US20190225611A1 - Substituted spirocyclic inhibitors of autotaxin - Google Patents
Substituted spirocyclic inhibitors of autotaxin Download PDFInfo
- Publication number
- US20190225611A1 US20190225611A1 US16/256,429 US201916256429A US2019225611A1 US 20190225611 A1 US20190225611 A1 US 20190225611A1 US 201916256429 A US201916256429 A US 201916256429A US 2019225611 A1 US2019225611 A1 US 2019225611A1
- Authority
- US
- United States
- Prior art keywords
- phenyl
- methyl
- triazaspiro
- alkyl
- decan
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 102100021977 Ectonucleotide pyrophosphatase/phosphodiesterase family member 2 Human genes 0.000 title claims description 37
- 108050004000 Ectonucleotide pyrophosphatase/phosphodiesterase family member 2 Proteins 0.000 title claims description 36
- 239000003112 inhibitor Substances 0.000 title claims description 17
- 150000001875 compounds Chemical class 0.000 claims abstract description 170
- 238000000034 method Methods 0.000 claims abstract description 108
- 150000003839 salts Chemical class 0.000 claims abstract description 21
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 13
- -1 —OCHF2 Chemical group 0.000 claims description 156
- 229910052739 hydrogen Inorganic materials 0.000 claims description 31
- WRGQSWVCFNIUNZ-GDCKJWNLSA-N 1-oleoyl-sn-glycerol 3-phosphate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](O)COP(O)(O)=O WRGQSWVCFNIUNZ-GDCKJWNLSA-N 0.000 claims description 30
- AWUCVROLDVIAJX-UHFFFAOYSA-N alpha-glycerophosphate Natural products OCC(O)COP(O)(O)=O AWUCVROLDVIAJX-UHFFFAOYSA-N 0.000 claims description 30
- 125000001424 substituent group Chemical group 0.000 claims description 26
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 25
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 25
- 229910052805 deuterium Inorganic materials 0.000 claims description 16
- 125000003118 aryl group Chemical group 0.000 claims description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims description 8
- 125000004400 (C1-C12) alkyl group Chemical group 0.000 claims description 7
- 125000003342 alkenyl group Chemical group 0.000 claims description 5
- 125000001072 heteroaryl group Chemical group 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
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- 108010037462 Cyclooxygenase 2 Proteins 0.000 claims description 4
- 102100038280 Prostaglandin G/H synthase 2 Human genes 0.000 claims description 4
- 229940043355 kinase inhibitor Drugs 0.000 claims description 4
- 239000003757 phosphotransferase inhibitor Substances 0.000 claims description 4
- 230000009467 reduction Effects 0.000 claims description 4
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 claims description 3
- 125000004189 3,4-dichlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(Cl)C([H])=C1* 0.000 claims description 3
- 125000006275 3-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C([H])C(*)=C1[H] 0.000 claims description 3
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 claims description 3
- 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 0.000 claims description 3
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 3
- 125000004801 4-cyanophenyl group Chemical group [H]C1=C([H])C(C#N)=C([H])C([H])=C1* 0.000 claims description 3
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 3
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 3
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 3
- 125000004863 4-trifluoromethoxyphenyl group Chemical group [H]C1=C([H])C(OC(F)(F)F)=C([H])C([H])=C1* 0.000 claims description 3
- 125000004199 4-trifluoromethylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C(F)(F)F 0.000 claims description 3
- 229940124639 Selective inhibitor Drugs 0.000 claims description 3
- 239000013543 active substance Substances 0.000 claims description 3
- 108010022198 alkylglycerophosphoethanolamine phosphodiesterase Proteins 0.000 claims description 3
- 125000004531 indol-5-yl group Chemical group [H]N1C([H])=C([H])C2=C([H])C(*)=C([H])C([H])=C12 0.000 claims description 3
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 3
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 3
- 125000006652 (C3-C12) cycloalkyl group Chemical group 0.000 claims description 2
- 229940122444 Chemokine receptor antagonist Drugs 0.000 claims description 2
- 108010037464 Cyclooxygenase 1 Proteins 0.000 claims description 2
- 102100038277 Prostaglandin G/H synthase 1 Human genes 0.000 claims description 2
- 229940122144 Prostaglandin receptor antagonist Drugs 0.000 claims description 2
- 108060008682 Tumor Necrosis Factor Proteins 0.000 claims description 2
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 claims description 2
- 108010016133 acylglycerol kinase Proteins 0.000 claims description 2
- 125000000304 alkynyl group Chemical group 0.000 claims description 2
- 239000002260 anti-inflammatory agent Substances 0.000 claims description 2
- 229940121363 anti-inflammatory agent Drugs 0.000 claims description 2
- 239000002246 antineoplastic agent Substances 0.000 claims description 2
- 229940124630 bronchodilator Drugs 0.000 claims description 2
- 239000002559 chemokine receptor antagonist Substances 0.000 claims description 2
- 239000003246 corticosteroid Substances 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 230000009977 dual effect Effects 0.000 claims description 2
- 229960003444 immunosuppressant agent Drugs 0.000 claims description 2
- 239000003018 immunosuppressive agent Substances 0.000 claims description 2
- 230000002401 inhibitory effect Effects 0.000 claims description 2
- 239000003199 leukotriene receptor blocking agent Substances 0.000 claims description 2
- 150000002617 leukotrienes Chemical class 0.000 claims description 2
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 claims description 2
- 239000003358 phospholipase A2 inhibitor Substances 0.000 claims description 2
- 150000003180 prostaglandins Chemical class 0.000 claims description 2
- 125000001475 halogen functional group Chemical group 0.000 claims 3
- 229940122849 Autotaxin inhibitor Drugs 0.000 claims 1
- 229940123977 Lysophosphatidic acid receptor antagonist Drugs 0.000 claims 1
- 108010014865 PLIalpha Proteins 0.000 claims 1
- 229940121927 Phospholipase A1 inhibitor Drugs 0.000 claims 1
- 229940123898 Phospholipase A2 inhibitor Drugs 0.000 claims 1
- 230000000202 analgesic effect Effects 0.000 claims 1
- 230000001861 immunosuppressant effect Effects 0.000 claims 1
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 claims 1
- 239000002089 prostaglandin antagonist Substances 0.000 claims 1
- 239000000203 mixture Substances 0.000 abstract description 327
- 206010028980 Neoplasm Diseases 0.000 abstract description 15
- 201000010099 disease Diseases 0.000 abstract description 15
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 15
- 208000004296 neuralgia Diseases 0.000 abstract description 12
- 208000021722 neuropathic pain Diseases 0.000 abstract description 12
- 201000011510 cancer Diseases 0.000 abstract description 10
- 230000003176 fibrotic effect Effects 0.000 abstract description 10
- 206010064190 Cholestatic pruritus Diseases 0.000 abstract description 7
- 208000007536 Thrombosis Diseases 0.000 abstract description 7
- 208000037976 chronic inflammation Diseases 0.000 abstract description 7
- 230000006020 chronic inflammation Effects 0.000 abstract description 7
- 210000004698 lymphocyte Anatomy 0.000 abstract description 7
- 230000001404 mediated effect Effects 0.000 abstract description 7
- 238000011282 treatment Methods 0.000 abstract description 7
- 239000000543 intermediate Substances 0.000 abstract description 6
- 238000009472 formulation Methods 0.000 abstract description 4
- 238000003786 synthesis reaction Methods 0.000 abstract description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 525
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 516
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 417
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 396
- 239000007787 solid Substances 0.000 description 385
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 336
- 239000000243 solution Substances 0.000 description 300
- 238000005160 1H NMR spectroscopy Methods 0.000 description 290
- 230000002829 reductive effect Effects 0.000 description 252
- 235000019439 ethyl acetate Nutrition 0.000 description 172
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 152
- 238000006243 chemical reaction Methods 0.000 description 143
- 239000012044 organic layer Substances 0.000 description 139
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 137
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 126
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 125
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 124
- 239000005457 ice water Substances 0.000 description 103
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 102
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 102
- 238000010898 silica gel chromatography Methods 0.000 description 90
- 239000002904 solvent Substances 0.000 description 90
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 75
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 69
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 69
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 69
- 239000003208 petroleum Substances 0.000 description 68
- 238000003756 stirring Methods 0.000 description 64
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 56
- 239000003921 oil Substances 0.000 description 49
- 235000019198 oils Nutrition 0.000 description 49
- 239000007821 HATU Substances 0.000 description 47
- 238000001914 filtration Methods 0.000 description 40
- 238000004809 thin layer chromatography Methods 0.000 description 35
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 34
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 32
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 30
- 238000000746 purification Methods 0.000 description 30
- 229920006395 saturated elastomer Polymers 0.000 description 29
- 239000002244 precipitate Substances 0.000 description 28
- HTUHXGLKWIWJTR-SNVBAGLBSA-N (2r)-2-[[2-fluoro-5-(trifluoromethyl)benzoyl]amino]-3-methylbutanoic acid Chemical compound CC(C)[C@H](C(O)=O)NC(=O)C1=CC(C(F)(F)F)=CC=C1F HTUHXGLKWIWJTR-SNVBAGLBSA-N 0.000 description 26
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 26
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 26
- 229910052757 nitrogen Inorganic materials 0.000 description 25
- 238000010791 quenching Methods 0.000 description 25
- 230000000171 quenching effect Effects 0.000 description 25
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 25
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 24
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 24
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 24
- 239000012065 filter cake Substances 0.000 description 24
- 239000012312 sodium hydride Substances 0.000 description 24
- 229910000104 sodium hydride Inorganic materials 0.000 description 24
- 239000000725 suspension Substances 0.000 description 23
- 125000005843 halogen group Chemical group 0.000 description 22
- 229910052760 oxygen Inorganic materials 0.000 description 22
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 22
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 21
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 21
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 21
- 238000002953 preparative HPLC Methods 0.000 description 19
- 239000000706 filtrate Substances 0.000 description 16
- 125000005842 heteroatom Chemical group 0.000 description 16
- 239000010410 layer Substances 0.000 description 16
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 15
- 235000019270 ammonium chloride Nutrition 0.000 description 15
- 239000001257 hydrogen Substances 0.000 description 15
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 13
- 229910000027 potassium carbonate Inorganic materials 0.000 description 13
- 238000010992 reflux Methods 0.000 description 13
- ROUYFJUVMYHXFJ-UHFFFAOYSA-N tert-butyl 4-oxopiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(=O)CC1 ROUYFJUVMYHXFJ-UHFFFAOYSA-N 0.000 description 13
- 239000012298 atmosphere Substances 0.000 description 12
- 239000011541 reaction mixture Substances 0.000 description 12
- LEIMLDGFXIOXMT-UHFFFAOYSA-N trimethylsilyl cyanide Chemical compound C[Si](C)(C)C#N LEIMLDGFXIOXMT-UHFFFAOYSA-N 0.000 description 12
- 150000001721 carbon Chemical group 0.000 description 11
- 229910052799 carbon Inorganic materials 0.000 description 11
- 239000012230 colorless oil Substances 0.000 description 11
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 10
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 10
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 10
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 10
- 238000002360 preparation method Methods 0.000 description 10
- 230000008569 process Effects 0.000 description 10
- 206010016654 Fibrosis Diseases 0.000 description 9
- 239000003054 catalyst Substances 0.000 description 9
- 230000004761 fibrosis Effects 0.000 description 9
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 8
- WRJWRGBVPUUDLA-UHFFFAOYSA-N chlorosulfonyl isocyanate Chemical compound ClS(=O)(=O)N=C=O WRJWRGBVPUUDLA-UHFFFAOYSA-N 0.000 description 8
- 238000001816 cooling Methods 0.000 description 8
- 239000012279 sodium borohydride Substances 0.000 description 8
- 229910000033 sodium borohydride Inorganic materials 0.000 description 8
- CXNIUSPIQKWYAI-UHFFFAOYSA-N xantphos Chemical compound C=12OC3=C(P(C=4C=CC=CC=4)C=4C=CC=CC=4)C=CC=C3C(C)(C)C2=CC=CC=1P(C=1C=CC=CC=1)C1=CC=CC=C1 CXNIUSPIQKWYAI-UHFFFAOYSA-N 0.000 description 8
- SYGQPIYWVFQCPY-UHFFFAOYSA-N C(C)(C)(C)OC(=O)N1CCC2(C(N(CN2C2=CC=C(C=C2)C#N)C)=O)CC1 Chemical compound C(C)(C)(C)OC(=O)N1CCC2(C(N(CN2C2=CC=C(C=C2)C#N)C)=O)CC1 SYGQPIYWVFQCPY-UHFFFAOYSA-N 0.000 description 7
- BATXBDIAUCCELA-UHFFFAOYSA-N C(C)(C)(C)OC(=O)N1CCC2(C(N(CN2C2=CC=C(C=C2)C(N)=O)C)=O)CC1 Chemical compound C(C)(C)(C)OC(=O)N1CCC2(C(N(CN2C2=CC=C(C=C2)C(N)=O)C)=O)CC1 BATXBDIAUCCELA-UHFFFAOYSA-N 0.000 description 7
- 102000004137 Lysophosphatidic Acid Receptors Human genes 0.000 description 7
- 108090000642 Lysophosphatidic Acid Receptors Proteins 0.000 description 7
- 239000012267 brine Substances 0.000 description 7
- 125000006239 protecting group Chemical group 0.000 description 7
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 7
- YGNGSBREWOHUMA-UHFFFAOYSA-N C(C)(C)(C)OC(=O)N1CCC(CC1)(NC1=CC=C(C=C1)C(=O)OC)C#N Chemical compound C(C)(C)(C)OC(=O)N1CCC(CC1)(NC1=CC=C(C=C1)C(=O)OC)C#N YGNGSBREWOHUMA-UHFFFAOYSA-N 0.000 description 6
- DSIRTMPQIVXJGI-UHFFFAOYSA-N C(C)(C)(C)OC(=O)N1CCC(CC1)(NC1=CC=C(C=C1)OC)C#N Chemical compound C(C)(C)(C)OC(=O)N1CCC(CC1)(NC1=CC=C(C=C1)OC)C#N DSIRTMPQIVXJGI-UHFFFAOYSA-N 0.000 description 6
- GPNGSTGBUDAMNV-UHFFFAOYSA-N C(C)(C)(C)OC(=O)N1CCC2(C(N(C(N2C2=CC=C(C(=O)O)C=C2)=O)C)=O)CC1 Chemical compound C(C)(C)(C)OC(=O)N1CCC2(C(N(C(N2C2=CC=C(C(=O)O)C=C2)=O)C)=O)CC1 GPNGSTGBUDAMNV-UHFFFAOYSA-N 0.000 description 6
- DDGDZFFHSTYJSB-UHFFFAOYSA-N C(C)(C)(C)OC(=O)N1CCC2(C(N(CN2C2=CC=C(C(=O)O)C=C2)C)=O)CC1 Chemical compound C(C)(C)(C)OC(=O)N1CCC2(C(N(CN2C2=CC=C(C(=O)O)C=C2)C)=O)CC1 DDGDZFFHSTYJSB-UHFFFAOYSA-N 0.000 description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 6
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
- 230000014759 maintenance of location Effects 0.000 description 6
- 125000004433 nitrogen atom Chemical group N* 0.000 description 6
- 229910052717 sulfur Inorganic materials 0.000 description 6
- 210000001519 tissue Anatomy 0.000 description 6
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 description 6
- ALBOFFXGHBTZSA-LLVKDONJSA-N (2r)-2-[(2-fluoro-3-methylbenzoyl)amino]-3-methylbutanoic acid Chemical compound CC(C)[C@H](C(O)=O)NC(=O)C1=CC=CC(C)=C1F ALBOFFXGHBTZSA-LLVKDONJSA-N 0.000 description 5
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 5
- IRMJSOUZKXJYPI-UHFFFAOYSA-N C(C)(C)(C)OC(=O)N1CCC2(C(N(C(N2C2=CC=C(C=C2)OC)=O)C)=O)CC1 Chemical compound C(C)(C)(C)OC(=O)N1CCC2(C(N(C(N2C2=CC=C(C=C2)OC)=O)C)=O)CC1 IRMJSOUZKXJYPI-UHFFFAOYSA-N 0.000 description 5
- URESMEKPWQXCAC-UHFFFAOYSA-N C(C)(C)(C)OC(=O)N1CCC2(C(N(CN2C2=CC=C(C=C2)C(=O)OC)C)=O)CC1 Chemical compound C(C)(C)(C)OC(=O)N1CCC2(C(N(CN2C2=CC=C(C=C2)C(=O)OC)C)=O)CC1 URESMEKPWQXCAC-UHFFFAOYSA-N 0.000 description 5
- IZYSHHCPXDNKHA-UHFFFAOYSA-N C(C)(C)(C)OC(=O)N1CCC2(C(NCN2C2=CC=C(C=C2)C(=O)OC)=O)CC1 Chemical compound C(C)(C)(C)OC(=O)N1CCC2(C(NCN2C2=CC=C(C=C2)C(=O)OC)=O)CC1 IZYSHHCPXDNKHA-UHFFFAOYSA-N 0.000 description 5
- YXTBPQNTBMEZTB-GFCCVEGCSA-N C(C)C=1C=CC(=C(C(=O)N[C@@H](C(=O)O)C(C)C)C1)F Chemical compound C(C)C=1C=CC(=C(C(=O)N[C@@H](C(=O)O)C(C)C)C1)F YXTBPQNTBMEZTB-GFCCVEGCSA-N 0.000 description 5
- JVLPHMQUKCMZNW-UHFFFAOYSA-N Cl.CN1C(N(C2(C1=O)CCNCC2)C2=CC=C(C(=O)O)C=C2)=O Chemical compound Cl.CN1C(N(C2(C1=O)CCNCC2)C2=CC=C(C(=O)O)C=C2)=O JVLPHMQUKCMZNW-UHFFFAOYSA-N 0.000 description 5
- 241000124008 Mammalia Species 0.000 description 5
- 206010027476 Metastases Diseases 0.000 description 5
- 150000001408 amides Chemical class 0.000 description 5
- 210000004027 cell Anatomy 0.000 description 5
- 238000004296 chiral HPLC Methods 0.000 description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 5
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 5
- 238000010189 synthetic method Methods 0.000 description 5
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 5
- HODWPRQQRJVYGG-LLVKDONJSA-N (2r)-3-methyl-2-[(3-methylbenzoyl)amino]butanoic acid Chemical compound CC(C)[C@H](C(O)=O)NC(=O)C1=CC=CC(C)=C1 HODWPRQQRJVYGG-LLVKDONJSA-N 0.000 description 4
- HOFUGGFJBSCHEW-UHFFFAOYSA-N (4-prop-2-enoxyphenyl)boronic acid Chemical compound OB(O)C1=CC=C(OCC=C)C=C1 HOFUGGFJBSCHEW-UHFFFAOYSA-N 0.000 description 4
- IFYWBEDKWLNJTM-UHFFFAOYSA-N 3-methyl-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one;hydrochloride Chemical compound Cl.C1CNCCC21C(=O)N(C)CN2C1=CC=CC=C1 IFYWBEDKWLNJTM-UHFFFAOYSA-N 0.000 description 4
