (M+H) 391.1.
Following the procedure used for compound 239, intermediate compounds
242A, 242C and 242D were successively prepared. Compound 242A (1.41 g, yield 60.9%,
colorless oil): H NMR (DMSO-d 400 MHz): δ 8.31 (s, 1H), 4.60 - 4.53 (m, 1H), 4.22 (q, J =
7.2 Hz, 2H), 1.41 (d, J = 6.4 Hz, 6H), 1.28 (t, J = 7.2 Hz, 3H).
Compound 242C (318 mg, yield 76.0%, colorless liquid): H NMR (DMSO-
d 400 MHz): δ 8.39 (s, 1H), 7.73 - 7.67 (m, 2H), 7.42 - 7.34 (m, 3H), 4.64 - 4.52 (m, 1H), 4.16
(q, J = 7.0 Hz, 2H), 1.46 (d, J = 6.8 Hz, 6H), 1.21 (t, J = 7.2 Hz, 3H). Compound 242D (119 mg,
crude, white solid): H NMR (DMSO-d 400 MHz): δ 12.19 (s, 1H), 8.33 (s, 1H), 7.76 - 7.71 (m,
2H), 7.41 - 7.32 (m, 3H), 4.61 - 4.51 (m, 1H), 1.46 (d, J = 6.8 Hz, 3H).
Compound 242 (47 mg, yield 46.7%, white solid) was prepared as in Example
from the corresponding intermediate carboxylic acid, compound 242D. Compound 242: H
NMR (CDCl 400 MHz): δ 7.99 (s, 1H), 7.55 - 7.49 (m, 2H), 7.47 - 7.37 (m, 3H), 7.23 - 7.14
17681897_1 (GHMatters) P110989.NZ
(m, 3H), 6.85 - 6.78 (m, 2H), 6.73 (s, 1H), 6.13 - 6.05 (m, J = 6.2 Hz, 1H), 5.57 - 5.42 (m, 2H),
4.51 (spt, J = 6.7 Hz, 1H), 3.25 (dd, J = 4.7, 14.0 Hz, 1H), 2.90 (dd, J = 8.0, 14.2 Hz, 1H), 1.53
(d, J = 6.6 Hz, 6H). MS (ESI) m/z (M+H) 405.2.
N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)ETHYL(2-FLUOROPHENYL)-
1H-PYRAZOLECARBOXAMIDE (469)
Compound 469 (130 mg, yield 49%, white solid) was prepared as in compound
12 from the corresponding intermediate carboxylic acid, 1-ethyl(2-fluorophenyl)-1H-pyrazole-
4-carboxylic acid which was prepared using procedure similar to compound 239E. Compound
469: H NMR (DMSO-d 400 MHz): δ 8.21 (s, 1H), 7.89 - 7.45 (m, 3H), 7.43 - 7.31 (m, 2H),
7.30 - 7.10 (m, 7H), 5.33 - 5.22 (m, 1H), 4.20 (q, J = 7.1 Hz, 2H), 3.22 - 3.15 (m, 1H), 2.92 -
2.82 (m, 1H), 1.45 (br t, J = 7.2 Hz, 3H). MS (ESI) m/z (M+H) 409.1.
N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)ETHYL(3-FLUOROPHENYL)-
1H-PYRAZOLECARBOXAMIDE (470)
Compound 470 (140 mg, yield 66.8%, white solid) was prepared as in
compound 12 from the corresponding intermediate carboxylic acid, 1-ethyl(3-fluorophenyl)-
1H-pyrazolecarboxylic acid which was prepared using procedure similar to compound 239E.
Compound 470: H NMR (DMSO-d6, 400 MHz): δ 8.44 (d, J = 7.5 Hz, 1H), 8.11 (s, 1H), 8.04
(s, 1H), 7.78 (s, 1H), 7.47 - 7.39 (m, 2H), 7.36 - 7.29 (m, 1H), 7.28 - 7.23 (m, 4H), 7.22 - 7.16
(m, 1H), 7.14 - 7.07 (m, 1H), 5.35 - 5.25 (m, 1H), 4.21 - 4.11 (m, 2H), 3.15 (dd, J = 3.9, 14.0 Hz,
1H), 2.81 (dd, J = 9.9, 13.9 Hz, 1H), 1.40 (t, J = 7.3 Hz, 3H). MS (ESI) m/z (M+H) 409.1.
N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)ETHYL(4-FLUOROPHENYL)-
1H-PYRAZOLECARBOXAMIDE (471)
Compound 471 (90 mg, yield 32.9%, white solid) was prepared as in
compound 12 from the corresponding intermediate carboxylic acid, 1-ethyl(4-fluorophenyl)-
1H-pyrazolecarboxylic acid which was prepared using procedure similar to compound 239E.
Compound 471: H NMR (DMSO-d 400 MHz): δ 8.37 (d, J = 7.5 Hz, 1H), 8.08 (s, 1H), 8.05 -
7.96 (m, 1H), 7.77 (s, 1H), 7.63 - 7.52 (m, 2H), 7.31 - 7.14 (m, 5H), 7.13 - 7.01 (m, 2H), 5.31 -
.16 (m, 1H), 4.24 - 4.03 (m, 2H), 3.18 - 3.06 (m, 1H), 2.87 - 2.75 (m, 1H), 1.38 (t, J = 7.3 Hz,
3H). MS (ESI) m/z (M+H) 409.1.
17681897_1 (GHMatters) P110989.NZ
N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)(2-FLUOROPHENYL)
ISOPROPYL-1H-PYRAZOLECARBOXAMIDE (472)
Compound 472 (88 mg, yield 45.8%, white solid) was prepared as in
compound 12 from the corresponding intermediate carboxylic acid, 3-(2-fluorophenyl)
isopropyl-1H-pyrazolecarboxylic acid which was prepared using procedure similar to
compound 242D. Compound 472: H NMR (DMSO-d 400 MHz): δ 8.25 (s, 1H), 8.17 (d, J =
7.5 Hz, 1H), 7.96 (s, 1H), 7.73 (s, 1H), 7.40 - 7.05 (m, 9H), 5.26 - 5.16 (m, 1H), 4.52 (td, J = 6.8,
13.2 Hz, 1H), 3.09 (br, dd, J = 3.9, 14.2 Hz, 1H), 2.78 (br.dd, J = 9.7, 13.9 Hz, 1H), 1.48 - 1.39
(m, 6H). MS (ESI) m/z (M+H) 423.2.
N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)(3-FLUOROPHENYL)
ISOPROPYL-1H-PYRAZOLECARBOXAMIDE (473)
Compound 473 (51 mg, yield 41.2%, pale yellow solid) was prepared as in
compound 12 from the corresponding intermediate carboxylic acid, 3-(3-fluorophenyl)
isopropyl-1H-pyrazolecarboxylic acid which was prepared using procedure similar to
compound 242D. Compound 473: H NMR (DMSO-d 400 MHz): δ 8.42 (d, J = 7.3 Hz, 1H),
8.14 (s, 1H), 8.07 - 8.01 (m, 1H), 7.78 (s, 1H), 7.51 - 7.42 (m, 2H), 7.36 - 7.29 (m, 1H), 7.28 -
7.24 (m, 4H), 7.22 - 7.16 (m, 1H), 7.14 - 7.05 (m, 1H), 5.34 - 5.25 (m, 1H), 4.60 - 4.48 (m, 1H),
3.15 (dd, J = 4.0, 14.1 Hz, 1H), 2.82 (dd, J=9.8, 14.0 Hz, 1H), 1.44 (d, J=6.4 Hz, 6H). MS (ESI)
m/z (M+H) 423.2.
N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)(4-FLUOROPHENYL)
ISOPROPYL-1H-PYRAZOLECARBOXAMIDE (474)
Compound 474 (80 mg, yield 52.6%, white solid) was prepared as in
compound 12 from the corresponding intermediate carboxylic acid, 3-(4-fluorophenyl)
isopropyl-1H-pyrazolecarboxylic acidwhich was prepared using procedure similar to
compound 242D. Compound 474: H NMR (DMSO-d 400 MHz): δ 8.10 (s, 1H), 7.97 (s, 1H),
7.85 - 7.39 (m, 4H), 7.34 - 7.17 (m, 5H), 7.15 - 7.03 (m, 2H), 5.37 - 5.27 (m, 1H), 4.59 - 4.47 (m,
1H), 3.26 - 3.16 (m, 1H), 2.97 - 2.87 (m, 1H), 1.49 (d, J = 6.8 Hz, 6H). MS (ESI) m/z (M+H)
423.2.
17681897_1 (GHMatters) P110989.NZ
EXAMPLE 132
COMPOUNDS 240-241
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)ETHYLPHENYL-1H-
PYRAZOLECARBOXAMIDE (240)
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)METHYLPHENYL-1H-
PYRAZOLECARBOXAMIDE (241)
NaOH
PhB(OH)2 O
, Cs CO , DMF THF, MeOH, H O
Pd(PPh3)4 2 3 2
o OH
80 16 h h
16
C, C,
240A
240C
240D
NaOH
PhB(OH)2
, Cs CO , DMF THF, MeOH, H O
Pd(PPh3)4 2 3 2
80 16 h 25 16 h
O C,
240B N N
241B
241A
To a mixture of methyl 4-bromo-1H-pyrazolecarboxylate (15.0 g, 73.2
mmol,) and Cs CO (59.6 g, 182.9 mmol) in DMF (150 mL) was added MeI (14.7 mL, 236.0
mmol) drop-wise at 0°C under N . The mixture was stirred at 25 °C for 16 hours. The reaction
mixture was filtered, the cake washed with ethyl acetate (200 mL x 2). The filtrate was washed
with water (70 mL x 4) and the aqueous phase extracted with ethyl acetate (150 mL). The
combined organic extracts were dried over Na SO , filtered and concentrated to dryness under
reduced pressure to dryness. The crude product which was purified by FCC (gradient eluent:
petroleum ether/ethyl acetate from 100/0 to 50/50) to afford the title compound 240A (8.3 g,
yield 51.8%) as a white solid and the title compound 240B (7.0 g, yield 43.7%) as white solid.
Compound 240A: H NMR (400MHz, CDCl ): δ 7.48 (s, 1H), 4.15 (s, 3H), 3.93 (s, 3H). MS
+ 1
(ESI) m/z (M+H) 219.0. Compound 240B: H NMR (400MHz, CDCl ): δ 7.47 (s, 1H), 3.95 (s,
3H), 3.92 (s, 3H). MS (ESI) m/z (M+H) 219.0.
Compound 240A (2.0 g, 9.1 mmol), phenylboronic acid (1.3 g, 11.0 mmol),
Cs CO (8.9 g, 27.4 mmol) and Pd(PPh ) (211 mg, 183 umol) in DMF (30 mL) was de-gassed
2 3 3 4
and then heated to 80°C for 16 hours under N2. The reaction mixture was filtered, the cake
washed with ethyl acetate (30 mL x 2). The filtrate was washed with water (20 mL x 4) and the
17681897_1 (GHMatters) P110989.NZ
aqueous phase extracted with ethyl acetate (50 mL). The combined organic extracts were dried
over Na SO , filtered and concentrated to dryness under reduced pressure to dryness. The crude
product which was purified by FCC (gradient eluent: petroleum ether/ethyl acetate from 100/0 to
50/50) to afford the title compound 240C (1.0 g, yield 47.3%) as a light yellow solid. Compound
240C: H NMR (400MHz, CDCl ): δ 7.52 (s, 1H), 7.40 - 7.36 (m, 4H), 7.35 - 7.31 (m, 1H), 4.20
(s, 3H), 3.76 (s, 3H). MS (ESI) m/z (M+H) 217.0.
A solution of NaOH (370 mg, 9.2 mmol) in H O (10 mL) was added to a
solution of compound 240C (1.0 g, 4.6 mmol) in THF (10 mL) and MeOH (10 mL) at 25 °C.
The mixture was stirred at 25 °C for 16 hours. The mixture was adjusted to pH ~ 6 with 1N HCl
(10 mL) at 25 °C, and extracted with ethyl acetate (30 mL x 3). The combined organic extracts
were dried over Na SO , filtered, and concentrated to afford compound 240D (900 mg, yield
94.1%) as light yellow solid. Compound 240D: H NMR (400MHz, CD OD): δ 7.54 - 7.49 (m,
1H), 7.44 - 7.38 (m, 2H), 7.37 - 7.27 (m, 3H), 4.14 (s, 3H). MS (ESI) m/z (M+H) 202.9.
Compound 240 (68.6 mg, yield 41.4%) was prepared as in Example 12 from
the corresponding intermediate carboxylic acid, compound 240D. Compound 240: H NMR
(400MHz, DMSO-d ): δ 7.46 - 7.39 (m, 4H), 7.39 - 7.34 (m, 2H), 7.20 - 7.13 (m, 3H), 6.73 -
6.68 (m, 2H), 6.14 - 6.07 (m, 1H), 5.57 - 5.46 (m, 2H), 4.09 (s, 3H), 3.19 (dd, J = 4.8, 14.0 Hz,
1H), 2.80 (dd, J = 8.0, 14.0 Hz, 1H). MS (ESI) m/z (M+H) 377.1.
Following the procedure used for compound 240, compound 241 (90 mg, yield
58.5%, white solid) was prepared from intermediate compound 241B. Compound 241: H NMR
(400MHz, CDCl ): δ 7.53 - 7.47 (m, 2H), 7.41 (s, 1H), 7.37 - 7.27 (m, 6H), 7.19 - 7.13 (m, 2H),
6.72 (br s, 1H), 5.69 - 5.62 (m, 1H), 5.43 (br s, 1H),3.94 (s, 3H), 3.42 (dd, J = 5.2, 14.0 Hz, 1H),
3.20 (dd, J = 7.6, 14.0 Hz, 1H). MS (ESI) m/z (M+H) 377.1.
17681897_1 (GHMatters) P110989.NZ
EXAMPLE 133
COMPOUNDS 244-245
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)METHYL(2-
METHYLPYRIMIDINYL)-1H-PYRAZOLECARBOXAMIDE (244)
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)METHYL(PYRIMIDIN
YL)-1H-PYRAZOLECARBOXAMIDE (245)
N NHNH
N LiOH
CH OH/H O
3 2 N
HOAc
244A
244B 244D
N LiOH
N NHNH
CH OH/H O
°C, 0.5 hr
HOAc, 120 °C, 2h
245A
245B
245D
A mixture of 4-chloromethylpyrimidine (5.00 g, 38.89 mmol) and
N H .H O (22.91 g, 388.90 mmol, 22.24 mL, 85% purity) in EtOH (100 mL) was degassed and
2 4 2
purged with N for 3 times, then the mixture was stirred at 70 °C for 2 hour under N
atmosphere. The mixture was concentrated under reduced pressure to give a crude, the
crude was washed by PE (50 mL) and filtered, the residue was purified by column
chromatography (DCM: CH OH=10:1) to obtain compound 244A (1.60 g, 33.14% yield) as a
yellow solid. H NMR (400 MHz, DMSO-d ) δ 8.21 (s, 1H), 7.99 (d, J = 5.6 Hz, 1H), 6.48 (br s,
1H), 4.31 (br s, 2H), 2.30 (s, 3H).
To a solution of compound 244A (900.0 mg, 7.25 mmol) in CH COOH (12
mL) was added ethyl 2-(methoxyimino)oxopentanoate (1.36 g, 7.25 mmol), then the mixture
was stirred at 120 °C for 2 hours. The residue was diluted with solvent EtOAc (70 mL) and
washed with solvent satutaed NaHCO solution (20 mL x 3), dried over anhydrous Na SO ,
3 2 4
filtered and concentrated under reduced pressure to give a residue. The residue was purified by
column chromatography (PE: EA = 30/1 to 10/1) to afford crude. The crude was further
separated by preparatory-HPLC (Basic condition) to give compound 244B (158.0 mg, 8.85%
yield) as a white solid. H NMR (400 MHz, CDCl ) δ 8.66 (d, J = 5.6 Hz, 1H), 7.53 (d, J = 3.6
17681897_1 (GHMatters) P110989.NZ
Hz, 1H), 6.59 (s, 1H), 4.39 – 4.33 (m, 2H), 2.66 (s, 3H), 2.35 (s, 3H), 1.35 – 1.32 (m, 3H). MS
(ESI) m/z (M+1) 247.1.
To a mixture of compound 244B (130.0 mg, 527.90 umol) in MeOH (8 mL)
and H O (4 mL) was added LiOH.H O (88.6 mg, 2.11 mmol) in one portion and the mixture was
stirred at 25 °C for 0.5 hours. The reaction mixture was concentrated under reduced pressure to
remove MeOH. The residue was diluted with H O (10 mL), adjusted to pH ~ 3 with 1N HCl,
and then extracted with EtOAc (40 mL x 3). The combined organic layers were washed with
brine (30 mL), dried over anhydrous Na SO , filtered and concentrated under reduced pressure to
give intermediate compound 244D (110.00mg, 95.49% yield) as a white solid. H NMR (400
MHz, DMSO-d ) δ 8.77 (d, J = 5.6 Hz, 1H), 7.56 (d, J = 3.6 Hz, 1H), 6.76 (s, 1H), 2.65 (s, 3H),
2.27 (s, 3H). MS (ESI) m/z (M+1) 219.1.
Compound 244 (40.0 mg, 33.17% yield, white solid) was prepared as in
Example 5 from the corresponding intermediate carboxylic acid, compound 244D. Compound
244: H NMR (400 MHz, CDCl ) δ 9.48 (d, J = 5.2 Hz, 1H), 8.66 (d, J = 4.8 Hz, 1H), 7.70 (d, J
= 5.2 Hz, 1H), 7.26 – 7.20 (m, 3H), 7.10 (s, 2H), 6.84 (s, 1H), 6.78 (s, 1H), 5.81 (d, J = 6.0Hz,
1H), 5.58 (s, 1H), 3.47 – 3.38 (m, 1H), 3.39 – 3.34 (m, 1H), 2.37 (s, 3H), 2.34 (s, 3H). MS (ESI)
m/z (M+1) 393.1.
Following the procedure used for compound 244A, compound 245A (1.80 g,
49.37% yield, brown solid) was obtained from 4-chloropyrimidine and NH2NH2.H2O.
Compound 245A: H NMR (400 MHz, DMSO-d ): δ 8.32 (s, 2H), 8.06 (d, J = 5.2 Hz, 1H), 6.65
(s, 1H), 4.32 (m, 2H).
Following the procedure used for compound 244B, compound 245B (586.0
mg, 2.52 mmol, 17.39 % yield) was obtained as a white solid. H NMR (400 MHz, CDCl ) δ
8.92 (s, 1H), 8.71 (d, J = 5.6 Hz, 1H), 7.70 – 7.69 (m, 1H), 6.56 (s, 1H), 4.34 – 4.38 (m, 2H),
2.29 (s, 1H), 1.31 – 1.24 (m, 3H). MS (ESI) m/z (M+1) 233.1.
Following the procedure for compound 244D, compound 245D (476.0 mg,
2.33 mmol, 93.30% yield) was obtained as white solid. H NMR (400 MHz, DMSO-d ) δ 9.04
(s, 1H), 8.90 (d, J = 5.2 Hz, 1H), 7.81 (d, J = 5.6 Hz, 1H), 6.79 (s, 1H), 2.27 (s, 3H).
Compound 245 (35.0 mg, 28.33% yield, white solid) was prepared as in
Example 5 from the corresponding carboxylic acid, compound 245D. Compound 245: H NMR
17681897_1 (GHMatters) P110989.NZ
(400 MHz, DMSO-d ) δ 9.18 (d, J = 7.2 Hz, 1H), 8.83 (d, J = 5.6 Hz, 1H), 8.74 (s, 1H), 8.11 (s,
1H), 7.87 (s, 1H), 7.73 (d, J = 4.8 Hz, 1H), 7.28 – 7.23 (m, 5H), 6.50 (s, 1H), 5.38 (s, 1H), 3.19 –
3.16 (m, 1H), 2.88 – 2.82 (m, 1H), 2.29 (s, 3H). MS (ESI) m/z (M+1) 379.1.
EXAMPLE 134
Compounds 246, 431-437, 448
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)(2-CHLOROPYRIMIDIN
YL)METHYL-1H-PYRAZOLECARBOXAMIDE (246)
Cl N
Cl N NHNH N
HOAc, 118 °C, 1h
246A
246C
246B
LiOH N
N OH
THF, H O
246D
246B
To a solution of 2,4-dichloropyrimidine (10 g, 67.12 mmol) and Et N (10.2
mL, 73.83 mmol) in EtOH (120 mL) was added NH NH .H O (4.6 mL, 80.54 mmol) at 0~5 °C.
2 2 2
The mixture was stirred at 5 °C for 1.5h. The mixture was concentrated. The residue was
triturated in EtOH (15 mL) and water (15 mL) to afford compound compound 246A (4 g, 41.22%
yield) as yellow oil. H NMR (400MHz, DMSO-d ) δ 9.00 - 8.79 (m, 1H), 8.09 - 7.63 (m, 1H),
6.82 - 6.59 (m, 1H), 4.82 - 4.30 (m, 2H).
A mixture of ethyl 2,4-dioxopentanoate (4.38 g, 27.67 mmol), compound
246A (4 g, 27.67 mmol) in AcOH (60 mL) was stirred at 118 °C for 1h. The mixture was in
DCM (50 mL). The organic layer was washed with water (10 mL), NaHCO to pH ~ 8~9 and
dried over Na SO and concentrated. The residue was purified by column chromatography
(SiO , Petroleum ether/Ethyl acetate=10/1 to 5:1). Compound 246B (650 mg, 8.81% yield) was
obtained as white solid. Compound 246C (240 mg, 3.25% yield) was obtained as white solid.
Compound 246B: H NMR (400MHz, DMSO-d ) δ 8.87 (d, J=5.6 Hz, 1H), 7.98 (d, J=5.6 Hz,
1H), 6.89 (s, 1H), 4.34 (q, J=7.2 Hz, 2H), 2.71 (s, 3H), 1.32 (t, J=7.2 Hz, 3H). Compound 246C:
17681897_1 (GHMatters) P110989.NZ
H NMR (400MHz, DMSO- d ) δ 8.84 (d, J=5.6 Hz, 1H), 7.86 (d, J=5.6 Hz, 1H), 6.91 (s, 1H),
4.32 (q, J=7.2 Hz, 2H), 2.31 (s, 3H), 1.30 - 1.20 (m, 3H).
A mixture of compound 246B (300 mg, 1.12 mmol) in THF (36 mL) and H O
(12 mL) was added LiOH.H O (27.1 mg, 645.87 umol). The mixture was stirred at 31 °C for 1h.
The mixture was concentrated and acidified to pH ~ 5 with 1M HCl, then extracted with
chloroform: isopropyl alcohol = 10 : 1 (10 ml x 2). This combined organic phase was washed
with saturated aqueous NaCl and dried over Na SO , filtered and the solvent was removed in
vacuo to give compound 246D (200 mg, 74.83% yield) as white solid. H NMR (400 MHz,
DMSO-d ): δ 14.19 - 13.39 (m, 1H), 8.83 (d, J = 5.4 Hz, 1H), 7.83 (d, J=5.6 Hz, 1H), 6.84 (s,
1H), 2.28 (s, 3H).
Compound 246 (2.7 mg, yield, 12.35%, white solid) was prepared as in
Example 5 from the corresponding carboxylic acid, compound 246D. Compound 246: H NMR
(400MHz, DMSO-d ): δ 9.16 - 9.11 (m, 1H), 8.77 - 8.72 (m, 1H), 8.03 (br s, 1H), 7.80 (br s, 1H),
7.73 - 7.68 (m, 1H), 7.23 (br s, 4H), 7.21 - 7.17 (m, 1H), 6.53 (s, 1H), 5.42 (br s, 1H), 3.17 - 3.13
(m, 1H), 2.88 - 2.84 (m, 1H), 2.27 (s, 3H). MS (ESI) m/z (M+H) 413.1.
N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)(2-ISOPROPYLPYRIMIDIN
YL)METHYL-1H-PYRAZOLECARBOXAMIDE (431)
Compound 431 (65 mg, yield, 87.0%, white solid) was prepared using
intermediate 246B which was subjected to suzuki coupling using 4,4,5,5-tetramethyl(prop
enyl)-1,3,2-dioxaborolane followed by ester hydrolysis using procedure as for compound 12
and hydrogenation and coupling with intermediate 274D as in compound 12 to obtain compound
431. Compound 431: H NMR (400MHz, DMSO-d ): δ 9.11 (d, J = 7.5 Hz, 1H), 8.74 (d, J =
.5 Hz, 1H), 8.12 (s, 1H), 7.87 (s, 1H), 7.52 (d, J = 5.5 Hz, 1H), 7.32 - 7.20 (m, 5H), 6.47 (s,
1H), 5.52 - 5.41 (m, 1H), 3.16 (dd, J = 3.6, 13.8 Hz, 1H), 2.80 - 2.75 (m, 1H), 2.29 (s, 3H), 1.04
(dd, J = 6.9, 12.2 Hz, 6H). MS (ESI) m/z (M+H) 421.2.
N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)(2-ETHYNYLPYRIMIDINYL)-
3-METHYL-1H-PYRAZOLECARBOXAMIDE (432)
Compound 432 (35 mg, yield, 43.5%, white solid) was prepared using
intermediate 246B which was subjected to coupling with 4ethynyltrimethylsilane followed by
removal of trimethylsilyl group and then ester hydrolysis using procedure as for compound 12
17681897_1 (GHMatters) P110989.NZ
and coupling with intermediate 274D as in compound 12 to obtain compound 432. Compound
432: H NMR (400MHz, DMSO-d ): δ 9.14 (d, J = 7.0 Hz, 1H), 8.82 (d, J = 5.5 Hz, 1H), 8.02
(s, 1H), 7.80 (s, 1H), 7.70 (d, J = 5.5 Hz, 1H), 7.31 - 7.17 (m, 5H), 6.55 (s, 1H), 5.46 - 5.35 (m,
1H), 4.39 (s, 1H), 3.19 (dd, J = 4.8, 14.1 Hz, 1H), 2.93 (dd, J = 9.0, 14.1 Hz, 1H), 2.29 (s, 3H).
MS (ESI) m/z (M+H) 403.1.
(S)(2-ETHYNYLPYRIMIDINYL)-N-(4-FLUOROOXOPHENYLBUTAN
YL)METHYL-1H-PYRAZOLECARBOXAMIDE (433)
Compound 433 (35 mg, yield, 43.5%, white solid) was prepared using
intermediate 246B which was subjected to coupling with 4ethynyltrimethylsilane followed by
removal of trimethylsilyl group and then ester hydrolysis using procedure as for compound 12
and coupling with (2S,3S)aminofluorophenylbutanol hydrochloride using procedure
as in compound 12 to obtain compound 433. Compound 433: H NMR (400MHz, DMSO-d ): δ
9.24 (d, J = 7.8 Hz, 1H), 8.85 (d, J = 5.5 Hz, 1H), 7.78 (d, J = 5.5 Hz, 1H), 7.34 - 7.29 (m, 2H),
7.29 - 7.21 (m, 3H), 6.38 s, 1H), 5.50 - 5.21 (m, 2H), 4.73 - 4.64 (m, 1H), 4.45 (s, 1H), 3.19 (dd,
J = 4.9, 13.9 Hz, 1H), 2.93 (dd, J = 9.8, 14.1 Hz, 1H), 2.28 (s, 3H). MS (ESI) m/z (M+H) 392.1.
N-(4-AMINOHYDROXYOXOPHENYLBUTANYL)(2-
CHLOROPYRIMIDINYL)METHYL-1H-PYRAZOLECARBOXAMIDE (434)
Compound 434 (80 mg, yield, 15.2%, white solid) was prepared using
intermediate 246B which was subjected to coupling with intermediate 274D using procedure as
in compound 12 to obtain compound 434. Compound 434: H NMR (400MHz, DMSO-d ): δ
8.76 (t, J = 5.6 Hz, 1H), 8.63 (d, J = 8.8 Hz, 1H), 8.36 (d, J = 9.0 Hz, 1H), 7.68 (dd, J = 5.5, 19.6
Hz, 1H), 7.39 - 7.14 (m, 7H), 6.55 - 6.41 (m, 1H), 4.57 - 4.31 (m, 1H), 4.19 (d, J = 3.3 Hz, 1H),
3.85 (d, J = 2.4 Hz, 1H), 3.04 - 2.66 (m, 2H), 2.28 (d, J = 5.5 Hz, 3H). MS (ESI) m/z (M+H)
415.0.
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)(2-CHLOROPYRIMIDIN
YL)METHYL-1H-PYRAZOLECARBOXAMIDE (435)
Compound 435 (160 mg, yield, 46.02%, white solid) was prepared using
intermediate 246C which was subjected to coupling with intermediate 12G using procedure as in
compound 12 to obtain compound 435. Compound 435: H NMR (400MHz, DMSO-d ): δ 8.88
(d, J = 5.7 Hz, 1H), 8.09 (d, J = 5.5 Hz, 1H), 7.82 (d, J = 9.3 Hz, 1H), 7.42 (s, 1H), 7.27 (d, J =
17681897_1 (GHMatters) P110989.NZ
4.4 Hz, 4H), 7.23 - 7.13 (m, 1H), 6.72 (s, 1H), 6.21 (s, 1H), 4.49 (d, J = 7.3 Hz, 1H), 3.88 (d, J =
2.4 Hz, 1H), 3.02 - 2.87 (m, 1H), 2.86 - 2.74 (m, 1H), 2.68 (s, 3H). MS (ESI) m/z (M+H) 415.0.
N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)(2-METHOXYPYRIMIDIN
YL)METHYL-1H-PYRAZOLECARBOXAMIDE (436)
Compound 436 (25 mg, yield, 57.7%, white solid) was prepared using
intermediate 246D which was subjected to treatment with sodium methoxide and coupling with
intermediate 274D using procedure as in compound 12 to obtain compound 436. Compound
436: H NMR (400MHz, DMSO-d ): δ 9.14 (d, J = 7.5 Hz, 1H), 8.60 (d, J = 5.3 Hz, 1H), 8.15
(s, 1H), 7.91 (s, 1H), 7.34 (d, J = 5.3 Hz, 1H), 7.30 - 7.19 (m, 5H), 6.50 (s, 1H), 5.45 - 5.36 (m,
1H), 3.48 (s, 3H), 3.16 (dd, J = 3.3, 13.9 Hz, 1H), 2.77 (dd, J = 10.1, 13.9 Hz, 1H), 2.29 (s, 3H).
MS (ESI) m/z (M+H) 409.2.
N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)(2-CYANOPYRIMIDINYL)
METHYL-1H-PYRAZOLECARBOXAMIDE (437)
Compound 437 (30 mg, yield, 81.32%, white solid) was prepared using
intermediate 246D which was subjected to treatment with zinc cyanide using palladium catalyzed
coupling conditions followed by coupling with intermediate 274D using procedure as in
compound 12 to obtain compound 437. Compound 437: H NMR (400MHz, DMSO-d6): δ 9.13
(d, J = 7.3 Hz, 1H), 8.96 (d, J = 5.5 Hz, 1H), 8.05 - 7.93 (m, 2H), 7.84 (s, 1H), 7.27 - 7.15 (m,
5H), 6.57 (s, 1H), 5.51 - 5.31 (m, 1H), 3.15 (dd, J = 4.2, 13.9 Hz, 1H), 2.79 (dd, J = 9.4, 14.0 Hz,
1H), 2.30 - 2.24 (m, 3H). MS (ESI) m/z (M+H) 404.1.
N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)(2-CYANOPYRIMIDINYL)
METHYL-1H-PYRAZOLECARBOXAMIDE (448)
17681897_1 (GHMatters) P110989.NZ
Cl N
O tBuOH
p-TsCl DMF
O Bu
O Bu
246D
448A 448B
F N F
TFA, DCM O
N NH
448C
To a solution of compound 246D (400 mg, 1.68 mmol) in 2-methylpropanol
(6.2 g, 83.65 mmol, 8.00 mL) and THF (10 mL) was added pyridine (928 mg, 11.73 mmol, 947
uL) and then added p-TsCl (799 mg, 4.19 mmol) in one portion at 0 °C. The mixture was stirred
at 25 °C for 48 h. The reaction was quenched with sat. NaHCO at 0 °C, the mixture was
extracted with EA (20 mL x 2), dried over Na SO , filtered, and concentrated to give a residue.
The residue was purified by flash silica gel chromatography (ISCO ; 24g SepaFlash Silica
Flash Column, eluent of 0~10%~20% Ethyl acetate/Petroleum ethergradient @ 35 mL/min).
Compound 448A (400 mg, yield 81.0%) was obtained as a white solid. H NMR (400MHz,
CDCl ) δ 8.63 (d, J = 5.3 Hz, 1H), 7.80 - 7.63 (m, 1H), 6.59 (s, 1H), 2.34 (m, 3H), 1.59 (m, 9H).
MS (ESI) m/z (M+H) 295.1.
To a solution of compound 448A (400 mg, 1.36 mmol) in DMF (13 mL) was
added KF (788 mg, 13.57 mmol) and Dicyclohexanocrown-6 (51 mg, 135.71 umol). The
mixture was stirred at 120 °C for 3 h under N . The reaction was cooled to rt and added ice-
water (80 mL), white precipitate was formed. The solid was collected by filtration. The residue
was purified by preparatory-HPLC (HCl condition). Column: YMC-Actus Triart C18
100*30mm*5um; mobile phase: [water (0.05%HCl)-ACN]; B%: 55%-85%, 9.5min. Compound
448B (130 mg, yield: 34.4%) was obtained as a white solid. H NMR (400MHz, CDCl ) δ 8.63
(dd, J = 2.0, 5.3 Hz, 1H), 7.72 (dd, J = 3.2, 5.4 Hz, 1H), 6.57 (s, 1H), 2.36 (s, 3H), 1.59 (s, 9H).
MS (ESI) m/z (M+H) 279.1.
To a solution of compound 448B (130 mg, 467.15 umol) in DCM (15 mL) was
added TFA (2.31 g, 20.26 mmol, 1.5 mL). The mixture was stirred at 25 °C for 5 h. The
17681897_1 (GHMatters) P110989.NZ
reaction was concentrated to give a residue. The residue was used to the next step without
purification. Compound 448C (105 mg, crude) was obtained as a yellow solid. H NMR
(400MHz, DMSO-d ) δ 8.84 (dd, J = 2.1, 5.4 Hz, 1H), 7.81 (dd, J = 3.5, 5.5 Hz, 1H), 6.89 - 6.78
(m, 1H), 2.25 (s, 3H). MS (ESI) m/z (M+H) 222.9.
Compound 448 (35 mg, yield, 69.7%, white solid) was prepared using
intermediate 246D and 448C using procedure as in compound 12 to obtain compound 448.
Compound 448: H NMR (400MHz, DMSO-d ): δ 9.14 (d, J = 7.3 Hz, 1H), 8.76 (dd, J = 2.0,
.5 Hz, 1H), 8.06 (s, 1H), 7.83 (s, 1H), 7.70 (dd, J = 3.5, 5.5 Hz, 1H), 7.27 - 7.17 (m, 5H), 6.53
(s, 1H), 5.42 - 5.37 (m, 1H), 3.14 (dd, J = 4.0, 14.1 Hz, 1H), 2.82 (dd, J = 9.3, 14.1 Hz, 1H), 2.28
(s, 3H). MS (ESI) m/z (M+H) 397.1.
EXAMPLE 135
(S)-N-(3,4-DIOXOPHENYL((4-
(TRIFLUOROMETHOXY)BENZYL)AMINO)BUTANYL)METHYL
PHENYLISOXAZOLECARBOXAMIDE (247)
OH O
H EDCI,DIEA,HOBT
OH CF
N OH 3
101E
247A
To a solution of compound 101E (500.0 mg, 1.31 mmol) in DMF (10 mL) was
added [4-(trifluoromethoxy)phenyl]methanamine (250.4 mg, 1.31 mmol, 200 uL), DIEA (507.9
mg, 3.93 mmol, 690 uL), HOBt (53.1 mg, 393.00 umol) and EDCI (301.4 mg, 1.57 mmol). The
mixture was stirred at 25 °C for 12 hours. The mixture was diluted with H O (100 mL),
extracted with EA (30 mL), washed with HCl (1M, 30 mL), saturated NaHCO3 (aq, 30mL), brine
(30 mL), dried over Na SO and concentrated. The residue was purified by preparatory-HPLC
(basic condition). Compound 247A (80.0 mg, crude) was obtained as a white solid. H NMR
(400MHz, DMSO-d ) δ 8.46 - 8.20 (m, 1H), 7.57 - 7.11 (m, 15H), 5.90 - 5.64 (m, 1H), 4.71 -
4.56 (m, 1H), 4.10 - 3.90 (m, 2H), 2.99 - 2.89 (m, 1H), 2.86 - 2.74 (m, 1H), 2.11 - 2.01 (m, 3H).
To a solution of compound 247A (80.0 mg, 144.53 umol) in DCM (10 mL) and
DMSO (1mL) was added DMP (183.9 mg, 433.59 umol). The mixture was stirred at 25 °C for 3
17681897_1 (GHMatters) P110989.NZ
hours. The mixture quenched with 10% Na S O (aqueous): saturated NaHCO (aqueous) (1:1,
2 2 3 3
mL), extracted with DCM (10 mL) and washed with brine (20 mLx3). The combined organic
layers were dried over Na SO and concentrated. The crude product was triturated with CH CN
2 4 3
(5 mL) and filtered. Compound 247 (20.0 mg, yield 25.1%) was obtained as a white solid. H
NMR (400MHz, DMSO-d ) δ 9.50 - 9.43 (m, 1H), 9.12 - 9.06 (m, 1H), 7.66 - 7.57 (m, 2H), 7.51
- 7.36 (m, 5H), 7.34 - 7.19 (m, 7H), 5.53 - 5.45 (m, 1H), 4.41 - 4.16 (m, 2H), 3.27 - 3.20 (m, 1H),
2.82 - 2.72 (m, 1H), 2.10 - 2.01 (m, 1H), 2.05 (s, 2H). MS (ESI) m/z (M+H) 552.1.
EXAMPLE 136
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)(4-FLUOROPHENYL)
METHYLOXAZOLECARBOXAMIDE (248)
NH OAc, EtOH
4 PhI(OAc)2
4 hrs
DCE, 0-25 °C,
78 °C, 16 hrs O
H N O
H N O
248A
248B
LiOH•H O
HOAc: DCE
(1:2)
90 °C, 3 hrs MeOH, H 25 °C
1.5 hrs
248C
248D
A mixture of ethyl 3-(4-fluorophenyl)oxopropanoate (8 g, 38.06 mmol) and
NH OAc (5.87 g, 76.12 mmol) in EtOH (450 mL) was stirred at 78 °C for 16 hours. The
reaction mixture was concentrated under reduced pressure, and the residue was diluted with
water (60 mL) and then extracted with EtOAc (100 mL x 3). The combined organic phase was
washed with sat. NaHCO (50 mL x 3) and brine (50 mL), dried over anhydrous Na SO , filtered
3 2 4
and the solvent was removed under reduced pressure to give a residue, which was purified by
column chromatography (SiO , petroleum ether/ethyl acetate = 100:1 to 10:1) to afford
compound 248A (7.10 g, 89.16% yield) as a light yellow oil. H NMR (400 MHz, CDCl ): δ
7.56 - 7.48 (m, 2H), 7.12 - 7.04 (m, 2H), 4.90 (s, 1H), 4.16 (q, J = 7.2 Hz, 2H), 1.32 - 1.24 (m,
3H).
To a mixture of compound 248A (9 g, 43.02 mmol) in DCE (90 mL) was
(18.0 g, 55.93 mmol) in three portions at 0 °C under N , the mixture was stirred
added PhI(OAc)2 2
17681897_1 (GHMatters) P110989.NZ
at 0 °C for 3 hours and then warmed to 25 °C slowly. The mixture was then stirred at 25 °C for 1
hour. The reaction mixture was quenched with saturated aqueous NaHCO (200 mL) and
extracted with DCM (200 mL x 3). The combined organic layers were dried over anhydrous
Na SO filtered and concentrated under reduced pressure to give a residue. The residue was
2 4,
purified by column chromatography (SiO , petroleum ether/ethyl acetate = 20:1 to 5:1) to afford
compound 248B (6.0 g, 52.19% yield) as a yellow oil. H NMR (400 MHz, CDCl ): δ 7.49 -
7.35 (m, 2H), 7.12 - 7.00 (m, 2H), 4.27 - 4.16 (m, 2H), 1.93 (s, 3H), 1.27 (t, J = 7.2 Hz, 3H).
A mixture of ethyl compound 248B (6.0 g, 22.45 mmol) in DCE (30 mL) and
AcOH (15 mL) was stirred at 90 °C for 3 hours. The reaction mixture was cooled to room-
temperature and then concentrated to dryness under reduced pressure to afford a residue, which
was purified by column chromatography (SiO , Petroleum ether/Ethyl acetate=100:1 to 10:1) to
afford compound 248C (2.80 g, 50.04% yield) as a white solid. H NMR (400 MHz, CDCl ): δ
8.10 - 8.00 (m, 2H), 7.11 (t, J = 8.4 Hz, 2H), 4.38 (q, J = 7.2 Hz, 2H), 2.57 (s, 3H), 1.37 (t, J =
7.2 Hz, 3H).
To a mixture of compound 248C (1 g, 4.01 mmol) in MeOH (30 mL) and H O
(15 mL) was added LiOH•H2O (505.1 mg, 12.03 mmol) in one portion and the mixture was
stirred at 25 °C for 1.5 hours. The reaction mixture was concentrated under reduced pressure to
remove MeOH. The residue was adjusted to pH ~ 3 with 1N HCl, diluted with water (30 mL)
and then extracted with EtOAc (100 mL x 4). The combined organic layers were washed with
brine (80 mL), dried over anhydrous Na SO , filtered and concentrated under reduced pressure to
afford intermediate compound 248D (820 mg, 92.45% yield) as a white solid. H NMR (400
MHz, CDCl ): δ 8.10 - 8.00 (m, 2H), 7.17 - 7.07 (m, 2H), 2.60 (s, 3H).
Compound 248 (36.1 mg, 24.19% yield, white solid) was prepared as in
Example 5 from the corresponding intermediate carboxylic acid, compound 248D. Compound
248: H NMR (400 MHz, CDCl ): δ 8.19 - 8.12 (m, 2H), 7.34 - 7.26 (m, 3H), 7.17 - 7.11 (m,
2H), 7.10 - 7.03 (m, 2H), 6.80 - 6.71 (m, 2H), 5.74 - 5.68 (m, 1H), 5.58 (br s, 1H), 3.48 - 3.40
(m, 1H), 3.28 - 3.19 (m, 1H), 2.53 (s, 3H). MS (ESI) m/z (M+H) 396.0.
17681897_1 (GHMatters) P110989.NZ
EXAMPLE 137
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)PHENYLBENZOFURAN
CARBOXAMIDE (249)
NaOH
FeCl , , DCE
(t-BuO)
249A
249B
To a mixture of ethyl 3-oxophenylpropanoate (2 g, 10.41 mmol, 1.8 mL),
phenol (2.94 g, 31.23 mmol, 2.75 mL), and FeCl .6H O (281 mg, 1.04 mmol) was added DCE
(70 mL) under nitrogen at 25°C. Then di-tert-butylperoxide (3.04 g, 20.82 mmol, 3.85 mL) was
dropped into the mixture under nitrogen. The reaction temperature was raised to 100 °C for 3h.
The temperature of the reaction was cooled to room temperature. The resulting reaction solution
was quenched with 30 mL of saturated NaHCO and extracted with DCM (20 mL x 3). The
extract was washed with 100 mL of saturated NaHCO and 100 mL of 10 % Na S O . The
3 2 2 3
extract was dried over Na SO . The solvent was evaporated in vacuo to afford the crude
products. The residue was purified by column chromatography (SiO , PE ~ Petroleum
ether/Ethyl acetate = 10/1) to give compound 249A (1.5 g, yield: 54.08%) as a yellow oil. H
NMR (400MHz, CDCl ) δ 8.09 - 7.99 (m, 3H), 7.57 - 7.45 (m, 4H), 7.39 - 7.32 (m, 2H), 4.41 (q,
J = 7.1 Hz, 2H), 1.43 - 1.39 (m, 3H). MS (ESI) m/z (M+H) 267.0..
To a solution of compound 249A (600 mg, 2.25 mmol) in MeOH (30 mL) and
H O (15 mL) was added NaOH (270 mg, 6.75 mmol). The mixture was stirred at 25 °C for 16h.
The reaction mixture was concentrated and added 20 mL of water, the mixture was extracted
with MTBE (10 mL x 2), the aqueous layer was acidified by 1N HCl to pH ~ 2~3 at 0 °C, and
extracted with EtOAc (20 mL x 2), the organic phase was dried over Na SO , concentrated to
give a residue. Compound 249B (330 mg, yield: 61.78%) was obtained as a white solid, which
was used to the next step without purification. H NMR (400MHz, DMSO-d6) δ 13.10 (br s, 1H),
8.05 - 7.92 (m, 3H), 7.72 - 7.62 (m, 1H), 7.57 - 7.47 (m, 3H), 7.41 - 7.34 (m, 2H). MS (ESI) m/z
(M+H) 239.0.
Compound 249 (65 mg, yield: 60.09%, white solid) was prepared as in
Example 5 from the corresponding intermediate carboxylic acid, compound 249B. Compound
17681897_1 (GHMatters) P110989.NZ
249: H NMR (400MHz, DMSO-d ) δ 9.08 (d, J = 7.3 Hz, 1H), 8.23 (br s, 1H), 7.94 (br s, 1H),
7.69 (br s, 2H), 7.63 (d, J = 7.9 Hz, 1H), 7.40 (br s, 3H), 7.39 - 7.20 (m, 8H), 5.56 (br s, 1H),
3.26 (br s, 1H), 2.79 (t, J = 12.2 Hz, 1H). MS (ESI) m/z (M+H) 413.1.
EXAMPLE 138
COMPOUNDS 250-251
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)CYCLOPROPYLPHENYL-
1H-PYRAZOLECARBOXAMIDE (250)
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)(CYCLOPROPYLMETHYL)-
3-PHENYL-1H-PYRAZOLECARBOXAMIDE (251)
B(OH)2 PhB(OH)2 KOH
O N OH
CO MeOH, H O
,Pd(dppf)Cl
2 3 2 2
HN 4A° N N
, MS,
Cu(OAc)
dioxane, H O
Pyridine, 250D
250A
239A
250C
PhB(OH)
MeOH, H O
Na CO 2
N 2 3,Pd(dppf)Cl2
dioxane, H O
251A
251C
251D
To a mixture of compound 239A (2.0 g, 7.5 mmol) and cyclopropylboronic
acid (1.29 g, 15.0 mmol) in DMF (40 mL) was added Cu(OAc) (2.05 g, 11.28 mmol), 4A° MS
(20 g) and pyridine (1.2 mL 15.0 mmol) at 25 °C under O (15 psi). The mixture was stirred at
°C for 38h. Additional cyclopropylboronic acid (1.29 g, 15.04 mmol) was added to the
mixture, which was stirred at 70 - 80 °C for 20h. The reaction mixture was added Cu(OAc)2
(2.05 g, 11.28 mmol) and stirred at 70 - 80 °C for 22h. The mixture was filtered, the filtrate was
diluted with H O (200 mL), extracted with EA (150 mL x 3), the combined organic phase was
washed with brine (100 mL), dried over Na SO and concentrated to give a residue. The residue
was purified by FCC (SiO , Petroleum ether/Ethyl acetate=1:0 to 10:1) to afford compound 250A
(552 mg, yield 24.0%) as white solid. Compound 250A: H NMR (DMSO-d 400 MHz): δ 8.32
(s, 1H), 4.20 (q, J = 7.1 Hz, 2H), 3.82 (tt, J = 3.8, 7.4 Hz, 1H), 1.27 (t, J = 7.1 Hz, 3H), 1.12 -
1.07 (m, 2H), 1.00 - 0.94 (m, 2H). MS (ESI) m/z (M+H) 307.0.
17681897_1 (GHMatters) P110989.NZ
To a mixture of compound 250A (544 mg, 1.7 mmol) and phenylboronic acid
(434 mg, 3.5 mmol) in dioxane (50 mL) and H O (10 mL) was added Pd(dppf)Cl (130 mg, 0.18
mmol) and Na CO (377 mg, 3.5 mmol) at 25 °C under N . The mixture was stirred at 80 °C for
2 3 2
12h. The mixture was filtered over Celite. The filtrate was added EA (150 mL), and then
washed with H O (100 mL x 3). The organic layer was dried over Na SO and concentrated.
2 2 4
The residue was purified by FCC (SiO , Petroleum ether/Ethyl acetate=1:0 to 5:1) to afford
compound 250C (431 mg, yield 94.5%) as light yellow liquid. H NMR (DMSO-d 400 MHz):
δ 8.42 (s, 1H), 7.71 - 7.65 (m, 2H), 7.42 - 7.36 (m, 3H), 4.16 (q, J = 7.1 Hz, 2H), 3.85 (tt, J = 3.8,
7.4 Hz, 1H), 1.21 (t, J = 7.1 Hz, 3H), 1.18 - 1.13 (m, 2H), 1.04 - 0.96 (m, 2H). MS (ESI) m/z
(M+H) 257.0.
To a mixture of compound 250C (425 mg, 1.7 mmol) in MeOH (10 mL) was
added the mixture of KOH (931 mg, 16.6 mmol) and H O (2 mL) in one portion at 25 °C. The
mixture was stirred at 70 °C for 1h 40 mins. The reaction mixture was concentrated under
reduced pressure to move MeOH, the aqueous phase was acidified with aqueous HCl (0.5M) till
pH ~ 4 – 5. The precipitate was filtered and dried to afford compound 250D (333 mg, crude) as
white solid, which was used directly for the next step without purification. H NMR (DMSO-d
400 MHz): δ 12.24 (s, 1H), 8.35 (s, 1H), 7.73 - 7.69 (m, 2H), 7.41 - 7.34 (m, 3H), 3.83 (tt, J =
3.7, 7.5 Hz, 1H), 1.17 - 1.12 (m, 2H), 1.02 - 0.97 (m, 2H).
Compound 250 (70.0 mg, yield 46.3%, yellow solid) was prepared as in
Example 5 from the corresponding intermediate carboxylic acid, compound 250D. Compound
250: H NMR (DMSO-d 400 MHz): δ 8.09 (s, 1H), 7.95 - 7.86 (m, 1H), 7.81 - 7.46 (m, 4H),
7.42 - 7.12 (m, 8H), 5.33 (s, 1H), 3.79 (s, 1H), 3.25 - 3.16 (m, 1H), 2.96 - 2.84 (m, 1H), 1.16 -
0.97 (m, 4H). MS (ESI) m/z (M+H) 403.1.
Following the procedure used for compound 250D, compound 251D (150 mg,
yield 95.64%, white solid) was prepared from the corresponding starting materials, compound
239A and bromomethylcyclopropane. Compound 251D: H NMR (DMSO-d 400MHz) δ 8.33 (s,
1H), 7.73 (dd, J = 1.5, 7.9 Hz, 2H), 7.40 - 7.34 (m, 3H), 4.01 (d, J = 7.1 Hz, 2H), 1.31 (br d, J =
7.7 Hz, 1H), 0.57 - 0.52 (m, 2H), 0.42 - 0.37 (m, 2H).
Compound 251 (70 mg, yield 43.27%, white solid) was prepared as in Example
from the corresponding intermediate carboxylic acid, compound 251D. Compound 251: H
17681897_1 (GHMatters) P110989.NZ
NMR (DMSO-d 400MHz) δ 8.40 (br d, J = 7.3 Hz, 1H), 8.15 - 8.05 (m, 2H), 7.82 (br s, 1H),
7.62 - 7.52 (m, 2H), 7.30 (br s, 4H), 7.28 - 7.20 (m, 4H), 5.33 - 5.24 (m, 1H), 4.06 - 3.95 (m, 2H),
3.17 (br dd, J = 3.5, 13.9 Hz, 1H), 2.84 (br dd, J = 9.9, 13.7 Hz, 1H), 1.34 - 1.18 (m, 1H), 0.58
(br d, J = 6.8 Hz, 2H), 0.42 (br d, J = 4.4 Hz, 2H). MS (ESI) m/z (M+H) 417.2.
EXAMPLE 139
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)(PHENYLETHYNYL)-1H-
INDOLECARBOXAMIDE (252)
KOH, 70°C
MeOH
Pyridine,
252B
CO , O ,
2 3 2
CuCl Toluene
252A
To a solution of methyl 1H-indolecarboxylate (5.0 g, 28.55 mmol) in
toluene (50 mL) was added Na CO (1.2 g, 11.42 mmol), CuCl (153 mg, 1.14 mmol), pyridine
2 3 2
(922 uL, 11.42 mmol), then ethynylbenzene (627 uL, 5.71 mmol) was added to the mixture. The
mixture was heated to 70 °C and stirred for 4h under O atmosphere. The reaction was diluted
with H O (15 mL) and EA (15 mL), filtered. The mixture was extracted with EA (15 mL x 2),
the organic layer was collected and washed with NaHCO (25 mL x 2), washed with brine(20
mL), dried over anhydrous Na SO , filtered, concentrated under reduced pressure. The product
was purified by FCC (PE/EA:0 to 10/1) to afford compound 252A (630 mg, yield 40.08%) as
light red solid. H NMR (DMSO-d 400MHz) δ 8.46 (s, 1H), 8.09 (d, J = 7.7 Hz, 1H), 7.75 (d, J
= 7.9 Hz, 1H), 7.68 - 7.65 (m, 2H), 7.49 - 7.44 (m, 4H), 7.43 - 7.38 (m, 1H), 3.86 (s, 3H).
To a solution of compound 252A (300 mg, 1.09 mmol) in MeOH (10 mL) was
added KOH (611mg, 10.90 mmol) and then the mixture was stirred at 70 °C for 3h. The reaction
was diluted with H O (5 mL) and evaporated under reduced pressure, the water phase was
extracted with TBME (5 mL) and then the water phase was treat with HCl (1 M) until pH ~ 4.
The mixture was extracted with EA (10 mL x 3), the organic layer was collected, washed with
brine (10 mL), dried over anhydrous Na SO4, filtered and concentrated under reduced pressure.
17681897_1 (GHMatters) P110989.NZ
Compound 252B (240 mg, yield 84.27%) was obtained as white solid. H NMR (DMSO-d
400MHz) δ 8.37 (s, 1H), 8.11 (d, J = 7.5 Hz, 1H), 7.75 (d, J = 7.9 Hz, 1H), 7.69 - 7.65 (m, 2H),
7.50 - 7.45 (m, 4H), 7.45 - 7.36 (m, 2H).
Compound 252 (70 mg, yield 24.39%, yellow solid) was prepared as in
Example 5 from intermediate compound 252B. Compound 252: H NMR (DMSO-d 400MHz)
δ 8.61 (d, J = 7.5 Hz, 1H), 8.45 (s, 1H), 8.14 - 8.05 (m, 2H), 7.85 (s, 1H), 7.73 (d, J = 8.2 Hz,
1H), 7.67 (dd, J = 2.4, 7.3 Hz, 2H), 7.50 - 7.46 (m, 3H), 7.42 (t, J = 7.7 Hz, 1H), 7.38 - 7.35 (m,
2H), 7.33 - 7.29 (m, 3H), 7.23 - 7.19 (m, 1H), 5.47 - 5.36 (m, 1H), 3.23 (dd, J = 3.6, 14.0 Hz,
1H), 2.91 (dd, J = 10.0, 13.8 Hz, 1H). MS (ESI) m/z (M+H) 436.1.
EXAMPLE 140
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)(3-FLUOROPHENYL)
METHYLOXAZOLECARBOXAMIDE (254)
NH Ac
4 (2eq) eq)
PhI(OAc) (1.3
EtOH, 78 °C, 9 hours
DCE 0-25 °C 3 hours
H N O
H N O
254A 254B
HOAc: DCE O
O LiOH.H O
(1:2) eq)
2 (3
90 °C 2 hours MeOH:H 25
O(2:1), OH
°C 0.5 hour
254D
To a solution of ethyl 3-(3-fluorophenyl)oxopropanoate (3.00 g, 14.27
mmol) in EtOH (40 mL) was added CH COONH (2.20 g, 28.54 mmol), then the mixture was
stirred at 78 °C for 9 hours. The reaction mixture was concentrated under reduced pressure to
remove the solvent. The residue was diluted with EA (100 mL) and washed with sat. NaHCO
solution (30 mL x 3) and saturated aqueous NaCl (30 mL x 3). The organic layer were dried over
anhydrous Na SO , filtered and concentrated under reduced pressure to give a residue. The
residue was purified flash column chromatography (PE: EA=20/1 to 10:1). Compound 254A
(2.40 g, 80.39% yield) was obtained as yellow oil. H NMR (400 MHz, CDCl ): δ 7.38 – 7.35
(m, 1H), 7.35 – 7.32 (m, 1H), 7.22(d, J = 9.6 Hz, 1H), 7.13 – 7.09 (m, 1H), 4.93 (s, 1H), 4.19 –
4.13 (m, 2H), 1.29 – 1.26 (m, 3H). MS (ESI) m/z (M+1) 210.1.
17681897_1 (GHMatters) P110989.NZ
To a mixture of compound 254A (2.00 g, 9.56 mmol) in DCE (25 mL) was
added PhI(OAc) (4.00 g, 12.43 mmol) at 0 °C under N in five portions, the mixture was stirred
at 0 °C for 3h and then warmed to 25 °C slowly. The mixture was then stirred at 25 °C for 0.5h.
The reaction mixture was quenched with saturated aqueous NaHCO (150 mL) at 0 °C, warmed
to 25 °C slowly, and extracted with DCM (70 mL x 3). The combined organic layers were dried
over anhydrous Na SO filtered and concentrated under reduced pressure to give the residue.
2 4,
The residue was purified by column chromatography (SiO , Petroleum ether/Ethyl acetate = 20: 1
to 10: 1). Compound 254B (1.24 g, 48.53% yield) was obtained as white solid. H NMR (400
MHz, CDCl ): δ 7.37 – 7.34 (m, 1H), 7.22 – 7.00 (m, 1H), 7.17 – 7.13 (m, 1H), 7.12 – 7.09 (m,
1H), 4.23 – 4.18 (m, 2H), 1.94 (s, 3H), 1.29 – 1.26 (m, 3H). MS (ESI) m/z (M+1) 268.1.
A mixture of compound 254B (1.20 g, 4.49 mmol) in DCE (20 mL) and
CH COOH (10 mL) was stirred at 90 °C for 2 hrs. The reaction mixture was concentrated under
reduced pressure to remove the solvent and to give the residue. The residue was purified by flash
column chromatography (PE:EA = 20/1 to 10/1). Compound 544 (360.0 mg, 32.07% yield) was
obtained as a white solid. H NMR (400 MHz, CDCl ) δ 7.87 – 7.86 (m, 1H), 7.83 – 7.80 (m,
1H), 7.41 – 7.39 (m, 1H), 7.13 – 7.09 (m, 1H), 4.43 – 4.37 (m, 2H), 2.58 (s, 3H), 1.40 – 1.37 (m,
3H). MS (ESI) m/z (M+1) 250.1.
To a mixture of ethyl compound 544 (350.0 mg, 1.40 mmol)in MeOH (10 mL)
and H O (5 mL) was added LiOH.H O (235.0 mg, 5.60 mmol) in one portion and the mixture
was stirred at 25 °C for 0.5 hours. The reaction mixture was concentrated under reduced
pressure to remove MeOH. The residue was diluted with H O (20 mL), adjusted to pH ~ 3 with
1N HCl, and then extracted with EtOAc (50 mL x 3). The combined organic layers were washed
with brine (30 mL), dried over anhydrous Na SO , filtered and concentrated under reduced
pressure to give intermediate compound 254D (300.0 mg, 96.88% yield) as a white solid. H
NMR (400 MHz, DMSO-d ) δ 7.92 – 7.87 (m, 1H), 7.52 – 7.46 (m, 1H), 7.29 – 7.24 (m, 1H),
2.51 (s, 3H).
Compound 254 (90.3 mg, 58.91% yield, white solid) was prepared as in
Example 5 from the corresponding intermediate carboxylic acid, compound 254D. Compound
254: H NMR (400 MHz, CDCl ) δ 7.98 – 7.95 (m, 1H), 7.94 – 7.91 (m, 1H), 7.39 – 7.35 (m,
1H), 7.33 – 7.30 (m, 1H), 7.29 – 7.26 (m, 2H), 7.15 – 7.13 (m, 2H), 7.09 – 7.04 (m, 1H), 6.79 (d,
17681897_1 (GHMatters) P110989.NZ
J = 7.2 Hz, 1H), 6.76(s, 1H), 5.74 – 5.69 (m, 1H), 5.53 (s, 1H), 3.47 – 3.42 (m, 1H), 3.27 – 3.22
(m, 1H), 2.54 (s, 3H). MS (ESI) m/z (M+1) 396.1.
EXAMPLE 141
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)PHENYL
(TRIFLUOROMETHYL)OXAZOLECARBOXAMIDE (255)
PhI(OCOCF )
LiOH•H O
DCE, 45 °C, 2 hrs
MeOH: H O
2 (2:1)
H N O
2 25°C, 3 hrs
F C 255A 3
255B
To a mixture of ethyl (E)aminophenylacrylate (1.5 g, 7.84 mmol) in DCE
(400 mL) was added phenyliodine bis(2,2,2-trifluoroacetate) (4.38 g, 10.19 mmol) in three
portions at 45 °C under N , the mixture was stirred at 45 °C for 2 hours. The reaction mixture
was cooled to 25 °C and concentrated under reduced pressure to give a residue, which was
purified by column chromatography (SiO , Petroleum ether/Ethyl acetate = 100: 1 to 10: 1) to
afford compound 255A (650 mg, 28.43% yield) as a white solid. H NMR (400 MHz, CDCl ): δ
8.11 - 8.05 (m, 2H), 7.50 - 7.45 (m, 3H), 4.44 (q, J = 7.2 Hz, 2H), 1.40 (t, J = 7.2 Hz, 3H). MS
(ESI) m/z (M+H) 285.9.
Compound 255B (200 mg, 51.2% purity, yellow oil) was prepared as in
Example 85 from compound 255A. Compound 255B: MS (ESI) m/z (M+H) 258.0.
Compound 255 (7.0 mg, 9.89% yield, off-white solid) was prepared as in
Example 5 from the corresponding intermediate carboxylic acid, compound 255B. Compound
255: H NMR (400 MHz, CDCl ): δ 8.17 - 8.08 (m, 2H), 7.48 - 7.41 (m, 3H), 7.34 - 7.28 (m,
3H), 7.17 - 7.10 (m, 2H), 6.88 - 6.80 (m, 1H), 6.77 (br s, 1H), 5.78 - 5.71 (m, 1H), 5.55 (br s,
1H), 3.50 - 3.42 (m, 1H), 3.27 - 3.20 (m, 1H). MS (ESI) m/z (M+H) 432.2.
17681897_1 (GHMatters) P110989.NZ
EXAMPLE 142
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)(BENZO[d]OXAZOLYL)
METHYL-1H-PYRAZOLECARBOXAMIDE (256)
LIiOH.H2O
O OH
dioxane reflux
256A
256B
A mixture of 2-hydrazineylbenzo[d]oxazole (320 mg, 2.15 mmol) and methyl
(E)(methoxyimino)oxopentanoate (447 mg, 2.58 mmol) in dioxane (10 mL) was heated to
110 °C for 12 hrs. The mixture was concentrated, the residue was purified by preparatory-TLC
(Petroleum ether: Ethyl acetate = 2:1) to give compound 256A (0.12 g, yield: 16.6%) as yellow
oil.
A mixture of compound 256A (120 mg, 466 umol) and LiOH.H O (17.6 mg,
420 umol) in THF (5 mL), H O (1 mL) was stirred at 25 °C for 20 min. The organic solvent was
removed under reduced pressure, the water layer was extracted with ethyl acetate (2 mL), and
then adjusted to pH ~ 6 with 1N HCl to give a precipitate, the solid was filtered and dried to give
compound 256B (90 mg, yield: 79.3%) as white solid. H NMR (400MHz, DMSO-d ) δ 8.02 -
7.87 (m, 2H), 7.61 (dq, J = 1.4, 7.7 Hz, 2H), 7.11 (s, 1H), 2.43 (s, 3H).
Compound 256 (22.2 mg, yield: 44.6%, white solid) was prepared as in
Example 5 from the corresponding intermediate carboxylic acid, compound 256B. Compound
256: H NMR (400MHz, DMSO-d ) δ 8.97 (s, 1H), 7.82 (br s, 1H), 7.64 (br s, 1H), 7.55 - 7.44
(m, 2H), 7.30 - 7.21 (m, 2H), 6.94 (q, J = 7.9 Hz, 4H), 6.90 - 6.83 (m, 1H), 6.64 (s, 1H), 5.37 (dd,
J = 4.1, 8.0 Hz, 1H), 3.39 (dd, J = 4.1, 14.2 Hz, 1H), 2.83 (dd, J = 8.4, 14.1 Hz, 1H), 2.24 (s, 3H).
MS (ESI) m/z (M+H) 418.1.
17681897_1 (GHMatters) P110989.NZ
EXAMPLE 143
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)METHYLPHENYL-1H-
PYRAZOLECARBOXAMIDE (257)
, HOAc
2 Br Br
NaOAc
O SEMCl O
HN HN
o NaH THF
100 C N
0 25 C
257A
257B
257C
PhB(OH)2
.CH Cl ,
THF H O MeOH
Pd(dppf)Cl2. 2 2
Na CO HN
257D
H O N 257E
1,4-dioxane
N NH
257G
To a solution of ethyl 3-oxobutanoate (20.0 g, 153.7 mmol) in THF (150 mL)
was added DMF-DMA (19.2 g, 161.4 mmol). The mixture was stirred at 70 °C for 2 hours. The
reaction mixture was concentrated under reduced pressure to give a residue. To a solution of the
crude product dissolving in EtOH (150 mL) was added drop-wise NH NH .H O (9.2 g, 184.4
2 2 2
mmol). The mixture was stirred at 80°C for 16 hours. The reaction mixture was concentrated
under reduced pressure to remove EtOH. The residue was diluted with brine 80 mL and
extracted with ethyl acetate (200 mL x 2). The combined organic layers were dried over MgSO ,
filtered and concentrated under reduced pressure to afford compound 257A (21.0 g, yield 87.8%)
as light green solid. H NMR (CDCl 400 MHz): δ 7.96 (s, 1H), 4.29 (q, J = 7.2 Hz, 2H), 2.55
(s, 3H), 1.34 (t, J = 7.2 Hz, 3H). MS (ESI) m/z (M+H) 154.8.
To a solution of compound 257A (12.0 g, 77.8 mmol) in AcOH (120 mL) was
added NaOAc (19.2 g, 233.5 mmol) and Br (12 mL, 233.5 mmol) at 25 °C. The mixture was
stirred at 100 °C for 16 hours under N . The reaction mixture was concentrated under reduced
pressure to remove solvent. The residue was diluted with water 150 mL and extracted with ethyl
acetate (200 mL x 2). The combined organic extracts were washed with saturated aqueous
NaHCO (80 mL x 2), dried over Na SO , filtered and concentrated to dryness under reduced
3 2 4
17681897_1 (GHMatters) P110989.NZ
pressure to dryness. The crude product was purified by flash column (gradient eluent: petroleum
ether/ethyl acetate from 100/0 to 50/50) to afford compound 257B (8.2 g, yield 43.3%) as light
yellow solid. H NMR (CDCl 400 MHz): δ 10.89 (br s, 1H), 4.34 (q, J = 7.2 Hz, 2H), 2.64 (s,
3H), 1.38 (t, J = 7.2 Hz, 3H). MS (ESI) m/z (M+H) 235.1
To a solution of compound 257B (5.0 g, 21.5 mmol) in THF (50 mL) was
added NaH (944 mg, 23.6 mmol, 60% purity) at 0 °C and the reaction stirred for 30 minutes.
SEM-Cl (3.9 g, 23.6 mmol) was added, and the reaction stirred at 25°C for 16 hours. The
reaction was quenched with water (30 ml) and extracted with ethyl acetate (50 mL x 3). The
organic extract was dried over MgSO and concentrated in vacuo. Compound 257C (6.2 g, yield
78.1%, colorless oil): H NMR (CDCl 400 MHz): δ 5.52 - 5.39 (m, 2H), 4.35 (q, J = 7.2 Hz,
2H), 3.62 (td, J = 8.4, 17.2 Hz, 2H), 2.66 - 2.44 (m, 3H), 1.40 (dt, J = 2.4, 7.2 Hz, 3H), 0.92 (td, J
= 8.4, 13.6 Hz, 2H), 0.08 - -0.05 (m, 9H). MS (ESI) m/z (M+H) 364.9.
To a solution consisting of compound 257C (2.0 g, 5.5 mmol), phenylboronic
acid (871.8 mg, 7.2 mmol), Na CO (1.8 g, 16.5 mmol) in 1,4-dioxane (20 mL) and H O (4 mL)
2 3 2
was added Pd(dppf)Cl .CH Cl (89.9 mg, 110.0 umol) at 25 °C and the reaction mixture stirred
2 2 2
for 10 minutes. The reaction mixture was heated to 80 °C for 16 hours under N . The mixture
was concentrated under reduced pressure at 40 °C. The reaction mixture was quenched with
brine (40 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic extracts were
dried over Na SO , filtered, and concentrated to dryness under reduced pressure. The crude
product was purified by flash column (Petroleum ether: Ethyl acetate=100: 0~1:1) to give
compound 257D (1.6 g, yield 79.4%) as light yellow solid. H NMR (CDCl 400 MHz): δ 7.62 -
7.53 (m, 1H), 7.48 - 7.34 (m, 4H), 5.48 (s, 1H), 5.18 (s, 1H), 4.25 - 4.06 (m, 2H), 3.62 (td, J =
8.0, 15.6 Hz, 2H), 2.67 - 2.50 (m, 3H), 1.23 - 1.03 (m, 3H), 0.96 - 0.83 (m, 2H), 0.03 -0.07 (m,
9H). MS (ESI) m/z (M+H) 361.1.
KOH (2.5 g, 44.4 mmol) was added to a solution consisting of compound
257D (1.6 g, 4.4 mmol), THF (10 mL), H O (5 mL) and MeOH (10 mL). The resultant mixture
was stirred at 25 °C for 16 hours. The resultant mixture was stirred at 75 °C for 48 hours. The
reaction solution was concentrated under reduced pressure. 2N HCl (30 mL) was added, and
extracted with EtOAc (30 mL x 3). Combined EtOAc extractions were washed with brine (20
mL), dried over MgSO , filtered and concentrated. The crude product was purified by flash
17681897_1 (GHMatters) P110989.NZ
column (Petroleum ether: Ethyl acetate=100: 0~3:2) to give compound 257E (1.0 g, yield 62.8%)
as a colorless oil. H NMR (CDCl 400 MHz): δ 7.63 - 7.58 (m, 1H), 7.48 - 7.36 (m, 4H), 5.49
(s, 1H), 5.17 (s, 1H), 3.62 (td, J = 8.4, 18.4 Hz, 2H), 2.66 (s, 1.5H), 2.52 (s, 1.5H), 0.95 - 0.83
(m, 2H), 0.00 - -0.06 (m, 9H). MS (ESI) m/z (M+H) 333.2.
Intermediate compound 257G (150 mg, crude, white solid) was prepared as in
Example 5 from the corresponding intermediate carboxylic acid, compound 257E. Compound
257G: H NMR (DMSO-d , 400 MHz): δ 8.68 - 8.61 (m, 0.1H), 8.26 - 7.88 (m, 1H), 7.59 - 7.09
(m, 10H), 5.52 - 5.41 (m, 1H), 5.24 (s, 1H), 3.69 - 3.52 (m, 1H), 2.42 - 2.28 (m, 1H), 2.27 - 2.19
(m, 2H), 0.96 - 0.79 (m, 2H), 0.08 - 0.02 (m, 4.4H), 0.02 - -0.06 (m, 4.3H). MS (ESI) m/z
(M+H)+ 507.2.
To a solution consisting of compound 257G (100 mg, 0.20 mmol), in EA (20
mL) was added HCl/EtOAc (4M, 2 mL) at 25 °C. The mixture was stirred at 25 °C under N for
16 hours. The reaction solution was concentrated under reduced pressure to give the crude
product. The crude product was purified by preparatory-HPLC (0.05% ammonia hydroxide) to
give 257 (15 mg, yield 19.3%) as a white solid. Compound 257: H NMR (DMSO-d , 400
MHz): δ 12.67 (br.s., 1H), 7.85 - 7.72 (m, 2H), 7.64 - 7.57 (m, 1H), 7.57 - 7.49 (m, 2H), 7.38 -
7.17 (m, 8H), 5.45 - 5.32 (m, 1H), 3.21 (dd, J = 4.0, 14.0 Hz, 1H), 2.85 (dd, J = 9.2, 14.0 Hz,
1H), 2.19 (s, 3H). MS (ESI) m/z (M+H) 377.1.
EXAMPLE 144
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)FLUOROPHENYL-1H-
PYRAZOLECARBOXAMIDE (258)
Select-F, MeCN LiOH, THF/H O
HOAc N
258A
258D
258C
To a mixture of ethyl 1H-pyrazolecarboxylate (5.00 g, 35.68 mmol),
phenylboronic acid (6.53 g, 53.52 mmol), Py (3.10 g, 39.25 mmol, 3.17 mL) in DCM (70 mL)
was added 4A° MS (20.0 g) and Cu(OAc) (7.13 g, 39.25 mmol), the mixture was stirred at 30°C
for 20h. The reaction mixture was filtered, the filtrate was concentrated in vacuo. The residue
was purified by flash silica gel chromatography (PE: EA=1:0 to 0:1) to give the compound 258A
17681897_1 (GHMatters) P110989.NZ
(1.10 g, yield: 14.3%) was obtained as a rofous oil. Compound 258A: H NMR (400MHz,
DMSO-d ) δ 7.81 (d, J = 2.0 Hz, 1H), 7.53 - 7.40 (m, 5H), 7.09 (d, J = 2.0 Hz, 1H), 4.17 (q, J =
7.0 Hz, 2H), 1.15 (t, J = 7.0 Hz, 3H).
To a solution of compound 258A (1.00 g, 4.62 mmol) in MeCN (60 mL) was
added CH COOH (20 mL), and then Select F (4.91 g, 13.86 mmol) was added in the mixture.
The mixture was stirred at 105°C for 21h under N atmosphere. The mixture was cooled to room
temperature and the volatiles were removed in vacuo. The residue was purified by flash silica gel
chromatography (PE:EA = 1:0 to 10:1) to give the compound 258C (194 mg, yield: 17.9%)was
obtained as a colorless oil. H NMR (400MHz, CHLOROFORM-d) δ 7.71 - 7.56 (m, 1H), 7.51 -
7.36 (m, 5H), 4.29 (q, J = 7.2 Hz, 2H), 1.27 (t, J = 7.1 Hz, 3H).
To a solution of compound 258C (190 mg, 811.17 umol) in THF (15 mL) was
added LiOH.H O (170 mg, 4.06 mmol) in H O (5 mL). The mixture was stirred at 25°C for
.3h. The reaction mixture was diluted with MTBE (15 mL) and extracted with H O (15 mL x
3). The combined aqueous layers were ajusted pH ~ 3 by addtion 1N HCl, and then the aqueous
layer was extracted with EA (20 mL x 3). The combine organic layer was washed with brine (15
mL x 2), dried over Na SO , filtered and concentrated under reduced pressure to give the
compound 258D (160 mg, yield: 95.7%) was obtained as a white solid. H NMR (400MHz,
CHLOROFORM-d) δ 7.76 - 7.60 (m, 1H), 7.55 - 7.33 (m, 5H).
Compound 258 (25 mg, yield: 44.3%, light yellow solid) was prepared as in
Example 5 from the corresponding starting materials, compounds 258D and 12G. Compound
258: H NMR (400MHz, DMSO-d ) δ 9.33 (d, J = 7.7 Hz, 1H), 8.18 (s, 1H), 8.00 - 7.85 (m, 2H),
7.39 - 7.36 (m, 2H), 7.33 - 7.27 (m, 5H), 7.26 - 7.19 (m, 3H), 5.42 - 5.28 (m, 1H), 3.22 (br dd, J
= 3.3, 14.1 Hz, 1H), 2.82 (br dd, J = 10.5, 13.8 Hz, 1H).
17681897_1 (GHMatters) P110989.NZ
EXAMPLE 145
COMPOUNDS 259-261
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)METHYLPHENYL-2H-
1,2,3-TRIAZOLECARBOXAMIDE (259)
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)METHYLPHENYL-1H-
1,2,3-TRIAZOLECARBOXAMIDE (260)
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)METHYLPHENYL-1H-
1,2,3-TRIAZOLECARBOXAMIDE (261)
259C 259D
259B
259A
NaOH NaOH
NaOH
260A
259E
261A
To a solution of benzaldehyde (5 g, 47.12 mmol, 4.76 mL) in DMF (100 mL)
was added N,N-diethylethanamine;hydrochloride (19.46 g, 141.36 mmol) NaN (9.19 g, 141.36
mmol) and ethyl 2-cyanoacetate (5.33 g, 47.12 mmol, 5.03 mL). The reaction mixture was
heated at 70 C for 18h under nitrogen protection. After completion of the reaction, the mixture
was poured into water (500 mL) and extracted with CHCl : i-PrOH = 3:1 (50 mL x 4). The
organic layers were dried over Na SO , filtered and concentrated. The residue was purified by
chromatography (PE:EA = 5:1). Compound 259A (4 g, yield: 38.3%) was obtained as a yellow
oil. H NMR (400MHz, CDCl ) δ 7.81 (dd, J = 2.9, 6.4 Hz, 2H), 7.49 - 7.38 (m, 3H), 4.38 (q, J
= 7.2 Hz, 2H), 1.43 - 1.26 (m, 3H). MS (ESI) m/z (M+H) 217.9.
MeI (6.53 g, 46.03 mmol, 2.86 mL) was added to a solution of compound
259A (4 g, 18.41 mmol) and K CO (5.09 g, 36.82 mmol) in CH CN (50 mL) and DMF (50 mL).
2 3 3
The reaction mixture was stirred at 25 °C for 16h. The mixture was filtered, the filtrate was
added with H O (200 mL), extracted with EA (50 mL x 3). The organic phase was dried over
17681897_1 (GHMatters) P110989.NZ
Na SO , filtered and concentrated to give a residue. The residue was purified by column
chromatography (SiO , Petroleum ether/Ethyl acetate = PE ~ 10/1 to 2/1).
Compound 259B (1.8 g, yield: 41.9%, white solid): H NMR (400MHz, CDCl )
δ 7.83 - 7.77 (m, 2H), 7.45 - 7.36 (m, 3H), 4.45 - 4.35 (m, 2H), 4.27 (s, 3H), 1.40 - 1.31 (m, 3H).
Compound 259C (1.2 g, yield: 27.9%, white solid): H NMR (400MHz, CDCl ) δ 7.75 - 7.67 (m,
2H), 7.48 - 7.38 (m, 3H), 4.37 - 4.30 (m, 5H), 1.27 (t, J = 7.1 Hz, 3H). Compound 259D (700 mg,
yield: 16.3%, white solid): H NMR (400MHz, CDCl ) δ 7.55 - 7.48 (m, 3H), 7.40 - 7.35 (m,
2H), 4.36 - 4.25 (m, 2H), 3.95 (s, 3H), 1.31 - 1.23 (m, 3H).
To a solution of compound 259B (400 mg, 1.73 mmol) in MeOH (15 mL) and
H O (15 mL) was added NaOH (345.95 mg, 8.65 mmol). The mixture was stirred at 25 °C for
1h. The reaction mixture was acidified by 1N HCl to pH ~ 2~3 at 0 °C and white precipitate was
formed. The solid was collected by filtration, the filtrate was extracted with EtOAc (20 mL x 2),
the organic phase was dried over Na SO , filtered and concentrated to give a residue, the residue
was combined with the solid to give compound 259E (337 mg, yield: 95.9%) as a white solid. H
NMR (400MHz, DMSO-d ) δ 7.82 - 7.69 (m, 2H), 7.46 - 7.34 (m, 3H), 4.22 (s, 3H). MS (ESI)
m/z (M+H) 204.0.
Compound 259 (78 mg, yield: 77.2%, white solid) was prepared as in Example
from the corresponding intermediate carboxylic acid, compound 259E. Compound 259: H
NMR (400MHz, DMSO-d ) δ 8.81 (br d, J = 7.5 Hz, 1H), 8.13 (br s, 1H), 7.87 (br s, 1H), 7.70
(br s, 2H), 7.38 (br s, 3H), 7.29 (br d, J = 4.0 Hz, 4H), 7.23 (br d, J = 4.3 Hz, 1H), 5.47 (br s, 1H),
4.25 (s, 3H), 3.21 (br d, J = 10.8 Hz, 1H), 3.04 - 2.91 (m, 1H). MS (ESI) m/z (M+H) 378.1.
Following the procedure used for compound 259E, intermediate compounds
261A and 260A were prepared from compound 259C and 259D, respectively. Compound 261A
(240 mg, yield: 91. 6%, white solid): H NMR (400MHz, CDCl ) δ 7.69 - 7.63 (m, 2H), 7.38 -
7.29 (m, 3H), 4.26 (s, 3H). MS (ESI) m/z (M+H) 203.9. Compound 260A (260 mg, yield:
98.5%, white solid): H NMR (400MHz, DMSO-d ) δ 12.81 (br s, 1H), 7.60 - 7.42 (m, 5H), 4.02
- 3.74 (m, 3H). MS (ESI) m/z (M+H) 204.0.
Following the procedure used for compound 259, compounds 261 and 260
were prepared from the corresponding intermediate carboxylic acid, compounds 261A and 260A,
respectively. Compound 260 (75 mg, yield: 72.4%, white solid): H NMR (400MHz, DMSO-d )
17681897_1 (GHMatters) P110989.NZ
δ 8.63 (d, J = 7.5 Hz, 1H), 8.09 (s, 1H), 7.84 (s, 1H), 7.51 - 7.41 (m, 5H), 7.32 - 7.20 (m, 5H),
.45 - 5.33 (m, 1H), 3.91 (s, 3H), 3.23 - 3.14 (m, 1H), 3.11 - 2.97 (m, 1H). MS (ESI) m/z
(M+H) 378.1.
Compound 261 (52 mg, yield: 59.5%, yellow solid): H NMR (400MHz,
DMSO-d ) δ 9.54 (dd, J = 7.9 Hz, 1H), 8.26 (s, 1H), 7.99 (s, 1H), 7.60 (dd, J = 3.0, 6.5 Hz, 2H),
7.36 - 7.25 (m, 8H), 5.58 (dd, J = 3.3, 7.7, 10.9 Hz, 1H), 3.83 (s, 3H), 3.29 (dd, J=3.3 Hz, 1H),
2.77 (dd, J = 10.9, 14.0 Hz, 1H). MS (ESI) m/z (M+H) 378.1.
EXAMPLE 146
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)PHENYL-1H-1,2,3-
TRIAZOLECARBOXAMIDE (262)
Compound 262 (8.1 mg, 20.36% yield, white solid) was prepared as in
Example 5 from the corresponding intermediate carboxylic acid, compound 204A. Compound
262: H NMR (400 MHz, DMSO-d ) δ 8.38 - 7.89 (m, 2H), 7.87 - 7.69 (m, 2H), 7.63 - 7.34 (m,
4H), 7.31 - 7.06 (m, 6H), 5.55 - 5.42 (m, 1H), 3.32 - 3.24 (m, 1H), 3.12 - 3.06 (m, 1H). MS (ESI)
m/z (M+H) 364.1.
EXAMPLE 147
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)PHENYL-1H-1,2,3-
TRIAZOLECARBOXAMIDE (263)
TBAF O
N TMS LiOH
N OH
O 263C 263E
263A
263B
To a solution of azidobenzene (0.5M, 11.8 mL) in toluene (20 mL) was added
ethyl 3-(trimethylsilyl)propiolate (1 g, 5.87 mmol). The mixture was stirred at 100 °C for 12h.
The solvent was removed in vacuo to afford a mixture of compound 263A and 263B (1.7 g,
crude) as yellow oil, which was used directly for the next step without purification. MS (ESI)
m/z (M+H) 290.1.
To a mixture of 263A and 263B (1.7 g, 5.87 mmol) in THF (20 mL) was added
TBAF (1M, 8.8 mL). The mixture was stirred at 25 °C for 12h. The reaction was washed with
H O (40 mL), extracted with EtOAc (20 mL x 3). The organics were collected and concentrated.
17681897_1 (GHMatters) P110989.NZ
The residue was purified by column (PE: EA = 5:1) to give compound 263C (400 mg, yield:
31.37%) as yellow oil; H NMR (CDCl 400 MHz): δ 8.26 (s, 1H), 7.56 - 7.47 (m, 5H), 4.29 (q,
J = 7.2 Hz, 2H), 1.28 (t, J = 7.2 Hz, 3H).
To a solution of compound 263C (400 mg, 1.84 mmol) in H O (5 mL) and
THF (5 mL) was added LiOH.H O (386 mg, 9.20 mmol). The mixture was stirred at 25 °C for
12h. The reaction was acidified with 1N HCl to pH ~ 3. The mixture was extracted with EtOAc
(20 mL x 2). The organics were collected, washed with brine (20 mL), dried with Na SO ,
filtered and concentrated to afford compound 263E (340 mg, yield: 97.68%) as yellow solid. MS
(ESI) m/z (M+1) 189.9.
Compound 263 (6.5 mg, yield: 6.10%, white solid) was prepared as in
Example 5 from the corresponding intermediate carboxylic acid, compound 263E.Compound
263: MS (ESI) m/z (M+1) 364.1. H NMR (DMSO-d 400 MHz): δ 9.39 (d, J = 8.0 Hz, 1H),
8.16 (s, 1H), 8.12 (br. s, 1H), 7.87 (br. s, 1H), 7.53 - 7.43 (m, 3H), 7.34 - 7.20 (m, 7H), 5.35 -
.26 (m, 1H), 3.23 - 3.14 (m, 1H), 2.85 - 2.75 (m, 1H).
EXAMPLE 148
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)METHYL(PYRIDIN
YL)OXAZOLECARBOXAMIDE (266)
PhI(OAc)
NH OAc, EtOH
H N O
80 °C, 15 hrs DCE, 0-25 °C, 4 hrs
O O O O
H N O
266A
266B
LiOH•H O
HOAc: DCE
(1:2)
MeOH:H O OH
90 °C, 3 hrs (2:1)
°C, 2 hrs
266D
266C
To a mixture of ethyl 3-oxo(pyridinyl)propanoate (5 g, 25.88 mmol) in
EtOH (50 mL) was added NH OAc (3.99 g, 51.76 mmol) and purged with N for 3 times, and
then the mixture was stirred at 80 °C for 15 hours under N atmosphere. After removal of the
solvent, the residue was dissolved in water (50 mL), extracted with EtOAc (100 mL x 2). This
combined organic phase was washed with saturated aqueous NaHCO (50 mL x 2) and brine (50
mL), dried over Na SO , filtered and the solvent was removed in vacuum. The residue was
17681897_1 (GHMatters) P110989.NZ
purified by column chromatography (SiO , Petroleum ether/Ethyl acetate = 0: 1 to 10: 1) to give
compound 266A (3.80 g, 69.23% yield) as a yellow solid. H NMR (CDCl 400 MHz): δ 8.62
(d, J = 4.4 Hz, 1H), 7.78 - 7.71 (m, 2H), 7.37 - 7.29 (m, 1H), 5.33 (s, 1H), 4.20 (q, J = 7.2 Hz,
2H), 1.31 (t, J = 7.2 Hz, 3H). MS (ESI) m/z (M+H) 193.1.
To a mixture of iodosobenzene diacetate (2 g, 10.41 mmol) in DCE (21 mL)
was added compound 266A (4.36 g, 13.53 mmol) in six portions at 0 °C under N , the mixture
was stirred at 0 °C for 3 hours and then warmed to 25 °C slowly. The mixture was stirred at
°C for 1h. The reaction mixture was quenched with saturated aqueous NaHCO (60 mL) and
extracted with DCM (60 mL x 3). The combined organic layers were dried over anhydrous
Na SO filtered and concentrated under reduced pressure to give a residue, which was purified
2 4,
by column chromatography (SiO , Petroleum ether/Ethyl acetate = 20: 1 to 1: 1) to afford
compound 266B (1.30 g, 49.90% yield) as a yellow oil. H NMR (400 MHz, CDCl ): δ 8.72 -
8.61 (m, 1H), 7.81 - 7.69 (m, 2H), 7.36 - 7.29 (m, 1H), 4.24 (q, J = 7.2 Hz, 2H), 2.13 (s, 3H),
1.29 (t, J = 7.2 Hz, 3H).
A solution of compound 266B (1.30 g, 5.19 mmol) in DCE (20 mL) and AcOH
(10 mL) was stirred at 90 °C for 3 hours. The reaction mixture was cooled to room-temperature
and the mixture concentrated under reduced pressure to give a residue which was purified by
column chromatography (SiO , Petroleum ether/Ethyl acetate = 10:1 to 0:1) to afford compound
266C (300 mg, 23.06% yield) as a yellow solid. H NMR (400 MHz, CDCl3): δ 8.78 - 8.73 (m,
1H), 8.13 - 8.08 (m, 1H), 7.80 - 7.74 (m, 1H), 7.33 - 7.28 (m, 1H), 4.40 - 4.34 (m, 2H), 2.60 (s,
3H), 1.37 - 1.33 (m, 3H). MS (ESI) m/z (M+ H) 233.1.
To a mixture of compound 266C (300 mg, 1.29 mmol) in MeOH (10 mL) and
H O (5 mL) was added LiOH•H O (162.4 mg, 3.87 mmol) in one portion and the mixture was
stirred at 25 °C for 2 hours. The reaction mixture was concentrated under reduced pressure to
remove MeOH. The residue was adjusted to pH ~ 3 with 1 N HCl, diluted with water (20 mL)
and then extracted with EtOAc (50 mL x 4). The combined organic layers were washed with
brine (50 mL), dried over anhydrous Na SO , filtered and concentrated under reduced pressure to
afford intermediate compound 266D (170 mg, 64.54% yield) as a yellow solid. H NMR (400
MHz, CDCl : δ 8.59 (d, J = 4.8 Hz, 1H), 8.31 (d, J = 8.0 Hz, 1H), 8.11 - 8.03 (m, 1H), 7.54 -
7.49 (m, 1H), 2.61 (s, 3H). MS (ESI) m/z (M+ H) 204.8.
17681897_1 (GHMatters) P110989.NZ
Compound 266 (15.3 mg, 14.91% yield, light yellow solid) was prepared as in
Example 5 from the corresponding intermediate carboxylic acid, compound 266D. Compound
266: H NMR (CDCl 400 MHz): δ 12.79 (d, J = 6.0 Hz, 1H), 8.17 (d, J = 8.0 Hz, 1H), 8.00 (d, J
= 4.4 Hz, 1H), 7.82 (t, J = 7.6 Hz, 1H), 7.23 - 7.19 (m, 1H), 7.14 - 7.04 (m, 5H), 6.76 (br s, 1H),
.89 (q, J = 6.0 Hz, 1H), 5.56 (br s, 1H), 3.47 - 3.30 (m, 2H), 2.59 - 2.54 (m, 3H). MS (ESI) m/z
(M+ H) 379.1.
EXAMPLE 149
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)(2-FLUOROPHENYL)
METHYLOXAZOLECARBOXAMIDE (267)
NH EtOH
OAc,
PhI(OAc)2
F F O
O O O O O
267A
267B
LiOH
HOAc: DCE
(1:2)
MeOH OH
90 °C, 3 hrs
267D
267C
To a mixture of ethyl 3-oxo(pyridinyl)propanoate (5 g, 25.88 mmol) in
EtOH (50 mL) was added NH4OAc (3.99 g, 51.76 mmol) and purged with N2 for 3 times, and
then the mixture was stirred at 80 °C for 15 hours under N atmosphere. After removal of the
solvent, the residue was dissolved in water (50 mL), extracted with EtOAc (100 mL x 2). This
combined organic phase was washed with saturated aqueous NaHCO (50 mL x 2) and brine (50
mL), dried over Na SO , filtered and the solvent was removed in vacuum. The residue was
purified by column chromatography (SiO , Petroleum ether/Ethyl acetate = 0: 1 to 10: 1) to give
compound 266A (3.80 g, 69.23% yield) as a yellow solid. H NMR (CDCl 400 MHz): δ 8.62
(d, J = 4.4 Hz, 1H), 7.78 - 7.71 (m, 2H), 7.37 - 7.29 (m, 1H), 5.33 (s, 1H), 4.20 (q, J = 7.2 Hz,
2H), 1.31 (t, J = 7.2 Hz, 3H). MS (ESI) m/z (M+H) 193.1.
To a mixture of iodosobenzene diacetate (2 g, 10.41 mmol) in DCE (21 mL)
was added compound 266A (4.36 g, 13.53 mmol) in six portions at 0 °C under N , the mixture
was stirred at 0 °C for 3 hours and then warmed to 25 °C slowly. The mixture was stirred at
17681897_1 (GHMatters) P110989.NZ
°C for 1h. The reaction mixture was quenched with saturated aqueous NaHCO (60 mL) and
extracted with DCM (60 mL x 3). The combined organic layers were dried over anhydrous
Na SO filtered and concentrated under reduced pressure to give a residue, which was purified
2 4,
by column chromatography (SiO , Petroleum ether/Ethyl acetate = 20: 1 to 1: 1) to afford
compound 266B (1.30 g, 49.90% yield) as a yellow oil. H NMR (400 MHz, CDCl ): δ 8.72 -
8.61 (m, 1H), 7.81 - 7.69 (m, 2H), 7.36 - 7.29 (m, 1H), 4.24 (q, J = 7.2 Hz, 2H), 2.13 (s, 3H),
1.29 (t, J = 7.2 Hz, 3H).
A solution of compound 266B (1.30 g, 5.19 mmol) in DCE (20 mL) and AcOH
(10 mL) was stirred at 90 °C for 3 hours. The reaction mixture was cooled to room-temperature
and the mixture concentrated under reduced pressure to give a residue which was purified by
column chromatography (SiO , Petroleum ether/Ethyl acetate = 10:1 to 0:1) to afford compound
266C (300 mg, 23.06% yield) as a yellow solid. H NMR (400 MHz, CDCl ): δ 8.78 - 8.73 (m,
1H), 8.13 - 8.08 (m, 1H), 7.80 - 7.74 (m, 1H), 7.33 - 7.28 (m, 1H), 4.40 - 4.34 (m, 2H), 2.60 (s,
3H), 1.37 - 1.33 (m, 3H). MS (ESI) m/z (M+ H) 233.1.
To a mixture of compound 266C (300 mg, 1.29 mmol) in MeOH (10 mL) and
H O (5 mL) was added LiOH•H O (162.4 mg, 3.87 mmol) in one portion and the mixture was
stirred at 25 °C for 2 hours. The reaction mixture was concentrated under reduced pressure to
remove MeOH. The residue was adjusted to pH ~ 3 with 1 N HCl, diluted with water (20 mL)
and then extracted with EtOAc (50 mL x 4). The combined organic layers were washed with
brine (50 mL), dried over anhydrous Na SO , filtered and concentrated under reduced pressure to
afford intermediate compound 266D (170 mg, 64.54% yield) as a yellow solid. H NMR (400
MHz, CDCl : δ 8.59 (d, J = 4.8 Hz, 1H), 8.31 (d, J = 8.0 Hz, 1H), 8.11 - 8.03 (m, 1H), 7.54 -
7.49 (m, 1H), 2.61 (s, 3H). MS (ESI) m/z (M+ H) 204.8.
Compound 267 (15.3 mg, 14.91% yield, light yellow solid) was prepared as in
Example 5 from the corresponding intermediate carboxylic acid, compound 267D. Compound
267: H NMR (CDCl 400 MHz): δ 12.79 (d, J = 6.0 Hz, 1H), 8.17 (d, J = 8.0 Hz, 1H), 8.00 (d, J
= 4.4 Hz, 1H), 7.82 (t, J = 7.6 Hz, 1H), 7.23 - 7.19 (m, 1H), 7.14 - 7.04 (m, 5H), 6.76 (br s, 1H),
.89 (q, J = 6.0 Hz, 1H), 5.56 (br s, 1H), 3.47 - 3.30 (m, 2H), 2.59 - 2.54 (m, 3H). MS (ESI) m/z
(M+ H) 379.1.
17681897_1 (GHMatters) P110989.NZ
EXAMPLE 150
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)PHENYLTHIOPHENE
CARBOXAMIDE (270)
Br O
O NaOH, EtOH,
Suzki reaction THF/H O
2 OH
270B
270A
Ethyl 2-bromothiophenecarboxylate (2 g, 8.51 mmol), phenylboronic acid
(1.35 g, 11.1 mmol), K CO (2.35 g, 17 mmol) and Pd(dppf)Cl (622 mg, 851 umol) in dioxane
2 3 2
(30 mL), H O (3 mL) was de-gassed and then heated to 100 °C for 6 hours under N . The
mixture was concentrated, the residue was purified by silica gel chromatography (Petroleum
ether to Petroleum ether: Ethyl acetate = 25: 1) to give compound 270A (1.9 g, yield: 96.11%), as
yellow oil. H NMR (400MHz, CDCl -d) δ 7.53 (d, J = 5.4 Hz, 1H), 7.52 - 7.47 (m, 2H), 7.44 -
7.38 (m, 3H), 7.25 (d, J = 5.4 Hz, 1H), 4.20 (q, J = 7.1 Hz, 2H), 1.19 (t, J = 7.1 Hz, 3H).
A mixture of 270A (150 mg, 646 umol) and NaOH (51.7 mg, 1.29 mmol) in
THF (5 mL), EtOH (3 mL), H O (2 mL) was stirred at 15 °C for 12 hrs. TLC (petroleum
ether/ethyl acetate = 10:1) showed unreacted starting material and then the mixture was heated to
60 °C for another 3 hrs. The organic solvent was removed under reduced pressure, the water
layer was adjusted to pH ~ 6 with 1N HCl to give a precipitate, the solid was filtered and dried to
give 270B (100 mg, yield: 75.8%), as white solid. H NMR (400MHz, DMSO-d ) δ 12.63 (br s,
1H), 7.55 (d, J = 5.3 Hz, 1H), 7.49 - 7.41 (m, 2H), 7.41 - 7.31 (m, 4H).
Compound 270 (16.00 mg, yield: 20.1%, white solid) was prepared as in
Example 5 from the corresponding intermediate carboxylic acid, compound 270B. Compound
270: H NMR (400MHz, DMSO-d6) δ 8.73 (d, J = 7.5 Hz, 1H), 8.12 (s, 1H), 7.87 (s, 1H), 7.58
(d, J = 5.3 Hz, 1H), 7.36 - 7.20 (m, 10H), 7.09 (d, J = 5.3 Hz, 1H), 5.29 (ddd, J=3.6, 7.3, 10.4
Hz, 1H), 3.17 (dd, J = 3.6, 13.8 Hz, 1H), 2.80 (dd, J = 10.4, 13.9 Hz, 1H). MS (ESI) m/z
(M+H) 379.1.
17681897_1 (GHMatters) P110989.NZ
EXAMPLE 151
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)CHLORO
PHENYLTHIOPHENECARBOXAMIDE (271)
NaOH, EtOH,
NCS, DMF
THF/H
271A Cl
270A
Cl 271B
To a solution of 270A (300 mg, 1.29 mmol) in DMF (5 mL) was added NCS
(345 mg, 2.58 mmol) at 80 °C, and the mixture was stirred at 80 °C for 1.5 hrs. The mixture was
poured into water (20 mL) and extracted with ethyl acetate (10 mL x 2), the combined organic
layer was washed with brine (10 mL), dried over Na SO , filtered and concentrated. The residue
was purified by silica gel chromatography (Petroleum ether to Petroleum ether: Ethyl acetate =
: 1) to give 271A (0.38 g, yield: 82.8%), as white solid (combined with page 158). H NMR
(400MHz, CDCl ) δ 7.50 - 7.44 (m, 2H), 7.43 - 7.37 (m, 3H), 7.34 (s, 1H), 4.19 (q, J=7.1 Hz,
2H), 1.18 (t, J=7.2 Hz, 3H).
A mixture of 271A (380 mg, 1.42 mmol) and NaOH (114 mg, 2.84 mmol) in
THF (5 mL), EtOH (3 mL), H2O (2 mL) was stirred at 15°C for 12 hrs. The organic solvent was
removed under vacuum, the water layer was adjusted to pH ~ 3 with 1N HCl and extracted with
ethyl acetated (10 mL x 2), the organic layer was washed with brine (10 mL), dried over Na SO ,
filtered and concentrated to give 271B (330 mg, yield: 97.4%), as white solid. H NMR
(400MHz, CDCl -d) δ 7.43 - 7.36 (m, 2H), 7.36 - 7.29 (m, 3H), 7.28 (s, 1H).
Compound 271 (28.2 mg, yield: 30.4%, white solid) was prepared as in
Example 5 from the corresponding intermediate carboxylic acid, compound 271B. Compound
271: H NMR (400MHz, CDCl ) δ 7.40 (br s, 5H), 7.19 (br s, 4H), 6.76 (br s, 2H), 6.66 (br s,
1H), 5.93 (br s, 1H), 5.44 (br d, J = 19.3 Hz, 2H), 3.18 (br d, J = 16.7 Hz, 1H), 2.94 - 2.81 (m,
1H). MS (ESI) m/z (M+H) 413.0, 415.0.
17681897_1 (GHMatters) P110989.NZ
EXAMPLE 152
COMPOUNDS 272-273
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)CYANOPHENYL-1H-
PYRAZOLECARBOXAMIDE (272)
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)CYANOPHENYL-1H-
PYRAZOLECARBOXAMIDE (273)
PhB(OH)
Cu(OAc)2 Pyridine, N
272A
MS, O , DCM
272C
272B
THF/H THF/H
LiOH, O/MeOH LiOH, O/MeOH
273A
272D
To a solution of ethyl propiolate (4.30 g, 43.83 mmol) and 2-aminoacetonitrile
hydrochloride (8.11 g, 87.67 mmol, HCl) in CHCl (250 mL) and H O (10 mL) was added
NaNO (9.07 g, 131.50 mmol). The mixture was stirred for 14 h at 25 °C. Then, the reaction
mixture was diluted with DCM (50 mL) and filtered. The filtrate was washed with H O (20 mL)
and brine (20 mL), dried over Na SO , filtered and concentrated under reduced pressure to give a
residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash®
Silica Flash Column, Eluent of 0~30% Ethylacetate/Petroleum ethergradient) to give 272A (1.40
g yield: 19.34%) as a white solid. H NMR (400MHz, CHLOROFORM-d) δ 12.19 (br s, 1H),
7.21 (s, 1H), 4.45 (q, J = 7.2 Hz, 2H), 1.41 (t, J = 7.2 Hz, 3H).
To a mixture of 272A (1.40 g, 8.48 mmol), phenylboronic acid (1.55 g, 12.72
mmol), pyridine (737.60 mg, 9.32 mmol) in DCM (50 mL) was added 4A° MS (20 g) (activated
4A° MS) and Cu(OAc)2 (1.69 g, 9.32 mmol). After that, the mixture was stirred at 40 °C for 72
hours under O atmosphere (15 psi). The reaction mixture was filtered and concentrated under
reduced pressure to give a residue. The residue was purified by flash silica gel chromatography
17681897_1 (GHMatters) P110989.NZ
(ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0~30% Ethyl acetate/Petroleum
ethergradient) and then by prep-HPLC (HCl condition) to give 272B (170 mg, yield: 8.23%) and
272C (264 mg, yield: 12.78%) as white solid.
Compound 272B: H NMR (400MHz, CHLOROFORM-d) δ 7.73 (dd, J = 1.3,
8.3 Hz, 2H), 7.64 -7.46 (m, 4H), 4.46 (q, J = 7.2 Hz, 2H), 1.42 (t, J = 7.0 Hz, 3H). MS (ESI) m/z
(M+H) 241.9.
Compound 272C: H NMR (400MHz, CHLOROFORM-d) δ 7.55 - 7.47 (m,
3H), 7.45 - 7.39 (m, 2H), 7.37 (s, 1H), 4.27 (q, J = 7.0 Hz, 2H), 1.25 (t, J = 7.2 Hz, 3H). MS
(ESI) m/z (M+H) 241.9.
To a solution of 272B (170 mg, 704.69 umol) in THF (5 mL) and MeOH (5
mL) was added a solution of LiOH.H O (148 mg, 3.52 mmol) in H O (5 mL) at 0 °C. After
addition, the reaction mixture was stirred for 3h at 25 °C, and then diluted with H O (10 mL) and
extracted with MTBE (30 mL). The aqueous phase was neutralized by 1N HCl to the pH ~ 4,
and then extracted with EtOAc (30 mL x 3). The combined organic layers were washed with
brine (30 mL), dried over Na SO , filtered and concentrated under reduced pressure. Compound
272D (98 mg, yield: 64.58%, white solid): H NMR (400MHz, CHLOROFORM-d) δ 7.76-7.74
(m, 2H), 7.61 - 7.52 (m, 4H), 2.83 (br s, 1H).
Compound 272 (40 mg, yield: 53.56%, white solid) was prepared as in
Example 6 from the corresponding starting materials, compounds 272D and 12G. Compound
272: H NMR (400MHz, DMSO-d ) δ 8.88 (br d, J = 7.8 Hz, 1H), 8.12 (br s, 1H), 7.91 - 7.74 (m,
4H), 7.71 - 7.57 (m, 3H), 7.31 - 7.15 (m, 5H), 5.47 (br s, 1H), 3.25 - 2.96 (m, 2H). MS (ESI) m/z
(M + H) 388.1.
Following the procedure used for compound 274, compound 273 (19 mg, yield:
44.44%, white solid) was prepared from the corresponding intermediate carboxylic acid,
compound 273A. Compound 273A (201 mg, yield: 55.94%, white solid): H NMR (400MHz,
CHLOROFORM-d) δ 7.58 - 7.53 (m, 1H), 7.46 - 7.42 (m, 5H), 4.05 (br s, 1H). Compound 273:
H NMR (400MHz, DMSO-d ) δ 9.43 (br d, J = 7.8 Hz, 1H), 8.15 (br s, 1H), 7.90 (br s, 1H),
7.44 (br d, J = 8.5 Hz, 4H), 7.36 - 7.25 (m, 7H), 5.42 - 5.22 (m, 1H), 3.21 (br d, J = 11.5 Hz, 1H),
2.90 - 2.75 (m, 1H). MS (ESI) m/z (M +H) 388.1.
17681897_1 (GHMatters) P110989.NZ
EXAMPLE 153
COMPOUNDS 274, 320
N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)BROMOCHLORO
METHYL-1H-PYRAZOLECARBOXAMIDE (274)
O Br
NaOH
NCS O
160 C
274B
274A
To a solution of ethyl 3-bromomethyl-1H-pyrazolecarboxylate (500 mg,
2.15 mmol) and NCS (574 mg, 4.30 mmol) was stirred. The mixture was stirred at 160 °C for 3h
under N . The reaction mixture was added by addition of CCl (20 mL), and then diluted with
NaHCO (30 mL). The mixture was extracted with DCM (20 mL x 3). The combined organic
layers were dried over Na SO , filtered and concentrated under reduced pressure to give a
residue. The residue was purified by preparatory-TLC (SiO , PE:EA = 5:1). Compound 274A
(180 mg, yield: 31.30%) was obtained as a yellow oil. H NMR (400MHz, CDCl ) δ 4.34 (q, J =
7.1 Hz, 2H), 3.85 (s, 3H), 1.46 - 1.24 (m, 3H). MS (ESI) m/z (M+H) 266.9.
To a solution of compound 274A (300 mg, 1.12 mmol) in MeOH (10 mL) and
H O (10 mL) was added NaOH (134 mg, 3.36 mmol). The mixture was stirred at 25 °C for 3h.
The reaction mixture was concentrated and added 20 mL of water, the mixture was extracted
with MTBE (10 mL x 2), the aqueous layer was acidified by 1N HCl to pH ~ 2~3 at 0 °C, and
extracted with EtOAc (20 mL x 2), the organic phase was dried over Na SO , filtered and
concentrated to give a residue. Compound 274B (250 mg, yield: 93.22%) was obtained as a
white solid, which was used to the next step without purification. H NMR (400MHz, CDCl3) δ
4.02 - 3.72 (m, 3H). MS (ESI) m/z (M+H) 238.9.
Compound 274 (70 mg, yield: 66.75%, light yellow solid) was prepared as in
Example 5 from the corresponding starting materials, compounds 274B and 3-aminohydroxy-
4-phenyl-butanamide (274D). Compound 274: H NMR (400MHz, DMSO-d ) δ 8.41 - 8.27 (m,
1H), 8.12 (s, 1H), 7.87 (s, 1H), 7.29 (dd, J = 4.0 Hz, 4H), 7.22 (dd, J = 4.0 Hz, 1H), 5.36 (s, 1H),
3.78 (s, 3H), 3.20 (dd, J = 10.4 Hz, 1H), 2.90 - 2.81 (m, 1H). MS (ESI) m/z (M+H) 415.0.
17681897_1 (GHMatters) P110989.NZ
N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)METHYL(3-PHENYL-1H-
PYRAZOLYL)THIOPHENECARBOXAMIDE (320)
H N NH
N O O
HBTU,DIPEA
N NH
320A
320B
Compound 320 (33.7 mg, yield: 51.5%, white solid) was prepared as in
Example 153 from the corresponding carboxylic acid, compound 320A, and 3-aminohydroxy-
4-phenyl-butanamide (274D). Compound 320: H NMR (400MHz, DMSO-d6) δ 8.88 (d, J = 7.6
Hz, 1H), 8.12 (s, 1H), 7.97 (d, J = 2.6 Hz, 1H), 7.85 (br d, J = 7.1 Hz, 3H), 7.50 - 7.42 (m, 2H),
7.41 - 7.34 (m, 1H), 7.33 - 7.19 (m, 5H), 6.92 (d, J = 2.6 Hz, 1H), 6.84 (d, J = 1.0 Hz, 1H), 5.40 -
.31 (m, 1H), 3.19 (dd, J = 3.6, 14.0 Hz, 1H), 2.80 (dd, J = 10.3, 13.8 Hz, 1H), 2.44 (s, 3H). MS
(ESI) m/z (M+H) 459.1.
EXAMPLE 154
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)METHYLPHENYL-1H-
PYRAZOLECARBOXAMIDE (276)
NaOH
MeOH
HOAc, reflux
1) N
NHNH O
separation
276C
276A
To a mixture of phenylhydrazine (50 g, 462.3 mmol) and ethyl 2,4-
dioxopentanoate (76.8 g, 485.5 mmol) in AcOH (600 mL) at 25 °C. The mixture was stirred at
100 °C for 16h. The reaction mixture was concentrated under reduced pressure to remove
AcOH. The residue was added H O (200 mL) and EA (200 mL), and then the mixture was
alkalized with saturated aqueous NaHCO till the aqueous phase pH ~ 7 - 8. The separated
aqueous layer was extracted with EA (150 mL x 3), the combined organic layers were washed
with saturated aqueous NaHCO (200 mL), saturated aqueous NaCl (200 mL), dried over
Na SO , filtered under reduced pressure to give crude product. The crude product was purified
by FCC (SiO2, Petroleum ether: Ethyl acetate =1: 0 ~ 3: 1). Compound 276A (39.0 g, yield:
17681897_1 (GHMatters) P110989.NZ
36.7%, yellow solid): H NMR (DMSO-d 400 MHz): δ 7.50 - 7.37 (m, 5H), 6.88 (s, 1H), 4.16
(q, J = 7.0 Hz, 2H), 2.26 (s, 3H), 1.14 (t, J = 7.2 Hz, 3H).
To a mixture of compound 276A (250 mg, 1.1 mmol) in MeOH (10 mL) was
added NaOH (2M, 3 mL) in one portion at 25 °C. The mixture was stirred at 25 °C for 2h. The
reaction mixture was concentrated under reduced pressure to move MeOH. H O (10 mL) was
added into the mixture, which was acidified with aqueous HCl (1M) till pH ~ 3 - 4. The aqueous
phase was extracted with EA (10 mL x 3). The combined organic phase was washed with
saturated aqueous NaCl (15 mL x 2), dried over Na SO and filtered under reduced pressure to
afford compound 276C (170 mg, crude) as yellow solid, which was used directly for next step
without purification. H NMR (DMSO-d 400 MHz): δ 7.49 - 7.37 (m, 5H), 6.82 (s, 1H), 2.25
(s, 3H).
Compound 276 (100 mg, yield: 65.68%, white solid) was prepared as in
Example 5 from the corresponding intermediate carboxylic acid, compound 276C. Compound
276: H NMR (CDCl 400 MHz): δ 9.14 - 9.00 (m, 1H), 8.09 (s, 1H), 7.85 (s, 1H), 7.44 - 7.11
(m, 10H), 6.56 (s, 1H), 5.28 (s, 1H), 3.26 - 3.16 (m, 1H), 2.91 - 2.76 (m, 1H), 2.26 (s, 3H). MS
(ESI) m/z (M+H) 377.1.
EXAMPLE 155
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)(2-
FLUOROPHENYL)ISOXAZOLECARBOXAMIDE (277)
EtOOC
HOAc
TEA EtOH
277C 277D
277A 277B
To a suspension of 2-fluorobenzaldehyde (10 g, 80.6 mmol) and NH OH.HCl
(6.2 g, 88.6 mmol) in EtOH (10 mL) and H O (20 mL) was added ice (50 g). Then an aqueous
solution of NaOH (8 g, 201 mmol) in H O (25 mL) was added dropwise within a 10 min period
where upon most of the solid dissolves. Then the mixture was stirred 2 hours at 16 °C. The
resulting mixture was then acidified with HCl (5N). The mixture was then extracted with
dichloromethane (100 mL) for two times. The residue was purified by column chromatography
(SiO , Petroleum ether: Ethyl acetate = 1: 0 to 200: 1) to give compound 277A (10 g, yield:
17681897_1 (GHMatters) P110989.NZ
89.2%) as a pale yellow solid. H NMR (400MHz, CDCl ) δ 8.68 (s, 1H), 8.39 (s, 1H), 7.74 (br t,
J = 7.5 Hz, 1H), 7.39 (q, J = 6.8 Hz, 1H), 7.18 (t, J = 7.4 Hz, 1H), 7.14 - 7.06 (m, 1H).
A solution of compound 277A (5 g, 35.9 mmol) in DMF (20 mL) was added 1-
chloropyrrolidine-2, 5-dione (5.3 g, 39.5 mmol) followed by stirring at 20 °C for 3 hours. The
reaction mixture was diluted with H O (60 mL), and extracted with ethyl acetate (100 mL x 2).
The organic layers were dried over Na SO , filtered and concentrated under reduced pressure to
give intermediate compound 277B (5 g, yield: 80.2%) as a yellow solid. H NMR (400MHz,
CDCl ) δ 9.15 (s, 1H), 7.68 (br t, J = 7.5 Hz, 1H), 7.50 - 7.39 (m, 1H), 7.23 (t, J = 7.6 Hz, 1H),
7.20 - 7.13 (m, 1H).
To a solution of ethyl 3-(dimethylamino)acrylate (165 mg, 1.2 mmol) and TEA
(233 mg, 2.3 mmol) in THF (15 mL) was added a solution of compound 277B (400 mg, 2.3
mmol) in THF (5 mL) drop-wise over 30 mins. The mixture was stirred at 20 °C for 12 hours.
The reaction mixture was concentrated under reduced pressure to give a residue. The residue
was purified by preparatory-TLC (SiO , Petroleum ether: Ethyl acetate = 1: 1) to give compound
277C (240 mg, yield: 44.4%) as a pale yellow oil. H NMR (400MHz, CDCl ) δ 8.94 (s, 1H),
7.51 - 7.36 (m, 2H), 7.21 - 7.14 (m, 1H), 7.13 - 7.04 (m, 1H), 4.17 (q, J = 7.1 Hz, 2H), 1.15 (t, J
= 7.2 Hz, 3H).
A mixture of compound 277C (230 mg, 977.9 umol) in H O (2.00 mL), HOAc
(1.5 mL) and HCl (3 mL) was heated to 130 °C and stirred for 12 hours. The reaction mixture
was concentrated under reduced pressure to give compound 277D (120 mg, yield: 59.2%) as a
brown solid. The product was used into the next step without future purification. MS (ESI) m/z
(M+H) 208.1.
Compound 277 (33 mg, yield: 37.7%, white solid) was prepared as in Example
from the corresponding intermediate carboxylic acid, compound 277D. Compound 277: H
NMR (400MHz, DMSO-d ) δ 9.43 (br s, 1H), 8.94 (br d, J = 6.8 Hz, 1H), 8.09 (br s, 1H), 7.83
(br s, 1H), 7.54 (br d, J = 5.3 Hz, 1H), 7.47 - 7.40 (m, 1H), 7.36 - 7.16 (m, 9H), 5.31 (br s, 1H),
3.17 (br d, J = 13.5 Hz, 1H), 2.89 - 2.75 (m, 1H), 2.89 - 2.75 (m, 1H). MS (ESI) m/z (M+H)
382.1.
17681897_1 (GHMatters) P110989.NZ
EXAMPLE 156
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)PHENYL
(TRIFLUOROMETHYL)ISOXAZOLECARBOXAMIDE (278)
278B
278A
To a mixture of N-hydroxybenzimidoyl chloride (1 g, 6.43 mmol) and ethyl
4,4,4-trifluorobutynoate (1.28 g, 7.71 mmol) in THF (10 mL) was added TEA (1.3 g, 12.9
mmol) at 25 °C. The mixture was stirred at 25°C for 1h and H O (10 mL) was added to the
mixture and extracted with ethyl acetate (10 mL x 2). The combined organic phase was washed
with brine (10 mL x 2), dried with anhydrous Na SO , filtered and concentrated in vacuum. The
residue was purified by preparatory-TLC to get compound 278A (1 g, yield: 54.5%) as yellow
oil. H NMR (400MHz, CDCl ) δ 7.68 (dd, J = 1.3, 7.9 Hz, 2H), 7.56 - 7.47 (m, 3H), 4.39 - 4.31
(m, 2H), 1.34 - 1.28 (m, 3H).
To a mixture of compound 278A (750 mg, 2.63 mmol) in HOAc (2 mL) was
added HCl (12M, 939 uL). The mixture was stirred at 130 °C for 48h. TLC (dichloromethane:
methanol = 10:1, R ~ 0.09) showed desired point. The mixture was concentrated to get crude
product compound 278B (450 mg, crude) as yellow solid. H NMR (400MHz, DMSO-d ) δ 7.68
(br d, J = 7.9 Hz, 2H), 7.62 - 7.50 (m, 3H).
Compound 278 (15 mg, yield: 12.6%, white solid) was prepared as in Example
from the corresponding intermediate carboxylic acid, compound 278B. Compound 278: H
NMR (400MHz, DMSO-d ) δ 9.17 (br d, J = 9.2 Hz, 1H), 7.55 - 7.48 (m, 3H), 7.43 - 7.36 (m,
4H), 7.28 - 7.14 (m, 5H), 5.88 (d, J = 5.3 Hz, 1H), 4.60 (br s, 1H), 4.04 (br s, 1H), 3.31 (s, 12H),
2.73 - 2.61 (m, 1H). MS (ESI) m/z (M+H) 432.1.
17681897_1 (GHMatters) P110989.NZ
EXAMPLE 157
N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)CHLOROPHENYL-1H-
PYRAZOLECARBOXAMIDE (280)
NaClO NaOH,
PhB(OH)2 O O
N MeOH
CH COOH /H O
O Cu(OAc)2 pyridine 3
O OH
4A° MS, O
280A
280D
280C
To a mixture of ethyl 1H-pyrazolecarboxylate (10.00 g, 71.36 mmol),
phenylboronic acid (13.05 g, 107.04 mmol), Py (8.82 g, 111.50 mmol, 9.0 mL) in DCM (120
mL) was added 4A° MS (40.00 g) and Cu(OAc) (14.26 g, 78.50 mmol), the mixture was stirred
at 30 °C for 154h. The reaction mixture was filtered, the filtrate was concentrated in vacuo. The
residue was purified by flash silica gel chromatography (PE: EA = 1:0 to 10:1) to give the
compound 280A (3.10 g, yield:19.1%) as a yellow oil. Compound 280A: H NMR (400MHz,
DMSO-d ) δ 7.81 (d, J = 2.0 Hz, 1H), 7.57 - 7.37 (m, 5H), 7.09 (d, J = 2.0 Hz, 1H), 4.17 (q, J =
7.0 Hz, 2H), 1.15 (t, J = 7.0 Hz, 3H).
To a solution of compound 280A (1.0 g, 4.62 mmol) in CH COOH (15 mL)
was added NaClO (24.2 g, 47.12 mmol, 20.00 mL, 14.5% purity). The mixture was stirred at
°C for 21h under N atmosphere. The reaction mixture was quenched by addition H O (25
mL), and diluted with EA (20 mL) and stirred for 30 min, and then extracted with EA (25 mL).
The combined organic layers were washed with H O (20 mL x 2), and then washed with
NaHCO (20 mL x 2), and then washed with brine (15 mL x 2), dried over Na SO , filtered and
3 2 4
concentrated under reduced pressure to give a residue. The residue was purified by flash silica
gel chromatography (PE: EA = 1:0 to 1:1) to give the compound 280C (327 mg, yield: 28.1%) as
a white solid. H NMR (400MHz, CHLOROFORM-d) δ 7.69 (s, 1H), 7.53 - 7.31 (m, 5H), 4.27
(q, J = 7.1 Hz, 2H), 1.22 (t, J = 7.2 Hz, 3H).
To a solution of compound 280C (300 mg, 1.20 mmol) in MeOH (15 mL) was
added NaOH (240 mg, 6.00 mmol) in H O (5 mL). The mixture was stirred at 20 °C for 2h. The
reaction mixture was diluted with MTBE (15 mL) and H O (15 mL), and then stirred for 10
mins. The water layer was seperated, and the organic layer was extracted with H O (15 mL x 2).
The combined aqueous layers were ajusted pH ~ 3 by addtion 1N HCl, and then the aqueous
17681897_1 (GHMatters) P110989.NZ
layer was extracted with EA (20 mL x 3). The combine organic layer was washed with brine (20
mL), dried over Na SO , filtered and concentrated under reduced pressure to give the compound
280D (252 mg, yield:94.1%) as a white solid. H NMR (400MHz, METHANOL-d ) δ 7.76 (s,
1H), 7.52 - 7.38 (m, 5H).
Compound 280 (61 mg, yield: 61.2%, light yellow solid) was prepared as in
Example 5 from the corresponding intermediate carboxylic acid, compound 280D. Compound
280: H NMR (400MHz, DMSO-d ) δ 9.46 (d, J = 7.5 Hz, 1H), 8.20 (s, 1H), 7.97 - 7.86 (m, 2H),
7.41 - 7.24 (m, 10H), 5.48 - 5.35 (m, 1H), 3.21 (br dd, J = 3.2, 14.0 Hz, 1H), 2.80 (dd, J = 10.5,
14.0 Hz, 1H). MS (ESI) m/z (M+H) 397.1.
EXAMPLE 158
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)CHLOROPHENYL-1H-
PYRAZOLECARBOXAMIDE (281)
K S O H SO NaOH
POCl MeCN , ,
, 2 2 8 2 4 N
N N O
MeCN, reflux
O O OH
HN N N
281C
281D
O Cl Cl
281A
281B
To EtOH (40 mL) was added Na (470 mg, 20.34 mmol) at 20°C. After all
sodium was reacted, the mixture was heated to 78°C and phenylhydrazine (2.0 g, 18.49 mmol,
1.82 mL) was added, and stirred for 0.1h and then diethyl maleate (3.5 g, 20.34 mmol, 3.27 mL)
was added dropwise. The mixture was stirred at 78°C for 4h. After being cooled to 65°C, the
reaction mixture was treated with AcOH (2.0 g, 33.28 mmol, 1.9 mL). The reaction mixture was
concentrated under reduced pressure to remove solvent. The residue was diluted with H O (80
mL) and extracted with EtOAc (80 mL x 2). The combined organic layers were washed with
brine (50 mL x 2), dried over Na SO , filtered and concentrated under reduced pressure to give a
residue. The residue was purified by column chromatography (SiO , Petroleum ether/Ethyl
acetate=5/1 to 1:1) to give the compound 281A (2.72 g, yield: 58.40%) as a yellow solid. H
NMR (400MHz, DMSO-d ) δ 10.24 (s, 1H), 7.34 - 7.24 (m, 2H), 7.02 - 6.92 (m, 3H), 4.59 (dd, J
= 2.0, 9.7 Hz, 1H), 4.24 - 4.13 (m, 2H), 3.00 - 2.86 (m, 1H), 2.46 - 2.39 (m, 1H), 1.23 (t, J = 7.1
Hz, 3H). MS (ESI) m/z (M+H) 235.0.