- IPBXLTHOJUWUIJ-UHFFFAOYSA-N 3-methyl-1-phenyl-1,3,8-triazaspiro[4.5]decane-2,4-dione;hydrochloride Chemical compound Cl.C1CNCCC21C(=O)N(C)C(=O)N2C1=CC=CC=C1 IPBXLTHOJUWUIJ-UHFFFAOYSA-N 0.000 description 4
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 4
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 4
- MKGNJQSRKQKKKO-UHFFFAOYSA-N C(C)(C)(C)OC(=O)N1CCC(CC1)(NC1=CC=C(C=C1)OC)C(N)=O Chemical compound C(C)(C)(C)OC(=O)N1CCC(CC1)(NC1=CC=C(C=C1)OC)C(N)=O MKGNJQSRKQKKKO-UHFFFAOYSA-N 0.000 description 4
- HSIIXVXTSGPOEL-UHFFFAOYSA-N C(C)(C)(C)OC(=O)N1CCC(CC1)(NC1=CC=C(C=C1)[N+](=O)[O-])C#N Chemical compound C(C)(C)(C)OC(=O)N1CCC(CC1)(NC1=CC=C(C=C1)[N+](=O)[O-])C#N HSIIXVXTSGPOEL-UHFFFAOYSA-N 0.000 description 4
- VZYWAOURFXYQOC-UHFFFAOYSA-N C(C)(C)(C)OC(=O)N1CCC2(C(N(C(N2C2=CC=C(C=C2)C(=O)OC)=O)C)=O)CC1 Chemical compound C(C)(C)(C)OC(=O)N1CCC2(C(N(C(N2C2=CC=C(C=C2)C(=O)OC)=O)C)=O)CC1 VZYWAOURFXYQOC-UHFFFAOYSA-N 0.000 description 4
- APKAWEMBTQIXLM-UHFFFAOYSA-N C(C)(C)(C)OC(=O)N1CCC2(C(N(C(N2C2=CC=C(C=C2)[N+](=O)[O-])=O)C)=O)CC1 Chemical compound C(C)(C)(C)OC(=O)N1CCC2(C(N(C(N2C2=CC=C(C=C2)[N+](=O)[O-])=O)C)=O)CC1 APKAWEMBTQIXLM-UHFFFAOYSA-N 0.000 description 4
- NYQQQXGOFHEULC-UHFFFAOYSA-N C(C)(C)(C)OC(=O)N1CCC2(C(N(CN2C2=CC=C(C=C2)Br)C)=O)CC1 Chemical compound C(C)(C)(C)OC(=O)N1CCC2(C(N(CN2C2=CC=C(C=C2)Br)C)=O)CC1 NYQQQXGOFHEULC-UHFFFAOYSA-N 0.000 description 4
- DIDHUZSBHMELII-UHFFFAOYSA-N C(C)(C)(C)OC(=O)N1CCC2(C(NC(N2C2=CC=C(C=C2)C(=O)OC)=O)=O)CC1 Chemical compound C(C)(C)(C)OC(=O)N1CCC2(C(NC(N2C2=CC=C(C=C2)C(=O)OC)=O)=O)CC1 DIDHUZSBHMELII-UHFFFAOYSA-N 0.000 description 4
- AIPKEPCUXGMQEE-UHFFFAOYSA-N Cl.C(C1=CC=CC=C1)OC(=O)N1N=CC2=CC(=CC=C12)N1C(N(C(C12CCNCC2)=O)C)=O Chemical compound Cl.C(C1=CC=CC=C1)OC(=O)N1N=CC2=CC(=CC=C12)N1C(N(C(C12CCNCC2)=O)C)=O AIPKEPCUXGMQEE-UHFFFAOYSA-N 0.000 description 4
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 4
- FNWFYYUCVVMUMO-HXUWFJFHSA-N FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CC=NC=C3)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F Chemical compound FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CC=NC=C3)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F FNWFYYUCVVMUMO-HXUWFJFHSA-N 0.000 description 4
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 4
- GUXRKOGGQHNTIY-UHFFFAOYSA-N benzyl 3-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate Chemical compound C(C1=CC=CC=C1)OC(=O)N1CCC2(C(N(C(N2)=O)C)=O)CC1 GUXRKOGGQHNTIY-UHFFFAOYSA-N 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 230000008878 coupling Effects 0.000 description 4
- 238000010168 coupling process Methods 0.000 description 4
- 238000005859 coupling reaction Methods 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- DNUTZBZXLPWRJG-UHFFFAOYSA-M piperidine-1-carboxylate Chemical compound [O-]C(=O)N1CCCCC1 DNUTZBZXLPWRJG-UHFFFAOYSA-M 0.000 description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- KYZRXNLDSCFSAY-UHFFFAOYSA-N tert-butyl 4-carbamoyl-4-(4-methoxycarbonylanilino)piperidine-1-carboxylate Chemical compound C(C)(C)(C)OC(=O)N1CCC(CC1)(NC1=CC=C(C=C1)C(=O)OC)C(N)=O KYZRXNLDSCFSAY-UHFFFAOYSA-N 0.000 description 4
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 4
- PYOKUURKVVELLB-UHFFFAOYSA-N trimethyl orthoformate Chemical compound COC(OC)OC PYOKUURKVVELLB-UHFFFAOYSA-N 0.000 description 4
- PZAOANXPKWANOY-LLVKDONJSA-N (2R)-2-[(3-fluoro-5-methylbenzoyl)amino]-3-methylbutanoic acid Chemical compound FC=1C=C(C(=O)N[C@@H](C(=O)O)C(C)C)C=C(C1)C PZAOANXPKWANOY-LLVKDONJSA-N 0.000 description 3
- IZKYDFLRAAPPQE-CQSZACIVSA-N (2R)-2-cyclohexyl-2-[(3-methylbenzoyl)amino]acetic acid Chemical compound C1(CCCCC1)[C@H](C(=O)O)NC(C1=CC(=CC=C1)C)=O IZKYDFLRAAPPQE-CQSZACIVSA-N 0.000 description 3
- GUMINBOCIUCMJL-UHFFFAOYSA-N (3-phenylmethoxycyclobutyl)methanol Chemical compound C1C(CO)CC1OCC1=CC=CC=C1 GUMINBOCIUCMJL-UHFFFAOYSA-N 0.000 description 3
- LQLGKCHDVVPGRT-UHFFFAOYSA-N (3-phenylmethoxycyclobutyl)methyl methanesulfonate Chemical compound C1C(COS(=O)(=O)C)CC1OCC1=CC=CC=C1 LQLGKCHDVVPGRT-UHFFFAOYSA-N 0.000 description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 3
- IAWQUHCVFXQBMC-UHFFFAOYSA-N 1,3-benzoxazol-5-amine Chemical compound NC1=CC=C2OC=NC2=C1 IAWQUHCVFXQBMC-UHFFFAOYSA-N 0.000 description 3
- RYCNUMLMNKHWPZ-SNVBAGLBSA-N 1-acetyl-sn-glycero-3-phosphocholine Chemical compound CC(=O)OC[C@@H](O)COP([O-])(=O)OCC[N+](C)(C)C RYCNUMLMNKHWPZ-SNVBAGLBSA-N 0.000 description 3
- KSQLNMJXRMQLEG-UHFFFAOYSA-N 1-benzyl-4-(cyclopropylmethylamino)piperidine-4-carbonitrile Chemical compound C1CC(C#N)(NCC2CC2)CCN1CC1=CC=CC=C1 KSQLNMJXRMQLEG-UHFFFAOYSA-N 0.000 description 3
- YHOYYHYBFSYOSQ-UHFFFAOYSA-N 3-methylbenzoyl chloride Chemical compound CC1=CC=CC(C(Cl)=O)=C1 YHOYYHYBFSYOSQ-UHFFFAOYSA-N 0.000 description 3
- PSTDHCWYBBDDSK-UHFFFAOYSA-N 4-[(3-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decan-1-yl)methyl]benzonitrile hydrobromide Chemical compound Br.CN1C(=O)N(Cc2ccc(cc2)C#N)C2(CCNCC2)C1=O PSTDHCWYBBDDSK-UHFFFAOYSA-N 0.000 description 3
- WQDYHDDZLRURKY-UHFFFAOYSA-N 4-anilino-1-[(2-methylpropan-2-yl)oxycarbonyl]piperidine-4-carboxylic acid Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1(C(O)=O)NC1=CC=CC=C1 WQDYHDDZLRURKY-UHFFFAOYSA-N 0.000 description 3
- MNEOLRFGVQZMLA-UHFFFAOYSA-N 5-nitro-1,3-benzoxazole Chemical compound [O-][N+](=O)C1=CC=C2OC=NC2=C1 MNEOLRFGVQZMLA-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- DOFZLTZQMVGCLP-HSZRJFAPSA-N BrC1=CC=C(C=C1)N1CN(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C(=CC=C2)C)F)=O)=O)=O)C Chemical compound BrC1=CC=C(C=C1)N1CN(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C(=CC=C2)C)F)=O)=O)=O)C DOFZLTZQMVGCLP-HSZRJFAPSA-N 0.000 description 3
- BVYYDEKYMCUJBZ-XMMPIXPASA-N C(#N)C1=CC=C(C=C1)N1CN(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C(=CC=C2)C)F)=O)=O)=O)C Chemical compound C(#N)C1=CC=C(C=C1)N1CN(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C(=CC=C2)C)F)=O)=O)=O)C BVYYDEKYMCUJBZ-XMMPIXPASA-N 0.000 description 3
- UDPBOQDAZUOVNC-HSZRJFAPSA-N C(#N)C1=CC=C(CN2C(N(C(C23CCN(CC3)C([C@@H](C(C)C)NC(C3=C(C=CC(=C3)C(F)(F)F)F)=O)=O)=O)C)=O)C=C1 Chemical compound C(#N)C1=CC=C(CN2C(N(C(C23CCN(CC3)C([C@@H](C(C)C)NC(C3=C(C=CC(=C3)C(F)(F)F)F)=O)=O)=O)C)=O)C=C1 UDPBOQDAZUOVNC-HSZRJFAPSA-N 0.000 description 3
- AJASGMZXUFJNGO-AREMUKBSSA-N C(C)(=O)NC1=CC=C(C=C1)N1CN(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)CC)F)=O)=O)=O)C Chemical compound C(C)(=O)NC1=CC=C(C=C1)N1CN(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)CC)F)=O)=O)=O)C AJASGMZXUFJNGO-AREMUKBSSA-N 0.000 description 3
- APBQAUYNYAQRQD-MUUNZHRXSA-N C(C)(C)(C)OC(=O)N1CC(C1)COC1=CC=C(C=C1)N1C(N(C(C11CCN(CC1)C([C@@H](C(C)C)NC(C1=C(C=CC(=C1)C(F)(F)F)F)=O)=O)=O)C)=O Chemical compound C(C)(C)(C)OC(=O)N1CC(C1)COC1=CC=C(C=C1)N1C(N(C(C11CCN(CC1)C([C@@H](C(C)C)NC(C1=C(C=CC(=C1)C(F)(F)F)F)=O)=O)=O)C)=O APBQAUYNYAQRQD-MUUNZHRXSA-N 0.000 description 3
- AOBQSERDSHCDKU-UHFFFAOYSA-N C(C)(C)(C)OC(=O)N1CC(C1)COC1=CC=C(C=C1)N1C(N(C(C11CCNCC1)=O)C)=O Chemical compound C(C)(C)(C)OC(=O)N1CC(C1)COC1=CC=C(C=C1)N1C(N(C(C11CCNCC1)=O)C)=O AOBQSERDSHCDKU-UHFFFAOYSA-N 0.000 description 3
- QXNQRXLHKYDMLW-UHFFFAOYSA-N C(C)(C)(C)OC(=O)N1CC(C1)NC1=CC=C(C=C1)N1C(N(C(C11CCNCC1)=O)C)=O Chemical compound C(C)(C)(C)OC(=O)N1CC(C1)NC1=CC=C(C=C1)N1C(N(C(C11CCNCC1)=O)C)=O QXNQRXLHKYDMLW-UHFFFAOYSA-N 0.000 description 3
- KFGNJVIGLYFLND-UHFFFAOYSA-N C(C)(C)(C)OC(=O)N1CCC(CC1)(C#N)NC1=CC(=CC=C1)Cl Chemical compound C(C)(C)(C)OC(=O)N1CCC(CC1)(C#N)NC1=CC(=CC=C1)Cl KFGNJVIGLYFLND-UHFFFAOYSA-N 0.000 description 3
- GAHAORRDBVBAPJ-UHFFFAOYSA-N C(C)(C)(C)OC(=O)N1CCC(CC1)(C#N)NC1=CC=C(C=C1)Br Chemical compound C(C)(C)(C)OC(=O)N1CCC(CC1)(C#N)NC1=CC=C(C=C1)Br GAHAORRDBVBAPJ-UHFFFAOYSA-N 0.000 description 3
- SDDGOOXEAMHSOO-UHFFFAOYSA-N C(C)(C)(C)OC(=O)N1CCC(CC1)(C#N)NC=1C=C2C=NNC2=CC=1 Chemical compound C(C)(C)(C)OC(=O)N1CCC(CC1)(C#N)NC=1C=C2C=NNC2=CC=1 SDDGOOXEAMHSOO-UHFFFAOYSA-N 0.000 description 3
- SCVUZWWWMAPPRU-UHFFFAOYSA-N C(C)(C)(C)OC(=O)N1CCC(CC1)(C#N)NC=1C=CC2=C(N=CO2)C=1 Chemical compound C(C)(C)(C)OC(=O)N1CCC(CC1)(C#N)NC=1C=CC2=C(N=CO2)C=1 SCVUZWWWMAPPRU-UHFFFAOYSA-N 0.000 description 3
- WDTOENJUPDDZAF-UHFFFAOYSA-N C(C)(C)(C)OC(=O)N1CCC(CC1)(C(N)=O)NC1=CC=C(C=C1)Br Chemical compound C(C)(C)(C)OC(=O)N1CCC(CC1)(C(N)=O)NC1=CC=C(C=C1)Br WDTOENJUPDDZAF-UHFFFAOYSA-N 0.000 description 3
- NLMSAEVUMSRICL-UHFFFAOYSA-N C(C)(C)(C)OC(=O)N1CCC(CC1)(NC1=CC(=CC=C1)Cl)C(N)=O Chemical compound C(C)(C)(C)OC(=O)N1CCC(CC1)(NC1=CC(=CC=C1)Cl)C(N)=O NLMSAEVUMSRICL-UHFFFAOYSA-N 0.000 description 3
- MCROZCZLRSFKDQ-UHFFFAOYSA-N C(C)(C)(C)OC(=O)N1CCC(CC1)(NC1=CC(=NC=C1)OC)C#N Chemical compound C(C)(C)(C)OC(=O)N1CCC(CC1)(NC1=CC(=NC=C1)OC)C#N MCROZCZLRSFKDQ-UHFFFAOYSA-N 0.000 description 3
- OIAOLAZZXWVGSF-UHFFFAOYSA-N C(C)(C)(C)OC(=O)N1CCC(CC1)(NC1=CC=CC=C1)C#N Chemical compound C(C)(C)(C)OC(=O)N1CCC(CC1)(NC1=CC=CC=C1)C#N OIAOLAZZXWVGSF-UHFFFAOYSA-N 0.000 description 3
- NCTIHFMOMGFBLQ-UHFFFAOYSA-N C(C)(C)(C)OC(=O)N1CCC(CC1)(NC1=CC=CC=C1)CO Chemical compound C(C)(C)(C)OC(=O)N1CCC(CC1)(NC1=CC=CC=C1)CO NCTIHFMOMGFBLQ-UHFFFAOYSA-N 0.000 description 3
- WIEMKGGNYUFVEB-UHFFFAOYSA-N C(C)(C)(C)OC(=O)N1CCC(CC1)(NC=1C=C2C=NN(C2=CC=1)COCC[Si](C)(C)C)C(N)=O Chemical compound C(C)(C)(C)OC(=O)N1CCC(CC1)(NC=1C=C2C=NN(C2=CC=1)COCC[Si](C)(C)C)C(N)=O WIEMKGGNYUFVEB-UHFFFAOYSA-N 0.000 description 3
- HFYGISWDWJNTLB-UHFFFAOYSA-N C(C)(C)(C)OC(=O)N1CCC2(C(N(C(N2C2=CC(=NC=C2)O)=O)C)=O)CC1 Chemical compound C(C)(C)(C)OC(=O)N1CCC2(C(N(C(N2C2=CC(=NC=C2)O)=O)C)=O)CC1 HFYGISWDWJNTLB-UHFFFAOYSA-N 0.000 description 3
- GPLTVAVDEWWYFT-UHFFFAOYSA-N C(C)(C)(C)OC(=O)N1CCC2(C(N(C(N2C2=CC(=NC=C2)OC)=O)C)=O)CC1 Chemical compound C(C)(C)(C)OC(=O)N1CCC2(C(N(C(N2C2=CC(=NC=C2)OC)=O)C)=O)CC1 GPLTVAVDEWWYFT-UHFFFAOYSA-N 0.000 description 3
- WOJSGWVFKPDRHM-UHFFFAOYSA-N C(C)(C)(C)OC(=O)N1CCC2(C(N(C(N2C2=CC(=NC=C2)OS(=O)(=O)C(F)(F)F)=O)C)=O)CC1 Chemical compound C(C)(C)(C)OC(=O)N1CCC2(C(N(C(N2C2=CC(=NC=C2)OS(=O)(=O)C(F)(F)F)=O)C)=O)CC1 WOJSGWVFKPDRHM-UHFFFAOYSA-N 0.000 description 3
- SAYMBROXOUBWMR-UHFFFAOYSA-N C(C)(C)(C)OC(=O)N1CCC2(C(N(C(N2C2=CC=C(C(=O)O)C=C2)C)C)=O)CC1 Chemical compound C(C)(C)(C)OC(=O)N1CCC2(C(N(C(N2C2=CC=C(C(=O)O)C=C2)C)C)=O)CC1 SAYMBROXOUBWMR-UHFFFAOYSA-N 0.000 description 3
- VHMFQJKDNYCRIE-UHFFFAOYSA-N C(C)(C)(C)OC(=O)N1CCC2(C(N(C(N2C2=CC=C(C=C2)C#N)=O)C)=O)CC1 Chemical compound C(C)(C)(C)OC(=O)N1CCC2(C(N(C(N2C2=CC=C(C=C2)C#N)=O)C)=O)CC1 VHMFQJKDNYCRIE-UHFFFAOYSA-N 0.000 description 3
- BVAUFGCBZRJRGV-UHFFFAOYSA-N C(C)(C)(C)OC(=O)N1CCC2(C(N(C(N2C2=CC=C(C=C2)C(=O)OC)=O)CCBr)=O)CC1 Chemical compound C(C)(C)(C)OC(=O)N1CCC2(C(N(C(N2C2=CC=C(C=C2)C(=O)OC)=O)CCBr)=O)CC1 BVAUFGCBZRJRGV-UHFFFAOYSA-N 0.000 description 3
- KRUOTHARIULLEV-UHFFFAOYSA-N C(C)(C)(C)OC(=O)N1CCC2(C(N(C(N2C2=CC=C(C=C2)C(=O)OC)=O)CCN(C)C)=O)CC1 Chemical compound C(C)(C)(C)OC(=O)N1CCC2(C(N(C(N2C2=CC=C(C=C2)C(=O)OC)=O)CCN(C)C)=O)CC1 KRUOTHARIULLEV-UHFFFAOYSA-N 0.000 description 3
- OIROUZMDDMAMCN-UHFFFAOYSA-N C(C)(C)(C)OC(=O)N1CCC2(C(N(C(N2C2=CC=C(C=C2)C(=O)OC)C)C)=O)CC1 Chemical compound C(C)(C)(C)OC(=O)N1CCC2(C(N(C(N2C2=CC=C(C=C2)C(=O)OC)C)C)=O)CC1 OIROUZMDDMAMCN-UHFFFAOYSA-N 0.000 description 3
- OICVXECOQJPTBP-UHFFFAOYSA-N C(C)(C)(C)OC(=O)N1CCC2(C(N(C(N2C2=CC=C(C=C2)C(N)=O)=O)C)=O)CC1 Chemical compound C(C)(C)(C)OC(=O)N1CCC2(C(N(C(N2C2=CC=C(C=C2)C(N)=O)=O)C)=O)CC1 OICVXECOQJPTBP-UHFFFAOYSA-N 0.000 description 3
- JXSZVQVKYRHWBB-UHFFFAOYSA-N C(C)(C)(C)OC(=O)N1CCC2(C(N(C(N2C2=CC=C(C=C2)C=2N=NNN=2)=O)C)=O)CC1 Chemical compound C(C)(C)(C)OC(=O)N1CCC2(C(N(C(N2C2=CC=C(C=C2)C=2N=NNN=2)=O)C)=O)CC1 JXSZVQVKYRHWBB-UHFFFAOYSA-N 0.000 description 3
- GVLUWVFMTONYDP-UHFFFAOYSA-N C(C)(C)(C)OC(=O)N1CCC2(C(N(C(N2C2=CC=C(C=C2)O)=O)C)=O)CC1 Chemical compound C(C)(C)(C)OC(=O)N1CCC2(C(N(C(N2C2=CC=C(C=C2)O)=O)C)=O)CC1 GVLUWVFMTONYDP-UHFFFAOYSA-N 0.000 description 3
- XHDNUBMRUXUZIA-UHFFFAOYSA-N C(C)(C)(C)OC(=O)N1CCC2(C(N(C(N2C2=CC=C(C=C2)OC)C)C)=O)CC1 Chemical compound C(C)(C)(C)OC(=O)N1CCC2(C(N(C(N2C2=CC=C(C=C2)OC)C)C)=O)CC1 XHDNUBMRUXUZIA-UHFFFAOYSA-N 0.000 description 3
- JBYDHQTWWGELDH-UHFFFAOYSA-N C(C)(C)(C)OC(=O)N1CCC2(C(N(C(N2C2=CC=CC=C2)=O)C)=O)CC1 Chemical compound C(C)(C)(C)OC(=O)N1CCC2(C(N(C(N2C2=CC=CC=C2)=O)C)=O)CC1 JBYDHQTWWGELDH-UHFFFAOYSA-N 0.000 description 3
- BYOPNQOEDNNTKG-UHFFFAOYSA-N C(C)(C)(C)OC(=O)N1CCC2(C(N(C(N2C2=CC=NC=C2)=O)C)=O)CC1 Chemical compound C(C)(C)(C)OC(=O)N1CCC2(C(N(C(N2C2=CC=NC=C2)=O)C)=O)CC1 BYOPNQOEDNNTKG-UHFFFAOYSA-N 0.000 description 3
- MRNNILOUSRRAFP-UHFFFAOYSA-N C(C)(C)(C)OC(=O)N1CCC2(C(N(C(N2C=2C=CC3=C(N=CO3)C=2)=O)C)=O)CC1 Chemical compound C(C)(C)(C)OC(=O)N1CCC2(C(N(C(N2C=2C=CC3=C(N=CO3)C=2)=O)C)=O)CC1 MRNNILOUSRRAFP-UHFFFAOYSA-N 0.000 description 3
- ZJHMHNHHAHOXCB-UHFFFAOYSA-N C(C)(C)(C)OC(=O)N1CCC2(C(N(C(N2CC2CC(C2)O)=O)C)=O)CC1 Chemical compound C(C)(C)(C)OC(=O)N1CCC2(C(N(C(N2CC2CC(C2)O)=O)C)=O)CC1 ZJHMHNHHAHOXCB-UHFFFAOYSA-N 0.000 description 3
- NRBQZDXLVILEIS-UHFFFAOYSA-N C(C)(C)(C)OC(=O)N1CCC2(C(N(C(N2CC2CC(C2)OCC2=CC=CC=C2)=O)C)=O)CC1 Chemical compound C(C)(C)(C)OC(=O)N1CCC2(C(N(C(N2CC2CC(C2)OCC2=CC=CC=C2)=O)C)=O)CC1 NRBQZDXLVILEIS-UHFFFAOYSA-N 0.000 description 3
- DZKMPXUGPUTYNW-UHFFFAOYSA-N C(C)(C)(C)OC(=O)N1CCC2(C(N(CN2C2=CC(=CC=C2)Cl)C)=O)CC1 Chemical compound C(C)(C)(C)OC(=O)N1CCC2(C(N(CN2C2=CC(=CC=C2)Cl)C)=O)CC1 DZKMPXUGPUTYNW-UHFFFAOYSA-N 0.000 description 3
- QUNSWIHCZYWEFI-BUVRLJJBSA-N C(C)(C)(C)OC(=O)N1CCC2(C(N(CN2C2=CC=C(C=C2)C(/N=C/N(C)C)=O)C)=O)CC1 Chemical compound C(C)(C)(C)OC(=O)N1CCC2(C(N(CN2C2=CC=C(C=C2)C(/N=C/N(C)C)=O)C)=O)CC1 QUNSWIHCZYWEFI-BUVRLJJBSA-N 0.000 description 3
- BGSXYEGDZXPJEE-UHFFFAOYSA-N C(C)(C)(C)OC(=O)N1CCC2(C(N(CN2C2=CC=C(C=C2)C(=O)OC)CCBr)=O)CC1 Chemical compound C(C)(C)(C)OC(=O)N1CCC2(C(N(CN2C2=CC=C(C=C2)C(=O)OC)CCBr)=O)CC1 BGSXYEGDZXPJEE-UHFFFAOYSA-N 0.000 description 3
- QWUPDRKBVJUNGN-UHFFFAOYSA-N C(C)(C)(C)OC(=O)N1CCC2(C(N(CN2C2=CC=C(C=C2)C(=O)OC)CCN(C)C)=O)CC1 Chemical compound C(C)(C)(C)OC(=O)N1CCC2(C(N(CN2C2=CC=C(C=C2)C(=O)OC)CCN(C)C)=O)CC1 QWUPDRKBVJUNGN-UHFFFAOYSA-N 0.000 description 3
- SUJOJJFVULOWHX-UHFFFAOYSA-N C(C)(C)(C)OC(=O)N1CCC2(C(N(CN2C2=CC=C(C=C2)C2=NNC=N2)C)=O)CC1 Chemical compound C(C)(C)(C)OC(=O)N1CCC2(C(N(CN2C2=CC=C(C=C2)C2=NNC=N2)C)=O)CC1 SUJOJJFVULOWHX-UHFFFAOYSA-N 0.000 description 3
- TZHZZUDHZUSHJA-UHFFFAOYSA-N C(C)(C)(C)OC(=O)N1CCC2(C(N(CN2C2=CC=C(C=C2)N)C)=O)CC1 Chemical compound C(C)(C)(C)OC(=O)N1CCC2(C(N(CN2C2=CC=C(C=C2)N)C)=O)CC1 TZHZZUDHZUSHJA-UHFFFAOYSA-N 0.000 description 3
- OOVVKNFMLSFFAD-UHFFFAOYSA-N C(C)(C)(C)OC(=O)N1CCC2(C(N(CN2C2=CC=C(C=C2)NC(C)=O)C)=O)CC1 Chemical compound C(C)(C)(C)OC(=O)N1CCC2(C(N(CN2C2=CC=C(C=C2)NC(C)=O)C)=O)CC1 OOVVKNFMLSFFAD-UHFFFAOYSA-N 0.000 description 3
- CWEVONFHMWRZLP-UHFFFAOYSA-N C(C)(C)(C)OC(=O)N1CCC2(C(N(CN2C2=CC=C(C=C2)NC2COC2)C)=O)CC1 Chemical compound C(C)(C)(C)OC(=O)N1CCC2(C(N(CN2C2=CC=C(C=C2)NC2COC2)C)=O)CC1 CWEVONFHMWRZLP-UHFFFAOYSA-N 0.000 description 3
- LYASDIQXWDNTSF-UHFFFAOYSA-N C(C)(C)(C)OC(=O)N1CCC2(C(N(CN2C2=CC=C(C=C2)OC)C)=O)CC1 Chemical compound C(C)(C)(C)OC(=O)N1CCC2(C(N(CN2C2=CC=C(C=C2)OC)C)=O)CC1 LYASDIQXWDNTSF-UHFFFAOYSA-N 0.000 description 3
- HWRPPENWMLJOEM-UHFFFAOYSA-N C(C)(C)(C)OC(=O)N1CCC2(C(N(CN2C2=CC=C(C=C2)OCC(=O)OCC)C)=O)CC1 Chemical compound C(C)(C)(C)OC(=O)N1CCC2(C(N(CN2C2=CC=C(C=C2)OCC(=O)OCC)C)=O)CC1 HWRPPENWMLJOEM-UHFFFAOYSA-N 0.000 description 3
- ZTPHEAZZALRYHO-UHFFFAOYSA-N C(C)(C)(C)OC(=O)N1CCC2(C(N(CN2C2=CC=C(C=C2)[N+](=O)[O-])C)=O)CC1 Chemical compound C(C)(C)(C)OC(=O)N1CCC2(C(N(CN2C2=CC=C(C=C2)[N+](=O)[O-])C)=O)CC1 ZTPHEAZZALRYHO-UHFFFAOYSA-N 0.000 description 3
- ZLHOBMOBBUWMED-UHFFFAOYSA-N C(C)(C)(C)OC(=O)N1CCC2(C(N(CN2C=2C=C3C=NN(C3=CC=2)COCC[Si](C)(C)C)C)=O)CC1 Chemical compound C(C)(C)(C)OC(=O)N1CCC2(C(N(CN2C=2C=C3C=NN(C3=CC=2)COCC[Si](C)(C)C)C)=O)CC1 ZLHOBMOBBUWMED-UHFFFAOYSA-N 0.000 description 3
- KAQRMDGACFBJEN-UHFFFAOYSA-N C(C)(C)(C)OC(=O)N1CCC2(C(NC(N2C2=CC(=C(C=C2)O)N)=O)=O)CC1 Chemical compound C(C)(C)(C)OC(=O)N1CCC2(C(NC(N2C2=CC(=C(C=C2)O)N)=O)=O)CC1 KAQRMDGACFBJEN-UHFFFAOYSA-N 0.000 description 3
- HDJPDABCTZWWIS-UHFFFAOYSA-N C(C)(C)(C)OC(=O)N1CCC2(C(NC(N2C2=CC(=NC=C2)OC)=O)=O)CC1 Chemical compound C(C)(C)(C)OC(=O)N1CCC2(C(NC(N2C2=CC(=NC=C2)OC)=O)=O)CC1 HDJPDABCTZWWIS-UHFFFAOYSA-N 0.000 description 3
- LQZZXBWNRGKVGX-UHFFFAOYSA-N C(C)(C)(C)OC(=O)N1CCC2(C(NC(N2C2=CC=C(C=C2)OC)=O)=O)CC1 Chemical compound C(C)(C)(C)OC(=O)N1CCC2(C(NC(N2C2=CC=C(C=C2)OC)=O)=O)CC1 LQZZXBWNRGKVGX-UHFFFAOYSA-N 0.000 description 3
- XVEVFQDPENSLGR-UHFFFAOYSA-N C(C)(C)(C)OC(=O)N1CCC2(C(NC(N2C2=CC=C(C=C2)OC)C)=O)CC1 Chemical compound C(C)(C)(C)OC(=O)N1CCC2(C(NC(N2C2=CC=C(C=C2)OC)C)=O)CC1 XVEVFQDPENSLGR-UHFFFAOYSA-N 0.000 description 3
- DUXXJMZQZQBKHL-UHFFFAOYSA-N C(C)(C)(C)OC(=O)N1CCC2(C(NC(N2C2=CC=C(C=C2)[N+](=O)[O-])=O)=O)CC1 Chemical compound C(C)(C)(C)OC(=O)N1CCC2(C(NC(N2C2=CC=C(C=C2)[N+](=O)[O-])=O)=O)CC1 DUXXJMZQZQBKHL-UHFFFAOYSA-N 0.000 description 3
- FSQBKIVHXLJAAA-UHFFFAOYSA-N C(C)(C)(C)OC(=O)N1CCC2(C(NC(N2C=2C=CC3=C(N=CO3)C2)=O)=O)CC1 Chemical compound C(C)(C)(C)OC(=O)N1CCC2(C(NC(N2C=2C=CC3=C(N=CO3)C2)=O)=O)CC1 FSQBKIVHXLJAAA-UHFFFAOYSA-N 0.000 description 3
- WECFQTXIHDOCRA-UHFFFAOYSA-N C(C)(C)(C)OC(=O)N1CCC2(C(NC(N2CC2CC2)=O)=O)CC1 Chemical compound C(C)(C)(C)OC(=O)N1CCC2(C(NC(N2CC2CC2)=O)=O)CC1 WECFQTXIHDOCRA-UHFFFAOYSA-N 0.000 description 3
- WFZYPGVYWFOYEL-UHFFFAOYSA-N C(C)(C)(C)OC(=O)N1CCC2(C(NCN2C2=CC=C(C=C2)Br)=O)CC1 Chemical compound C(C)(C)(C)OC(=O)N1CCC2(C(NCN2C2=CC=C(C=C2)Br)=O)CC1 WFZYPGVYWFOYEL-UHFFFAOYSA-N 0.000 description 3
- VRHJKSPNKOHAAG-UHFFFAOYSA-N C(C)(C)(C)OC(=O)N1CCC2(C(NCN2C2=CC=C(C=C2)[N+](=O)[O-])=O)CC1 Chemical compound C(C)(C)(C)OC(=O)N1CCC2(C(NCN2C2=CC=C(C=C2)[N+](=O)[O-])=O)CC1 VRHJKSPNKOHAAG-UHFFFAOYSA-N 0.000 description 3
- ZQVRZDYSBNRPGA-UHFFFAOYSA-N C(C)(C)(C)OC(=O)N1CCC2(C(NCN2C=2C=C3C=NN(C3=CC=2)COCC[Si](C)(C)C)=O)CC1 Chemical compound C(C)(C)(C)OC(=O)N1CCC2(C(NCN2C=2C=C3C=NN(C3=CC=2)COCC[Si](C)(C)C)=O)CC1 ZQVRZDYSBNRPGA-UHFFFAOYSA-N 0.000 description 3
- CVXCEPBXIZNYNI-UHFFFAOYSA-N C(C)(C)(C)OC(=O)N1CCC2(COC(N2C2=CC=CC=C2)=O)CC1 Chemical compound C(C)(C)(C)OC(=O)N1CCC2(COC(N2C2=CC=CC=C2)=O)CC1 CVXCEPBXIZNYNI-UHFFFAOYSA-N 0.000 description 3
- GZSXHVISWUQELG-PKOBYXMFSA-N C(C)(C)(C)OC(N[C@@H](C(=O)N1CCC2(C(N(CN2C2=CC=CC=C2)C)=O)CC1)[C@H](C)OC)=O Chemical compound C(C)(C)(C)OC(N[C@@H](C(=O)N1CCC2(C(N(CN2C2=CC=CC=C2)C)=O)CC1)[C@H](C)OC)=O GZSXHVISWUQELG-PKOBYXMFSA-N 0.000 description 3
- PYZWTJUUYLSWCJ-AREMUKBSSA-N C(C)C=1C=CC(=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(CN3C3=CC=C(OCC(=O)O)C=C3)C)=O)CC2)C(C)C)C1)F Chemical compound C(C)C=1C=CC(=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(CN3C3=CC=C(OCC(=O)O)C=C3)C)=O)CC2)C(C)C)C1)F PYZWTJUUYLSWCJ-AREMUKBSSA-N 0.000 description 3
- GOECOLXTEALSPU-YADARESESA-N C(C)C=1C=CC(=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(CN3C3=CC=CC=C3)C)=O)CC2)[C@H](C)OC)C1)F Chemical compound C(C)C=1C=CC(=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(CN3C3=CC=CC=C3)C)=O)CC2)[C@H](C)OC)C1)F GOECOLXTEALSPU-YADARESESA-N 0.000 description 3
- KIYAHTYTVMZFTM-UQBPGWFLSA-N C(C)C=1C=CC(=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N([C@@H](N3C3=CC=C(C(=O)O)C=C3)C)C)=O)CC2)C(C)C)C1)F Chemical compound C(C)C=1C=CC(=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N([C@@H](N3C3=CC=C(C(=O)O)C=C3)C)C)=O)CC2)C(C)C)C1)F KIYAHTYTVMZFTM-UQBPGWFLSA-N 0.000 description 3
- VNOMDZYUHYQSCO-MUUNZHRXSA-N C(C)OC(COC1=CC=C(C=C1)N1CN(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)CC)F)=O)=O)=O)C)=O Chemical compound C(C)OC(COC1=CC=C(C=C1)N1CN(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)CC)F)=O)=O)=O)C)=O VNOMDZYUHYQSCO-MUUNZHRXSA-N 0.000 description 3
- OLKPUYYYNAVLGE-UHFFFAOYSA-N C(C1=CC=CC=C1)OC(=O)N1CCC2(C(N(C(N2C2=CC=C(C=C2)N)=O)C)=O)CC1 Chemical compound C(C1=CC=CC=C1)OC(=O)N1CCC2(C(N(C(N2C2=CC=C(C=C2)N)=O)C)=O)CC1 OLKPUYYYNAVLGE-UHFFFAOYSA-N 0.000 description 3
- BWSIWBLHEPRLRT-UHFFFAOYSA-N C(C1=CC=CC=C1)OC(=O)N1CCC2(C(N(C(N2C2=CC=C(C=C2)NC(=O)OC)=O)C)=O)CC1 Chemical compound C(C1=CC=CC=C1)OC(=O)N1CCC2(C(N(C(N2C2=CC=C(C=C2)NC(=O)OC)=O)C)=O)CC1 BWSIWBLHEPRLRT-UHFFFAOYSA-N 0.000 description 3
- YRWJXOMBVJMHMM-UHFFFAOYSA-N C(C1=CC=CC=C1)OC(=O)N1CCC2(C(N(C(N2C2=CC=C(C=C2)NC2CN(C2)C(=O)OC(C)(C)C)=O)C)=O)CC1 Chemical compound C(C1=CC=CC=C1)OC(=O)N1CCC2(C(N(C(N2C2=CC=C(C=C2)NC2CN(C2)C(=O)OC(C)(C)C)=O)C)=O)CC1 YRWJXOMBVJMHMM-UHFFFAOYSA-N 0.000 description 3
- GRIZPACFGLDLIG-UHFFFAOYSA-N C(C1=CC=CC=C1)OC(=O)N1CCC2(C(N(C(N2C2=CC=C(C=C2)O)=O)C)=O)CC1 Chemical compound C(C1=CC=CC=C1)OC(=O)N1CCC2(C(N(C(N2C2=CC=C(C=C2)O)=O)C)=O)CC1 GRIZPACFGLDLIG-UHFFFAOYSA-N 0.000 description 3
- GSIQCECTWFVLNZ-UHFFFAOYSA-N C(C1=CC=CC=C1)OC(=O)N1CCC2(C(N(C(N2C2=CC=C(C=C2)OCC2CN(C2)C(=O)OC(C)(C)C)=O)C)=O)CC1 Chemical compound C(C1=CC=CC=C1)OC(=O)N1CCC2(C(N(C(N2C2=CC=C(C=C2)OCC2CN(C2)C(=O)OC(C)(C)C)=O)C)=O)CC1 GSIQCECTWFVLNZ-UHFFFAOYSA-N 0.000 description 3
- DAYRLROUUVCIQC-UHFFFAOYSA-N C(C1=CC=CC=C1)OC(=O)N1CCC2(C(N(C(N2C2=CC=C(C=C2)[N+](=O)[O-])=O)C)=O)CC1 Chemical compound C(C1=CC=CC=C1)OC(=O)N1CCC2(C(N(C(N2C2=CC=C(C=C2)[N+](=O)[O-])=O)C)=O)CC1 DAYRLROUUVCIQC-UHFFFAOYSA-N 0.000 description 3
- LFYKFDTWFWSDGN-UHFFFAOYSA-N C(C1=CC=CC=C1)OC(=O)N1CCC2(C(N(C(N2CC2=CC=C(C=C2)C#N)=O)C)=O)CC1 Chemical compound C(C1=CC=CC=C1)OC(=O)N1CCC2(C(N(C(N2CC2=CC=C(C=C2)C#N)=O)C)=O)CC1 LFYKFDTWFWSDGN-UHFFFAOYSA-N 0.000 description 3
- MHXYHDLOSGZGGZ-AREMUKBSSA-N C(C1=CC=CC=C1)OC(=O)N1N=CC2=CC(=CC=C12)N1C(N(C(C11CCN(CC1)C([C@@H](C(C)C)NC(=O)OC(C)(C)C)=O)=O)C)=O Chemical compound C(C1=CC=CC=C1)OC(=O)N1N=CC2=CC(=CC=C12)N1C(N(C(C11CCN(CC1)C([C@@H](C(C)C)NC(=O)OC(C)(C)C)=O)=O)C)=O MHXYHDLOSGZGGZ-AREMUKBSSA-N 0.000 description 3
- YIPKBYQEYHKEHN-MUUNZHRXSA-N C(C1=CC=CC=C1)OC(=O)N1N=CC2=CC(=CC=C12)N1C(N(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=NC=CC=C2)=O)=O)=O)C)=O Chemical compound C(C1=CC=CC=C1)OC(=O)N1N=CC2=CC(=CC=C12)N1C(N(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=NC=CC=C2)=O)=O)=O)C)=O YIPKBYQEYHKEHN-MUUNZHRXSA-N 0.000 description 3
- YEQXRRNUXJHGEH-MUUNZHRXSA-N C(C1=CC=CC=C1)OC(C1=CC=C(C=C1)N1C(N(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)C(F)(F)F)F)=O)=O)=O)C)=O)=O Chemical compound C(C1=CC=CC=C1)OC(C1=CC=C(C=C1)N1C(N(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)C(F)(F)F)F)=O)=O)=O)C)=O)=O YEQXRRNUXJHGEH-MUUNZHRXSA-N 0.000 description 3
- DNQCOHUOAHQAOD-YNKGCYCKSA-N C(C1=CC=CC=C1)OC(C1=CC=C(C=C1)N1C(N(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)CC)F)=O)=O)=O)C)C)=O Chemical compound C(C1=CC=CC=C1)OC(C1=CC=C(C=C1)N1C(N(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)CC)F)=O)=O)=O)C)C)=O DNQCOHUOAHQAOD-YNKGCYCKSA-N 0.000 description 3
- IMDCEXZKOIPWHX-GDLZYMKVSA-N C(C1=CC=CC=C1)OC(C1=CC=C(C=C1)N1CN(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)C(F)(F)F)F)=O)=O)=O)C)=O Chemical compound C(C1=CC=CC=C1)OC(C1=CC=C(C=C1)N1CN(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)C(F)(F)F)F)=O)=O)=O)C)=O IMDCEXZKOIPWHX-GDLZYMKVSA-N 0.000 description 3
- WNZZCFYRMROUMP-HSZRJFAPSA-N C(N)(=O)C1=CC=C(C=C1)N1CN(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C(=CC=C2)C)F)=O)=O)=O)C Chemical compound C(N)(=O)C1=CC=C(C=C1)N1CN(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C(=CC=C2)C)F)=O)=O)=O)C WNZZCFYRMROUMP-HSZRJFAPSA-N 0.000 description 3
- GNLVIJDIHHCHMW-LJQANCHMSA-N C1(CC1)CN1C(N(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)C(F)(F)F)F)=O)=O)=O)C)=O Chemical compound C1(CC1)CN1C(N(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)C(F)(F)F)F)=O)=O)=O)C)=O GNLVIJDIHHCHMW-LJQANCHMSA-N 0.000 description 3
- XYFFYFXZKIBNEK-OAQYLSRUSA-N C1(CCCCC1)N1C(N(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)C(F)(F)F)F)=O)=O)=O)C)=O Chemical compound C1(CCCCC1)N1C(N(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)C(F)(F)F)F)=O)=O)=O)C)=O XYFFYFXZKIBNEK-OAQYLSRUSA-N 0.000 description 3
- GDGRYKTUQLSQOO-XMMPIXPASA-N CC(C)[C@@H](NC(=O)c1cc(ccc1F)C(F)(F)F)C(=O)N1CCC2(CC1)N(C(=O)N(CCN(C)C)C2=O)c1ccc(cc1)C(O)=O Chemical compound CC(C)[C@@H](NC(=O)c1cc(ccc1F)C(F)(F)F)C(=O)N1CCC2(CC1)N(C(=O)N(CCN(C)C)C2=O)c1ccc(cc1)C(O)=O GDGRYKTUQLSQOO-XMMPIXPASA-N 0.000 description 3
- XNSIWDJGVGEHNG-KRZHYRLCSA-N CC([C@H](C(=O)N1CCC2(C(N(C(N2C2=CC=C(C=C2)OC([2H])([2H])[2H])=O)C)=O)CC1)NC(C1=CC(=CC(=C1)F)C(F)(F)F)=O)C Chemical compound CC([C@H](C(=O)N1CCC2(C(N(C(N2C2=CC=C(C=C2)OC([2H])([2H])[2H])=O)C)=O)CC1)NC(C1=CC(=CC(=C1)F)C(F)(F)F)=O)C XNSIWDJGVGEHNG-KRZHYRLCSA-N 0.000 description 3
- YVWMYJOXTKDKMW-OAQYLSRUSA-N CC([C@H](C(=O)N1CCC2(C(N(C(N2C2=CC=CC=C2)=O)C)=O)CC1)NC(C1=CC(=CC=C1)C(F)(F)F)=O)C Chemical compound CC([C@H](C(=O)N1CCC2(C(N(C(N2C2=CC=CC=C2)=O)C)=O)CC1)NC(C1=CC(=CC=C1)C(F)(F)F)=O)C YVWMYJOXTKDKMW-OAQYLSRUSA-N 0.000 description 3
- LEQNBKIUGXBMTP-UHFFFAOYSA-N CC=1C=C(C(=O)NC(C(=O)N2CCC3(C(N(CN3C3=CC=CC=C3)C)=O)CC2)C2CCOCC2)C=CC=1 Chemical compound CC=1C=C(C(=O)NC(C(=O)N2CCC3(C(N(CN3C3=CC=CC=C3)C)=O)CC2)C2CCOCC2)C=CC=1 LEQNBKIUGXBMTP-UHFFFAOYSA-N 0.000 description 3
- UDZHMKJRHGZCGG-UHFFFAOYSA-N CC=1C=C(C(=O)NC(C(=O)O)C2CCOCC2)C=CC=1 Chemical compound CC=1C=C(C(=O)NC(C(=O)O)C2CCOCC2)C=CC=1 UDZHMKJRHGZCGG-UHFFFAOYSA-N 0.000 description 3
- NYLKTDGFIYPAJX-JOCHJYFZSA-N CC=1C=C(C(=O)N[C@@H](C(N2CCC3(COC(N3C3=CC=CC=C3)=O)CC2)=O)C(C)C)C=CC1 Chemical compound CC=1C=C(C(=O)N[C@@H](C(N2CCC3(COC(N3C3=CC=CC=C3)=O)CC2)=O)C(C)C)C=CC1 NYLKTDGFIYPAJX-JOCHJYFZSA-N 0.000 description 3
- NGJPRALBUUSWHM-RUZDIDTESA-N CCC1=CC=C(F)C(=C1)C(=O)N[C@H](C(C)C)C(=O)N1CCC2(CC1)N(CN(CC(O)=O)C2=O)C1=CC=CC=C1 Chemical compound CCC1=CC=C(F)C(=C1)C(=O)N[C@H](C(C)C)C(=O)N1CCC2(CC1)N(CN(CC(O)=O)C2=O)C1=CC=CC=C1 NGJPRALBUUSWHM-RUZDIDTESA-N 0.000 description 3
- FBPXBCANIWAMAK-RUZDIDTESA-N CN(CCN1CN(C2(C1=O)CCN(CC2)C([C@@H](C(C)C)NC(C1=C(C=CC(=C1)C(F)(F)F)F)=O)=O)C1=CC=C(C(=O)O)C=C1)C Chemical compound CN(CCN1CN(C2(C1=O)CCN(CC2)C([C@@H](C(C)C)NC(C1=C(C=CC(=C1)C(F)(F)F)F)=O)=O)C1=CC=C(C(=O)O)C=C1)C FBPXBCANIWAMAK-RUZDIDTESA-N 0.000 description 3
- WNGGVNLXXCHXLF-UHFFFAOYSA-N CN1CN(C2(C1=O)CCNCC2)C2=CC=C(C=C2)NC2COC2 Chemical compound CN1CN(C2(C1=O)CCNCC2)C2=CC=C(C=C2)NC2COC2 WNGGVNLXXCHXLF-UHFFFAOYSA-N 0.000 description 3
- QAERKTUSUHHSGT-UHFFFAOYSA-N COC(C(C1CCOCC1)NC(C1=CC(=CC=C1)C)=O)=O Chemical compound COC(C(C1CCOCC1)NC(C1=CC(=CC=C1)C)=O)=O QAERKTUSUHHSGT-UHFFFAOYSA-N 0.000 description 3
- KTXSXZPBZJDAMC-AREMUKBSSA-N COC(C1=CC=C(C=C1)N1CN(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)C(F)(F)F)F)=O)=O)=O)CCN(C)C)=O Chemical compound COC(C1=CC=C(C=C1)N1CN(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)C(F)(F)F)F)=O)=O)=O)CCN(C)C)=O KTXSXZPBZJDAMC-AREMUKBSSA-N 0.000 description 3
- ISVCOTZIKKNJSU-JOCHJYFZSA-N COC(NC1=CC=C(C=C1)N1C(N(C(C11CCN(CC1)C([C@@H](C(C)C)NC(C1=C(C=CC(=C1)C(F)(F)F)F)=O)=O)=O)C)=O)=O Chemical compound COC(NC1=CC=C(C=C1)N1C(N(C(C11CCN(CC1)C([C@@H](C(C)C)NC(C1=C(C=CC(=C1)C(F)(F)F)F)=O)=O)=O)C)=O)=O ISVCOTZIKKNJSU-JOCHJYFZSA-N 0.000 description 3
- DDLODZNYRISUEJ-GFCCVEGCSA-N COC([C@@H](C(C)C)NC(C1=C(C(=CC=C1)C)F)=O)=O Chemical compound COC([C@@H](C(C)C)NC(C1=C(C(=CC=C1)C)F)=O)=O DDLODZNYRISUEJ-GFCCVEGCSA-N 0.000 description 3
- ATEYDVFDXSKYOB-LLVKDONJSA-N COC([C@@H](C(C)C)NC(C1=C(C=CC(=C1)C(F)(F)F)F)=O)=O Chemical compound COC([C@@H](C(C)C)NC(C1=C(C=CC(=C1)C(F)(F)F)F)=O)=O ATEYDVFDXSKYOB-LLVKDONJSA-N 0.000 description 3
- REXZRKVSHFOVJY-CYBMUJFWSA-N COC([C@@H](C(C)C)NC(C1=C(C=CC(=C1)CC)F)=O)=O Chemical compound COC([C@@H](C(C)C)NC(C1=C(C=CC(=C1)CC)F)=O)=O REXZRKVSHFOVJY-CYBMUJFWSA-N 0.000 description 3
- QKNXAXGHTVYQJQ-GFCCVEGCSA-N COC([C@@H](C(C)C)NC(C1=CC(=CC(=C1)C)F)=O)=O Chemical compound COC([C@@H](C(C)C)NC(C1=CC(=CC(=C1)C)F)=O)=O QKNXAXGHTVYQJQ-GFCCVEGCSA-N 0.000 description 3
- VOLSRGHOVRKEKR-UHFFFAOYSA-N Cl.BrC1=CC=C(C=C1)N1CN(C(C12CCNCC2)=O)C Chemical compound Cl.BrC1=CC=C(C=C1)N1CN(C(C12CCNCC2)=O)C VOLSRGHOVRKEKR-UHFFFAOYSA-N 0.000 description 3
- BOVRBJIKOACTQN-UHFFFAOYSA-N Cl.C(C)OC(CN1CN(C2(C1=O)CCNCC2)C2=CC=CC=C2)=O Chemical compound Cl.C(C)OC(CN1CN(C2(C1=O)CCNCC2)C2=CC=CC=C2)=O BOVRBJIKOACTQN-UHFFFAOYSA-N 0.000 description 3
- UXUBGTXSWGYPQI-UHFFFAOYSA-N Cl.C(C)OC(COC1=CC=C(C=C1)N1CN(C(C12CCNCC2)=O)C)=O Chemical compound Cl.C(C)OC(COC1=CC=C(C=C1)N1CN(C(C12CCNCC2)=O)C)=O UXUBGTXSWGYPQI-UHFFFAOYSA-N 0.000 description 3
- DVTMIPFVPWWLJV-GNAFDRTKSA-N Cl.C(C1=CC=CC=C1)OC(=O)N1N=CC2=CC(=CC=C12)N1C(N(C(C12CCN(CC2)C([C@@H](C(C)C)N)=O)=O)C)=O Chemical compound Cl.C(C1=CC=CC=C1)OC(=O)N1N=CC2=CC(=CC=C12)N1C(N(C(C12CCN(CC2)C([C@@H](C(C)C)N)=O)=O)C)=O DVTMIPFVPWWLJV-GNAFDRTKSA-N 0.000 description 3
- PKIJKKJZABCKII-UHFFFAOYSA-N Cl.C(C1=CC=CC=C1)OC(C1=CC=C(C=C1)N1C(N(C(C12CCNCC2)=O)C)=O)=O Chemical compound Cl.C(C1=CC=CC=C1)OC(C1=CC=C(C=C1)N1C(N(C(C12CCNCC2)=O)C)=O)=O PKIJKKJZABCKII-UHFFFAOYSA-N 0.000 description 3
- YTSJPDKTTKPZBT-UHFFFAOYSA-N Cl.C(C1=CC=CC=C1)OC(C1=CC=C(C=C1)N1CN(C(C12CCNCC2)=O)C)=O Chemical compound Cl.C(C1=CC=CC=C1)OC(C1=CC=C(C=C1)N1CN(C(C12CCNCC2)=O)C)=O YTSJPDKTTKPZBT-UHFFFAOYSA-N 0.000 description 3
- PDAHLAFJCZBDJG-UHFFFAOYSA-N Cl.C1(CCCCC1)N1C(N(C(C12CCNCC2)=O)C)=O Chemical compound Cl.C1(CCCCC1)N1C(N(C(C12CCNCC2)=O)C)=O PDAHLAFJCZBDJG-UHFFFAOYSA-N 0.000 description 3
- ZIIJERLVLBETKE-UHFFFAOYSA-N Cl.CC1N(C2(C(N1C)=O)CCNCC2)C2=CC=C(C(=O)OCC1=CC=CC=C1)C=C2 Chemical compound Cl.CC1N(C2(C(N1C)=O)CCNCC2)C2=CC=C(C(=O)OCC1=CC=CC=C1)C=C2 ZIIJERLVLBETKE-UHFFFAOYSA-N 0.000 description 3
- CJVWOXHLAZETRN-UHFFFAOYSA-N Cl.CN(CCN1CN(C2(C1=O)CCNCC2)C2=CC=C(C(=O)OC)C=C2)C Chemical compound Cl.CN(CCN1CN(C2(C1=O)CCNCC2)C2=CC=C(C(=O)OC)C=C2)C CJVWOXHLAZETRN-UHFFFAOYSA-N 0.000 description 3
- YISYEKGFDVXRFR-UHFFFAOYSA-N Cl.CN1C(N(C2(C1=O)CCNCC2)C2=CC=C(C=C2)[N+](=O)[O-])=O Chemical compound Cl.CN1C(N(C2(C1=O)CCNCC2)C2=CC=C(C=C2)[N+](=O)[O-])=O YISYEKGFDVXRFR-UHFFFAOYSA-N 0.000 description 3
- WSFHNQHIUBJNQS-UHFFFAOYSA-N Cl.CN1C(N(C2(C1=O)CCNCC2)C2=CC=NC=C2)=O Chemical compound Cl.CN1C(N(C2(C1=O)CCNCC2)C2=CC=NC=C2)=O WSFHNQHIUBJNQS-UHFFFAOYSA-N 0.000 description 3
- QQRJKHSCUCGNAH-UHFFFAOYSA-N Cl.CN1CN(C2(C1=O)CCNCC2)C2=CC=C(C#N)C=C2 Chemical compound Cl.CN1CN(C2(C1=O)CCNCC2)C2=CC=C(C#N)C=C2 QQRJKHSCUCGNAH-UHFFFAOYSA-N 0.000 description 3
- RCBFIMHUYSXGFW-UHFFFAOYSA-N Cl.CN1CN(C2(C1=O)CCNCC2)C2=CC=C(C(=O)N)C=C2 Chemical compound Cl.CN1CN(C2(C1=O)CCNCC2)C2=CC=C(C(=O)N)C=C2 RCBFIMHUYSXGFW-UHFFFAOYSA-N 0.000 description 3
- ARPPGVQFALGDFM-UHFFFAOYSA-N Cl.CN1CN(C2(C1=O)CCNCC2)C2=CC=C(C=C2)NC(C)=O Chemical compound Cl.CN1CN(C2(C1=O)CCNCC2)C2=CC=C(C=C2)NC(C)=O ARPPGVQFALGDFM-UHFFFAOYSA-N 0.000 description 3
- JRJPEHCWBIWZLG-UHFFFAOYSA-N Cl.COC(C1=CC=C(C=C1)N1C(N(C(C12CCNCC2)=O)CCN(C)C)=O)=O Chemical compound Cl.COC(C1=CC=C(C=C1)N1C(N(C(C12CCNCC2)=O)CCN(C)C)=O)=O JRJPEHCWBIWZLG-UHFFFAOYSA-N 0.000 description 3
- GQTZDMZZQXXADN-UHFFFAOYSA-N Cl.COC1=CC=C(C=C1)N1C(N(C(C12CCNCC2)=O)C)C Chemical compound Cl.COC1=CC=C(C=C1)N1C(N(C(C12CCNCC2)=O)C)C GQTZDMZZQXXADN-UHFFFAOYSA-N 0.000 description 3
- KDPJSZWBEYYGGM-UHFFFAOYSA-N Cl.ClC=1C=C(C=CC1)N1CN(C(C12CCNCC2)=O)C Chemical compound Cl.ClC=1C=C(C=CC1)N1CN(C(C12CCNCC2)=O)C KDPJSZWBEYYGGM-UHFFFAOYSA-N 0.000 description 3
- AIMYLSTYNUSWOF-UHFFFAOYSA-N Cl.N1N=C(N=C1)C1=CC=C(C=C1)N1CN(C(C12CCNCC2)=O)C Chemical compound Cl.N1N=C(N=C1)C1=CC=C(C=C1)N1CN(C(C12CCNCC2)=O)C AIMYLSTYNUSWOF-UHFFFAOYSA-N 0.000 description 3
- BUQUATZPZHRSFL-UHFFFAOYSA-N Cl.N1N=CC2=CC(=CC=C12)N1CN(C(C12CCNCC2)=O)C Chemical compound Cl.N1N=CC2=CC(=CC=C12)N1CN(C(C12CCNCC2)=O)C BUQUATZPZHRSFL-UHFFFAOYSA-N 0.000 description 3
- CAKQNJGHSUJCEV-UHFFFAOYSA-N Cl.N=1NN=NC1C1=CC=C(C=C1)N1C(N(C(C12CCNCC2)=O)C)=O Chemical compound Cl.N=1NN=NC1C1=CC=C(C=C1)N1C(N(C(C12CCNCC2)=O)C)=O CAKQNJGHSUJCEV-UHFFFAOYSA-N 0.000 description 3
- PYFYPWVBEJICJJ-UHFFFAOYSA-N Cl.N=1NN=NC1C1=CC=C(C=C1)N1CN(C(C12CCNCC2)=O)C Chemical compound Cl.N=1NN=NC1C1=CC=C(C=C1)N1CN(C(C12CCNCC2)=O)C PYFYPWVBEJICJJ-UHFFFAOYSA-N 0.000 description 3
- HEQMBSJYJNODGD-XFULWGLBSA-N Cl.N[C@@H](C(=O)N1CCC2(C(N(C(N2C2=CC=CC=C2)=O)C)=O)CC1)C(C)C Chemical compound Cl.N[C@@H](C(=O)N1CCC2(C(N(C(N2C2=CC=CC=C2)=O)C)=O)CC1)C(C)C HEQMBSJYJNODGD-XFULWGLBSA-N 0.000 description 3
- YJSVSYAAIWLGOX-KUARMEPBSA-N Cl.N[C@@H](C(=O)N1CCC2(C(N(CN2C2=CC=CC=C2)C)=O)CC1)[C@H](C)OC Chemical compound Cl.N[C@@H](C(=O)N1CCC2(C(N(CN2C2=CC=CC=C2)C)=O)CC1)[C@H](C)OC YJSVSYAAIWLGOX-KUARMEPBSA-N 0.000 description 3
- AEOGPETYCDHTTQ-UHFFFAOYSA-N Cl.O1C=NC2=C1C=CC(=C2)N2C(N(C(C21CCNCC1)=O)C)=O Chemical compound Cl.O1C=NC2=C1C=CC(=C2)N2C(N(C(C21CCNCC1)=O)C)=O AEOGPETYCDHTTQ-UHFFFAOYSA-N 0.000 description 3
- YIHKQVVAQIJGNW-MUTAZJQDSA-N Cl.[2H]C([2H])([2H])Oc1ccc(cc1)N1C(=O)N(C)C(=O)C11CCNCC1 Chemical compound Cl.[2H]C([2H])([2H])Oc1ccc(cc1)N1C(=O)N(C)C(=O)C11CCNCC1 YIHKQVVAQIJGNW-MUTAZJQDSA-N 0.000 description 3
- LEQGWCFLSAHFNZ-HSZRJFAPSA-N ClC=1C=C(C=CC1)N1CN(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=CC(=CC=C2)C)=O)=O)=O)C Chemical compound ClC=1C=C(C=CC1)N1CN(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=CC(=CC=C2)C)=O)=O)=O)C LEQGWCFLSAHFNZ-HSZRJFAPSA-N 0.000 description 3
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 3
- FNQOHPHAPZGYHQ-OAQYLSRUSA-N FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CC4=C(NC(O4)=O)C=C3)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F Chemical compound FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CC4=C(NC(O4)=O)C=C3)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F FNQOHPHAPZGYHQ-OAQYLSRUSA-N 0.000 description 3
- CWSQVYFGLYCBFT-OAQYLSRUSA-N FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CC=C(C(=O)O)C=C3)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F Chemical compound FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CC=C(C(=O)O)C=C3)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F CWSQVYFGLYCBFT-OAQYLSRUSA-N 0.000 description 3
- GQXJQATUXRXHHZ-VCUSLETLSA-N FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CC=C(C=C3)OC)C)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F Chemical compound FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CC=C(C=C3)OC)C)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F GQXJQATUXRXHHZ-VCUSLETLSA-N 0.000 description 3
- SVIMIKSMBLUDTA-OBFZPWGMSA-N FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3CCC(CC3)OC)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F Chemical compound FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3CCC(CC3)OC)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F SVIMIKSMBLUDTA-OBFZPWGMSA-N 0.000 description 3
- FDAWOYJCBVRUDO-QYGXFBIXSA-N FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3CC3CC(C3)OC)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F Chemical compound FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3CC3CC(C3)OC)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F FDAWOYJCBVRUDO-QYGXFBIXSA-N 0.000 description 3
- QJCCUDVULRJUPE-HSZRJFAPSA-N FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(CN3C3=CC=C(C=C3)B(O)O)C)=O)CC2)C(C)C)C=CC=C1C Chemical compound FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(CN3C3=CC=C(C=C3)B(O)O)C)=O)CC2)C(C)C)C=CC=C1C QJCCUDVULRJUPE-HSZRJFAPSA-N 0.000 description 3
- QUJPPYISLDYWBK-RUZDIDTESA-N FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(CN3C3=CC=C(C=C3)NC3COC3)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F Chemical compound FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(CN3C3=CC=C(C=C3)NC3COC3)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F QUJPPYISLDYWBK-RUZDIDTESA-N 0.000 description 3
- WFHYLAWROUXHOF-RUZDIDTESA-N N-[(1R)-1-cyclohexyl-2-(3-methyl-2,4-dioxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-8-yl)-2-oxoethyl]-3-methylbenzamide Chemical compound C1(CCCCC1)[C@H](C(=O)N1CCC2(C(N(C(N2C2=CC=CC=C2)=O)C)=O)CC1)NC(C1=CC(=CC=C1)C)=O WFHYLAWROUXHOF-RUZDIDTESA-N 0.000 description 3
- LCJOQRSTIMFYCP-HSZRJFAPSA-N N1N=C(N=C1)C1=CC=C(C=C1)N1CN(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)C(F)(F)F)F)=O)=O)=O)C Chemical compound N1N=C(N=C1)C1=CC=C(C=C1)N1CN(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)C(F)(F)F)F)=O)=O)=O)C LCJOQRSTIMFYCP-HSZRJFAPSA-N 0.000 description 3
- CDSKRHGFXHZEQL-JOCHJYFZSA-N N1N=CC2=CC(=CC=C12)N1C(N(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)C(F)(F)F)F)=O)=O)=O)C)=O Chemical compound N1N=CC2=CC(=CC=C12)N1C(N(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)C(F)(F)F)F)=O)=O)=O)C)=O CDSKRHGFXHZEQL-JOCHJYFZSA-N 0.000 description 3
- TWKSGEPTRAKZPK-OAQYLSRUSA-N N1N=CC2=CC(=CC=C12)N1C(N(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=NC=CC=C2)=O)=O)=O)C)=O Chemical compound N1N=CC2=CC(=CC=C12)N1C(N(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=NC=CC=C2)=O)=O)=O)C)=O TWKSGEPTRAKZPK-OAQYLSRUSA-N 0.000 description 3