17681897_1 (GHMatters) P110989.NZ
To a solution of Compound 281A (2.7 g, 11.53 mmol) in MeCN (50 mL) was
added POCl (2.15 g, 14.02 mmol). The mixture was stirred at 85 °C for 5h. The reaction
mixture was concentrated under reduced pressure to remove solvent. The residue was
neutralized by sat. NaHCO to pH~8, then extracted with DCM (50 mL x 2). The combined
organic layers were washed with brine (50 mL), dried over Na SO , filtered and concentrated
under reduced pressure to give a residue. The residue was purified by column chromatography
(SiO , Petroleum ether/Ethyl acetate=10/1 to 5:1) to give the Compound 281B (1.9 g, yield:
65.21%) as a yellow solid. H NMR (400MHz, CDCl ) δ 7.31 - 7.17 (m, 2H), 6.98 (br d, J = 7.3
Hz, 2H), 6.89 (br t, J = 7.2 Hz, 1H), 4.86 - 4.60 (m, 1H), 4.34 - 4.14 (m, 2H), 3.62 - 3.37 (m, 1H),
3.33 - 3.17 (m, 1H), 1.37 - 1.11 (m, 3H). MS (ESI) m/z (M+H) 252.9.
To a solution of Compound 281B (800 mg, 3.17 mmol) in MeCN (20 mL) was
added H SO (620 mg, 6.34 mmol, 337.95 uL) and K S O (1.29 g, 4.76 mmol). The mixture
2 4 2 2 8
was stirred at 80 °C for 6h. The reaction mixture was concentrated under reduced pressure to
remove most solvent. The residue was dropped in H O (30 mL), filtered and concentrated under
reduced pressure to give a residue. The residue was washed with 30% MeCN (5 mL x 2). The
residue was purified by column chromatography (SiO , Petroleum ether/Ethyl acetate=20/1 to
:1) to give the compound 281C (190 mg, yield: 21.52%) as a white solid. H NMR (400MHz,
DMSO-d ) δ 7.47 (d, J=1.3 Hz, 4H), 7.23 - 7.14 (m, 1H), 4.15 (q, J=7.1 Hz, 2H), 1.12 (t, J=7.2
Hz, 3H). MS (ESI) m/z (M+H) 250.9.
To a solution of Compound 281C (150 mg, 598.37 umol) in THF/H2O (5 mL/5
mL) was added NaOH (120 mg, 2.99 mmol). The mixture was stirred at 25 °C for 4h. The
reaction mixture was diluted with H O (20 mL), then the mixture was concentrated under
reduced pressure to remove THF, and extracted with MTBE (15 mL x 2). The water layers were
neutralized by 1N HCl to pH ~ 3 and then extracted with DCM (20 mL x 2). The combined
organic layers were washed with brine (20 mL), dried over Na SO , filtered and concentrated
under reduced pressure to give the Compound 281D (120 mg, yield: 90.08%) as a white solid.
H NMR (400MHz, CDCl ) δ 7.50 - 7.34 (m, 5H), 6.97 (s, 1H).
Compound 281 (20 mg, yield: 40.20%, white solid) was prepared as in
Example 5 from the corresponding intermediate carboxylic acid, compound 281D. Compound
281: H NMR (400MHz, DMSO-d ) δ 9.27 (d, J = 7.7 Hz, 1H), 8.11 (s, 1H), 7.87 (s, 1H), 7.41 -
17681897_1 (GHMatters) P110989.NZ
7.34 (m, 3H), 7.30 (br d, J = 7.1 Hz, 2H), 7.28 - 7.23 (m, 3H), 7.21 - 7.16 (m, 2H), 6.80 (s, 1H),
.31 - 5.19 (m, 1H), 3.24 – 3.
EXAMPLE 159
N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)-3,5-DICHLOROMETHYL-1H-
PYRAZOLECARBOXAMIDE (282)
O NCS
NaOH
O OH
160 C
Cl N
282B
282A
282C 282D
To a solution of ethyl 1H-pyrazolecarboxylate (5 g, 35.68 mmol) and
Cs CO (23.25 g, 71.36 mmol) in DMF (100 mL) was added MeI (10.13 g, 71.36 mmol, 4.44
mL). The mixture was stirred at 25°C for 16h. The mixture was filtered, the filtrate was diluted
with H O (500 mL), extracted with EA (50 mL x 3), dried over Na SO , filtered and concentrated
2 2 4
to give a residue. The residue was purified by column chromatography (SiO , Petroleum
ether/Ethyl acetate = 5/1). Compound 282A (4.5 g, yield: 81.81%) was obtained as a yellow oil.
H NMR (400MHz, CDCl ) δ 7.84 (d, J = 8.5 Hz, 2H), 4.24 (q, J = 7.3 Hz, 2H), 4.03 - 3.70 (m,
3H), 1.30 (t, J = 7.2 Hz, 3H). MS (ESI) m/z (M+H) 155.0.
To a solution of compound 282A (1.5 g, 9.73 mmol) was added NCS (2.6 g,
19.46 mmol) under N . The mixture was stirred at 160 °C for 3h. The reaction mixture was
added CCl (10 mL) and saturated aqueous NaHCO (10 mL). The mixture was extracted with
DCM (20 mL x 2), and then combined the organic layers and the organic phase was dried with
over Na SO , filtered and the filtrate was concentrated in vacuum. Compound 282B (1.84 g,
crude) was obtained as a brown oil, which was used for next step directly. MS (ESI) m/z
(M+H) 188.9.
To a solution of compound 282B (1.84 g, 9.76 mmol) was added NCS (2.61 g,
19.52 mmol) under N and the mixture was stirred at 160 °C for 4h under N To the reaction
2 2.
mixture was added CCl (10 mL) and saturated aqueous NaHCO (10 mL) and the mixture was
extracted with DCM (20 mL x 2), and then combined the organic layers and the organic phase
was dried with over Na SO , filtered and the filtrate was concentrated in vacuum. The residue
was purified by column chromatography (SiO , Petroleum ether/Ethyl acetate = 5/1). Compound
17681897_1 (GHMatters) P110989.NZ
282C (482 mg, yield: 22.14%) was obtained as a yellow solid. H NMR (400MHz, CDCl ) δ
4.35 (q, J = 7.1 Hz, 2H), 3.84 (s, 3H), 1.38 (t, J = 7.2 Hz, 3H). MS (ESI) m/z (M+H) 222.9.
To a mixture of compound 282C (480 mg, 2.15 mmol) in H O (5 mL) and
MeOH (10 mL) was added NaOH (258 mg, 6.45 mmol) in portion at 20 °C and stirred for 2h.
The mixture was concentrated to remove MeOH, then the mixture was diluted with H O (20 mL)
and extracted with MTBE (50 mL x 2). The water layers were acidified to pH ~ 2 with 1N HCl,
then the solution was extracted with EA (50 mL x 3). The organic layers were dried over Na SO
and concentrated to give intermediate compound 282D (390 mg, yield: 93.02%) as white solid.
H NMR (400MHz, CDCl ) δ 7.27 (s, 1H), 3.77 (s, 3H). MS (ESI) m/z (M+H) 194.8 & 196.8.
Compound 282 (50 mg, yield: 46.25%, off-white solid) was prepared as in
Example 5 from the corresponding intermediate carboxylic acid, compound 282D. Compound
282: H NMR (400MHz, DMSO-d ) δ 8.32 (dd, J = 7.7 Hz, 1H), 8.21 - 8.07 (m, 1H), 7.87 (s,
1H), 7.36 - 7.16 (m, 5H), 5.33 (s, 1H), 3.82 - 3.69 (m, 3H), 3.19 (dd, J = 13.2 Hz, 1H), 2.95 -
2.78 (m, 1H). MS (ESI) m/z (M+H) 369.1 & 371.1.
EXAMPLE 160
COMPOUNDS 283-284
N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)BENZYL-1H-PYRAZOLE
CARBOXAMIDE (283)
N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)BENZYL-1H-PYRAZOLE
CARBOXAMIDE (284)
NaOH
MeOH
283C
283A
NaOH N
MeOH
284A
283B
To a mixture of ethyl 1H-pyrazolecarboxylate (1 g, 7.14 mmol)
and benzyl bromide (0.93 mL, 7.8 mmol) in DMF (30 mL) was added K CO (1.18 g, 8.6 mmol)
in one portion at 25 °C. The mixture was stirred at 25 °C for 14h. The reaction mixture was
added H O (80 mL) and extracted by EA (50 mL x 3). The combined organic phase was washed
17681897_1 (GHMatters) P110989.NZ
with Sat. NaCl (50 mL x 2). The organic phase was dried over Na SO , filtered and
concentrated. The residue was purified by FCC (SiO , Petroleum ether/Ethyl acetate=1/0 to 3/1)
to afford compound 283A (523 mg, yield 31.7%) as colorless liquid and compound 283B (989
mg, yield 60.1%) as white solid.
Compound 283A: H NMR (DMSO-d 400 MHz) δ 7.65 (d, J = 2.0 Hz, 1H),
7.36 - 7.23 (m, 3H), 7.13 (d, J = 7.0 Hz, 2H), 6.95 (d, J = 2.0 Hz, 1H), 5.72 (s, 2H), 4.27 (q, J =
7.2 Hz, 2H), 1.26 (t, J = 7.0 Hz, 3H). MS (ESI) m/z (M+H) 231.0.
Compound 283B: H NMR (DMSO-d 400 MHz) δ 7.99 (d, J = 2.5 Hz, 1H),
7.40 - 7.29 (m, 3H), 7.28 - 7.23 (m, 2H), 6.77 (d, J = 2.3 Hz, 1H), 5.43 (s, 2H), 4.25 (q, J = 7.0
Hz, 2H), 1.27 (t, J = 7.0 Hz, 3H). MS (ESI) m/z (M+H) 231.0.
To a mixture of compound 283A (517 mg, 2.2 mmol) in MeOH (10 mL) was
added NaOH (2M, 6 mL, 12.0 mmol) in one portion at 25 °C. After stirred at 25 °C for 2h, the
reaction mixture was concentrated under reduced pressure to move MeOH, the aqueous phase
was acidified with aqueous HCl (1M) till pH ~ 4 – 5. The precipitae was filtered and dried to
afford compound 283C (389 mg, crude) as white solid, which was used directly for next step
without purification. H NMR (DMSO-d 400 MHz) δ 7.60 (d, J = 2.0 Hz, 1H), 7.34 - 7.22 (m,
3H), 7.15 - 7.08 (m, 2H), 6.88 (d, J = 2.0 Hz, 1H), 5.73 (s, 2H).
Compound 283 (177 mg, yield 89.0%) was prepared as in Example 12 from the
corresponding intermediate carboxylic acid, compound 283C. Compound 283: H NMR
(DMSO-d 400 MHz) δ 8.91 (d, J = 7.1 Hz, 1H), 8.11 (s, 1H), 7.84 (s, 1H), 7.52 (s, 1H), 7.26 (s,
8H), 7.14 - 7.01 (m, 2H), 6.89 (s, 1H), 5.60 (s, 2H), 5.40 - 5.24 (m, 1H), 3.27 - 3.13 (m, 1H),
2.95 - 2.80 (m, 1H). MS (ESI) m/z (M+H) 377.1.
Following the same procedure as is used for compound 283, compound 284 (35
mg, yield 35.7%, white solid) was prepared from the corresponding intermediate carboxylic acid,
compound 284A. Compound 284: H NMR (DMSO-d 400MHz) δ 8.18 (br d, J = 7.5 Hz, 1H),
8.05 (br s, 1H), 7.94 - 7.79 (m, 2H), 7.40 - 7.30 (m, 3H), 7.28 - 7.18 (m, 7H), 6.64 (s, 1H), 5.40
(s, 3H), 3.19 (br dd, J = 3.7, 13.7 Hz, 1H), 3.04 (br dd, J = 8.9, 13.8 Hz, 1H). MS (ESI) m/z
(M+H) 377.1.
17681897_1 (GHMatters) P110989.NZ
EXAMPLE 161
(S)METHYL-N-(1-OXOPHENYLPROPANYL)(PYRAZINYL)-1H-
PYRAZOLECARBOXAMIDE (285)
LiOH•H O
MeOH:H
2O(1:1)
°C,1 hr
285A
285C
A mixture of 2-hydrazineylpyrazine (2 g, 18.16 mmol) and ethyl 2,4-
dioxopentanoate (2.87 g, 18.16 mmol) in AcOH (40 mL) was stirred at 118 °C for 1 hour. The
reaction mixture was concentrated under reduced pressure to remove AcOH. The residue was
diluted with H O (8 mL), adjusted to pH ~ 7 with Na CO , and then extracted with DCM (200
2 2 3
mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous
Na SO , filtered and concentrated under reduced pressure to give the crude product. The residue
was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column,
Eluent of 0~20% Ethyl acetate/Petroleum ethergradient @ 40 mL/min). Compound 285A (1.5 g,
.57% yield) was obtained as a white solid. Compound 285A: H NMR (400MHz, CDCl ) δ
8.98 - 8.93 (m, 1H), 8.60 - 8.54 (m, 1H), 8.46 - 8.41 (m, 1H), 6.78 (s, 1H), 4.34 - 4.25 (m, 2H),
2.38 (s, 3H), 1.27 (t, J=7.2 Hz, 3H).
Intermediate compound 285C (1.2 g, 92.84% yield, white solid) was
deprotected as in Example 85 from compound 285A. Compound 285C: H NMR (400MHz,
DMSO-d ): δ 8.96 - 8.92 (m, 1H), 8.70 - 8.66 (m, 1H), 8.58 - 8.54 (m, 1H), 6.84 (s, 1H), 2.25 -
2.24 (m, 1H), 2.26 (s, 2H).
Compound 285 (143.0 mg, 53.28% yield, white solid) was prepared as in
Example 6 from the corresponding intermediate compounds 285C and 21G ((S)amino
phenylpropanol). Compound 285: H NMR (400MHz, CDCl ) δ 9.74 (s, 1H), 9.19 - 9.16 (m,
1H), 9.03 - 8.96 (m, 1H), 8.48 - 8.43 (m, 1H), 8.06 - 8.03 (m, 1H), 7.27 - 7.25 (m, 1H), 7.24 -
7.20 (m, 3H), 7.17 - 7.12 (m, 2H), 6.80 (s, 1H), 5.00 - 4.91 (m, 1H), 3.39 - 3.31 (m, 1H), 3.30 -
3.23 (m, 1H), 2.37 (s, 3H). MS (ESI) m/z (M+H O+H) 354.2.
17681897_1 (GHMatters) P110989.NZ
EXAMPLE 162
(S)METHYL-N-(1-OXOPHENYLPROPANYL)(PYRAZINYL)-1H-
PYRAZOLECARBOXAMIDE (286)
NaOH,
CF COONa,
MeOH/THF/H O
CuI,DMA O 2
F C 286B
Br 286A CF 286C
To a solution of compound 270A (1 g, 4.30 mmol) in DMF (20 mL) was added
NBS (1.53 g, 8.60 mmol) at 80 °C, and the mixture was stirred at 80 °C for 1.5 hrs. The mixture
was poured into water (40 mL) and extracted with ethyl acetate (20 mL x 2), the combined
organic layer was washed with saturated NaHCO (20 mL), brine (20 mL), dried over Na SO ,
3 2 4
filtered and concentrated. The residue was purified by silica gel chromatography (Petroleum
ether to Petroleum ether: Ethyl acetate = 20: 1) to give compound 286A (1.3 g, yield: 97.2%) as
white solid. H NMR (400MHz, CDCl ) δ 7.49 - 7.41 (m, 3H), 7.40 - 7.34 (m, 3H), 4.16 (q, J =
7.2 Hz, 2H), 1.16 (t, J = 7.1 Hz, 3H).
A mixture of compound 286A (1 g, 3.21 mmol), CuI (1.22 g, 6.42 mmol) and
sodium 2,2,2-trifluoroacetate (4.37 g, 32.1 mmol) in DMA (20 mL) was heated to 160 °C for 5
hrs. The mixture was added ethyl acetate (30 mL), water (50 mL), 1N HCl (50 mL), the mixture
was filtered, and the filtrate was separated. The organic solvent was washed with water (30 mL),
brine (30 mL), dried over Na SO , filtered and concentrated. The residue was purified by MPLC
(Petroleum ether to Petroleum ether: Ethyl acetate = 30: 1) to give compound 286B (210 mg,
yield: 21.8%), as yellow oil. H NMR (400MHz, CDCl ) δ 7.85 (d, J = 1.1 Hz, 1H), 7.53 - 7.47
(m, 2H), 7.47 - 7.37 (m, 3H), 4.21 (q, J = 7.2 Hz, 2H), 1.20 (t, J = 7.1 Hz, 3H).
A mixture of compound 286B (210 mg, 699 umol) and NaOH (55.9 mg, 1.40
mmol) in THF (5 mL), EtOH (3 mL), H O (2 mL) was stirred at 10 °C for 12 hrs. The organic
solvents was removed under vacuum, the water layer was adjusted to pH ~ 5 with 1N HCl, and
extracted with ethyl acetate (20 mL), the organic layer was dried over Na SO , filtered and
concentrated to give compound 286C (160 mg, yield: 84%), as yellow solid. H NMR (400MHz,
CDCl ) δ 7.81 (d, J = 1.1 Hz, 1H), 7.46 - 7.41 (m, 2H), 7.40 - 7.31 (m, 3H).
17681897_1 (GHMatters) P110989.NZ
Compound 286 (28.3 mg, yield: 45.5%, white solid) was prepared as in
Example 5 from the corresponding starting materials, compounds 286C and 3-aminohydroxy-
4-phenyl-butanamide (274D). Compound 286: H NMR (400MHz, CDCl ) δ 7.76 (s, 1H), 7.61 -
7.38 (m, 5H), 7.26 - 7.16 (m, 3H), 6.80 (br d, J = 5.6 Hz, 2H), 6.70 (br s, 1H), 6.01 (br d, J = 5.9
Hz, 1H), 5.61 - 5.47 (m, 2H), 3.24 (dd, J = 5.0, 14.2 Hz, 1H), 2.93 (dd, J = 7.6, 14.2 Hz, 1H).
MS (ESI) m/z (M+H) 447.1.
EXAMPLE 163
(S)METHYL-N-(1-OXOPHENYLPROPANYL)(PYRAZINYL)-1H-
PYRAZOLECARBOXAMIDE (287)
NH O
O O 2
F C N
F C N 3
t-BUOK
NH OAc, EtOH O
CH COOC H
3 2 5 78 °C, 2 hrs
287C
°C, 0.25 hr
287A 287B
NH O
HOAc:
3 DCE
PhI(OAc)2
(2:1) LiOH.H O
90 C
DCE MeOH-H 25 °C
O O O O,
2 hrs
0-25 6.5 hrs
C, 0.5 hr
287D
287F
287E
To a solution of 6-(trifluoromethyl)picolinic acid (10 g, 52.33 mmol) in MeOH
(150 mL) was added H SO (1.03 g, 10.47 mmol, 557.88 uL) dropwise. After stirred at 65 °C for
hours, the mixture was cooled to room temperature, neutralized with a saturated aqueous
NaHCO solution, and extracted with CH Cl (70 mL x 3). The organic phases were combined,
3 2 2
dried with anhydrous Na SO , and evaporated to afford crude intermediate compound 287A
(9.20 g, 85.71% yield) as white solid. H NMR (400 MHz, CDCl ) δ 8.32 (d, J = 8.0 Hz, 1H),
8.09 – 8.05 (m, 1H), 7.88 (d, J = 8.0 Hz, 1H), 4.03 (s, 3H).
A solution of compound 287A (4.5 g, 21.94 mmol) in CH COOC H (150 mL)
3 2 5
was added t-BuOK (3.20 g, 28.52 mmol). The mixture was stirred for 0.25 hour at 25 °C. The
mixture was quenched with H O (150 mL). The organic layer was separated and the aqueous
was extracted with EA (70mL x 3). The organic phases were combined, dried with anhydrous
Na SO , filtered and evaporated to afford intermediate compound 287B (3.95 g, 66.86% yield) as
yellow oil. H NMR (400 MHz, CDCl ) δ 8.24 (d, J = 8.0 Hz, 1H), 8.09 – 8.06 (m, 1H), 7.87 (d,
J = 7.2 Hz, 1H), 4.22 – 4.16 (m, 4H), 1.26 – 1.23 (m, 3H).
17681897_1 (GHMatters) P110989.NZ
To a solution of compound 287B (3.90 g, 14.93 mmol) in EtOH (80 mL) was
added NH OAc (5.75 g, 74.65 mmol), then the mixture was stirred at 78 °C for 2 hours. The
reaction mixture was concentrated under reduced pressure to remove the solvent. The residue
was diluted with EA (500 mL) and washed with saturated aqueous NaHCO solution (30 mL x 3)
and brine (30 mL x 3). The organic layer were dried over anhydrous Na SO , filtered and
concentrated under reduced pressure to give a residue. The residue was purified by flash column
chromatography (PE:EA=30/1 to 10/1) to afford compound 287C (2.52 g, 64.87% yield) as white
solid. H NMR (400 MHz, CDCl ) δ 7.94 – 7.93 (m, 2H), 7.73 – 7.71 (m, 1H), 5.38 (s, 1H), 4.23
– 4.18 (m, 2H), 1.33 – 1.29 (m, 3H).
To a mixture of compound 287C (2.5 g, 9.61 mmol) in DCE (60.00 mL) was
added PhI(OAc) (4.02 g, 12.49 mmol) at 0 °C under N in four portions, the mixture was stirred
at 0 °C for 6h and then warmed to 25 °C slowly. The mixture was then stirred at 25 °C for 0.5h.
The reaction mixture was quenched with saturated aqueous NaHCO (150 mL) at 0 °C, warmed
to 25 °C slowly, and extracted with DCM (100 mL x 3). The combined organic layers were dried
over anhydrous Na SO filtered and concentrated under reduced pressure to give a residue. The
2 4,
residue was purified by flash column chromatography (PE: EA=20/1 to 10/1) to afford compound
287D (650 mg, 21.23% yield) as yellow oil. H NMR (400 MHz, CDCl ) δ 8.34 – 8.18 (m, 1H),
8.16 – 8.13(s, 1H), 7.96 – 7.90 (m, 1H), 4.28 – 4.23 (m, 2H), 2.13 (s, 3H), 1.28 – 1.23 (m, 3H).
A mixture of compound 287D (600 mg, 1.89 mmol) in DCE (5 mL) and
CH3COOH (10 mL) was stirred at 90 °C for 2 hours. The reaction mixture was concentrated
under reduced pressure to remove the solvent and to give the residue. The residue was purified
by flash column chromatography (PE:EA=30/1 to 10/1) to afford compound 287E (120 mg,
221.31 umol, 11.71% yield, 55.37% purity)as yellow solid. H NMR (400 MHz, CDCl ) δ 8.42
– 8.33 (m, 1H), 8.17 – 8.15 (m, 1H), 7.99 – 7.26 (m, 1H), 4.40 – 4.37 (m, 2H), 2.62 (s, 3H), 1.35
– 1.32 (m, 3H).
To a soluton of compound 287E (110 mg, 366.39 umol) in MeOH (6 mL) and
H O (3mL) was added LiOH.H O (61 mg, 1.47 mmol), then the mixture was stirred at 25 °C for
0.5 hour. The reaction mixture was concentrated under reduced pressure to remove MeOH. The
residue was diluted with H O (20 mL), adjusted to pH ~ 3 with 1N HCl, then extracted with
EtOAc (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over
17681897_1 (GHMatters) P110989.NZ
anhydrous Na SO , filtered and concentrated under reduced pressure to give intermediate
compound 287F (86 mg, 59.17% yield) as a white solid. H NMR (400 MHz, DMSO-d ) δ 8.45
– 8.26 (m, 2H), 8.10 – 8.07 (m, 1H), 2.58 (s, 3H).
Compound 287 (12.1 mg, 20.26% yield, off-white solid) was prepared as in
Example 5 from the corresponding starting materials, compounds 287F and 3-aminohydroxy-
4-phenyl-butanamide (274D). Compound 287: H NMR (400 MHz, CDCl ): δ 11.10 (d, J=7.2
Hz, 1H), 8.46 (d, J=8.0 Hz, 1H), 8.18 – 7.99 (m, 1H), 7.72 (d, J=8.0 Hz, 1H), 7.23 - 7.04 (m, 5H),
6.70 (br s, 1H), 5.64 - 5.52 (m, 1H), 5.45 (br s, 1H), 3.57 - 3.47 (m, 1H), 3.10 – 2.94 (m, 1H),
2.55 (d, J=0.80 Hz, 3H). MS (ESI) m/z (M+1) 447.2.
EXAMPLE 164
COMPOUNDS 288-289
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)(PYRIDIN
YL)ISOXAZOLECARBOXAMIDE (288)
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)(4-
FLUOROPHENYL)ISOXAZOLECARBOXAMIDE (289)
N Cl
288D
COOEt
NCS LiOH, O
N N O
DMF TEA, THF
THF, H
288A O O
288C
288B
N Cl
LiOH H O
COOEt
THF, H O
TEA, THF
289C
289B
289D
289A
NH OH.HCl (156 mg, 2.24 mmol) and NaOAc (184 mg, 2.24 mmol) was
added in a solution of picolinaldehyde (200 mg, 1.87 mmol) in EtOH (15 mL). The mixture was
heated at 60 °C for 2 hours. The reaction mixture was concentrated. Dichloromethane (50 mL)
was added. The organic phase was washed with H O (10 mL) and brine (10 mL), dried with
anhydrous Na SO , filtered and concentrated in vacuum to give intermediate compound 288A
(180 mg, yield: 78.8%) as a yellow solid. H NMR (400MHz, CDCl ) δ 9.47 (br s, 1H), 8.57 (br
17681897_1 (GHMatters) P110989.NZ
d, J = 4.2 Hz, 1H), 8.50 (br d, J = 4.4 Hz, 1H), 8.26 (s, 1H), 7.85 (t, J = 7.7 Hz, 1H), 7.76 (d, J =
7.9 Hz, 1H), 7.69 - 7.62 (m, 1H), 7.40 - 7.32 (m, 1H), 7.26 - 7.17 (m, 1H).
To a mixture of compound 288A (180 mg, 1.47 mmol) in DMF (2 mL) was
added NCS (216 mg, 1.62 mmol) in one portion at 20 °C. The mixture was stirred at 20 °C for
12 hours. The reaction mixture was concentrated. The residue was poured into water (20 mL).
The aqueous phase was extracted with ethyl acetate (50 mL x 3). The combined organic phase
was washed with brine (20 mL x 2), dried with anhydrous Na SO , filtered and concentrated in
vacuum to give intermediate compound 288B (200 mg, yield: 87.1%) as a brown solid. H NMR
(400MHz, CDCl ) δ 10.79 (br s, 1H), 8.72 (d, J = 4.2 Hz, 1H), 7.94 (d, J = 8.2 Hz, 1H), 7.80 (dt,
J = 1.7, 7.8 Hz, 1H), 7.39 (ddd, J = 0.8, 5.0, 7.4 Hz, 1H), 2.79 (s, 1H).
To a mixture of ethyl 3-(dimethylamino)acrylate (92 mg, 639 umol), TEA (129
mg, 1.28 mmol) in THF (10 mL) was added a solution of compound 288B (200 mg, 1.28 mmol)
in THF (10 mL) over a period of 20 min. The mixture was stirred at 20 °C and stirred for 12
hours. The reaction mixture was concentrated. The residue was purified by preparatory-TLC
(SiO , Petroleum ether: Ethyl acetate = 1: 1) to give compound 288C (150 mg, yield: 53.8%) as
yellow oil. H NMR (400MHz, CDCl -d) δ 9.02 - 8.97 (m, 1H), 8.75 (d, J = 4.6 Hz, 1H), 7.87 -
7.76 (m, 2H), 7.45 - 7.36 (m, 1H), 4.27 (q, J = 7.3 Hz, 2H), 1.26 (t, J = 7.2 Hz, 3H).
To a mixture of compound 288C (150 mg, 687 umol) in THF (5 mL) and H O
(1 mL) was added LiOH.H2O (58 mg, 1.4 mmol). The mixture was stirred at 15 °C for 12 hours.
The mixture was concentrated to remove solvent. The mixture was adjusted to pH ~ 5 with
aqueous HCl (1M) and concentrated to give intermediate compound 288D (130 mg, yield:
99.5%) as a brown solid. H NMR (400MHz, DMSO-d ) δ 9.57 (s, 1H), 8.76 (d, J = 4.9 Hz, 1H),
8.11 - 8.05 (m, 2H), 7.65 (dt, J = 3.1, 5.3 Hz, 1H).
Compound 288 (73.8 mg, yield: 81.7%, yellow solid) was prepared as in
Example 5 from the corresponding intermediate carboxylic acid, compound 288D. Compound
288: H NMR (400MHz, DMSO-d ) δ 11.10 (br d, J = 7.0 Hz, 1H), 9.44 (s, 1H), 8.46 (d, J = 4.4
Hz, 1H), 8.11 - 8.01 (m, 2H), 7.81 (br s, 1H), 7.65 - 7.51 (m, 2H), 7.17 - 7.08 (m, 5H), 5.62 -
.52 (m, 1H), 3.27 (dd, J = 5.0, 13.8 Hz, 1H), 3.13 - 3.06 (m, 1H). MS (ESI) m/z (M+H) 365.1.
Following the procedure used for compound 288, compound 289 (83.1 mg,
yield: 70.9%, white solid) was prepared from the corresponding intermediate carboxylic acid,
17681897_1 (GHMatters) P110989.NZ
compound 289D. Intermediate compound 289D (100 mg, yield: 56.8%, white solid): H NMR
(400MHz, DMSO-d ) δ 9.55 (s, 1H), 7.89 - 7.81 (m, 2H), 7.39 - 7.28 (m, 2H). Compound 289:
H NMR (400MHz, DMSO-d ) δ 9.32 (s, 1H), 9.10 (d, J = 7.6 Hz, 1H), 8.11 (s, 1H), 7.86 (s, 1H),
7.65 - 7.56 (m, 2H), 7.33 - 7.21 (m, 7H), 5.40 - 5.29 (m, 1H), 3.19 (dd, J = 3.9, 13.9 Hz, 1H),
2.84 (dd, J = 10.0, 13.9 Hz, 1H). MS (ESI) m/z (M+H) 382.1.
EXAMPLE 165
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)METHYLPHENYL-1H-
IMIDAZOLECARBOXAMIDE (290)
NaOH
O PhB(OH)2
THF,H O
Cu(OAc)2,Pyridine
290A DCE N
290B N
290C
A mixture of ethyl 2-chlorooxobutanoate (16 g, 97.2 mmol), formamide
(43.8 g, 972 mmol), H O (3.50 g, 194 mmol) in autoclave was stirred at 180 °C for 3.5 hours.
The reaction mixture was filtered and the filtered cake was dissolved in DCM (200 mL). The
mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue.
Compound 290A (2 g, crude) was obtained as a yellow solid. MS (ESI) m/z (M+H) 154.8.
A mixture of 290A (1.8 g, 11.7 mmol), phenylboronic acid (2.85 g, 23.4
mmol), Cu(OAc) (3.18 g, 17.5 mmol), pyridine (1.85 g, 23.4 mmol) and 4A° MS (2 g) in DCE
(60 mL) was degassed and purged with O for 3 times, and then the mixture was stirred at 60 °C
for 12 hours under O atmosphere. The reaction mixture was filtered and concentrated under
reduced pressure to give a residue. The residue was purified by column chromatography
(Petroleum ether: Ethyl acetate = 50: 1 to 2: 1). Compound 290B (1.15 g, yield: 42.7%) was
obtained as a yellow solid. H NMR (400MHz, CDCl ) δ 7.53 (s, 1H), 7.45 - 7.35 (m, 3H), 7.27
- 7.16 (m, 2H), 4.18 - 4.05 (m, 2H), 2.53 (s, 3H), 1.10 (t, J = 7.1 Hz, 3H). MS (ESI) m/z
(M+H) 231.0 .
A mixture of 290B (300 mg, 1.30 mmol), LiOH.H O (109 mg, 2.60 mmol) in
THF (10 mL), H O (10 mL) was stirred at 15 °C for 12hrs. LCMS showed most of 290B was
remained. To the mixture was added NaOH (416 mg, 10.4 mmol), and the mixture was stirred at
70°C for 12hrs. The reaction mixture was added aq. HCl to adjust the pH ~5. And then the
17681897_1 (GHMatters) P110989.NZ
mixture was filtered, and the filter cake was concentrated to give the product. Compound 290C
(300 mg, crude) was obtained as a yellow solid. H NMR (400MHz, DMSO-d ) δ 7.90 (s, 1H),
7.50 - 7.37 (m, 3H), 7.36 - 7.28 (m, 2H), 2.39 (s, 3H). MS (ESI) m/z (M+H) 203.1.
Compound 290 (15.3 mg, yield: 11.5%, white solid) was prepared as in
Example 5 from the corresponding intermediate carboxylic acid, compound 290C. Compound
290: H NMR (400MHz, DMSO-d ) δ 8.23 (br d, J = 7.0 Hz, 1H), 7.73 (s, 1H), 7.80 - 7.56 (m,
1H), 7.41 - 7.13 (m, 11H), 5.31 (br s, 1H), 3.20 (dd, J =3.7, 13.8 Hz, 1H), 2.92 - 2.80 (m, 1H),
2.18 - 2.13 (m, 3H). MS (ESI) m/z (M+H) 377.2.
EXAMPLE 166
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)CHLOROPHENYL-1H-
IMIDAZOLECARBOXAMIDE (291)
LiOH O
THF,H O
O 80 O 2
CH CN
C, 3 OH
291A
Cl 291B
291C
A mixture of ethyl 1H-imidazolecarboxylate (10 g, 71.4 mmol),
phenylboronic acid (13.1 g, 107 mmol), Cu(OAc) (19.4 g, 107 mmol), pyridine (11.3 g, 142.72
mmol) and 4A MS (4.0 g) in DCE (200 mL) was degassed and purged with O for 3 times, and
then the mixture was stirred at 60 °C for 12 hours under O atmosphere. The reaction mixture
was filtered and concentrated under reduced pressure to give a residue. The residue was purified
by column chromatography (SiO , Petroleum ether: Ethyl acetate = 20: 1 to 5: 1). Compound
291A (2.8 g, yield: 18.2%) was obtained as a yellow solid. (Note: The structure was confirmed
by NOE). H NMR (400MHz, CDCl ) δ 7.79 (s, 1H), 7.63 (s, 1H), 7.47 - 7.33 (m, 3H), 7.32 -
7.22 (m, 2H), 4.14 (q, J = 7.2 Hz, 2H), 1.16 (t, J = 7.1 Hz, 3H).
To a solution of 291A (1 g, 4.62 mmol) in CH CN (20 mL) was added NCS
(925 mg, 6.93 mmol) at 80 °C. The mixture was stirred at 80 °C for 2hrs. The reaction mixture
was concentrated under reduced pressure to give a residue. The residue was dissolved in DCM
(50 mL), filtered, and the filtrate was concentrated under reduced pressure to give a residue. The
residue was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate = 80:1 to
50:1) and then purified by preparatory-TLC (Petroleum ether: Ethyl acetate= 3:1). Compound
17681897_1 (GHMatters) P110989.NZ
291B (150 mg, yield: 13.0%) was obtained as a yellow oil. (Note: The structure was confirmed
by HMBC). H NMR (400MHz, CDCl ) δ 7.77 - 7.62 (m, 1H), 7.54 - 7.37 (m, 3H), 7.29 - 7.10
(m, 2H), 4.09 (q, J = 7.1 Hz, 2H), 1.11 (t, J = 7.2 Hz, 3H).
A mixture of 291B (150 mg, 598 umol), LiOH.H O (50.2 mg, 1.20 mmol) in
THF (5 mL), H O (5 mL) was stirred at 15 °C for 12 hours. The reaction mixture was added aq.
HCl to adjust the pH ~ 5. And then the mixture was filtered, and the filter cake was concentrated
to give the product. Compound 291C (130 mg, crude) was obtained as a white solid. H NMR
(400MHz, DMSO-d ) δ 7.45 (br d, J = 2.2 Hz, 4H), 7.29 (br s, 2H). MS (ESI) m/z (M+H) 222.8 .
Compound 291 (47.1 mg, yield: 47.6%, brown solid) was prepared as in
Example 5 from the corresponding intermediate carboxylic acid, compound 291C. Compound
291: H NMR (400MHz, DMSO-d ) δ 8.74 (br d, J = 7.7 Hz, 1H), 8.02 (br s, 1H), 7.79 (br s, 1H),
7.66 (s, 1H), 7.43 (br d, J = 4.0 Hz, 3H), 7.37 - 7.10 (m, 7H), 5.16 (br t, J = 6.8 Hz, 1H), 3.13 (br
d, J = 10.8 Hz, 1H), 2.86 - 2.68 (m, 1H). MS (ESI) m/z (M+H) 397.1 .
EXAMPLE 167
(2S,4R)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)METHYL
PHENYLPYRROLIDINECARBOXAMIDE (292)
B(OH)2
NaOH
OEt OH
Pyridine
Cu(OAc)2
292A
292B
292C
To the mixture of 1-(tert-butyl) 2-ethyl (2S,4R)methylpyrrolidine-1,2-
dicarboxylate (2 g, 7.77 mmol) in EtOAc (5 mL) was added HCl/EtOAc (4M, 20 mL) at 25 °C.
The mixture was stirred at 25 °C for 10h. The mixture was concentrated to get residue and
saturated aqueous Na CO (1.5 mL) was added to the residue, then DCM (200 mL) was added.
Then the mixture was dried with anhydrous Na SO , filtered and concentrated in vacuum to get
crude compound 292A (1.9 g, crude) as yellow oil. H NMR (400MHz, CDCl ) δ 8.76 (br s, 2H),
.29 (s, 1H), 4.48 (dd, J = 4.1, 9.2 Hz, 1H), 4.27 (q, J = 7.2 Hz, 2H), 3.73 (dd, J = 7.4, 11.3 Hz,
1H), 2.95 (dd, J = 9.1, 11.3 Hz, 1H), 2.48 - 2.28 (m, 2H), 2.05 - 1.95 (m, 1H), 1.31 (t, J = 7.2 Hz,
3H), 1.13 (d, J = 6.6 Hz, 3H).
17681897_1 (GHMatters) P110989.NZ
To a mixture of compound 292A (1.9 g, 12.1 mmol) and phenylboronic acid
(2.95 g, 24.2 mmol) in DCE (15 mL) was added 4A° MS (4 g), pyridine (1.91 g, 24.2 mmol),
Cu(OAc) (3.29 g, 18.1 mmol) in one portion at 25 °C. The mixture was stirred at 60°C for 10 h
under O (15psi). The reaction was filtered and the filtrate was concentrated in vacuum. The
residue was purified by silica gel chromatography (petroleum ether/ethyl acetate = 100/1, 50/1) to
get compound 292B (900 mg, yield: 31.9%) as light oil. H NMR (400MHz, CDCl ) δ 7.42 -
7.32 (m, 2H), 7.29 - 7.17 (m, 3H), 4.28 - 4.08 (m, 3H), 3.67 (t, J = 8.0 Hz, 1H), 2.90 (t, J = 8.7
Hz, 1H), 2.69 - 2.55 (m, 1H), 2.24 - 2.14 (m, 1H), 1.96 - 1.83 (m, 1H), 1.24 (t, J = 7.1 Hz, 3H),
1.12 (d, J = 6.6 Hz, 3H).
To the mixture of compound 292B (300 mg, 1.29 mmol) in EtOH (5 mL) and
H O (1 mL) was added NaOH (129 mg, 3.23 mmol) at 25 °C. The mixture was stirred at 25°C
for 10h. The reaction was concentrated and the aqueous phase was extracted with ethyl acetate
(15 mL x 2). Then to the aqueous phase was added HCl (1M) till pH ~ 3. Desired product was
extracted with ethyl acetate (15 mL x 2). The combined organic phase was washed with brine (20
mL x 2), dried with anhydrous Na SO , filtered and concentrated in vacuum to get crude
compound 292C (100 mg, crude) as yellow oil.
Compound 292 (12.7 mg, yield: 25.5%, off-white solid) was prepared as in
Example 5 from the corresponding intermediate carboxylic acid, compound 292C. Compound
292: H NMR (400MHz, CDCl ) δ 7.30 - 7.19 (m, 4H), 7.16 - 7.09 (m, 1H), 7.09 - 6.97 (m, 3H),
6.88 - 6.77 (m, 2H), 6.73 (br s, 1H), 6.55 (dd, J = 8.2, 18.3 Hz, 2H), 5.75 - 5.61 (m, 1H), 5.61 -
.36 (m, 1H), 4.04 - 3.92 (m, 1H), 3.65 - 3.47 (m, 1H), 3.42 (dd, J = 5.0, 14.0 Hz, 1H), 3.23 -
3.02 (m, 1H), 2.90 (dd, J = 8.9, 14.0 Hz, 1H), 2.82 - 2.68 (m, 1H), 2.41 - 2.29 (m, 1H), 2.28 -
2.04 (m, 1H), 2.03 - 1.89 (m, 1H), 1.88 - 1.70 (m, 1H), 1.13 - 1.00 (m, 3H). MS (ESI) m/z
(M+H) 380.2.
17681897_1 (GHMatters) P110989.NZ
EXAMPLE 168
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)PHENYL-1,2,5-
OXADIAZOLECARBOXAMIDE (293)
293B
293A 293C
To a solution of methyl cinnamate (1 g, 1 eq) in pyridine (20 mL) was added
NOBF (2.34 g, 3.2 eq) at 0°C. The reaction mixture was stirred at 0°C for 2 days. The solution
was poured into ice water and extracted with EtOAc (3 times). The combined organic phase was
washed with water, dried over NaSO and concentrated under reduced pressure. The residue was
purified on ISCO to afford compound 293A.
The solution of compound 293A (0.5 g) in trimethyl phosphite (5 mL) was
heated at 100°C under N overnight. The reaction was cooled to room temperature and quenched
with 1N HCl (10 mL). The mixture was extracted with EtOAc (3 times). The combined organic
phase was washed with water, dried over NaSO and concentrated under reduced pressure. The
residue was purified on ISCO to afford compound 293B.
Compound 293 was prepared as in Example 5 from the corresponding acid,
intermediate compound 293C, which was obtained by treating compound 293B (720mg) with
LiOH in MeOH and water. H NMR (400 MHz, DMSO): δ 9.81 (d, 1H), 8.22 (s, 1H), 7.95 (s,
1H), 7.6 - 7.2 (m, 10H), 5.53 (m, 1H), 3.25 (dd, 1H), 2.83 (dd, 1H) ppm. MS (ESI) m/z (M+Na)
387.2.
EXAMPLE 169
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)METHYL(1-METHYL-1H-
BENZO[d]IMIDAZOLYL)-1H-PYRAZOLECARBOXAMIDE (294)
N H H O
NaOH
2 4. 2
NHNH
EtOH
AcOH, reflux MeOH/H O
N N 2
294A
294B N
N OH
294C 294E
17681897_1 (GHMatters) P110989.NZ
MeI (6.1 mL, 98.3 mmol) was added to a mixture of 2-chloro-1H-
benzo[d]imidazole (5.0 g, 32.8 mmol) and K CO (13.6 g, 98.3 mmol) in DMF (20 mL). The
mixture was stirred at 25 °C for 1h. The insoluble substance was removed by filtration and the
filtrate was treated with EA (50 mL), H O (50 mL). The organic layer was separated and the
aqueous layer was extracted with EA (35 mL x 3). The combined organic layer was washed with
H O (35 mL x 2), brine (35 mL x 2), dried over MgSO , filtered and concentrated. The residue
was triturated with TBME/PE (v/v = 1/1, ~20 mL) to afford compound 294A (3.3 g, yield
60.38%) as pale yellow solid. H NMR (DMSO-d 400 MHz) δ 7.60 - 7.56 (m, 2H), 7.31 - 7.24
(m, 2H), 3.80 (s, 3H). MS (ESI) m/z (M+H) 167.0.
To a mixture of compound 294A (3.3 g, 19.8 mmol in EtOH (10 mL) was
added N H .H O (5.8 g, 99.1 mmol, 85% purity) in one portion. The mixture was stirred at
2 4 2
110 °C for 12h. The reaction mixture was concentrated under reduced pressure. The residue was
triturated with MTBE (20 mL), the precipitate was filtered and dried in vacuum to afford
compound 294B (2.4 g, yield 73.1%) as white solid. H NMR (DMSO-d 400 MHz) δ 7.25 -
7.21 (m, 1H), 7.17 - 7.13 (m, 1H), 6.98 - 6.89 (m, 2H), 3.45 (s, 3H).
To a mixture of compound 294B (1.0 g, 6.17 mmol) and ethyl 2,4-
dioxopentanoate (1.0 g, 6.48 mmol) in AcOH (20 mL) was stirred at 110 °C for 5h. The reaction
mixture was concentrated under reduced pressure to remove AcOH. The residue was added H O
(50 mL) and EA (50 mL), and then the mixture was acidified with saturated aqueous NaHCO till
the aqueous phase pH ~ 7-8. The separated aqueous layer was extracted with EA (100 mL x 3),
the combined organic layers were washed with saturated aqueous NaCl (150 mL), dried over
Na SO , filtered under reduced pressure to give crude product. The crude product was purified
by FCC (SiO , Petroleum ether: Ethyl acetate =1: 0 ~ 3:1) to afford compound 294C (494 mg,
yield 27.9%) as yellow liquid.
Compound 294C: H NMR (DMSO-d 400 MHz) δ 7.69 - 7.63 (m, 2H), 7.41 -
7.35 (m, 1H), 7.33 - 7.28 (m, 1H), 7.05 (s, 1H), 4.10 (q, J = 7.1 Hz, 2H), 3.55 (s, 3H), 2.32 (s,
3H), 0.99 (t, J = 7.2 Hz, 3H). MS (ESI) m/z (M+H) 285.1.
To a mixture of compound 294C (645 mg, 2.3 mmol) in MeOH (10 mL) was
added NaOH (2 M, 5.7 mL) in one portion at 25 °C. The mixture was stirred at 25 °C for 1.5h.
The reaction mixture was concentrated under reduced pressure to move MeOH, the residue was
17681897_1 (GHMatters) P110989.NZ
added H O (10 mL) and acidified with 1N HCl solution till the aqueous phase pH ~ 6 - 7. The
solid was separated and filtered under reduced pressure to afford compound 294E (482 mg,
crude) as white solid, which was used directly for the next step without purification. H NMR
(DMSO-d 400 MHz) δ 13.58 (s, 1H), 7.69 - 7.61 (m, 2H), 7.40 - 7.34 (m, 1H), 7.33 - 7.26 (m,
1H), 6.96 (s, 1H), 3.54 (s, 3H), 2.31 (s, 3H). MS (ESI) m/z (M+H) 257.0.
Compound 294 (27 mg, yield 57.7%, white solid) was prepared as in Example
from the corresponding intermediate carboxylic acid, compound 294E. Compound 294: H
NMR (CDCl 400 MHz) δ 9.98 (d, J = 6.0 Hz, 1H), 7.63 (d, J = 7.9 Hz, 1H), 7.44 - 7.29 (m,
4H), 7.04 (m, 3H), 6.99 (m, 2H), 6.90 - 6.85 (m, 1H), 6.78 - 6.71 (m, 1H), 5.74 - 5.65 (m, 1H),
3.81 (s, 3H), 3.36 (m, 1H), 3.09 (m, 1H), 2.37 (s, 3H). MS (ESI) m/z (M+H) 431.1.
EXAMPLE 170
(S)-N-(4-(CYCLOPROPYLAMINO)-3,4-DIOXOPHENYLBUTANYL)METHYL-
1-(1-METHYL-1H-BENZO[d]IMIDAZOLYL)-1H-PYRAZOLECARBOXAMIDE
(295)
Compound 295 (50.0 mg, yield: 50.16%, white solid) was prepared as in
Example 20 from the corresponding intermediate carboxylic acid, compound 294E. Compound
295: H NMR (CDCl 400 MHz) δ 9.89 - 9.76 (m, 1H), 7.66 - 7.62 (m, 1H), 7.43 - 7.37 (m, 2H),
7.36 - 7.30 (m, 1H), 7.06 - 7.00 (m, 3H), 7.00 - 6.94 (m, 2H), 6.92 - 6.85 (m, 2H), 5.77 - 5.65 (m,
1H), 3.79 (s, 3H), 3.43 - 3.32 (m, 1H), 3.13 - 3.02 (m, 1H), 2.86 - 2.73 (m, 1H), 2.37 (s, 3H),
0.91 - 0.81 (m, 2H), 0.65 - 0.52 (m, 2H). MS (ESI) m/z (M+H) 471.1.
17681897_1 (GHMatters) P110989.NZ
EXAMPLE 171
COMPOUNDS 296-297
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)(6-
METHOXYBENZO[d]THIAZOLYL)METHYL-1H-PYRAZOLE
CARBOXAMIDE (296)
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)(6-
METHOXYBENZO[d]THIAZOLYL)METHYL-1H-PYRAZOLE
CARBOXAMIDE (297)
NHNH
HOAc, reflux
S N N
296A
296C
296B
aq. NaOH
aq. NaOH
COOH
296D
297A
HCl (12 M, 5.50 mL) was added to NH NH .H O (6.9 mL, 120 mmol) with
2 2 2
stirring at 0-5 °C, followed by ethylene glycol (30 mL). Then 6-methoxybenzo[d]thiazol
amine (3.6 g, 20.0 mmol) was added in portions. The mixture was heated to 125 °C and stirred
for 3h. After cooling to room temperature, the precipitate was collected by filtration. The cake
was washed with EtOH (5 mL x 3) to afford compound 296A (3.0 g, 15.37 mmol, yield 76.8%)
was obtained as pale green solid.
A mixture of compound 296A (1.0 g, 5.1 mmol) and ethyl 2,4-dioxopentanoate
(0.7 mL, 5.1 mmol,) in HOAc (20 mL) was heated to 120 °C and stirred for 3h. The mixture was
concentrated. The residue was treated with MeOH (15 mL). The insoluble substance was
removed by filter. The filtrate was concentrated and the residue was purified by preparatory-
17681897_1 (GHMatters) P110989.NZ
HPLC to afford compound 296C (670 mg, yield 41.2%) as pale yellow solid and compound
296B (74 mg, yield 4.6% )as pink solid. The insoluble substance (0.5 g, impure) as pink solid
was treated with DCM (50 mL). The insoluble substance was removed off by filtration. The
filtrate was washed with saturated NaHCO (15 mL x 3), brine (15 mL x 2), dried over MgSO ,
filter and concentrated to afford compound 296B (0.35 g, yield 21.5%) as pink solid.
Compound 296B: H NMR (CDCl 400 MHz) δ 7.80 (d, J = 9.2 Hz, 1H), 7.30
(d, J = 2.4 Hz, 1H), 7.06 (dd, J = 2.4, 8.8 Hz, 1H), 6.72 (s, 1H), 4.42 (q, J = 6.8 Hz, 2H), 3.89 (s,
3H), 2.82 (s, 3H), 1.42 (t, J = 7.2 Hz, 3H). MS (ESI) m/z (M+H) 317.9.
Compound 296C: H NMR (CDCl 400 MHz) δ 7.80 (d, J = 8.8 Hz, 1H), 7.30
(d, J = 2.4 Hz, 1H), 7.80 (dd, J = 2.0, 8.8 Hz, 1H) 6.71 (s, 1H), 4.37 (q, J = 7.2 Hz, 2H), 3.88 (s,
3H), 2.37 (s, 3H), 1.30 (t, J = 7.2 Hz, 3H). MS (ESI) m/z (M+H) 317.9.
[1432] NaOH (2 M, 3.15 mL, 6.3 mmol) was added to a solution of
compound 296C (400 mg, 1.26 mmol,) in MeOH (15 mL). The mixture was stirred at 25 °C for
12h. The mixture was diluted with H O (50 mL) and the volatile solvent was removed by
evaporation. The resulting aqueous solution was acidified to pH ~ 3 with 1N HCl. The
precipitate was collected and azeotroped with toluene to afford compound 296D (320 mg, yield
87.8%) was obtained as white solid. H NMR (DMSO-d , 400MHz) δ 7.78 (d, J = 9.0 Hz, 1H),
7.70 (d, J = 2.6 Hz, 1H), 7.11 (dd, J = 2.5, 8.9 Hz, 1H), 6.86 (s, 1H), 3.82 (s, 3H), 2.28 (s, 3H).
Compound 296 (100 mg, yield 43.9%, pale yellow solid) was prepared as in
Example 5 from the corresponding intermediate carboxylic acid, compound 296D. Compound
296: H NMR (DMSO-d , 400MHz) δ 10.20 (br d, J = 7.3 Hz, 1H), 8.12 (s, 1H), 7.86 (br s, 1H),
7.64 (d, J=2.4 Hz, 1H), 7.56 (d, J=9.0 Hz, 1H), 7.18 (q, J = 7.8 Hz, 4H), 7.12 (br d, J=6.8 Hz,
1H), 7.05 (dd, J=2.6, 9.0 Hz, 1H), 6.73 (s, 1H), 5.59 - 5.49 (m, 1H), 3.81 (s, 3H), 3.22 (br dd,
J=4.5, 14.0 Hz, 1H), 3.02 (br dd, J=8.5, 14.4 Hz, 1H), 2.27 (s, 3H). MS (ESI) m/z (M+H)
464.1.
Following the same procedure as is used for compound 296, compound 297 (30
mg, yield 54.3%, white solid) was prepared from the corresponding intermediate carboxylic acid,
compound 297A. Compound 297: H NMR (DMSO-d , 400MHz) δ 8.55 (br d, J = 7.5 Hz, 1H),
8.12 (s, 1H), 7.88 - 7.80 (m, 2H), 7.72 (d, J = 2.6 Hz, 1H), 7.31 - 7.25 (m, 4H), 7.22 - 7.17 (m,
17681897_1 (GHMatters) P110989.NZ
1H), 7.11 (dd, J = 2.6, 8.8 Hz, 1H), 6.76 (s, 1H), 5.45 - 5.35 (m, 1H), 3.83 (s, 3H), 3.22 (br dd,
J=4.1, 13.8 Hz, 1H), 3.04 (dd, J=9.4, 13.8 Hz, 1H), 2.73 (s, 3H). MS (ESI) m/z (M+H) 464.1.
EXAMPLE 172
COMPOUNDS 298-299
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)METHYL(4-
METHYLBENZO[d]THIAZOLYL)-1H-PYRAZOLECARBOXAMIDE (298)
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)METHYL(4-
METHYLBENZO[d]THIAZOLYL)-1H-PYRAZOLECARBOXAMIDE (299)
+ N O
NHNH
HOAc, reflux N
298A
298C
298B
NaOH
NaOH
MeOH/H O
MeOH/H O
COOH
299A
298D
HCl (12M, 2.5 mL) was added to a mixture of 4-methylbenzo[d]thiazol
amine (5.0 g, 30. 5 mmol) and NH NH .H O (19.2 mL, 335 mmol) in ethylene glycol (30 mL).
2 2 2
The mixture was heated 120 °C and stirred for 5h. After cooling to room temperature,
precipitation was observed. The precipitate was collected by filtration, and washed with EtOH
(15 mL) to afford compound 298A (2.3 g, yield 41.7%) as white needle crystal. H NMR
(DMSO-d , 400MHz) δ 8.98 (br.s., 1H), 7.46 (d, J = 8.0 Hz, 1H), 7.00 (d, J = 7.6 Hz, 1H), 6.88 -
6.84 (m, 2H), 4.98 (s, 2H), 2.38 (s, 3H). MS (ESI) m/z (M+H) 179.8.
A mixture of compound 298A (1.7 g, 9.5 mmol) and ethyl 2,4-dioxopentanoate
(1.5 g, 9.5 mmol) in AcOH (30 mL) was heated to 125 °C and stirred for 3h. The mixture was
concentrated. The residue was treated with MeOH (15 mL). The insoluble substance was
removed by filtration. The filtrate was concentrated and the residue was purified by prep-HPLC
(FA) to afford compound 298B (260 mg, 9.1% yield) was obtained as yellow solid and
17681897_1 (GHMatters) P110989.NZ
compound 298C (1.12 g, yield 39.2%). The insoluble substance (1.4 g, impure) was treated with
DCM (50 mL) and saturated aqueous NaHCO (15 mL). The organic layer was separated, and
then washed with saturated NaHCO (15 mL x 2), brine (15 mL x 3), dried over MgSO , filtered
and concentrated. The residue was purified by FCC (PE/EA = 10/1) to afford compound 298B
(620 mg, 21.7% yield) as yellow solid.
Compound 298B: H NMR (CDCl , 400MHz) δ 7.71 - 7.65 (m, 1H), 7.28 (d, J
= 5.3 Hz, 2H), 6.74 (d, J=0.9 Hz, 1H), 4.43 (q, J = 7.3 Hz, 2H), 2.87 (d, J = 0.9 Hz, 3H), 2.69 (s,
3H), 1.43 (t, J = 7.2 Hz, 3H). MS (ESI) m/z (M+H) 302.0.
Compound 298C: H NMR (CDCl , 400MHz) δ 7.681 - 7.66 (m, 1H), 7.30 -
7.26 (m, 2H), 6.66 (s, 1H), 4.39 (q, J = 7.2 Hz, 2H), 2.65 (s, 3H), 2.38 (s, 3H), 1.30 (t, J = 6.8 Hz,
3H). MS (ESI) m/z (M+H) 301.9.
NaOH (2M, 2.5 mL, 5.0 mmol) was added to a solution of ethyl compound
298B (300 mg, 1.0 mmol) in MeOH (10 mL). The mixture was stirred at 25 °C for 2h. Thick
white precipitate was observed. The mixture was diluted with H O (30 mL). And the volatile
solvent was removed by evaporated. The residue was acidified to pH ~ 3 with 1N HCl. The
precipitate was collected and azeotroped with toluene to afford compound 298D (190 mg, yield
69.8%) as white solid. H NMR (DMSO-d , 400MHz) δ 13.32 (br s, 1H), 7.93 - 7.87 (m, 1H),
7.37 - 7.31 (m, 2H), 6.83 (s, 1H), 2.79 (s, 3H), 2.62 (s, 3H).
Compound 298 (35 mg, yield 42.1%, white solid) was prepared as in Example
from the corresponding intermediate carboxylic acid, compound 298D. Compound 298: H
NMR (DMSO-d 400 MHz) δ 8.60 (br d, J = 7.0 Hz, 1H), 8.14 (br s, 1H), 7.94 (br s, 1H), 7.88
(br s, 1H), 7.41 - 7.17 (m, 8H), 6.81 (s, 1H), 5.44 (br s, 1H), 3.23 (br s, 1H), 3.27 - 3.23 (m, 1H),
3.13 - 3.02 (m, 1H), 2.81 (br s, 3H), 2.65 (br s, 3H). MS (ESI) m/z (M+H) 448.1.
Following the same procedure as is used for compound 298, compound 299 (30
mg, yield 25.0%, white solid) was prepared from the corresponding intermediate carboxylic acid,
compound 299A. Compound 299: H NMR (DMSO-d 400 MHz) δ 11.49 (d, J = 6.8 Hz, 1H),
7.68 - 7.62 (m, 1H), 7.32 - 7.28 (m, 1H), 7.26 - 7.21 (m, 1H), 7.20 - 7.04 (m, 6H), 6.73 (s, 1H),
.56 - 5.43 (m, 2H), 3.55 - 3.47 (m, 1H), 3.25 - 3.16 (m, 1H), 2.39 (s, 3H), 2.36 (s, 3H). MS
(ESI) m/z (M+H) 448.1.
17681897_1 (GHMatters) P110989.NZ
EXAMPLE 173
COMPOUNDS 306-307
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)CYCLOPROPYLPHENYL-
1H-PYRAZOLECARBOXAMIDE (306)
H N NH
2 2 O O
N OH
DMP, DCM
OH N
N 12G
N NH
N NH
HBTU, TEA, DMF
306A
306B 306
Compound 306 (25 mg, 24%, white solid) was prepared as in Example 5 from
the corresponding starting materials, compounds 306A and 12G. Compound 306: MS (ESI) m/z
(M+H) 403.
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)PHENYL-1H-INDOLE
CARBOXAMIDE (307)
Compound 307 was synthesized from the corresponding starting materials
using same procedures as described earlier for compound 306.
EXAMPLE 174
COMPOUNDS 314, 494
N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)METHYL(PYRIDIN
YL)OXAZOLECARBOXAMIDE (314)
Cl O
N DCM
Cs CO ,
THF, H O O
2 3 Pd(OAc)2
314B
314A
, Tol
P(o-Tol)3
314D
314C
Na (29.55 mg, 1.29 mmol) was dissolved in MeOH (90 mg). The solution was
added to a mixture of MeOH (10 mL) and DCM (90 mL) at 0 - 5 °C and 5 mins later, 2-
chloroacetonitrile (10.2 mL, 160.7 mmol,) was added, and the mixture was stirred at 0 - 5 °C for
1.5 h. Then ethyl acetimidate hydrochloride (20 g, 128.55 mmol, HCl salt) was added at 0 - 5
°C. The slurry was allowed to warm to 20 °C and stirred for 18h. H O (50 mL) was added to the
mixture and the mixture was stirred for 15 mins to ensure the precipitate was dissolved. The
17681897_1 (GHMatters) P110989.NZ
organic layer was separated, washed with brine (30 mL), dried over MgSO , filtered and
concentrated to afford compound 314A (20.2 g, yield 88.5%) as clear oil, which was used for
next step directly. H NMR (DMSO-d 400 MHz) δ 4.87 - 4.82 (m, 1H), 4.55 - 4.46 (m, 2H),
4.39 (s, 2H), 3.71 (s, 3H).
DBU (17.2 mL, 113.75 mmol) was added to a solution of compound 314A
(20.2 g, 113.75 mmol) in DCM (100mL) slowly. The mixture was stirred at 25 °C for 1h. The
mixture was treated with 2N HCl (40 mL). The organic layer was separated and then washed
with H O (30 mL), brine (30 mL), dried over MgSO , filtered and concentrated to afford
compound 314B (13.5 g, yield 84.1%) as white solid, which was used for next step directly. H
NMR (DMSO-d 400 MHz) δ 8.68 (s, 1H), 3.76 (s, 3H), 2.42 (s, 3H).
Cs CO (4.6 g, 14.2 mmol) was added to a mixture of compound 314B (1.0 g,
7.1 mmol) and 2-iodopyridine (2.9 g, 14.2 mmol) in toluene (20.00 mL). Then P(o-tolyl) (216
mg, 0.71 mmol) and Pd(OAc) (80 mg, 0.35 mmol) was added. The mixture was de-gassed for 3
times. Then the mixture was heated to 110 °C and stirred for 18h. The mixture was filtered
through Celite; the cake was washed with EA (15 mL x 2). The combined filtrates were
concentrated. The residue was purified by Flash Column Chromatography (PE/EA = 10/1 to 1/1)
to afford compound 314C (1.0 g, yield 64.6%) as pale yellow solid. H NMR (DMSO-d 400
MHz) δ 8.69 - 8.67 (m, 1H), 8.08 - 8.06 (m, 1H), 7.96 -7.91 (m, 1H), 7.48 - 7.45 (m, 1H), 3.77
(s, 3H), 2.50 (s, 3H).