- HTLMYSKXWHNOPG-HSZRJFAPSA-N N1N=CC2=CC(=CC=C12)N1CN(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)C(F)(F)F)F)=O)=O)=O)C Chemical compound N1N=CC2=CC(=CC=C12)N1CN(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)C(F)(F)F)F)=O)=O)=O)C HTLMYSKXWHNOPG-HSZRJFAPSA-N 0.000 description 3
- DBEAPVRCIGSENG-OAQYLSRUSA-N N=1NN=NC1C1=CC=C(C=C1)N1C(N(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)C(F)(F)F)F)=O)=O)=O)C)=O Chemical compound N=1NN=NC1C1=CC=C(C=C1)N1C(N(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)C(F)(F)F)F)=O)=O)=O)C)=O DBEAPVRCIGSENG-OAQYLSRUSA-N 0.000 description 3
- MSXIOGSTPFCARR-JOCHJYFZSA-N N=1NN=NC1C1=CC=C(C=C1)N1CN(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)C(F)(F)F)F)=O)=O)=O)C Chemical compound N=1NN=NC1C1=CC=C(C=C1)N1CN(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)C(F)(F)F)F)=O)=O)=O)C MSXIOGSTPFCARR-JOCHJYFZSA-N 0.000 description 3
- KWOKRNLQLCBPBQ-JOCHJYFZSA-N O1C=NC2=C1C=CC(=C2)N2C(N(C(C21CCN(CC1)C([C@@H](C(C)C)NC(C1=C(C=CC(=C1)C(F)(F)F)F)=O)=O)=O)C)=O Chemical compound O1C=NC2=C1C=CC(=C2)N2C(N(C(C21CCN(CC1)C([C@@H](C(C)C)NC(C1=C(C=CC(=C1)C(F)(F)F)F)=O)=O)=O)C)=O KWOKRNLQLCBPBQ-JOCHJYFZSA-N 0.000 description 3
- VQJKWNQTZOTJSH-GJFSDDNBSA-N OC(=O)C(F)(F)F.CC(C)[C@@H](NC(=O)C1=C(F)C=CC(=C1)C(F)(F)F)C(=O)N1CCC2(CC1)N(C(=O)N(C)C2=O)C1=CC=C(NC2CNC2)C=C1 Chemical compound OC(=O)C(F)(F)F.CC(C)[C@@H](NC(=O)C1=C(F)C=CC(=C1)C(F)(F)F)C(=O)N1CCC2(CC1)N(C(=O)N(C)C2=O)C1=CC=C(NC2CNC2)C=C1 VQJKWNQTZOTJSH-GJFSDDNBSA-N 0.000 description 3
- 206010033128 Ovarian cancer Diseases 0.000 description 3
- 206010061535 Ovarian neoplasm Diseases 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 230000004913 activation Effects 0.000 description 3
- 230000033115 angiogenesis Effects 0.000 description 3
- HGOPYEWWZGZVJI-UHFFFAOYSA-N benzyl 2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate Chemical compound C1CC2(C(NC(=O)N2)=O)CCN1C(=O)OCC1=CC=CC=C1 HGOPYEWWZGZVJI-UHFFFAOYSA-N 0.000 description 3
- KIBBQMUFFRTOAS-GDLZYMKVSA-N benzyl 5-[8-[(2R)-2-[[2-fluoro-5-(trifluoromethyl)benzoyl]amino]-3-methylbutanoyl]-3-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decan-1-yl]indazole-1-carboxylate Chemical compound C(C1=CC=CC=C1)OC(=O)N1N=CC2=CC(=CC=C12)N1C(N(C(C11CCN(CC1)C([C@@H](C(C)C)NC(C1=C(C=CC(=C1)C(F)(F)F)F)=O)=O)=O)C)=O KIBBQMUFFRTOAS-GDLZYMKVSA-N 0.000 description 3
- ANHDLZKAIXZCMD-UHFFFAOYSA-N benzyl 5-[[4-cyano-1-[(2-methylpropan-2-yl)oxycarbonyl]piperidin-4-yl]amino]indazole-1-carboxylate Chemical compound C(C1=CC=CC=C1)OC(=O)N1N=CC2=CC(=CC=C12)NC1(CCN(CC1)C(=O)OC(C)(C)C)C#N ANHDLZKAIXZCMD-UHFFFAOYSA-N 0.000 description 3
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 3
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 description 3
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 3
- 150000002170 ethers Chemical class 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 230000009401 metastasis Effects 0.000 description 3
- LDZCACILIBPLQU-GFCCVEGCSA-N methyl (2R)-3-methyl-2-[(3-methylbenzoyl)amino]butanoate Chemical compound COC([C@@H](C(C)C)NC(C1=CC(=CC=C1)C)=O)=O LDZCACILIBPLQU-GFCCVEGCSA-N 0.000 description 3
- PJTDHGUEFPHGGZ-JOCHJYFZSA-N methyl 4-[8-[(2R)-2-[[2-fluoro-5-(trifluoromethyl)benzoyl]amino]-3-methylbutanoyl]-3-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decan-1-yl]benzoate Chemical compound COC(C1=CC=C(C=C1)N1C(N(C(C11CCN(CC1)C([C@@H](C(C)C)NC(C1=C(C=CC(=C1)C(F)(F)F)F)=O)=O)=O)C)=O)=O PJTDHGUEFPHGGZ-JOCHJYFZSA-N 0.000 description 3
- HQTPWERZTKULDL-UHFFFAOYSA-N methyl N-[4-(3-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decan-1-yl)phenyl]carbamate Chemical compound COC(NC1=CC=C(C=C1)N1C(N(C(C12CCNCC2)=O)C)=O)=O HQTPWERZTKULDL-UHFFFAOYSA-N 0.000 description 3
- 230000037361 pathway Effects 0.000 description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- ILVXOBCQQYKLDS-UHFFFAOYSA-N pyridine N-oxide Chemical compound [O-][N+]1=CC=CC=C1 ILVXOBCQQYKLDS-UHFFFAOYSA-N 0.000 description 3
- 230000004044 response Effects 0.000 description 3
- 239000012453 solvate Substances 0.000 description 3
- 230000004083 survival effect Effects 0.000 description 3
- LOVOSGLSVNCCMB-UHFFFAOYSA-N tert-butyl 1-(3-chlorophenyl)-4-oxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate Chemical compound C(C)(C)(C)OC(=O)N1CCC2(C(NCN2C2=CC(=CC=C2)Cl)=O)CC1 LOVOSGLSVNCCMB-UHFFFAOYSA-N 0.000 description 3
- AIWVSUBUVALELS-UHFFFAOYSA-N tert-butyl 1-(4-hydroxyphenyl)-3-methyl-4-oxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate Chemical compound C(C)(C)(C)OC(=O)N1CCC2(C(N(CN2C2=CC=C(C=C2)O)C)=O)CC1 AIWVSUBUVALELS-UHFFFAOYSA-N 0.000 description 3
- NHAKTECXIBGECS-UHFFFAOYSA-N tert-butyl 1-(4-methoxyphenyl)-4-oxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate Chemical compound C1=CC(OC)=CC=C1N1C2(CCN(CC2)C(=O)OC(C)(C)C)C(=O)NC1 NHAKTECXIBGECS-UHFFFAOYSA-N 0.000 description 3
- OVPSYZROZKRIFN-UHFFFAOYSA-N tert-butyl 2,4-dioxo-1-(1-phenylmethoxycarbonylindazol-5-yl)-1,3,8-triazaspiro[4.5]decane-8-carboxylate Chemical compound C(C1=CC=CC=C1)OC(=O)N1N=CC2=CC(=CC=C12)N1C(NC(C11CCN(CC1)C(=O)OC(C)(C)C)=O)=O OVPSYZROZKRIFN-UHFFFAOYSA-N 0.000 description 3
- PHDGZQLUGXVXNS-UHFFFAOYSA-N tert-butyl 2,4-dioxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate Chemical compound C(C)(C)(C)OC(=O)N1CCC2(C(NC(N2C2=CC=CC=C2)=O)=O)CC1 PHDGZQLUGXVXNS-UHFFFAOYSA-N 0.000 description 3
- BHSCFWOFSDZQIK-UHFFFAOYSA-N tert-butyl 3-(2-ethoxy-2-oxoethyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC21C(=O)N(CC(=O)OCC)CN2C1=CC=CC=C1 BHSCFWOFSDZQIK-UHFFFAOYSA-N 0.000 description 3
- MRVISGVUICZVHZ-HHHXNRCGSA-N tert-butyl 3-[4-[8-[(2R)-2-[[2-fluoro-5-(trifluoromethyl)benzoyl]amino]-3-methylbutanoyl]-3-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decan-1-yl]anilino]azetidine-1-carboxylate Chemical compound C(C)(C)(C)OC(=O)N1CC(C1)NC1=CC=C(C=C1)N1C(N(C(C11CCN(CC1)C([C@@H](C(C)C)NC(C1=C(C=CC(=C1)C(F)(F)F)F)=O)=O)=O)C)=O MRVISGVUICZVHZ-HHHXNRCGSA-N 0.000 description 3
- WFYWNZAFKBBGCF-UHFFFAOYSA-N tert-butyl 3-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate Chemical compound O=C1N(C)C(=O)NC11CCN(C(=O)OC(C)(C)C)CC1 WFYWNZAFKBBGCF-UHFFFAOYSA-N 0.000 description 3
- GXTJTMSNIPLUEK-UHFFFAOYSA-N tert-butyl 3-methyl-2,4-dioxo-1-(1-phenylmethoxycarbonylindazol-5-yl)-1,3,8-triazaspiro[4.5]decane-8-carboxylate Chemical compound C(C1=CC=CC=C1)OC(=O)N1N=CC2=CC(=CC=C12)N1C(N(C(C11CCN(CC1)C(=O)OC(C)(C)C)=O)C)=O GXTJTMSNIPLUEK-UHFFFAOYSA-N 0.000 description 3
- JQGRFJHWZLUQRP-UHFFFAOYSA-N tert-butyl 3-methyl-2,4-dioxo-1-(4-phenylmethoxycarbonylphenyl)-1,3,8-triazaspiro[4.5]decane-8-carboxylate Chemical compound C(C)(C)(C)OC(=O)N1CCC2(C(N(C(N2C2=CC=C(C=C2)C(=O)OCC2=CC=CC=C2)=O)C)=O)CC1 JQGRFJHWZLUQRP-UHFFFAOYSA-N 0.000 description 3
- IRMJSOUZKXJYPI-VPYROQPTSA-N tert-butyl 3-methyl-2,4-dioxo-1-[4-(trideuteriomethoxy)phenyl]-1,3,8-triazaspiro[4.5]decane-8-carboxylate Chemical compound [2H]C([2H])([2H])OC1=CC=C(C=C1)N1C(=O)N(C)C(=O)C11CCN(CC1)C(=O)OC(C)(C)C IRMJSOUZKXJYPI-VPYROQPTSA-N 0.000 description 3
- JDVUZHVFTUGTCS-UHFFFAOYSA-N tert-butyl 3-methyl-4-oxo-1-(4-phenylmethoxycarbonylphenyl)-1,3,8-triazaspiro[4.5]decane-8-carboxylate Chemical compound C(C)(C)(C)OC(=O)N1CCC2(C(N(CN2C2=CC=C(C=C2)C(=O)OCC2=CC=CC=C2)C)=O)CC1 JDVUZHVFTUGTCS-UHFFFAOYSA-N 0.000 description 3
- ZBTCTIDRZAHCCK-UHFFFAOYSA-N tert-butyl 3-methyl-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC21C(=O)N(C)CN2C1=CC=CC=C1 ZBTCTIDRZAHCCK-UHFFFAOYSA-N 0.000 description 3
- 230000009466 transformation Effects 0.000 description 3
- 238000000844 transformation Methods 0.000 description 3
- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 description 2
- SZXBQTSZISFIAO-SSDOTTSWSA-N (2r)-3-methyl-2-[(2-methylpropan-2-yl)oxycarbonylamino]butanoic acid Chemical compound CC(C)[C@H](C(O)=O)NC(=O)OC(C)(C)C SZXBQTSZISFIAO-SSDOTTSWSA-N 0.000 description 2
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 description 2
- NDQXKKFRNOPRDW-UHFFFAOYSA-N 1,1,1-triethoxyethane Chemical compound CCOC(C)(OCC)OCC NDQXKKFRNOPRDW-UHFFFAOYSA-N 0.000 description 2
- PAAZPARNPHGIKF-UHFFFAOYSA-N 1,2-dibromoethane Chemical compound BrCCBr PAAZPARNPHGIKF-UHFFFAOYSA-N 0.000 description 2
- FPIRBHDGWMWJEP-UHFFFAOYSA-N 1-hydroxy-7-azabenzotriazole Chemical compound C1=CN=C2N(O)N=NC2=C1 FPIRBHDGWMWJEP-UHFFFAOYSA-N 0.000 description 2
- NNJSDVWFUJMHSO-UHFFFAOYSA-N 5-ethyl-2-fluorobenzoic acid Chemical compound CCC1=CC=C(F)C(C(O)=O)=C1 NNJSDVWFUJMHSO-UHFFFAOYSA-N 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N Benzoic acid Natural products OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- MMNWNPBLZSZYBH-UHFFFAOYSA-N C(C)(C)(C)OC(=O)N1CCC(CC1)(NC1=CC(=NC=C1)OC)C(N)=O Chemical compound C(C)(C)(C)OC(=O)N1CCC(CC1)(NC1=CC(=NC=C1)OC)C(N)=O MMNWNPBLZSZYBH-UHFFFAOYSA-N 0.000 description 2
- QVAXHGOCYXFCIW-UHFFFAOYSA-N C(C)(C)(C)OC(=O)N1CCC(CC1)(NC1=CC2=C(NC(O2)=O)C=C1)C#N Chemical compound C(C)(C)(C)OC(=O)N1CCC(CC1)(NC1=CC2=C(NC(O2)=O)C=C1)C#N QVAXHGOCYXFCIW-UHFFFAOYSA-N 0.000 description 2
- BDBIAAZHIAQIRE-UHFFFAOYSA-N C(C)(C)(C)OC(=O)N1CCC(CC1)(NC1=CC=C(C=C1)[N+](=O)[O-])C(N)=O Chemical compound C(C)(C)(C)OC(=O)N1CCC(CC1)(NC1=CC=C(C=C1)[N+](=O)[O-])C(N)=O BDBIAAZHIAQIRE-UHFFFAOYSA-N 0.000 description 2
- QKPYLVKCFVPACU-UHFFFAOYSA-N C(C)(C)(C)OC(=O)N1CCC(CC1)(NC=1C=C2C=NN(C2=CC=1)COCC[Si](C)(C)C)C#N Chemical compound C(C)(C)(C)OC(=O)N1CCC(CC1)(NC=1C=C2C=NN(C2=CC=1)COCC[Si](C)(C)C)C#N QKPYLVKCFVPACU-UHFFFAOYSA-N 0.000 description 2
- GQGXFLNSEISWND-UHFFFAOYSA-N C(C)(C)(C)OC(=O)N1CCC2(C(N(C(N2C2=CC=C(C=C2)C(=O)OCC2=CC=CC=C2)C)C)=O)CC1 Chemical compound C(C)(C)(C)OC(=O)N1CCC2(C(N(C(N2C2=CC=C(C=C2)C(=O)OCC2=CC=CC=C2)C)C)=O)CC1 GQGXFLNSEISWND-UHFFFAOYSA-N 0.000 description 2
- YXEDDJIPWHFHAZ-UHFFFAOYSA-N C(C)(C)(C)OC(=O)N1CCC2(C(N(C(N2C2CCC(CC2)OC)=O)C)=O)CC1 Chemical compound C(C)(C)(C)OC(=O)N1CCC2(C(N(C(N2C2CCC(CC2)OC)=O)C)=O)CC1 YXEDDJIPWHFHAZ-UHFFFAOYSA-N 0.000 description 2
- LJWJLZLFECFSHM-UHFFFAOYSA-N C(C)(C)(C)OC(=O)N1CCC2(C(N(C(N2CC2CC(C2)OC)=O)C)=O)CC1 Chemical compound C(C)(C)(C)OC(=O)N1CCC2(C(N(C(N2CC2CC(C2)OC)=O)C)=O)CC1 LJWJLZLFECFSHM-UHFFFAOYSA-N 0.000 description 2
- YNCWQCCUIPAVEL-UHFFFAOYSA-N C(C)(C)(C)OC(=O)N1CCC2(C(N(CN2C2=CC=C(C=C2)C=2N=NNN=2)C)=O)CC1 Chemical compound C(C)(C)(C)OC(=O)N1CCC2(C(N(CN2C2=CC=C(C=C2)C=2N=NNN=2)C)=O)CC1 YNCWQCCUIPAVEL-UHFFFAOYSA-N 0.000 description 2
- STDQQRFXZPCTCG-UHFFFAOYSA-N C(C)(C)(C)OC(=O)N1CCC2(C(NC(N2C2=CC=C(C=C2)C(=O)OC)C)=O)CC1 Chemical compound C(C)(C)(C)OC(=O)N1CCC2(C(NC(N2C2=CC=C(C=C2)C(=O)OC)C)=O)CC1 STDQQRFXZPCTCG-UHFFFAOYSA-N 0.000 description 2
- ZPDLYFXVRXEUAO-GOSISDBHSA-N C(C)(C)(C)OC(N[C@@H](C(=O)N1CCC2(C(N(C(N2C2=CC=CC=C2)=O)C)=O)CC1)C(C)C)=O Chemical compound C(C)(C)(C)OC(N[C@@H](C(=O)N1CCC2(C(N(C(N2C2=CC=CC=C2)=O)C)=O)CC1)C(C)C)=O ZPDLYFXVRXEUAO-GOSISDBHSA-N 0.000 description 2
- KIYAHTYTVMZFTM-KBMIEXCESA-N C(C)C=1C=CC(=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N([C@H](N3C3=CC=C(C(=O)O)C=C3)C)C)=O)CC2)C(C)C)C1)F Chemical compound C(C)C=1C=CC(=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N([C@H](N3C3=CC=C(C(=O)O)C=C3)C)C)=O)CC2)C(C)C)C1)F KIYAHTYTVMZFTM-KBMIEXCESA-N 0.000 description 2
- UMUSRQDHGFIKBG-VCUSLETLSA-N C(C)C=1C=CC(=C(C(=O)N[C@@H](C(=O)N2CCC3(C(NC(N3C3=CC=C(C(=O)O)C=C3)C)=O)CC2)C(C)C)C1)F Chemical compound C(C)C=1C=CC(=C(C(=O)N[C@@H](C(=O)N2CCC3(C(NC(N3C3=CC=C(C(=O)O)C=C3)C)=O)CC2)C(C)C)C1)F UMUSRQDHGFIKBG-VCUSLETLSA-N 0.000 description 2
- KTOMLKZVNNYBLC-AREMUKBSSA-N C(C)OC(CN1CN(C2(C1=O)CCN(CC2)C([C@@H](C(C)C)NC(C2=CC(=CC(=C2)C)F)=O)=O)C2=CC=CC=C2)=O Chemical compound C(C)OC(CN1CN(C2(C1=O)CCN(CC2)C([C@@H](C(C)C)NC(C2=CC(=CC(=C2)C)F)=O)=O)C2=CC=CC=C2)=O KTOMLKZVNNYBLC-AREMUKBSSA-N 0.000 description 2
- RCIAPROBMWTWJM-UHFFFAOYSA-N C1(CCCCC1)N1C(N(C(C11CCN(CC1)C(=O)OC(C)(C)C)=O)C)=O Chemical compound C1(CCCCC1)N1C(N(C(C11CCN(CC1)C(=O)OC(C)(C)C)=O)C)=O RCIAPROBMWTWJM-UHFFFAOYSA-N 0.000 description 2
- HOZZPCLPYSGHNM-JOCHJYFZSA-N CC(C)[C@@H](NC(=O)C1=C(F)C=CC(=C1)C(F)(F)F)C(=O)N1CCC2(CC1)N(CN(C)C2=O)C1=CC=C(C=C1)C(O)=O Chemical compound CC(C)[C@@H](NC(=O)C1=C(F)C=CC(=C1)C(F)(F)F)C(=O)N1CCC2(CC1)N(CN(C)C2=O)C1=CC=C(C=C1)C(O)=O HOZZPCLPYSGHNM-JOCHJYFZSA-N 0.000 description 2
- LEQNBKIUGXBMTP-RUZDIDTESA-N CC=1C=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(CN3C3=CC=CC=C3)C)=O)CC2)C2CCOCC2)C=CC=1 Chemical compound CC=1C=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(CN3C3=CC=CC=C3)C)=O)CC2)C2CCOCC2)C=CC=1 LEQNBKIUGXBMTP-RUZDIDTESA-N 0.000 description 2
- KPYNEPNUIWWVBW-RUZDIDTESA-N COC(C1=CC=C(C=C1)N1C(N(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)C(F)(F)F)F)=O)=O)=O)CCN(C)C)=O)=O Chemical compound COC(C1=CC=C(C=C1)N1C(N(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)C(F)(F)F)F)=O)=O)=O)CCN(C)C)=O)=O KPYNEPNUIWWVBW-RUZDIDTESA-N 0.000 description 2
- PBVNMJPEZBMLMD-UHFFFAOYSA-N Cl.C1(=CC=CC=C1)N1C(OCC12CCNCC2)=O Chemical compound Cl.C1(=CC=CC=C1)N1C(OCC12CCNCC2)=O PBVNMJPEZBMLMD-UHFFFAOYSA-N 0.000 description 2
- XKPZXXVIAFDYCT-UHFFFAOYSA-N Cl.COC1CCC(CC1)N1C(N(C(C12CCNCC2)=O)C)=O Chemical compound Cl.COC1CCC(CC1)N1C(N(C(C12CCNCC2)=O)C)=O XKPZXXVIAFDYCT-UHFFFAOYSA-N 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- WVJFJUVNPHYXQD-HXUWFJFHSA-N FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CC=[N+](C=C3)[O-])=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F Chemical compound FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CC=[N+](C=C3)[O-])=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F WVJFJUVNPHYXQD-HXUWFJFHSA-N 0.000 description 2
- 201000003741 Gastrointestinal carcinoma Diseases 0.000 description 2
- 201000009794 Idiopathic Pulmonary Fibrosis Diseases 0.000 description 2
- 206010061218 Inflammation Diseases 0.000 description 2
- 208000028389 Nerve injury Diseases 0.000 description 2
- UGHRRXXJNLINJN-VQIWEWKSSA-N OC(=O)C(F)(F)F.CC(C)[C@@H](NC(=O)C1=C(F)C=CC(=C1)C(F)(F)F)C(=O)N1CCC2(CC1)N(C(=O)N(C)C2=O)C1=CC=C(OCC2CNC2)C=C1 Chemical compound OC(=O)C(F)(F)F.CC(C)[C@@H](NC(=O)C1=C(F)C=CC(=C1)C(F)(F)F)C(=O)N1CCC2(CC1)N(C(=O)N(C)C2=O)C1=CC=C(OCC2CNC2)C=C1 UGHRRXXJNLINJN-VQIWEWKSSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 2
- 239000012346 acetyl chloride Substances 0.000 description 2
- 206010064930 age-related macular degeneration Diseases 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 239000000908 ammonium hydroxide Substances 0.000 description 2
- 230000000259 anti-tumor effect Effects 0.000 description 2
- 239000012300 argon atmosphere Substances 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 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
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 2
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 description 2
- 208000014829 head and neck neoplasm Diseases 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- DCPMPXBYPZGNDC-UHFFFAOYSA-N hydron;methanediimine;chloride Chemical compound Cl.N=C=N DCPMPXBYPZGNDC-UHFFFAOYSA-N 0.000 description 2
- 230000004054 inflammatory process Effects 0.000 description 2
- 208000036971 interstitial lung disease 2 Diseases 0.000 description 2
- 201000002313 intestinal cancer Diseases 0.000 description 2
- 210000003734 kidney Anatomy 0.000 description 2
- 150000002632 lipids Chemical class 0.000 description 2
- 239000012280 lithium aluminium hydride Substances 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 210000004072 lung Anatomy 0.000 description 2
- 208000002780 macular degeneration Diseases 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 201000001441 melanoma Diseases 0.000 description 2
- LZXXNPOYQCLXRS-UHFFFAOYSA-N methyl 4-aminobenzoate Chemical compound COC(=O)C1=CC=C(N)C=C1 LZXXNPOYQCLXRS-UHFFFAOYSA-N 0.000 description 2
- 230000005012 migration Effects 0.000 description 2
- 238000013508 migration Methods 0.000 description 2
- 230000008764 nerve damage Effects 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- BHAAPTBBJKJZER-UHFFFAOYSA-N p-anisidine Chemical compound COC1=CC=C(N)C=C1 BHAAPTBBJKJZER-UHFFFAOYSA-N 0.000 description 2
- 230000001575 pathological effect Effects 0.000 description 2
- SIOXPEMLGUPBBT-UHFFFAOYSA-N picolinic acid Chemical compound OC(=O)C1=CC=CC=N1 SIOXPEMLGUPBBT-UHFFFAOYSA-N 0.000 description 2
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 2
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 2
- 230000035755 proliferation Effects 0.000 description 2
- 230000000644 propagated effect Effects 0.000 description 2
- 208000005069 pulmonary fibrosis Diseases 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 2
- AXQWXZHEKRUMHR-UHFFFAOYSA-N tert-butyl 1-(cyclopropylmethyl)-3-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate Chemical compound C(C)(C)(C)OC(=O)N1CCC2(C(N(C(N2CC2CC2)=O)C)=O)CC1 AXQWXZHEKRUMHR-UHFFFAOYSA-N 0.000 description 2
- BNYZRZNNKWZTKG-UHFFFAOYSA-N tert-butyl 4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC21C(=O)NCN2C1=CC=CC=C1 BNYZRZNNKWZTKG-UHFFFAOYSA-N 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- VXUYXOFXAQZZMF-UHFFFAOYSA-N titanium(IV) isopropoxide Chemical compound CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C VXUYXOFXAQZZMF-UHFFFAOYSA-N 0.000 description 2
- AQRLNPVMDITEJU-UHFFFAOYSA-N triethylsilane Chemical compound CC[SiH](CC)CC AQRLNPVMDITEJU-UHFFFAOYSA-N 0.000 description 2
- 210000004881 tumor cell Anatomy 0.000 description 2
- VCGRFBXVSFAGGA-UHFFFAOYSA-N (1,1-dioxo-1,4-thiazinan-4-yl)-[6-[[3-(4-fluorophenyl)-5-methyl-1,2-oxazol-4-yl]methoxy]pyridin-3-yl]methanone Chemical compound CC=1ON=C(C=2C=CC(F)=CC=2)C=1COC(N=C1)=CC=C1C(=O)N1CCS(=O)(=O)CC1 VCGRFBXVSFAGGA-UHFFFAOYSA-N 0.000 description 1
- WAMWSIDTKSNDCU-SSDOTTSWSA-N (2r)-2-azaniumyl-2-cyclohexylacetate Chemical compound OC(=O)[C@H](N)C1CCCCC1 WAMWSIDTKSNDCU-SSDOTTSWSA-N 0.000 description 1
- VWSUOKFUIPMDDX-NKWVEPMBSA-N (2r,3s)-3-methoxy-2-[(2-methylpropan-2-yl)oxycarbonylamino]butanoic acid Chemical compound CO[C@@H](C)[C@H](C(O)=O)NC(=O)OC(C)(C)C VWSUOKFUIPMDDX-NKWVEPMBSA-N 0.000 description 1
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 1
- MAYZWDRUFKUGGP-VIFPVBQESA-N (3s)-1-[5-tert-butyl-3-[(1-methyltetrazol-5-yl)methyl]triazolo[4,5-d]pyrimidin-7-yl]pyrrolidin-3-ol Chemical compound CN1N=NN=C1CN1C2=NC(C(C)(C)C)=NC(N3C[C@@H](O)CC3)=C2N=N1 MAYZWDRUFKUGGP-VIFPVBQESA-N 0.000 description 1
- 125000006716 (C1-C6) heteroalkyl group Chemical group 0.000 description 1
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 description 1