To a mixture of compound 314C (500 mg, 2.3 mmol) in THF (10 mL) and
H O (2 mL) was added KOH (1.28 g, 22.9 mmol) in one portion at 25 °C. The mixture was
stirred at 25 °C for 1.5h. The reaction mixture was concentrated under reduced pressure to move
THF. The aqueous phase was acidified with aqueous HCl (1M) till pH ~ 4-5, and then extracted
with DCM (20 mL x 5). The combined organic phase was dried over Na SO , filtered and
concentrated to afford compound 314D (600 mg, crude) as light yellow solid, which was used
directly for next step without purification. H NMR (DMSO-d 400 MHz) δ 8.84 - 8.75 (m, 1H),
8.25 - 8.19 (m, 1H), 8.06 (d, J = 8.2 Hz, 1H), 7.71 - 7.66 (m, 1H), 2.56 (s, 3H).
Compound 314 (30 mg, yield 26.2%, white solid) was prepared as in
compound 12 from the corresponding starting materials, compounds 314D and 3-amino
hydroxyphenyl-butanamide (274D). Compound 314: H NMR (CDCl 400 MHz) δ 11.59 (d,
17681897_1 (GHMatters) P110989.NZ
J = 6.2 Hz, 1H), 8.14 - 8.09 (m, 1H), 8.03 - 7.98 (m, 1H), 7.87 - 7.80 (m, 1H), 7.26 - 7.22 (m,
1H), 7.18 - 7.05 (m, 5H), 6.81 (s, 1H), 5.86 - 5.78 (m, 1H), 5.64 (s, 1H), 3.50 - 3.41 (m, 1H),
3.37 - 3.29 (m, 1H), 2.58 (s, 3H). MS (ESI) m/z (M+H) 379.1.
N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)METHYL
PHENYLOXAZOLECARBOXAMIDE (494)
Compound 494 (40 mg, yield 25.1%, white solid) was prepared as in
compound 314 from the corresponding starting materials, compounds 314B and iodobenzene
followed by using procedures as in compound 12 to obtain compound 494. Compound 494: H
NMR (CDCl 400 MHz) δ 8.20 - 7.97 (m, 3H), 7.80 (br s, 1H), 7.61 (br d, J=10.0 Hz, 1H), 7.49
- 7.34 (m, 3H), 7.31 - 7.04 (m, 5H), 6.22 (br s, 0.22H), 6.09 (br s, 0.22H), 5.46 (dt, J=4.8, 8.0 Hz,
0.75H), 4.59 (dt, J=3.0, 10.3 Hz, 0.28H), 3.27 (dd, J=5.0, 14.1 Hz, 1H), 3.11 (br dd, J=8.3, 14.1
Hz, 1H), 2.54 - 2.50 (m, 3H). MS (ESI) m/z (M+H) 378.1.
EXAMPLE 175
(S)METHYL-N-(1-OXOPHENYLPROPANYL)PHENYL-1H-PYRAZOLE
CARBOXAMIDE (317)
O KOH
O , K CO
Pd(dppf)Cl2 2 3
THF, MeOH, H O OH
Dioxane/H
317B
317C
317D
To a mixture of ethyl 3-iodo-1H-pyrazolecarboxylate (30 g, 112.7 mmol) in
DMF (200 mL) was added Cs CO (110.22 g, 338.28 mmol) in one portion at 25 °C. Then
iodomethane (18.83 mL, 302.45 mmol) was added. The mixture was stirred at 25 °C for 3h. The
reaction mixture was concentrated under reduced pressure to remove most of DMF. The mixture
was treated with EA (100 mL) and H O (100 mL). The organic layer was separated and the
aqueous layer was extracted with EA (50 mL x 3). The combined organic layer was washed with
brine (100 mL x 2), dried over Na SO , filtered and concentrated. The residue was purified by
FCC (SiO , PE: EA = 1: 0 - 5: 1) to afford compound 317B (17.24 g, yield 54.59%) as white
solid. Compound 317B: H NMR (DMSO-d 400 MHz) δ 8.25 (s, 1H), 4.20 (q, J = 7.1 Hz, 2H),
3.87 (s, 3H), 1.29 - 1.23 (m, 3H).
17681897_1 (GHMatters) P110989.NZ
To a mixture of compound 317B (10.0 g, 35.7 mmol) and phenylboronic acid
(8.71 g, 71.4 mmol) in 1, 4-dioxane (300 mL) and H O (80 mL) was added K CO (9.87 g, 71.4
2 2 3
mmol) and Pd(dppf)Cl (2.61 g, 3.57 mmol). The mixture was degassed and purged with N for
3 times, and then stirred at 80 °C for 18h. The reaction mixture was concentrated under reduced
pressure to move 1, 4-dioxane. The mixture was added EA (150 mL), and then washed with H O
(100 mL x 3). The organic layer was dried over Na SO and concentrated. The residue was
purified by Flash Column Chromatography (SiO , Petroleum ether: Ethyl acetate=1: 0 to 3: 1) to
afford compound 317C (8.30 g, crude) as light red solid. H NMR (DMSO-d 400 MHz) δ 8.34
(s, 1H), 7.71 - 7.64 (m, 2H), 7.41 - 7.33 (m, 3H), 4.20 - 4.06 (m, 2H), 3.88 (s, 3H), 1.26 - 1.12
(m, 3H). MS (ESI) m/z (M+H) 231.0.
To a mixture of compound 317C (8.29 g, 36.0 mmol) in THF (15 mL) and
MeOH (10 mL) was added the mixture of KOH (20.20 g, 360.0 mmol) and H O (10 mL) at 25
°C. The mixture was stirred at 70 °C for 1.5h. The reaction mixture was concentrated under
reduced pressure to move MeOH and THF, the aqueous phase was acidified with concentrated
HCl (36-38 %) till pH ~ 3 - 4, precipitated solid was filtered and dried to afford compound 317D
(5.95 g, yield 81.72%) as white solid, which was used directly for the next step without
purification. H NMR (DMSO-d 400 MHz) δ 8.29 (s, 1H), 7.75 - 7.70 (m, 2H), 7.42 - 7.30 (m,
3H), 3.89 (s, 3H).
Compound 317 (1.29 g, yield 63.83%) was prepared as in Example 6 from the
corresponding intermediate compounds 317D and 21G ((S)aminophenylpropanol).
Compound 317: H NMR (DMSO-d 400 MHz) δ 9.56 (s, 1H), 8.38 (d, J = 7.5 Hz, 1H), 8.05 (s,
1H), 7.60 - 7.48 (m, 2H), 7.34 - 7.13 (m, 8H), 4.51 - 4.37 (m, 1H), 3.87 (s, 3H), 3.26 - 3.15 (m,
1H), 2.90 - 2.76 (m, 1H). MS (ESI) m/z (M+H) 334.1.
EXAMPLE 176
N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)METHYLPHENYL-1H-
IMIDAZOLECARBOXAMIDE (318)
N HO O
LiOH O
N OH
Cu(OAc)2 pyridine,
DCE, 4A° MS
318A
318B
318C
17681897_1 (GHMatters) P110989.NZ
A mixture of N'-hydroxyacetimidamide (5 g, 67.5 mmol) and ethyl prop
ynoate (8.94 g, 91.1 mmol) in MeOH (50 mL) was stirred at 65 °C for 4h. Then the solvent was
evaporated and Ph O (25 mL) was added. The reaction mixture was stirred at 250 °C for 4h.
The mixture was cooled to 70 °C and poured into MTBE (100 mL) portion-wise. The mixture
was stirred for 10 min. Filtered and the filter cake was collected. The solid was dissolved in
EtOAc (200 mL) and MeOH (50 mL). Filtered and the filtrate was collected. The filtrate was
concentrated to give the crude product as brown oil. The residue was suspended in MTBE (100
mL) and stirred for 10 mins. Filtered and the filter cake was collected to give compound 318A (2
g, yield: 19.2%) as a brown solid. H NMR (400MHz, DMSO-d ) δ 12.32 (br s, 1H), 7.72 - 7.49
(m, 1H), 4.25 - 4.10 (m, 2H), 3.33 (br d, J = 8.8 Hz, 1H), 2.33 - 2.23 (m, 3H), 1.25 (t, J = 7.2 Hz,
3H).
To a mixture of compound 318A (2 g, 13.0 mmol), phenylboronic acid (3.16 g,
.9 mmol), pyridine (2.05 g, 25.9 mmol) and 4A° molecular sieve (2 g) in DCE (50 mL) was
added Cu(OAc) (3.53 g, 19.5 mmol). The mixture was stirred at 60 °C for 12h under O (15
psi). Filtered and the filtrate was purified by silica gel chromatography eluting with Petroleum
ether: Ethyl acetate = 4: 1 to give the crude product. The crude product was then purified again
by preparatory-TLC (EtOAc, R ~ 0.5) twice to give compound 318B (160 mg, yield: 5.36%) as a
yellow solid. H NMR (400 MHz, CDCl ) δ 7.77 (s, 1H), 7.53 - 7.48 (m, 3H), 7.26 - 7.20 (m,
2H), 4.15 (q, J = 7.2 Hz, 2H), 2.24 (s, 3H), 1.19 (t, J = 7.1 Hz, 3H).
To a solution of compound 318B (100 mg, 434 umol) in THF (6 mL) and H2O
(2 mL) was added LiOH.H O (36.5 mg, 869 umol). The mixture was stirred at 15 °C for 24 hr.
TLC (EtOAc, R ~ 0) showed the reaction was completed. The pH of the mixture was adjusted
to ~ 7.0 using 1N HCl. Then solvent was removed under vacuum to give crude compound 318C
(87.0 mg, crude) as yellow oil.
Compound 318 (30.3 mg, yield: 28.0%, white solid) was prepared as in
Example 5 from the corresponding starting materials, compounds 318C and 3-aminohydroxy-
4-phenyl-butanamide (274D). Compound 318: H NMR (400MHz, CDCl ) δ 7.57 - 7.39 (m,
5H), 7.30 (br s, 2H), 7.24 - 7.17 (m, 2H), 7.11 - 6.96 (m, 2H), 6.70 (br s, 1H), 6.13 (br s, 1H),
.63 - 5.46 (m, 2H), 3.34 (dd, J = 5.5, 14.2 Hz, 1H), 3.12 (dd, J = 6.8, 14.1 Hz, 1H), 2.22 (s, 3H).
MS (ESI) m/z (M+H) 377.1.
17681897_1 (GHMatters) P110989.NZ
EXAMPLE 177
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)METHYLPHENYL-1H-
IMIDAZOLECARBOXAMIDE (319)
O SEM O
SEM O
Cl O
SEMCl/NaH
n-BuLi/THF N N
N THF/0 C-20 C N
319C
319A 319B
319D
N HO OH LiOH
HCl/EtOAc
O THF/H O
pyridine/Cu(OAc) 2 OH
12 h
DCE/60 C/
319E 319F
319C
319G
To a solution of 4-methyl-1H-imidazole (5 g, 60.9 mmol) in THF (100 mL)
was slowly added NaH (2.68 g, 67 mmol) at 0 °C. The suspension was stirred at 0 °C for 30
mins and then SEM-Cl (12.2 g, 73.1 mmol) was added. The reaction mixture was stirred at 20
°C for 12 hours. The mixture was quenched with saturated aqueous NaHCO (200 ml) and
extracted with EtOAc (300 mL x 2). The combined organics were dried over Na SO ,
concentrated to give crude product. The crude product was purified by silica gel chromatography
eluting with EtOAc to give a mixture of compound 319A and 319B (10 g, crude) as yellow oil.
To a solution of compound 319A and 319B (10 g, 47.1 mmol) in THF (40 mL)
was added n-BuLi (2.5 M, 28.3 mL) at -78 °C. The mixture was stirred at -78 °C for 1h. Ethyl
carbonochloridate (7.67 g, 70.6 mmol) was added to the solution and stirred at 20 °C for 12h.
The mixture was quenched with NH Cl (aqueous; 200 ml), extracted with EtOAc (300 mL x 2).
The combined organics were dried over Na SO , concentrated to give the crude product as
orange oil. The crude product was purified by silica gel chromatography eluting with Petroleum
ether: Ethyl acetate = 5:1 to give a mixture of compound 319C and 319D (2.9 g, crude) as yellow
oil.
A solution of 319C and 319D (2 g, 7.03 mmol) in HCl/EtOAc (50 mL) was
stirred at 20°C for 24h. LCMS showed most 319C and 319D were consumed. The solvent was
removed and the residue was extracted with EtOAc (50 ml) and water (50 mL). Then the pH of
water layer was adjusted to ~ 8.0 using saturated aqueous NaHCO and the residue was extracted
with EtOAc (50 ml x 6). The combined organics were dried over Na SO , concentrated to give
17681897_1 (GHMatters) P110989.NZ
319E (900 mg, crude) as a brown solid. The crude product was used directly in the next step. H
NMR (400 MHz, CDCl ) δ 10.42 (br s, 1H), 10.62 - 10.25 (m, 1H), 6.96 (s, 1H), 4.42 (q, J = 7.3
Hz, 2H), 2.33 (s, 3H), 1.41 (t, J = 7.2 Hz, 3H).
To a mixture of compound 319E (405 mg, 2.63 mmol), phenylboronic acid
(480 mg, 3.94 mmol), pyridine (416 mg, 5.25 mmol) and 4A° molecular sieve (500 mg) in DCE
(30 mL) was added Cu(OAc) (716 mg, 3.94 mmol). The mixture was stirred at 60 °C for 12h
under O (15 psi). Filtered and the residue was purified by silica gel chromatography eluting
with Petroleum ether: Ethyl acetate = 5:1 to give compound 319F (400 mg, crude) as a clear oil.
H NMR (400 MHz, CDCl ) δ 7.49 - 7.44 (m, 3H), 7.33 - 7.28 (m, 2H), 6.93 (s, 1H), 4.30 (q, J =
7.1 Hz, 2H), 2.35 (s, 3H), 1.31 (t, J = 7.1 Hz, 4H).
A solution of compound 319F (75 mg, 326 umol) and LiOH.H O (13.7 mg,
326 umol) in THF (3 mL) and H O (1 mL) was stirred at 15 °C for 12h. TLC (Petroleum ether:
Ethyl acetate=1:1, R ~ 0.01) and LCMS showed the reaction was completed. The pH of the
mixture was adjusted to ~ 7.0 and THF was removed by N . Then the residue was lyophilized to
give crude compound 319G (130 mg, crude) as a white solid. The crude product was used
directly in the next step. MS (ESI) m/z (M+H) 202.8.
Compound 319 (38.3 mg, yield: 42.3%, off-white solid) was prepared as in
Example 5 from the corresponding intermediate carboxylic acid, compound 319G. Compound
319: H NMR (400 MHz, CDCl ) δ 7.80 (br s, 1H), 7.41 (br s, 3H), 7.33 - 7.28 (m, 2H), 7.21 (br
d, J = 7.2 Hz, 4H), 6.85 (s, 1H), 6.70 (br s, 1H), 5.69 - 5.57 (m, 1H), 5.42 (br s, 1H), 3.39 (br dd,
J = 5.0, 14.2 Hz, 1H), 3.15 (br dd, J = 7.6, 14.1 Hz, 1H), 2.28 (s, 3H). MS (ESI) m/z (M +H)
377.2.
EXAMPLE 178
COMPOUNDS 321, 519-520
N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)(3-FLUOROPHENYL)-1,2,5-
THIADIAZOLECARBOXAMIDE (321)
NH O
S Cl , DMF LiOH
2 2 HO OH
THF/ H O
S Pd(PPh3)4
KF/toluene/H O N
321A
321B
321C
321D
17681897_1 (GHMatters) P110989.NZ
To a mixture of ethyl (E)cyano(hydroxyimino)acetate (25 g, 1.76 mol) in
EtOH (100 mL) was added PtO (2 g, 8.8 mmol). The mixture was stirred at 25 °C for 12h under
H (50 psi). Filtered and the filtrate was concentrated to give compound 321A (44 g, crude) as
red oil. The crude product was used directly in the next step.
To a solution of compound 321A (22 g, 172 mmol) in DMF (500 mL) was
added chlorosulfanyl thiohypochlorite (69.6 g, 515 mmol). The mixture was stirred at 20 °C for
12h. The mixture was poured into ice-water (1000 mL), extracted with EtOAc (500 mL x 3).
The combined organic layers were dried over sodium sulfate, filtered and concentrated under
vacuum. The crude product was purified by silica gel column chromatography eluting with
Petroleum ether: Ethyl acetate = 30:1. Compound 321B (12 g, yield: 18.1%, yellow clear oil): H
NMR (400MHz, CDCl ) δ 4.50 (q, J = 7.1 Hz, 2H), 1.46 (t, J = 7.2 Hz, 3H).
A mixture of compound 321B (1 g, 5.19 mmol) and (3-fluorophenyl)boronic
acid (1.09 g, 7.79 mmol) in H O (2 mL) and toluene (20 mL) was added KF (603 mg, 10.38
mmol) and Pd(PPh ) (300 mg, 260 umol) under N . Then the reaction mixture was stirred at
3 4 2
100 °C under N for 16 h. The solvent was evaporated. The crude product was purified by
preparatory-TLC (petroleum ether: ethyl acetate = 5:1, R = 0.69) to give compound 321C (100
mg, yield: 7.64%) as white solid.
A mixture of compound 321C (120 mg, 476 umol) in THF (4 mL) and H2O (2
mL) was added LiOH.H O (39.9 mg, 951 umol). Then the reaction mixture was stirred at 20 °C
for 16 h. 1M HCl was added to the reaction mixture until pH ~ 6. The solvent was removed
under vacuum to give crude compound 321D (100 mg, crude) as a white solid. The crude
product was used in the next step without purification. H NMR (400MHz, CDCl ) δ 7.70 - 7.50
(m, 3H), 7.36 - 7.33 (m, 1H).
Compound 321 (43.8 mg, yield: 61.6%, white solid) was prepared as in
Example 6 from the corresponding starting materials, compounds 321D and 3-aminohydroxy-
4-phenyl-butanamide (274D). Compound 321: H NMR (400MHz, DMSO-d ) δ 9.39 (d, J = 7.7
Hz, 1H), 8.16 (s, 1H), 7.91 (s, 1H), 7.48 - 7.17 (m, 8H), 5.73 (s, 1H), 5.55 - 5.43 (m, 1H), 3.21
(dd, J = 3.6, 14.0 Hz, 1H), 2.85 (dd, J = 10.0, 14.0 Hz, 1H). MS (ESI) m/z (M+H) 399.1.
17681897_1 (GHMatters) P110989.NZ
3-(2-FLUOROPHENYL)METHYL-N-(2-OXO(2-
(TRIFLUOROMETHYL)PHENYL)ETHYL)-1H-PYRAZOLECARBOXAMIDE (519)
Compound 519 (50 mg, yield: 17.5%, white solid) was prepared as in
compound 21 from the corresponding starting materials, 3-(2-fluorophenyl)methyl-1H-
pyrazolecarboxylic acid and 2-amino(2-(trifluoromethyl)phenyl)ethanol. Compound
519: H NMR (400MHz, DMSO-d ) δ 9.61 (s, 1H), 8.98 (d, J = 6.8 Hz, 1H), 8.37 (s, 1H), 7.80
(d, J = 8.0 Hz, 1H), 7.75 - 7.70 (m, 1H), 7.62 - 7.56 (m, 2H), 7.49 - 7.40 (m, 2H), 7.26 - 7.17 (m,
2H), 5.77 (d, J = 6.8 Hz, 1H), 3.95 (s, 3H). MS (ESI) m/z (M+H) 406.1.
3-(2-FLUOROPHENYL)METHYL-N-(1-OXOPHENYLPROPANYL)-1H-
PYRAZOLECARBOXAMIDE (520)
Compound 520 (60 mg, yield: 39.6%, light yellow solid) was prepared as in
compound 21 from the corresponding starting materials, 3-(2-fluorophenyl)methyl-1H-
pyrazolecarboxylic acid and 3-aminohydroxyphenyl-butanamide (274D). Compound
520: H NMR (400MHz, DMSO-d ) δ 9.56 (s, 1H), 7.93 (s, 1H), 7.47 - 7.33 (m, 2H), 7.23 - 7.08
(m, 5H), 6.95 (dd, J = 2.9, 6.6 Hz, 2H), 6.00 (d, J = 6.2 Hz, 1H), 4.70 (q, J = 6.7 Hz, 1H), 3.96
(s, 3H), 3.07 (d, J = 6.4 Hz, 2H). MS (ESI) m/z (M+H) 392.0.
EXAMPLE 179
(S)-N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)(3-
FLUOROPHENYL)ISOXAZOLECARBOXAMIDE (323)
COOEt NaOH O
N DMF
F OH
THF, H O
TEA, THF 2 OH
OH O
323A
323B O
323D
323C
To a suspension of 3-fluorobenzaldehyde (10 g, 80.6 mmol) and NH OH.HCl
(6.2 g, 88.6 mmol) in EtOH (10 mL) and H O (20 mL) was added ice (50 g). Then an aqueous
solution of NaOH (8.1 g, 201.4 mmol) in H O (20 mL) was added dropwise over a period of 10
min where upon most of the solid dissolves. Then the mixture was stirred 2 hours at 16 °C. The
resulting mixture was then acidified with HCl (5N). The mixture was then extracted with
dichloromethane (80 mL) for three times to give compound 323A (10 g, yield: 89.2%) as a light
17681897_1 (GHMatters) P110989.NZ
yellow solid. The product was used into the next step without future purification. H NMR
(400MHz, CDCl ) δ 8.13 (s, 1H), 7.95 (br s, 1H), 7.39 - 7.30 (m, 3H), 7.13 - 7.06 (m, 1H).
NCS (5.3 g, 39.5 mmol) was added to a solution of compound 323A (5 g, 35.9
mmol) in DMF (20 mL) followed by stirring at 20 °C for 3 hours. The reaction mixture was
diluted with H O (60 mL), and extracted with Ethyl acetate (100 mL x 2). The organic layers
were dried over Na SO , filtered and concentrated under reduced pressure to give compound
323B (5.7 g, yield: 91.4%) as a yellow solid. The product was used into the next step without
future purification. H NMR (400MHz, CDCl ) δ 8.21 (s, 1H), 7.66 (d, J = 7.9 Hz, 1H), 7.57 (br
d, J = 10.1 Hz, 1H), 7.43 - 7.33 (m, 1H), 7.16 (tt, J = 1.1, 8.3 Hz, 1H).
To a solution of ethyl 3-(dimethylamino)acrylate (825 mg, 5.8 mmol) and TEA
(583 mg, 5.8 mmol) in THF (15 mL) was added a solution of compound 323B (1 g, 5.8 mmol) in
THF (35 mL) dropwise over a period of 30 mins. The mixture was stirred at 16 °C for 12 hours.
The reaction mixture was concentrated under reduced pressure to give a residue. The residue
was purified by column chromatography (SiO , Petroleum ether: Ethyl acetate = 1: 0 to 30: 1) to
give compound 323C (800 mg, yield: 59%) as a pale yellow oil. H NMR (400MHz, CDCl ) δ
9.03 (s, 1H), 7.62 - 7.51 (m, 2H), 7.45 (dt, J = 5.8, 8.0 Hz, 1H), 7.25 - 7.17 (m, 1H), 4.32 (q, J =
7.1 Hz, 2H), 1.33 (t, J = 7.2 Hz, 3H).
To a mixture of compound 323C (224 mg, 952 umol) in THF (5 mL) and H O
(1 mL) was added LiOH.H2O (80 mg, 1.90 mmol). The mixture was stirred at 15 °C for 12
hours. The mixture was concentrated to remove solvent and adjusted to pH ~ 5 with aqueous
HCl (1M). The mixture was filtered and the solid was washed with H O (3 mL) to give
intermediate compound 323D (200 mg, crude) as a white solid. H NMR (400MHz, DMSO-d )
δ 9.40 (s, 1H), 7.74 (td, J = 1.9, 10.3 Hz, 1H), 7.66 (d, J = 7.7 Hz, 1H), 7.52 (dt, J = 6.2, 7.9 Hz,
1H), 7.34 (dt, J = 2.2, 8.4 Hz, 1H).
Compound 323 (68.9 mg, yield: 66.0%, white solid) was prepared as in
Example 5 from the corresponding starting materials, compounds 323D and 12G. Compound
323: H NMR (400MHz, DMSO-d ) δ 9.31 (s, 1H), 9.05 (br d, J = 7.5 Hz, 1H), 8.13 (br s, 1H),
7.87 (br s, 1H), 7.54 - 7.17 (m, 9H), 5.38 (br s, 1H), 3.26 - 3.15 (m, 1H), 2.81 (br dd, J = 10.6,
13.2 Hz, 1H). MS (ESI) m/z (M+H) 382.1.
17681897_1 (GHMatters) P110989.NZ
EXAMPLE 180
N-(4-AMINO-3,4-DIOXOPHENYLBUTANYL)(PYRIMIDINYL)ISOXAZOLE-
4-CARBOXAMIDE (324)
OH OH
N NH N N
NaNO , HCl, H O COOEt O
2 2 LiOH.H O O
N N O N
N OH
324C
324D
324B
324A
A mixture of pyrimidinecarbonitrile (10 g, 95.2 mmol), NH OH.HCl (6.94
g, 99.9 mmol) and CH ONa (5.40 g, 99.9 mmol) in MeOH (100 mL) was heated to 70 °C for 2h.
The mixture was concentrated, the residue was added water (50 mL) to give a precipitate, the
solid was filtered, washed with water (5 mL x 2), MTBE (10 mL) to give compound 324A (10.4
g, yield: 79.1%) as white solid. H NMR (400MHz, DMSO-d ) δ 10.18 (s, 1H), 8.84 (d, J = 4.9
Hz, 2H), 7.51 (t, J = 4.9 Hz, 1H), 5.84 (br s, 2H).
NaNO (1.25 g, 18.1 mmol) in H O (7 mL) was added to a solution of
compound 324A (2 g, 14.5 mmol) in HCl (40 mL) at 0 °C, the mixture was stirred at 0 °C for 2h.
The mixture was adjusted to pH ~ 6 with saturated aqueous NaHCO to give a precipitate. The
solid was filtered, washed with water (5 mL x 2) and dried to give compound 324B (1.40 g,
yield: 61.4%), as white solid. H NMR (400MHz, DMSO-d ) δ 12.95 (s, 1H), 8.92 (d, J = 4.9
Hz, 2H), 7.60 (t, J = 5.0 Hz, 1H).
A suspension of compound 324B (500 mg, 3.17 mmol) in THF (4 mL) was
added in portions to a mixture of 3-aminohydroxyphenylbutanamide (454 mg, 3.17 mmol)
and TEA (321 mg, 3.17 mmol) in THF (6 mL), the mixture was stirred at 10 °C for 12h. The
mixture was filtered and the filtrate was concentrated, the residue was purified by preparatory-
TLC (Petroleum ether: Ethyl acetate = 1: 1) to give compound 324C (300 mg, yield: 43.2%) as
yellow oil. H NMR (400MHz, CDCl3) δ 7.46 - 7.39 (m, 1H), 7.39 - 7.32 (m, 2H), 7.30 - 7.27
(m, 1H), 7.25 - 7.19 (m, 4H), 7.05 - 7.00 (m, 2H), 6.87 (br s, 1H), 5.92 - 5.85 (m, 2H), 5.40 (br s,
1H), 4.22 (dd, J = 1.3, 4.9 Hz, 1H), 4.17 - 4.09 (m, 1H), 2.92 - 2.81 (m, 2H).
A mixture of compound 324C (150 mg, 684 umol) and LiOH.H O (43.1 mg,
1.03 mmol) in THF (5 mL), EtOH (3 mL), H O (2 mL) was stirred at 10 °C for 12h. LCMS
showed desired MS, the organic solvent was removed under vacuum, the water layer was
17681897_1 (GHMatters) P110989.NZ
extracted with MTBE (5 mL) and then adjusted to pH ~ 4 with 1N HCl, the mixture was
concentrated to give crude compound 324D (130 mg, crude) as black solid.
Compound 324 (27.9 mg, yield: 62.3%, yellow solid) was prepared as in
Example 6 from the corresponding starting materials, compounds 324D and 3-aminohydroxy-
4-phenyl-butanamide (274D). Compound 324:. H NMR (400MHz, DMSO-d ) δ 10.16 (d, J =
7.3 Hz, 1H), 9.56 (s, 1H), 8.84 (d, J = 5.1 Hz, 2H), 8.13 (s, 1H), 7.88 (s, 1H), 7.66 (t, J = 5.0 Hz,
1H), 7.27 - 7.05 (m, 5H), 5.51 (dt, J = 5.0, 7.6 Hz, 1H), 3.21 (dd, J = 4.9, 14.1 Hz, 1H), 3.00 (dd,
J = 7.8, 14.0 Hz, 1H). MS (ESI) m/z (M+H) 366.1.
EXAMPLE 181
(S)-N-((S)AMINO-3,4-DIOXOPHENYLBUTANYL)PHENYLPYRROLIDINE-
2-CARBOXAMIDE (308)
N NH
308A
The mixture of L-proline (1.15 g, 1 eq) and iodobenzene (2.04 g, 1 eq), K CO
(2.07 g, 1.5 eq) and CuI (0.19 g, 0.1 eq) in DMA (15 mL) was heated to 90 °C under N
atmosphere for 48 hours. The reaction mixture was diluted with ethyl acetate and water after
cooling to room temperature and adjusted pH to ~ 3 with HCl. The organic layer was separated
and the aqueous layer was extracted with ethyl acetate (5 times). The combined organic layer
was washed with brine, dried over Na SO and concentrated. The residue was purified on ISCO
to afford compound acid 308A.
Compound 308 was prepared as in Example 5 from acid, intermediate
compound 308A. H NMR (400 MHz, DMSO): H NMR (400 MHz, DMSO): δ 8.3 - 7.5 (m,
2H), 7.38 -7 (m, 7H), 6.7 -6.2 (m, 4 H), 5.2 (m, 0.5 H), 4.35 (m, 0.5H), 3.9-3.3 (m, 3H), 3.2 - 2.8
(m, 2H) 2.2 - 1.7 (m, 4H) ppm. MS (ESI) m/z (M+H) 356.9.
EXAMPLE 182
COMPOUNDS 325-327
Compounds 325-327 were synthesized from the corresponding starting
materials using same procedures as described earlier for compound 321.
17681897_1 (GHMatters) P110989.NZ
Compound 325: N-(4-amino-3,4-dioxophenylbutanyl)(M-tolyl)-
1,2,5-thiadiazolecarboxamide: H NMR (400MHz, DMSO-d ) δ 9.42 (br d, J = 7.3 Hz, 1H),
8.17 (br s, 1H), 7.92 (br s, 1H), 7.49 (s, 1H), 7.39 - 7.13 (m, 8H), 5.55 - 5.43 (m, 1H), 3.20 (br
dd, J = 3.0, 14.2 Hz, 1H), 2.85 (br dd, J = 10.0, 14.0 Hz, 1H), 2.30 (s, 3H). MS (ESI) m/z
(M+H) 395.1.
Compound 326: N-(4-amino-3,4-dioxophenylbutanyl)(o-tolyl)-1,2,5-
thiadiazolecarboxamide: H NMR (400MHz, CDCl ) δ 7.52 (br d, J = 7.7 Hz, 1H), 7.39 -
7.32 (m, 1H), 7.31 - 7.19 (m, 6H), 7.13 (br d, J = 6.6 Hz, 2H), 6.71 (br s, 1H), 5.66 (dt, J = 5.3,
7.5 Hz, 1H), 5.59 (br s, 1H), 3.41 (dd, J = 5.1, 14.1 Hz, 1H), 3.18 (dd, J = 7.3, 14.1 Hz, 1H), 2.17
- 2.01 (m, 3H). MS (ESI) m/z (M+H) 395.1.
Compound 327: N-(4-amino-3,4-dioxophenylbutanyl)(2-
fluorophenyl)-1,2,5-thiadiazolecarboxamide: H NMR (400MHz, CDCl ) δ 7.58 - 7.41 (m,
3H), 7.33 - 7.21 (m, 4H), 7.19 - 7.08 (m, 3H), 6.74 (br s, 1H), 5.79 - 5.68 (m, 1H), 5.65 (br s,
1H), 3.50 - 3.37 (m, 1H), 3.36 - 3.23 (m, 1H). MS (ESI) m/z (M+H) 399.1.
EXAMPLE 183
COMPOUNDS 328-329
Compounds 328-329 were synthesized from the corresponding starting
materials using same procedures as described earlier for compound 317.
MeOH,THF
N OH
K PO
3 4,Pd(dtbpf)Cl2
dioxane,H O
2 589
Compound 328 was synthesized using ethyl 3-bromomethyl-1H-pyrazole
carboxylate and (3-fluorophenyl)boronic acid via intermediates 545 and 589 using the same
procedures as in compound 317. Compound 328: (S)(3-fluorophenyl)methyl-N-(1-oxo
phenylpropanyl)-1H-pyrazolecarboxamide: H NMR (400MHz, DMSO-d ) δ 9.57 (s,
1H), 8.51 (d, J = 8.0 Hz, 1H), 8.08 (s, 1H), 7.48 - 7.41 (m, 2H), 7.37 - 7.29 (m, 1H), 7.29 - 7.21
17681897_1 (GHMatters) P110989.NZ
(m, 4H), 7.21 - 7.09 (m, 2H), 4.50 - 4.42 (m, 1H), 3.88 (s, 3H), 3.24 - 3.18 (m, 1H), 2.85 - 2.77
(m, 1H). MS (ESI) m/z (M+H) 352.1.
Compound 329: (S)methyl-N-(1-oxophenylpropanyl)(M-tolyl)-
1H-pyrazolecarboxamide: H NMR (400MHz, DMSO-d ) δ 9.56 (s, 1H), 8.35 (d, J = 7.2
Hz, 1H), 8.03 (s, 1H), 7.42 (s, 1H), 7.32 (d, J = 7.6 Hz, 1H), 7.29 - 7.18 (m, 5H), 7.17 - 7.14 (m,
1H), 7.12 - 7.07 (m, 1H), 4.47 - 4.40 (m, 1H), 3.86 (s, 3H), 3.22 - 3.16 (m, 1H), 2.85 - 2.78 (m,
1H), 2.29 - 2.25 (m, 1H), 2.27 (s, 2H). MS (ESI) m/z (M+H) 348.1.
EXAMPLE 184
COMPOUNDS 330
Compound 330 was synthesized from the intermediate 250D and using same
procedures as described earlier for compound 317.
Compound 330: (S)cyclopropyl-N-(1-oxophenylpropanyl)
phenyl-1H-pyrazolecarboxamide: H NMR (400MHz, CD CN) δ 9.59 (s, 1H), 7.92 (s, 1H),
7.56 - 7.08 (m, 10H), 6.65 (s, 1H), 4.58 - 4.44 (m, 1H), 3.77 - 3.58 (m, 1H), 3.30 - 3.15 (m, 1H),
2.95 - 2.86 (m, 1H), 1.15 - 0.99 (m, 4H). MS (ESI) m/z (M+H) 360.1.
EXAMPLE 185
COMPOUNDS 331-333, 415-424
Compounds 331-333 were synthesized from the intermediate 32F and using
same procedures as described earlier for compound 168
Compound 331: (S)-N-(4-amino-3,4-dioxo(m-tolyl)butanyl)methyl-
3-phenyl-1H-pyrazolecarboxamide: H NMR (400MHz, DMSO-d ) δ 8.25 (d, J=7.3 Hz,
1H), 8.09 - 8.01 (m, 2H), 7.80 (s, 1H), 7.61 - 7.56 (m, 2H), 7.40 - 7.22 (m, 3H), 6.85 (s, 3H),
.28 (br s, 1H), 3.90 (s, 3H), 3.11 - 3.04 (m, 1H), 2.77 - 2.68 (m, 1H), 2.22 (s, 6H). MS (ESI)
m/z (M+H) 405.2.
Compound 332: (S)-N-(1-amino-1,2-dioxopentanyl)methylphenyl-
1H-pyrazolecarboxamide: H NMR (400MHz, DMSO-d ) δ 8.26 (br d, J = 6.8 Hz, 1H),
8.19 (s, 1H), 8.02 (br s, 1H), 7.76 (br s, 1H), 7.69 (br d, J = 7.0 Hz, 2H), 7.39 - 7.28 (m, 3H),
4.95 (br t, J = 10.0 Hz, 1H), 3.91 (s, 3H), 1.90 - 1.75 (m, 1H), 1.66 - 1.50 (m, 1H), 0.94 (t, J =
7.3 Hz, 3H). MS (ESI) m/z (M+H) 315.1.
17681897_1 (GHMatters) P110989.NZ
Compound 333: N-((3S,4R)aminomethyl-1,2-dioxohexanyl)
methylphenyl-1H-pyrazolecarboxamide: H NMR (400MHz, DMSO-d ) δ 8.19 (s, 1H),
8.07 - 7.94 (m, 2H), 7.75 - 7.59 (m, 3H), 7.43 - 7.27 (m, 3H), 5.06 (t, J = 6.9 Hz, 1H), 3.90 (s,
3H), 2.11 - 1.88 (m, 1H), 1.36 (ddd, J = 3.9, 7.3, 13.7 Hz, 1H), 1.20 - 1.04 (m, 1H), 0.91 - 0.79
(m, 6H). MS (ESI) m/z (M +H) 343.2.
Compound 415 (45 mg, yield: 60.98%): (S)-N-(1-aminomethyl-1,2-
dioxohexanyl)methylphenyl-1H-pyrazolecarboxamide: H NMR (400MHz,
DMSO-d ) δ 8.24 (d, J = 6.8 Hz, 1H), 8.14 (s, 1H), 8.00 (s, 1H), 7.73 (s, 1H), 7.66 (d, J = 7.4 Hz,
2H), 7.35 - 7.26 (m, 3H), 5.13 - 5.07 (m, 1H), 3.88 (s, 3H), 1.75 - 1.65 (m, 1H), 1.51 - 1.42 (m,
2H), 0.88 (d, J = 6.6 Hz, 6H). MS (ESI) m/z (M+H) 343.1.
Compound 416 (25 mg, yield: 34.6%): (S)-N-(1-amino-5,5-dimethyl-1,2-
dioxohexanyl)methylphenyl-1H-pyrazolecarboxamide: H NMR (400MHz,
DMSO-d ) δ 8.26 (d, J = 7.5 Hz, 1H), 8.13 - 8.09 (m, 1H), 8.04 (s, 1H), 7.78 - 7.66 (m, 3H), 7.38
- 7.28 (m, 3H), 5.19 (br t, J = 6.9 Hz, 1H), 3.93 - 3.87 (m, 3H), 1.61 - 1.46 (m, 2H), 0.95 (s, 9H).
MS (ESI) m/z (M+H) 357.2.
Compound 417 (25 mg, yield: 71.7%): N-(1-amino-1,2-dioxo
phenylpentanyl)methylphenyl-1H-pyrazolecarboxamide: H NMR (400MHz,
DMSO-d ) δ 8.44 (d, J = 6.8 Hz, 1H), 8.19 (s, 1H), 8.00 (s, 1H), 7.74 (s, 1H), 7.68 (d, J = 6.8 Hz,
2H), 7.36 - 7.23 (m, 5H), 7.22 - 7.14 (m, 3H), 4.99 - 4.91 (m, 1H), 3.90 (s, 3H), 2.79 - 2.69 (m,
1H), 2.67 - 2.59 (m, 1H), 2.10 - 1.99 (m, 1H), 1.87 - 1.76 (m, 1H). MS (ESI) m/z (M+H) 391.2.
Compound 418 (25.1 mg, yield: 22.25%): N-(4-amino(3,5-
dichlorophenyl)-3,4-dioxobutanyl)methylphenyl-1H-pyrazolecarboxamide: H
NMR (400MHz, DMSO-d ) δ 8.47 (d, J = 7.6 Hz, 1H), 8.05 (br. s, 1H), 7.98 (s, 1H), 7.79 (br. s,
1H), 7.55 - 7.44 (m, 3H), 7.32 - 7.21 (m, 5H), 5.25 - 5.17 (m, 1H), 3.87 (s, 3H), 3.19 - 3.11 (m,
1H), 2.88 - 2.77 (m, 1H). MS (ESI) m/z (M+H) 445.0.
Compound 419 (10 mg, yield: 17.6%): (S)-N-(1-amino-1,2-dioxoheptan
yl)methylphenyl-1H-pyrazolecarboxamide: H NMR (400MHz, DMSO-d ) δ 8.23
(br d, J = 6.6 Hz, 1H), 8.15 (s, 1H), 8.00 (s, 1H), 7.74 (s, 1H), 7.65 (br d, J = 6.6 Hz, 2H), 7.36 -
7.25 (m, 3H), 5.07 - 4.93 (m, 1H), 3.88 (s, 3H), 1.79 - 1.67 (m, 1H), 1.57 - 1.44 (m, 1H), 1.37 -
1.20 (m, 4H), 0.84 (br t, J = 6.9 Hz, 3H). MS (ESI) m/z (M+H) 343.2.
17681897_1 (GHMatters) P110989.NZ
Compound 420 (25 mg, yield: 38.7%): (S)-N-(4-amino(4-methoxyphenyl)-
3,4-dioxobutanyl)methylphenyl-1H-pyrazolecarboxamide: H NMR (400MHz,
DMSO-d ) δ 8.04 (s, 1H), 7.85 - 7.67 (m, 2H), 7.66 - 7.46 (m, 3H), 7.37 - 7.29 (m, 3H), 7.17 -
7.09 (m, 2H), 6.89 - 6.77 (m, 2H), 5.33 - 5.24 (m, 1H), 3.94 - 3.85 (m, 3H), 3.76 - 3.71 (m, 3H),
3.16 - 3.10 (m, 1H), 2.88 - 2.80 (m, 1H). MS (ESI) m/z (M+H) 407.1.
Compound 421 (10 mg, yield: 28.2%): (S)-N-(4-amino(4-hydroxyphenyl)-
3,4-dioxobutanyl)methylphenyl-1H-pyrazolecarboxamide: H NMR (400MHz,
DMSO-d ) δ 9.25 (s, 1H), 8.25 (br d, J = 7.3 Hz, 1H), 8.06 (s, 2H), 7.80 (s, 1H), 7.60 - 7.52 (m,
2H), 7.36 - 7.26 (m, 3H), 7.03 (d, J = 8.6 Hz, 2H), 6.67 (d, J = 8.6 Hz, 2H), 5.28 - 5.17 (m, 1H),
3.92 - 3.85 (m, 3H), 3.03 (dd, J = 4.1, 13.8 Hz, 1H), 2.73 - 2.68 (m, 1H). MS (ESI) m/z (M+H)
393.1.
Compound 422 (20.3 mg, yield: 27.2%): N-(1-amino-6,6,6-trifluoro-1,2-
dioxohexanyl)methylphenyl-1H-pyrazolecarboxamide: H NMR (400MHz,
DMSO-d ) δ 8.54 (br d, J = 6.8 Hz, 1H), 8.20 (s, 1H), 8.03 (br s, 1H), 7.78 (br s, 1H), 7.68 (br d,
J = 7.6 Hz, 2H), 7.39 - 7.27 (m, 3H), 5.00 - 4.90 (m, 1H), 3.91 (s, 3H), 2.43 - 2.36 (m, 2H), 2.12
- 1.98 (m, 1H), 1.87 - 1.72 (m, 1H). MS (ESI) m/z (M+1) 383.1.
Compound 423 (23 mg, yield: 35.5%): (S)-N-(4-amino(1H-indolyl)-3,4-
dioxobutanyl)methylphenyl-1H-pyrazolecarboxamide: H NMR (400MHz,
DMSO-d ) δ 10.81 (s, 1H), 8.18 (d, J = 6.8 Hz, 1H), 8.11 - 8.01 (m, 2H), 7.80 (s, 1H), 7.62 (d, J
= 7.6 Hz, 1H), 7.56 - 7.46 (m, 2H), 7.32 (d, J = 7.6 Hz, 1H), 7.28 - 7.21 (m, 3H), 7.14 - 7.08 (m,
1H), 7.08 - 7.02 (m, 1H), 6.99 - 6.93 (m, 1H), 5.39 - 5.31 (m, 1H), 3.85 (s, 3H), 3.30 - 3.23 (m,
1H), 2.96 - 2.87 (m, 1H). MS (ESI) m/z (M+H)+ 416.2.
Compound 424 (23.6 mg, yield: 24.48%): N-(5-amino-1,1,1-trifluoro-4,5-
dioxopentanyl)methylphenyl-1H-pyrazolecarboxamide: H NMR (400MHz,
DMSO-d ) δ 8.78 (d, J = 7.2 Hz, 1H), 8.14 - 8.02 (m, 2H), 7.81 (s, 1H), 7.70 - 7.63 (m, 2H), 7.39
- 7.29 (m, 3H), 5.20 - 5.13 (m, 1H), 3.91 (s, 3H), 2.97 - 2.80 (m, 1H), 2.74 - 2.60 (m, 1H). MS
(ESI) m/z (M+1) 369.1.
17681897_1 (GHMatters) P110989.NZ
EXAMPLE 186
COMPOUNDS 334-340
NaHSO MeOH, H O
NaCN, EtOAc
N 2)
334A
HCl/MeOH O O
2M NaOH
MeOH, H O
2 THF, H O N OH
N OH
334B
334C
Compound 317 was subjected to reaction conditions as used for converting
intermediate 98C to 98D to obtain the intermediate 334A (1.82 g, yield 89.9%) as white solid,
which was used directly for the next step without purification. H NMR (DMSO-d , 400 MHz) δ
8.17 - 8.05 (m, 1H), 8.03 - 7.89 (m, 1H), 7.51 - 7.40 (m, 2H), 7.29 - 7.13 (m, 8H), 6.89 - 6.76 (m,
1H), 4.69 - 4.42 (m, 1H), 4.40 - 4.26 (m, 1H), 3.85 (s, 3H), 3.10 - 2.94 (m, 1H), 2.84 - 2.60 (m,
1H). MS (ESI) m/z (M+H)+ 361.1.
To a mixture of compound 334A (1.82 g, 5.1 mmol) in MeOH (20 mL) was
added HCl/MeOH (20 mL) at 25 °C. The mixture was stirred at 25 °C for 15h. After solvent of
the reaction mixture was removed under reduced pressure, MeOH (25 mL) and H O (25 mL)
were added, and then the mixture was stirred at 25 °C for 1h. The reaction mixture was
concentrated under reduced pressure to remove solvents to afford compound 334B (2 g, crude) as
white solid, which was used directly for next step without purification.
To a mixture of compound 334B (2 g, 5.1 mmol) in THF (15 mL) and MeOH
(15 mL) was added aqueous NaOH (2M, 13 mL) at 25 °C. The mixture was stirred at 25 °C for
6h. The reaction mixture was concentrated under reduced pressure to move MeOH and THF.
H O (10 mL) was added into the mixture, which was washed with TBME (10 mL x 2), and then
the aqueous phase was acidified with aqueous HCl (1M) till pH ~ 4–5. The precipitate was
filtered and dried to afford compound 334C (1.33 g, yield 69.1%) as white solid, which was used
directly for next step without purification. H NMR (DMSO-d 400 MHz) δ 12.55 (s, 1H), 8.03
17681897_1 (GHMatters) P110989.NZ
- 7.93 (m, 1H), 7.90 - 7.39 (m, 3H), 7.32 - 7.14 (m, 8H), 5.74 - 5.25 (m, 1H), 4.54 - 4.36 (m, 1H),
4.10 - 3.94 (m, 1H), 3.85 (d, J = 4.9 Hz, 3H), 2.92 - 2.71 (m, 2H). MS (ESI) m/z (M+H) 380.1.
Compounds 334-340 were synthesized from the intermediate 334C and the
corresponding amine and using same procedures as described earlier for compound 168.
Compound 334: (S)methyl-N-(4-((oxazolylmethyl)amino)-3,4-dioxo
phenylbutanyl)phenyl-1H-pyrazolecarboxamide: H NMR (400MHz, CDCl ) δ 7.90
(s, 1H), 7.64 (s, 1H), 7.54 - 7.33 (m, 6H), 7.22 - 7.12 (m, 3H), 7.10 (s, 1H), 6.84 - 6.77 (m, 2H),
6.10 (d, J = 6.0 Hz, 1H), 5.60 - 5.46 (m, 1H), 4.76 - 4.53 (m, 2H), 3.92 (s, 3H), 3.33 - 3.22 (m,
1H), 2.96 - 2.87 (m, 1H). MS (ESI) m/z (M+H) 458.2.
Compound 335: (S)-N-(4-((2-(2-methoxyethoxy)ethyl)amino)-3,4-dioxo
phenylbutanyl)methylphenyl-1H-pyrazolecarboxamide: H NMR (CDCl 400
MHz) δ 7.89 (s, 1H), 7.53 - 7.45 (m, 2H), 7.44 - 7.29 (m, 4H), 7.18 (s, 3H), 6.80 (s, 2H), 6.09 (d,
J = 4.5 Hz, 1H), 5.58 (d, J = 4.8 Hz, 1H), 3.91 (s, 3H), 3.68 - 3.48 (m, 8H), 3.38 (s, 3H), 3.28 (d,
J = 10.3 Hz, 1H), 2.97 - 2.84 (m, 1H) . MS (ESI) m/z (M+H) 479.2.
Compound 336: (S)methyl-N-(4-((2-(methylamino)oxoethyl)amino)-
3,4-dioxophenylbutanyl)phenyl-1H-pyrazolecarboxamide: H NMR (CDCl 400
MHz) δ 7.83 (s, 1H), 7.58 - 7.32 (m, 6H), 7.18 (s, 3H), 6.82 (s, 2H), 6.32 (s, 1H), 6.11 (s, 1H),
.31 (s, 1H), 4.15 - 3.80 (m, 5H), 3.28 - 3.08 (m, 1H), 2.93 - 2.64 (m, 4H). MS (ESI) m/z (M+H)
448.2.
Compound 337: (S)-N-(4-((2-(dimethylamino)oxoethyl)amino)-3,4-dioxo-
1-phenylbutanyl)methylphenyl-1H-pyrazolecarboxamide: H NMR (CDCl 400
MHz) δ 7.92 - 7.79 (m, 2H), 7.52 - 7.44 (m, 2H), 7.44 - 7.33 (m, 3H), 7.21 - 7.11 (m, 3H), 6.85 -
6.74 (m, 2H), 6.09 (d, J = 6.3 Hz, 1H), 5.62 (q, J = 6.5 Hz, 1H), 4.18 - 3.99 (m, 2H), 3.91 (s,
3H), 3.31 - 3.22 (m, 1H), 3.01 (d, J = 3.3 Hz, 6H), 2.95 - 2.86 (m, 1H). MS (ESI) m/z (M+H)
462.2.
Compound 338: (S)-N-(4-((3-aminooxopropyl)amino)-3,4-dioxo
phenylbutanyl)methylphenyl-1H-pyrazolecarboxamide: H NMR (CDCl 400
MHz) δ 7.86 (s, 1H), 7.52 - 7.46 (m, 2H), 7.45 - 7.35 (m, 4H), 7.21 - 7.13 (m, 3H), 6.86 - 6.74
(m, 2H), 6.08 (d, J = 5.8 Hz, 1H), 5.71 (s, 1H), 5.58 - 5.46 (m, 1H), 5.34 (s, 1H), 3.91 (s, 3H),
17681897_1 (GHMatters) P110989.NZ
3.73 - 3.51 (m, 2H), 3.24 (dd, J = 4.8, 14.1 Hz, 1H), 2.86 (dd, J = 7.8, 14.3 Hz, 1H), 2.49 (t, J =
.9 Hz, 2H). MS (ESI) m/z (M+H) 448.2.
Compound 339: (S)-N-(4-((2-aminooxoethyl)amino)-3,4-dioxo
phenylbutanyl)methylphenyl-1H-pyrazolecarboxamide: H NMR (CDCl 400
MHz) δ 7.83 (s, 1H), 7.55 - 7.34 (m, 6H), 7.22 - 7.14 (m, 3H), 6.89 - 6.77 (m, 2H), 6.33 (s, 1H),
6.14 (d, J = 4.6 Hz, 1H), 5.52 (s, 1H), 5.37 - 5.19 (m, 1H), 4.12 - 4.02 (m, 1H), 3.99 - 3.94 (m,
1H), 3.90 (s, 3H), 3.28 - 3.13 (m, 1H), 2.99 - 2.77 (m, 1H). MS (ESI) m/z (M+H) 434.2.
Compound 340: Tert-butyl (S)-(2-(3-(1-methylphenyl-1H-pyrazole
carboxamido)oxophenylbutanamido)ethyl)carbamate: H NMR (CDCl 400 MHz) δ
7.89 (s, 1H), 7.50 - 7.35 (m, 5H), 7.26 - 7.23 (m, 1H), 7.20 - 7.13 (m, 3H), 6.86 - 6.70 (m, 2H),
6.09 (d, J = 6.0 Hz, 1H), 5.58 - 5.42 (m, 1H), 4.97 - 4.82 (m, 1H), 3.91 (s, 3H), 3.48 - 3.39 (m,
2H), 3.35 - 3.20 (m, 3H), 2.93 - 2.85 (m, 1H), 1.44 (s, 9H). MS (ESI) m/z (M+H) 520.3.
EXAMPLE 187
COMPOUND 341
NH N
N NH
2 HOAc,118°C,1h N N O
341B
341A
N N N N
LiOH•H O
OH O
MeOH:H HBTU,DIEA,DMF,25°C,2.1
2O(1:1) N
°C,3 hrs
341D
341C
DMSO:DCM H
(20:1)
0°C,4
Compounds 341C was synthesized from 2-hydrazinylpyrimidine and using
same procedures as described earlier for compound 38.
Compound 341 was synthesized from 341C using same procedures as
described earlier for compound 317. Compound 341: (S)methyl-N-(1-oxophenylpropan-
2-yl)(pyrimidinyl)-1H-pyrazolecarboxamide: H NMR (400MHz, CDCl ) δ 9.75 (d,
17681897_1 (GHMatters) P110989.NZ
J=1.8 Hz, 1H), 8.70 - 8.60 (m, 3H), 7.28 - 7.26 (m, 1H), 7.25 - 7.16 (m, 5H), 6.74 (s, 1H), 5.00 -
4.94 (m, 1H), 3.40 - 3.33 (m, 1H), 3.32 - 3.24 (m, 1H), 2.42 - 2.39 (m, 3H). MS (ESI) m/z
(M+H O+H) 354.2.
EXAMPLE 188
COMPOUND 342
Compounds 342 was synthesized from 2,2,3,3,3-pentafluoropropanamine
hydrochloride and using same procedures as described earlier for compound 272.
Compound 342: N-(4-amino-3,4-dioxophenylbutanyl)
(perfluoroethyl)phenyl-1H-pyrazolecarboxamide: H NMR (400MHz, DMSO-d6) δ
9.36 (d, J=7.7 Hz, 1H), 8.10 (s, 1H), 7.85 (s, 1H), 7.48 - 7.34 (m, 4H), 7.32 - 7.18 (m, 9H), 5.31 -
.24 (m, 1H), 3.24 - 3.13 (m, 1H), 2.85 - 2.69 (m, 1H). MS (ESI) m/z (M+H) 481.1.
EXAMPLE 189
COMPOUND 343
HN O
NH •HCl
343A
Compound 343 was synthesized from ethyl 1-(3-(aminomethyl)phenyl)
methyl-1H-pyrazolecarboxylate hydrochloride (343A) and using same procedures as described
earlier for compound 153. Compound 343: Benzyl (S)-(3-(5-((4-amino-3,4-dioxo
phenylbutanyl)carbamoyl)methyl-1H-pyrazolyl)benzyl)carbamate: H NMR
(400MHz, DMSO-d6) δ 9.14 - 9.05 (m, 0.4H), 8.16 - 8.00 (m, 0.9H), 7.93 - 7.82 (m, 1.3H), 7.59
- 7.06 (m, 14.2H), 7.00 - 6.87 (m, 0.5H), 6.77 - 6.64 (m, 0.5H), 6.31 - 6.50 (m, 0.9H), 6.49 - 6.40
(m, 0.4H), 6.29 - 6.17 (m, 0.4H), 5.34 - 5.23 (m, 0.4H), 5.04 (s, 1.9H), 4.53 - 4.34 (m, 0.5H),
4.31 - 4.09 (m, 1.9H), 3.24 - 2.99 (m, 0.8H), 2.90 - 2.63 (m, 1.4H), 2.30 - 2.16 (m, 3H). MS
(ESI) m/z (M+H) 540.2.
17681897_1 (GHMatters) P110989.NZ
EXAMPLE 190
COMPOUND 344
344A 344
Compound 344 was synthesized from ethyl 1-(3-(((tert-
butoxycarbonyl)amino)methyl)phenyl)methyl-1H-pyrazolecarboxylate 344A and using
same procedures as described earlier for compound 162. Compound 344: Phenyl (S)-(3-(5-((4-
amino-3,4-dioxophenylbutanyl)carbamoyl)methyl-1H-pyrazol
yl)benzyl)carbamate: H NMR (400MHz, DMSO-d6) δ 9.14 – 9.08 (m, 1H), 8.40 - 8.33 (m,
1H), 8.13 - 8.04 (m, 1H), 7.87 (s, 1H), 7.45 - 7.09 (m, 13H), 6.99 - 6.71 (m, 1H), 6.60 - 6.20 (m,
1H), 5.31 - 5.23 (m, 1H), 4.46 - 3.97 (m, 2H), 3.26 - 3.01 (m, 1H), 2.90 - 2.68 (m, 1H), 2.31 -
2.19 (m, 3H). MS (ESI) m/z (M+H) 526.2.
17681897_1 (GHMatters) P110989.NZ
EXAMPLE 191
COMPOUNDS 345-346
AcOH
346A
345A
345B
NH NH
O N 2
345B
NH NH
346A
Compounds 345 and 346 were prepared from 2-hydrazinylmethylpyridine
and methyl 2,4-dioxopentanoate using procedures for compounds 38 and 317.
Compound 345: N-(4-amino-3,4-dioxophenylbutanyl)methyl(3-
methylpyridinyl)-1H-pyrazolecarboxamide: H NMR (400MHz, CDCl ) δ 8.36 (br d, J
= 4.0 Hz, 1H), 7.67 (br d, J = 7.6 Hz, 1H), 7.33 - 7.24 (m, 2H), 7.18 - 7.05 (m, 5H), 6.67 (br s,
1H), 6.62 (s, 1H), 5.69 - 5.60 (m, 1H), 5.46 (br s, 1H), 3.35 (dd, J = 5.3, 14.0 Hz, 1H), 3.13 (dd, J
= 7.2, 14.0 Hz, 1H), 2.19 (s, 3H), 2.12 (s, 3H).
Compound 346: N-(4-amino-3,4-dioxophenylbutanyl)methyl(3-
methylpyridinyl)-1H-pyrazolecarboxamide: H NMR (400MHz, CDCl ) δ 8.23 (br d, J
= 4.6 Hz, 1H), 7.67 (d, J = 7.5 Hz, 1H), 7.33 (br d, J = 7.3 Hz, 1H), 7.26 - 7.18 (m, 4H), 7.01 (br
d, J = 3.7 Hz, 2H), 6.68 (br s, 1H), 6.57 (s, 1H), 5.62 (q, J = 6.5 Hz, 1H), 5.50 (br s, 1H), 3.34
(dd, J = 5.3, 14.1 Hz, 1H), 3.17 (dd, J = 6.5, 14.2 Hz, 1H), 2.34 (s, 3H), 2.17 (s, 3H). MS (ESI)
m/z (M+H) 392.2.
17681897_1 (GHMatters) P110989.NZ
EXAMPLE 192
COMPOUND 347
N N N
LDA,CO
,THF
K CO , DMF N
347A 347B
NCS, DMF
N N NH
Cl Cl
347C
A mixture of 2-chloropyrimidine (10 g, 87.3 mmol), 1H-pyrazole (7.73 g, 114
mmol) and K CO (24.1 g, 175 mmol) in DMF (150 mL) was heated to 120 °C for 12 hr. LCMS
showed desired MS. TLC (Petroleum ether : Ethyl acetate = 3:1, R ~ 0) showed new point, after
cooling the mixture was filtered and the filtrate was concentrated, the residue was purified by
MPLC (Petroleum ether: Ethyl acetate = 1:1) to give Compound 347A (10.4 g, yield: 81.5%) as
yellow solid. H NMR (400MHz, CDCl ) δ 8.76 (d, J = 4.8 Hz, 2H), 8.60 (d, J = 2.4 Hz, 1H),
7.84 (s, 1H), 7.21 (t, J = 4.8 Hz, 1H), 6.51 (s, 1H).
To a solution of compound 347A (500 mg, 3.42 mmol) in THF (10 mL) was
added LDA (1M, 4.45 mL) dropwise at -70 °C and stirred for 10 min, then carbon dioxide was
bubbled to the mixture for 30 min, the mixture was slowly warm to 15 °C for 20 min. The
mixture was added MTBE (20 mL) and H O (20 mL), the water layer was adjusted to pH ~ 4
with 1N HCl and extracted with ethyl acetate (20 mL x 4), the organic layer was dried over
Na SO , filtered and concentrated to give compound 347B (480 mg, yield: 73.8%) as brown
solid. H NMR (400MHz, DMSO-d ) δ 13.49 (br s, 1H), 8.94 (d, J = 4.9 Hz, 2H), 7.83 (d, J =
1.8 Hz, 1H), 7.63 (t, J = 4.9 Hz, 1H), 6.98 (d, J = 1.8 Hz, 1H).
A mixture of compound 347B (200 mg, 1.05 mmol) and NCS (154 mg, 1.16
mmol) in DMF (3 mL) was heated to 90 °C for 4 hr. LCMS showed desired MS, the mixture
was purified by preparatory-HPLC (TFA) to give compound 347C (0.2 g , yield: 56.5%) as
yellow solid. H NMR (400MHz, DMSO-d6) δ 14.05 (br s, 1H), 8.96 (d, J = 4.9 Hz, 2H), 8.07
(s, 1H), 7.66 (t, J = 4.9 Hz, 1H).
17681897_1 (GHMatters) P110989.NZ
Compound 347 was synthesized from 347C and using same procedures
described earlier for converting compound 321D to compound 321. Compound 347: N-(4-
amino-3,4-dioxophenylbutanyl)chloro(pyrimidinyl)-1H-pyrazole
carboxamide: H NMR (400MHz, DMSO-d6) δ 9.25 (d, J = 7.3 Hz, 1H), 8.67 (d, J = 4.9 Hz,
2H), 8.12 (s, 1H), 7.96 (s, 1H), 7.86 (s, 1H), 7.46 (t, J = 4.9 Hz, 1H), 7.32 - 7.15 (m, 5H), 5.50 -
.38 (m, 1H), 3.13 (dd, J = 3.6, 14.2 Hz, 1H), 2.77 (dd, J = 9.9, 14.1 Hz, 1H). MS (ESI) m/z
(M+H) 399.1.