- UKGJZDSUJSPAJL-YPUOHESYSA-N (e)-n-[(1r)-1-[3,5-difluoro-4-(methanesulfonamido)phenyl]ethyl]-3-[2-propyl-6-(trifluoromethyl)pyridin-3-yl]prop-2-enamide Chemical compound CCCC1=NC(C(F)(F)F)=CC=C1\C=C\C(=O)N[C@H](C)C1=CC(F)=C(NS(C)(=O)=O)C(F)=C1 UKGJZDSUJSPAJL-YPUOHESYSA-N 0.000 description 1
- ZGYIXVSQHOKQRZ-COIATFDQSA-N (e)-n-[4-[3-chloro-4-(pyridin-2-ylmethoxy)anilino]-3-cyano-7-[(3s)-oxolan-3-yl]oxyquinolin-6-yl]-4-(dimethylamino)but-2-enamide Chemical compound N#CC1=CN=C2C=C(O[C@@H]3COCC3)C(NC(=O)/C=C/CN(C)C)=CC2=C1NC(C=C1Cl)=CC=C1OCC1=CC=CC=N1 ZGYIXVSQHOKQRZ-COIATFDQSA-N 0.000 description 1
- MOWXJLUYGFNTAL-DEOSSOPVSA-N (s)-[2-chloro-4-fluoro-5-(7-morpholin-4-ylquinazolin-4-yl)phenyl]-(6-methoxypyridazin-3-yl)methanol Chemical compound N1=NC(OC)=CC=C1[C@@H](O)C1=CC(C=2C3=CC=C(C=C3N=CN=2)N2CCOCC2)=C(F)C=C1Cl MOWXJLUYGFNTAL-DEOSSOPVSA-N 0.000 description 1
- DIOHEXPTUTVCNX-UHFFFAOYSA-N 1,1,1-trifluoro-n-phenyl-n-(trifluoromethylsulfonyl)methanesulfonamide Chemical compound FC(F)(F)S(=O)(=O)N(S(=O)(=O)C(F)(F)F)C1=CC=CC=C1 DIOHEXPTUTVCNX-UHFFFAOYSA-N 0.000 description 1
- APWRZPQBPCAXFP-UHFFFAOYSA-N 1-(1-oxo-2H-isoquinolin-5-yl)-5-(trifluoromethyl)-N-[2-(trifluoromethyl)pyridin-4-yl]pyrazole-4-carboxamide Chemical compound O=C1NC=CC2=C(C=CC=C12)N1N=CC(=C1C(F)(F)F)C(=O)NC1=CC(=NC=C1)C(F)(F)F APWRZPQBPCAXFP-UHFFFAOYSA-N 0.000 description 1
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 1
- ABDDQTDRAHXHOC-QMMMGPOBSA-N 1-[(7s)-5,7-dihydro-4h-thieno[2,3-c]pyran-7-yl]-n-methylmethanamine Chemical compound CNC[C@@H]1OCCC2=C1SC=C2 ABDDQTDRAHXHOC-QMMMGPOBSA-N 0.000 description 1
- SJZKULRDWHPHGG-UHFFFAOYSA-N 1-benzylpiperidin-4-one Chemical compound C1CC(=O)CCN1CC1=CC=CC=C1 SJZKULRDWHPHGG-UHFFFAOYSA-N 0.000 description 1
- XBTOSRUBOXQWBO-UHFFFAOYSA-N 1h-indazol-5-amine Chemical compound NC1=CC=C2NN=CC2=C1 XBTOSRUBOXQWBO-UHFFFAOYSA-N 0.000 description 1
- BPXKZEMBEZGUAH-UHFFFAOYSA-N 2-(chloromethoxy)ethyl-trimethylsilane Chemical compound C[Si](C)(C)CCOCCl BPXKZEMBEZGUAH-UHFFFAOYSA-N 0.000 description 1
- VLZVIIYRNMWPSN-UHFFFAOYSA-N 2-Amino-4-nitrophenol Chemical compound NC1=CC([N+]([O-])=O)=CC=C1O VLZVIIYRNMWPSN-UHFFFAOYSA-N 0.000 description 1
- DGNAETGARNTCIL-UHFFFAOYSA-N 2-fluoro-3-methylbenzoic acid Chemical compound CC1=CC=CC(C(O)=O)=C1F DGNAETGARNTCIL-UHFFFAOYSA-N 0.000 description 1
- LIFKXWNFWIUMJT-UHFFFAOYSA-N 2-fluoro-5-(trifluoromethyl)benzoic acid Chemical compound OC(=O)C1=CC(C(F)(F)F)=CC=C1F LIFKXWNFWIUMJT-UHFFFAOYSA-N 0.000 description 1
- YEWZFWXYHXWLPS-JOCHJYFZSA-N 2-fluoro-N-[(2R)-1-(1-imidazo[1,2-a]pyridin-6-yl-3-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decan-8-yl)-3-methyl-1-oxobutan-2-yl]-5-(trifluoromethyl)benzamide Chemical compound CC(C)[C@@H](NC(=O)c1cc(ccc1F)C(F)(F)F)C(=O)N1CCC2(CC1)N(C(=O)N(C)C2=O)c1ccc2nccn2c1 YEWZFWXYHXWLPS-JOCHJYFZSA-N 0.000 description 1
- OAPFEWZOCPGHMQ-HSZRJFAPSA-N 2-fluoro-N-[(2R)-3-methyl-1-[3-methyl-1-(2-methyl-3H-benzimidazol-5-yl)-2,4-dioxo-1,3,8-triazaspiro[4.5]decan-8-yl]-1-oxobutan-2-yl]-5-(trifluoromethyl)benzamide Chemical compound CC(C)[C@@H](NC(=O)c1cc(ccc1F)C(F)(F)F)C(=O)N1CCC2(CC1)N(C(=O)N(C)C2=O)c1ccc2nc(C)[nH]c2c1 OAPFEWZOCPGHMQ-HSZRJFAPSA-N 0.000 description 1
- KFTMKTOJVHOBGJ-HSZRJFAPSA-N 2-fluoro-N-[(2R)-3-methyl-1-[3-methyl-1-(2-methylindazol-5-yl)-2,4-dioxo-1,3,8-triazaspiro[4.5]decan-8-yl]-1-oxobutan-2-yl]-5-(trifluoromethyl)benzamide Chemical compound FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CC4=CN(N=C4C=C3)C)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F KFTMKTOJVHOBGJ-HSZRJFAPSA-N 0.000 description 1
- CALWUCIHXRLQQU-HSZRJFAPSA-N 2-fluoro-N-[(2R)-3-methyl-1-[3-methyl-1-[(2-methyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)methyl]-2,4-dioxo-1,3,8-triazaspiro[4.5]decan-8-yl]-1-oxobutan-2-yl]-5-(trifluoromethyl)benzamide Chemical compound FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3CC3=CC=4N(C=C3)N=C(N=4)C)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F CALWUCIHXRLQQU-HSZRJFAPSA-N 0.000 description 1
- XSPPBSRUOZLLIM-WBPHRXDCSA-N 2-fluoro-N-[(2R)-3-methyl-1-[3-methyl-2,4-dioxo-1-(1-phenylethyl)-1,3,8-triazaspiro[4.5]decan-8-yl]-1-oxobutan-2-yl]-5-(trifluoromethyl)benzamide Chemical compound FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C(C)C3=CC=CC=C3)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F XSPPBSRUOZLLIM-WBPHRXDCSA-N 0.000 description 1
- ZGWXCVZYJDJXBF-OAQYLSRUSA-N 2-fluoro-N-[(2R)-3-methyl-1-[3-methyl-2,4-dioxo-1-(2-oxo-3H-1,3-benzoxazol-5-yl)-1,3,8-triazaspiro[4.5]decan-8-yl]-1-oxobutan-2-yl]-5-(trifluoromethyl)benzamide Chemical compound FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C=3C=CC4=C(NC(O4)=O)C=3)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F ZGWXCVZYJDJXBF-OAQYLSRUSA-N 0.000 description 1
- OJQHZZIHMKRVBA-UHFFFAOYSA-N 2-fluoro-N-[1-[1-(1H-indazol-5-yl)-3-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decan-8-yl]-2-methyl-1-oxopropan-2-yl]-5-(trifluoromethyl)benzamide Chemical compound N1N=CC2=CC(=CC=C12)N1C(N(C(C11CCN(CC1)C(C(C)(C)NC(C1=C(C=CC(=C1)C(F)(F)F)F)=O)=O)=O)C)=O OJQHZZIHMKRVBA-UHFFFAOYSA-N 0.000 description 1
- CFPHMNIOKBKSMY-UHFFFAOYSA-N 2-fluoro-N-[3-[1-(1H-indazol-5-yl)-3-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-carbonyl]oxetan-3-yl]-5-(trifluoromethyl)benzamide Chemical compound N1N=CC2=CC(=CC=C12)N1C(N(C(C11CCN(CC1)C(=O)C1(COC1)NC(C1=C(C=CC(=C1)C(F)(F)F)F)=O)=O)C)=O CFPHMNIOKBKSMY-UHFFFAOYSA-N 0.000 description 1
- SVEQHRSELNPKJJ-UHFFFAOYSA-N 2-methoxypyridin-4-amine Chemical compound COC1=CC(N)=CC=N1 SVEQHRSELNPKJJ-UHFFFAOYSA-N 0.000 description 1
- NZWUAGSHISPXTR-UHFFFAOYSA-N 2-oxo-1,3,8-triazaspiro[4.5]decane-8-carboxylic acid Chemical compound OC(=O)N1CCC2(CNC(=O)N2)CC1 NZWUAGSHISPXTR-UHFFFAOYSA-N 0.000 description 1
- HCDMJFOHIXMBOV-UHFFFAOYSA-N 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholin-4-ylmethyl)-4,7-dihydropyrrolo[4,5]pyrido[1,2-d]pyrimidin-2-one Chemical compound C=1C2=C3N(CC)C(=O)N(C=4C(=C(OC)C=C(OC)C=4F)F)CC3=CN=C2NC=1CN1CCOCC1 HCDMJFOHIXMBOV-UHFFFAOYSA-N 0.000 description 1
- BYHQTRFJOGIQAO-GOSISDBHSA-N 3-(4-bromophenyl)-8-[(2R)-2-hydroxypropyl]-1-[(3-methoxyphenyl)methyl]-1,3,8-triazaspiro[4.5]decan-2-one Chemical compound C[C@H](CN1CCC2(CC1)CN(C(=O)N2CC3=CC(=CC=C3)OC)C4=CC=C(C=C4)Br)O BYHQTRFJOGIQAO-GOSISDBHSA-N 0.000 description 1
- YGYGASJNJTYNOL-CQSZACIVSA-N 3-[(4r)-2,2-dimethyl-1,1-dioxothian-4-yl]-5-(4-fluorophenyl)-1h-indole-7-carboxamide Chemical compound C1CS(=O)(=O)C(C)(C)C[C@@H]1C1=CNC2=C(C(N)=O)C=C(C=3C=CC(F)=CC=3)C=C12 YGYGASJNJTYNOL-CQSZACIVSA-N 0.000 description 1
- WNEODWDFDXWOLU-QHCPKHFHSA-N 3-[3-(hydroxymethyl)-4-[1-methyl-5-[[5-[(2s)-2-methyl-4-(oxetan-3-yl)piperazin-1-yl]pyridin-2-yl]amino]-6-oxopyridin-3-yl]pyridin-2-yl]-7,7-dimethyl-1,2,6,8-tetrahydrocyclopenta[3,4]pyrrolo[3,5-b]pyrazin-4-one Chemical compound C([C@@H](N(CC1)C=2C=NC(NC=3C(N(C)C=C(C=3)C=3C(=C(N4C(C5=CC=6CC(C)(C)CC=6N5CC4)=O)N=CC=3)CO)=O)=CC=2)C)N1C1COC1 WNEODWDFDXWOLU-QHCPKHFHSA-N 0.000 description 1
- SRVXSISGYBMIHR-UHFFFAOYSA-N 3-[3-[3-(2-amino-2-oxoethyl)phenyl]-5-chlorophenyl]-3-(5-methyl-1,3-thiazol-2-yl)propanoic acid Chemical compound S1C(C)=CN=C1C(CC(O)=O)C1=CC(Cl)=CC(C=2C=C(CC(N)=O)C=CC=2)=C1 SRVXSISGYBMIHR-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- WSEGCWYPQULGME-HSZRJFAPSA-N 3-chloro-4-cyano-N-[(2R)-3-methyl-1-(3-methyl-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-8-yl)-1-oxobutan-2-yl]benzamide Chemical compound ClC=1C=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(CN3C3=CC=CC=C3)C)=O)CC2)C(C)C)C=CC=1C#N WSEGCWYPQULGME-HSZRJFAPSA-N 0.000 description 1
- PNPCRKVUWYDDST-UHFFFAOYSA-N 3-chloroaniline Chemical compound NC1=CC=CC(Cl)=C1 PNPCRKVUWYDDST-UHFFFAOYSA-N 0.000 description 1
- 125000003852 3-chlorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C(Cl)=C1[H])C([H])([H])* 0.000 description 1
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 1
- DTYCLGGQXDHUCS-HSZRJFAPSA-N 3-ethyl-5-fluoro-N-[(2R)-3-methyl-1-(3-methyl-2,4-dioxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-8-yl)-1-oxobutan-2-yl]benzamide Chemical compound C(C)C=1C=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CC=CC=C3)=O)C)=O)CC2)C(C)C)C=C(C=1)F DTYCLGGQXDHUCS-HSZRJFAPSA-N 0.000 description 1
- POTURENPSFEWGN-HSZRJFAPSA-N 3-ethyl-N-[(2R)-3-methyl-1-(3-methyl-2,4-dioxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-8-yl)-1-oxobutan-2-yl]benzamide Chemical compound C(C)C=1C=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CC=CC=C3)=O)C)=O)CC2)C(C)C)C=CC=1 POTURENPSFEWGN-HSZRJFAPSA-N 0.000 description 1
- XPUFVYIUPYNLPD-UHFFFAOYSA-N 3-fluoro-5-methylbenzoic acid Chemical compound CC1=CC(F)=CC(C(O)=O)=C1 XPUFVYIUPYNLPD-UHFFFAOYSA-N 0.000 description 1
- ROADCYAOHVSOLQ-UHFFFAOYSA-N 3-oxetanone Chemical compound O=C1COC1 ROADCYAOHVSOLQ-UHFFFAOYSA-N 0.000 description 1
- YNNOFVDQHAHVFG-UHFFFAOYSA-N 3-phenylmethoxycyclobutane-1-carboxylic acid Chemical compound C1C(C(=O)O)CC1OCC1=CC=CC=C1 YNNOFVDQHAHVFG-UHFFFAOYSA-N 0.000 description 1
- FQXQBFUUVCDIRK-UHFFFAOYSA-N 3-trifluoromethylbenzoic acid Chemical compound OC(=O)C1=CC=CC(C(F)(F)F)=C1 FQXQBFUUVCDIRK-UHFFFAOYSA-N 0.000 description 1
- UMLFTCYAQPPZER-UHFFFAOYSA-N 4-(bromomethyl)benzonitrile Chemical compound BrCC1=CC=C(C#N)C=C1 UMLFTCYAQPPZER-UHFFFAOYSA-N 0.000 description 1
- VJPPLCNBDLZIFG-ZDUSSCGKSA-N 4-[(3S)-3-(but-2-ynoylamino)piperidin-1-yl]-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide Chemical compound C(C#CC)(=O)N[C@@H]1CN(CCC1)C1=C2C(=C(NC2=C(C=C1F)C(=O)N)C)C VJPPLCNBDLZIFG-ZDUSSCGKSA-N 0.000 description 1
- QGHDLJAZIIFENW-UHFFFAOYSA-N 4-[1,1,1,3,3,3-hexafluoro-2-(4-hydroxy-3-prop-2-enylphenyl)propan-2-yl]-2-prop-2-enylphenol Chemical group C1=C(CC=C)C(O)=CC=C1C(C(F)(F)F)(C(F)(F)F)C1=CC=C(O)C(CC=C)=C1 QGHDLJAZIIFENW-UHFFFAOYSA-N 0.000 description 1
- YFCIFWOJYYFDQP-PTWZRHHISA-N 4-[3-amino-6-[(1S,3S,4S)-3-fluoro-4-hydroxycyclohexyl]pyrazin-2-yl]-N-[(1S)-1-(3-bromo-5-fluorophenyl)-2-(methylamino)ethyl]-2-fluorobenzamide Chemical compound CNC[C@@H](NC(=O)c1ccc(cc1F)-c1nc(cnc1N)[C@H]1CC[C@H](O)[C@@H](F)C1)c1cc(F)cc(Br)c1 YFCIFWOJYYFDQP-PTWZRHHISA-N 0.000 description 1
- UUYBVFLEZNJLEX-RUZDIDTESA-N 4-[8-[(2R)-2-[(5-cyclopropyl-2-fluorobenzoyl)amino]-3-methylbutanoyl]-3-methyl-4-oxo-1,3,8-triazaspiro[4.5]decan-1-yl]benzoic acid Chemical compound C1(CC1)C=1C=CC(=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(CN3C3=CC=C(C(=O)O)C=C3)C)=O)CC2)C(C)C)C=1)F UUYBVFLEZNJLEX-RUZDIDTESA-N 0.000 description 1
- VJJKTFFNAHQWJT-OAQYLSRUSA-N 4-[8-[(2R)-2-[[2-fluoro-5-(trifluoromethoxy)benzoyl]amino]-3-methylbutanoyl]-3-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decan-1-yl]benzoic acid Chemical compound FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CC=C(C(=O)O)C=C3)=O)C)=O)CC2)C(C)C)C=C(C=C1)OC(F)(F)F VJJKTFFNAHQWJT-OAQYLSRUSA-N 0.000 description 1
- FUGRDPNAIONVQE-JOCHJYFZSA-N 4-[8-[(2R)-2-[[2-fluoro-5-(trifluoromethoxy)benzoyl]amino]-3-methylbutanoyl]-3-methyl-4-oxo-1,3,8-triazaspiro[4.5]decan-1-yl]benzoic acid Chemical compound CC(C)[C@@H](NC(=O)C1=C(F)C=CC(OC(F)(F)F)=C1)C(=O)N1CCC2(CC1)N(CN(C)C2=O)C1=CC=C(C=C1)C(O)=O FUGRDPNAIONVQE-JOCHJYFZSA-N 0.000 description 1
- XTHYGPKTTMYUHE-JOCHJYFZSA-N 4-[8-[(2R)-2-[[3-chloro-5-(trifluoromethyl)benzoyl]amino]-3-methylbutanoyl]-3-methyl-4-oxo-1,3,8-triazaspiro[4.5]decan-1-yl]benzoic acid Chemical compound ClC=1C=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(CN3C3=CC=C(C(=O)O)C=C3)C)=O)CC2)C(C)C)C=C(C=1)C(F)(F)F XTHYGPKTTMYUHE-JOCHJYFZSA-N 0.000 description 1
- XYWIPYBIIRTJMM-IBGZPJMESA-N 4-[[(2S)-2-[4-[5-chloro-2-[4-(trifluoromethyl)triazol-1-yl]phenyl]-5-methoxy-2-oxopyridin-1-yl]butanoyl]amino]-2-fluorobenzamide Chemical compound CC[C@H](N1C=C(OC)C(=CC1=O)C1=C(C=CC(Cl)=C1)N1C=C(N=N1)C(F)(F)F)C(=O)NC1=CC(F)=C(C=C1)C(N)=O XYWIPYBIIRTJMM-IBGZPJMESA-N 0.000 description 1
- KVCQTKNUUQOELD-UHFFFAOYSA-N 4-amino-n-[1-(3-chloro-2-fluoroanilino)-6-methylisoquinolin-5-yl]thieno[3,2-d]pyrimidine-7-carboxamide Chemical compound N=1C=CC2=C(NC(=O)C=3C4=NC=NC(N)=C4SC=3)C(C)=CC=C2C=1NC1=CC=CC(Cl)=C1F KVCQTKNUUQOELD-UHFFFAOYSA-N 0.000 description 1
- WDFQBORIUYODSI-UHFFFAOYSA-N 4-bromoaniline Chemical compound NC1=CC=C(Br)C=C1 WDFQBORIUYODSI-UHFFFAOYSA-N 0.000 description 1
- 125000006283 4-chlorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Cl)C([H])([H])* 0.000 description 1
- 125000004176 4-fluorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1F)C([H])([H])* 0.000 description 1
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 description 1
- TYMLOMAKGOJONV-UHFFFAOYSA-N 4-nitroaniline Chemical compound NC1=CC=C([N+]([O-])=O)C=C1 TYMLOMAKGOJONV-UHFFFAOYSA-N 0.000 description 1
- IRPVABHDSJVBNZ-RTHVDDQRSA-N 5-[1-(cyclopropylmethyl)-5-[(1R,5S)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl]pyrazol-3-yl]-3-(trifluoromethyl)pyridin-2-amine Chemical compound C1=C(C(F)(F)F)C(N)=NC=C1C1=NN(CC2CC2)C(C2[C@@H]3CN(C[C@@H]32)C2COC2)=C1 IRPVABHDSJVBNZ-RTHVDDQRSA-N 0.000 description 1
- IJIBRSFAXRFPPN-UHFFFAOYSA-N 5-bromo-2-methoxybenzaldehyde Chemical compound COC1=CC=C(Br)C=C1C=O IJIBRSFAXRFPPN-UHFFFAOYSA-N 0.000 description 1
- LAAYUKAQBBWYLR-RUZDIDTESA-N 5-ethyl-2-fluoro-N-[(2R)-1-[1-[4-(methanesulfonamido)phenyl]-3-methyl-4-oxo-1,3,8-triazaspiro[4.5]decan-8-yl]-3-methyl-1-oxobutan-2-yl]benzamide Chemical compound C(C)C=1C=CC(=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(CN3C3=CC=C(C=C3)NS(=O)(=O)C)C)=O)CC2)C(C)C)C=1)F LAAYUKAQBBWYLR-RUZDIDTESA-N 0.000 description 1
- OGGLMNLWYAICPS-VCUSLETLSA-N 5-ethyl-2-fluoro-N-[(2R)-3-methoxy-1-[1-(4-methoxyphenyl)-3-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decan-8-yl]-1-oxobutan-2-yl]benzamide Chemical compound CCC1=CC=C(F)C(=C1)C(=O)N[C@H](C(C)OC)C(=O)N1CCC2(CC1)N(C(=O)N(C)C2=O)C1=CC=C(OC)C=C1 OGGLMNLWYAICPS-VCUSLETLSA-N 0.000 description 1
- QAOOLUZJYCKTHT-XMMPIXPASA-N 5-ethyl-2-fluoro-N-[(2R)-3-methyl-1-(3-methyl-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-8-yl)-1-oxobutan-2-yl]benzamide Chemical compound C(C)C=1C=CC(=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(CN3C3=CC=CC=C3)C)=O)CC2)C(C)C)C=1)F QAOOLUZJYCKTHT-XMMPIXPASA-N 0.000 description 1
- BEACBKSSNMPOOI-RUZDIDTESA-N 5-ethyl-2-fluoro-N-[(2R)-3-methyl-1-[3-methyl-1-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)-4-oxo-1,3,8-triazaspiro[4.5]decan-8-yl]-1-oxobutan-2-yl]benzamide Chemical compound C(C)C=1C=CC(=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(CN3C=3C=CC4=C(N(C(O4)=O)C)C=3)C)=O)CC2)C(C)C)C=1)F BEACBKSSNMPOOI-RUZDIDTESA-N 0.000 description 1
- AISJEVBDBCFJKD-RUZDIDTESA-N 5-ethyl-2-fluoro-N-[(2R)-3-methyl-1-[3-methyl-1-(4-methylsulfonylphenyl)-4-oxo-1,3,8-triazaspiro[4.5]decan-8-yl]-1-oxobutan-2-yl]benzamide Chemical compound C(C)C=1C=CC(=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(CN3C3=CC=C(C=C3)S(=O)(=O)C)C)=O)CC2)C(C)C)C=1)F AISJEVBDBCFJKD-RUZDIDTESA-N 0.000 description 1
- KCBWAFJCKVKYHO-UHFFFAOYSA-N 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-[[4-[1-propan-2-yl-4-(trifluoromethyl)imidazol-2-yl]phenyl]methyl]pyrazolo[3,4-d]pyrimidine Chemical compound C1(CC1)C1=NC=NC(=C1C1=NC=C2C(=N1)N(N=C2)CC1=CC=C(C=C1)C=1N(C=C(N=1)C(F)(F)F)C(C)C)OC KCBWAFJCKVKYHO-UHFFFAOYSA-N 0.000 description 1
- STLPJYGZOIEDAJ-UHFFFAOYSA-N 6-amino-3h-1,3-benzoxazol-2-one Chemical compound NC1=CC=C2NC(=O)OC2=C1 STLPJYGZOIEDAJ-UHFFFAOYSA-N 0.000 description 1
- CYJRNFFLTBEQSQ-UHFFFAOYSA-N 8-(3-methyl-1-benzothiophen-5-yl)-N-(4-methylsulfonylpyridin-3-yl)quinoxalin-6-amine Chemical compound CS(=O)(=O)C1=C(C=NC=C1)NC=1C=C2N=CC=NC2=C(C=1)C=1C=CC2=C(C(=CS2)C)C=1 CYJRNFFLTBEQSQ-UHFFFAOYSA-N 0.000 description 1
- ZRPZPNYZFSJUPA-UHFFFAOYSA-N ARS-1620 Chemical compound Oc1cccc(F)c1-c1c(Cl)cc2c(ncnc2c1F)N1CCN(CC1)C(=O)C=C ZRPZPNYZFSJUPA-UHFFFAOYSA-N 0.000 description 1
- 208000009304 Acute Kidney Injury Diseases 0.000 description 1
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 description 1
- 206010003445 Ascites Diseases 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 description 1
- 208000003950 B-cell lymphoma Diseases 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 206010005949 Bone cancer Diseases 0.000 description 1
- 208000018084 Bone neoplasm Diseases 0.000 description 1
- GIBOXIQBZGLXHE-HSZRJFAPSA-N BrC1=CC=C(C=C1)N1CN(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=CC(=CC=C2)C)=O)=O)=O)C Chemical compound BrC1=CC=C(C=C1)N1CN(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=CC(=CC=C2)C)=O)=O)=O)C GIBOXIQBZGLXHE-HSZRJFAPSA-N 0.000 description 1
- XQWCVMSRUVGIQX-HSZRJFAPSA-N BrC=1C=C(C=CC1)N1CN(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=CC(=CC=C2)C)=O)=O)=O)C Chemical compound BrC=1C=C(C=CC1)N1CN(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=CC(=CC=C2)C)=O)=O)=O)C XQWCVMSRUVGIQX-HSZRJFAPSA-N 0.000 description 1
- 208000003174 Brain Neoplasms Diseases 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- XVIBTKMWNLYCKN-JOCHJYFZSA-N C(#N)C1=CC=C(C=C1)N1C(N(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)C(F)(F)F)F)=O)=O)=O)C)=O Chemical compound C(#N)C1=CC=C(C=C1)N1C(N(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)C(F)(F)F)F)=O)=O)=O)C)=O XVIBTKMWNLYCKN-JOCHJYFZSA-N 0.000 description 1
- GPAQFTVLRMRQPG-JOCHJYFZSA-N C(#N)C=1C=C(C=CC1)N1C(N(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)C(F)(F)F)F)=O)=O)=O)C)=O Chemical compound C(#N)C=1C=C(C=CC1)N1C(N(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)C(F)(F)F)F)=O)=O)=O)C)=O GPAQFTVLRMRQPG-JOCHJYFZSA-N 0.000 description 1
- CDOKFUWXYBXRHN-HSZRJFAPSA-N C(#N)C=1C=C(CN2C(N(C(C22CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)C(F)(F)F)F)=O)=O)=O)C)=O)C=CC=1 Chemical compound C(#N)C=1C=C(CN2C(N(C(C22CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)C(F)(F)F)F)=O)=O)=O)C)=O)C=CC=1 CDOKFUWXYBXRHN-HSZRJFAPSA-N 0.000 description 1
- JQXPNFVKZCESQZ-RUZDIDTESA-N C(#N)CN1C(N(C2(C1=O)CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)CC)F)=O)=O)C2=CC=C(C=C2)OC)=O Chemical compound C(#N)CN1C(N(C2(C1=O)CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)CC)F)=O)=O)C2=CC=C(C=C2)OC)=O JQXPNFVKZCESQZ-RUZDIDTESA-N 0.000 description 1