EXAMPLE 193
COMPOUND 348
Compound 348 was synthesized from 2,3-difluoropyridine and using same
procedures described earlier for Example 313. Compound 348: N-(4-amino-3,4-dioxo
phenylbutanyl)(3-fluoropyridinyl)methyl-1H-pyrazolecarboxamide: H NMR
(400MHz, DMSO-d6) δ 8.97 (d, J = 7.5 Hz, 1H), 8.29 (d, J = 4.6 Hz, 1H), 8.07 (s, 1H), 7.92 -
7.80 (m, 2H), 7.57 (td, J = 4.2, 8.4 Hz, 1H), 7.32 - 7.25 (m, 4H), 7.21 (dt, J = 2.5, 6.1 Hz, 1H),
6.91 (s, 1H), 5.26 - 5.17 (m, 1H), 3.16 (dd, J = 3.3, 13.9 Hz, 1H), 2.91 - 2.79 (m, 1H), 2.27 (s,
3H). MS (ESI) m/z (M+H) 396.1.
EXAMPLE 194
COMPOUND 349
N N N
OH NH
349B 3 349
Compound 349B was prepared 3-(trifluoromethyl)-1H-pyrazole using the same
procedure as described for Compound 347B.
Compound 349 was synthesized from 349B and using same procedures
described earlier for converting compound 347C to compound 347. Compound 349: N-(4-
amino-3,4-dioxophenylbutanyl)(pyrimidinyl)(trifluoromethyl)-1H-pyrazole
carboxamide: H NMR (400MHz, CDCl ) δ 8.69 (br s, 2H), 8.11 (br s, 1H), 7.33 (br s, 1H),
7.38 - 7.31 (m, 1H), 7.24 (br s, 4H), 7.15 - 7.08 (m, 1H), 7.15 - 7.08 (m, 1H), 7.15 - 7.01 (m,
17681897_1 (GHMatters) P110989.NZ
1H), 6.77 (br s, 1H), 5.82 (br s, 1H), 5.63 (br s, 1H), 3.47 (br s, 1H), 3.35 (br s, 1H). MS (ESI)
m/z (M+H) 433.1.
EXAMPLE 195
COMPOUNDS 350, 457
N H , K CO
2 4 2 3
Na, EtOH
350B
350A
POCl
MnO , MeCN, LiOH H O
CH CN
O reflux N
N THF, H O
350C
Cl 350D
H N NH
O O O
N NH
HBTU, DIEA, DMF N 2
350E Cl 350F
DMP, DCM
N NH
A mixture of 2-chloropyrimidine (15 g, 131 mmol), NH NH .H O (30 mL),
2 2 2
K CO (15 g, 109 mmol) was stirred at 100 °C for 30 min. The mixture was ice cooled and the
resulting crude crystals were collected by filtration. The crystals were washed with cold water,
air dried, and recrystallized from Petroleum ether (150 mL) to give compound 350A (14.4 g, 131
mmol, yield: 99.8%) as a yellow solid. H NMR (400MHz, DMSO-d ) δ 8.30 (d, J = 4.8 Hz,
2H), 8.12 (br s, 1H), 6.59 (t, J = 4.7 Hz, 1H), 4.13 (s, 2H).
To a mixture of compound 350A (2 g, 18.2 mmol) and Na (1.46 g, 63.6 mmol)
in EtOH (60 mL) was added diethyl maleate (3.75 g, 21.8 mmol) at 15 °C. The mixture was
stirred at 60 °C for 3 hours. The reaction was cooled to 15 °C and quenched with acetic acid to
pH ~ 7. The mixture was concentrated to give residue. The residue was purified by prep-HPLC
17681897_1 (GHMatters) P110989.NZ
(TFA condition) to give compound 350B (3.5 g, 14.8 mmol, yield: 81.6%) as brown oil. H
NMR (400MHz, CDCl ) δ 8.49 (d, J = 4.9 Hz, 2H), 6.85 (t, J = 5.0 Hz, 1H), 5.23 (dd, J = 4.2,
11.0 Hz, 1H), 4.33 - 4.20 (m, 2H), 3.41 - 3.28 (m, 1H), 3.01 (dd, J = 4.2, 17.6 Hz, 1H), 2.05 -
1.96 (m, 1H), 1.32 - 1.21 (m, 3H).
To a mixture of compound 350B (3.5 g, 14.8 mmol) in MeCN (40 mL) was
added POCl (2.73 g, 17.8 mmol, 1.65 mL). The mixture was stirred at 80 °C for 12 hours. The
reaction mixture was concentrated. The residue was poured into saturated NaHCO (30 mL) and
stirred for 10 min. The aqueous phase was extracted with ethyl acetate (50 mL x 4). The
combined organic phase was dried with anhydrous Na SO , filtered and concentrated in vacuum.
The residue was purified by column chromatography (SiO , Petroleum ether: Ethyl acetate = 0:1
to 1:1) to give compound 350C (900 mg, yield: 23.9%) as a yellow solid. H NMR (400MHz,
CDCl ) δ 8.44 (d, J = 4.9 Hz, 2H), 6.75 (t, J = 4.9 Hz, 1H), 5.11 (dd, J = 6.5, 12.7 Hz, 1H), 4.27 -
4.16 (m, 2H), 3.56 (dd, J = 12.7, 18.0 Hz, 1H), 3.21 (dd, J = 6.6, 18.1 Hz, 1H), 1.23 (t, J = 7.2
Hz, 3H).
To a mixture of compound 350C (900 mg, 3.53 mmol) in MeCN (15 mL) was
added MnO (3.07 g, 35.3 mmol). The mixture was stirred at 80 °C for 12 hours. The reaction
mixture was filtered and the filtrate was concentrated. The residue was purified by column
chromatography (SiO , Petroleum ether: Ethyl acetate = 1: 0 to 0: 1) to give compound 350D
(215 mg, yield: 24.1%) as brown oil. H NMR (400MHz, CDCl ) δ 8.81 (d, J = 4.9 Hz, 2H),
7.36 (t, J = 4.9 Hz, 1H), 6.80 (s, 1H), 4.35 (q, J = 7.2 Hz, 2H), 1.31 (t, J = 7.2 Hz, 3H).
Compounds 350 were synthesized from the intermediate 350D and using same
procedures as described earlier for converting compound 38B to compound 38. Compound 350:
N-(4-amino-3,4-dioxophenylbutanyl)chloro(pyrimidinyl)-1H-pyrazole
carboxamide: H NMR (400MHz, DMSO-d ) δ 9.23 (d, J = 7.3 Hz, 1H), 8.78 (d, J = 4.9 Hz,
2H), 8.09 (s, 1H), 7.85 (s, 1H), 7.55 (t, J = 4.9 Hz, 1H), 7.33 - 7.19 (m, 5H), 6.84 (s, 1H), 5.35 -
.25 (m, 1H), 3.16 (dd, J = 3.6, 14.0 Hz, 1H), 2.82 (dd, J = 10.0, 14.0 Hz, 1H). MS (ESI) m/z
(M+H) 399.1.
Compound 457 were synthesized from the intermediate 350E and 3-amino-N-
cyclopropylhydroxyphenylbutanamide hydrochloride using same procedures as described
earlier for compound 350. Compound 457 (70.21 g, yield: 70.32%): 3-chloro-N-(4-
17681897_1 (GHMatters) P110989.NZ
(cyclopropylamino)-3,4-dioxophenylbutanyl)(pyrimidinyl)-1H-pyrazole
carboxamide: H NMR (400MHz, DMSO-d ) δ 9.29 (d, J = 7.5 Hz, 1H), 8.84 (d, J = 5.1 Hz,
1H), 8.77 (d, J = 4.9 Hz, 2H), 7.56 (t, J = 4.7 Hz, 1H), 7.32 - 7.20 (m, 5H), 6.90 (s, 1H), 5.36 -
.29 (m, 1H), 3.16 (dd, J = 3.6, 14.0 Hz, 1H), 2.83 (dd, J = 9.9, 13.9 Hz, 1H), 2.79 - 2.72 (m,
1H), 0.71 - 0.56 (m, 4H). MS (ESI) m/z (M+H) 439.1.
EXAMPLE 196
COMPOUND 351
Compound 351 was synthesized from 341C using same procedures as
described earlier for converting compound 321D to compound 321. Compound 341: N-(4-
amino-3,4-dioxophenylbutanyl)methyl(pyrimidinyl)-1H-pyrazole
carboxamide: H NMR (400MHz, DMSO-d ) δ 9.05 (d, J = 7.2 Hz, 1H), 8.71 (d, J = 4.8 Hz,
2H), 8.07 (s, 1H), 7.83 (s, 1H), 7.47 - 7.42 (m, 1H), 7.32 - 7.17 (m, 5H), 6.56 (s, 1H), 5.29 - 5.21
(m, 1H), 3.16 -3.08 (m, 1H), 2.85 - 2.77 (m, 1H), 2.25 (s, 3H). MS (ESI) m/z (M+H) 379.0.
EXAMPLE 197
COMPOUND 352
Cl N Cl N
NH NH H O, Et N
2 2 2 3
EtOH
HOAc
352A
Cl N
352C
352B
(HO)2 O
K PO
, , O
N Pd(dppf)Cl2 3 4
dioxane, H
352B
352D
N NH
352D 352
17681897_1 (GHMatters) P110989.NZ
Compound 352 was prepared from 2-chlorohydrazinylpyrimidine and ethyl
2,4-dioxopentanoate using procedures for compounds 345 and 321. Compound 352: N-(4-
amino-3,4-dioxophenylbutanyl)(2-cyclopropylpyrimidinyl)methyl-1H-
pyrazolecarboxamide: H NMR (400MHz, DMSO-d ) δ 9.10 (br d, J = 7.0 Hz, 1H), 8.62 (d,
J = 5.5 Hz, 1H), 8.12 (br s, 1H), 7.87 (br s, 1H), 7.45 (d, J = 5.5 Hz, 1H), 7.35 - 7.19 (m, 5H),
6.44 (s, 1H), 5.56 - 5.48 (m, 1H), 3.18 (br dd, J = 3.8, 13.8 Hz, 1H), 2.81 (br dd, J = 9.8, 13.8 Hz,
1H), 2.28 (s, 3H), 2.00 - 1.90 (m, 1H), 0.94 - 0.67 (m, 4H). MS (ESI) m/z (M+H) 419.2.
EXAMPLE 198
COMPOUND 353
Compound 353 was synthesized from 254D using same procedures as
described earlier for synthesis of compound 322. Compound 353: (S)(3-fluorophenyl)
methyl-N-(1-oxophenylpropanyl)oxazolecarboxamide: H NMR (400MHz, CDCl )
δ 9.71 (s, 1H), 8.05 - 7.94 (m, 2H), 7.43 - 7.27 (m, 4H), 7.21 (br d, J = 6.8 Hz, 2H), 7.13 - 7.05
(m, 1H), 6.89 - 6.84 (m, 1H), 4.98 - 4.90 (m, 1H), 3.37 - 3.31 (m, 1H), 3.29 - 3.20 (m, 1H), 2.55
(s, 3H). MS (ESI) m/z (M+H O+H) 353.1.
EXAMPLE 199
COMPOUND 354
LAH,THF
EDC,HOBt, N
0 °C, 2h
CHCl , 25 °C
354A
NaHSO
3,NaCN
K CO , H O ,
2 2 2
HN MeOH/H O/EtOAc
2 DMSO
354B
O -25 h
0 °C, 20
354C
TMSOTf,
2,6-lutidine
TMSCl/MeOH
BocHN DCM
H N Si
O NH
O NH
354D
354E
17681897_1 (GHMatters) P110989.NZ
H N O
107B
N NH
O NH
2 O OH
HBTU, DIPEA, DMF
354G
354F
DMP HCl/EA,
N NH
N NH H
354H
Compound 354D was prepared using procedure for compound 213D. To a
solution of compound 354D (2.50 g, 6.82 mmol) and 2,6-lutidine (6.36 mL, 54.56 mmol) in
DCM (25 mL) was added trimethylsilyl trifluoromethanesulfonate (7.40 mL, 40.92 mmol) at 0
°C under N atmosphere. After addition, the reaction mixture was stirred at 0 °C for 0.25 h, then
stirred at 20 °C for 3h. The reaction mixture was cooled to 0 °C and added into cooled
sat.NH Cl (50 mL), then the mixture was extracted with EtOAc (100 mL x 2), the combined
extracts were washed with sat.NaHCO (100 mL), then the mixture was dried over Na SO and
3 2 4
filtered, the filtrate was concentrated in vacuum to afford compound 354E (2.50 g, crude) as red
oil. MS (ESI) m/z (M +H)+ 339.1.
To a solution of compound 354E (2.50 g, 7.39 mmol) in MeOH (40 mL) was
added TMSCl (1.50 mL, 11.87 mmol) at 0 °C. After addition, the reaction mixture was stirred at
0 °C for 0.5 h. TEA was added into the reaction mixture to pH ~ 8, then the mixture was
concentrated in vacuum to afford crude compound 354F (2.50 g, crude) as red solid. MS (ESI)
m/z (M +H)+ 266.9..
To a solution of compound 107B (700 mg, 3.45 mmol), compound 354F (1.01
g, 3.80 mmol) and HBTU (1.57 g, 4.13 mmol) in DMF (40 mL) was added DIEA (2.41 mL,
13.78 mmol) at 0-10 °C. After addition, the reaction mixture was stirred at 20 °C for 2h. 5 mL
of water was added into the reaction mixture and the mixture was concentrated in vacuum to
remove the most of DMF. Then 100 mL of water and 80 mL of EtOAc were added into the
mixture and stirred for 2 min. The mixture was separated and the aqueous layer was extracted
17681897_1 (GHMatters) P110989.NZ
with EtOAc (80 mL). The combined extracts were washed with 0.3N HCl (80 mL x 2),
sat.NaHCO (80 mL x 2) and brine (80 mL). Then the mixture was dried over Na SO and
3 2 4
filtered, the mixture was concentrated in vacuum to afford crude product. The residue was
purified by preparatory-HPLC (neutral condition) to afford compound 354G (1.0 g, yield
63.55%) as white solid. H NMR (400MHz, DMSO-d ) δ 8.12 - 7.55 (m, 3H), 7.45 - 7.25 (m,
5H), 7.22 - 7.05 (m, 2H), 6.91 - 6.77 (m, 2H), 6.10 - 5.84 (m, 1H), 4.64 - 4.46 (m, 1H), 4.11 -
3.99 (m, 1H), 2.94 - 2.80 (m, 1H), 2.79 - 2.61 (m, 1H), 2.56 - 2.52 (m, 3H), 1.23 - 1.17 (m, 9H).
MS (ESI) m/z (M +H)+ 452.1.
To a solution of compound 354G (863.1 mg, 1.91 mmol) in DCM (200 mL)
was added DMP (3.24 g, 7.65 mmol) at 0 °C under N atmosphere. After addition, the reaction
mixture was stirred at 10 °C for 1h. 50 mL of sat.Na S O and 50 mL of NaHCO was added
2 2 3 3
into the reaction mixture, the mixture was stirred for 20 min. Then the mixture was separated,
the organic layer was washed with 50 mL of sat.Na S O and 50 mL of NaHCO , then water (80
2 2 3 3
mL), brine (80 mL). The mixture was dried over Na2SO4 and filtered, then the mixture was
concentrated in vacuum to afford compound 354H (640 mg, yield 74.45%) as white solid. H
NMR (400MHz, DMSO-d ) δ 8.77 (d, J=7.5 Hz, 1H), 8.17 - 7.94 (m, 3H), 7.87 - 7.74 (m, 1H),
7.45 - 7.31 (m, 3H), 7.16 (d, J=8.4 Hz, 2H), 6.88 - 6.81 (m, 2H), 5.45 - 5.31 (m, 1H), 3.18 - 3.05
(m, 1H), 2.99 - 2.86 (m, 1H), 2.55 - 2.49 (m, 3H), 1.23 - 1.18 (m, 9H). MS (ESI) m/z (M +H)+
448.2.
To a solution of compound 354H (440 mg, 978.87 umol) in DCM (30 mL) was
added HCl/EtOAc (4M, 22 mL) at 0 °C. After addition, the reaction mixture was stirred at 10 °C
for 2h. The reaction mixture was concentrated and the residue was dissolved into 80 mL of
EtOAc, the mixture was washed with water (80 mL), 0.1% NaHCO (80 mL) and brine (80 mL).
Then the mixture was dried over Na SO and filtered, then concentrated in vacuum to afford
compound 354. Compound 354 (650 mg, 1.49 mmol) was dissolved into 3 mL of CH CN and
mL of 2-isopropoxypropane was added into the stirring mixture. After that, the mixture was
filtered to afford pure compound 354 (450 mg, yield 71.40%) as light yellow solid. H NMR
(400MHz, DMSO-d ) δ 9.25 (s, 1H), 8.70 (d, J=7.5 Hz, 1H), 8.11 (s, 1H), 8.07 - 8.00 (m, 2H),
7.84 (s, 1H), 7.42 - 7.36 (m, 3H), 7.08 (d, J=8.5 Hz, 2H), 6.67 (d, J=8.5 Hz, 2H), 5.45 - 5.29 (m,
1H), 3.13 - 3.05 (m, 1H), 2.93 - 2.84 (m, 1H), 2.56 (s, 3H). MS (ESI) m/z (M +H)+ 394.1.
17681897_1 (GHMatters) P110989.NZ
EXAMPLE 200
COMPOUND 355
OH O
2 Pyridine
O O O O
N NH N NH
N 2 N 2
O O O
To a solution of compound 354 (40 mg, 101.68 umol) and pyridine (19 mg,
233.86 umol) in DCM (2 mL) was added Tf O (34 mg, 122.02 umol) in DCM (0.5 mL) at 0 °C
under N2 atmosphere. After addition, the reaction mixture was stirred at 0 °C for 4h. The
reaction mixture was diluted with EtOAc (50 mL), the mixture was washed with 0.2 N HCl (20
mL), NaHCO (20 mL) and brine (20 mL), then the mixture was dried over Na SO and filtered,
3 2 4
the mixture was concentrated in vacuum to afford compound 355 (40 mg, yield 63.64%) as
yellow solid. H NMR (400MHz, DMSO-d ) δ 8.89 (d, J=7.5 Hz, 1H), 8.09 (s, 1H), 8.01 - 7.95
(m, 2H), 7.82 (s, 1H), 7.47 - 7.42 (m, 2H), 7.42 - 7.38 (m, 2H), 7.37 - 7.32 (m, 3H), 5.44 - 5.28
(m, 1H), 3.26 - 3.21 (m, 1H), 3.06 - 2.96 (m, 1H), 2.52 (s, 3H). MS (ESI) m/z (M +H)+ 526.1.
EXAMPLE 201
COMPOUND 356
t-BuOK
conc.
H SO
OH O O
CH COOC H
N N 3 2 5 N
CH OH
0.25 h
O O O O
65 °C, 10 h 356A
356B
C H I
HO S NO
6 5 N
mCPBA, CHCl
3 CH CONH , Microwave
°C, 2 h N
356C
NO ~
2 80 100 °C, 2 h
356D
LiOH•H O N
MeOH H O O
(2:1)
N NH
OH N
°C, 0.5 h N
356E
17681897_1 (GHMatters) P110989.NZ
To a solution of quinoxalinecarboxylic acid (6 g, 34.45 mmol) in MeOH (80
mL) was added con. H SO (675.8 mg, 6.89 mmol) dropwise, then the mixture was stirred at 65
°C for 10 hours. After cooling to room temperature, the mixture was neutralized with a sat.
NaHCO and extracted with DCM (60 mL x 3). The organic phases were combined, dried with
anhydrous Na SO , and evaporated to afford compound 356A (5.80 g, yield: 89.47%) as a brown
solid. The crude product was used directly in the next step without further purification. H
NMR (CDCl , 400 MHz) δ 9.56 (s, 1H), 8.31 (d, J = 7.6 Hz, 1H), 8.20 (d, J = 8.0 Hz, 1H), 7.97 -
7.84 (m, 2H), 4.13 (s, 3H).
A solution of compound 356A (2.5 g, 13.29 mmol) in CH COOC H (60 mL)
3 2 5
was added t-BuOK (1.94 g, 17.28 mmol). The mixture was stirred for 0.25 hour at 25°C. The
mixture was quenched with H O (50 mL). The organic layer was separated and the aqueous was
extracted with EA (50 mL x 3). The organic phases were combined, dried with anhydrous
Na SO , filtered and evaporated. The residue was purified by flash chromatography (PE: EA
=20/1 to 10/1) to afford compound 356B (2.45 g, 75.48% yield) as pale yellow solid. H NMR
(CDCl , 400 MHz) δ 9.57 - 9.33 (m, 1H), 8.19 - 8.06 (m, 2H), 7.96 - 7.74 (m, 2H), 4.35 - 4.26
(m, 2H), 4.24 - 4.13 (m, 2H), 1.28 - 1.18 (m, 3H).
A mixture of 2,4-dinitrobenzenesulfonic acid (7.83 g, 29.41 mmol, H O) and
iodobenzene (5 g, 24.51 mmol) in CHCl (20 mL) was added m-CPBA (4.23 g, 24.51 mmol), the
mixture was stirred at 25 °C for 2 hours under N atmosphere. After the reaction, MTBE (20
mL) was added to the reaction mixture, and the resulting mixture was filtered and the solid was
washed with MTBE (30 mL). The resulting mixture was filtered and the solid was washed with
MTBE (30 mL) to give compound 356C (8.7 g, 75.82% yield) as a white solid. H NMR
(400MHz, DMSO-d ) δ 9.60 (br s, 1H), 8.53 (d, J = 2.0 Hz, 1H), 8.39 - 8.36 (m, 1H), 8.18 (d, J =
7.6 Hz, 2H), 8.07 (d, J = 8.8 Hz, 1H), 7.71 - 7.64 (m, 1H), 7.63 - 7.55 (m, 2H).
A mixture of compound 356C (3.49 g, 7.45 mmol) and compound 356B (1.4 g,
.73 mmol) were stirred at 80 °C for 1h, and acetamide (4.06 g, 68.76 mmol) was added to the
mixture, then the mixture was stirred at 120 °C for 1h under microwave irradiation. The reaction
mixture was concentrated under reduced pressure to remove solvent and concentrated under
reduced pressure to give a residue. The residue was purified by column chromatography (SiO ,
17681897_1 (GHMatters) P110989.NZ
Petroleum ether/Ethyl acetate = 1/0 to 0:1) to give compound 356D (300 mg, crude) as dull-red
solid. MS (ESI) m/z (M+ H)+ 284.1.
Compound 356 was synthesized from 356D and using same procedures
described earlier for converting compound 321C to compound 321. Compound 356: N-(4-
amino-3,4-dioxophenylbutanyl)methyl(quinoxalinyl)oxazolecarboxamide:
H NMR (400MHz, DMSO-d ) δ 11.39 (d, J = 8.4 Hz, 1H), 9.58 (s, 1H), 8.24 (br s, 1H), 8.12 (d,
J = 8.0 Hz, 1H), 7.95 (br s, 1H), 7.89 (t, J = 7.6 Hz, 1H), 7.76 (t, J = 7.6 Hz, 1H), 7.60 (d, J = 8.4
Hz, 1H), 6.98 - 6.86 (m, 4H), 6.85 - 6.78 (m, 1H), 5.90 - 5.78 (m, 1H), 3.27 - 3.19 (m, 2H), 2.59
(s, 3H). MS (ESI) m/z (M+H) 430.1.
EXAMPLE 202
COMPOUND 357
Compound 357 was synthesized from 107B and using same procedures
described earlier for converting compound 321D to compound 321. Compound 357: N-(4-
amino-3,4-dioxophenylbutanyl)methylphenyloxazolecarboxamide: H NMR
(400 MHz, CDCl ) δ 8.12 - 8.05 (m, 2H), 7.43 - 7.37 (m, 3H), 7.32 - 7.26 (m, 3H), 7.15 - 7.10
(m, 2H), 6.78 - 6.71 (m, 2H), 5.75 - 5.68 (m, 1H), 5.54 (br s, 1H), 3..50 – 3.38 (m, 1H), 3.29 -
3.18 (m, 1H), 2.55 (s, 3H). H NMR (400 MHz, DMSO-d6) δ 8.82 (d, J = 7.2 Hz, 1H), 8.15 -
7.92 (m, 3H), 7.86 (s, 1H), 7.41 - 7.35 (m, 3H), 7.32 - 7.26 (m, 4H), 7.25 - 7.17 (m, 1H), 5.48 -
.38 (m, 1H), 3.27 - 3.15 (m, 1H), 3.06 - 2.93 (m, 1H), 2.55 (s, 3H). MS (ESI) m/z (M+1)
378.1.
EXAMPLE 203
COMPOUNDS 358-359
Compounds 358 and 359 were synthesized using same procedures described
earlier for compound 255. Compound 358: N-(4-amino-3,4-dioxophenylbutanyl)(2-
fluorophenyl)(trifluoromethyl)oxazolecarboxamide: H NMR (CDCl 400 MHz) δ
7.52 (t, J = 7.6 Hz, 1H), 7.45 - 7.35 (m, 1H), 7.28 - 7.20 (m, 3H), 7.19 - 7.07 (m, 2H), 7.02 (d, J
= 7.6 Hz, 2H), 6.68 (d, J = 4.8 Hz, 2H), 5.70 - 5.60 (m, 1H), 5.49 (br s, 1H), 3.42 - 3.32 (m, 1H),
3.24 - 3.14 (m, 1H). MS (ESI) m/z (M+H) 450.1. Compound 359: N-(4-amino-3,4-dioxo
phenylbutanyl)(o-tolyl)(trifluoromethyl)oxazolecarboxamide: H NMR (CDCl
400 MHz) δ 7.43 - 7.34 (m, 1H), 7.33 - 7.26 (m, 2H), 7.25 - 7.19 (m, 4H), 6.92 (br s, 2H), 6.69
17681897_1 (GHMatters) P110989.NZ
(br s, 1H), 6.44 (d, J = 6.4 Hz, 1H), 5.66 - 5.58 (m, 1H), 5.50 (br s, 1H), 3.41 - 3.28 (m, 1H), 3.08
- 2.97 (m, 1H), 2.21 (s, 3H). MS (ESI) m/z (M+H) 446.1.
EXAMPLE 204
COMPOUND 360
Compound 360 was synthesized using same procedures described earlier for
compound 26. Compound 360: N-((2S)aminohydroxyoxophenylbutanyl)
methylphenyloxazolecarboxamide: H NMR (400 MHz, DMSO-d ) δ 8.19 - 7.58 (m,
3H), 7.47 - 7.34 (m, 5H), 7.32 - 7.26 (m, 2H), 7.25 - 7.06 (m, 3H), 6.16 - 5.82 (m, 1H), 4.73 -
4.39 (m, 1H), 4.06 -3.88 (m, 1H), 3.04 - 2.65 (m, 2H), 2.59 - 2.53 (m, 3H). MS (ESI) m/z
(M+1) 380.0.
EXAMPLE 205
COMPOUND 361
Compound 361 was synthesized from ethyl 3-(2,3-difluorophenyl)
oxopropanoate using same procedures described earlier for compound 267. Compound 361: N-
(4-amino-3,4-dioxophenylbutanyl)(2,3-difluorophenyl)methyloxazole
carboxamide: H NMR (CDCl , 400MHz) δ 7.36 - 7.27 (m, 3H), 7.26 - 7.17 (m, 2H), 7.15 -
7.06 (m, 3H), 6.78 - 6.63 (m, 2H), 5.74 - 5.62 (m, 1H), 5.55 (br s, 1H), 3.42 (dd, J = 5.5, 14.3 Hz,
1H), 3.25 (dd, J = 6.6, 14.3 Hz, 1H), 2.57 (s, 3H). MS (ESI) m/z (M+H)+ 414.1.
EXAMPLE 206
COMPOUNDS 362-377, 462-468
Compounds 362-377, 462-468 were synthesized from the corresponding
intermediate or intermediate 321B and using same procedures as described earlier for compound
321.
Compound 362 (35.2 mg, 47.49% yield, 94% purity, EE%: 97%): (S)-N-(4-
fluorooxophenylbutanyl)(4-((propynyloxy)methyl)phenyl)-1,2,5-
thiadiazolecarboxamide: H NMR (400MHz, DMSO-d ) δ 9.50 - 9.40 (m, 1H), 9.45 (d,
J=7.7 Hz, 1H), 7.50 (d, J=8.2 Hz, 2H), 7.38 - 7.22 (m, 7H), 5.44 - 5.14 (m, 2H), 4.99 - 4.88 (m,
1H), 4.58 (s, 2H), 4.23 (d, J=2.4 Hz, 2H), 3.53 (t, J=2.3 Hz, 1H), 3.21 (dd, J=4.1, 14.2 Hz, 1H),
2.89 (dd, J=10.5, 14.0 Hz, 1H). MS (ESI) m/z (M+H) 438.1, (M+Na) 460.0.
17681897_1 (GHMatters) P110989.NZ
Compound 363 (39.2 mg, 36.85% yield, 94% purity): N-(4-amino-3,4-dioxo-
1-phenylbutanyl)(4-((4-fluorobenzamido)methyl)phenyl)-1,2,5-thiadiazole
carboxamide: H NMR (400MHz, DMSO-d ) δ 9.44 (d, J=7.7 Hz, 1H), 9.14 (t, J=6.0 Hz, 1H),
8.21 (s, 1H), 8.06 - 7.97 (m, 2H), 7.93 (s, 1H), 7.51 (d, J=8.2 Hz, 2H), 7.37 - 7.23 (m, 8H), 7.20 -
7.12 (m, 1H), 5.60 - 5.44 (m, 1H), 4.52 (d, J=6.0 Hz, 2H), 3.24 (dd, J=3.2, 14.0 Hz, 1H), 2.85
(dd, J=10.3, 14.0 Hz, 1H). MS (ESI) m/z (M+H) 532.2.
Compound 364 (27.5 mg, 26.56% yield, 96% purity): N-(4-amino-3,4-dioxo-
1-phenylbutanyl)chloro-1,2,5-thiadiazolecarboxamide: H NMR (400MHz, DMSO-
d ) δ 9.24 (d, J=7.5 Hz, 1H), 8.19 (s, 1H), 7.92 (s, 1H), 7.49 - 7.19 (m, 5H), 5.47 (ddd, J=3.9, 7.7,
9.6 Hz, 1H), 3.24 (dd, J=3.9, 14.0 Hz, 1H), 2.95 (dd, J=9.8, 14.0 Hz, 1H). MS (ESI) m/z
(M+H) 339.0.
Compound 365 (60 mg, 39.4% yield): N-(4-amino-3,4-dioxophenylbutan-
2-yl)(pyrazinyl)-1,2,5-thiadiazolecarboxamide: H NMR (400MHz, DMSO-d ) δ
9.23 (d, J = 7.3 Hz, 1H), 9.06 (d, J = 1.5 Hz, 1H), 8.69 (d, J = 2.4 Hz, 1H), 8.51 (dd, J = 1.5, 2.4
Hz, 1H), 8.13 (s, 1H), 7.87 (s, 1H), 7.29 - 7.14 (m, 6H), 5.47 (ddd, J = 4.1, 7.6, 9.3 Hz, 1H), 3.16
(dd, J = 4.0, 14.1 Hz, 1H), 2.87 (dd, J = 9.3, 14.3 Hz, 1H). MS (ESI) m/z (M+H) 383.1.
Compound 366 (50 mg, 36.9% yield): N-(4-amino-3,4-dioxophenylbutan-
2-yl)bromo-1,2,5-thiadiazolecarboxamide: H NMR (400MHz, DMSO-d ) δ 9.23 (d, J =
7.5 Hz, 1H), 8.18 (s, 1H), 7.91 (s, 1H), 7.35 - 7.17 (m, 4H), 5.54 - 5.41 (m, 1H), 3.23 (dd, J =
3.9, 14.2 Hz, 1H), 2.95 (dd, J = 9.7, 13.9 Hz, 1H). MS (ESI) m/z (M+H) 383.0.
Compound 367 (50 mg, 18.43% yield): N-(4-amino-3,4-dioxo
phenylbutanyl)(benzo[d][1,3]dioxolyl)-1,2,5-thiadiazolecarboxamide: H NMR
(400MHz, DMSO-d ) δ 8.92 (d, J = 8.0 Hz, 1H), 7.94 - 7.52 (m, 2H), 7.36 - 7.18 (m, 5H), 7.08 -
6.93 (m, 2H), 6.92 - 6.79 (m, 1H), 5.87 (d, J = 10.0 Hz, 2H), 5.55 - 5.38 (m, 1H), 3.23 (dd, J =
3.5, 14.1 Hz, 1H), 3.03 - 2.97 (m, 1H). MS (ESI) m/z (M+H) 425.1.
Compound 368 (130 mg, 60.3% yield): N-(4-amino-3,4-dioxo
phenylbutanyl)(2-fluoromethylphenyl)-1,2,5-thiadiazolecarboxamide: H NMR
(400MHz, DMSO-d ) δ 9.22 (d, J = 7.7 Hz, 1H), 8.12 (s, 1H), 7.87 (s, 1H), 7.39 (t, J = 6.9 Hz,
1H), 7.31 - 7.19 (m, 6H), 7.17 - 7.10 (m, 1H), 5.42 (ddd, J = 3.7, 7.7, 9.7 Hz, 1H), 3.19 (dd, J =
17681897_1 (GHMatters) P110989.NZ
3.7, 14.1 Hz, 1H), 2.96 (dd, J = 9.7, 13.9 Hz, 1H), 2.22 (d, J = 2.0 Hz, 3H). MS (ESI) m/z
(M+H) 413.1.
Compound 369 (55 mg, 27.8% yield): N-(4-aminohydroxyoxo
phenylbutanyl)(4-((benzyloxy)methyl)phenyl)-1,2,5-thiadiazolecarboxamide: H
NMR (400MHz, DMSO-d ) δ 9.45 (d, J = 7.5 Hz, 1H), 8.21 (s, 1H), 7.94 (s, 1H), 7.63 - 7.52 (m,
2H), 7.44 - 7.16 (m, 12H), 5.54 - 5.49 (m, 1H), 4.62 - 4.56 (m, 4H), 3.24 (dd, J = 3.6, 14.0 Hz,
1H), 2.86 (dd, J = 10.1, 13.9 Hz, 1H). MS (ESI) m/z (M+H) 501.1.
Compound 370 (55 mg, 20.1% yield): N-(4-amino-3,4-dioxophenylbutan-
2-yl)(3-((benzyloxy)methyl)phenyl)-1,2,5-thiadiazolecarboxamide: H NMR (400MHz,
DMSO-d ) δ 9.42 (d, J = 7.7 Hz, 1H), 8.18 (s, 1H), 7.93 (s, 1H), 7.71 (s, 1H), 7.49 - 7.43 (m,
2H), 7.42 - 7.33 (m, 5H), 7.32 - 7.24 (m, 5H), 7.24 - 7.19 (m, 1H), 6.49 - 6.39 (m, 1H), 5.55 -
.48 (m, 1H), 4.55 (d, J = 5.7 Hz, 4H), 3.22 (dd, J = 3.6, 14.0 Hz, 1H), 2.88 (dd, J = 9.9, 13.9
Hz, 1H). MS (ESI) m/z (M+H O) 518.2.
Compound 371 (90 mg, 63.2% yield): N-(4-amino-3,4-dioxophenylbutan-
2-yl)(pyridinyl)-1,2,5-thiadiazolecarboxamide: H NMR (400MHz, DMSO-d ) δ
9.47 (d, J = 7.8 Hz, 1H), 8.65 - 8.55 (m, 2H), 8.21 (s, 1H), 7.95 (s, 1H), 7.52 - 7.38 (m, 2H), 7.33
- 7.22 (m, 5H), 6.53 - 6.39 (m, 1H), 5.55 - 5.47 (m, 1H), 3.28 - 3.22 (m, 1H), 2.92 - 2.83 (m, 1H).
MS (ESI) m/z (M+H) 382.1.
Compound 372 (50 mg, 22.8% yield): N-(4-amino-3,4-dioxophenylbutan-
2-yl)(2,3-difluorophenyl)-1,2,5-thiadiazolecarboxamide: H NMR (400MHz, DMSO-
d ) δ 9.24 (d, J = 7.6 Hz, 1H), 8.12 (s, 1H), 7.86 (s, 1H), 7.59 - 7.50 (m, 1H), 7.29 - 7.16 (m, 7H),
.44 - 5.37 (m, 1H), 3.21 - 3.14 (m, 1H), 2.98 - 2.90 (m, 1H). MS (ESI) m/z (M+H) 417.1.
Compound 373 (85 mg, 44.6% yield): N-(4-amino-3,4-dioxophenylbutan-
2-yl)(pyridinyl)-1,2,5-thiadiazolecarboxamide: H NMR (400MHz, DMSO-d ) δ
9.36 (d, J = 7.1 Hz, 1H), 8.42 (d, J = 5.6 Hz, 1H), 8.10 (s, 1H), 7.97 - 7.79 (m, 3H), 7.50 - 7.34
(m, 1H), 7.21 (s, 5H), 5.54 - 5.46 (m, 1H), 3.20 - 3.11 (m, 1H), 2.90 (dd, J = 8.8, 14.1 Hz, 1H).
MS (ESI) m/z (M+H) 382.1.
Compound 374 (100 mg, 49.9% yield): N-(4-amino-3,4-dioxo
phenylbutanyl)(pyrimidinyl)-1,2,5-thiadiazolecarboxamide: H NMR (400MHz,
DMSO-d ) δ 9.27 (d, J = 7.5 Hz, 1H), 9.05 (d, J = 1.3 Hz, 1H), 8.94 (d, J = 5.1 Hz, 1H), 8.14 (s,
17681897_1 (GHMatters) P110989.NZ
1H), 7.94 - 7.83 (m, 2H), 7.28 - 7.16 (m, 5H), 5.50 (ddd, J = 4.2, 7.5, 9.3 Hz, 1H), 3.18 (dd, J =
4.1, 14.2 Hz, 1H), 2.88 (dd, J = 9.5, 14.1 Hz, 1H). MS (ESI) m/z (M+H) 383.1.
Compound 375 (60 mg, 28.5% yield): N-(4-amino-3,4-dioxophenylbutan-
2-yl)(3-fluoromethylphenyl)-1,2,5-thiadiazolecarboxamide: H NMR (400MHz,
DMSO-d ) δ 9.19 (d, J = 8.0 Hz, 1H), 8.10 (s, 1H), 7.84 (s, 1H), 7.27 - 7.15 (m, 7H), 6.98 - 6.94
(m, 1H), 5.39 - 5.31 (m, 1H), 3.18 - 3.12 (m, 1H), 2.93 - 2.85 (m, 1H), 1.87 - 1.83 (m, 3H). MS
(ESI) m/z (M+H) 413.1.
Compound 376 (300 mg, 47.9% yield): (S)-N-(4-amino-3,4-dioxo
phenylbutanyl)phenyl-1,2,5-thiadiazolecarboxamide: H NMR (400MHz, DMSO-
d ) δ 9.46 (d, J = 8.0 Hz, 1H), 8.22 (s, 1H), 7.95 (s, 1H), 7.58 (d, J = 6.8 Hz, 2H), 7.50 - 7.45 (m,
1H), 7.44 - 7.38 (m, 2H), 7.35 - 7.24 (m, 5H), 5.56 - 5.49 (m, 1H), 3.29 - 3.21 (m, 1H), 2.93 -
2.83 (m, 1H). (ESI) m/z (M+H) 381.1.
Compound 377 (80 mg, 39.9% yield): N-(4-amino-3,4-dioxophenylbutan-
2-yl)(pyridinyl)-1,2,5-thiadiazolecarboxamide: H NMR (400MHz, DMSO-d ) δ
9.39 (d, J = 7.7 Hz, 1H), 8.82 (d, J = 2.2 Hz, 1H), 8.65 (dd, J = 1.5, 4.9 Hz, 1H), 8.19 (s, 1H),
7.96 - 7.82 (m, 2H), 7.43 (dd, J = 4.9, 7.9 Hz, 1H), 7.33 - 7.20 (m, 5H), 5.53 - 5.45 (m, 1H), 3.23
(dd, J = 3.6, 14.0 Hz, 1H), 2.90 (dd, J = 10.0, 14.0 Hz, 1H). MS (ESI) m/z (M+H) 382.1.
Compound 462 (150 mg, 73.8% yield): N-(4-(cyclopropylamino)-3,4-dioxo
phenylbutanyl)phenyl-1,2,5-thiadiazolecarboxamide: H NMR (400MHz, DMSO-
d ) δ 9.45 (d, J = 7.7 Hz, 1H), 8.91 (br d, J = 5.1 Hz, 1H), 7.57 (d, J = 7.1 Hz, 2H), 7.50 - 7.43
(m, 1H), 7.42 - 7.34 (m, 2H), 7.34 - 7.25 (m, 5H), 5.59 - 5.48 (m, 1H), 3.24 (dd, J = 3.1, 13.9 Hz,
1H), 2.93 - 2.76 (m, 2H), 0.72 - 0.59 (m, 4H). MS (ESI) m/z (M+H) 421.1.
Compound 463 was prepared from the corresponding intermediates, 4-phenyl-
1,2,5-thiadiazolecarboxylic acid and 3-aminohydroxyphenylpentanamide hydrochloride
using same procedures as for compound 321. Compound 463 (120 mg, 35% yield): N-(1-amino-
1,2-dioxophenylpentanyl)phenyl-1,2,5-thiadiazolecarboxamide: H NMR
(400MHz, DMSO-d ) δ 9.49 (br d, J = 7.1 Hz, 1H), 8.14 (br s, 1H), 7.91 - 7.78 (m, 3H), 7.56 -
7.45 (m, 3H), 7.33 - 7.25 (m, 2H), 7.22 - 7.15 (m, 3H), 5.15 (br t, J = 6.6 Hz, 1H), 2.77 - 2.58 (m,
2H), 2.21 - 2.08 (m, 1H), 1.96 - 1.81 (m, 1H). MS (ESI) m/z (M+H) 395.1.
17681897_1 (GHMatters) P110989.NZ
Compound 464 was prepared from the corresponding intermediates, 4-phenyl-
1,2,5-thiadiazolecarboxylic acid and 3-amino(4-fluorophenyl)hydroxybutanamide
hydrochloride using same procedures as for compound 321. Compound 464 (120 mg, 47%
yield): N-(4-amino(4-fluorophenyl)-3,4-dioxobutanyl)phenyl-1,2,5-thiadiazole
carboxamide: H NMR (400MHz, DMSO-d ) δ 9.45 (d, J = 6.4 Hz, 1H), 8.20 (s, 1H), 7.94 (s,
1H), 7.56 (d, J = 7.1 Hz, 2H), 7.50 - 7.37 (m, 3H), 7.31 (s, 2H), 7.18 - 7.05 (m, 2H), 5.47 (s, 1H),
3.29 - 3.15 (m, 1H), 2.91 - 2.78 (m, 1H). MS (ESI) m/z (M+H) 399.0.
Compound 465 was prepared from the corresponding intermediates, 4-phenyl-
1,2,5-thiadiazolecarboxylic acid and 3-aminohydroxymethylhexanamide hydrochloride
using same procedures as for compound 321. Compound 465 (110 mg, 38.2% yield): N-(1-
aminomethyl-1,2-dioxohexanyl)phenyl-1,2,5-thiadiazolecarboxamide: H NMR
(400MHz, DMSO-d ) δ 9.32 (d, J = 6.6 Hz, 1H), 8.14 (s, 1H), 7.95 - 7.69 (m, 3H), 7.51 (s, 3H),
.30 (s, 1H), 1.78 - 1.39 (m, 3H), 0.90 (dd, J = 5.8, 15.3 Hz, 6H). MS (ESI) m/z (M+H) 347.1.
Compound 466 was prepared from the corresponding intermediates, 4-phenyl-
1,2,5-thiadiazolecarboxylic acid and 3-amino(3,5-dimethylphenyl)hydroxybutanamide
hydrochloride using same procedures as for compound 321. Compound 466 (70 mg, 39.2%
yield): N-(4-amino(3,5-dimethylphenyl)-3,4-dioxobutanyl)phenyl-1,2,5-thiadiazole-
H NMR (400MHz, DMSO-d ) δ 9.40 (d, J = 7.5 Hz, 1H), 8.19 (s, 1H), 7.92
3-carboxamide: 6
(s, 1H), 7.62 (d, J = 7.3 Hz, 2H), 7.53 - 7.35 (m, 3H), 6.89 (s, 3H), 5.56 - 5.40 (m, 1H), 3.20 -
3.08 (m, 1H), 2.85 - 2.71 (m, 1H), 2.21 (s, 6H). MS (ESI) m/z (M+H) 409.1.
Compound 467 was prepared from the corresponding intermediates, 4-phenyl-
1,2,5-thiadiazolecarboxylic acid and 3-aminohydroxyheptanamide hydrochloride using
same procedures as for compound 321. Compound 467 (80 mg, 73% yield): N-(1-amino-1,2-
dioxoheptanyl)phenyl-1,2,5-thiadiazolecarboxamide: H NMR (400MHz, DMSO-
d ) δ 9.31 (br d, J = 7.0 Hz, 1H), 8.14 (br s, 1H), 7.94 - 7.69 (m, 3H), 7.58 - 7.43 (m, 3H), 5.30 -
.15 (m, 1H), 1.82 (br d, J = 7.5 Hz, 1H), 1.57 (br d, J = 4.8 Hz, 1H), 1.40 - 1.39 (m, 1H), 1.36 -
1.22 (m, 1H), 1.36 - 1.20 (m, 3H), 0.88 - 0.81 (m, 3H). MS (ESI) m/z (M+H) 347.1.
Compound 468 was prepared from the corresponding intermediates, 4-phenyl-
1,2,5-thiadiazolecarboxylic acid and 3-aminohydroxybutanamide hydrochloride using same
procedures as for compound 321. Compound 468 (70 mg, 54.2% yield): N-(4-amino-3,4-
17681897_1 (GHMatters) P110989.NZ
dioxobutanyl)phenyl-1,2,5-thiadiazolecarboxamide: H NMR (400MHz, DMSO-d )
δ 9.40 (d, J = 6.4 Hz, 1H), 8.12 (br s, 1H), 7.92 - 7.75 (m, 3H), 7.58 - 7.43 (m, 3H), 5.25 - 5.18
(m, 1H), 1.36 (d, J = 7.3 Hz, 3H). MS (ESI) m/z (M+H) 305.1.
EXAMPLE 207
COMPOUNDS 378, 578, 599
PhCH Br, acetone, B B
Cs CO , 18-crown-6
Br N
O Pd(dppf)Cl2
KOAc
378A
dioxane
Pd(P , Cs CO
3)2 2 3
378B dioxane, O
378C
N NH
To a solution of 6-bromoisoindolinone (0.5 g, 2.36 mmol) in acetone (20
mL) was added BnBr (605 mg, 3.54 mmol, 0.420 mL), Cs CO (1.92 g, 5.90 mmol) and 18-
crown-6 (62 mg, 235.80 umol), then the mixture was stirred at 70 °C for 16h. The reaction
mixture was concentrated to remove solvent, then diluted with water (50 mL) and extracted with
EA (40 mL x 2), and the organic layers were dried over Na SO , filtered and concentrated to give
a residue. The residue was purified by flash silica gel chromatography (ISCO ; 12 g SepaFlash
Silica Flash Column, Eluent of 0~20% Ethyl acetate/Petroleum ethergradient @ 30 mL/min).
Compound 378A (0.46 g, yield: 59.5%) was obtained as white solid. H NMR (400MHz,
CDCl ) δ 8.02 (d, J = 1.8 Hz, 1H), 7.63 (dd, J = 1.9, 8.0 Hz, 1H), 7.39 - 7.16 (m, 6H), 4.79 (s,
2H), 4.21 (s, 2H). MS (ESI) m/z (M+H) 302.0.
To a solution of compound 378A (0.46 g, 1.52 mmol) and 4,4,4',4',5,5,5',5'-
octamethyl-2,2'-bi(1,3,2-dioxaborolane) (580 mg, 2.28 mmol) in dioxane (20 mL) was added
17681897_1 (GHMatters) P110989.NZ
KOAc (299 mg, 3.04 mmol), and then Pd(dppf)Cl (111 mg, 152.23 umol) was added under N
atmosphere, the mixture was stirred at 85 °C for 16 h. The reaction mixture was diluted with EA
(20 mL), then filtered and washed with EA (20 mL x 3), the filtrate was concentrated to give a
residue. The residue was purified by flash silica gel chromatography (ISCO ; 12 g SepaFlash
Silica Flash Column, Eluent of 0 ~ 30 % Ethyl acetate/Petroleum ethergradient @ 30 mL/min).
Then further purified by preparatory-TLC (PE:EA = 2: 1). Compound 378B (0.35 g, yield:
46.1%) was obtained as light yellow solid. H NMR (400MHz, DMSO-d ) δ 7.98 (t, J = 0.9 Hz,
1H), 7.86 (dd, J = 1.1, 7.5 Hz, 1H), 7.57 (dd, J = 0.9, 7.5 Hz, 1H), 7.38 - 7.32 (m, 2H), 7.31 -
7.23 (m, 3H), 4.77 - 4.69 (m, 2H), 4.39 (s, 2H), 1.31 (s, 12H). MS (ESI) m/z (M+H) 349.9.
To a solution of methyl 4-bromo-1,2,5-thiadiazolecarboxylate (186 mg,
835.17 umol) and compound 378B (0.35 g, 1.00 mmol) in dioxane (20 mL) and H O (2 mL) was
added K CO (231 mg, 1.67 mmol), then Pd(dppf)Cl (61 mg, 83.52 umol) was added under N
2 3 2 2
atmosphere, then the mixture was stirred at 85 °C for 16 h under N atmosphere. The reaction
mixture was diluted with EA (30 mL), then filtered and concentrated to give a residue. The
residue was purified by flash silica gel chromatography (ISCO ; 12 g SepaFlash Silica Flash
Column, Eluent of 0~30 % Ethyl acetate/Petroleum ethergradient @ 30 mL/min). Compound
378C (0.13 g, yield: 37.3%) was obtained as a white solid. H NMR (400MHz, CDCl ) δ 8.20
(d, J = 1.8 Hz, 1H), 7.87 (dd, J = 1.8, 7.9 Hz, 1H), 7.51 (d, J = 7.7 Hz, 1H), 7.41 - 7.28 (m, 5H),
4.84 (s, 2H), 4.35 (s, 2H), 4.03 - 3.95 (m, 3H). MS (ESI) m/z (M+H)+ 366.0.
Compound 378 was synthesized from 378C and using same procedures
described earlier for compound 321. Compound 378 (20 mg, 13.5% yield): N-(4-amino-3,4-
dioxophenylbutanyl)(2-benzyloxoisoindolinyl)-1,2,5-thiadiazole
carboxamide: H NMR (400MHz, DMSO-d ) δ 9.07 (br s, 1H), 8.20 - 8.00 (m, 1H), 7.96 - 7.48
(m, 4H), 7.42 - 7.12 (m, 10H), 5.58 - 5.38 (m, 1H), 4.78 (s, 2H), 4.45 (s, 2H), 3.26 (dd, J = 3.8,
14.3 Hz, 1H), 2.98 (d, J = 14.1 Hz, 1H). MS (ESI) m/z (M+H) 526.1.
Compound 578 was synthesized by the coupling of methyl 4-bromo-1,2,5-
thiadiazolecarboxylate and (2,2-difluorobenzo[d][1,3]dioxolyl)boronic acid followed by
subjecting the product to same procedures described earlier for compound 321. Compound 578
(100 mg, 57.9% yield): N-(4-amino-3,4-dioxophenylbutanyl)(2,2-
difluorobenzo[d][1,3]dioxolyl)-1,2,5-thiadiazolecarboxamide: H NMR (400MHz,
17681897_1 (GHMatters) P110989.NZ
DMSO-d ) δ 9.36 - 9.32 (m, 1H), 8.12 (s, 1H), 7.88 (s, 1H), 7.52 - 7.49 (m, 1H), 7.28 - 7.17 (m,
7H), 5.50 - 5.43 (m, 1H), 3.22 - 3.15 (m, 1H), 2.94 - 2.86 (m, 1H). MS (ESI) m/z (M+H) 461.0.
Compound 599 was synthesized by the coupling of methyl 4-bromo-1,2,5-
thiadiazolecarboxylate and (2,2-difluorobenzo[d][1,3]dioxolyl)boronic acid followed by
subjecting the product to same procedures described earlier for compound 321. Compound 599
(140 mg, 69.6% yield): N-(4-amino-3,4-dioxophenylbutanyl)(2,2-
difluorobenzo[d][1,3]dioxolyl)-1,2,5-thiadiazolecarboxamide: H NMR (400MHz,
DMSO-d ) δ 9.40 (d, J = 7.7 Hz, 1H), 8.19 (s, 1H), 7.93 (s, 1H), 7.59 (s, 1H), 7.42 (d, J = 0.9 Hz,
2H), 7.29 - 7.18 (m, 5H), 5.55 - 5.41 (m, 1H), 3.23 (dd, J = 3.5, 13.9 Hz, 1H), 2.86 (dd, J = 10.1,
14.1 Hz, 1H). MS (ESI) m/z (M+H) 461.0.
EXAMPLE 208
COMPOUNDS 379-380
Compounds 379-380 were synthesized from the corresponding intermediate 1-
(difluoromethyl)phenyl-1H-pyrazolecarboxylic acid using same procedures as described
earlier for Example 5.
Compound 379 (240 mg, 76.2% yield): (S)-N-(4-amino-3,4-dioxo
phenylbutanyl)(difluoromethyl)phenyl-1H-pyrazolecarboxamide: H NMR
(400MHz, DMSO-d ) δ 8.79 (d, J = 7.5 Hz, 1H), 8.48 (s, 1H), 8.14 - 7.72 (m, 3H), 7.55 (dd, J =
2.0, 7.3 Hz, 2H), 7.37 - 7.20 (m, 8H), 5.40 - 5.26 (m, 1H), 3.18 (dd, J = 3.6, 14.0 Hz, 1H), 2.80
(dd, J = 10.1, 13.9 Hz, 1H). MS (ESI) m/z (M+H) 413.1.
Compound 380 (50 mg, 61.7% yield): (R)-N-(4-amino-3,4-dioxo
phenylbutanyl)(difluoromethyl)phenyl-1H-pyrazolecarboxamide: H NMR
(400MHz, DMSO-d ) δ 8.79 (d, J = 7.3 Hz, 1H), 8.47 (s, 1H), 8.15 - 7.71 (m, 3H), 7.60 - 7.48
(m, 2H), 7.39 - 7.21 (m, 8H), 5.40 - 5.25 (m, 1H), 3.17 (dd, J = 3.7, 13.9 Hz, 1H), 2.80 (dd, J =
.0, 14.0 Hz, 1H). MS (ESI) m/z (M+H) 413.1.
17681897_1 (GHMatters) P110989.NZ
EXAMPLE 209
COMPOUNDS 381-384, 403, 522-524, 546-547, 550-552, 554-555, 575-577, 588, 596, 598,
608, 610, 622, 630
Cl ONa
381A
Cs CO ,
To a solution of ethyl 3-iodo-1H-pyrazolecarboxylate (20 g, 75.18 mmol) in
DMF (100 mL) was added sodium 2-chloro-2,2-difluoroacetate (22.92 g, 150.36 mmol) and
Cs CO (48.99 g, 150.36 mmol). The mixture was stirred at 100 °C for 16 h. The reaction
mixture was concentrated, the residue was diluted with H O (200 mL) and extracted with EtOAc
(100 mL x 3). The combined organic layers were washed with brine (200 mL), dried over
Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was
purified by flash silica gel chromatography (ISCO ; X g SepaFlash Silica Flash Column, eluent
of 0% ~ 10% ~20% Ethyl acetate/Petroleum ether gradient). Compound 381A (9.1 g, yield:
38.30%) was obtained as a white solid. H NMR (400MHz, CDCl ) δ 8.47 - 7.95 (m, 1H), 7.44 -
6.95 (m, 1H), 4.53 - 4.17 (m, 2H), 1.54 - 1.17 (m, 3H).
Compounds 381-384, 403, 522-524, 546-547, 550-552, 554-555, 561, 563-566,
575-577, 581-582, 586, 588, 596, 598, 608, 610, 622, and 630 were synthesized from the
corresponding intermediate ethyl 1-(difluoromethyl)iodo-1H-pyrazolecarboxylate (381A)
using same procedures as described earlier for Compound 242.
Compound 381 (125 mg, 43.5% yield): N-(4-amino-3,4-dioxo
phenylbutanyl)(difluoromethyl)(3-fluorophenyl)-1H-pyrazolecarboxamide: H
NMR (400MHz, DMSO-d ) δ 8.87 (br d, J = 7.3 Hz, 1H), 8.56 (s, 1H), 8.18 - 8.04 (m, 1H), 7.99
- 7.75 (m, 2H), 7.51 - 7.36 (m, 3H), 7.33 - 7.18 (m, 6H), 5.35 (br s, 1H), 3.20 (br dd, J = 3.0, 13.8
Hz, 1H), 2.89 - 2.76 (m, 1H). MS (ESI) m/z (M+H) 431.1..
Compound 382 (70 mg, 40.9% yield): N-(4-amino-3,4-dioxophenylbutan-
2-yl)(difluoromethyl)(o-tolyl)-1H-pyrazolecarboxamide: H NMR (400MHz,
DMSO-d6) δ 8.69 (s, 1H), 8.35 (br d, J = 7.3 Hz, 1H), 8.06 (br s, 1H), 7.95 - 7.75 (m, 2H), 7.27
17681897_1 (GHMatters) P110989.NZ
(br d, J = 6.8 Hz, 3H), 7.25 - 7.10 (m, 6H), 5.26 (br s, 1H), 3.19 - 3.10 (m, 1H), 2.81 - 2.70 (m,
1H), 2.02 (s, 3H). MS (ESI) m/z (M+H) 427.1.
Compound 383 (150 mg, 58.2% yield): N-(4-amino-3,4-dioxo
phenylbutanyl)(difluoromethyl)(2-fluorophenyl)-1H-pyrazolecarboxamide: H
NMR (400MHz, DMSO-d ) δ 8.77 - 8.62 (m, 2H), 8.16 - 7.76 (m, 3H), 7.50 - 7.17 (m, 9H), 5.36
- 5.23 (m, 1H), 3.17 (dd, J = 3.9, 14.0 Hz, 1H), 2.82 (dd, J = 10.0, 13.8 Hz, 1H). MS (ESI) m/z
(M+H) 431.1.
Compound 384 (130 mg, 39.4% yield): N-(4-amino-3,4-dioxo
phenylbutanyl)(difluoromethyl)(3-methoxyphenyl)-1H-pyrazolecarboxamide:
H NMR (400MHz, DMSO-d ) δ 8.54 - 8.35 (m, 2H), 8.03 - 7.51 (m, 3H), 7.35 - 7.14 (m, 8H),
6.96 (d, J = 7.8 Hz, 1H), 5.37 (br s, 1H), 3.76 (s, 3H), 3.22 (d, J = 14.3 Hz, 1H), 2.97 - 2.83 (m,
1H). MS (ESI) m/z (M+H) 443.1.
Compound 403 (3.1 g, 49.74% yield): N-(4-amino-3,4-dioxophenylbutan-
2-yl)(difluoromethyl)phenyl-1H-pyrazolecarboxamide: H NMR (400MHz, DMSO-
d ) δ 8.80 (d, J = 7.5 Hz, 1H), 8.58 - 8.37 (m, 1H), 8.10 (s, 1H), 8.05 - 7.69 (m, 2H), 7.58 - 7.47
(m, 2H), 7.36 - 7.19 (m, 8H), 5.47 - 5.19 (m, 1H), 3.19 - 3.14 (m, 1H), 2.82 - 2.75 (m, 1H). MS
(ESI) m/z (M+H) 413.2.
Compound 522 (25 mg, 16.6% yield; white solid): N-(4-amino-3,4-dioxo
phenylbutanyl)(difluoromethyl)(4-methylpyridinyl)-1H-pyrazole
carboxamide: H NMR (400MHz, DMSO-d ) δ 8.77 (s, 1H), 8.65 (d, J = 7.3 Hz, 1H), 8.39 (d, J
= 5.1 Hz, 1H), 8.24 (s, 1H), 8.09 - 8.02 (m, 1H), 7.93 (s, 1H), 7.78 (d, J = 6.2 Hz, 1H), 7.29 -
7.13 (m, 7H), 5.27 - 5.19 (m, 1H), 3.13 (dd, J = 3.7, 13.9 Hz, 1H), 2.76 (dd, J = 9.9, 13.9 Hz,
1H), 1.99 (s, 3H). MS (ESI) m/z (M+H) 428.1.
Compound 523 (63 mg, 63.6% yield; light yellow solid): N-(4-amino-3,4-
dioxophenylbutanyl)(difluoromethyl)(3,5-difluorophenyl)-1H-pyrazole
carboxamide: H NMR (400MHz, DMSO-d ) δ 8.89 (d, J = 7.5 Hz, 1H), 8.62 (s, 1H), 8.14 -
8.08 (m, 1H), 7.97 - 7.79 (m, 2H), 7.39 - 7.25 (m, 7H), 7.23 - 7.19 (m, 1H), 5.42 - 5.33 (m, 1H),
3.20 (dd, J = 3.7, 13.9 Hz, 1H), 2.82 (dd, J = 10.3, 14.0 Hz, 1H). MS (ESI) m/z (M+H) 449.0.
Compound 524 (50 mg, 31.5% yield): N-(4-amino-3,4-dioxophenylbutan-
2-yl)(difluoromethyl)(2,5-dimethylphenyl)-1H-pyrazolecarboxamide: H NMR
17681897_1 (GHMatters) P110989.NZ
(400MHz, DMSO-d ) δ 8.69 (s, 1H), 8.23 (d, J = 7.3 Hz, 1H), 8.05 (s, 1H), 7.92 - 7.73 (m, 2H),
7.31 - 7.24 (m, 2H), 7.24 - 7.15 (m, 3H), 7.13 - 7.09 (m, 2H), 6.97 (s, 1H), 5.28-5.24 (m, 1H),
3.14 (dd, J = 3.6, 14.0 Hz, 1H), 2.75 (dd, J = 9.7, 14.1 Hz, 1H), 2.25 (s, 3H), 1.96 (s, 3H). MS
(ESI) m/z (M+H) 441.1.
Compound 546 (120 mg, 47.9% yield; white solid): N-(4-amino-3,4-dioxo
phenylbutanyl)(2,2-difluorobenzo[d][1,3]dioxolyl)(difluoromethyl)-1H-pyrazole-
4-carboxamide: H NMR (400MHz, DMSO-d ) δ δ 8.87 (d, J = 7.5 Hz, 1H), 8.72 (s, 1H), 8.19
- 7.79 (m, 3H), 7.44 (d, J = 7.7 Hz, 1H), 7.32 - 7.17 (m, 7H), 5.42 - 5.24 (m, 1H), 3.17 (dd, J =
3.5, 13.7 Hz, 1H), 2.81 (dd, J = 10.1, 13.9 Hz, 1H). MS (ESI) m/z (M+H) 493.1.
Compound 547 (140 mg, 67.0% yield; white solid): N-(4-amino-3,4-dioxo
phenylbutanyl)(difluoromethyl)(naphthalenyl)-1H-pyrazolecarboxamide: H
NMR (400MHz, DMSO-d ) δ 8.79 (s, 1H), 8.46 (d, J = 7.5 Hz, 1H), 8.15 - 7.71 (m, 5H), 7.62 (d,
J = 7.9 Hz, 1H), 7.54 - 7.45 (m, 2H), 7.44 - 7.35 (m, 2H), 7.28 - 7.13 (m, 5H), 5.19 - 5.15 (m,
1H), 3.08 (dd, J = 3.7, 13.9 Hz, 1H), 2.72 (dd, J = 9.9, 13.9 Hz, 1H). MS (ESI) m/z
(M+H) 463.1.
Compound 550 (25 mg, 30.3% yield; light yellow solid): N-(4-amino-3,4-
dioxophenylbutanyl)(difluoromethyl)(pyridinyl)-1H-pyrazolecarboxamide:
H NMR (400MHz, DMSO-d ) δ 11.78 (s, 1H), 8.71 (s, 1H), 8.40 (d, J = 4.5 Hz, 1H), 8.15 (d, J
= 8.0 Hz, 1H), 8.03 - 7.99 (m, 1H), 7.91 - 7.56 (m, 3H), 7.55 - 7.46 (m, 1H), 7.23 - 7.08 (m, 5H),
.67 - 5.53 (m, 1H), 3.31 (dd, J = 5.0, 14.3 Hz, 1H), 3.18 - 3.11 (m, 1H). MS (ESI) m/z
(M+H) 414.1.
Compound 551 (65 mg, 82.3% yield; white solid): N-(4-amino-3,4-dioxo
phenylbutanyl)(difluoromethyl)(naphthalenyl)-1H-pyrazolecarboxamide: H
NMR (400MHz, DMSO-d ) δ 8.90 (d, J = 7.3 Hz, 1H), 8.53 (s, 1H), 8.16 (d, J = 9.9 Hz, 2H),
8.09 - 7.79 (m, 5H), 7.67 (dd, J = 1.7, 8.5 Hz, 1H), 7.56 - 7.50 (m, 2H), 7.30 - 7.25 (m, 4H), 7.23
- 7.18 (m, 1H), 5.39 - 5.29 (m, 1H), 3.18 (dd, J = 3.9, 13.8 Hz, 1H), 2.82 (dd, J = 10.3, 14.0 Hz,
1H). MS (ESI) m/z (M+H) 463.1.
Compound 552 (60 mg, 53.6% yield; white solid): N-(4-amino-3,4-dioxo
phenylbutanyl)(difluoromethyl)(2,5-difluorophenyl)-1H-pyrazolecarboxamide:
17681897_1 (GHMatters) P110989.NZ
H NMR (400MHz, DMSO-d ) δ 8.75 - 8.67 (m, 2H), 8.09 - 7.76 (m, 3H), 7.32 - 7.15 (m, 8H),
.30 - 5.22 (m, 1H), 3.16 - 3.09 (m, 1H), 2.82 - 2.73 (m, 1H). MS (ESI) m/z (M+H) 449.1.
Compound 554 (174 mg, 86.6% yield; white solid): N-(4-amino-3,4-dioxo
phenylbutanyl)(difluoromethyl)(3-fluoromethylphenyl)-1H-pyrazole
carboxamide: H NMR (400MHz, DMSO-d ) δ 8.83 (d, J = 7.3 Hz, 1H), 8.53 (s, 1H), 8.21 -
7.72 (m, 3H), 7.34 - 7.23 (m, 5H), 7.21 (br dd, J = 2.5, 8.5 Hz, 2H), 7.06 (br d, J = 9.9 Hz, 1H),
.46 - 5.22 (m, 1H), 3.17 (dd, J = 3.9, 14.0 Hz, 1H), 2.80 (dd, J = 10.1, 13.9 Hz, 1H), 2.31 (s,
3H). MS (ESI) m/z (M+H) 445.1.
Compound 555 (85 mg, 57.0% yield; white solid): N-(4-amino-3,4-dioxo
phenylbutanyl)(2,2-difluorobenzo[d][1,3]dioxolyl)(difluoromethyl)-1H-pyrazole
carboxamide: H NMR (400MHz, DMSO-d ) δ 8.34 (s, 1H), 7.57 - 7.27 (m, 1H), 7.24 (br s,
3H), 7.05 - 6.97 (m, 4H), 6.96 - 6.92 (m, 1H), 6.90 (t, J = 6.9 Hz, 1H), 6.71 (d, J = 6.6 Hz, 1H),
6.26 (br s, 1H), 5.55 - 5.42 (m, 1H), 4.16 (br s, 2H), 4.11 - 4.05 (m, 1H), 4.11 - 4.05 (m, 1H),
4.00 - 3.92 (m, 1H), 3.22 (m, J = 4.7, 14.2 Hz, 1H), 2.93 - 2.82 (m, 1H). MS (ESI) m/z
(M+H) 471.1.
Compound 561 (100 mg, 46.4% yield; white solid): N-(4-amino-3,4-dioxo
phenylbutanyl)(difluoromethyl)(isoquinolinyl)-1H-pyrazolecarboxamide: H
NMR (400MHz, DMSO-d ) δ 9.35 (s, 1H), 8.89 (s, 1H), 8.73 (d, J = 7.5 Hz, 1H), 8.39 (s, 1H),
8.24 - 7.88 (s, 3H), 7.78 (s, 1H), 7.74 - 7.66 (m, 2H), 7.66 - 7.59 (m, 1H), 7.33 - 7.15 (m, 5H),
.25 - 5.14 (m, 1H), 3.21 - 3.05 (m, 1H), 2.83 - 2.72 (m, 1H). MS (ESI) m/z (M+H) 464.1.
Compound 563 (110 mg, 84.1% yield; light yellow solid): N-(4-amino-3,4-
dioxophenylbutanyl)(benzo[d][1,3]dioxolyl)(difluoromethyl)-1H-pyrazole
carboxamide: H NMR (400MHz, DMSO-d ) δ 8.67 (d, J = 7.3 Hz, 1H), 8.53 (s, 1H), 8.08 (s,
1H), 7.97 - 7.76 (m, 2H), 7.34 - 7.19 (m, 5H), 6.97 - 6.91 (m, 1H), 6.90 - 6.80 (m, 2H), 5.90 (s,
1H), 5.78 (s, 1H), 5.33 - 5.23 (m, 1H), 3.15 (dd, J = 3.9, 14.0 Hz, 1H), 2.81 (dd, J = 9.7, 13.9 Hz,
1H). MS (ESI) m/z (M+H) 457.1.
Compound 564 (128 mg, 79.3% yield; white solid): N-(4-amino-3,4-dioxo
phenylbutanyl)(difluoromethyl)(2-fluoromethylphenyl)-1H-pyrazole
carboxamide: H NMR (400MHz, DMSO-d ) δ 8.71 - 8.60 (m, 2H), 8.11 - 8.02 (m, 1H), 7.97 -
17681897_1 (GHMatters) P110989.NZ
7.76 (m, 2H), 7.33 - 7.16 (m, 7H), 7.11 - 7.02 (m, 1H), 5.32 - 5.23 (m, 1H), 3.15 (dd, J = 3.9,
14.0 Hz, 1H), 2.81 (dd, J = 9.9, 13.9 Hz, 1H), 2.29 (s, 3H). MS (ESI) m/z (M+H) 445.1.
Compound 565 (75 mg, 80.2% yield; white solid): N-(4-amino-3,4-dioxo
phenylbutanyl)(difluoromethyl)(3,5-dimethylphenyl)-1H-pyrazolecarboxamide:
H NMR (400MHz, DMSO-d ) δ 8.42 (s, 1H), 8.34 - 8.23 (m, 1H), 7.98 - 7.47 (m, 3H), 7.28 -
7.20 (m, 7H), 7.03 (s, 1H), 5.39 - 5.33 (m, 1H), 3.23 - 3.19 (m, 1H), 2.90 (dd, J = 9.2, 13.9 Hz,
1H), 2.29 (s, 6H). MS (ESI) m/z (M+H) 441.1.
Compound 566 (135 mg, 78.7% yield; white solid): N-(4-amino-3,4-dioxo
phenylbutanyl)(difluoromethyl)(5-fluoromethylphenyl)-1H-pyrazole
carboxamide: H NMR (400MHz, DMSO-d ) δ 8.74 (s, 1H), 8.49 (d, J = 7.7 Hz, 1H), 8.10 -
7.77 (m, 3H), 7.31 - 7.18 (m, 6H), 7.17 - 7.10 (m, 1H), 6.96 (dd, J = 2.9, 9.5 Hz, 1H), 5.32 - 5.23
(m, 1H), 3.15 (dd, J = 3.7, 13.9 Hz, 1H), 2.78 (dd, J = 9.9, 13.9 Hz, 1H), 1.97 (s, 3H). MS (ESI)
m/z (M+H) 445.1.
Compound 575 (20 mg, 66.9% yield; white solid): N-(4-amino-3,4-dioxo
phenylbutanyl)(difluoromethyl)(quinolinyl)-1H-pyrazolecarboxamide: H
NMR (400MHz, DMSO-d ) δ 8.94 (dd, J = 1.6, 4.1 Hz, 1H), 8.67 - 8.48 (m, 2H), 8.43 - 8.33 (m,
2H), 7.98 - 7.71 (m, 4H), 7.58 - 7.53 (m, 1H), 7.31 - 7.17 (m, 6H), 5.48 - 5.28 (m, 1H), 3.24 (dd,
J = 4.5, 14.1 Hz, 1H), 2.93 (dd, J = 9.3, 14.1 Hz, 1H). MS (ESI) m/z (M+H) 464.1.
Compound 576 (125 mg, 66.2% yield; white solid): N-(4-amino-3,4-dioxo
phenylbutanyl)(difluoromethyl)(quinolinyl)-1H-pyrazolecarboxamide: H
NMR (400MHz, DMSO-d ) δ 8.94 - 8.82 (m, 2H), 8.66 (br d, J = 7.5 Hz, 1H), 8.20 - 7.98 (m,
4H), 7.87 - 7.72 (m, 2H), 7.55 - 7.40 (m, 2H), 7.32 - 7.17 (m, 5H), 5.27 - 5.14 (m, 1H), 3.13 (br
dd, J = 3.5, 13.9 Hz, 1H), 2.78 (br dd, J = 10.0, 13.8 Hz, 1H). MS (ESI) m/z (M+H) 471.1.
Compound 577 (110 mg, 47.2% yield; white solid): N-(4-amino-3,4-dioxo
phenylbutanyl)(difluoromethyl)(isoquinolinyl)-1H-pyrazolecarboxamide: H
NMR (400MHz, DMSO-d ) δ 9.31 (s, 1H), 8.93 (d, J = 7.5 Hz, 1H), 8.58 (s, 1H), 8.51 (d, J = 5.7
Hz, 1H), 8.23 - 8.17 (m, 1H), 8.15 - 7.81 (m, 6H), 7.31 - 7.25 (m, 4H), 7.24 - 7.17 (m, 1H), 5.45
- 5.26 (m, 1H), 3.19 (dd, J = 4.0, 13.9 Hz, 1H), 2.90 - 2.77 (m, 1H). MS (ESI) m/z (M+H) 471.1.
Compound 581 (30 mg, 37.5% yield; white solid): N-(4-amino-3,4-dioxo
phenylbutanyl)(difluoromethyl)(pyrazinyl)-1H-pyrazolecarboxamide: H
17681897_1 (GHMatters) P110989.NZ
NMR (400MHz, DMSO-d ) δ 10.55 (d, J = 7.0 Hz, 1H), 9.40 - 9.27 (m, 1H), 8.91 - 8.83 (m,
2H), 8.73 - 8.15 (m, 1H), 8.06 - 7.67 (m, 3H), 7.30 - 7.23 (m, 5H), 5.75 - 5.62 (m, 1H), 3.28 -
3.16 (m, 2H). MS (ESI) m/z (M+H) 415.1.
Compound 582 (11.4 mg, 13.6% yield; white solid): N-(4-amino-3,4-dioxo
phenylbutanyl)(difluoromethyl)(5-methylpyridinyl)-1H-pyrazole
carboxamide: H NMR (400MHz, DMSO-d ) δ 8.83 (d, J = 7.5 Hz, 1H), 8.62 (s, 1H), 8.55 (d, J
= 2.0 Hz, 1H), 8.40 (d, J = 1.3 Hz, 1H), 8.08 - 7.79 (m, 3H), 7.76 (s, 1H), 7.30 - 7.25 (m, 4H),
7.21 (td, J = 4.5, 8.8 Hz, 1H), 5.36 - 5.27 (m, 1H), 3.17 (dd, J = 3.7, 13.7 Hz, 1H), 2.81 (dd, J =
.0, 14.0 Hz, 1H), 2.29 (s, 3H). MS (ESI) m/z (M+H) 428.1.
Compound 586 (56 mg, 32.4% yield; white solid): N-(4-amino-3,4-dioxo
phenylbutanyl)(difluoromethyl)(5-fluoropyridinyl)-1H-pyrazolecarboxamide:
H NMR (400MHz, DMSO-d ) δ 8.94 - 8.86 (m, 1H), 8.74 (s, 1H), 8.69 - 8.58 (m, 2H), 8.15 -
8.08 (m, 1H), 8.01 - 7.81 (m, 3H), 7.29 (br d, J = 4.2 Hz, 4H), 7.21 (br d, J = 4.4 Hz, 1H), 5.36
(br s, 1H), 3.23 - 3.14 (m, 1H), 2.87 - 2.77 (m, 1H). MS (ESI) m/z (M+H) 431.0.
Compound 588 (95 mg, 63.0% yield; white solid): N-(4-amino-3,4-dioxo
phenylbutanyl)(difluoromethyl)(quinolinyl)-1H-pyrazolecarboxamide: H
NMR (400MHz, DMSO-d ) δ 11.90 (d, J = 8.2 Hz, 1H), 8.87 (s, 1H), 8.59 (d, J = 8.6 Hz, 1H),
8.27 (d, J = 8.6 Hz, 1H), 8.20 - 8.04 (m, 2H), 7.98 - 7.79 (m, 2H), 7.76 - 7.64 (m, 3H), 7.02 -
6.91 (m, 5H), 5.78 - 5.70 (m, 1H), 3.32 - 3.27 (m, 1H), 3.14 (dd, J=8.0, 14.0 Hz, 1H). MS (ESI)
m/z (M+H) 464.1.
Compound 596 (110 mg, 58.1% yield; white solid): N-(4-amino-3,4-dioxo
phenylbutanyl)(difluoromethyl)(quinolinyl)-1H-pyrazolecarboxamide: H
NMR (400MHz, DMSO-d ) δ 8.94 - 8.77 (m, 3H), 8.19 - 7.86 (m, 3H), 7.83 - 7.69 (m, 3H), 7.55
- 7.51 (m, 1H), 7.41 - 7.20 (m, 6H), 5.28 - 5.12 (m, 1H), 3.14 (dd, J = 3.6, 14.0 Hz, 1H), 2.79
(dd, J = 9.9, 14.1 Hz, 1H). MS (ESI) m/z (M+H) 464.1.
Compound 598 (85 mg, 53.3% yield; white solid): N-(4-amino-3,4-dioxo
phenylbutanyl)(difluoromethyl)(isoquinolinyl)-1H-pyrazolecarboxamide: H
NMR (400MHz, DMSO-d ) δ 9.35 (s, 1H), 8.90 - 8.63 (m, 2H), 8.41 (d, J = 6.0 Hz, 1H), 8.30 -
7.94 (m, 3H), 7.90 - 7.64 (m, 3H), 7.51 (d, J = 6.0 Hz, 1H), 7.32 - 7.17 (m, 5H), 5.29 - 5.12 (m,
17681897_1 (GHMatters) P110989.NZ
1H), 3.13 (dd, J = 3.9, 14.0 Hz, 1H), 2.77 (dd, J = 10.0, 13.8 Hz, 1H). MS (ESI) m/z (M+H)
464.1.
Compound 608 (25 mg, 37.2% yield; white solid): N-(4-amino-3,4-dioxo
phenylbutanyl)(difluoromethyl)(isoquinolinyl)-1H-pyrazolecarboxamide: H
NMR (400MHz, DMSO-d ) δ 11.96 (d, J = 7.1 Hz, 1H), 9.03 (s, 1H), 8.78 (s, 1H), 8.60 (s, 1H),
8.22 - 7.84 (m, 6H), 7.80 - 7.75 (m, 1H), 7.12 - 7.05 (m, 4H), 7.03 - 6.96 (m, 1H), 5.69 - 5.55 (m,
1H), 3.30 - 3.24 (m, 1H), 3.12 (dd, J = 7.6, 14.0 Hz, 1H). MS (ESI) m/z (M+H) 464.1.
Compound 610 (42 mg, 15.5% yield; pale yellow solid): N-(4-amino-3,4-
dioxophenylbutanyl)(difluoromethyl)(quinolinyl)-1H-pyrazole
carboxamide: H NMR (400MHz, DMSO-d ) δ 9.12 (s, 1H), 8.73 - 8.55 (m, 3H), 8.13 - 7.89
(m, 3H), 7.79 (d, J = 8.8 Hz, 2H), 7.65 (d, J = 7.0 Hz, 2H), 7.28 (s, 5H), 5.39 (s, 1H), 3.00 - 2.82
(m, 1H), 3.3 - 3.15 (m, 1H). MS (ESI) m/z (M+H) 464.1.
Compound 622 (25 mg, 22.7% yield; white solid): N-(4-amino-3,4-dioxo
phenylbutanyl)(difluoromethyl)(quinolinyl)-1H-pyrazolecarboxamide
hydrochloride: H NMR (400MHz, DMSO-d ) δ 9.13 (d, J = 3.7 Hz, 1H), 8.99 (d, J = 7.5 Hz,
1H), 8.86 - 8.75 (m, 1H), 8.67 (s, 1H), 8.44 (s, 1H), 8.19 - 8.12 (m, 2H), 8.12 - 8.07 (m, 1H),
8.00 - 7.80 (m, 3H), 7.32 - 7.25 (m, 4H), 7.24 - 7.18 (m, 1H), 5.43 - 5.26 (m, 1H), 3.26 - 3.12 (m,
1H), 2.90 - 2.80 (m, 1H). MS (ESI) m/z (M+H) 464.1.
Compound 630 (20 mg, 42.58% yield; pale yellow solid): N-(4-amino-3,4-
dioxophenylbutanyl)(difluoromethyl)(isoquinolinyl)-1H-pyrazole
carboxamide: H NMR (400MHz, DMSO-d ) δ 9.31 (s, 1H), 8.68 - 8.48 (m, 3H), 8.41 (s, 1H),
8.08 - 7.71 (m, 5H), 7.60 (br s, 1H), 7.31 - 7.16 (m, 5H), 5.39 (br t, J = 10.5 Hz, 1H), 3.24 (br dd,
J = 4.3, 14.1 Hz, 1H), 2.99 - 2.86 (m, 1H). MS (ESI) m/z (M+H) 464.2.
EXAMPLE 210
COMPOUNDS 385-391, 532
Compounds 385-391, 532 were synthesized from the corresponding starting
material using same procedures as described earlier for Compound 265.
Compound 385 (25 mg, 38.7% yield): (S)-N-(4-amino(4-methoxyphenyl)-
3,4-dioxobutanyl)methylphenyloxazolecarboxamide: H NMR (400MHz, DMSO-
d ) δ 8.74 (br d, J = 7.6 Hz, 1H), 8.10 (br s, 1H), 8.06 - 7.95 (m, 2H), 7.83 (s, 1H), 7.43 - 7.29
17681897_1 (GHMatters) P110989.NZ
(m, 3H), 7.18 (br d, J = 8.4 Hz, 2H), 6.83 (br d, J = 8.4 Hz, 2H), 5.40 - 5.29 (m, 1H), 3.73 - 3.62
(m, 3H), 3.15 - 3.06 (m, 1H), 2.97 - 2.86 (m, 1H), 2.53 (s, 3H). MS (ESI) m/z (M+H) 408.1.
Compound 386 (14 mg, 22.8% yield): (S)-N-(1-amino-1,2-dioxo
phenylpentanyl)methylphenyloxazolecarboxamide: H NMR (400MHz, DMSO-
d ) δ 8.87 (br d, J = 7.2 Hz, 1H), 8.13 - 8.04 (m, 3H), 7.77 (br s, 1H), 7.43 - 7.34 (m, 3H), 7.30 -
7.13 (m, 5H), 5.09 (br s, 1H), 2.81 - 2.70 (m, 1H), 2.67 - 2.61 (m, 1H), 2.56 (s, 3H), 2.15 - 1.90
(m, 2H). MS (ESI) m/z (M+H) 392.1.
Compound 387 (18 mg, 29.4% yield): N-((3S,4R)aminomethyl-1,2-
dioxohexanyl)methylphenyloxazolecarboxamide: H NMR (400MHz, DMSO-d )
δ 8.48 (br d, J = 7.2 Hz, 1H), 8.09 - 8.03 (m, 3H), 7.77 (br s, 1H), 7.43 - 7.32 (m, 3H), 5.17 -
.09 (m, 1H), 2.53 (s, 3H), 2.04 (br s, 1H), 1.41 (br s, 1H), 1.24 - 1.13 (m, 1H), 0.91 - 0.78 (m,
6H). MS (ESI) m/z (M+H) 344.2.
Compound 388 (35 mg, 47.8% yield): (S)-N-(4-amino(3,5-
dimethylphenyl)-3,4-dioxobutanyl)methylphenyloxazolecarboxamide: H NMR
(400MHz, DMSO-d ) δ 8.71 (d, J = 7.2 Hz, 1H), 8.10 (s, 1H), 8.06 - 7.98 (m, 2H), 7.82 (s, 1H),
7.42 - 7.32 (m, 3H), 6.87 (s, 2H), 6.81 (s, 1H), 5.41 - 5.35 (m, 1H), 3.13 - 3.06 (m, 1H), 2.92 -
2.84 (m, 1H), 2.52 (s, 3H), 2.18 (s, 6H). MS (ESI) m/z (M+H) 406.1.
Compound 389 (55 mg, 15.9% yield): (S)-N-(4-amino(1H-indolyl)-3,4-
dioxobutanyl)methylphenyloxazolecarboxamide: H NMR (400MHz, DMSO-d )
δ 10.83 (s, 1H), 8.60 (d, J = 7.2 Hz, 1H), 8.11 (s, 1H), 8.04 - 7.99 (m, 2H), 7.85 (s, 1H), 7.66 (d,
J = 8.0 Hz, 1H), 7.38 - 7.28 (m, 4H), 7.19 - 7.16 (m, 1H), 7.08 - 7.01 (m, 1H), 7.00 - 6.94 (m,
1H), 5.51 - 5.44 (m, 1H), 3.36 - 3.32 (m, 1H), 3.15 - 3.06 (m, 1H), 2.50 (s, 3H). MS (ESI) m/z
(M+H) 417.1.
Compound 390 (50.1 mg, 83.9% yield): N-(4-amino(3,5-dichlorophenyl)-
3,4-dioxobutanyl)methylphenyloxazolecarboxamide: H NMR (400MHz, DMSO-
d ) δ 8.93 (d, J = 7.6 Hz, 1H), 8.09 (br. s, 1H), 8.02 - 7.92 (m, 2H), 7.81 (br. s, 1H), 7.46 - 7.29
(m, 6H), 5.38 - 5.26 (m, 1H), 3.25 - 3.17 (m, 1H), 3.02 -2.88 (m, 1H), 2.52 (s, 3H). MS (ESI)
m/z (M+H) 446.0.
Compound 391 (60 mg, 45.63% yield): (S)-N-(1-amino-5,5-dimethyl-1,2-
dioxohexanyl)methylphenyloxazolecarboxamide: H NMR (400MHz, DMSO-d )
17681897_1 (GHMatters) P110989.NZ
δ 8.06 (br. s, 0.23H), 7.78 (br. s, 0.23H), 7.65 (d, J = 10.0 Hz, 0.73H), 7.43 - 7.33 (m, 3H), 7.32 -
7.26 (m, 1.4H), 6.39 - 6.14 (m, 1H), 5.31 - 5.24 (m, 0.25H), 4.35 - 4.28 (m, 0.74H), 2.55 - 2.50
(m, 3H), 1.74 - 1.66 (m, 0.3H), 1.62 - 1.50 (m, 1H), 1.33 - 1.24 (m, 0.79H), 0.95 - 0.82 (m, 9H).
MS (ESI) m/z (M+H) 358.1.
Compound 532 (65 mg, 27.6% yield; light yellow solid): N-(4-amino(1H-
indolyl)-3,4-dioxobutanyl)phenyl-1,2,5-thiadiazolecarboxamide: H NMR
(400MHz, DMSO-d ) δ 10.67 (br s, 1H), 9.00 (br d, J = 7.3 Hz, 1H), 7.87 (br s, 1H), 7.73 - 7.58
(m, 4H), 7.46 - 7.39 (m, 1H), 7.34 (q, J = 7.5 Hz, 3H), 7.15 (d, J = 2.3 Hz, 1H), 7.09 (t, J = 7.2
Hz, 1H), 7.02 - 6.96 (m, 1H), 5.59 (ddd, J = 4.3, 7.3, 9.0 Hz, 1H), 3.40 (dd, J = 4.1, 14.7 Hz,
1H), 3.16 - 3.10 (m, 1H). MS (ESI) m/z (M+H) 420.1.
EXAMPLE 211
COMPOUND 392
NH O
O MeI
HOAc, Toluene K CO , DMF
392A 392B
O 392
392B
A stirred solution of dimethyl butynedioate (5.4 mL, 44.7 mmol) in toluene
(35 mL) and AcOH (35 mL, 612.0 mmol) at 0 °C was treated cautiously with phenylhydrazine (4
mL, 40.6 mmol). The mixture was stirred at 20 °C for 1 h. Then the mixture was heated to 115
°C and stirred for 4 h. The reaction was on standing at 20 °C for12 h. The reaction was filtered
and the filtered cake was washed with EtOH (30 mL x 3). The cake was dried under reduced
pressure to afford compound 392A (2.2 g, yield 24.7 %) was obtained as white solid, which was
used directly in next step. H NMR (DMSO-d , 400MHz): δ 12.16 (br s, 1H), 7.77 - 7.70 (m,
2H), 7.54 - 7.47 (m, 2H), 7.40 - 7.37 (m, 1H), 5.97 (s, 1H), 3.80 (s, 3H).
To a solution of compound 392A (1 g, 4.5 mmol) in DMF (20 mL) was added
K CO (1.2 g, 9.1 mmol) and MeI (855 uL, 13.7 mmol). Then mixture was stirred at 15 °C for
17681897_1 (GHMatters) P110989.NZ
12h. The mixture was filtered and the residue was washed with EA (20 mL x 2). H O (20 mL)
was added to the mixture and the organic layer was separated, the aqueous was extracted with
EA (20 mL x 2). The combined organic layer was washed with brine, dried over anhydrous
Na SO , filtered, concentrated under reduced pressure to afford compound 392B (0.515 g, yield
48.3 %) as white solid, which was used directly in next step. H NMR (DMSO-d , 400MHz): δ
7.67 (d, J = 7.9 Hz, 2H), 7.51 (t, J = 7.8 Hz, 2H), 7.44 - 7.37 (m, 1H), 6.41 (s, 1H), 3.98 (s, 3H),
3.83 (s, 3H).
Compound 392 was synthesized from 392B and using same procedures
described earlier for compound 66. Compound 392 (40 mg, 21.8% yield): N-(4-amino-3,4-
dioxophenylbutanyl)methoxyphenyl-1H-pyrazolecarboxamide: H NMR
(400MHz, DMSO-d ) δ 8.38 (br d, J=7.8 Hz, 1H), 8.11 (br s, 1H), 7.86 (br s, 1H), 7.71 (br d,
J=8.0 Hz, 2H), 7.53 (br t, J=7.7 Hz, 2H), 7.44 - 7.35 (m, 1H), 7.32 - 7.15 (m, 5H), 6.26 (s, 1H),
.44 (br d, J=3.3 Hz, 1H), 3.96 (s, 3H), 3.21 (br dd, J=3.8, 14.1 Hz, 1H), 3.11 - 3.00 (m, 1H).
MS (ESI) m/z (M+H) 393.1.
EXAMPLE 212
COMPOUND 393
O O O
HO S NO
MeCN
393A
O O 2
393A 2
MeCN
393B
N NH
CH CN N
393C 393
To a solution of 2,4-dinitrobenzenesulfonic acid (10.0 g, 31.05 mmol) in
CH CN (150 mL) was added phenyliodosobenzene diacetate (15.4 g, 62.09 mmol). The mixture
was stirred at 25 °C for 1 h. The mixture was added MTBE (400 mL), cooled by ice water 10
17681897_1 (GHMatters) P110989.NZ
min. Then the mixture was filtered and the filter was collected. Compound 393A (11 g, crude)
was obtained as a yellow solid. The crude product was used in next step directly.
To a solution of compound 393A (11.3 g, 24.14 mmol) in CH CN (100 mL)
was added ethyl 3-oxophenylpropanoate (4.23 g, 21.98 mmol). The mixture was stirred at 90
°C for 1 h. The reaction mixture was used in next step directly.
To a solution of compound 393B (9.69 g, 21.95 mmol) in CH CN (100 mL)
was added cyclopropanecarboxamide (2.24 g, 26.34 mmol). The mixture was stirred at 90 °C for
12 h. The mixture was concentrated. The residue was purified by column chromatography SiO ,
Petroleum ether/Ethyl acetate = 10/1. Compound 393C (800.0 mg, crude) was obtained as a
colorless oil. The crude product was used in next step directly.
Compound 393 was synthesized from 393C and using same procedures
described earlier for compound 66. Compound 393 (60 mg, 29.0% yield): N-(4-amino-3,4-
dioxophenylbutanyl)cyclopropylphenyloxazolecarboxamide: H NMR
(400MHz, DMSO-d ) δ 8.71 (d, J = 7.6 Hz, 1H), 8.11 (s, 1H), 8.04 - 7.96 (m, 2H), 7.84 (s, 1H),
7.40 - 7.14 (m, 8H), 5.39 - 5.31 (m, 1H), 3.23 - 3.15 (m, 1H), 2.99 - 2.91 (m, 1H), 2.24 - 2.14 (m,
1H), 1.23 - 1.03 (m, 4H). MS (ESI) m/z (M+H) 404.1.
EXAMPLE 213
COMPOUND 394
O OH
PhCOCl
HN O
LiHMDS
EDCI,HOBT,DIEA
394A
394B
PPh , I O
N NH
394C
A mixture of ethyl 2-((diphenylmethylene)amino)acetate (5.00 g, 18.70 mmol)
in THF (100 mL) was degassed and purged with N for 3 times, and LiHMDS (1M, 22 mL) was
added at -78 °C, then the mixture was stirred for 0.5 h, then benzoyl chloride (22.44 mmol, 2.61
mL) was added at -78°C, and the mixture was stirred at 25 °C for 2h under N atmosphere. The
mixture was quenched with HCl (2N, 240 mL), and stirred for 1h, then washed with EA (50 mL).
17681897_1 (GHMatters) P110989.NZ
The aqueous phase was collected, added NaHCO (aqueous) to pH ~ 9, then extracted with EA
(100 mL). The organic layer was washed with brine (100 mL), dried over Na SO and
concentrated. Compound 394A (2.6 g, crude) was obtained as a yellow oil. The crude product
was used in next step directly.
To a solution of compound 394A (1.30 g, 6.27 mmol) in DMF (20 mL) was
added DIEA (25.09 mmol, 4.4 mL), cyclopropanecarboxylic acid (648.1 mg, 7.53 mmol), and
HBTU (2.62 g, 6.90 mmol). The mixture was stirred at 25 °C for 1 hr. The mixture was
concentrated, diluted with EA (200 mL), washed with HCl (1M, 200 mL), NaHCO (aqueous,
200 mL), brine (200 mL), dried over Na SO and concentrated. The residue was purified by
preparatory-HPLC (TFA condition). Compound 394B (400.0 mg, 1.45 mmol, 23.2% yield) was
obtained as a white solid. H NMR (400MHz, DMSO-d ) δ 9.13 (d, J = 8.0 Hz, 1H), 7.98 - 7.92
(m, 2H), 7.71 - 7.64 (m, 1H), 7.58 - 7.50 (m, 2H), 6.17 (d, J = 8.0 Hz, 1H), 4.16 - 4.05 (m, 2H),
1.83 - 1.74 (m, 1H), 1.11 - 1.04 (m, 3H), 0.74 - 0.60 (m, 4H).
To a solution of compound 394B (400.0 mg, 1.45 mmol) in DCM (15 mL) was
added Et N (5.96 mmol, 800 uL), I2 (737.6 mg, 2.91 mmol) and PPh (762.2 mg, 2.91 mmol).
The mixture was stirred at 25 °C for 2h. The mixture was concentrated. The residue was
purified by column chromatography (SiO , Petroleum ether/Ethyl acetate = 5/1 to 0:1).
Compound 394C (300.0 mg, crude) was obtained as a yellow oil. The crude product was used in
next step without further purification..
Compound 394 was synthesized from 394C and using same procedures
described earlier for compound 66. Compound 394 (50 mg, 31.4% yield): N-(4-amino-3,4-
dioxophenylbutanyl)cyclopropylphenyloxazolecarboxamide: H NMR
(400MHz, DMSO-d ) δ 8.31 (d, J = 7.6 Hz, 1H), 8.11 (s, 1H), 8.05 - 7.99 (m, 2H), 7.86 (s, 1H),
7.45 - 7.36 (m, 3H), 7.29 - 7.16 (m, 5H), 5.45 - 5.38 (m, 1H), 3.23 - 3.16 (m, 1H), 3.11 - 3.03 (m,
1H), 2.22 - 2.13 (m, 1H), 1.13 - 1.04 (m, 4H). MS (ESI) m/z (M+H) 404.2.
17681897_1 (GHMatters) P110989.NZ
EXAMPLE 214
COMPOUND 395
Br O
,K CO O
Pd(dppf)Cl
2 2 3
CHCl
dioxane/H O
395B
395A
CONH
395B
To a mixture of ethyl 3-bromomethyl-1H-pyrazolecarboxylate (1 g, 4.29
mmol), 2-benzyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.12 g, 5.15 mmol), K CO (1.19 g,
8.58 mmol) in dioxane (15 mL) and H O (5 mL) was added Pd(dppf)Cl (314 mg, 429.07 umol)
in portion at 15 °C under N . The mixture was stirred at 90 °C for 16 h. The reaction was diluted
with H O (20 mL), extracted with EtOAc (40 mL x 2), the organic phase was dried over Na SO ,
2 2 4
filtered and concentrated to give a residue. The residue was purified by column chromatography
(SiO , Petroleum ether: Ethyl acetate = 5:1 to 3:1) to give compound 395A (1g, yield: 35.4%) as
yellow solid. H NMR (400MHz, CDCl ) δ 7.82 (s, 1H), 7.82 (s, 1H), 7.38 - 7.10 (m, 5H), 4.25 -
4.19 (m, 2H), 3.89 (s, 3H), 3.85 (s, 2H), 1.34 (t, J = 7.1 Hz, 3H). MS (ESI) m/z (M+H) 245.0.
To a mixture of compound 395A (0.85 g, 3.48 mmol) in CHCl (30 mL) was
added MnO (4.54 g, 52.19 mmol) in one portion at 15 °C. The mixture was stirred at 70 °C for
36 h. The reaction mixture was filtered and concentrated under reduced pressure to give a
residue. The residue was purified by column chromatography (SiO , Petroleum ether: Ethyl
acetate= 5:1 to 1:1) to give compound 395B (0.25 g, yield: 24.12%) as a white solid. H NMR
(400MHz, CDCl ) δ 7.97 (s, 1H), 7.95 - 7.91 (m, 2H), 7.59 (t, J = 6.9 Hz, 1H), 7.46 (t, J = 7.2
Hz, 2H), 4.12 - 4.06 (m, 2H), 4.01 (s, 3H), 1.03 (t, J = 7.2 Hz, 3H). MS (ESI) m/z (M+H) 258.9.
Compound 395 was synthesized from 395B and using same procedures
described earlier for compound 66. Compound 395 (20 mg, 18.61% yield): N-(4-amino-3,4-
dioxophenylbutanyl)benzoylmethyl-1H-pyrazolecarboxamide: H NMR
(400MHz, CD CN) δ 9.77 (d, J = 5.3 Hz, 1H), 8.13 (s, 1H), 8.02 (d, J = 7.9 Hz, 2H), 7.75 - 7.62
17681897_1 (GHMatters) P110989.NZ
(m, 1H), 7.52 (t, J = 7.3 Hz, 2H), 7.24 - 7.16 (m, 5H), 7.07 - 6.95 (m, 1H), 6.22 (s, 1H), 5.62 -
.44 (m, 1H), 3.92 (s, 3H), 3.33 (dd, J = 4.5, 13.8 Hz, 1H), 3.03 (dd, J = 8.4, 13.9 Hz, 1H). MS
(ESI) m/z (M+H) 405.1.
EXAMPLE 215
COMPOUNDS 396-402
Compounds 396-402 were synthesized from the corresponding starting material
using same procedures as described earlier for Compound 21.
Compound 396 (260 mg, 81.12% yield): 1-(difluoromethyl)-N-(1-oxo
phenylpropanyl)phenyl-1H-pyrazolecarboxamide: H NMR (400MHz, CD CN) δ
9.61 (s, 1H), 8.27 (s, 1H), 7.59 - 7.51 (m, 2H), 7.44 - 7.35 (m, 3H), 7.33 - 7.23 (m, 3H), 7.22 -
7.16 (m, 2H), 6.93 (d, J = 7.7 Hz, 1H), 4.60 (ddd, J = 5.0, 7.6, 9.1 Hz, 1H), 3.26 (dd, J = 5.1,
14.1 Hz, 1H), 2.92 (dd, J = 9.0, 14.1 Hz, 1H). MS (ESI) m/z (M+H) 370.0.
Compound 397 (153 mg, 50.5% yield): N-(1-oxophenylpropanyl)
phenylisoxazolecarboxamide: H NMR (400MHz, DMSO-d ) δ 9.61 (s, 1H), 8.96 (d, J =
7.3 Hz, 1H), 8.83 (s, 1H), 7.82 (d, J = 7.3 Hz, 2H), 7.57 - 7.39 (m, 3H), 7.31 - 7.13 (m, 5H), 4.55
(s, 1H), 3.28 - 3.19 (m, 1H), 2.92 - 2.76 (m, 1H). MS (ESI) m/z (M+H) 321.0.
Compound 398 (180 mg, 52.4% yield): 3-methyl-N-(1-oxophenylpropan-
2-yl)(pyridinyl)-1H-pyrazolecarboxamide: H NMR (400MHz, CD CN) δ 9.59 (s,
1H), 9.17 (d, J = 7.2 Hz, 1H), 8.29 - 8.24 (m, 1H), 7.94 - 7.87 (m, 1H), 7.61 (d, J = 8.0 Hz, 1H),
7.34 - 7.23 (m, 5H), 7.22 - 7.16 (m, 1H), 6.46 (s, 1H), 4.37 - 4.29 (m, 1H), 3.20 - 3.12 (m, 1H),
2.89 - 2.80 (m, 1H), 2.24 (s, 3H). MS (ESI) m/z (M+H) 375.0.
Compound 399 (580 mg, 85.67% yield): 3-methyl-N-(1-oxophenylpropan-
2-yl)(5-(trifluoromethyl)pyridinyl)-1H-pyrazolecarboxamide: H NMR (400MHz,
CD CN) δ 9.69 (s, 1H), 8.52-8.40 (m, 1H), 8.16 (dd, J = 2.4, 8.6 Hz, 1H), 7.99 (br d, J = 6.2 Hz,
1H), 7.89 (d, J = 8.6 Hz, 1H), 7.34-7.16 (m, 5H), 6.55 (s, 1H), 4.57 (ddd, J = 5.1, 7.2, 8.9 Hz,
1H), 3.28 (dd, J = 5.1, 14.3 Hz, 1H), 3.01 (dd, J = 8.9, 14.2 Hz, 1H), 2.31 (s, 3H). MS (ESI) m/z
(M+H) 403.1.
Compound 400 (135 mg, 46.3% yield): 1-(3-((benzyloxy)methyl)phenyl)
methyl-N-(1-oxophenylpropanyl)-1H-pyrazolecarboxamide: H NMR (400MHz,
CDCl ) δ 9.60 (s, 1H), 7.45 (s, 1H), 7.42 - 7.28 (m, 10H), 7.09 - 7.04 (m, 2H), 6.51 (s, 1H), 6.32
17681897_1 (GHMatters) P110989.NZ
(d, J = 6.0 Hz, 1H), 4.78 (q, J = 6.6 Hz, 1H), 4.59 (d, J = 14.3 Hz, 5H), 3.22 - 3.10 (m, 2H), 2.35
(s, 3H). MS (ESI) m/z (M+H) 454.2.
Compound 401 (180 mg, 37.0% yield): N-(1-oxophenylpropanyl)
phenyl-1,2,5-thiadiazolecarboxamide: H NMR (400MHz, DMSO-d ) δ 9.64 (s, 1H), 9.35
(br d, J = 8.0 Hz, 1H), 7.57 - 7.53 (m, 2H), 7.47 - 7.41 (m, 1H), 7.40 - 7.34 (m, 2H), 7.29 - 7.18
(m, 5H), 4.75 - 4.68 (m, 1H), 3.29 - 3.25 (m, 1H), 2.89 - 2.81 (m, 1H). MS (ESI) m/z (M+H)
338.0.
Compound 402 (250 mg, 35.9% yield): 4-(2-fluorophenyl)methyl-N-(1-
oxophenylpropanyl)oxazolecarboxamide: H NMR (400MHz, DMSO-d ) δ 9.53 (s,
1H), 8.85 (d, J = 7.6 Hz, 1H), 7.49 - 7.40 (m, 2H), 7.28 - 7.14 (m, 7H), 4.50 - 4.44 (m, 1H), 3.25
- 3.18 (m, 1H), 2.94 - 2.86 (m, 1H), 2.52 (s, 3H). MS (ESI) m/z (M+H) 353.1.
EXAMPLE 216
COMPOUNDS 404-405, 609, 618
Compounds 404-405, 609, and 618 were synthesized from the corresponding
starting materials using same procedures as described earlier for Example 254.
Compound 404 (3.69 g, 85.6% yield): N-(4-amino-3,4-dioxophenylbutan-
2-yl)(3-fluorophenyl)methyloxazolecarboxamide: H NMR (400MHz, CDCl3) δ 8.02
- 7.89 (m, 2H), 7.44 - 7.26 (m, 4H), 7.21 - 7.01 (m, 3H), 6.88 - 6.69 (m, 2H), 5.79 - 5.70 (m, 1H),
.66 (br s, 1H), 3.53 - 3.39 (m, 1H), 3.35 - 3.18 (m, 1H), 2.56 (s, 3H). MS (ESI) m/z (M+1)
396.1.
Compound 405 was prepared by oxidation of N-(4-aminohydroxyoxo
phenylbutanyl)(2-fluorophenyl)methyloxazolecarboxamide using the same conditons
as used for oxidation of intermediate 12H to 12. Compound 405 (3.97 g, 34.6% yield): N-(4-
amino-3,4-dioxophenylbutanyl)(2-fluorophenyl)methyloxazolecarboxamide:
H NMR (400MHz, DMSO-d ) δ 8.78 (d, J = 7.2 Hz, 1H), 8.07 (br. s, 1H), 7.82 (br. s, 1H), 7.48
- 7.38 (m, 2H), 7.31 - 7.14 (m, 7H), 5.38 - 5.29 (m, 1H), 3.17 - 3.09 (m, 1H), 2.98 - 2.88 (m, 1H),
2.53 (s, 3H). MS (ESI) m/z (M+H) 396.1.
Alternately, N-(4-aminohydroxyoxophenylbutanyl)(2-
fluorophenyl)methyloxazolecarboxamide was oxidized using EDC and dichloroacetic acid
as shown below to yield compound 405.
17681897_1 (GHMatters) P110989.NZ
N-(3-Dimethylaminopropyl)-N’-ethylcarbodiimide hydrochloride (351.5 mg,
2.3 mmol, 9 eq) was added to a solution of compound N-(4-aminohydroxyoxo
phenylbutanyl)(2-fluorophenyl)methyloxazolecarboxamide (100 mg, 0.25 mmol, 1.0
equiv) in DMSO (5 mL) at room temperature. After stirring for 10 minutes, dichloroacetic acid
(0.083 mL, 1 mmol, 4 equiv) was added. The reaction was stirred at room temperature for 1
hour, at which point LC-MS indicated the reaction was complete. The mixture was diluted with
dichloromethane (10 mL) and sequentially washed with saturated sodium bicarbonate (2 x 10
mL), 1N HCl (2 x 10 mL) and saturated brine (10 mL). The organic layer was dried over sodium
sulfate and concentrated under reduced pressure. The resulting solid was triturated with ethyl
acetate (2 x 1 mL) at room temperature for 2 hours and dried under vacuum at 45 °C overnight to
give compound 405 as a white solid ( 69 mg, 70% yield; (M+H) 396.1.
Compound 609 (70 mg, 35.13% yield, white solid): N-(4-amino-3,4-dioxo
phenylbutanyl)(benzo[d][1,3]dioxolyl)methyloxazolecarboxamide: H NMR
(400MHz, DMSO-d ) δ 8.31 - 8.18 (m, 1H), 7.80 (br. s, 1H), 7.61 (br. s, 1H), 7.33 - 7.14 (m,
5H), 7.06 - 6.98 (m, 1H), 6.94 - 6.79 (m, 2H), 5.96 - 5.85 (m, 2H), 5.45 - 5.34 (m, 1H), 3.27 -
3.18 (m, 1H), 3.05 - 2.95 (m, 1H). MS (ESI) m/z (M+H) 422.1.
Compound 618 (80 mg, 39.73% yield, white solid): N-(4-amino-3,4-dioxo
phenylbutanyl)(2,2-difluorobenzo[d][1,3]dioxolyl)methyloxazolecarboxamide:
H NMR (400MHz, DMSO-d6) δ 7.52 - 7.45 (m, 1H), 7.32 - 7.26 (m, 2H), 7.25 - 7.18 (m, 1H),
7.13 - 7.05 (m, 4H), 6.79 - 6.68 (m, 2H), 5.71 - 5.63 (m, 1H), 5.56 (br. s, 1H), 3.48 - 3.40 (m,
1H), 3.30 - 3.21 (m, 1H), 2.57 (s, 3H). MS (ESI) m/z (M+H) 458.1.
EXAMPLE 217
COMPOUND 406
Compounds 406 was synthesized from the corresponding starting intermediates
274D and 250D using same procedures as described earlier for Example 306. Compound 406
(3.3 g): N-(4-amino-3,4-dioxophenylbutanyl)cyclopropylphenyl-1H-pyrazole
carboxamide: H NMR (400MHz, DMSO-d ) δ 8.34 (br d, J = 7.1 Hz, 1H), 8.12 (s, 1H), 8.06
(br s, 1H), 7.80 (br.s., 1H), 7.53 (br d, J = 3.1 Hz, 2H), 7.35 - 7.09 (m, 8H), 5.26 (br s, 1H), 3.78
(br s, 1H), 3.14 (br d, J = 11.5 Hz, 1H), 2.87 - 2.73 (m, 1H), 2.05 (s, 1H), 1.11 - 0.92 (m, 4H).
MS (ESI) m/z (M+H) 403.4.
17681897_1 (GHMatters) P110989.NZ
EXAMPLE 218
COMPOUND 410
H N N
Cl O
LDA,CO
K CO , C
DMF,110
CF CF
410A
410B
N NH
A mixture of 4-(trifluoromethyl)-1H-pyrazolecompound (1 g, 7.35 mmol), 2-
chloropyrimidine (926 mg, 8.09 mmol) and K CO (2.03 g, 14.7 mmol) in DMF (15 mL) was
heated to 110 °C for 12 hr. The mixture was added water (20 mL) and extracted with ethyl
acetate (20 mL x 2), the organic phases were washed with brine (10 mL), dried over Na SO ,
filtered and concentrated. The residue was recrystallized by MTBE to give compound 410A (800
mg, yield: 50.8%) as yellow solid. H NMR (400MHz, CDCl ) δ 8.94 (s, 1H), 8.83 (d, J = 4.8
Hz, 2H), 8.03 (s, 1H), 7.34 (t, J = 4.8 Hz, 1H).
To a solution of compound 410A (350 mg, 1.63 mmol) in THF (10 mL) was
added LDA (2M, 1.06 mL) dropwise at -78 °C and stirred for 10 min, then CO was bubbled into
the mixture for 20 min at -78 °C, then slowly warmed to 15 °C for 1hr. The mixture was added
water (20 mL) and extracted with ethyl acetate (10 mL x 2), the water layer was adjusted to pH ~
3 with 1N HCl and extracted with ethyl acetate (10 mL x 2), the organic phases were dried and
concentrated to give compound 410B (140 mg, yield: 33.3%), as yellow solid. H NMR
(400MHz, CDCl ) δ 8.79 (d, J = 4.9 Hz, 2H), 7.93 (s, 1H), 7.34 (t, J = 4.7 Hz, 1H).
Compounds 410 was synthesized from the corresponding starting intermediates
274D and 410B using same procedures as described earlier for Example 305. Compound 410
(3.3 g): N-(4-amino-3,4-dioxophenylbutanyl)(pyrimidinyl)(trifluoromethyl)-
1H-pyrazolecarboxamide: H NMR (400MHz, DMSO-d ) δ 8.68 (d, J = 4.6 Hz, 2H), 7.94
(s, 1H), 7.32 - 7.26 (m, 2H), 7.24 - 7.14 (m, 4H), 6.81 (br d, J = 7.1 Hz, 1H), 6.71 (br s, 1H), 5.85
17681897_1 (GHMatters) P110989.NZ
(q, J=6.4 Hz, 1H), 5.51 (br s, 1H), 3.49 - 3.40 (m, 1H), 3.39 - 3.29 (m, 1H). MS (ESI) m/z
(M+H) 433.1.
EXAMPLE 219
COMPOUND 411
HCl/MeOH CuI,Cs CO 24h
,20 C,DMF,
2-(2-methylpropanoyl)cyclohexanone
411A
411B
LiOH
THF,H O
2 OH N
N NH
411C
A mixture of (S)(tert-butoxycarbonyl)azaspiro[2.4]heptanecarboxylic
acid (2 g, 8.29 mmol) in MeOH (5 mL), HCl/MeOH (50 mL) was stirred at 1 °C for 12 hour.
The reaction mixture was concentrated under reduced pressure to give a residue. Compound
411A (1.3 g, crude) was obtained as a yellow solid. H NMR (400MHz, CDCl3) δ 11.09 (br s,
1H), 9.14 (br s, 1H), 4.64 (br s, 1H), 3.85 (s, 3H), 3.55 - 3.33 (m, 3H), 2.87 - 2.64 (m, 2H), 2.38
(br dd, J = 8.2, 13.0 Hz, 1H), 2.10 (br dd, J = 5.3, 13.0 Hz, 1H), 0.87 - 0.71 (m, 3H), 0.71 - 0.61
(m, 1H).
A mixture of compound 411A (1 g, 6.44 mmol), iodobenzene (5.26 g, 25.8
mmol), Cs CO (6.30 g, 19.3 mmol), CuI (981.76 mg, 5.15 mmol) in DMF (40 mL) was
degassed and purged with N for 3 times, and then the mixture was stirred at 110 °C for 12 hours
under N atmosphere. The reaction mixture was filtered and concentrated under reduced
pressure to give a residue. The residue was purified by column chromatography (SiO ,
Petroleum ether: Ethyl acetate = 95:1 to 90:1). And then the residue was purified by preparatory-
HPLC (TFA condition). Compound 411B (120 mg, yield: 8.06%) was obtained as a yellow oil.
H NMR (400MHz, CDCl ) δ 7.32 - 7.12 (m, 2H), 6.72 (t, J = 7.3 Hz, 1H), 6.50 (d, J = 7.9 Hz,
2H), 4.40 (dd, J = 2.4, 8.6 Hz, 1H), 3.80 - 3.62 (m, 3H), 3.48 (d, J = 8.6 Hz, 1H), 3.29 (d, J = 8.6
Hz, 1H), 2.50 (dd, J = 8.8, 12.6 Hz, 1H), 1.87 (dd, J = 2.4, 12.6 Hz, 1H), 0.79 - 0.51 (m, 4H).
Compounds 411 was synthesized from the corresponding starting intermediates
274D and 411B using same procedures as described earlier for Example 321. Compound 411
17681897_1 (GHMatters) P110989.NZ
(53.2 mg, yield: 50.5%): (6S)-N-(4-amino-3,4-dioxophenylbutanyl)phenyl
azaspiro[2.4]heptanecarboxamide: H NMR (400MHz, CDCl ) δ 7.16 - 7.06 (m, 4H), 7.04
- 6.87 (m, 3H), 6.77 - 6.66 (m, 2H), 6.60 (br s, 1H), 6.54 - 6.38 (m, 2H), 5.58 - 5.21 (m, 2H),
4.05 - 3.93 (m, 1H), 3.39 - 3.22 (m, 1H), 3.09 - 2.90 (m, 2H), 2.82 - 2.69 (m, 1H), 2.45 - 2.30 (m,
1H), 1.68 - 1.53 (m, 1H), 0.56 - 0.34 (m, 3H), 0.17 -0.05 (m, 1H). MS (ESI) m/z (M+H) 392.2.
EXAMPLE 220
2-(1,1-DIOXIDO-1,2-THIAZINANYL)METHYL-N-(4-METHYLOXOPENTAN-
2-YL)BUTANAMIDE (412)
Cl N
TEA, DCM
412A
K CO NaOH
2 3 S O
S OH
DMF THF
MeOH
412B
2 412C
HOSu
DCC, THF
O EA
412D
DMP N
412E
To a mixture of methyl L-valinate (2.63 g, 15.7 mmol, HCl) in DCM (50 mL)
was added TEA (4.5 mL, 32.3 mmol) in one portion. After 4-chlorobutanesulfonyl chloride
(2.5 g, 13.1 mmol) was dropwise added at 0 °C, the mixture was stirred for 30 min at 0 °C, then
stirred at 15 °C for 1.5 h. The reaction mixture was washed with 0.5N HCl (20 mL), sat.
NaHCO (20 mL) and sat. NaCl (20 mL). The separated organic layer was dried over Na SO ,
3 2 4
filtered and concentrated under reduced pressure to afford compound 412A (2.26 g, yield 60.4%)
as light yellow viscous oil, which was used directly for next step without purification. MS (ESI)
m/z (M+H) 286.1.
17681897_1 (GHMatters) P110989.NZ
To a mixture of compound 412A (3.16 g, 11.1 mmol) in DMF (150 mL) was
added K CO (3.82 g, 27.6 mmol) in one portion. The mixture was stirred at 15 °C for 18 h.
H O (200 mL) was added into the mixture, which was extracted with EA (150 mL x 3). The
combined organic phase was washed with sat. NaCl (200 mL x 2) and dried over Na SO . The
solvent was evaporated under reduced pressure to afford compound 412B (2.7 g, crude) as light
yellow liquid, which was used directly for next step without purification. H NMR (DMSO-d
400 MHz): δ 3.94 (d, J = 10.6 Hz, 1H), 3.69 - 3.64 (m, 3H), 3.40 - 3.34 (m, 0.72H), 3.33 - 3.30
(m, 0.24H), 3.29 - 3.20 (m, 1H), 3.16 - 3.07 (m, 1H), 3.06 - 2.97 (m, 1H), 2.11 - 1.95 (m, 3H),
1.61 - 1.47 (m, 2H), 0.87 (dd, J = 6.7, 14.0 Hz, 6H). MS (ESI) m/z (M+H) 250.1.
To a mixture of compound 412B (1 g, 4.0 mmol) in THF (10 mL) and MeOH
(10 mL) was added a solution of NaOH (802.1 mg, 20.0 mmol) in H O (2 mL) in one portion.
The mixture was stirred at 55 °C for 1h. The reaction mixture was added H O (15 mL), and then
concentrated under reduced pressure to move MeOH. The aqueous phase was washed with
TBME (10 mL). The separated aqueous phase was acidified with aqueous HCl (1 M) till pH ~ 5
- 6 before extracting with EA (15 mL x 5). Then the organic phase was dried over anhydrous
Na SO , filtered and concentrated in vacuo to afford compound 412C (88.6 mg, crude) as yellow
solid, which was used directly for next step without purification. H NMR (DMSO-d 400
MHz): δ 12.83 (s, 1H), 3.82 (d, J = 10.4 Hz, 1H), 3.29 - 3.23 (m, 2H), 3.14 - 2.90 (m, 2H), 2.10 -
1.89 (m, 3H), 1.65 - 1.44 (m, 2H), 0.85 (dd, J = 4.2, 6.6 Hz, 6H).
To a mixture of compound 412C (88.5 mg, 3.7 mmol) in THF (20 mL) was
added 1-hydroxypyrrolidine-2,5-dione (HOSu) (432.9 mg, 3.8 mmol), followed by DCC (776.0
mg, 3.7 mmol) in one portion at 0 °C. The mixture was stirred at 15 °C for 12h. The insoluble
substance was removed by filter. The filtrate was concentrated in vacum. The residue was
triturated with isopropanol (10 mL). The solid was collected and dried in vacuum to afford
compound 412D (95.8 mg, yield 76.6%) as colorless liquid. H NMR (DMSO-d 400 MHz): δ
4.26 (d, J = 11.0 Hz, 1H), 3.45 - 3.37 (m, 2H), 3.28 - 3.22 (m, 1H), 3.15 - 3.05 (m, 1H), 2.81 (s,
4H), 2.19 - 2.09 (m, 1H), 2.08 - 2.02 (m, 2H), 1.58 - 1.45 (m, 2H), 0.93 (dd, J = 6.6, 18.7 Hz,
6H).
To a mixture of compound 412D (950 mg, 2.9 mmol) in EA (25 mL) was
added (S)aminomethylpentanol (40.2 mg, 3.4 mmol) in one portion. The mixture was
17681897_1 (GHMatters) P110989.NZ
stirred at 15 °C for 12h. The mixture was washed with aq. HCl (0.5 N, 10 mL), sat. NaHCO (10
mL), sat. NaCl (10 mL). The separated organic phase was dried over Na SO , filtered and
concentrated. The residue was purified by preparatory-HPLC (basic condition) to afford
compound 412E (220 mg, yield 23.0%) as white solid. H NMR (DMSO-d 400 MHz): δ 7.78
(d, J = 8.8 Hz, 1H), 4.57 (t, J = 5.5 Hz, 1H), 3.85 - 3.70 (m, 2H), 3.55 - 3.44 (m, 1H), 3.41 - 3.37
(m, 0.52H), 3.32 - 3.25 (m, 1.45H), 3.20 - 3.06 (m, 2H), 2.88 - 2.75 (m, 1H), 2.08 - 1.88 (m, 3H),
1.73 - 1.61 (m, 1H), 1.60 - 1.41 (m, 2H), 1.38 - 1.21 (m, 2H), 0.84 (td, J = 6.6, 17.4 Hz, 12H).
To a mixture of compound 412E (0.1 g, 299 umol) in DCM (15 mL) was added
DMP (380.4 mg, 896.93 umol) in one portion. The mixture was stirred at 15 °C for 1.5 h. The
reaction was quenched by 30 mL of 10 % Na S O solution and 30 mL of sat. NaHCO solution
2 2 3 3
and stirred for 10 min. After quenching the reaction, the reaction mixture was poured into
separatory funnel and separated. The separated aqueous phase was extracted with DCM (20 mL
x 3). The combined organic phase was washed with brine (30 mL x 2), dried over anhydrous
Na SO , filtered and concentrated in vacuo. The residue was triturated with CH CN: i-propyl
2 4 3
ether (1:8, 2 mL). The solid was collected and dried in vacuum to afford compound 412 (45 mg,
yield 45.1%) as white solid. H NMR (DMSO-d 400 MHz): δ 9.39 (s, 1H), 8.64 (d, J = 6.5 Hz,
1H), 4.06 (s, 1H), 3.88 (d, J = 10.8 Hz, 1H), 3.50 - 3.37 (m, 2H), 3.19 - 3.06 (m, 1H), 2.96 - 2.83
(m, 1H), 2.03 (s, 3H), 1.77 - 1.38 (m, 5H), 0.97 - 0.79 (m, 12H). MS (ESI) m/z (M+H) 333.1.
EXAMPLE 221
COMPOUNDS 413-414, 525-529
Compounds 413-414 were synthesized from the corresponding starting
intermediates 274D and 250A using same procedures as described earlier for Example 250.
Compound 413 (55 mg, yield: 53.4%): N-(4-amino-3,4-dioxophenylbutan-
2-yl)(6-cyanopyridinyl)cyclopropyl-1H-pyrazolecarboxamide: H NMR
(400MHz, DMSO-d ) δ 9.04 - 8.86 (m, 1H), 8.36 - 8.06 (m, 3H), 7.95 - 7.86 (m, 1H), 7.76 (s,
1H), 7.62 - 7.43 (m, 1H), 7.35 - 7.04 (m, 5H), 5.40 - 5.24 (m, 1H), 3.94 - 3.73 (m, 1H), 3.26 -
3.18 (m, 1H), 2.95 - 2.86 (m, 1H), 1.19 - 1.02 (m, 4H). MS (ESI) m/z (M+H) 429.1.
Compound 414 (42 mg, yield: 26.9%): N-(4-amino-3,4-dioxophenylbutan-
2-yl)cyclopropyl(6-(trifluoromethyl)pyridinyl)-1H-pyrazolecarboxamide: H
NMR (400MHz, DMSO-d ) δ 8.98 (s, 1H), 8.34 - 8.11 (m, 3H), 7.82 (d, J = 8.0 Hz, 1H), 7.78 -
17681897_1 (GHMatters) P110989.NZ
7.66 (m, 1H), 7.54 (s, 1H), 7.34 - 7.06 (m, 5H), 5.39 - 5.24 (m, 1H), 3.94 - 3.57 (m, 1H), 3.28 -
3.16 (m, 1H), 2.97 - 2.84 (m, 1H), 1.18 - 1.04 (m, 4H). MS (ESI) m/z (M+H) 472.1.
Compounds 525-526 were synthesized from the corresponding starting
intermediate 250A and the corresponding alkylating agent followed by subjecting the resulting
intermediates to the procedures as in compound 12 to obtrain the final compounds.