- DSWPYXJSXDRMLQ-RUZDIDTESA-N C(#N)CN1CN(C2(C1=O)CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)CC)F)=O)=O)C2=CC=CC=C2 Chemical compound C(#N)CN1CN(C2(C1=O)CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)CC)F)=O)=O)C2=CC=CC=C2 DSWPYXJSXDRMLQ-RUZDIDTESA-N 0.000 description 1
- VGXFLCRXSINQSQ-HSZRJFAPSA-N C(#N)COC1=CC=C(C=C1)N1C(N(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)C(F)(F)F)F)=O)=O)=O)C)=O Chemical compound C(#N)COC1=CC=C(C=C1)N1C(N(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)C(F)(F)F)F)=O)=O)=O)C)=O VGXFLCRXSINQSQ-HSZRJFAPSA-N 0.000 description 1
- BYUJUUYDYMRQPL-AREMUKBSSA-N C(#N)COC1=CC=C(C=C1)N1CN(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)CC)F)=O)=O)=O)C Chemical compound C(#N)COC1=CC=C(C=C1)N1CN(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)CC)F)=O)=O)=O)C BYUJUUYDYMRQPL-AREMUKBSSA-N 0.000 description 1
- MBAPDORGNGYDFP-OAQYLSRUSA-N C(C)(=O)N1CC(C1)CN1C(N(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)C(F)(F)F)F)=O)=O)=O)C)=O Chemical compound C(C)(=O)N1CC(C1)CN1C(N(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)C(F)(F)F)F)=O)=O)=O)C)=O MBAPDORGNGYDFP-OAQYLSRUSA-N 0.000 description 1
- IQTWFKCQHWMKFP-UHFFFAOYSA-N C(C)(C)(C)OC(=O)N1CCC2(C(N(C(N2C2=CN(C(C=C2)=O)C)=O)C)=O)CC1 Chemical compound C(C)(C)(C)OC(=O)N1CCC2(C(N(C(N2C2=CN(C(C=C2)=O)C)=O)C)=O)CC1 IQTWFKCQHWMKFP-UHFFFAOYSA-N 0.000 description 1
- XYZFYBDUACTQKS-HSZRJFAPSA-N C(C)C=1C(=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CC=CC=C3)=O)C)=O)CC2)C(C)C)C=CC1)F Chemical compound C(C)C=1C(=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CC=CC=C3)=O)C)=O)CC2)C(C)C)C=CC1)F XYZFYBDUACTQKS-HSZRJFAPSA-N 0.000 description 1
- PKLSBRDTQQVDFK-FDDCHVKYSA-N C(C)C=1C=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CC=CC=C3)=O)C)=O)CC2)[C@H](C)OC)C=C(C1)F Chemical compound C(C)C=1C=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CC=CC=C3)=O)C)=O)CC2)[C@H](C)OC)C=C(C1)F PKLSBRDTQQVDFK-FDDCHVKYSA-N 0.000 description 1
- FDMPIRZDCYAKSK-YADARESESA-N C(C)C=1C=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(CN3C3=CC=CC=C3)C)=O)CC2)[C@H](C)OC)C=C(C=1)F Chemical compound C(C)C=1C=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(CN3C3=CC=CC=C3)C)=O)CC2)[C@H](C)OC)C=C(C=1)F FDMPIRZDCYAKSK-YADARESESA-N 0.000 description 1
- QYGDBEKYTXDNBG-GBXCKJPGSA-N C(C)C=1C=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(CN3C3=CC=CC=C3)C)=O)CC2)[C@H](C)OC)C=CC1 Chemical compound C(C)C=1C=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(CN3C3=CC=CC=C3)C)=O)CC2)[C@H](C)OC)C=CC1 QYGDBEKYTXDNBG-GBXCKJPGSA-N 0.000 description 1
- WKDRXSOILDXIPA-HSZRJFAPSA-N C(C)C=1C=CC(=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CC4=C(NC(O4)=O)C=C3)=O)C)=O)CC2)C(C)C)C=1)F Chemical compound C(C)C=1C=CC(=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CC4=C(NC(O4)=O)C=C3)=O)C)=O)CC2)C(C)C)C=1)F WKDRXSOILDXIPA-HSZRJFAPSA-N 0.000 description 1
- GJGLRORVXVDGLT-XMMPIXPASA-N C(C)C=1C=CC(=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CC=C(C=C3)OC)=O)C)=O)CC2)C(C)C)C1)F Chemical compound C(C)C=1C=CC(=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CC=C(C=C3)OC)=O)C)=O)CC2)C(C)C)C1)F GJGLRORVXVDGLT-XMMPIXPASA-N 0.000 description 1
- RTIHBKINNPLROJ-HSZRJFAPSA-N C(C)C=1C=CC(=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CC=CC=C3)=O)C)=O)CC2)C(C)C)C1)F Chemical compound C(C)C=1C=CC(=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CC=CC=C3)=O)C)=O)CC2)C(C)C)C1)F RTIHBKINNPLROJ-HSZRJFAPSA-N 0.000 description 1
- CAMLYXXGGGUBTP-FDDCHVKYSA-N C(C)C=1C=CC(=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CC=CC=C3)=O)C)=O)CC2)[C@H](C)OC)C1)F Chemical compound C(C)C=1C=CC(=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CC=CC=C3)=O)C)=O)CC2)[C@H](C)OC)C1)F CAMLYXXGGGUBTP-FDDCHVKYSA-N 0.000 description 1
- YXAWXHAIPIUYAF-RUZDIDTESA-N C(C)C=1C=CC(=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C=3C=CC=4N(C=3)C(=NC=4)C)=O)C)=O)CC2)C(C)C)C=1)F Chemical compound C(C)C=1C=CC(=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C=3C=CC=4N(C=3)C(=NC=4)C)=O)C)=O)CC2)C(C)C)C=1)F YXAWXHAIPIUYAF-RUZDIDTESA-N 0.000 description 1
- RDEALTAUSNJWHE-XMMPIXPASA-N C(C)C=1C=CC(=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(CN3C3=CC=C(C(=O)O)C=C3)C)=O)CC2)C(C)C)C1)F Chemical compound C(C)C=1C=CC(=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(CN3C3=CC=C(C(=O)O)C=C3)C)=O)CC2)C(C)C)C1)F RDEALTAUSNJWHE-XMMPIXPASA-N 0.000 description 1
- UPMJDGRLZVVPFX-RUZDIDTESA-N C(C)C=1C=CC(=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(CN3C3=CC=C(C=C3)OC)C)=O)CC2)C(C)C)C=1)F Chemical compound C(C)C=1C=CC(=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(CN3C3=CC=C(C=C3)OC)C)=O)CC2)C(C)C)C=1)F UPMJDGRLZVVPFX-RUZDIDTESA-N 0.000 description 1
- CSUDRQYUGZFSQX-XMMPIXPASA-N C(C)C=1C=CC(=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(CN3C3=CN(C(C=C3)=O)C)C)=O)CC2)C(C)C)C1)F Chemical compound C(C)C=1C=CC(=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(CN3C3=CN(C(C=C3)=O)C)C)=O)CC2)C(C)C)C1)F CSUDRQYUGZFSQX-XMMPIXPASA-N 0.000 description 1
- JVTNMLIYHXJHRM-QGZVFWFLSA-N C(C)N1C(N(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)C(F)(F)F)F)=O)=O)=O)C)=O Chemical compound C(C)N1C(N(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)C(F)(F)F)F)=O)=O)=O)C)=O JVTNMLIYHXJHRM-QGZVFWFLSA-N 0.000 description 1
- FEEIXHTXTABLRV-JOCHJYFZSA-N C(C1=CC=CC=C1)N1C(N(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)C(F)(F)F)F)=O)=O)=O)C)=O Chemical compound C(C1=CC=CC=C1)N1C(N(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)C(F)(F)F)F)=O)=O)=O)C)=O FEEIXHTXTABLRV-JOCHJYFZSA-N 0.000 description 1
- RIBHIMIYEIPLAE-JOCHJYFZSA-N C(N)(=O)C1=CC=C(C=C1)N1CN(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)C(F)(F)F)F)=O)=O)=O)C Chemical compound C(N)(=O)C1=CC=C(C=C1)N1CN(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)C(F)(F)F)F)=O)=O)=O)C RIBHIMIYEIPLAE-JOCHJYFZSA-N 0.000 description 1
- DTQQOOVTIDJDJA-HSZRJFAPSA-N C(N)(=O)C=1C=C(C=CC=1)N1CN(C(C11CCN(CC1)C([C@@H](C(C)C)NC(C1=C(C(=CC=C1)C)F)=O)=O)=O)C Chemical compound C(N)(=O)C=1C=C(C=CC=1)N1CN(C(C11CCN(CC1)C([C@@H](C(C)C)NC(C1=C(C(=CC=C1)C)F)=O)=O)=O)C DTQQOOVTIDJDJA-HSZRJFAPSA-N 0.000 description 1
- UISRURNJKGWKBC-XMMPIXPASA-N C1(CC1)C(=O)NC1=CC=C(C=C1)N1C(N(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)C(F)(F)F)F)=O)=O)=O)C)=O Chemical compound C1(CC1)C(=O)NC1=CC=C(C=C1)N1C(N(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)C(F)(F)F)F)=O)=O)=O)C)=O UISRURNJKGWKBC-XMMPIXPASA-N 0.000 description 1
- UBCHOWVYKLDUSP-RUZDIDTESA-N C1(CC1)C=1C=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(CN3C3=CC=CC=C3)C)=O)CC2)C(C)C)C=CC1 Chemical compound C1(CC1)C=1C=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(CN3C3=CC=CC=C3)C)=O)CC2)C(C)C)C=CC1 UBCHOWVYKLDUSP-RUZDIDTESA-N 0.000 description 1
- LMBIYMSSVZDHLJ-XMMPIXPASA-N C1(CC1)C=1C=CC(=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CC=C(C(=O)O)C=C3)=O)C)=O)CC2)C(C)C)C1)F Chemical compound C1(CC1)C=1C=CC(=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CC=C(C(=O)O)C=C3)=O)C)=O)CC2)C(C)C)C1)F LMBIYMSSVZDHLJ-XMMPIXPASA-N 0.000 description 1
- CVJCFLXYSPTJMF-RUZDIDTESA-N C1(CC1)C=1C=CC(=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CC=C(C=C3)OC)=O)C)=O)CC2)C(C)C)C=1)F Chemical compound C1(CC1)C=1C=CC(=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CC=C(C=C3)OC)=O)C)=O)CC2)C(C)C)C=1)F CVJCFLXYSPTJMF-RUZDIDTESA-N 0.000 description 1
- MZTDGOBVIVLPLI-XMMPIXPASA-N C1(CC1)C=1C=CC(=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CC=CC=C3)=O)C)=O)CC2)C(C)C)C1)F Chemical compound C1(CC1)C=1C=CC(=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CC=CC=C3)=O)C)=O)CC2)C(C)C)C1)F MZTDGOBVIVLPLI-XMMPIXPASA-N 0.000 description 1
- IBGQJSIESRIIGY-RUZDIDTESA-N C1(CC1)CN1CN(C2(C1=O)CCN(CC2)C([C@@H](C(C)C)NC(C1=C(C=CC(=C1)C(F)(F)F)F)=O)=O)C1=CC=C(C(=O)O)C=C1 Chemical compound C1(CC1)CN1CN(C2(C1=O)CCN(CC2)C([C@@H](C(C)C)NC(C1=C(C=CC(=C1)C(F)(F)F)F)=O)=O)C1=CC=C(C(=O)O)C=C1 IBGQJSIESRIIGY-RUZDIDTESA-N 0.000 description 1
- RHGOOCOZFJUGBH-GOSISDBHSA-N C1(CC1)N1C(N(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)C(F)(F)F)F)=O)=O)=O)C)=O Chemical compound C1(CC1)N1C(N(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)C(F)(F)F)F)=O)=O)=O)C)=O RHGOOCOZFJUGBH-GOSISDBHSA-N 0.000 description 1
- RZGNARJWKCFBAQ-XMMPIXPASA-N C1(CC1)[C@H](C(=O)N1CCC2(C(N(C(N2CC=2C=C3N=CC=NC3=CC2)=O)C)=O)CC1)NC(C1=C(C=CC(=C1)C(F)(F)F)F)=O Chemical compound C1(CC1)[C@H](C(=O)N1CCC2(C(N(C(N2CC=2C=C3N=CC=NC3=CC2)=O)C)=O)CC1)NC(C1=C(C=CC(=C1)C(F)(F)F)F)=O RZGNARJWKCFBAQ-XMMPIXPASA-N 0.000 description 1
- WHPATJXDBBZCEP-RUZDIDTESA-N C1(CCC1)[C@H](C(=O)N1CCC2(C(N(C(N2CC=2C=C3N=CC=NC3=CC2)=O)C)=O)CC1)NC(C1=C(C=CC(=C1)C(F)(F)F)F)=O Chemical compound C1(CCC1)[C@H](C(=O)N1CCC2(C(N(C(N2CC=2C=C3N=CC=NC3=CC2)=O)C)=O)CC1)NC(C1=C(C=CC(=C1)C(F)(F)F)F)=O WHPATJXDBBZCEP-RUZDIDTESA-N 0.000 description 1
- WCISFVYDMADJPX-HXUWFJFHSA-N C1(CCCC1)N1C(N(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)C(F)(F)F)F)=O)=O)=O)C)=O Chemical compound C1(CCCC1)N1C(N(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)C(F)(F)F)F)=O)=O)=O)C)=O WCISFVYDMADJPX-HXUWFJFHSA-N 0.000 description 1
- GZJQPKPODOFAKS-RUZDIDTESA-N C1(CCCC1)[C@H](C(=O)N1CCC2(C(N(C(N2CC2=CC=3N(C=C2)N=C(N3)C)=O)C)=O)CC1)NC(C1=C(C=CC(=C1)C(F)(F)F)F)=O Chemical compound C1(CCCC1)[C@H](C(=O)N1CCC2(C(N(C(N2CC2=CC=3N(C=C2)N=C(N3)C)=O)C)=O)CC1)NC(C1=C(C=CC(=C1)C(F)(F)F)F)=O GZJQPKPODOFAKS-RUZDIDTESA-N 0.000 description 1
- YOWLSYKKSDSAAN-XMMPIXPASA-N C1(CCCC1)[C@H](C(=O)N1CCC2(C(N(CN2C2=CN(C(C=C2)=O)C)C)=O)CC1)NC(C1=C(C=CC(=C1)C(F)(F)F)F)=O Chemical compound C1(CCCC1)[C@H](C(=O)N1CCC2(C(N(CN2C2=CN(C(C=C2)=O)C)C)=O)CC1)NC(C1=C(C=CC(=C1)C(F)(F)F)F)=O YOWLSYKKSDSAAN-XMMPIXPASA-N 0.000 description 1
- CLUALAHWDCTPJK-QDOZOBACSA-N CC(C)[C@@H](NC(=O)C12CC3CC(CC(C3)C1)C2)C(=O)N1CCC2(CC1)N(CN(C)C2=O)C1=CC=C(C=C1)C(O)=O Chemical compound CC(C)[C@@H](NC(=O)C12CC3CC(CC(C3)C1)C2)C(=O)N1CCC2(CC1)N(CN(C)C2=O)C1=CC=C(C=C1)C(O)=O CLUALAHWDCTPJK-QDOZOBACSA-N 0.000 description 1
- AQAUWVJPVMGTSC-XMMPIXPASA-N CC(C)[C@@H](NC(=O)C1=C(F)C(C)=CC=C1)C(=O)N1CCC2(CC1)N(CN(C)C2=O)C1=CC(=CC=C1)C#N Chemical compound CC(C)[C@@H](NC(=O)C1=C(F)C(C)=CC=C1)C(=O)N1CCC2(CC1)N(CN(C)C2=O)C1=CC(=CC=C1)C#N AQAUWVJPVMGTSC-XMMPIXPASA-N 0.000 description 1
- OEARUEAHUJSOKP-XMMPIXPASA-N CC(C)[C@@H](NC(=O)C1=C(F)C=CC(=C1)C(F)(F)F)C(=O)N1CCC2(CC1)N(C(=O)N(C)C2=O)C1=CC=C(NC2COC2)C=C1 Chemical compound CC(C)[C@@H](NC(=O)C1=C(F)C=CC(=C1)C(F)(F)F)C(=O)N1CCC2(CC1)N(C(=O)N(C)C2=O)C1=CC=C(NC2COC2)C=C1 OEARUEAHUJSOKP-XMMPIXPASA-N 0.000 description 1
- CYOBGAMYYQDLPT-HSZRJFAPSA-N CC(C)[C@@H](NC(=O)c1cc(ccc1F)C(F)(F)F)C(=O)N1CCC2(CC1)N(CN(C)C2=O)c1ccc2nccn2c1 Chemical compound CC(C)[C@@H](NC(=O)c1cc(ccc1F)C(F)(F)F)C(=O)N1CCC2(CC1)N(CN(C)C2=O)c1ccc2nccn2c1 CYOBGAMYYQDLPT-HSZRJFAPSA-N 0.000 description 1
- KXNNKJQRDXERPN-OTOKDRCRSA-N CC(C)[C@H](C(=O)N1CCC2(CC1)C(=O)N(C(=O)N2C3C=CC(=O)N=C3)C)NC(=O)C4=C(C=CC(=C4)C(F)(F)F)F Chemical compound CC(C)[C@H](C(=O)N1CCC2(CC1)C(=O)N(C(=O)N2C3C=CC(=O)N=C3)C)NC(=O)C4=C(C=CC(=C4)C(F)(F)F)F KXNNKJQRDXERPN-OTOKDRCRSA-N 0.000 description 1
- OODKHHDCOOFVEO-JOCHJYFZSA-N CC=1C=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(CN3C3=CC=CC=C3)C)=O)CC2)C(C)C)C=CN=1 Chemical compound CC=1C=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(CN3C3=CC=CC=C3)C)=O)CC2)C(C)C)C=CN=1 OODKHHDCOOFVEO-JOCHJYFZSA-N 0.000 description 1
- GFEIJPUCUOEGQN-JOCHJYFZSA-N CC=1C=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(CN3C=3C=NC=CC=3)C)=O)CC2)C(C)C)C=CC=1 Chemical compound CC=1C=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(CN3C=3C=NC=CC=3)C)=O)CC2)C(C)C)C=CC=1 GFEIJPUCUOEGQN-JOCHJYFZSA-N 0.000 description 1
- LEQNBKIUGXBMTP-VWLOTQADSA-N CC=1C=C(C(=O)N[C@H](C(=O)N2CCC3(C(N(CN3C3=CC=CC=C3)C)=O)CC2)C2CCOCC2)C=CC1 Chemical compound CC=1C=C(C(=O)N[C@H](C(=O)N2CCC3(C(N(CN3C3=CC=CC=C3)C)=O)CC2)C2CCOCC2)C=CC1 LEQNBKIUGXBMTP-VWLOTQADSA-N 0.000 description 1
- YEBVGOIYHPKGTI-HSZRJFAPSA-N CC=1OC2=C(N=1)C=C(C=C2)N1C(N(C(C11CCN(CC1)C([C@@H](C(C)C)NC(C1=C(C=CC(=C1)C(F)(F)F)F)=O)=O)=O)C)=O Chemical compound CC=1OC2=C(N=1)C=C(C=C2)N1C(N(C(C11CCN(CC1)C([C@@H](C(C)C)NC(C1=C(C=CC(=C1)C(F)(F)F)F)=O)=O)=O)C)=O YEBVGOIYHPKGTI-HSZRJFAPSA-N 0.000 description 1
- LLBPNKXHARGZSU-XMMPIXPASA-N CCC1=CC=CC(=C1)C(=O)N[C@H](C(C)C)C(=O)N1CCC2(CC1)N(CN(C)C2=O)C1=CC=CC=C1 Chemical compound CCC1=CC=CC(=C1)C(=O)N[C@H](C(C)C)C(=O)N1CCC2(CC1)N(CN(C)C2=O)C1=CC=CC=C1 LLBPNKXHARGZSU-XMMPIXPASA-N 0.000 description 1
- JGLMVXWAHNTPRF-CMDGGOBGSA-N CCN1N=C(C)C=C1C(=O)NC1=NC2=CC(=CC(OC)=C2N1C\C=C\CN1C(NC(=O)C2=CC(C)=NN2CC)=NC2=CC(=CC(OCCCN3CCOCC3)=C12)C(N)=O)C(N)=O Chemical compound CCN1N=C(C)C=C1C(=O)NC1=NC2=CC(=CC(OC)=C2N1C\C=C\CN1C(NC(=O)C2=CC(C)=NN2CC)=NC2=CC(=CC(OCCCN3CCOCC3)=C12)C(N)=O)C(N)=O JGLMVXWAHNTPRF-CMDGGOBGSA-N 0.000 description 1
- NSBSPXKDMKAISE-XMMPIXPASA-N CN(C(C1=CC(=CC=C1)C)=O)[C@@H](C(=O)N1CCC2(C(N(CN2C2=CC=CC=C2)C)=O)CC1)C(C)C Chemical compound CN(C(C1=CC(=CC=C1)C)=O)[C@@H](C(=O)N1CCC2(C(N(CN2C2=CC=CC=C2)C)=O)CC1)C(C)C NSBSPXKDMKAISE-XMMPIXPASA-N 0.000 description 1
- HZDDNNJFFAHLIL-MRXNPFEDSA-N CN1C(N(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)C(F)(F)F)F)=O)=O)=O)C)=O Chemical compound CN1C(N(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)C(F)(F)F)F)=O)=O)=O)C)=O HZDDNNJFFAHLIL-MRXNPFEDSA-N 0.000 description 1
- HIDNZZJXDDHNIT-HSZRJFAPSA-N CN1CN(C2(C1=O)CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)C(F)(F)F)C)=O)=O)C2=CC=C(C(=O)O)C=C2 Chemical compound CN1CN(C2(C1=O)CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)C(F)(F)F)C)=O)=O)C2=CC=C(C(=O)O)C=C2 HIDNZZJXDDHNIT-HSZRJFAPSA-N 0.000 description 1
- DGQSCTYDBGYFLL-XMMPIXPASA-N CN1CN(C2=CC=C(C=C2)C(O)=O)C2(CCN(CC2)C(=O)[C@H](NC(=O)C2=C(F)C=CC(=C2)C(F)(F)F)C2CCCC2)C1=O Chemical compound CN1CN(C2=CC=C(C=C2)C(O)=O)C2(CCN(CC2)C(=O)[C@H](NC(=O)C2=C(F)C=CC(=C2)C(F)(F)F)C2CCCC2)C1=O DGQSCTYDBGYFLL-XMMPIXPASA-N 0.000 description 1
- CQXUXMITFAPFPB-IXXGTQFESA-N COC(C)[C@@H](NC(=O)C1=CC(=CC=C1F)C1CC1)C(=O)N1CCC2(CC1)N(C(=O)N(C)C2=O)C1=CC=C(OC)C=C1 Chemical compound COC(C)[C@@H](NC(=O)C1=CC(=CC=C1F)C1CC1)C(=O)N1CCC2(CC1)N(C(=O)N(C)C2=O)C1=CC=C(OC)C=C1 CQXUXMITFAPFPB-IXXGTQFESA-N 0.000 description 1
- UIBIBCDLALGGEQ-HSZRJFAPSA-N COC1=CC(CN2C(=O)N(C)C(=O)C22CCN(CC2)C(=O)[C@H](NC(=O)C2=C(F)C=CC(=C2)C(F)(F)F)C(C)C)=C(F)C=C1 Chemical compound COC1=CC(CN2C(=O)N(C)C(=O)C22CCN(CC2)C(=O)[C@H](NC(=O)C2=C(F)C=CC(=C2)C(F)(F)F)C(C)C)=C(F)C=C1 UIBIBCDLALGGEQ-HSZRJFAPSA-N 0.000 description 1
- QQXOMARFNQGCBI-HSZRJFAPSA-N COC1=CC=C(CN2C(=O)N(C)C(=O)C22CCN(CC2)C(=O)[C@H](NC(=O)C2=C(F)C=CC(=C2)C(F)(F)F)C(C)C)C=C1 Chemical compound COC1=CC=C(CN2C(=O)N(C)C(=O)C22CCN(CC2)C(=O)[C@H](NC(=O)C2=C(F)C=CC(=C2)C(F)(F)F)C(C)C)C=C1 QQXOMARFNQGCBI-HSZRJFAPSA-N 0.000 description 1
- YIKQJSUNKOCSEN-XMMPIXPASA-N COC=1C=C(C=CC1)N1CN(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=CC(=CC=C2)C)=O)=O)=O)C Chemical compound COC=1C=C(C=CC1)N1CN(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=CC(=CC=C2)C)=O)=O)=O)C YIKQJSUNKOCSEN-XMMPIXPASA-N 0.000 description 1
- BMPQFGJILDCURA-NZQKXSOJSA-N CO[C@H]([C@H](C(=O)N1CCC2(C(N(CN2C2=CC=CC=C2)C)=O)CC1)NC(C1=CC(=CC=C1)C)=O)C Chemical compound CO[C@H]([C@H](C(=O)N1CCC2(C(N(CN2C2=CC=CC=C2)C)=O)CC1)NC(C1=CC(=CC=C1)C)=O)C BMPQFGJILDCURA-NZQKXSOJSA-N 0.000 description 1
- 206010058019 Cancer Pain Diseases 0.000 description 1
- 201000009030 Carcinoma Diseases 0.000 description 1
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 1
- VLNHDIUXVAENAZ-OAQYLSRUSA-N ClC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CC=CC=C3)=O)C)=O)CC2)C(C)C)C=C(C=C1)Cl Chemical compound ClC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CC=CC=C3)=O)C)=O)CC2)C(C)C)C=C(C=C1)Cl VLNHDIUXVAENAZ-OAQYLSRUSA-N 0.000 description 1
- VHXSAZIFLREOKP-JOCHJYFZSA-N ClC1=C(C(=O)O)C=CC(=C1)N1CN(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)C(F)(F)F)F)=O)=O)=O)C Chemical compound ClC1=C(C(=O)O)C=CC(=C1)N1CN(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)C(F)(F)F)F)=O)=O)=O)C VHXSAZIFLREOKP-JOCHJYFZSA-N 0.000 description 1
- CEGYCUYQYZXRGH-HSZRJFAPSA-N ClC1=C(C=CC=C1)N1CN(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=CC(=CC=C2)C)=O)=O)=O)C Chemical compound ClC1=C(C=CC=C1)N1CN(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=CC(=CC=C2)C)=O)=O)=O)C CEGYCUYQYZXRGH-HSZRJFAPSA-N 0.000 description 1
- ZBMKHKUSHQYCES-HSZRJFAPSA-N ClC1=C(CN2C(N(C(C22CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)C(F)(F)F)F)=O)=O)=O)C)=O)C=CC(=C1)OC Chemical compound ClC1=C(CN2C(N(C(C22CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)C(F)(F)F)F)=O)=O)=O)C)=O)C=CC(=C1)OC ZBMKHKUSHQYCES-HSZRJFAPSA-N 0.000 description 1
- FWQXBPDCDUMPMX-OAQYLSRUSA-N ClC1=CC=C(C=C1)N1C(N(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)C(F)(F)F)F)=O)=O)=O)C)=O Chemical compound ClC1=CC=C(C=C1)N1C(N(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)C(F)(F)F)F)=O)=O)=O)C)=O FWQXBPDCDUMPMX-OAQYLSRUSA-N 0.000 description 1
- VJJQKISUHQUKSP-HSZRJFAPSA-N ClC1=CC=C(C=C1)N1CN(C(C11CCN(CC1)C([C@@H](C(C)C)NC(C1=CC(=CC=C1)C)=O)=O)=O)C Chemical compound ClC1=CC=C(C=C1)N1CN(C(C11CCN(CC1)C([C@@H](C(C)C)NC(C1=CC(=CC=C1)C)=O)=O)=O)C VJJQKISUHQUKSP-HSZRJFAPSA-N 0.000 description 1
- YRCRZSGBPWHVRA-JOCHJYFZSA-N ClC1=CC=C(CN2C(N(C(C23CCN(CC3)C([C@@H](C(C)C)NC(C3=C(C=CC(=C3)C(F)(F)F)F)=O)=O)=O)C)=O)C=C1 Chemical compound ClC1=CC=C(CN2C(N(C(C23CCN(CC3)C([C@@H](C(C)C)NC(C3=C(C=CC(=C3)C(F)(F)F)F)=O)=O)=O)C)=O)C=C1 YRCRZSGBPWHVRA-JOCHJYFZSA-N 0.000 description 1
- SIJYLVCLFNCHSA-OAQYLSRUSA-N ClC=1C=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CC=CC=C3)=O)C)=O)CC2)C(C)C)C=C(C1)Cl Chemical compound ClC=1C=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CC=CC=C3)=O)C)=O)CC2)C(C)C)C=C(C1)Cl SIJYLVCLFNCHSA-OAQYLSRUSA-N 0.000 description 1
- PUDOGKJIUDKIDW-OAQYLSRUSA-N ClC=1C=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CC=CC=C3)=O)C)=O)CC2)C(C)C)C=CC1Cl Chemical compound ClC=1C=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CC=CC=C3)=O)C)=O)CC2)C(C)C)C=CC1Cl PUDOGKJIUDKIDW-OAQYLSRUSA-N 0.000 description 1
- FLHHNKLGKZDSCR-JOCHJYFZSA-N ClC=1C=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(CN3C3=CN(C(C=C3)=O)C)C)=O)CC2)C(C)C)C=C(C=1)C(F)(F)F Chemical compound ClC=1C=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(CN3C3=CN(C(C=C3)=O)C)C)=O)CC2)C(C)C)C=C(C=1)C(F)(F)F FLHHNKLGKZDSCR-JOCHJYFZSA-N 0.000 description 1