Compound 525 (13 mg, yield: 5.84%; white solid): N-(4-amino-3,4-dioxo
phenylbutanyl)cyclopentylphenyl-1H-pyrazolecarboxamide: H NMR (400MHz,
DMSO-d ) δ 8.33 (d, J = 7.3 Hz, 1H), 8.09 (s, 1H), 8.05 (s, 1H), 7.79 (s, 1H), 7.59 - 7.54 (m,
2H), 7.33 - 7.18 (m, 8H), 5.27 (ddd, J = 4.0, 7.4, 9.8 Hz, 1H), 4.73 (quin, J = 6.8 Hz, 1H), 3.16
(dd, J = 4.1, 14.0 Hz, 1H), 2.82 (dd, J = 9.9, 13.9 Hz, 1H), 2.16 - 2.06 (m, 2H), 1.94 (td, J = 6.1,
12.2 Hz, 2H), 1.85 - 1.77 (m, 2H), 1.72 - 1.60 (m, 2H). MS (ESI) m/z (M+H) 431.2.
Compound 526 (69.7 mg, yield: 22.7%; pale yellow solid): N-(4-amino-3,4-
dioxophenylbutanyl)cyclobutylphenyl-1H-pyrazolecarboxamide: H NMR
(400MHz, DMSO-d ) δ 8.35 (d, J = 7.3 Hz, 1H), 8.15 (s, 1H), 8.06 (s, 1H), 7.80 (s, 1H), 7.60 -
7.54 (m, 2H), 7.33 - 7.17 (m, 8H), 5.29 (ddd, J = 4.0, 7.4, 9.8 Hz, 1H), 4.92 - 4.84 (m, 1H), 3.16
(dd, J = 4.0, 13.9 Hz, 1H), 2.82 (dd, J = 9.7,13.9 Hz, 1H), 2.48 - 2.30 (m, 4H), 1.86 - 1.75 (m,
2H). MS (ESI) m/z (M+Na) 441.1.
Compounds 527-529 were synthesized from the corresponding starting
intermediate 250A and the corresponding boronic acids agent as in compound 250 followed by
subjecting the resulting intermediates to the procedures as in compound 12 to obtain the final
compounds.
Compound 527 (69.9 mg, yield: 23.4%; white solid): N-(4-amino-3,4-dioxo
phenylbutanyl)(2-fluorophenyl)phenyl-1H-pyrazolecarboxamide: H NMR
(400MHz, DMSO-d ) δ 8.70 (d, J = 7.5 Hz, 1H), 8.53 (d, J = 2.2 Hz, 1H), 8.09 (s, 1H), 7.91 (dt,
J = 1.7, 8.0 Hz, 1H), 7.83 (s, 1H), 7.68 - 7.63 (m, 2H), 7.58 - 7.46 (m, 2H), 7.43 - 7.33 (m, 4H),
7.31 - 7.27 (m, 4H), 7.25 - 7.20 (m, 1H), 5.33 (ddd, J = 4.2, 7.4, 10.0 Hz, 1H), 3.20 (dd, J = 4.0,
13.9 Hz, 1H), 2.85 (dd, J = 10.1, 13.9 Hz, 1H). MS (ESI) m/z (M+H) 457.1.
Compound 528 (50 mg, yield: 16.2%; white solid): N-(4-amino-3,4-dioxo
phenylbutanyl)(3-fluorophenyl)phenyl-1H-pyrazolecarboxamide: H NMR
(400MHz, DMSO-d ) δ 8.87 (s, 1H), 8.59 (d, J = 7.3 Hz, 1H), 8.10 (s, 1H), 7.84 (s, 1H), 7.80 -
17681897_1 (GHMatters) P110989.NZ
7.72 (m, 2H), 7.70 - 7.57 (m, 3H), 7.40 - 7.20 (m, 9H), 5.49 - 5.31 (m, 1H), 3.24 - 3.16 (m, 1H),
2.91 - 2.82 (m, 1H). MS (ESI) m/z (M+H) 457.2.
Compound 529 (17.5 mg, yield: 10%; white solid): N-(4-amino-3,4-dioxo
phenylbutanyl)(4-fluorophenyl)phenyl-1H-pyrazolecarboxamide: H NMR
(400MHz, DMSO-d ) δ 8.76 (s, 1H), 8.54 (d, J=7.3 Hz, 1H), 8.09 (s, 1H), 7.95 - 7.81 (m, 3H),
7.67 (dd, J=3.0, 6.5 Hz, 2H), 7.46 - 7.21 (m, 10H), 5.43 - 5.31 (m, 1H), 3.20 (dd, J=4.0, 14.1 Hz,
1H), 2.90 - 2.82 (m, 1H). MS (ESI) m/z (M+H) 457.2.
EXAMPLE 222
COMPOUNDS 425-427
PhCHO
NaOH, NaBH
O OH
O OH
EtOH
425A
EtOH N
425B
D-glutamic acid (15.0 g, 101.9 mmol) was dissolved in aqueous NaOH (2M,
100 mL) and stirred for 15 minutes. The mixture was added a solution of benzaldehyde (11 mL,
108.84 mmol) in EtOH (30 mL) and stirred at 15 °C for 30 minutes. The mixture was cooled to
0 °C. NaBH (1.16 g, 30.6 mmol) was added into the mixture, which was allowed to warm to 15
°C with stirring over 3 hrs. The mixture was washed with TBME (30 mL x 2) before acidifying
with concentrated hydrochloric acid to pH ~ 4-5. The resulting precipitate was filtered off and
dried over to afford compound 425A (10.26 g, crude) as white solid, which was used directly for
the next step without purification. MS (ESI) m/z (M+H) 238.0.
The suspension of compound 425A (4.2 g, 17.7 mmol) in EtOH (400 mL) was
heated to reflux at 95 °C for 10 hours. The reaction mixture was concentrated under reduced
pressure to move EtOH. The residue was purified by preparatory-HPLC (TFA condition: column:
Phenomenex Synergi Max-RP 250 x 50mm x 10 um; mobile phase: [water (0.1%TFA)-ACN];
B%: 2% - 30%, 20 min) to afford compound 3 (2.7 g, yield 69.44%) as white solid. H NMR
(DMSO-d 400 MHz): δ 7.36 - 7.24 (m, 3H), 7.22 - 7.16 (m, 2H), 4.88 (d, J = 15.2 Hz, 1H), 3.96
- 3.81 (m, 2H), 2.41 - 2.21 (m, 3H), 2.01 - 1.89 (m, 1H). MS (ESI) m/z (M+H) 219.9.
17681897_1 (GHMatters) P110989.NZ
Compound 425 was synthesized from the corresponding starting intermediate
3-amino-N-cyclopropylhydroxyphenylbutanamide hydrochloride and 425B using same
procedures as described earlier for compound 65 followed by SFC separation to yield compounds
426 and 427.
Compound 425: (2R)benzyl-N-(4-(cyclopropylamino)-3,4-dioxo
phenylbutanyl)oxopyrrolidinecarboxamide: H NMR (400MHz, DMSO-d ) δ 8.83
(s, 1H), 8.66 (s, 1H), 7.38 - 7.18 (m, 8H), 7.17 - 6.97 (m, 2H), 5.18 (s, 1H), 4.90 - 4.67 (m, 1H),
3.87 (s, 1H), 3.56 - 3.41 (m, 1H), 3.26 - 3.13 (m, 1H), 2.85 - 2.65 (m, 2H), 2.30 - 1.97 (m, 3H),
1.77 - 1.45 (m, 1H), 0.73 - 0.52 (m, 4H). MS (ESI) m/z (M+H) 434.2.
Compound 426 (129 mg, yield: 49.5%): (2R)benzyl-N-(4-
(cyclopropylamino)-3,4-dioxophenylbutanyl)oxopyrrolidinecarboxamide: H
NMR (400MHz, DMSO-d ) δ 8.85 (d, J = 5.1 Hz, 1H), 8.68 (d, J = 7.5 Hz, 1H), 7.36 - 7.18 (m,
8H), 7.13 (d, J = 7.1 Hz, 2H), 5.24 - 5.11 (m, 1H), 4.84 (d, J = 15.0 Hz, 1H), 3.92 - 3.83 (m, 1H),
3.49 (d, J = 15.0 Hz, 1H), 3.18 (dd, J = 3.5, 13.9 Hz, 1H), 2.84 - 2.69 (m, 2H), 2.22 (t, J = 7.9
Hz, 2H), 2.12 - 1.97 (m, 1H), 1.59 - 1.47 (m, 1H), 0.73 - 0.56 (m, 4H). MS (ESI) m/z (M+H)
434.2.
Compound 427 (63.2 mg, yield: 25.2%): (2R)benzyl-N-(4-
(cyclopropylamino)-3,4-dioxophenylbutanyl)oxopyrrolidinecarboxamide: H
NMR (400MHz, DMSO-d ) δ 8.83 (d, J = 5.1 Hz, 1H), 8.67 (d, J = 7.5 Hz, 1H), 7.34 - 7.21 (m,
8H), 7.02 (d, J = 6.6 Hz, 2H), 5.27 - 5.16 (m, 1H), 4.75 (d, J = 15.0 Hz, 1H), 3.86 (dd, J = 3.3,
8.8 Hz, 1H), 3.33 (s, 1H), 3.19 (dd, J = 4.0, 14.1 Hz, 1H), 2.83 - 2.69 (m, 2H), 2.32 - 2.06 (m,
3H), 1.77 - 1.61 (m, 1H), 0.73 - 0.50 (m, 4H). MS (ESI) m/z (M+H) 434.2.
17681897_1 (GHMatters) P110989.NZ
EXAMPLE 223
COMPOUND 430
O AgBF4
n-Bu
(PPh )AuCl
430A
430B
O O O
O N NH
430B
To a solution of 3-phenylpropynol (2 g, 15.13 mmol) and ethyl propiolate
(1.48 g, 15.13 mmol) in DCM (20 mL) was added n-Bu P (307 mg, 1.51 mmol) dropwise. The
mixture was stirred at 25 °C for 12h. The solvent was removed in vacuo. The residue was
purified by column (PE:EA = 10:1) to give compound 425A (3.4 g, crude) as light yellow oil.
MS (ESI) m/z (M+H) 231.0.
To a solution of compound 425A (500 mg, 2.17 mmol) in toluene (10 mL) was
added (PPh )AuCl (22 mg, 43.40 umol) and AgBF (9 mg, 43.40 umol). The mixture was stirred
at 25 °C for 12h. The solvent was removed in vacuo. The residue was purified by column
(PE:EA = 10:1) to afford compound 425B (120 mg, yield: 24.02%) as colorless oil. H NMR
(CDCl 400 MHz): δ 7.95 (s, 1H), 7.45 - 7.29 (m, 5H), 4.20 - 4.14 (m, 2H), 2.26 (s, 3H), 1.22 -
1.17 (m, 3H).
Compound 430 was synthesized from the intermediate 430B using same
procedures as described earlier for compound 65 to yield compound 430.
Compound 430 (35 mg, yield: 33.25%) (S)-N-(4-amino-3,4-dioxo
phenylbutanyl)methylphenylfurancarboxamide: H NMR (400MHz, DMSO-d )
δ 7.82 (s, 1H), 7.38 - 7.14 (m, 11H), 7.04 - 6.94 (m, 2H), 6.35 (s, 1H), 6.11 (s, 1H), 4.43 - 4.30
(m, 1H), 3.04 - 2.85 (m, 1H), 2.61 - 2.53 (m, 1H), 2.21 (s, 3H). MS (ESI) m/z (M+H) 377.1.
17681897_1 (GHMatters) P110989.NZ
EXAMPLE 224
COMPOUND 449
SOCl
Cl O
MeOH
ClHH N
449A
To a mixture of (S)amino(4-fluorophenyl)propanoic acid (1 g, 5.46
mmol) in MeOH (10 mL) was added SOCl (2.60 g, 21.84 mmol, 1.6 mL) in portions at 0 °C
under N . The mixture was stirred at 60 °C for 1.5 h. The solvent was removed in vacuo to give
compound 449A (1.2 g, yield: 94.1%, HCl) as white solid which was used directly for next step
without further purification. H NMR (400MHz, DMSO-d ) δ 8.59 (s, 3H), 7.29 (t, J = 5.9 Hz,
2H), 7.17 (t, J = 8.2 Hz, 2H), 4.28 (s, 1H), 3.68 (s, 3H), 3.19 - 3.07 (m, 2H). MS (ESI) m/z
(M+H) 197.9.
To a mixture of compound 449A (1.2 g, 5.46 mmol, HCl) and ethyl
carbonochloridate (712 mg, 6.56 mmol, 0.6 mL) in DCM (20 mL) was added pyridine (1.30 g,
16.39 mmol, 1.3 mL) in one portion at 0 °C under N . The mixture was stirred at 20 °C for 2 h.
The reaction mixture was treated with DCM (30 mL), washed with 0.5N HCl (50 mL x 2) and
brine (50 mL), dried over anhydrous Na SO , filtered and concentrated. The residue was purified
by column chromatography (SiO , Petroleum ether: Ethyl acetate = 10: 1 to 4: 1) to give
compound 449 (1.2 g, yield: 80.6%) as colorless oil. Methyl (S)((ethoxycarbonyl)amino)
(4-fluorophenyl)propanoate: H NMR (400MHz, DMSO-d ) δ 7.64 (d, J = 8.0 Hz, 1H), 7.27
(dd, J = 5.8, 8.3 Hz, 2H), 7.10 (t, J = 8.8 Hz, 2H), 4.24 - 4.07 (m, 1H), 3.92 (dd, J = 4.0, 7.0 Hz,
2H), 3.61 (s, 3H), 3.00 (dd, J = 5.0, 14.1 Hz, 1H), 2.83 (dd, J = 10.5, 13.6 Hz, 1H), 1.14 - 0.97
(m, 3H). MS (ESI) m/z (M+H) 269.9.
17681897_1 (GHMatters) P110989.NZ
EXAMPLE 225
COMPOUND 450
NaBO
AcOH
450B
450A
Na CO EtOH, H O
, O O
2 3 2
Compound 450A was prepared from (S)amino(4-iodophenyl)propanoic
acid using procedures as in compound 449.
NaBO3 (1.63 g, 10.61 mmol) was added in portions to a solution of compound
450A (400 mg, 1.06 mmol) in AcOH (8.5 mL) and heated to 50 °C. The reaction mixture was
stirred at 50 °C for 6h. The reaction mixture was cooled to room temperature, diluted with DCM
(20 mL), filtered, the filtrate was diluted with water (30 mL), and extracted with DCM (10 mL x
2). The combined organic extracts were dried with anhydrous sodium sulfate, filtered, and
concentrated. The residue was triturated in DCM: PE = 1: 10 (10 mL x 2) to induce
precipitation, solids was collected. Compound 450B (380 mg, yield: 72.4%) was obtained as a
white solid. H NMR (400MHz, CDCl ) δ 7.99 (d, J = 8.4 Hz, 2H), 7.29 - 7.23 (m, 2H), 5.20 (d,
J = 7.7 Hz, 1H), 4.72 - 4.64 (m, 1H), 4.11 (q, J = 6.9 Hz, 2H), 3.76 - 3.72 (m, 3H), 3.25 - 3.08
(m, 2H), 2.00 (s, 6H), 1.23 (t, J = 7.1 Hz, 3H).
To a solution of compound 450B (380 mg, 767.27 umol) in Na CO (243.97
mg, 2.30 mmol) in H O (3 mL) was added EtOH (3 mL) followed quickly by 6,10-
dioxaspiro[4.5]decane-7,9-dione (130.56 mg, 767.27 umol). The reaction mixture was
vigorously stirred at 18 °C for 4h. The reaction mixture was then diluted with water (10 mL),
and extracted with DCM (10 mL x 3). The combined organic extracts were dried with anhydrous
Na SO , filtered, and concentrated. To the residue was added DCM (1 mL) and PE (15 mL) to
induce precipitation, solids was collected. Compound 450 (300 mg, yield: 71.7%) was obtained
as a white solid. Methyl (S)(4-((7,9-dioxo-6,10-dioxaspiro[4.5]decanylidene)-λ3-
17681897_1 (GHMatters) P110989.NZ
iodanyl)phenyl)((ethoxycarbonyl)amino)propanoate H NMR (400MHz, CDCl ) δ 7.78 (d, J =
8.4 Hz, 2H), 7.18 (d, J = 8.4 Hz, 2H), 5.18 (d, J = 7.7 Hz, 1H), 4.67 - 4.55 (m, 1H), 4.12 - 4.02
(m, 2H), 3.71 (s, 3H), 3.26 - 3.13 (m, 1H), 3.11 - 2.99 (m, 1H), 2.13 (t, J = 7.4 Hz, 4H), 1.84 -
1.74 (m, 4H), 1.21 (t, J = 7.1 Hz, 3H). MS (ESI) m/z (M-H) 544.0.
EXAMPLE 226
COMPOUNDS 451-453, 533-540
O KOH
NaBO 10% Na CO
3 2 3
AcOH MeOH,H O
EtOH 2
451B
451A
N NH
N NH
OH N 2 H
N OH
452 453
Sodium perborate tetrahydrate (8.99 g, 58.46 mmol) was added in portions to a
solution of methyl 3-(4-iodophenyl)methyl-1H-pyrazolecarboxylate (2 g, 5.85 mmol) in
AcOH (40 mL) and heated to 50 °C. The reaction mixture was stirred at 50 °C for 8 h, cooled to
room temperature, diluted with DCM (50 mL), filtered, the filtrate was diluted with water (100
mL), and extracted with methylenechloride (30 mL x 2). The combined organic extracts were
dried with anhydrous sodium sulfate, filtered, and concentrated. The residue was triturated in
DCM: PE (1: 20) (100 mL), filtered to give compound 451A (2.1 g, yield: 78.1%) as a white
solid. H NMR (400MHz, CDCl ) δ 8.30 - 8.01 (m, 2H), 7.98 - 7.84 (m, 3H), 4.10 - 3.90 (m,
3H), 3.86 - 3.70 (m, 3H), 2.17 - 1.83 (m, 6H).
To a solution of compound 451A (2.1 g, 4.56 mmol) in EtOH (60 mL) was
added Na CO (1.93 g, 18.25 mmol) in H O (30 mL) and 6,10-dioxaspiro[4.5]decane-7,9-dione
2 3 2
(932 mg, 5.48 mmol). The mixture was stirred at 25 °C for 4 h. The reaction mixture was then
diluted with water (50 mL), and extracted with DCM (20 mL x 3). The combined organic
extracts were dried with anhydrous Na SO , filtered, and concentrated. The residue was added
17681897_1 (GHMatters) P110989.NZ
DCM (5 mL) and PE (50 mL) to induce precipitation. Solids were collected to give compound
451B (1.6 g, yield: 68.7%) as a white solid. H NMR (400MHz, CDCl ) δ 7.95 (s, 1H), 7.90 -
7.80 (m, 4H), 3.94 (s, 3H), 3.79 - 3.72 (m, 3H), 2.14 (t, J = 7.5 Hz, 4H), 1.81 - 1.75 (m, 4H).
Compounds 451-453 were was synthesized from the intermediate 451B using
same procedures as described earlier for compound 12 to yield compounds 451-453.
Compound 451 (220 mg, yield: 58.1%) 3-(4-((7,9-dioxo-6,10-
dioxaspiro[4.5]decanylidene)-λ3-iodanyl)phenyl)methyl-1H-pyrazolecarboxylic
acid: H NMR (400MHz, DMSO-d ) δ 12.31 (br s, 1H), 8.35 - 8.28 (m, 1H), 7.82 - 7.73 (m,
4H), 3.88 (s, 3H), 2.02 - 1.93 (m, 4H), 1.70 - 1.62 (m, 4H). MS (ESI) m/z (M-H) 495.01.
Compound 452 (250 mg, yield: 35.1%) N-(4-aminohydroxyoxo
phenylbutanyl)(4-((7,9-dioxo-6,10-dioxaspiro[4.5]decanylidene)-λ -
iodanyl)phenyl)methyl-1H-pyrazolecarboxamide: H NMR (400MHz, DMSO-d ) δ
8.13 - 7.98 (m, 1H), 7.93 - 7.78 (m, 1H), 7.72 - 7.62 (m, 2H), 7.59 - 7.46 (m, 2H), 7.33 (d, J =
7.8 Hz, 2H), 7.28 - 7.17 (m, 6H), 5.87 - 5.73 (m, 1H), 4.49 (d, J = 9.5 Hz, 1H), 4.02 (br s, 1H),
3.89 (s, 3H), 2.84 - 2.65 (m, 2H), 2.01 (br s, 4H), 1.70 (br s, 4H). MS (ESI) m/z (M+H) 673.11.
Compound 453 (32 mg, yield: 64.2%) N-(4-amino-3,4-dioxophenylbutan-
2-yl)(4-((7,9-dioxo-6,10-dioxaspiro[4.5]decanylidene)-λ -iodanyl)phenyl)methyl-
1H-pyrazolecarboxamide: H NMR (400MHz, DMSO-d ) δ 8.52 (d, J = 7.5 Hz, 1H), 8.11 -
8.02 (m, 2H), 7.81 - 7.76 (m, 1H), 7.72 - 7.65 (m, 2H), 7.56 (d, J = 8.6 Hz, 2H), 7.29 - 7.24 (m,
4H), 7.21 (dd, J = 4.5, 8.7 Hz, 1H), 5.34 - 5.19 (m, 1H), 3.91 - 3.86 (m, 3H), 3.18 - 3.14 (m, 1H),
2.79 (dd, J = 10.3, 13.8 Hz, 1H), 1.97 (t, J = 7.3 Hz, 4H), 1.68 - 1.64 (m, 4H). MS (ESI) m/z
(M+H) 671.09.
17681897_1 (GHMatters) P110989.NZ
O O O
O O O
O O O O
O O O O
N NH
N NH
535 H
Compounds 533-536 were was synthesized from the corresponding
intermediate, ethyl 3-(3-iodophenyl)methyl-1H-pyrazolecarboxylate using same procedures
as described earlier for compounds 451B and 451-453 to yield compounds 533-536.
Compound 533 (1.3 g, yield: 67.8%; yellow solid) Ethyl 3-(3-((7,9-dioxo-
6,10-dioxaspiro[4.5]decanylidene)-λ -iodanyl)phenyl)methyl-1H-pyrazole
carboxylate: H NMR (400MHz, CDCl ) δ 8.35 (s, 1H), 8.07 (d, J = 8.2 Hz, 1H), 7.94 (s, 1H),
7.85 (dd, J = 0.9, 8.2 Hz, 1H), 7.43 (t, J = 7.9 Hz, 1H), 4.24 (q, J = 7.1 Hz, 2H), 3.94 (s, 3H),
2.14 (t, J = 7.5 Hz, 4H), 1.83 - 1.70 (m, 4H), 1.28 (t, J = 7.2 Hz, 3H).
Compound 534 (78 mg; white solid) 3-(3-((7,9-dioxo-6,10-
dioxaspiro[4.5]decanylidene)-λ -iodanyl)phenyl)methyl-1H-pyrazolecarboxylic
acid: H NMR (400MHz, DMSO-d ) δ 12.46 - 12.28 (m, 1H), 8.31 (s, 1H), 8.11 (t, J = 1.7 Hz,
1H), 7.94 (d, J = 8.2 Hz, 1H), 7.75 (d, J = 8.8 Hz, 1H), 7.46 (t, J = 7.9 Hz, 1H), 3.88 (s, 3H), 2.01
- 1.94 (m, 4H), 1.69 - 1.63 (m, 4H). MS (ESI) m/z (M-H) 495.0.
Compound 535 (250 mg, yield: 48%; white solid) N-(4-aminohydroxy
oxophenylbutanyl)(3-((7,9-dioxo-6,10-dioxaspiro[4.5]decanylidene)-λ -
iodanyl)phenyl)methyl-1H-pyrazolecarboxamide: H NMR (400MHz, DMSO-d ) δ
8.14 - 8.00 (m, 2H), 7.87 (d, J = 8.8 Hz, 0.5H), 7.66 (d, J = 7.9 Hz, 1H), 7.60 - 7.55 (m, 1H),
7.53 (d, J = 9.3 Hz, 0.5H), 7.35 - 7.10 (m, 8H), 5.86 - 5.68 (m, 1H), 4.49 - 4.33 (m, 1H), 4.02 -
3.98 (m, 0.5H), 3.88 - 3.81 (m, 3.5H), 2.90 - 2.83 (m, 0.5H), 2.79 - 2.71 (m, 1H), 2.67 - 2.62 (m,
0.5H), 2.00 - 1.94 (m, 4H), 1.69 - 1.62 (m, 4H). MS (ESI) m/z (M+H) 673.1.
17681897_1 (GHMatters) P110989.NZ
Compound 536 (200 mg, yield: 69.8%; pale yellow solid) N-(4-amino-3,4-
dioxophenylbutanyl)(3-((7,9-dioxo-6,10-dioxaspiro[4.5]decanylidene)-λ -
iodanyl)phenyl)methyl-1H-pyrazolecarboxamide: H NMR (400MHz, DMSO-d ) δ
8.49 (d, J = 7.5 Hz, 1H), 8.16 - 7.92 (m, 3H), 7.82 - 7.72 (m, 1H), 7.71 - 7.54 (m, 2H), 7.33 (t, J
= 7.7 Hz, 1H), 7.29 - 7.21 (m, 4H), 7.19 (d, J = 3.7 Hz, 1H), 5.24 (br s, 1H), 3.95 - 3.80 (m, 3H),
3.21 - 3.07 (m, 1H), 2.80 (dd, J = 10.0, 13.8 Hz, 1H), 2.02 - 1.91 (m, 4H), 1.65 (br s, 4H). MS
(ESI) m/z (M+H) 671.1.
O O O O O O
O OH
537 N N
O O O O O O O O
N NH N NH
N 2 540 N 2
O OH O O
Compounds 537-540 were was synthesized from the corresponding
intermediate, ethyl 3-(3-iodophenyl)oxopropanoate to convert it to ethyl 4-(3-iodophenyl)
methyloxazolecarboxylate using the procdures as for compound 248C and then ethyl 4-(3-
iodophenyl)methyloxazolecarboxylate was converted to compounds 537-540 using same
procedures as described earlier for compounds 451B and 451-453.
Compound 537 (1.3 g, yield: 41.5%; white solid) Ethyl 4-(3-((7,9-dioxo-6,10-
dioxaspiro[4.5]decanylidene)-λ -iodanyl)phenyl)methyloxazolecarboxylate: H
NMR (400MHz, CDCl ) δ 8.64 (t, J = 1.7 Hz, 1H), 8.42 - 8.35 (m, 1H), 7.98 - 7.80 (m, 1H), 7.50
(t, J = 7.9 Hz, 1H), 4.42 (q, J = 7.1 Hz, 2H), 2.59 (s, 3H), 2.21 - 2.14 (m, 4H), 1.83 - 1.76 (m,
4H), 1.41 (t, J = 7.2 Hz, 3H).
Compound 538 (300 mg; yield: 63.1% white solid) 4-(3-((7,9-dioxo-6,10-
dioxaspiro[4.5]decanylidene)-λ -iodanyl)phenyl)methyloxazolecarboxylic acid: H
NMR (400MHz, DMSO-d ) δ 8.37 (t, J = 1.7 Hz, 1H), 8.28 - 8.23 (m, 1H), 7.85 - 7.78 (m, 1H),
17681897_1 (GHMatters) P110989.NZ
7.53 (t, J = 7.9 Hz, 1H), 2.52 (s, 3H), 2.00 - 1.96 (m, 4H), 1.69 - 1.64 (m, 4H). MS (ESI) m/z
(M-H) 495.99.
Compound 539 (360 mg, yield: 68.7%; pale yellow solid) N-(4-amino
hydroxyoxophenylbutanyl)(3-((7,9-dioxo-6,10-dioxaspiro[4.5]decanylidene)-
λ -iodanyl)phenyl)methyloxazolecarboxamide: H NMR (400MHz, DMSO-d ) δ 8.47 -
8.38 (m, 1H), 8.29 (d, J = 8.2 Hz, 0.5H), 8.22 (t, J = 8.8 Hz, 1H), 7.83 - 7.68 (m, 1.5H), 7.44 (td,
J = 7.9, 13.0 Hz, 1H), 7.34 (d, J = 9.3 Hz, 1H), 7.27 - 7.08 (m, 6H), 6.03 (d, J = 6.0 Hz, 0.5H),
.87 (d, J = 5.7 Hz, 0.5H), 4.69 - 4.41 (m, 1H), 4.03 (t, J = 4.6 Hz, 0.5H), 3.90 - 3.83 (m, 0.5H),
2.98 - 2.85 (m, 1H), 2.82 - 2.71 (m, 1H), 2.52 (d, J = 3.7 Hz, 3H), 2.01 - 1.96 (m, 4H), 1.69 -
1.64 (m, 4H). MS (ESI) m/z (M-H) 672.0.
Compound 540 (150 mg, yield: 65.2%; white solid) N-(4-amino-3,4-dioxo
phenylbutanyl)(3-((7,9-dioxo-6,10-dioxaspiro[4.5]decanylidene)-λ -
iodanyl)phenyl)methyloxazolecarboxamide: H NMR (400MHz, DMSO-d ) δ 8.56 (br
s, 1H), 8.50 - 8.42 (m, 1H), 8.33 - 8.21 (m, 1H), 7.92 - 7.73 (m, 2H), 7.63 (br s, 1H), 7.50 - 7.41
(m, 1H), 7.30 - 7.20 (m, 5H), 5.50 - 5.39 (m, 1H), 3.28 (dd, J = 4.4, 14.2 Hz, 1H), 3.08 - 3.02 (m,
1H), 2.56 - 2.54 (m, 3H), 2.02 (t, J = 7.4 Hz, 4H), 1.75 - 1.67 (m, 4H). MS (ESI) m/z (M+H)
672.0.
EXAMPLE 227
COMPOUND 489
NaH, CF Br
AgBF4
N DMF
489B
489A
F Br
dioxane/H O
2 F O
Pd(dppf)Cl2
K CO
3 C 489D
489C 3
N NH
489D
3 489
17681897_1 (GHMatters) P110989.NZ
To a solution of ethyl 3-iodo-1H-pyrazolecarboxylate (4.3 g, 16.16 mmol) in
DMF (50 mL) was added NaH (1.29 g, 32.32 mmol, 60% purity) at 0 °C, the mixture was stirred
at 15 °C for 30min, then added dibromo(difluoro)methane (10.17 g, 48.48 mmol, 4.5 mL) at 0
°C. The mixture was stirred at 15 °C for 16 h. The mixture was quenched with NH Cl (15 mL),
diluted with H O (30 mL), extracted with EA (50 mL x 3), the organic phase was combined,
washed with NaCl (50 mL ), dried over Na SO , filtered and concentrated to give a residue. The
residue was purified by column chromatography (SiO , Petroleum ether: Ethyl acetate= 1: 0 to
: 1) to give compound 489A (4.4 g, yield: 61.15%) as a yellow oil. H NMR (400MHz,
CDCl ) δ 8.25 - 8.08 (m, 1H), 4.42 - 4.31 (m, 2H), 1.39 (t, J = 3.3, 7.2 Hz, 3H). MS (ESI) m/z
(M+H) 394.9.
To a mixture of compound 489A (2.6 g, 6.58 mmol) in DCM (30 mL) was
added AgBF (3.84 g, 19.74 mmol) in portion at -78 °C under N . The mixture was stirred at 15
°C for 16 h. The reaction mixture was diluted with DCM (50 mL), then, the mixture was wash
with H O (60mL) and brine (60ml), the organic was dried over Na SO , and concentrated under
2 2 4
reduced pressure to give a residue. The residue was purified by column chromatography (SiO ,
Petroleum ether: Ethyl acetate= 1: 0 to 10: 1) to give compound 489B (1.7 g, yield: 45.17%) as a
colorless oil. H NMR (400MHz, CDCl ) δ 8.24 - 8.03 (m, 1H), 4.44 - 4.31 (m, 2H), 1.46 - 1.34
(m, 3H). MS (ESI) m/z (M+H) 334.9.
To a mixture of compound 489B (200 mg, 598.75 umol), phenylboronic acid
(110 mg, 898.13 umol,), K2CO3 (166 mg, 1.20 mmol) in dioxane (10 mL) and H2O (0.5 mL) was
added Pd(dppf)Cl (44 mg, 59.88 umol) in portion at 15 °C under N . The mixture was stirred at
90 °C for 16 h. The reaction mixture was concentrated. The residue was purified by preparatory-
TLC (SiO , PE: EA= 15: 1) to give compound 489D (40 mg, yield: 9.31%) as yellow oil and
compound 489C (40 mg, yield: 20.97%) as yellow oil. Compound 489D: H NMR (400MHz,
CDCl ) δ 8.43 (s, 1H), 7.83 - 7.77 (m, 2H), 7.48 - 7.43 (m, 3H), 4.30 (q, J = 7.1 Hz, 2H), 1.31 (t,
J = 7.2 Hz, 4H). MS (ESI) m/z (M+H) 285.0. Compound 489C: H NMR (400MHz, CDCl ) δ
8.16 (s, 1H), 7.55 - 7.44 (m, 3H), 7.38 (d, J = 7.3 Hz, 2H), 4.15 (q, J = 7.2 Hz, 2H), 1.14 (t, J =
7.2 Hz, 3H). MS (ESI) m/z (M+H) 285.0.
Compound 489 were was synthesized from the intermediate 489D using same
procedures as described earlier for compound 12 to yield compound 489. Compound 489 (55
17681897_1 (GHMatters) P110989.NZ
mg, yield: 73.01%) N-(4-amino-3,4-dioxophenylbutanyl)phenyl(trifluoromethyl)-
1H-pyrazolecarboxamide: H NMR (400MHz, DMSO-d ) δ 8.93 (dd, J = 7.3 Hz, 1H), 8.76
(s, 1H), 8.11 (s, 1H), 7.85 (s, 1H), 7.54 (dd, J = 7.1 Hz, 2H), 7.41 - 7.31 (m, 3H), 7.29 - 7.20 (m,
5H), 5.39 - 5.32 (m, 1H), 3.17 (dd, J = 3.6, 14.0 Hz, 1H), 2.82 (dd, J = 10.0, 14.0 Hz, 1H). MS
(ESI) m/z (M+H) 431.1.
EXAMPLE 228
COMPOUND 490
O H B
H Br
NBS/MeCN
/DCE
Py/Cu(OAc)
490A
490B
H /Pd/C
N NH
490C
A solution of ethyl 4-methyl-1H-imidazolecarboxylate (800 mg, 5.19 mmol)
in MeCN (20 mL) was added NBS (970 mg, 5.45 mmol). The reaction mixture was stirred at
°C for 5hr. The solvent was evaporated under vacuum. The crude product was purified by
silica gel column chromatography (petroleum ether: ethyl acetate = 20:1 ~ 3:1) to give compound
490A (1.50 g, crude) as a yellow solid. H NMR (400MHz, CDCl ) δ 4.42 (q, J = 7.2 Hz, 2H),
2.32 (s, 3H), 1.40 (t, J = 7.1 Hz, 3H).
A mixture of compound 490A (1.5 g, 6.44 mmol), phenylboronic acid (1.57 g,
12.9 mmol), Cu(OAc) (2.34 g, 12.9 mmol), pyridine (1.53 g, 19.3 mmol) and 4A° MS in DCE
(20 mL) was stirred at 70°C under O for 12 hr. The mixture was filtered and the filtrate was
concentrated, the residue was purified by FCC (Petroleum ether: Ethyl acetate = 15: 1) to give
compound 490B (300 mg, yield: 15.1%) as yellow solid. H NMR (400MHz, CDCl ) δ 7.57 -
7.47 (m, 3H), 7.23 - 7.17 (m, 2H), 4.24 (q, J = 7.1 Hz, 2H), 2.02 (s, 3H), 1.25 (t, J = 7.2 Hz, 3H).
To a solution of compound 490B (50 mg, 162 umol) in EtOH (10 mL) was
added Pd-C (0.1 g) under N . The suspension was degassed under vacuum and purged with H
several times. The mixture was stirred under H (15 psi) at 15 °C for 12 hours. The mixture was
filtered and the filtrate was concentrated to give compound 490C (40 mg, crude) as yellow oil.
17681897_1 (GHMatters) P110989.NZ
H NMR (400MHz, CDCl ) δ 7.72 - 7.56 (m, 4H), 7.33 (br d, J = 7.1 Hz, 2H), 4.40 (q, J = 7.1
Hz, 2H), 1.40 (t, J = 7.2 Hz, 3H).
Compound 490 were was synthesized from the intermediate 490C using same
procedures as described earlier for compound 12 to yield compound 490. Compound 490 (26
mg, yield: 52.3%) N-(4-amino-3,4-dioxophenylbutanyl)methylphenyl-1H-
imidazolecarboxamide: H NMR (400MHz, DMSO-d ) δ 7.74 (br d, J = 7.9 Hz, 1H), 7.55 -
7.45 (m, 3H), 7.35 - 7.29 (m, 1H), 7.27 - 7.14 (m, 6H), 6.93 (d, J = 0.9 Hz, 1H), 6.70 (br s, 1H),
.63 (dt, J = 5.2, 7.7 Hz, 1H), 5.44 (br s, 1H), 3.38 (dd, J = 5.3, 14.1 Hz, 1H), 3.17 (dd, J = 7.3,
14.1 Hz, 1H), 2.02 (d, J = 0.9 Hz, 3H). MS (ESI) m/z (M+H) 377.1.
EXAMPLE 229
COMPOUND 491
DMFDMA
OH.HCl
491A
N NH
491B
A mixture of methyl 3-oxophenylbutanoate (1 g, 5.20 mmol) and DMF-
DMA (682 mg, 5.72 mmol) was stirred at 20°C for 1hr. The crude product was purified by silica
gel column chromatography (petroleum ether: ethyl acetate = 20:1 to 5:1) to give compound
491A (900 mg, yield: 70.0%) as yellow oil. H NMR (400MHz, CDCl ) δ 7.70 (s, 1H), 7.37 -
7.16 (m, 5H), 4.06 (s, 2H), 3.75 (s, 3H), 3.33 - 2.57 (m, 6H).
A solution of compound 491A (900 mg, 3.64 mmol) in MeOH (20 mL) was
added NH OH.HCl (253 mg, 3.64 mmol). The reaction mixture was stirred at 65 °C for 1hr.
The solvent was evaporated. The crude residue was purified by preparatory-TLC (petroleum
ether: ethyl acetate = 3:1) to give compound 491B (500 mg, yield: 63.2%) as a yellow oil. H
NMR (400MHz, CDCl ) δ 8.50 (s, 1H), 7.35 - 7.27 (m, 5H), 4.48 (s, 2H), 3.90 (s, 3H).
Compound 491 were was synthesized from the intermediate 491B using same
procedures as described earlier for compound 12 to yield compound 491. Compound 491 (20.4
mg, yield: 41.0%) N-(4-amino-3,4-dioxophenylbutanyl)benzylisoxazole
17681897_1 (GHMatters) P110989.NZ
carboxamide: H NMR (400MHz, CDCl ) δ 8.30 (s, 1H), 7.39 - 7.23 (m, 9H), 7.14 - 7.03 (m,
2H), 6.78 (br s, 1H), 6.21 (br d, J = 7.0 Hz, 1H), 5.72 - 5.66 (m, 1H), 5.59 (br s, 1H), 4.41 (s,
2H), 3.43 (dd, J = 5.5, 14.2 Hz, 1H), 3.21 (dd, J = 6.8, 14.2 Hz, 1H).
EXAMPLE 230
COMPOUND 497
POBr O
O CH CN
HN O
3 CH CN, reflux
497A
N NH
497B
To a solution of ethyl 5-oxo(pyrimidinyl)pyrazolidinecarboxylate (300
mg, 1.27 mmol) in CH CN (10 mL) was added POBr (291.26 mg, 1.02 mmol). The mixture
was stirred at 80 °C for 2 h. The reaction mixture was concentrated under reduced pressure to
remove CH CN. The residue was diluted with H O (10 mL) and extracted with DCM (10 mL x
2). The combined organic layers were washed with brine (20 mL), dried over Na SO , filtered
and concentrated under reduced pressure to give a residue. The residue was used in the next step
without purification. Compound 497A (300 mg, crude) was obtained as a yellow oil. H NMR
(400MHz, CDCl ) δ 8.42 (d, J = 4.9 Hz, 2H), 6.74 (t, J = 4.9 Hz, 1H), 5.03 (dd, J = 6.6, 12.6 Hz,
1H), 4.27 - 4.10 (m, 2H), 3.60 (dd, J = 12.7, 18.0 Hz, 1H), 3.25 (dd, J = 6.6, 18.1 Hz, 1H), 1.20
(t, J = 7.2 Hz, 3H). MS (ESI) m/z (M+H) 298.7.
To a solution of compound 497A (300 mg, 1.00 mmol) in CH CN (10 mL) was
added MnO (871.92 mg, 10.03 mmol). The mixture was stirred at 80 °C for 48 h. The mixture
was filtered. The filtrate was concentrated to give a residue. The residue was purified by
preparatory-TLC (SiO , PE: EA = 2: 1). Compound 497B (150 mg, yield 50.3%) was obtained
as a yellow oil. H NMR (400MHz, CDCl ) δ 8.79 (d, J = 4.9 Hz, 2H), 7.34 (t, J = 4.9 Hz, 1H),
6.95 - 6.78 (m, 1H), 4.33 (q, J = 7.1 Hz, 2H), 1.28 (t, J = 7.2 Hz, 3H). MS (ESI) m/z (M+H)
296.8.
Compound 497 were was synthesized from the intermediates, 497B and 3-
aminohydroxyphenylbutanamide hydrochloride and using same procedures as described
17681897_1 (GHMatters) P110989.NZ
earlier for compound 12 to yield compound 497. Compound 497 (6 mg, yield: 41.0%) N-(4-
amino-3,4-dioxophenylbutanyl)bromo(pyrimidinyl)-1H-pyrazole
carboxamide: H NMR (400MHz, CDCl ) δ 8.72 (d, J = 4.8 Hz, 2H), 7.70 (br.d, J = 7.3 Hz,
1H), 7.42 (t, J = 4.8 Hz, 1H), 7.35 - 7.20 (m, 5H), 7.03 (br.s, 1H), 6.76 (s, 1H), 6.27 (br s, 1H),
.50 (dt, J = 4.8, 8.0 Hz, 1H), 3.31 (dd, J = 4.9, 13.9 Hz, 1H), 2.99 (dd, J = 8.5, 14.1 Hz, 1H).
MS (ESI) m/z (M+H) 443.0.
EXAMPLE 231
COMPOUNDS 549, 556-560, 584, 594, 595, 600, 619
DMF, DMA
OH O
CDI, CH CN,
TEA,
MgCl2 549A
549B
O O O
HONH HCl, NaOAc F
O N NH
MeOH, MTBE DMSO, DCM
549C
In a round bottom flask a solution of 2-fluoromethylbenzoic acid (10 g, 64.9
mmol) in CH CN (40 mL) was added CDI (11.8 g, 72.7 mmol). The mixture was stirred at 25
°C for 4 h. In another flask a solution of potassium 3-ethoxyoxopropanoate (14.6 g, 85.6
mmol) in CH CN (130 mL) was added MgCl (6.2 g, 64.9 mmol) in portions over 15 min. The
mixture was stirred at 25 °C for 0.5 h, then TEA (27 mL, 194.0 mmol) was added and the slurry
was stirred for 0.5 h. The solution in the first round-bottom flask was transferred to the slurry of
the second flask. The mixture was stirred at 25 °C for 12 h. The reaction mixture was quenched
with HCl (3 N, 180 mL) and the solution was concentrated under reduce pressure. The resulting
was extracted with MTBE (200 mL x 2). The organic layer was washed with H O (200 mL), sat.
NaHCO (200 mL x 2), sat. NaCl (200 mL), dried over anhydrous Na SO , filtered and
3 2 4
concentrated under reduced pressure to afford compound 549A (6.7 g, yield 45.5%) as colorless
liquid, which was used in next step without further purification. H NMR (DMSO-d 400
MHz): δ 7.68 - 7.63 (m, 1H), 7.53 - 7.46 (m, 1H), 7.28 - 7.19 (m, 1H), 4.11 (q, J = 7.1 Hz, 2H),
224.9.
4.03 (d, J = 3.1 Hz, 2H), 2.33 (s, 3H), 1.16 (t, J = 7.1 Hz, 3H). MS (ESI) m/z (M+H)
17681897_1 (GHMatters) P110989.NZ
A mixture of compound 549A (6.7 g, 29.9 mmol) and DMF-DMA (16 mL,
120.4 mmol) in DMF (60 mL) was stirred at 80 °C for 12 h. The mixture was concentrated in
vacuum to afford compound 549B (8.4 g, yield 97.6%) as red liquid, which was used in next step
without further purification. MS (ESI) m/z (M+H) 280.1
To a mixture of compound 549B (8.4 g, 30.1 mmol) and hydroxylamine
hydrochloride (4.2 g, 60.2 mmol) in MTBE (70 mL) and MeOH (70 mL) was added NaOAc (4.9
g, 60.2 mmol) in one portion. The mixture was stirred at 25 °C for 12 h. The reaction mixture
was filtered and the solvent removed from the filtrate by concentration in vacuo. The residue was
purified by flash silica gel chromatography (Eluent of 0~10% Ethyl acetate/Petroleum ether
gradient) to afford compound 549C (3.6 g, yield 46.7%) as colorless liquid. H NMR (DMSO-
d 400 MHz): δ 9.11 (s, 1H), 7.60 - 7.54 (m, 1H), 7.52 - 7.44 (m, 1H), 7.37 - 7.28 (m, 1H), 4.20
(q, J = 7.2 Hz, 2H), 2.36 (s, 3H), 1.17 (t, J = 7.2 Hz, 3H). MS (ESI) m/z (M+H) 250.1.
Compound 549 was synthesized from the intermediates, 549C and 3-amino
hydroxyphenylbutanamide hydrochloride and using same procedures as described earlier for
compound 12 to yield compound 549. Compound 549 (100 mg, yield: 68.0%, white solid) N-
(4-amino-3,4-dioxophenylbutanyl)(2-fluoromethylphenyl)isoxazole
carboxamide: H NMR (400MHz, DMSO-d ) δ 8.96 (s, 1H), 8.92 - 8.81 (m, 1H), 8.08 (s, 1H),
7.83 (s, 1H), 7.40 (s, 2H), 7.33 - 7.11 (m, 6H), 5.33 (s, 1H), 3.24 - 3.05 (m, 1H), 2.93 - 2.75 (m,
1H), 2.31 (s, 3H). MS (ESI) m/z (M+H) 396.1.
Compound 556 was synthesized from ethyl 3-(2-fluorophenyl)
oxopropanoate using the procedures as in compound 549 followed by using same procedures as
described earlier for compound 12 to yield compound 556. Compound 556 (60 mg, yield:
39.8%, white solid) N-(4-amino-3,4-dioxophenylbutanyl)(2-fluorophenyl)isoxazole-
4-carboxamide: H NMR (400MHz, DMSO-d ) δ 9.00 - 8.89 (m, 2H), 8.11 (s, 1H), 7.85 (s,
1H), 7.65 - 7.55 (m, 2H), 7.38 - 7.19 (m, 7H), 5.37 - 5.28 (m, 1H), 3.18 (dd, J=3.6, 14.0 Hz, 1H),
2.91 - 2.63 (m, 1H). MS (ESI) m/z (M+H) 382.1.
Compound 557 was synthesized from ethyl 3-oxo(o-tolyl)propanoate using
the procedures as in compound 549 followed by using same procedures as described earlier for
compound 12 to yield compound 557. Compound 557 (80 mg, yield: 52.5%, white solid) N-(4-
amino-3,4-dioxophenylbutanyl)(o-tolyl)isoxazolecarboxamide: H NMR
17681897_1 (GHMatters) P110989.NZ
(400MHz, DMSO-d ) δ 8.99 (s, 1H), 8.73 (d, J = 7.3 Hz, 1H), 8.10 (s, 1H), 7.84 (s, 1H), 7.45 -
7.39 (m, 1H), 7.34 - 7.19 (m, 8H), 5.33 - 5.26 (m, 1H), 3.17 (dd, J = 3.7, 13.9 Hz, 1H), 2.80 (dd,
J = 9.9, 13.9 Hz, 1H), 2.08 (s, 3H). MS (ESI) m/z (M+H) 378.1.
Compound 558 was synthesized from ethyl 3-(5-fluoromethylphenyl)
oxopropanoate using the procedures as in compound 549 followed by using same procedures as
described earlier for compound 12 to yield compound 558. Compound 558 (100 mg, yield:
48.0%, white solid) N-(4-amino-3,4-dioxophenylbutanyl)(5-fluoro
methylphenyl)isoxazolecarboxamide: H NMR (400MHz, DMSO-d ) δ 9.04 (s, 1H), 8.79
(d, J = 7.5 Hz, 1H), 8.10 (s, 1H), 7.84 (s, 1H), 7.39 - 7.33 (m, 1H), 7.39 - 7.19 (m, 7H), 5.38 -
.27 (m, 1H), 3.18 (dd, J = 3.9, 13.9 Hz, 1H), 2.91 - 2.72 (m, 1H), 2.04 (s, 3H). MS (ESI) m/z
(M+H) 396.1.
Compound 559 was synthesized from ethyl 3-(3-fluorophenyl)
oxopropanoate using the procedures as in compound 549 followed by using same procedures as
described earlier for compound 12 to yield compound 559. Compound 559 (150 mg, yield:
74.3%, white solid) N-(4-amino-3,4-dioxophenylbutanyl)(3-fluorophenyl)isoxazole-
4-carboxamide: H NMR (400MHz, DMSO-d ) δ 9.04 (d, J = 7.3 Hz, 1H), 8.88 (s, 1H), 8.14
(s, 1H), 7.86 (s, 1H), 7.76 (d, J = 9.8 Hz, 1H), 7.70 (d, J = 7.8 Hz, 1H), 7.59 - 7.48 (m, 1H), 7.46
- 7.37 (m, 1H), 7.36 - 7.25 (m, 4H), 7.25 - 7.17 (m, 1H), 5.46 - 5.32 (m, 1H), 3.27 - 3.15 (m, 1H),
2.92 - 2.77 (m, 1H). MS (ESI) m/z (M+H) 382.1.
Compound 560 was synthesized from ethyl 3-oxo(m-tolyl)propanoate using
the procedures as in compound 549 followed by using same procedures as described earlier for
compound 12 to yield compound 560. Compound 560 (160 mg, yield: 61.3%, white solid) N-
(4-amino-3,4-dioxophenylbutanyl)(m-tolyl)isoxazolecarboxamide: H NMR
(400MHz, DMSO-d ) δ 9.08 - 8.88 (m, 1H), 8.80 (s, 1H), 8.15 (s, 1H), 7.88 (s, 1H), 7.73 - 7.52
(m, 2H), 7.43 - 7.11 (m, 7H), 5.43 - 5.29 (m, 1H), 3.27 - 3.15 (m, 1H), 2.91 - 2.78 (m, 1H), 2.34
(br s, 3H). MS (ESI) m/z (M+H) 378.1.
Compound 584 was synthesized from ethyl 3-(2-fluoromethylphenyl)
oxopropanoate using the procedures as in compound 549 followed by using same procedures as
described earlier for compound 12 to yield compound 584. Compound 584 (130 mg, yield:
60.1%, white solid) N-(4-amino-3,4-dioxophenylbutanyl)(2-fluoro
17681897_1 (GHMatters) P110989.NZ
methylphenyl)isoxazolecarboxamide: H NMR (400MHz, DMSO-d ) δ 8.93 (s, 1H), 8.84
(d, J = 7.5 Hz, 1H), 8.06 (s, 1H), 7.81 (s, 1H), 7.46 (t, J = 7.1 Hz, 1H), 7.40 - 7.33 (m, 1H), 7.30 -
7.15 (m, 6H), 5.31 (ddd, J = 4.0, 7.4, 9.8 Hz, 1H), 3.15 (dd, J = 4.0, 13.9 Hz, 1H), 2.80 (dd, J =
9.9, 13.9 Hz, 1H), 2.23 (d, J = 1.8 Hz, 3H). MS (ESI) m/z (M+H) 396.1.
Compound 594 was synthesized from ethyl 3-(3-fluoromethylphenyl)
oxopropanoate using the procedures as in compound 549 followed by using same procedures as
described earlier for compound 12 to yield compound 594. Compound 594 (30 mg, yield:
18.1%, white solid) N-(4-amino-3,4-dioxophenylbutanyl)(3-fluoro
methylphenyl)isoxazolecarboxamide: H NMR (400MHz, DMSO-d ) δ 9.00 (s, 1H), 8.77
(d, J = 7.3 Hz, 1H), 8.06 (s, 1H), 7.80 (s, 1H), 7.36 - 7.13 (m, 8H), 5.32 - 5.24 (m, 1H), 3.16(dd,
J = 4.1, 14.0 Hz, 1H), 2.79 (br dd, J = 10.0, 13.6 Hz, 1H), 1.93 (d, J = 2.2 Hz, 3H). F NMR
(400MHz, DMSO-d ) δ -115.508 - -115.531 (s, 1F). MS (ESI) m/z (M+H) 396.0.
Compound 595 was synthesized from ethyl 3-(2-fluoromethoxyphenyl)
oxopropanoate using the procedures as in compound 549 followed by using same procedures as
described earlier for compound 12 to yield compound 595. Compound 595 (86 mg, yield:
68.2%, light yellow solid) N-(4-amino-3,4-dioxophenylbutanyl)(2-fluoro
methoxyphenyl)isoxazolecarboxamide: H NMR (400MHz, DMSO-d ) δ 8.97 (s, 1H), 8.89
(d, J = 7.5 Hz, 1H), 8.09 (s, 1H), 7.84 (s, 1H), 7.40 - 7.33 (m, 1H), 7.32 - 7.17 (m, 6H), 7.12 -
7.04 (m, 1H), 5.43 - 5.25 (m, 1H), 3.87 (s, 3H), 3.22 - 3.13 (m, 1H), 2.89 - 2.75 (m, 1H). MS
(ESI) m/z (M+H) 412.1.
Compound 600 was synthesized from ethyl 3-(5-methylpyridinyl)
oxopropanoate using the procedures as in compound 549 followed by using same procedures as
described earlier for compound 12 to yield compound 600. Compound 600 (90 mg, yield:
49.1%, yellow solid) N-(4-amino-3,4-dioxophenylbutanyl)(5-methylpyridin
yl)isoxazolecarboxamide: H NMR (400MHz, DMSO-d ) δ 9.04 (d, J = 7.5 Hz, 1H), 8.96
(s, 1H), 8.81 (d, J = 1.8 Hz, 1H), 8.56 (d, J = 1.5 Hz, 1H), 8.15 (s, 1H), 8.06 (s, 1H), 7.86 (s, 1H),
7.29 (d, J = 4.3 Hz, 3H), 7.27 - 7.17 (m, 2H), 5.42 - 5.34 (m, 1H), 3.21 (dd, J = 3.8, 13.8 Hz,
1H), 2.85 (dd, J = 10.0, 14.1 Hz, 1H), 2.35 (s, 3H). MS (ESI) m/z (M+H) 412.1.
Compound 619 was synthesized from ethyl 3-(2-fluoromethoxyphenyl)
oxopropanoate using the procedures as in compound 549 followed by using same procedures as
17681897_1 (GHMatters) P110989.NZ
described earlier for compound 12 to yield compound 619. Compound 619 (72 mg, yield:
71.5%, white solid) N-(4-amino-3,4-dioxophenylbutanyl)(2-fluoro
methoxyphenyl)isoxazolecarboxamide: H NMR (400MHz, DMSO-d ) δ 8.97 (s, 1H), 8.88
(d, J = 7.5 Hz, 1H), 8.08 (s, 1H), 7.83 (s, 1H), 7.31 - 7.12 (m, 8H), 5.38 - 5.30 (m, 1H), 3.75 (s,
3H), 3.17 (dd, J = 3.8, 14.1 Hz, 1H), 2.83 (dd, J = 9.9, 13.9 Hz, 1H). MS (ESI) m/z (M+H)
412.1.
EXAMPLE 232
COMPOUNDS 553, 574, 579, 580, 592, 623
Compounds 553, 574, 579, 580, 592, 623 were synthesized by coupling
corresponding intermediates which in turn were synthesized using procedures as used for
intermediates 62F and 32F respectively followed by subjecting the coupled product with
conditions as in compound 107 to obtain the final product.
Compound 553 (100 mg, 66.9% yield, white solid) was synthesized from
intermediate (3S)amino(2,3-dihydro-1H-indenyl)hydroxypropanamide and 3-(2-
fluorophenyl)methyl-1H-pyrazolecarboxylic acid. Compound 553: (S)-N-(3-amino(2,3-
dihydro-1H-indenyl)-2,3-dioxopropyl)(2-fluorophenyl)methyl-1H-pyrazole
carboxamide: H NMR (400MHz, DMSO-d ) δ 8.24 - 8.19 (m, 2H), 7.97 - 7.91 (m, 1H), 7.70
(s, 1H), 7.40 - 7.33 (m, 2H), 7.19 - 7.05 (m, 6H), 5.16 - 5.10 (m, 1H), 3.87 (s, 3H), 2.89 - 2.67
(m, 5H). MS (ESI) m/z (M+H) 421.1.
Compound 574 (100 mg, 45.0% yield, light yellow solid) was synthesized from
intermediate (3S)aminohydroxyhexynamide and 3-(2-fluorophenyl)methyl-1H-
pyrazolecarboxylic acid. Compound 574: (S)-N-(1-amino-1,2-dioxohexynyl)(2-
fluorophenyl)methyl-1H-pyrazolecarboxamide: H NMR (400MHz, DMSO-d ) δ 8.31 -
8.24 (m, 2H), 7.97 (s, 1H), 7.74 (s, 1H), 7.44 - 7.37 (m, 2H), 7.23 - 7.15 (m, 2H), 5.11 - 5.02 (m,
1H), 3.92 (s, 3H), 2.88 (t, J = 2.5 Hz, 1H), 2.75 - 2.57 (m, 2H). MS (ESI) m/z (M+H) 343.1.
Compound 579 (52 mg, 33.85% yield, white solid) was synthesized from
intermediate 3-aminohydroxy(naphthalenyl)propanamide hydrochloride and 3-(2-
fluorophenyl)methyl-1H-pyrazolecarboxylic acid. Compound 579: N-(3-amino
(naphthalenyl)-2,3-dioxopropyl)(2-fluorophenyl)methyl-1H-pyrazole
carboxamide: H NMR (400MHz, DMSO-d ) δ 8.53 (d, J = 6.0 Hz, 1H), 8.34 (s, 1H), 8.01 (br.
17681897_1 (GHMatters) P110989.NZ
s, 1H), 7.93 - 7.85 (m, 3H), 7.81 (s, 1H), 7.68 (br. s, 1H), 7.55 - 7.36 (m, 5H), 7.23 - 7.13 (m,
2H), 6.45 (d, J = 6.0 Hz, 1H), 3.87 (s, 3H). MS (ESI) m/z (M+H) 431.1.
Compound 580 (60 mg, 40.15% yield, white solid) was synthesized from
intermediate (3S)amino(3,5-difluorophenyl)hydroxybutanamide hydrochloride and 3-(2-
fluorophenyl)methyl-1H-pyrazolecarboxylic acid. Compound 580: N-(4-amino(3,5-
difluorophenyl)-3,4-dioxobutanyl)(2-fluorophenyl)methyl-1H-pyrazole
carboxamide: H NMR (400MHz, DMSO-d ) δ 8.31 (d, J = 7.6 Hz, 1H), 8.13 (s, 1H), 7.95 (br.
s, 1H), 7.72 (br. s, 1H), 7.39 - 7.27 (m, 2H), 7.17 - 7.00 (m, 3H), 6.96 - 6.87 (m, 2H), 5.20 - 5.11
(m, 1H), 3.88 (s, 3H), 3.17 - 3.09 (m, 1H), 2.89 - 2.79 (m, 1H). MS (ESI) m/z (M+H) 431.1.
Compound 592 (320 mg, 60.69% yield, white solid) was synthesized from
intermediate (3R)aminohydroxyphenylbutanamide hydrochloride and 3-(2-
fluorophenyl)methyl-1H-pyrazolecarboxylic acid. Compound 592: (R)-N-(4-amino-3,4-
dioxophenylbutanyl)(2-fluorophenyl)methyloxazolecarboxamide: H NMR
(400MHz, DMSO-d ) δ 8.78 (d, J = 7.6 Hz, 1H), 8.06 (br. s, 1H), 7.81 (br. s, 1H), 7.47 - 7.37 (m,
2H), 7.30 - 7.13 (m, 7H), 5.37 - 5.28 (m, 1H), 3.16 - 3.09 (m, 1H), 2.97 - 2.88 (m, 1H), 2.52 (s,
3H). MS (ESI) m/z (M+H) 396.1.
Compound 623 (60 mg, 59.9% yield, white solid) was synthesized from
intermediate 3-aminohydroxy(3-(trifluoromethyl)phenyl)butanamide hydrochloride and 3-
(2-fluorophenyl)methyl-1H-pyrazolecarboxylic acid. Compound 623: N-(4-amino-3,4-
dioxo(3-(trifluoromethyl)phenyl)butanyl)(2-fluorophenyl)methyl-1H-pyrazole
carboxamide: H NMR (400MHz, DMSO-d ) δ 8.35 (br d, J = 6.6 Hz, 1H), 8.15 (s, 1H), 8.00
(br s, 1H), 7.76 (br s, 1H), 7.64 - 7.48 (m, 4H), 7.33 (br dd, J = 7.3, 15.4 Hz, 2H), 7.20 - 7.08 (m,
2H), 5.22 (br s, 1H), 3.90 (s, 3H), 3.28 - 2.84 (m, 2H). MS (ESI) m/z (M+H) 363.1.
17681897_1 (GHMatters) P110989.NZ
EXAMPLE 233
COMPOUND 562
PhB(OH)2
4A° MS, N
Cu(OAc)2
CuI, ,
Pd(PPh )
DMF, TEA
562A 562B
LiOH.H O DMP
N OH
MeOH, H O N NH
DMSO, DCM
2 N 2
562C
To a mixture of ethyl 3-iodo-1H-pyrazolecarboxylatecompound (1 g, 3.8
mmol) and phenylboronic acid (504.1 mg, 4.1 mmol) in pyridine (20 mL) were added Cu(OAc)
(751 mg, 4.1 mmol, 1.1 eq), and 4A° molecular sieve (1 g). The mixture was stirred at 80 °C for
12 h under O atmosphere (~15 psi). The mixture was diluted with EA (40 mL), filtered through
Celite. The filtrate was concentrated under reduce pressure to move solvent, then H O (60 mL)
and EA (50 mL) was added. The black insoluble substance was separated out and filtered
through Celite two times. The cake was washed with EA (40 mLx 2). The combined filtrate was
separated and aqueous phase was extracted with EA (40 mL x 2). The combined organic phase
was washed with brine (50 mL x 2), dried over Na2SO4, filtered and concentrated. The crude
product was purified by column chromatography (SiO , petroleum ether/ethyl acetate = 20/1 to
/1), then the fraction was collected and concentrated. The residue was triturated with PE (40
mL). The solid was collected and dried in vacuum to afford compound 2 (0.8 g, yield 61.4%) as
white solid. H NMR (DMSO-d 400MHz) δ 9.01 (s, 1H), 7.89 (d, J = 8.4 Hz, 2H), 7.58 - 7.49
(m, 2H), 7.44 - 7.36 (m, 1H), 4.28 (q, J = 7.2 Hz, 2H), 1.35 - 1.27 (m, 3H). MS (ESI) m/z
(M+H) 342.9.
To a mixture of compound 562A (0.3 g, 876.9 umol) and propyne (1M in
DMF, 1.8 mL, 1.8 mmol) in DMF (6 mL) was added TEA (2 mL), CuI (33.4 mg, 175.4 umol),
followed by Pd(PPh ) (101 mg, 87.7 umol). The mixture was degassed and purged with N for
3 4 2
3 times, and then stirred at 55 °C for 12 h. The reaction mixture was combined with the reaction
17681897_1 (GHMatters) P110989.NZ
mixture on page ES5524P1 for concentrating under reduce pressure. The residue was
purified by flash silica gel chromatography (eluent of 0~15% ethyl acetate/petroleum ether
gradient) to afford compound 562B (204.2 mg, yield 91.5%) as light yellow solid. H NMR
(DMSO-d 400 MHz): δ 9.07 (s, 1H), 7.98 - 7.85 (m, 2H), 7.59 - 7.47 (m, 2H), 7.45 - 7.33 (m,
1H), 4.26 (q, J = 7.0 Hz, 2H), 2.11 (s, 3H), 1.31 (t, J = 7.2 Hz, 3H). MS (ESI) m/z (M+H) 255.1
Compound 562 was synthesized from the intermediates, 562B by converting it
to 562C and treatment with (3S)aminohydroxyphenylbutanamide hydrochloride and
using same procedures as described earlier for compound 12 to yield compound 562. Compound
549 (100 mg, yield: 35.7%, white solid) N-(4-amino-3,4-dioxophenylbutanyl)phenyl-
3-(propynyl)-1H-pyrazolecarboxamide: H NMR (400MHz, DMSO-d ) δ 8.85 (s,
1H), 7.92 - 7.76 (m, 4H), 7.66 (s, 1H), 7.57 - 7.48 (m, 2H), 7.43 - 7.36 (m, 1H), 7.33 - 7.26 (m,
2H), 7.26 - 7.17 (m, 3H), 5.63 - 5.48 (m, 1H), 3.34 - 3.26 (m, 1H), 3.15 - 3.09 (m, 1H), 2.03 (s,
3H). MS (ESI) m/z (M+H) 401.2.
EXAMPLE 234
COMPOUND 583
NH NHMe•H SO
PhCOCl
2 2 4
DIEA, HOAc
, DCM O
MgCl Py. O O
583A
583B
583C
N NH
A mixture of ethyl 3-oxobutanoate (5 g, 38.42 mmol) and MgCl (4.39 g, 46.10
mmol) and pyridine (6.8 mL, 84.52 mmol) in DCM (100 mL) was stirred at 0 °C for 30 min.
Then a solution of benzoyl chloride (4.9 mL, 42.26 mmol) in DCM (20 mL) was added slowly.
The mixture was stirred at 25 °C for 10 h. The reaction was quenched by the addition of 6N HCl
(~ 20 mL). Then the mixture was diluted with H2O (60 mL). The organic layer was separated
and the aqueous solution was extracted with DCM (35 mL x 2). The combined organic layer was
washed with saturated NaHCO (50 mL), brine (50 mL), dried over Na SO , filtered and
3 2 4
17681897_1 (GHMatters) P110989.NZ
concentrated. The residue was purified by silica gel column chromatography (petroleum
ether/ethyl acetate = 8:1) to afford compound 583A (6.2 g, yield 68.9%) as colorless oil.
To a suspension of methylhydrazine (14.6 g, 101.6 mmol, H SO salt) in DMF
(15 mL) was added DIEA (35.3 mL, 203.2 mmol). The mixture was stirred at 25 °C for 15 min.
Then the mixture was added to mixture of compound 583A (11.9 g, 50.8 mmol) in HOAc (150
mL). The mixture was stirred at 25 °C for 8 h. The mixture was concentrated. The residue was
treated with H O (300 mL) and EA (100 mL). The organic layer was separated and the aqueous
layer was extracted with EA (100 mL). The combined organic layer was washed with saturated
NaHCO (100 mL), brine (100 mL), dried over MgSO , filtered and concentrated. The residue
was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 10:1 to 5:1) to
afford compound 583B (2.3 g, yield 18.5%) as colorless oil and compound 583C (6 g, yield
48.3%) as pale yellow oil. Compound 583B: H NMR (DMSO-d 400MHz): δ 7.49 - 7.43 (m,
3H), 7.39 - 7.34 (m, 2H), 3.95 (q, J = 7.1 Hz, 2H), 3.56 - 3.51 (m, 3H), 2.34 (s, 3H), 0.96 (t, J =
7.1 Hz, 3H). Compound 583C: H NMR (DMSO-d 400MHz): δ 7.51 - 7.47 (m, 2H), 7.38 -
7.31 (m, 3H), 4.09 (q, J = 7.1 Hz, 2H), 3.78 (s, 3H), 2.47 (br s, 3H), 1.11 (t, J=7.1 Hz, 3H).
Compound 583 was synthesized from the intermediates, 583C and 3-amino
hydroxyphenylbutanamide hydrochloride and using same procedures as described earlier for
compound 12 to yield compound 583. Compound 583 (100 mg, yield: 46.2%, white solid) N-
(4-amino-3,4-dioxophenylbutanyl)phenyl(propynyl)-1H-pyrazole
carboxamide: H NMR (400MHz, DMSO-d ) δ 8.38 (d, J = 7.5 Hz, 1H), 8.12 (s, 1H), 7.86 (s,
1H), 7.47 - 7.41 (m, 2H), 7.31 - 7.21 (m, 8H), 5.38 (ddd, J = 3.6, 7.4, 10.6 Hz, 1H), 3.72 (s, 3H),
3.19 (dd, J = 3.4, 14.0 Hz, 1H), 2.74 (dd, J = 10.6, 13.9 Hz, 1H), 2.12 (s, 3H). MS (ESI) m/z
(M+H) 391.1.
BIOLOGICAL DATA
EXAMPLE 235
Calpain 1, 2, and 9 activity and inhibition thereof was assessed by means of a
continuous fluorescence assay. The SensoLyte 520 Calpain substrate (Anaspec Inc) was
optimized for detecting calpain activity. This substrate contains an internally quenched 5-
FAM/QXLTM 520 FRET pair. Calpains 1, 2, and 9 cleave the FRET substrate into two separate
fragments resulting in an increase of 5-FAM fluorescence that is proportional to calpain activity
17681897_1 (GHMatters) P110989.NZ
Assays were typically setup in black 384-well plates using automated liquid
handling as follows. Calpain assay base buffer typically contains 50mM Tris, pH 7.5, 100mM
NaCl and 1mM DTT. Inhibitors were serially diluted in DMSO and used to setup 2x mixtures
with calpains in the aforementioned buffer. After incubation at ambient temperature (25C), the
reaction was initiated by adding a 2x mix of the fluorescent peptide substrate and CaCl2
(required for in-situ calpain activation) in the same buffer. Reaction progress curve data were
typically collected for 10min using excitation/emission wavelengths of 490 nm/520 nm on
SpectraMax i3x or the FLIPR-Tetra plate readers (Molecular Devices Inc). Reaction rates were
calculated from progress curve slopes typically over 1-5min. Dose response curves (rate vs. log
inhibitor concentration) were typically fit to a 4-parameter logistic function to extract IC50
values.
Calpain activity in SH-SY5Y cells and inhibition thereof were assessed by
means of a homogeneous, fluorescence assay that uses the cell-permeable and pro-fluorescent
calpain substrate Suc-LLVY-AMC (Sigma-Aldrich Inc). Upon intracellular calpain cleavage of
Suc-LLVY-AMC, fluorescent amino-methyl-coumarin (AMC) is released into the media
resulting in a continuous increase in fluorescence signal that is proportional to intra-cellular
calpain activity.
Assays were typically setup by seeding SH-SY5Y cells in black 384-well plates
at 40k/per well in RPMI-1640 containing 1% serum followed by 37C overnight incubation. Next
morning, cells were pre-incubated for 30min with serially diluted compounds followed by
addition of 100uM of Suc-LLVY-AMC substrate. The continuous increase in AMC fluorescence
is monitored using a FLIPR Tetra plate reader (Molecular Devices Inc) and slopes measured to
report calpain activity. Dose response curves (slopes vs. log inhibitor concentration) were
typically fit to a 4-parameter logistic function to extract IC50 values.
Calpain activity in SH-SY5Y cells and inhibition thereof were also assessed by
a western blot based assay that measures a calpain-specific breakdown product of the alpha chain
of non-erythrocytic spectrin (SBDP-150). Addition of the calcium ionophore A23187 was used
to induce calpain activity and SBDP-150 formation.
These assays were typically setup by seeding SH-SY5Y cells in 96-well plates
at 150k/per well in DMEM containing 10% serum, followed by 37C incubation for 24hrs. The
17681897_1 (GHMatters) P110989.NZ
cells were then pre-incubated for 60 min with serially diluted compounds followed by addition of
25uM A23187 and further incubation for 90min. Total cellular protein was extracted in RIPA
buffer, boiled in gel loading buffer and run on SDS-PAGE gel. The gel was processed via
Western Blotting (dry transfer) to quantify SBDP-150 (AA6 antibody, Enzo Inc) and either
GAPDH or HSP90 as loading controls. Normalized SBDP-150 levels vs. log inhibitor
concentration were plotted to get dose response curves that are typically fit to a 4-parameter
logistic function to extract IC50 values.
CALPAIN INHIBITION
Table 2. Calpain inhibition assay
Column A: Human Calpain 1/NS1 IC50
Column B: Human Calpain 2/NS1 IC50
Column C: Human Calpain 9/NS1 IC50
Column D: SH-SY5Y Spectrin IC50
Column E: SH-SY5Y + AMC IC50
Column Column Column Column Column
Compound No.
A B C D E
1 A A A ND ND
2 A A A E ND
3 A A A ND ND
4 A A A ND ND
C B B ND ND
6 A A A ND F
7 A A A ND ND
8 A A A ND ND
9 A A A ND E
A A A ND ND
11 A A A ND ND
12 A A A E D
17681897_1 (GHMatters) P110989.NZ
Column Column Column Column Column
Compound No.
A B C D E
13 A A A F ND
14 A A A ND ND
A A A D E
16 A A A E E
17 A A A D F
18 A A A ND ND
19 A A A E F
A A A ND ND
21 A A A ND ND
22 A A A ND ND
23 A A A E F
24 A A A F F
A A A ND E
26 A A A D D
27 A A A E F
28 A A A D D
29 A A A ND ND
A A A D E
31 A A A ND ND
32 A A A D F
33 A A A D D
34 A A A ND ND
A A A ND ND
36 C B B ND ND
37 A A A ND ND
38 A A A ND ND
39 A A A ND ND
40 A A A ND ND
17681897_1 (GHMatters) P110989.NZ
Column Column Column Column Column
Compound No.
A B C D E
41 B A B ND ND
42 A A C ND ND
43 A A A ND ND
44 A A A E F
45 A A A F E
46 A A A ND ND
47 A A A ND ND
48 B B B ND ND
49 A A A D D
50 A A A D F
51 B B C ND ND
52 A A A ND ND
53 A A B ND ND
54 A A A ND ND
55 A A A D F
56 A A A ND ND
57 A A A D E
58 A A A E F
59 A A A ND D
60 A A A D D
61 A A A ND ND
62 A A A ND ND
63 A A A D D
64 A A A ND ND
65 C C C ND ND
66 B A A ND ND
67 C C C ND ND
68 A A A ND ND
17681897_1 (GHMatters) P110989.NZ
Column Column Column Column Column
Compound No.
A B C D E
69 A A A ND ND
70 A A A ND ND
71 B B C ND ND
72 A A A D D
73 A A C ND ND
74 A A A ND ND
75 A A B ND ND
76 A A B ND ND
77 A B C ND ND
78 C B A ND ND
79 A A A ND ND
80 B A B ND ND
81 A A A D E
82 A A A D F
83 A A A D F
84 A A A D D
85 A A A ND ND
86 A A A ND ND
87 C A A ND ND
88 A A A ND ND
89 A A B ND ND
90 A A B ND ND
91 B A B ND ND
92 B B A ND ND
93 A A A ND ND
94 A A A ND ND
96 A A A ND ND
97 A A A ND ND
17681897_1 (GHMatters) P110989.NZ
Column Column Column Column Column
Compound No.
A B C D E
98 A A A ND ND
99 A A A E E
100 A A A ND ND
101 C C C ND ND
102 A A A ND ND
103 A A A F F
104 A A A ND ND
105 A A A F F
106 A A A D F
107 A A A D D
108 A A A ND ND
109 A A A ND ND
110 A A B ND ND
111 A A A ND ND
112 A A A D F
113 A A A D F
114 B A B ND ND
115 C A C ND ND
116 A B C ND ND
117 B B B ND ND
118 A A A D F
119 A A A ND ND
120 A A A D E
121 A A A D E
122 A A A ND ND
123 A A A ND ND
124 A A A ND ND
125 C C C ND ND
17681897_1 (GHMatters) P110989.NZ
Column Column Column Column Column
Compound No.
A B C D E
126 A A A D F
127 A A A ND ND
128 B C B ND ND
129 B C B ND ND
130 A A A D F
131 A A A E F
132 A A A ND ND
133 A A A ND ND
134 B B B ND ND
135 A A C ND ND
136 A A A E E
137 C C C ND ND
138 A A A ND ND
139 A A A ND ND
140 A A A ND E
141 A A A E ND
142 A A A E D
143 A A A E D
144 A A A D D
145 A A A D D
146 A A A E D
147 A A A E E
148 A A A ND ND
149 C C C ND ND
150 C C C ND ND
151 A A A ND ND
152 A A A ND ND
153 A A A D F
17681897_1 (GHMatters) P110989.NZ
Column Column Column Column Column
Compound No.
A B C D E
154 A A A E F
155 A A A F ND
156 A A A D F
157 A A A F F
158 A A A E F
159 A A A E F
160 A A A E F
161 A A A D F
162 A A A F F
163 A A A E E
164 A A A F F
165 A A A ND ND
166 A A A E F
167 A A A ND ND
168 A A A E D
169 A A A ND ND
170 A A A F F
171 A B A F E
172 A A A D F
173 A A A F F
174 A A A F F
175 A A A F D
176 A A A ND ND
177 A A A E D
178 A A A D D
179 A A A E F
180 A A A D E
181 A A A D D
17681897_1 (GHMatters) P110989.NZ
Column Column Column Column Column
Compound No.
A B C D E
182 A A A E D
183 A A A D E
184 A A A ND F
185 C B B F F
186 B B B F F
187 A A A E F
188 A A A E F
189 A A A ND ND
190 B C B ND ND
191 A A A ND ND
192 A A A ND ND
193 B A B ND F
194 A A A ND ND
195 A B A ND ND
196 A A B ND ND
197 B C B ND ND
198 A A A F F
199 A A A F ND
200 A A A E F
201 A A B ND ND
202 A A A E F
203 A A C ND F
204 C C C ND ND
205 A A A ND ND
206 A C C ND ND
207 A A A E D
208 A A A D F
209 A A A ND ND
17681897_1 (GHMatters) P110989.NZ
Column Column Column Column Column
Compound No.
A B C D E
210 A A A ND ND
211 A A A ND ND
212 A A A E D
213 A A A ND ND
214 A A A ND F
215 A A A ND ND
216 A A A D F
217 A A A D F
218 A A A E F
219 B B B ND ND
220 A A B ND ND
221 A A A F ND
222 A A A E F
223 A A A E F
224 A B B ND ND
225 A C C ND ND
226 A A A D D
227 A A A D F
228 A A A D F
229 A A A D D
230 A A A D D
231 A A A F F
232 C C B ND ND
233 A A B ND ND
234 A A A ND ND
235 A A A ND ND
238 B B A ND ND
239 A A A E D
17681897_1 (GHMatters) P110989.NZ
Column Column Column Column Column
Compound No.
A B C D E
240 A A A ND ND
241 A A A ND ND
242 A A A F D
243 A A A E F
244 A A A F D
245 A A A E D
246 A A A E D
247 B B B ND ND
248 A A A D D
249 A A A E F
250 A A A E E
251 A A A F F
252 C C C F F
253 A A A E F
254 A ND A E D
255 A A A D D
256 C C A ND ND
257 A A A E D
258 A A A ND ND
259 A A A D E
260 A A A ND ND
261 A A A ND ND
262 B B A ND ND
263 A A A ND ND
264 B B C ND ND
265 A A A D F
266 A A A F F
267 A A A E D
17681897_1 (GHMatters) P110989.NZ
Column Column Column Column Column
Compound No.
A B C D E
268 A A A F F
269 B B A ND ND
270 A A A ND ND
271 A A A ND F
272 C B B ND ND
273 C A A ND ND
274 A A A ND ND
276 A A A D D
277 A A A E D
278 A A A D F
279 A A B E D
280 A A A ND ND
281 A A A ND E
282 A A A E D
283 A A A ND ND
284 C C C ND ND
285 A A A F E
286 A A A D F
287 A B A ND ND
288 A A A F F
289 A A A E F
290 A A A ND ND
291 A A A ND ND
292 A A A ND F
293 A A A E D
294 B B A E F
295 C C C ND ND
296 A A A D F
17681897_1 (GHMatters) P110989.NZ
Column Column Column Column Column
Compound No.
A B C D E
297 C B A ND ND
298 C C C ND ND
299 A A A E ND
303 A A A E D
304 A A A ND ND
305 A A A ND D
306 B B B ND D
307 A A A ND ND
308 A A A ND F
309 A A A E D
310 A A B ND ND
311 A A A ND ND
312 A A B ND ND
313 A A A F F
314 B B B ND ND
315 B B A ND ND
316 C C B ND ND
317 A A A E F
318 A B A ND ND
319 A A A ND ND
320 A A A E F
321 A A A D F
322 A A A E F
323 A A A ND F
324 A A B ND ND
325 A A A F F
326 A A A E D
327 A A A D D
17681897_1 (GHMatters) P110989.NZ
Column Column Column Column Column
Compound No.
A B C D E
328 A A A E F
329 A A A F F
330 A A A E E
331 A A A D F
332 A A A F F
333 A A A F F
334 A A A F D
335 A A A ND D
336 A A A ND D
337 A A A D D
338 A A A F D
339 A A A F E
340 A A A F ND
341 A A B F E
342 A A A E E
343 A A A E ND
344 A A A F E
345 C C C F ND
346 C B B F ND
347 A A A E F
348 A A A F D
349 A A A F D
350 A A A E D
351 A A A E D
352 A A A F E
353 A A A E F
354 A A A D D
355 A A A ND E
17681897_1 (GHMatters) P110989.NZ
Column Column Column Column Column
Compound No.
A B C D E
356 A A A F F
357 A A A D D
358 A A A E D
359 A A A ND E
360 C C C F F
361 A A A D D
362 A A A D F
363 A A A D F
364 A A A E ND
365 A A A D D
366 A A A E D
367 A A A D D
368 A A A ND D
369 A A A D F
370 A A A E F
371 A A A D D
372 A A A D D
373 A A A D D
374 A A A D D
375 A A A D D
376 A A A D D
377 A A A D E
378 A A A D F
379 A ND A D D
380 A A A D D
381 A A A D D
382 A A A E D
383 A A A D D
17681897_1 (GHMatters) P110989.NZ
Column Column Column Column Column
Compound No.
A B C D E
384 A A A D D
385 A A A D F
386 A A A F E
387 A A A F F
388 A A A D E
389 A A A D D
390 A A A ND ND
391 A A A ND ND
392 C C C E D
393 A A A E D
394 A A A F F
395 C B B ND ND
396 A A A D E
397 A A A D F
398 A A A F F
399 A A B F F
400 A A A F F
401 A A A D F
402 A A A E F
403 A A A D D
404 A A A D D
405 A A A ND ND
406 A A A E D
407 A A A E E
408 C B C E D
409 A A A ND ND
410 B B B ND ND
411 A A A ND E
17681897_1 (GHMatters) P110989.NZ
Column Column Column Column Column
Compound No.
A B C D E
413 A A A F F
414 A A A ND F
415 A A A F F
416 A A A F F
417 A A A F F
418 A A A E E
419 A A A E F
420 A A A D F
421 A A A E D
422 C B B F F
423 A A A D D
424 B A A E F
428 A A A D F
429 A A A ND ND
430 A A A D D
431 A A A F D
432 A A A D D
433 B B C E F
434 C C C ND F
435 C B B F D
436 A A A F D
437 A A A F E
438 A A A E E
439 A A A D F
440 A A A D F
441 C C C F F
442 A A A E F
443 A A A D E
17681897_1 (GHMatters) P110989.NZ
Column Column Column Column Column
Compound No.
A B C D E
444 A A A E D
445 A A A D F
447 A A A E E
448 A A A D D
454 A A B E D
455 B A C F D
456 A A A F D
457 A A B ND D
458 A A A E D
459 A A A E D
460 A A A F F
461 A A A D F
462 A A A E ND
463 A A A D F
464 A A A D D
465 A A A D F
466 A A A D F
467 A A A D F
468 A A A D F
469 A A A E D
470 A A ND E D
471 A A A E E
472 A A A E D
473 A A A E E
474 A A A E E
475 B A B D F
476 A A A E F
477 B A B E F
17681897_1 (GHMatters) P110989.NZ
Column Column Column Column Column
Compound No.
A B C D E
478 A A B F F
479 A A A E F
480 A A A E E
481 A A A F ND
482 B B A ND ND
483 C B A F ND
484 A A A E D
485 A A A E E
486 A A A E D
487 B A A ND ND
488 B B B ND ND
489 A A A E E
490 C B A ND ND
491 A A B ND ND
492 A A A E F
493 A A B F ND
494 A A A ND F
495 A A A E D
496 A A A E F
497 A A A E D
498 A A A F E
499 A A A E D
500 A A A E D
501 A A A E D
502 A A A E D
503 A A A ND E
504 A A A F F
505 A A A D F
17681897_1 (GHMatters) P110989.NZ
Column Column Column Column Column
Compound No.
A B C D E
506 A A A E E
507 A A A E D
508 A A A D D
509 A A A E E
510 A A A E E
511 A A A ND F
512 B B B F D
513 B B B F D
514 A A A F D
515 A A A F F
516 A A A F ND
517 A A A E E
518 A A A E D
519 C C C ND F
520 A A A F E
521 A A B E ND
522 A A A F D
523 A ND ND E D
524 A A A E D
525 A A A F D
526 A A A F D
527 A A A F D
528 A A A F
529 A A A F D
530 A A A F F
531 A A A E F
532 A A A D D
541 A A A E F
17681897_1 (GHMatters) P110989.NZ
Column Column Column Column Column
Compound No.
A B C D E
546 A A A D D
547 A A A D D
548 A A A F F
549 A A A F D
550 A A A F E
551 A A A E F
552 A A A D D
553 A A A F D
554 A A A D D
555 A A A F D
556 A A A D D
557 A A A F D
558 A A A E D
559 A A A E F
560 A A A E F
561 A A A E E
562 C C C F D
563 A A A D D
564 A A A D D
565 A A A D F
566 A A A E D
567 A A A D D
568 A A A F D
569 A A A F E
570 A A A F F
571 A A A F F
572 A A A F D
573 A A A F D
17681897_1 (GHMatters) P110989.NZ
Column Column Column Column Column
Compound No.
A B C D E
574 A A A F F
575 A A A D F
576 A A A D D
577 A A A D D
578 A A A D D
579 A A A F D
580 A A A E D
581 A A A F E
582 A A A D E
583 A A A F F
584 A A A D E
585 A A A E F
586 A A A E E
587 A A B F F
588 A A A E F
591 A A A F F
592 A A A E D
593 A A A F F
594 A A A E D
595 A A A E F
596 A A A E D
597 A A A E E
598 A A A D D
599 ND ND A F F
600 A A A E F
601 B A B F F
602 A A A E F
603 B B B F F
17681897_1 (GHMatters) P110989.NZ
Column Column Column Column Column
Compound No.
A B C D E
604 A A A F D
605 A A A F F
607 A A A E F
608 A A A F ND
609 A A A D ND
610 A A A D ND
611 A A A E ND
613 B B A ND ND
614 B B B ND ND
615 A A A ND ND
616 B A B ND ND
617 B A A ND ND
618 A A A ND ND
619 A A A ND ND
620 A A B ND ND
621 A A A ND ND
622 A A A ND ND
623 A A A ND ND
624 A A A ND ND
625 A A A ND ND
626 A A A ND ND
627 B A B ND ND
628 A A A ND ND
629 A A A ND ND
630 A A A ND ND
A: < 3 uM;
B: 3-10 uM;
17681897_1 (GHMatters) P110989.NZ
C: > 10 uM;
D: < 10 uM;
E: 10-25 uM;
F: > 25 uM
ND: Not Determined
EXAMPLE 236: ANIMAL MODELS & STUDIES
Bleomycin-induced pulmonary fibrosis in mice or rats
The method for inducing pulmonary fibrosis in mice is described in Current
Protocols in Pharmacology: 5.46.1, entitled “Mouse Models of Bleomycin-induced Pulmonary
Fibrosis”. In order to induce pulmonary fibrosis, 6-8 week old C57Bl/6 mice or Wistar rats are
instilled once oropharyngeally with ~1.5 U/kg of bleomycin sulfate (Calbiochem, Billerica, MA).
Briefly, for oropharyngeal administration of bleomycin, mice or rats are anesthetized with
isofluorane and then suspended on its back at a ~ 60 degree angle on an inclined surface with a
rubber band running under the upper incisors. The airway is opened while securing the tongue
with one arm of padded forceps and bleomycin is administered into the back of the oral cavity
with a syringe. The animal’s tongue and mouth were held open until the liquid disappeared from
the oral cavity. The animal was then returned to its cage and monitored until fully recovered from
the anesthesia. The study is terminated on day 14-28 for oropharyngeally administered
bleomycin in mice and rats.
IN-VIVO EFFICACY DATA
Table 3. Bleomycin-induced pulmonary fibrosis in mice (14d)
% reduction compared to
Compound ID
vehicle
60 -24%
-35%
403 -29%
484 -35%
-13%
485 -41%
406 -25%
404 -24%
405 -33%
-27%
17681897_1 (GHMatters) P110989.NZ
pirfenidone -14%
Alternatively, for systemic bleomycin administration by osmotic pumps in
mice, the pumps are loaded with bleomycin and implanted subcutaneously under isofluorane
anesthesia as described in Lee, Am J Physiol Lung Cell Mol Physiol, 2014. Briefly, mice are
systemically administered ~50-100 U/kg bleomycin (Blenoxane; Teva Pharma, North Wales,
PA) via osmotic pumps for 7 days. On day 10, the osmotic pumps are removed, and the study is
continued until day 35.
All animals are euthanized at the termination of the studies by cervical
dislocation for gross necropsy, and blood collected by cardiac puncture. The lungs from each
animal are dissected from the animal and weighed. The BAL cells and fluid are collected by
lavaging the lung twice with 0.5 ml Hanks Balanced Salt Solution (HBSS; VWR, Radnor, PA).
After collection of BAL cells and fluid, lungs are dissected and removed from each animal.
Whole lungs are inflated with 10% NBF and then fixed in 10% NBF for histology. Severity of
fibrosis in the lungs is evaluated using a modified Ashcroft score (Hubner, Biotechniques, 2008)
and subjective fibrosis scores. Lung sections were graded by averaging 5 microscopic fields at
20X on an Ashcroft scale as follows: Grade 0 = normal lung; Grade 1 = minimally detectable
thickening of alveolar walls; Grade 2= Mild thickening of alveolar walls. Grade 3 = moderate
contiguous thickening of walls with fibrous nodules; Grade 4= Thickened septae and confluent
fibrotic masses that total less than 10% of microscopic field. Grade 5 = increased fibrosis with
definite damage to lung structure and formation of fibrous bands or small fibrous masses
between 10 and 50% of microscopic field; Grade 6=Large contiguous fibrotic masses
consolidating more than 50% of microscopic field. Grade 7 = severe distortion of structure and
large fibrous areas; Grade 8 = total fibrous obliteration of lung within microscopic field. Each
slide was examined at 20X magnification and the score for 5 separate representative fields was
averaged for each animal. Subjective scores (H&E and Trichrome-stained slides) were evaluated
at 2X magnification for an overall assessment of pathologic change. A score of 0 = no detectible
findings to 5 = complete involvement of consolidation. Scores in each group were averaged and
standard error was calculated using Excel 2010. Dense, organized inflammatory exudates were
scored as fibrosis. Other tissues were evaluated microscopically and scored routinely.
17681897_1 (GHMatters) P110989.NZ
Carbon tetrachloride-induced liver fibrosis in mice or rats
Carbon tetrachloride-induced liver fibrosis is a widely used and accepted model
for evaluating novel antifibrotic therapies. The methods for inducing liver fibrosis by carbon
tetrachloride administration is described in Lee, J Clin Invest, 1995 and Tsukamoto, Semin Liver
Dis, 1990. Briefly, male C57BL/6 mice are challenged with 1mg/kg carbon tetrachloride (Sigma
Aldrich, diluted 1:7 in corn or olive oil) administered by intraperitoneal injection twice weekly
for a period of 4 weeks. Mice are euthanized on day 28. In an alternative implementation,
Wistar rats are administered carbon tetrachloride by intraperitoneal injection three times per
week for 8-12 weeks. Rats are euthanized at the termination of the experiment, 8-12 after study
initiation.
Blood is collected by cardiac puncture and processed into serum for evaluation
of liver enzymes (including ALT, AST, ALP, etc) at several timepoints throughout the study and
at termination of the study. The liver tissues from all animals are collected and fixed by
immersion in 10% neutral buffered formalin, processed, paraffin embedded, sectioned, mounted,
and stained with Masson’s Trichrome (Tri) or Picrosirius Red (PSR) using standard histological
methods for evaluation of fibrosis severity.
Mouse Unilateral Ureteral Obstruction Kidney Fibrosis Model
Female C57BL/6 mice (Harlan, 4-6 weeks of age) will be given free access to
food and water and allowed to acclimate for at least 7 days prior to test initiation. After
acclimation, mice are anesthetized and undergo unilateral ureteral obstruction (UUO) surgery or
sham to left kidney. Briefly, a longitudinal, upper left incision is performed to expose the left
kidney. The renal artery is located and 6/0 silk thread is passed between the artery and the ureter.
The thread is looped around the ureter and knotted 3 times insuring full ligation of ureter. The
kidney is returned to abdomen, the abdominal muscle is sutured and the skin is stapled closed.
All animals are euthanized 4, 8, 14, 21, or 28 days after UUO surgery. Following sacrifice blood
is collected via cardiac puncture, the kidneys are harvested and one half of the kidney is frozen at
-80 °C and the other half is fixed in 10% neutral buffered formalin for histopathological
assessment of kidney fibrosis.
17681897_1 (GHMatters) P110989.NZ
Bleomycin Dermal Fibrosis Model
Bleomycin (Calbiochem, Billerica MA) is dissolved in phosphate buffered
saline (PBS) at 10 ug/ml, and sterilized by filtration. Bleomycin or PBS control is injected
subcutaneously into two locations on the shaved back of C57/BL6 or S129 mice (Charles
River/Harlan Labs, 20-25 g) once daily for 28 days while under isoflourane anesthesia (5% in
100% 02). After 28 days, mice are euthanized and 6 mm-full thickness punch biopsies are
obtained from each injection site. Dermal fibrosis is assessed by standard histopathology and
hydroxyproline biochemical assays.
EXAMPLE 237: TARGETING CALPAINS
Inhibition of EpMT
For assessment of in vitro EMT, NMuMG cells (ATCC) are grown to
confluence in 10% serum (Fetal Bovine Serum) growth media (Dubecco’s Modified Eagles
Medium supplemented with 10ug/mL insulin) and then are followed by 24h starvation in 0.5%
serum media +/- drug inhibitors. Cells are then treated with recombinant human TGFb1 (R&D
Systems 5ng/mL) +/- drug inhibitors in 0.5% serum media. For time points greater than 24h, the
aforementioned media is refreshed every 24 hours. Cell lysates were analyzed for aSMA protein
expression by western blot.
Miettinen et al. (1994). “TGF-beta induced transdifferentiation of mammary
epithelial cells to mesenchymal cells: involvement of type I receptors.” J Cell Biol 127(6 Pt
2):2021-36.
Lamouille et al. (2014). “Molecular mechanisms of epithelial-mesenchymal
transition.” Nat Rev Mol Cell Biol 15(3):178-96.
For assessment of in vitro FMT, Normal Human Lung Fibroblasts (NHLF)
cells (Lonza) were grown in Fibroblast Growth Media-2 (Lonza CC-3131/with CC-4126 bullet
kit) and then were followed by 24h starvation in serum/growth factor free Fibroblast Basal
Media-2 (Lonza CC-3131) +/- drug inhibitors. Cells were then treated with TGFb1 (5ng/mL)
Fibroblast Basal Media +/- drug inhibitors. Cell lysates are analyzed for aSMA protein
expression by western blot.
Further details may be found in Pegorier et al. (2010). “Bone Morphogenetic
Protein (BMP)-4 and BMP-7 regulate differentially Transforming Growth Factor (TGF)-B1 in
17681897_1 (GHMatters) P110989.NZ
normal human lung fibroblasts (NHLF)” Respir Res 11:85, which is incorporated herein by
reference in its entirety.
EXAMPLE 238: HUMAN TREATMENT
The efficacy of treatment with a compound of a preferred embodiment
compared with placebo in patients with idiopathic pulmonary fibrosis (IPF) and the safety of
treatment with a compound of a preferred embodiment compared with placebo in patients with
IPF is assessed. The primary outcome variable is the absolute change in percent predicted forced
vital capacity (FVC) from baseline to Week 52. Other possible end-points would include, but are
not limited to: mortality, progression free survival, change in rate of FVC decline, change in
Sp02, and change in biomarkers (HRCT image analysis; molecular and cellular markers of
disease activity). Secondary outcome measures include: composite outcomes of important IPF-
related events; progression-free survival; the rate of death from any cause; the rate of death from
IPF; categorical assessment of absolute change in percent predicted FVC from baseline to Week
52; change in Shortness-of-Breath from baseline to Week 52; change in percent predicted
hemoglobin (Hb)-corrected carbon monoxide diffusing capacity (DLco) of the lungs from
baseline to Week 52; change in oxygen saturation during the 6 minute walk test (6MWT) from
baseline to Week 52; change in high-resolution computed tomography (HRCT) assessment from
baseline to Week 52; change in distance walked in the 6MWT from baseline to Week 52.
Patients eligible for this study include, but are not limited to: those patients that satisfy the
following inclusion criteria: diagnosis of IPF; 40 to 80 years of age; FVC ≧50% predicted value;
DLco≧35% predicted value; either FVC or DLco ≦ 90% predicted value; no improvement in
past year; a ratio of the forced expiratory volume in 1 second (FEV1) to the FVC of 0.80 or
more; able to walk 150 meters in 6 minutes and maintain saturation ≧83% while on no more
than 6 L/min supplemental oxygen. Patients are excluded from this study if they satisfy any of
the following criteria: unable to undergo pulmonary function testing; evidence of significant
obstructive lung disease or airway hyper-responsiveness; in the clinical opinion of the
investigator, the patient is expected to need and be eligible for a lung transplant within 52 weeks
of randomization; active infection; liver disease; cancer or other medical condition likely to result
in death within 2 years; diabetes; pregnancy or lactation; substance abuse; personal or family
history of long QT syndrome; other IPF treatment; unable to take study medication; withdrawal
17681897_1 (GHMatters) P110989.NZ
from other IPF trials. Patients are orally dosed with either placebo or an amount of a compound
of a preferred embodiment (1 mg/day-1000 mg/day). The primary outcome variable will be the
absolute change in percent predicted FVC from Baseline to Week 52. Patients will receive
blinded study treatment from the time of randomization until the last patient randomized has
been treated for 52 weeks. Physical and clinical laboratory assessments will be performed at
defined intervals during the treatment duration, for example at weeks 2, 4, 8, 13, 26, 39, and 52.
Pulmonary function, exercise tolerance, and shortness-of-breath will be assessed at defined
intervals during the treatment duration, for example at weeks 13, 26, 39, and 52. A Data
Monitoring Committee (DMC) will periodically review safety and efficacy data to ensure patient
safety.
Example Trial in SSc
The efficacy of treatment with a compound of a preferred embodiment
compared with placebo in patients with systemic sclerosis (SSc) and the safety of treatment with
a compound of a preferred embodiment compared with placebo in patients with SSc is assessed.
The primary outcome variable is the absolute change in Modified Rodnan Skin Score (mRSS)
from baseline to Week 48. Other possible end-points would include, but are not limited to:
mortality, percentage of patients with treatment-emergent adverse events (AEs) and serious
adverse events (SAEs), composite measurement of disease progression, and change in
biomarkers (molecular and cellular markers of disease activity, such as C-reactive protein).
Secondary outcome measures include, but are not limited to: Scleroderma Health Assessment
Questionnaire (SHAQ) score; the Health Assessment Questionnaire Disability Index (HAQ-DI);
Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT) score; severity of pruritus as
measured by a standardized scale, such as the 5-D Itch Scale; St. George’s Respiratory
Questionnaire (SGRQ) score; Tender Joint Count 28 (TCJ28); lung function parameters;
standard vital signs (including blood pressure, heart rate, and temperature); electrocardiogram
measurements (ECGs); laboratory tests (clinical chemistry, hematology, and urinalysis);
pharmacokinetics (PK) measurements. Included in these measurements and in addition, clinical
and biomarker samples, such as skin biopsies and blood (or serum and/or plasma), will also be
collected prior to initiation of treatment. Additionally, patients eligible for this study include, but
are not limited to, those patients that satisfy the following criteria: Patients at least 18 years of
17681897_1 (GHMatters) P110989.NZ
age; diagnosis of SSc according to the American College of Rheumatology (ACR) and European
League Against Rheumatism (EULAR) Criteria, meeting criteria for active disease and with a
total disease duration of less than or equal to 60 months; 10 ≦ mRSS ≦ 35. Patients are
excluded from this study if they satisfy any of the following criteria: major surgery within 8
weeks prior to screening; scleroderma limited to area distal to the elbows or knees; rheumatic
autoimmune disease other than SSc; use of any investigational, biologic, or immunosuppressive
therapies, including intra-articular or parenteral corticosteroids within 4 weeks of screening.
Patients are orally dosed with either placebo or an amount of a compound of a preferred
embodiment (1 mg/day-1000 mg/day). The primary outcome variable will be the absolute
change in mRSS \from Baseline to Week 48. Patients will receive blinded study treatment from
the time of randomization until the last patient randomized has been treated for 48 weeks.
Physical and clinical laboratory assessments will be performed at defined intervals during the
treatment duration, such as Weeks 2, 4, 8, 12, 24, 36, and 48. Clinical and biomarker samples
will also be collected at Week 48. A Data Monitoring Committee (DMC) will periodically
review safety and efficacy data to ensure patient safety.
EXAMPLE 239: CALPAIN BINDING
Calpain 9 Protein Preparation: N-terminally hexa-histidine-tagged human
calpain 9, residues 27-347, was over expressed in E. coli BL21 (DE3) and purified via Ni-NTA
and size-exclusion chromatography with yields > 10mg/liter of culture and >99% purity. The
calpain 9 sequence is accession number O14815 at uniprot.org.
Calpain 9 Crystallization: A 10 mg/ml solution of rat calpain 1 or human
calpain 9 (obtained as described above) was prepared in 50 mM tris (pH 8), 0.5 M NaCl, 1mM
EDTA, 1mM CaCl2, and 1mM beta-mercaptoethanol against MCSG1 screen condition C2
(Anatrace, Maumee, OH) containing 0.2 M LiSO4, 0.1 M bis-tris (pH 5.5), and 25% PEG 3350.
The solution contained 2.5 mM of test compound supplemented with 20% ethylene glycol as a
cryo-protectant. The bound protein was crystallized using vapor diffusion, sitting drop, at 289º
K. The space group was P 41 21 2, with unit cell dimensions of 97.2 Å, 97.2 Å, 173.4 Å.
Calpain 9 Crystallography data collection and refinement: Data was collected
at the APS synchrotron, beamline 21-ID-F at 100º K. Reflections were collect between 45.0 - 2.1
Å with completeness of 100%. Reflection data was analyzed using XDS and Xscale (Heidelberg,
17681897_1 (GHMatters) P110989.NZ
Germany). Structure was solved using molecular replacement and was refined with PHENIX
(Berkeley, CA) to an R value of 0.168, Rfree = 0.210.
Calpain 9 modeling: The experimental distances measured from crystal
structures were supplemented with computational models of calpain 9 binding. The calpain 9 /
test compound crystal structure was used for the initial coordinates. It was stripped of solvent
and minimized in MOE 2016.08 (CCG, Montreal) using the standard quickprep protocol and the
Amber10:EHT force field. Various test compounds were then minimized in the active site. The
distances showed good agreement with the available crystal data.
Calpain 1 preparation, crystallization, and data collection: Suitable constructs
for expression of rat calpain 1 had been previously established. Expression was performed
according to previously established protocols. A purification protocol was established and
homogeneous protein was produced in preparative amounts. The calpain 1 protein was purified
comprising affinity and gel filtration chromatography steps. This procedure yielded homogenous
protein with a purity greater 95 % as judged from Coomassie stained SDS-PAGE. The purified
protein was used in crystallization trials with test compounds employing both, a standard screen
with approximately 1200 different conditions, as well as crystallization conditions identified
using literature data. Conditions initially obtained were optimised using standard strategies,
systematically varying parameters critically influencing crystallization, such as temperature,
protein concentration, drop ratio, and others. These conditions were also refined by
systematically varying pH or precipitant concentrations. Crystals were flashfrozen and measured
at a temperature of 100 K. The X-ray diffraction data were collected from complex crystals
ligands at a synchrotron source using cryogenic conditions. Data were processed using software
programs XDS and XSCALE
Key interactions between test compound moieties (with reference to the
variables of Formula II) and calpain 1 or calpain 9 residues were determined as set forth in
Tables 4-7 below.
17681897_1 (GHMatters) P110989.NZ
Table 4. Polar interactions with human calpain 9
Interaction Distances / Å
Compound
11 12 13 13
R -Gly253 R -Gly190 R -His254 R -Gln91 R -Cys97
3.2 2.9 2.7 2.8 2.9
72 3.2 2.9 2.6 2.8 2.9
44 2.9 3.2 2.5 2.8 3.0
265 2.9 3.2 2.4 2.9 3.1
Table 5. Polar interactions with rat calpain 1
Interaction Distances / Å
Compound
11 12 13 13
R -Gly271 R -Gly208 R -His272 R -Gln109 R -Cys115
60 3.21 2.9 2.9 2.91 2.91
250 3.28 2.98 2.81 3 2.96
17681897_1 (GHMatters) P110989.NZ
Table 6. Non-polar interactions with human calpain 9
Interaction Distances / Å
Compound P2- P2- P2- P2- P2- P3- P3- P3- P1- P1- P1- P1-
Gly190 Phe233 Gly253 His254 Ala255 Gly189 Gly190 Ser191 Gly95 Lys188 Gly189 Ser242
32 3.3 3.3 3.1 4.2 4.3 3.7 3.5 4.4 4.0 3.8 3.5 3.6
3.0 4.1 3.2 3.7 3.6 3.8 3.3 4.2 3.9 4.0 3.5 3.5
44 3.0 4.4 3.4 4.2 3.9 4.0 3.3 4.2 3.6 3.7 3.4 3.7
265 3.2 3.3 2.9 4.2 4.1 3.8 3.4 3.8 3.7 4.4 3.7 4.0
3.1 2.9 3.1 4.4 4.1 3.5 3.6 4.4 3.9 4.2 3.4 3.5
403*
484* 3.2 3.2 3.1 4.5 4.3 3.4 3.4 4.5 3.8 4.1 3.5 3.5
3.2 3.2 3.0 4.1 4.3 3.7 3.5 4.4 3.9 4.2 3.6 3.5
405*
* Based on computational modelling
Table 7. Non-polar interactions with rat calpain 1
Interaction Distances / Å
Compound P - P - P - P - P - P - P - P - P - P - P - P -
2 2 2 2 2 3 3 3 1 1 1 1
Gly208 Ser251 Gly271 His272 Ala273 Gly207 Gly208 Ser209 Gly113 Ser206 Gly207 Met260
3.2 4.4 3.2 4.2 4.1 3.7 3.3 4.4 4.0 4.4 3.7 3.3
3.3 3.7 3.4 4.6 4.4 3.6 3.5 3.8 3.8 4.1 3.5 3.5
17681897_1 (GHMatters) P110989.NZ
While some embodiments have been illustrated and described, a person
with ordinary skill in the art, after reading the foregoing specification, can effect changes,
substitutions of equivalents and other types of alterations to the compounds of the present
technology or salts, pharmaceutical compositions, derivatives, prodrugs, metabolites,
tautomers or racemic mixtures thereof as set forth herein. Each aspect and embodiment
described above can also have included or incorporated therewith such variations or aspects
as disclosed in regard to any or all of the other aspects and embodiments.
The present technology is also not to be limited in terms of the particular
aspects described herein, which are intended as single illustrations of individual aspects of
the present technology. Many modifications and variations of this present technology can be
made without departing from its spirit and scope, as will be apparent to those skilled in the
art. Functionally equivalent methods within the scope of the present technology, in addition
to those enumerated herein, will be apparent to those skilled in the art from the foregoing
descriptions. Such modifications and variations are intended to fall within the scope of the
appended claims. It is to be understood that this present technology is not limited to
particular methods, reagents, compounds, compositions, labeled compounds or biological
systems, which can, of course, vary. It is also to be understood that the terminology used
herein is for the purpose of describing particular aspects only, and is not intended to be
limiting. Thus, it is intended that the specification be considered as exemplary only with the
breadth, scope and spirit of the present technology indicated only by the appended claims,
definitions therein and any equivalents thereof.
The embodiments, illustratively described herein may suitably be practiced
in the absence of any element or elements, limitation or limitations, not specifically disclosed
herein. Thus, for example, the terms “comprising,” “including,” “containing,” etc. shall be
read expansively and without limitation. Additionally, the terms and expressions employed
herein have been used as terms of description and not of limitation, and there is no intention
in the use of such terms and expressions of excluding any equivalents of the features shown
and described or portions thereof, but it is recognized that various modifications are possible
within the scope of the claimed technology. Additionally, the phrase “consisting essentially
17681897_1 (GHMatters) P110989.NZ
of” will be understood to include those elements specifically recited and those additional
elements that do not materially affect the basic and novel characteristics of the claimed
technology. The phrase “consisting of” excludes any element not specified.
In addition, where features or aspects of the disclosure are described in
terms of Markush groups, those skilled in the art will recognize that the disclosure is also
thereby described in terms of any individual member or subgroup of members of the Markush
group. Each of the narrower species and subgeneric groupings falling within the generic
disclosure also form part of the present technology. This includes the generic description of
the present technology with a proviso or negative limitation removing any subject matter
from the genus, regardless of whether or not the excised material is specifically recited
herein.
All publications, patent applications, issued patents, and other documents
(for example, journals, articles and/or textbooks) referred to in this specification are herein
incorporated by reference as if each individual publication, patent application, issued patent,
or other document was specifically and individually indicated to be incorporated by reference
in its entirety. Definitions that are contained in text incorporated by reference are excluded to
the extent that they contradict definitions in this disclosure.
Other embodiments are set forth in the following claims, along with the full
scope of equivalents to which such claims are entitled.
While the invention has been particularly shown and described with
reference to a preferred embodiment and various alternate embodiments, it will be understood
by persons skilled in the relevant art that various changes in form and details can be made
therein without departing from the spirit and scope of the invention.
All references, issued patents and patent applications cited within the body
of the instant specification are hereby incorporated by reference in their entirety, for all
purposes.
Although the invention has been described with reference to embodiments
and examples, it should be understood that numerous and various modifications can be made
without departing from the spirit of the invention. Accordingly, the invention is limited only
by the following claims.
17681897_1 (GHMatters) P110989.NZ
REFERENCES CITED
1. U.S. Patent No. 5,145,684
2. Goll et al. (2003). “The calpain system.” Physiol Rev 83(3):731-801.
3. Schad et al. (2002). “A novel human small subunit of calpains.” Biochem J 362(Pt
2):383-8.
4. Ravulapalli et al. (2009). “Distinguishing between calpain heterodimerization and
homodimerization.” FEBS J 276(4):973-82.
. Dourdin et al. (2001). “Reduced cell migration and disruption of the actin
cytoskeleton in calpain-deficient embryonic fibroblasts.” J Biol Chem 276(51):48382-
6. Leloup et al. (2006). “Involvement of calpains in growth factor-mediated migration.”
Int J Biochem Cell Biol 38(12):2049-63.
7. Janossy et al. (2004). “Calpain as a multi-site regulator of cell cycle.” Biochem
Pharmacol 67(8):1513-21.
8. Santos et al. (2012). “Distinct regulatory functions of calpain 1 and 2 during neural
stem cell self-renewal and differentiation.” PLoS One 7(3):e33468.
9. Miettinen et al. (1994). “TGF-beta induced transdifferentiation of mammary epithelial
cells to mesenchymal cells: involvement of type I receptors.” J Cell Biol 127(6 Pt
2):2021-36.
. Lamouille et al. (2014). “Molecular mechanisms of epithelial-mesenchymal
transition.” Nat Rev Mol Cell Biol 15(3):178-96.
11. Pegorier et al. (2010). “Bone Morphogenetic Protein (BMP)-4 and BMP-7 regulate
differentially Transforming Growth Factor (TGF)-B1 in normal human lung
fibroblasts (NHLF)” Respir Res 11:85.
17681897_1 (GHMatters) P110989.NZ
Claims (43)
1. A compound having the structure selected from the formulas: A A A A R A R 2 X 2 2 Z 6 I-e I-f Y Y X I-g I-h or a pharmaceutically acceptable salt thereof, wherein: A is a single bond; A is -CH - or single bond; when A is single bond, A is directly attached to the ring-atom to which A is 4 3 2 attached; 17681897_1 (GHMatters) P110989.NZ A is selected from the group consisting of optionally substituted C aryl, optionally 3 6-10 substituted 5-10 membered heteroaryl, optionally substituted 3-10 membered heterocyclyl, and optionally substituted C carbocyclyl; 3-10 A is C alkyl; 5 1-4 A is selected from the group consisting of C aryl, 5-10 membered heteroaryl, C 6 6-10 1-4 alkyl, and C alkenyl, each optionally substituted with one or more halo, hydroxyl, C 2-4 1-4 alkyl, O–C alkyl , or O–C alkenyl; 1-6 2-6 A is single bond; 1 2 3 R is selected from the group consisting of H and -CONR R , each R and R are independently selected from –H, optionally substituted C - alkyl, 2- to 5-membered polyethylene glycol, C carbocyclyl, optionally substituted C aryl(C - 3-7 6-10 1 C )alkyl, and 5-10 membered heteroaryl; R is –H; and X and Z are each independently selected from the group consisting of C(R )and N; each R is independently selected from the group consisting of –H, C alkyl, C 1-4 1-2 haloalkyl, C carbocyclyl, halo, hydroxy, and C -C alkoxy; 3-7 1 3 Y is selected from the group consisting of O, S, and SO ; wherein an optionally substituted group can be substituted, unless otherwise specified, with one or more subsitutents independently selected from C -C alkyl, C -C carbocyclyl, 5- 1 6 3 7 10 membered heterocyclyl, aryl (optionally substituted with halo and C -C alkyl), 5-10 membered heteroaryl (optionally substituted with halo, C -C alkyl, and C -C haloalkyl), 1 6 1 6 halo, cyano, hydroxy, C -C alkoxy, C -C alkoxy(C -C )alkyl (i.e., ether), aryloxy, halo(C - 1 6 1 6 1 6 1 C )alkyl (e.g., –CF ), halo(C -C )alkoxy (e.g., –OCF ), amino, amino(C -C )alkyl, C-amido, 6 3 1 6 3 1 6 N-amido, N-sulfonamido, and sulfonyl.
2. The compound of claim 1, wherein when the structure of the compound is of formula I-c; X and Z are independently selected from the group consisting of CH and N.
3. The compound of claim 1, wherein when the structure of the compound is of formula I-d; X and Z are independently selected from the group consisting of CH and N 17681897_1 (GHMatters) P110989.NZ
4. The compound of claim 1, wherein when the structure of the compound is of formula I-e; X and Z are independently selected from the group consisting of CH and N.
5. The compound of claim 1, wherein when the structure of the compound is of formula I-f; Z is N, Y is O, and X is C(R ).
6. The compound of claim 1, wherein when the structure of the compound is of formula I-f; Z is N, Y is S, and X is C(R ).
7. The compound of claim 1, wherein when the structure of the compound is of formula I-f; Z is C(R ), Y is S, and X is C(R ).
8. The compound of claim 1, wherein when the structure of the compound is of formula I-f; Z is C(R ), Y is O, and X is C(R ).
9. The compound of claim 1, wherein when the structure of the compound is of formula I-f; Z is N, Y is S, and X is N.
10. The compound of claim 1, wherein when the structure of the compound is of formula I-f; Z is N, Y is O, and X is N.
11. The compound of claim 1, wherein when the structure of the compound is of formula I-g; X and Z are independently selected from the group consisting of CH and N.
12. The compound of claim 1, wherein when the structure of the compound is of formula I-h; X and Z are independently selected from the group consisting of CH and N.
13. The compound of claim 1, wherein when the structure of the compound is of formula I-h; X is N, Z is C(R ), and Y is O.
14. The compound of claim 13, wherein R is selected from –H and C alkyl.
15. The compound of claim 1, wherein when the structure of the compound is of formula I-h; X is N, Z is C(R ), and Y is S.
16. The compound of claim 1, wherein when the structure of the compound is of formula I-h; X is N, Z is N, and Y is S.
17. The compound of any one of claims 1-16, wherein at least one of the optionally substituted moieties of A is substituted with F. 17681897_1 (GHMatters) P110989.NZ
18. The compound of any one of claims 1-17, wherein A is selected from the X Z 2 1 X X 2 group consisting of , , , , , , , , , and ; and A is selected from the group consisting of H, C aryl, 5-10 membered heteroaryl, 5- 9 6-10 10 membered heterocyclyl, C carbocyclyl, and C - alkyl; 3-7 1 4 X , X , and Z are each independently selected from the group consisting of C(R ) 2 1 1 and N; Y is selected from the group consisting of NR , O, and S; J, L, M and M are each independently selected from the group consisting of C(R ) and N; 17681897_1 (GHMatters) P110989.NZ each R is independently selected from the group consisting of –H, C alkyl, C 1-4 1-2 haloalkyl, C carbocyclyl, halo, hydroxy, and C -C alkoxy; 3-7 1 3 R is selected from the group consisting of –H, C alkyl, C haloalkyl, and C 1-4 1-4 3-7 carbocyclyl (optionally substituted with halo, C -C alkyl, C -C alkoxy, C -C haloalkyl, and 1 6 1 6 1 6 C -C haloalkoxy).
19. The compound of any one of claims 1-17, wherein A is selected from the SO Me group consisting of , , , , , , and .
20. The compound of any one of the claims 1-17, wherein A is selected from the group consisting of , , , , , , and . 17681897_1 (GHMatters) P110989.NZ
21. The compound of any one of claims 1-17, wherein A is a single bond and A is an optionally substituted C aryl or an optionally substituted 5-10 membered heteroaryl. 6-10
22. The compound of claim 21, wherein A has the structure: , wherein J, L, M , M , and M are each independently selected from the group consisting of 1 2 3 C(R ) and N; and each R is independently selected from the group consisting of –H, C - alkyl, C 1 4 1-2 haloalkyl, C carbocyclyl, halo, hydroxy, and C -C alkoxy. 3-7 1 3
23. The compound of claim 22, wherein each of J, L, M , M , and M are C(R ). 1 2 3
24. The compound of claim 23, wherein each R is independently selected from –H and halo. 4A 4A
25. The compound of claim 22, wherein M is C(R ); R is halo and each of J, L, M , and M are CH. 4A 4A
26. The compound of claim 22, wherein L is C(R ); R is halo and each of J, M , M , and M are CH. 1 2 3
27. The compound of any one of claims 1-17, wherein A has a structure selected from the group consisting of: M M M M 2 3 2 3 5 L M and , wherein J, L, M , M , M , M , and M are each independently selected from the group 1 2 3 4 5 consisting of C(R ) and N; and each R is independently selected from the group consisting of –H, C - alkyl, C 1 4 1-2 haloalkyl, C carbocyclyl, halo, hydroxy, and C -C alkoxy. 3-7 1 3 17681897_1 (GHMatters) P110989.NZ
28. The compound of any one of claims 1-17, wherein A has the structure: , wherein Y in A is selected from O and S.
29. The compound of any one of claims 1-28, wherein A is substituted with F.
30. The compound of any one of the claims 1-28, wherein A is phenyl.
31. The compound of any one of claims 1-30, wherein A is -CH -.
32. The compound of any one of claims 1-28, wherein A is -CH - or -CH CH -; 5 2 2 2 A is a single bond; and A is selected from the group consisting of C -C alkyl, optionally 7 6 1 4 substituted phenyl, and optionally substituted 5-10 membered heteroaryl.
33. The compound of claim 32, wherein A is phenyl optionally substituted with one or more C - alkyl, halo, hydroxy, and C -C alkoxy. 1 4 1 6
34. The compound of claim 33, wherein A has the structure:
35. The compound of any one of claims 1-28, wherein –A -A -A is selected from 5 7 6 the group consisting of ethyl, n-propyl, isopropyl, isobutyl, 2,2-dimethylpropyl, and 1,2- dimethylpropyl. 1 2 3
36. The compound of any one of the claims 1-35, wherein R is CONR R .
37. The compound of claim 36, wherein R is –H and R is optionally substituted C alkyl.
38. The compound of claim 36, wherein R is –H and R is selected from the group consisting of –H, C -C alkyl optionally substituted with C-amido, and C -C 1 4 3 6 cycloalkyl. 17681897_1 (GHMatters) P110989.NZ
39. The compound of claim 38, wherein R is selected from the group consisting of –H, ethyl, cyclopropyl, and methyl substituted with C-amido.
40. The compound of claim 36, wherein R is selected from the group consisting of optionally substituted C alkyl and benzyl.
41. The compound of claim 1, wherein the compound has the structure selected from the group consisting of: compounds 6, 9, 11, 14, 18, 20-23, 25-28, 35, 37, 39, 40, 44, 46, 47, 54, 56-58, 60-62, 64, 72, 73, 86, 87, 96-98, 100, 101, 104, 107, 109, 116, 118, 124, 135, 139, 148, 150-152, 205, 207, 211, 213, 222, 224-226, 247, 248, 253-255, 265-267, 270, 271, 277, 278, 286-289, 293, 303, 304, 314, 320-327, 353, 354, 356-361, 363, 365, 367-378, 385-391, 393, 394, 397, 401, 402, 404, 405, 428-430, 459-467, 491-494, 532, 549, 556-560, 578, 584, 592, 594, 595, 599, 600, 609, 618, 619, and pharmaceutically acceptable salts thereof.
42. A pharmaceutical composition comprising: a pharmaceutically acceptable excipient; and an effective amount of at least one compound of any one of claims 1-41.
43. Use of a compound of any one of claims 1-41, or a pharmaceutical composition of claim 42, in the manufacture of a medicament for treating fibrotic disease or a secondary disease state or condition thereof, wherein the disease is selected from the group consisting of liver fibrosis, renal fibrosis, lung fibrosis, hypersensitivity pneumonitis, interstitial fibrosis, systemic scleroderma, macular degeneration, pancreatic fibrosis, fibrosis of the spleen, cardiac fibrosis, mediastinal fibrosis, myelofibrosis, endomyocardial fibrosis, retroperitoneal fibrosis, progressive massive fibrosis, nephrogenic systemic fibrosis, fibrotic complications of surgery, chronic allograft vasculopathy and/or chronic rejection in transplanted organs, ischemic-reperfusion injury associated fibrosis, injection fibrosis, cirrhosis, diffuse parenchymal lung disease, post-vasectomy pain syndrome, and rheumatoid arthritis. 17681897_1 (GHMatters) P110989.NZ
Applications Claiming Priority (7)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201662401093P | 2016-09-28 | 2016-09-28 | |
US62/401,093 | 2016-09-28 | ||
US201762459461P | 2017-02-15 | 2017-02-15 | |
US62/459,461 | 2017-02-15 | ||
US201762554939P | 2017-09-06 | 2017-09-06 | |
US62/554,939 | 2017-09-06 | ||
PCT/US2017/053629 WO2018064119A1 (en) | 2016-09-28 | 2017-09-27 | Calpain modulators and therapeutic uses thereof |
Publications (2)
Publication Number | Publication Date |
---|---|
NZ752865A NZ752865A (en) | 2021-05-28 |
NZ752865B2 true NZ752865B2 (en) | 2021-08-31 |
Family
ID=
Similar Documents
Publication | Publication Date | Title |
---|---|---|
AU2017336523B2 (en) | Calpain modulators and therapeutic uses thereof | |
JP7431961B2 (en) | Triazole carbamate pyridyl sulfonamides and their use as LPA receptor antagonists | |
CN104125956B (en) | The cyclic amides of inhibitor and application thereof as 11- beta-hydroxysteroid dehydrogenase | |
CA2735730A1 (en) | 2,4-diaminopyrimidine compound | |
US20210009564A1 (en) | Calpain modulators and therapeutic uses thereof | |
CN115942972A (en) | LPA receptor antagonists and uses thereof | |
TW202031659A (en) | Novel 6,7-dihydro-4h-pyrazolo[1,5-a]pyrazine indole-2-carboxamides active against the hepatitis b virus (hbv) | |
JP2021522253A (en) | Compounds and their use | |
CA3218569A1 (en) | Lpa receptor antagonists and uses thereof | |
EP3049394A1 (en) | Substituted phenylalanine derivatives as modulators of factor xia | |
WO2020006177A1 (en) | Vascular adhesion protein-1 (vap-1) modulators and therapeutic uses thereof | |
KR20160064100A (en) | Substituted phenylalanine derivatives | |
EP3481835A1 (en) | Calpain modulators and therapeutic uses thereof | |
JP2022531199A (en) | Novel phenyl and pyridyl urea active against hepatitis B virus (HBV) | |
NZ752865B2 (en) | Calpain modulators and therapeutic uses thereof | |
RU2773288C2 (en) | Calpain modulators and their therapeutic use | |
JP7427665B2 (en) | 6-Hydroxy-8-oxatricyclo[3.2.1.02,4]octane-2-carboxamide derivatives for inducing cartilage formation for treating joint injuries | |
TW202342060A (en) | Lonp1 inhibitor compounds, uses and methods | |
TW202200565A (en) | Antiviral 1,3-di-oxo-indene compounds | |
BR112018004956B1 (en) | COMPOUND, PHARMACEUTICAL COMPOSITION, AND, USE OF A COMPOUND | |
JP2010180177A (en) | Cyclic aminopyrazole amide derivative |