- QRTLPAYPYOBWKI-OAQYLSRUSA-N ClC=1C=C(C=CC1)N1C(N(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)C(F)(F)F)F)=O)=O)=O)C)=O Chemical compound ClC=1C=C(C=CC1)N1C(N(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)C(F)(F)F)F)=O)=O)=O)C)=O QRTLPAYPYOBWKI-OAQYLSRUSA-N 0.000 description 1
- LDFRGNYZKHANFH-OAQYLSRUSA-N ClC=1C=C(C=CC1Cl)N1C(N(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)C(F)(F)F)F)=O)=O)=O)C)=O Chemical compound ClC=1C=C(C=CC1Cl)N1C(N(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)C(F)(F)F)F)=O)=O)=O)C)=O LDFRGNYZKHANFH-OAQYLSRUSA-N 0.000 description 1
- UIEWINQXMGLYAY-JOCHJYFZSA-N ClC=1C=C(CN2C(N(C(C23CCN(CC3)C([C@@H](C(C)C)NC(C3=C(C=CC(=C3)C(F)(F)F)F)=O)=O)=O)C)=O)C=CC1 Chemical compound ClC=1C=C(CN2C(N(C(C23CCN(CC3)C([C@@H](C(C)C)NC(C3=C(C=CC(=C3)C(F)(F)F)F)=O)=O)=O)C)=O)C=CC1 UIEWINQXMGLYAY-JOCHJYFZSA-N 0.000 description 1
- TXCATJJIBMZMEX-OAQYLSRUSA-N ClC=1C=CC(=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CC=CC=C3)=O)C)=O)CC2)C(C)C)C=1)F Chemical compound ClC=1C=CC(=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CC=CC=C3)=O)C)=O)CC2)C(C)C)C=1)F TXCATJJIBMZMEX-OAQYLSRUSA-N 0.000 description 1
- 208000029147 Collagen-vascular disease Diseases 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- KZSNJWFQEVHDMF-SCSAIBSYSA-N D-valine Chemical compound CC(C)[C@@H](N)C(O)=O KZSNJWFQEVHDMF-SCSAIBSYSA-N 0.000 description 1
- 229930182831 D-valine Natural products 0.000 description 1
- 206010012689 Diabetic retinopathy Diseases 0.000 description 1
- FRPWXZRVHMHXCN-OAQYLSRUSA-N FC(OC=1C=CC(=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CC=C(C(=O)O)C=C3)=O)C)=O)CC2)C(C)C)C1)F)F Chemical compound FC(OC=1C=CC(=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CC=C(C(=O)O)C=C3)=O)C)=O)CC2)C(C)C)C1)F)F FRPWXZRVHMHXCN-OAQYLSRUSA-N 0.000 description 1
- DPEYSCNSVHLKSC-JOCHJYFZSA-N FC(OC=1C=CC(=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(CN3C3=CC=C(C(=O)O)C=C3)C)=O)CC2)C(C)C)C=1)F)F Chemical compound FC(OC=1C=CC(=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(CN3C3=CC=C(C(=O)O)C=C3)C)=O)CC2)C(C)C)C=1)F)F DPEYSCNSVHLKSC-JOCHJYFZSA-N 0.000 description 1
- WTDFHWLLTDTOOI-OAHLLOKOSA-N FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F Chemical compound FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F WTDFHWLLTDTOOI-OAHLLOKOSA-N 0.000 description 1
- GCJWXMQHKZMFQY-JOCHJYFZSA-N FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CC(=C(C=C3)OC)F)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F Chemical compound FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CC(=C(C=C3)OC)F)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F GCJWXMQHKZMFQY-JOCHJYFZSA-N 0.000 description 1
- PDFLRDQOOPRETN-JOCHJYFZSA-N FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CC(=CC=C3)OC)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F Chemical compound FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CC(=CC=C3)OC)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F PDFLRDQOOPRETN-JOCHJYFZSA-N 0.000 description 1
- ZSNFHJFANOXLOT-JOCHJYFZSA-N FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CC(=CC=C3)S(=O)(=O)C)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F Chemical compound FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CC(=CC=C3)S(=O)(=O)C)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F ZSNFHJFANOXLOT-JOCHJYFZSA-N 0.000 description 1
- NICOGKFOAIXLOQ-OAQYLSRUSA-N FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CC=C(C=C3)C(F)(F)F)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F Chemical compound FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CC=C(C=C3)C(F)(F)F)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F NICOGKFOAIXLOQ-OAQYLSRUSA-N 0.000 description 1
- BHKGLCMPKLMIIW-JOCHJYFZSA-N FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CC=C(C=C3)C)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F Chemical compound FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CC=C(C=C3)C)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F BHKGLCMPKLMIIW-JOCHJYFZSA-N 0.000 description 1
- HUVDKCPZKDJIRU-OAQYLSRUSA-N FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CC=C(C=C3)F)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F Chemical compound FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CC=C(C=C3)F)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F HUVDKCPZKDJIRU-OAQYLSRUSA-N 0.000 description 1
- WHVKKPNNIROQJR-JOCHJYFZSA-N FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CC=C(C=C3)OC)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F Chemical compound FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CC=C(C=C3)OC)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F WHVKKPNNIROQJR-JOCHJYFZSA-N 0.000 description 1
- NZYFOHBJKUCFLW-RUZDIDTESA-N FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CC=C(C=C3)OCC3COC3)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F Chemical compound FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CC=C(C=C3)OCC3COC3)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F NZYFOHBJKUCFLW-RUZDIDTESA-N 0.000 description 1
- MLOHOBZHEYWWGC-HSZRJFAPSA-N FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CC=C(C=C3)OCCO)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F Chemical compound FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CC=C(C=C3)OCCO)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F MLOHOBZHEYWWGC-HSZRJFAPSA-N 0.000 description 1
- JPKGBNHMWSHGPJ-JOCHJYFZSA-N FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CC=C(C=C3)S(=O)(=O)C)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F Chemical compound FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CC=C(C=C3)S(=O)(=O)C)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F JPKGBNHMWSHGPJ-JOCHJYFZSA-N 0.000 description 1
- TXPSXZIHPCEXFF-OAQYLSRUSA-N FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CC=CC=C3)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F Chemical compound FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CC=CC=C3)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F TXPSXZIHPCEXFF-OAQYLSRUSA-N 0.000 description 1
- JVAMAQLUVPYFRN-JOCHJYFZSA-N FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CC=CC=C3)=O)C)=O)CC2)C(C)C)C=CC=C1C Chemical compound FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CC=CC=C3)=O)C)=O)CC2)C(C)C)C=CC=C1C JVAMAQLUVPYFRN-JOCHJYFZSA-N 0.000 description 1
- OMGUNRUFPYKNOG-WZONZLPQSA-N FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CC=CC=C3)=O)C)=O)CC2)[C@@H](CC)C)C=CC=C1C Chemical compound FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CC=CC=C3)=O)C)=O)CC2)[C@@H](CC)C)C=CC=C1C OMGUNRUFPYKNOG-WZONZLPQSA-N 0.000 description 1
- QARWOGZYCQXGSQ-OAQYLSRUSA-N FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CN(C(C=C3)=O)C)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F Chemical compound FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CN(C(C=C3)=O)C)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F QARWOGZYCQXGSQ-OAQYLSRUSA-N 0.000 description 1
- JFJLUMPWZCAMGQ-HXUWFJFHSA-N FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=NC=CC=C3)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F Chemical compound FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=NC=CC=C3)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F JFJLUMPWZCAMGQ-HXUWFJFHSA-N 0.000 description 1
- WBYXLXUXBRZQMG-LJQANCHMSA-N FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=NN(C=C3)C)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F Chemical compound FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=NN(C=C3)C)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F WBYXLXUXBRZQMG-LJQANCHMSA-N 0.000 description 1
- FXWGYDPLALEKQP-HXUWFJFHSA-N FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3CCOCC3)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F Chemical compound FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3CCOCC3)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F FXWGYDPLALEKQP-HXUWFJFHSA-N 0.000 description 1
- WNXSJVVSLRKTOJ-OAQYLSRUSA-N FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C=3C=C4C(=NC3)NC=C4)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F Chemical compound FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C=3C=C4C(=NC3)NC=C4)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F WNXSJVVSLRKTOJ-OAQYLSRUSA-N 0.000 description 1
- CJYDPDOXVLTDPZ-HSZRJFAPSA-N FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C=3C=C4C=NN(C4=CC3)C)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F Chemical compound FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C=3C=C4C=NN(C4=CC3)C)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F CJYDPDOXVLTDPZ-HSZRJFAPSA-N 0.000 description 1
- AZKAEELFBAXCLK-HSZRJFAPSA-N FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C=3C=CC4=C(OCC(N4)=O)C=3)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F Chemical compound FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C=3C=CC4=C(OCC(N4)=O)C=3)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F AZKAEELFBAXCLK-HSZRJFAPSA-N 0.000 description 1
- JZWGMGWQHXSVTH-OAQYLSRUSA-N FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C=3C=NC(=CC=3)OC)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F Chemical compound FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C=3C=NC(=CC=3)OC)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F JZWGMGWQHXSVTH-OAQYLSRUSA-N 0.000 description 1
- ICGDCTCMAMLBLT-HXUWFJFHSA-N FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C=3C=NC=CC3)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F Chemical compound FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C=3C=NC=CC3)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F ICGDCTCMAMLBLT-HXUWFJFHSA-N 0.000 description 1
- HNOOHVKPFGVHJU-LJQANCHMSA-N FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C=3C=NN(C=3)C)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F Chemical compound FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C=3C=NN(C=3)C)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F HNOOHVKPFGVHJU-LJQANCHMSA-N 0.000 description 1
- UQAFTGVVBVVLNA-HSZRJFAPSA-N FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3CC3=C(C=C(C=C3)OC)F)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F Chemical compound FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3CC3=C(C=C(C=C3)OC)F)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F UQAFTGVVBVVLNA-HSZRJFAPSA-N 0.000 description 1
- IMHHPEPUHQCPDX-HSZRJFAPSA-N FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3CC3=CC(=CC=C3)S(=O)(=O)C)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F Chemical compound FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3CC3=CC(=CC=C3)S(=O)(=O)C)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F IMHHPEPUHQCPDX-HSZRJFAPSA-N 0.000 description 1
- BHOCDSKRDCALBO-JOCHJYFZSA-N FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3CC3=CC(=NC=C3)C)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F Chemical compound FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3CC3=CC(=NC=C3)C)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F BHOCDSKRDCALBO-JOCHJYFZSA-N 0.000 description 1
- ANZLAVRNEDYVEW-JOCHJYFZSA-N FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3CC3=CC(=NC=C3)OC)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F Chemical compound FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3CC3=CC(=NC=C3)OC)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F ANZLAVRNEDYVEW-JOCHJYFZSA-N 0.000 description 1
- MWGXXSBLEBXYHN-XMMPIXPASA-N FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3CC3=CC4=C(N=C(O4)C)C=C3)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F Chemical compound FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3CC3=CC4=C(N=C(O4)C)C=C3)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F MWGXXSBLEBXYHN-XMMPIXPASA-N 0.000 description 1
- NAYGITXNXIHYHT-HSZRJFAPSA-N FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3CC3=CC=4N(C=C3)C=CN=4)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F Chemical compound FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3CC3=CC=4N(C=C3)C=CN=4)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F NAYGITXNXIHYHT-HSZRJFAPSA-N 0.000 description 1
- KVHCMWYGUSHGEA-JOCHJYFZSA-N FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3CC3=CC=C(C=C3)F)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F Chemical compound FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3CC3=CC=C(C=C3)F)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F KVHCMWYGUSHGEA-JOCHJYFZSA-N 0.000 description 1
- KJHTYHAUNFWGTP-HSZRJFAPSA-N FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3CC3=CC=C(C=C3)S(=O)(=O)C)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F Chemical compound FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3CC3=CC=C(C=C3)S(=O)(=O)C)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F KJHTYHAUNFWGTP-HSZRJFAPSA-N 0.000 description 1
- NSNMFIWOXTXBIJ-JOCHJYFZSA-N FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3CC3=CN(C(C=C3)=O)C)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F Chemical compound FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3CC3=CN(C(C=C3)=O)C)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F NSNMFIWOXTXBIJ-JOCHJYFZSA-N 0.000 description 1
- SHWWECTZMNCFLG-HXUWFJFHSA-N FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3CC3=NC=CC=N3)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F Chemical compound FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3CC3=NC=CC=N3)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F SHWWECTZMNCFLG-HXUWFJFHSA-N 0.000 description 1
- OFTYQIXWGCTZEP-OAQYLSRUSA-N FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3CC3CCOCC3)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F Chemical compound FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3CC3CCOCC3)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F OFTYQIXWGCTZEP-OAQYLSRUSA-N 0.000 description 1
- QMXYZPVXWVDPON-XMMPIXPASA-N FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3CC=3C=C4N=CC=NC4=CC3)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F Chemical compound FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3CC=3C=C4N=CC=NC4=CC3)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F QMXYZPVXWVDPON-XMMPIXPASA-N 0.000 description 1
- AKJHYCVZXKCNER-HSZRJFAPSA-N FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3CC=3C=CC4=C(N(C(O4)=O)C)C=3)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F Chemical compound FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3CC=3C=CC4=C(N(C(O4)=O)C)C=3)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F AKJHYCVZXKCNER-HSZRJFAPSA-N 0.000 description 1
- NIPMGVAATRVWNE-XMMPIXPASA-N FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3CC=3C=CC4=C(N=C(O4)C)C3)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F Chemical compound FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3CC=3C=CC4=C(N=C(O4)C)C3)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F NIPMGVAATRVWNE-XMMPIXPASA-N 0.000 description 1
- KZRYBDLUQZFKGT-XMMPIXPASA-N FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3CC=3C=CC4=C(NC(=N4)C)C3)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F Chemical compound FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3CC=3C=CC4=C(NC(=N4)C)C3)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F KZRYBDLUQZFKGT-XMMPIXPASA-N 0.000 description 1
- UJMHKSRNVUZPTN-JOCHJYFZSA-N FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3CC=3C=NC(=CC=3)OC)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F Chemical compound FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3CC=3C=NC(=CC=3)OC)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F UJMHKSRNVUZPTN-JOCHJYFZSA-N 0.000 description 1
- ZRWJXKPVRKZSMD-HXUWFJFHSA-N FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3CC=3C=NN(C3)C)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F Chemical compound FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3CC=3C=NN(C3)C)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F ZRWJXKPVRKZSMD-HXUWFJFHSA-N 0.000 description 1
- JNXAQUUKDDPRNR-HXUWFJFHSA-N FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3CC=3SC=C(N3)C)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F Chemical compound FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3CC=3SC=C(N3)C)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F JNXAQUUKDDPRNR-HXUWFJFHSA-N 0.000 description 1
- HSGKPYRCMTXDPI-HXUWFJFHSA-N FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3CCC(C)C)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F Chemical compound FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3CCC(C)C)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F HSGKPYRCMTXDPI-HXUWFJFHSA-N 0.000 description 1
- XSPPBSRUOZLLIM-FDDCHVKYSA-N FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3[C@@H](C)C3=CC=CC=C3)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F Chemical compound FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3[C@@H](C)C3=CC=CC=C3)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F XSPPBSRUOZLLIM-FDDCHVKYSA-N 0.000 description 1
- XSPPBSRUOZLLIM-WZONZLPQSA-N FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3[C@H](C)C3=CC=CC=C3)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F Chemical compound FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3[C@H](C)C3=CC=CC=C3)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F XSPPBSRUOZLLIM-WZONZLPQSA-N 0.000 description 1
- UGGCRELAIDTUIN-HSZRJFAPSA-N FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(CN3C3=CC(=C(C(=O)O)C=C3)C)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F Chemical compound FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(CN3C3=CC(=C(C(=O)O)C=C3)C)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F UGGCRELAIDTUIN-HSZRJFAPSA-N 0.000 description 1
- SYMAHTMNWKYCSK-HSZRJFAPSA-N FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(CN3C3=CC(=C(C(=O)O)C=C3)OC)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F Chemical compound FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(CN3C3=CC(=C(C(=O)O)C=C3)OC)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F SYMAHTMNWKYCSK-HSZRJFAPSA-N 0.000 description 1
- IBXXLLHYSWPTPT-QFIPXVFZSA-N FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(CN3C3=CC=C(C(=O)O)C=C3)C)=O)CC2)C(C)(C)C)C=C(C=C1)C(F)(F)F Chemical compound FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(CN3C3=CC=C(C(=O)O)C=C3)C)=O)CC2)C(C)(C)C)C=C(C=C1)C(F)(F)F IBXXLLHYSWPTPT-QFIPXVFZSA-N 0.000 description 1
- GMXMCKXBUPLWRK-HSZRJFAPSA-N FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(CN3C3=CC=C(C(=O)O)C=C3)C)=O)CC2)C(C)C)C=C(C=C1)OC Chemical compound FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(CN3C3=CC=C(C(=O)O)C=C3)C)=O)CC2)C(C)C)C=C(C=C1)OC GMXMCKXBUPLWRK-HSZRJFAPSA-N 0.000 description 1
- LLXKRJNAHLSYTL-HSZRJFAPSA-N FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(CN3C3=CC=C(C(=O)O)C=C3)C)=O)CC2)C(C)C)C=CC=C1C Chemical compound FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(CN3C3=CC=C(C(=O)O)C=C3)C)=O)CC2)C(C)C)C=CC=C1C LLXKRJNAHLSYTL-HSZRJFAPSA-N 0.000 description 1
- MERXMKZCARLDQP-HSZRJFAPSA-N FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(CN3C3=CC=C(C=C3)NS(=O)(=O)C)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F Chemical compound FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(CN3C3=CC=C(C=C3)NS(=O)(=O)C)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F MERXMKZCARLDQP-HSZRJFAPSA-N 0.000 description 1
- UIAGFPZXZVFJAN-HSZRJFAPSA-N FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(CN3C3=CC=C(C=C3)S(=O)(=O)C)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F Chemical compound FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(CN3C3=CC=C(C=C3)S(=O)(=O)C)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F UIAGFPZXZVFJAN-HSZRJFAPSA-N 0.000 description 1
- YRPBCYXITJJJIU-HSZRJFAPSA-N FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(CN3C3=CC=CC=C3)C)=O)CC2)C(C)C)C=C(C=C1)C Chemical compound FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(CN3C3=CC=CC=C3)C)=O)CC2)C(C)C)C=C(C=C1)C YRPBCYXITJJJIU-HSZRJFAPSA-N 0.000 description 1
- DVRMLOUJYVMVII-AREMUKBSSA-N FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(CN3C3=CC=CC=C3)CCCS(=O)(=O)C)=O)CC2)C(C)C)C=CC=C1C Chemical compound FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(CN3C3=CC=CC=C3)CCCS(=O)(=O)C)=O)CC2)C(C)C)C=CC=C1C DVRMLOUJYVMVII-AREMUKBSSA-N 0.000 description 1
- CVJFHJQGKBIOJF-JOCHJYFZSA-N FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(CN3C3=CN(C(C=C3)=O)C)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F Chemical compound FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(CN3C3=CN(C(C=C3)=O)C)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F CVJFHJQGKBIOJF-JOCHJYFZSA-N 0.000 description 1
- SKIMFNPYHUYVFV-HSZRJFAPSA-N FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(CN3C=3C=C(C=CC3)B(O)O)C)=O)CC2)C(C)C)C=CC=C1C Chemical compound FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(CN3C=3C=C(C=CC3)B(O)O)C)=O)CC2)C(C)C)C=CC=C1C SKIMFNPYHUYVFV-HSZRJFAPSA-N 0.000 description 1
- IWULRNJVGTUITM-GAJHUEQPSA-N FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N([C@@H](N3C3=CC=C(C(=O)O)C=C3)C)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F Chemical compound FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N([C@@H](N3C3=CC=C(C(=O)O)C=C3)C)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F IWULRNJVGTUITM-GAJHUEQPSA-N 0.000 description 1
- IWULRNJVGTUITM-UZUQRXQVSA-N FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N([C@H](N3C3=CC=C(C(=O)O)C=C3)C)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F Chemical compound FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N([C@H](N3C3=CC=C(C(=O)O)C=C3)C)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F IWULRNJVGTUITM-UZUQRXQVSA-N 0.000 description 1
- MTJUBQAUVHBHKK-HSZRJFAPSA-N FC1=C(C=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(CN3C3=CC=CC=C3)C)=O)CC2)C(C)C)C=C1)C Chemical compound FC1=C(C=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(CN3C3=CC=CC=C3)C)=O)CC2)C(C)C)C=C1)C MTJUBQAUVHBHKK-HSZRJFAPSA-N 0.000 description 1
- ITVVCWQFQQWQCY-NTKDMRAZSA-N FC=1C=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CC=C(C=C3)OC)=O)C)=O)CC2)[C@@H](CC)C)C=C(C=1)C Chemical compound FC=1C=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CC=C(C=C3)OC)=O)C)=O)CC2)[C@@H](CC)C)C=C(C=1)C ITVVCWQFQQWQCY-NTKDMRAZSA-N 0.000 description 1
- QBMVYVJWNKXVLA-OAQYLSRUSA-N FC=1C=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CC=CC=C3)=O)C)=O)CC2)C(C)C)C=CC1 Chemical compound FC=1C=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CC=CC=C3)=O)C)=O)CC2)C(C)C)C=CC1 QBMVYVJWNKXVLA-OAQYLSRUSA-N 0.000 description 1
- LRPMEFKJMWMCGK-HSZRJFAPSA-N FC=1C=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(CN3C3=CC=CC=C3)C)=O)CC2)C(C)C)C=C(C1)C Chemical compound FC=1C=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(CN3C3=CC=CC=C3)C)=O)CC2)C(C)C)C=C(C1)C LRPMEFKJMWMCGK-HSZRJFAPSA-N 0.000 description 1
- GISRWBROCYNDME-PELMWDNLSA-N F[C@H]1[C@H]([C@H](NC1=O)COC1=NC=CC2=CC(=C(C=C12)OC)C(=O)N)C Chemical compound F[C@H]1[C@H]([C@H](NC1=O)COC1=NC=CC2=CC(=C(C=C12)OC)C(=O)N)C GISRWBROCYNDME-PELMWDNLSA-N 0.000 description 1
- 102000003688 G-Protein-Coupled Receptors Human genes 0.000 description 1
- 108090000045 G-Protein-Coupled Receptors Proteins 0.000 description 1
- 102100031415 Hepatic triacylglycerol lipase Human genes 0.000 description 1
- 101000897035 Homo sapiens Ectonucleotide pyrophosphatase/phosphodiesterase family member 2 Proteins 0.000 description 1
- 229930194542 Keto Natural products 0.000 description 1
- 108010013563 Lipoprotein Lipase Proteins 0.000 description 1
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 description 1
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 1
- 208000034578 Multiple myelomas Diseases 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- UTRKZLDCLOUQQG-HSZRJFAPSA-N N-[(1R)-1-cyclobutyl-2-[1-(1H-indazol-5-yl)-3-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decan-8-yl]-2-oxoethyl]-2-fluoro-5-(trifluoromethyl)benzamide Chemical compound N1N=CC2=CC(=CC=C12)N1C(N(C(C11CCN(CC1)C([C@@H](C1CCC1)NC(C1=C(C=CC(=C1)C(F)(F)F)F)=O)=O)=O)C)=O UTRKZLDCLOUQQG-HSZRJFAPSA-N 0.000 description 1
- FEQGCIWMINOGHQ-HSZRJFAPSA-N N-[(1R)-1-cyclopentyl-2-[3-methyl-1-(1-methyl-6-oxopyridin-3-yl)-2,4-dioxo-1,3,8-triazaspiro[4.5]decan-8-yl]-2-oxoethyl]-2-fluoro-5-(trifluoromethyl)benzamide Chemical compound C1(CCCC1)[C@H](C(=O)N1CCC2(C(N(C(N2C2=CN(C(C=C2)=O)C)=O)C)=O)CC1)NC(C1=C(C=CC(=C1)C(F)(F)F)F)=O FEQGCIWMINOGHQ-HSZRJFAPSA-N 0.000 description 1
- AYCPARAPKDAOEN-LJQANCHMSA-N N-[(1S)-2-(dimethylamino)-1-phenylethyl]-6,6-dimethyl-3-[(2-methyl-4-thieno[3,2-d]pyrimidinyl)amino]-1,4-dihydropyrrolo[3,4-c]pyrazole-5-carboxamide Chemical compound C1([C@H](NC(=O)N2C(C=3NN=C(NC=4C=5SC=CC=5N=C(C)N=4)C=3C2)(C)C)CN(C)C)=CC=CC=C1 AYCPARAPKDAOEN-LJQANCHMSA-N 0.000 description 1
- FUFDVMAPQXGZFO-HSZRJFAPSA-N N-[(2R)-1-[1-(1-benzofuran-5-yl)-3-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decan-8-yl]-3-methyl-1-oxobutan-2-yl]-2-fluoro-5-(trifluoromethyl)benzamide Chemical compound CC(C)[C@@H](NC(=O)c1cc(ccc1F)C(F)(F)F)C(=O)N1CCC2(CC1)N(C(=O)N(C)C2=O)c1ccc2occc2c1 FUFDVMAPQXGZFO-HSZRJFAPSA-N 0.000 description 1
- WOACRZWRSBSQRC-JOCHJYFZSA-N N-[(2R)-1-[1-(1H-indazol-5-yl)-3-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decan-8-yl]-3-methyl-1-oxobutan-2-yl]benzamide Chemical compound N1N=CC2=CC(=CC=C12)N1C(N(C(C11CCN(CC1)C([C@@H](C(C)C)NC(C1=CC=CC=C1)=O)=O)=O)C)=O WOACRZWRSBSQRC-JOCHJYFZSA-N 0.000 description 1
- MAAXIYXUGJBYKT-JOCHJYFZSA-N N-[(2R)-1-[1-(1H-indazol-5-yl)-3-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decan-8-yl]-3-methyl-1-oxobutan-2-yl]cyclohexanecarboxamide Chemical compound N1N=CC2=CC(=CC=C12)N1C(N(C(C11CCN(CC1)C([C@@H](C(C)C)NC(=O)C1CCCCC1)=O)=O)C)=O MAAXIYXUGJBYKT-JOCHJYFZSA-N 0.000 description 1
- HHMFKRVLEGYTEJ-XMMPIXPASA-N N-[(2R)-1-[1-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-3-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decan-8-yl]-3-methyl-1-oxobutan-2-yl]-2-fluoro-5-(trifluoromethyl)benzamide Chemical compound O1C2=C(OCC1)C=C(C=C2)CN1C(N(C(C11CCN(CC1)C([C@@H](C(C)C)NC(C1=C(C=CC(=C1)C(F)(F)F)F)=O)=O)=O)C)=O HHMFKRVLEGYTEJ-XMMPIXPASA-N 0.000 description 1
- FMWAZPTZCCGSEF-RUZDIDTESA-N N-[(2R)-1-[1-(3H-benzimidazol-5-yl)-3-methyl-4-oxo-1,3,8-triazaspiro[4.5]decan-8-yl]-3-methyl-1-oxobutan-2-yl]-5-ethyl-2-fluorobenzamide Chemical compound N1C=NC2=C1C=C(C=C2)N1CN(C(C11CCN(CC1)C([C@@H](C(C)C)NC(C1=C(C=CC(=C1)CC)F)=O)=O)=O)C FMWAZPTZCCGSEF-RUZDIDTESA-N 0.000 description 1
- LREGJECKQRKIRO-HSZRJFAPSA-N N-[(2R)-1-[1-(4-ethoxyphenyl)-3-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decan-8-yl]-3-methyl-1-oxobutan-2-yl]-3-fluoro-5-(trifluoromethyl)benzamide Chemical compound CC([C@H](C(=O)N1CCC2(C(N(C(N2C2=CC=C(C=C2)OCC)=O)C)=O)CC1)NC(C1=CC(=CC(=C1)F)C(F)(F)F)=O)C LREGJECKQRKIRO-HSZRJFAPSA-N 0.000 description 1
- NQALDIAARUAZJR-XMMPIXPASA-N N-[(2R)-1-[1-(4-methoxyphenyl)-3-methyl-4-oxo-1,3,8-triazaspiro[4.5]decan-8-yl]-3-methyl-1-oxobutan-2-yl]-3-methylbenzamide Chemical compound COC1=CC=C(C=C1)N1CN(C(C11CCN(CC1)C([C@@H](C(C)C)NC(C1=CC(=CC=C1)C)=O)=O)=O)C NQALDIAARUAZJR-XMMPIXPASA-N 0.000 description 1
- OGEVRNIAJCFHBG-AREMUKBSSA-N N-[(2R)-1-[1-[4-(2-amino-2-oxoethoxy)phenyl]-3-methyl-4-oxo-1,3,8-triazaspiro[4.5]decan-8-yl]-3-methyl-1-oxobutan-2-yl]-5-ethyl-2-fluorobenzamide Chemical compound NC(COC1=CC=C(C=C1)N1CN(C(C11CCN(CC1)C([C@@H](C(C)C)NC(C1=C(C=CC(=C1)CC)F)=O)=O)=O)C)=O OGEVRNIAJCFHBG-AREMUKBSSA-N 0.000 description 1
- GTUGLGLYOBKYGH-VQIWEWKSSA-N N-[(2R)-1-[1-[4-[2-(dimethylamino)ethoxy]phenyl]-3-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decan-8-yl]-3-methyl-1-oxobutan-2-yl]-2-fluoro-5-(trifluoromethyl)benzamide 2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.CC(C)[C@@H](NC(=O)c1cc(ccc1F)C(F)(F)F)C(=O)N1CCC2(CC1)N(C(=O)N(C)C2=O)c1ccc(OCCN(C)C)cc1 GTUGLGLYOBKYGH-VQIWEWKSSA-N 0.000 description 1
- SIHVYINVDLUUCJ-UFTMZEDQSA-N N-[(2R)-1-[1-[4-[2-(dimethylamino)ethoxy]phenyl]-3-methyl-4-oxo-1,3,8-triazaspiro[4.5]decan-8-yl]-3-methyl-1-oxobutan-2-yl]-2-fluoro-5-(trifluoromethyl)benzamide 2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.CC(C)[C@@H](NC(=O)c1cc(ccc1F)C(F)(F)F)C(=O)N1CCC2(CC1)N(CN(C)C2=O)c1ccc(OCCN(C)C)cc1 SIHVYINVDLUUCJ-UFTMZEDQSA-N 0.000 description 1
- DOLIKDVGXJOJGV-MRNPHLECSA-N N-[(2R)-3-[3-ethyl-1-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)-2,4-dioxo-1,3,8-triazaspiro[4.5]decan-8-yl]-1-oxobutan-2-yl]-2-fluoro-5-(trifluoromethyl)benzamide Chemical compound FC1=C(C(=O)N[C@@H](C=O)C(C)N2CCC3(C(N(C(N3C=3C=CC4=C(N(C(O4)=O)C)C=3)=O)CC)=O)CC2)C=C(C=C1)C(F)(F)F DOLIKDVGXJOJGV-MRNPHLECSA-N 0.000 description 1
- LFTLOKWAGJYHHR-UHFFFAOYSA-N N-methylmorpholine N-oxide Chemical compound CN1(=O)CCOCC1 LFTLOKWAGJYHHR-UHFFFAOYSA-N 0.000 description 1
- RJXBARGSHSCVSP-HSZRJFAPSA-N N1C=CC2=CC(=CC=C12)N1C(N(C(C11CCN(CC1)C([C@@H](C(C)C)NC(C1=C(C=CC(=C1)C(F)(F)F)F)=O)=O)=O)C)=O Chemical compound N1C=CC2=CC(=CC=C12)N1C(N(C(C11CCN(CC1)C([C@@H](C(C)C)NC(C1=C(C=CC(=C1)C(F)(F)F)F)=O)=O)=O)C)=O RJXBARGSHSCVSP-HSZRJFAPSA-N 0.000 description 1
- GWIAVVXQKVHMHU-HSZRJFAPSA-N N1N=CC2=CC(=CC=C12)CN1C(N(C(C11CCN(CC1)C([C@@H](C(C)C)NC(C1=C(C=CC(=C1)C(F)(F)F)F)=O)=O)=O)C)=O Chemical compound N1N=CC2=CC(=CC=C12)CN1C(N(C(C11CCN(CC1)C([C@@H](C(C)C)NC(C1=C(C=CC(=C1)C(F)(F)F)F)=O)=O)=O)C)=O GWIAVVXQKVHMHU-HSZRJFAPSA-N 0.000 description 1
- JMERCJISDFTFIU-UHFFFAOYSA-N N1N=CC2=CC(=CC=C12)N1C(N(C(C11CCN(CC1)C(=O)C1(CC1)NC(C1=C(C=CC(=C1)C(F)(F)F)F)=O)=O)C)=O Chemical compound N1N=CC2=CC(=CC=C12)N1C(N(C(C11CCN(CC1)C(=O)C1(CC1)NC(C1=C(C=CC(=C1)C(F)(F)F)F)=O)=O)C)=O JMERCJISDFTFIU-UHFFFAOYSA-N 0.000 description 1
- RTUNYIMDFLSMRE-UHFFFAOYSA-N N1N=CC2=CC(=CC=C12)N1C(N(C(C11CCN(CC1)C(CNC(C1=C(C=CC(=C1)C(F)(F)F)F)=O)=O)=O)C)=O Chemical compound N1N=CC2=CC(=CC=C12)N1C(N(C(C11CCN(CC1)C(CNC(C1=C(C=CC(=C1)C(F)(F)F)F)=O)=O)=O)C)=O RTUNYIMDFLSMRE-UHFFFAOYSA-N 0.000 description 1
- XAXMLHAIPMMIRV-HSZRJFAPSA-N N1N=CC2=CC(=CC=C12)N1C(N(C(C11CCN(CC1)C([C@@H](C(C)C)N(C(C1=C(C=CC(=C1)C(F)(F)F)F)=O)C)=O)=O)C)=O Chemical compound N1N=CC2=CC(=CC=C12)N1C(N(C(C11CCN(CC1)C([C@@H](C(C)C)N(C(C1=C(C=CC(=C1)C(F)(F)F)F)=O)C)=O)=O)C)=O XAXMLHAIPMMIRV-HSZRJFAPSA-N 0.000 description 1
- VBAORJMCLLHCQY-GOSISDBHSA-N N1N=CC2=CC(=CC=C12)N1C(N(C(C11CCN(CC1)C([C@@H](C(C)C)NC(=O)C=1SC=C(N=1)C(F)(F)F)=O)=O)C)=O Chemical compound N1N=CC2=CC(=CC=C12)N1C(N(C(C11CCN(CC1)C([C@@H](C(C)C)NC(=O)C=1SC=C(N=1)C(F)(F)F)=O)=O)C)=O VBAORJMCLLHCQY-GOSISDBHSA-N 0.000 description 1
- XBHMMZIIOXYSIV-GOSISDBHSA-N N1N=CC2=CC(=CC=C12)N1C(N(C(C11CCN(CC1)C([C@@H](C(C)C)NC(=O)C=1SC=CN=1)=O)=O)C)=O Chemical compound N1N=CC2=CC(=CC=C12)N1C(N(C(C11CCN(CC1)C([C@@H](C(C)C)NC(=O)C=1SC=CN=1)=O)=O)C)=O XBHMMZIIOXYSIV-GOSISDBHSA-N 0.000 description 1
- DEJMCQZHWIOHMD-LJQANCHMSA-N N1N=CC2=CC(=CC=C12)N1C(N(C(C11CCN(CC1)C([C@@H](C(C)C)NC(C(C)(C)C)=O)=O)=O)C)=O Chemical compound N1N=CC2=CC(=CC=C12)N1C(N(C(C11CCN(CC1)C([C@@H](C(C)C)NC(C(C)(C)C)=O)=O)=O)C)=O DEJMCQZHWIOHMD-LJQANCHMSA-N 0.000 description 1
- DJIQHFHIIHEAKJ-HSZRJFAPSA-N N1N=CC2=CC(=CC=C12)N1C(N(C(C11CCN(CC1)C([C@@H](C(C)C)NC(C1=C(C=CC(=C1)C(F)(F)F)C)=O)=O)=O)C)=O Chemical compound N1N=CC2=CC(=CC=C12)N1C(N(C(C11CCN(CC1)C([C@@H](C(C)C)NC(C1=C(C=CC(=C1)C(F)(F)F)C)=O)=O)=O)C)=O DJIQHFHIIHEAKJ-HSZRJFAPSA-N 0.000 description 1
- IKYDYHTYCMZFSI-JOCHJYFZSA-N N1N=CC2=CC(=CC=C12)N1C(N(C(C11CCN(CC1)C([C@@H](C(C)C)NC(C1=C(C=CC(=C1)C(F)(F)F)Cl)=O)=O)=O)C)=O Chemical compound N1N=CC2=CC(=CC=C12)N1C(N(C(C11CCN(CC1)C([C@@H](C(C)C)NC(C1=C(C=CC(=C1)C(F)(F)F)Cl)=O)=O)=O)C)=O IKYDYHTYCMZFSI-JOCHJYFZSA-N 0.000 description 1
- BDMKXRAWQIQRRY-HSZRJFAPSA-N N1N=CC2=CC(=CC=C12)N1C(N(C(C11CCN(CC1)C([C@@H](C(C)C)NC(C1=C(C=CC(=C1)C)F)=O)=O)=O)C)=O Chemical compound N1N=CC2=CC(=CC=C12)N1C(N(C(C11CCN(CC1)C([C@@H](C(C)C)NC(C1=C(C=CC(=C1)C)F)=O)=O)=O)C)=O BDMKXRAWQIQRRY-HSZRJFAPSA-N 0.000 description 1
- KDWUXZDBISLXEX-RUZDIDTESA-N N1N=CC2=CC(=CC=C12)N1C(N(C(C11CCN(CC1)C([C@@H](C(C)C)NC(C1=C(C=CC(=C1)C1CC1)F)=O)=O)=O)C)=O Chemical compound N1N=CC2=CC(=CC=C12)N1C(N(C(C11CCN(CC1)C([C@@H](C(C)C)NC(C1=C(C=CC(=C1)C1CC1)F)=O)=O)=O)C)=O KDWUXZDBISLXEX-RUZDIDTESA-N 0.000 description 1
- ZLEVKVIRYIXIFA-XMMPIXPASA-N N1N=CC2=CC(=CC=C12)N1C(N(C(C11CCN(CC1)C([C@@H](C(C)C)NC(C1=C(C=CC(=C1)CC)F)=O)=O)=O)C)=O Chemical compound N1N=CC2=CC(=CC=C12)N1C(N(C(C11CCN(CC1)C([C@@H](C(C)C)NC(C1=C(C=CC(=C1)CC)F)=O)=O)=O)C)=O ZLEVKVIRYIXIFA-XMMPIXPASA-N 0.000 description 1
- PHRMWNSITVSNDO-JOCHJYFZSA-N N1N=CC2=CC(=CC=C12)N1C(N(C(C11CCN(CC1)C([C@@H](C(C)C)NC(C1=C(C=CC(=C1)F)F)=O)=O)=O)C)=O Chemical compound N1N=CC2=CC(=CC=C12)N1C(N(C(C11CCN(CC1)C([C@@H](C(C)C)NC(C1=C(C=CC(=C1)F)F)=O)=O)=O)C)=O PHRMWNSITVSNDO-JOCHJYFZSA-N 0.000 description 1
- JNHPOOCMLKCZBW-JOCHJYFZSA-N N1N=CC2=CC(=CC=C12)N1C(N(C(C11CCN(CC1)C([C@@H](C(C)C)NC(C1=C(C=CC(=C1)OC(F)F)F)=O)=O)=O)C)=O Chemical compound N1N=CC2=CC(=CC=C12)N1C(N(C(C11CCN(CC1)C([C@@H](C(C)C)NC(C1=C(C=CC(=C1)OC(F)F)F)=O)=O)=O)C)=O JNHPOOCMLKCZBW-JOCHJYFZSA-N 0.000 description 1
- OGQAHJHTXZWVBP-HSZRJFAPSA-N N1N=CC2=CC(=CC=C12)N1C(N(C(C11CCN(CC1)C([C@@H](C(C)C)NC(C1=C(C=CC(=C1)OC)F)=O)=O)=O)C)=O Chemical compound N1N=CC2=CC(=CC=C12)N1C(N(C(C11CCN(CC1)C([C@@H](C(C)C)NC(C1=C(C=CC(=C1)OC)F)=O)=O)=O)C)=O OGQAHJHTXZWVBP-HSZRJFAPSA-N 0.000 description 1
- QXGFTXOSWCMLLT-JOCHJYFZSA-N N1N=CC2=CC(=CC=C12)N1C(N(C(C11CCN(CC1)C([C@@H](C(C)C)NC(C1=CC(=CC(=C1)C(F)(F)F)Cl)=O)=O)=O)C)=O Chemical compound N1N=CC2=CC(=CC=C12)N1C(N(C(C11CCN(CC1)C([C@@H](C(C)C)NC(C1=CC(=CC(=C1)C(F)(F)F)Cl)=O)=O)=O)C)=O QXGFTXOSWCMLLT-JOCHJYFZSA-N 0.000 description 1
- TXQTVHLHNXMKAX-JOCHJYFZSA-N N1N=CC2=CC(=CC=C12)N1C(N(C(C11CCN(CC1)C([C@@H](C(C)C)NC(C1=CC(=CC=C1)C(F)(F)F)=O)=O)=O)C)=O Chemical compound N1N=CC2=CC(=CC=C12)N1C(N(C(C11CCN(CC1)C([C@@H](C(C)C)NC(C1=CC(=CC=C1)C(F)(F)F)=O)=O)=O)C)=O TXQTVHLHNXMKAX-JOCHJYFZSA-N 0.000 description 1
- XYJHKVSHKNGDFO-OAQYLSRUSA-N N1N=CC2=CC(=CC=C12)N1C(N(C(C11CCN(CC1)C([C@@H](C(C)C)NC(C1=CC=NC=C1)=O)=O)=O)C)=O Chemical compound N1N=CC2=CC(=CC=C12)N1C(N(C(C11CCN(CC1)C([C@@H](C(C)C)NC(C1=CC=NC=C1)=O)=O)=O)C)=O XYJHKVSHKNGDFO-OAQYLSRUSA-N 0.000 description 1
- IKOCHMWIWKLSSW-OAQYLSRUSA-N N1N=CC2=CC(=CC=C12)N1C(N(C(C11CCN(CC1)C([C@@H](C(C)C)NC(C1=CN=CC=C1)=O)=O)=O)C)=O Chemical compound N1N=CC2=CC(=CC=C12)N1C(N(C(C11CCN(CC1)C([C@@H](C(C)C)NC(C1=CN=CC=C1)=O)=O)=O)C)=O IKOCHMWIWKLSSW-OAQYLSRUSA-N 0.000 description 1
- SPSNZEMRXPECKE-CQSZACIVSA-N N1N=CC2=CC(=CC=C12)N1C(N(C(C11CCN(CC1)C([C@@H](C)NC(C1=C(C=CC(=C1)C(F)(F)F)F)=O)=O)=O)C)=O Chemical compound N1N=CC2=CC(=CC=C12)N1C(N(C(C11CCN(CC1)C([C@@H](C)NC(C1=C(C=CC(=C1)C(F)(F)F)F)=O)=O)=O)C)=O SPSNZEMRXPECKE-CQSZACIVSA-N 0.000 description 1
- NDFQOGBANFMFIE-XMMPIXPASA-N N1N=CC2=CC(=CC=C12)N1C(N(C(C11CCN(CC1)C([C@@H](C1CCCC1)NC(C1=C(C=CC(=C1)C(F)(F)F)F)=O)=O)=O)C)=O Chemical compound N1N=CC2=CC(=CC=C12)N1C(N(C(C11CCN(CC1)C([C@@H](C1CCCC1)NC(C1=C(C=CC(=C1)C(F)(F)F)F)=O)=O)=O)C)=O NDFQOGBANFMFIE-XMMPIXPASA-N 0.000 description 1
- USPZQBGGBVVQBD-RUZDIDTESA-N N1N=CC2=CC(=CC=C12)N1CN(C(C11CCN(CC1)C([C@@H](C(C)C)NC(C1=C(C=CC(=C1)CC)F)=O)=O)=O)C Chemical compound N1N=CC2=CC(=CC=C12)N1CN(C(C11CCN(CC1)C([C@@H](C(C)C)NC(C1=C(C=CC(=C1)CC)F)=O)=O)=O)C USPZQBGGBVVQBD-RUZDIDTESA-N 0.000 description 1
- WMVCSISHKNOJTG-JOCHJYFZSA-N N1N=CC2=CC=C(C=C12)N1C(N(C(C11CCN(CC1)C([C@@H](C(C)C)NC(C1=C(C=CC(=C1)C(F)(F)F)F)=O)=O)=O)C)=O Chemical compound N1N=CC2=CC=C(C=C12)N1C(N(C(C11CCN(CC1)C([C@@H](C(C)C)NC(C1=C(C=CC(=C1)C(F)(F)F)F)=O)=O)=O)C)=O WMVCSISHKNOJTG-JOCHJYFZSA-N 0.000 description 1
- FMVXEMKDTKXPIO-OAQYLSRUSA-N N1N=NC2=C1C=CC(=C2)N1C(N(C(C11CCN(CC1)C([C@@H](C(C)C)NC(C1=C(C=CC(=C1)C(F)(F)F)F)=O)=O)=O)C)=O Chemical compound N1N=NC2=C1C=CC(=C2)N1C(N(C(C11CCN(CC1)C([C@@H](C(C)C)NC(C1=C(C=CC(=C1)C(F)(F)F)F)=O)=O)=O)C)=O FMVXEMKDTKXPIO-OAQYLSRUSA-N 0.000 description 1
- ACWGEDAKXFVTGW-OAQYLSRUSA-N N=1NN=NC=1C1=CC=C(C=C1)N1C(N(C(C11CCN(CC1)C([C@@H](C(C)C)NC(C1=C(C=CC(=C1)OC(F)(F)F)F)=O)=O)=O)C)=O Chemical compound N=1NN=NC=1C1=CC=C(C=C1)N1C(N(C(C11CCN(CC1)C([C@@H](C(C)C)NC(C1=C(C=CC(=C1)OC(F)(F)F)F)=O)=O)=O)C)=O ACWGEDAKXFVTGW-OAQYLSRUSA-N 0.000 description 1
- ONTHXIMRAUBPSG-OAQYLSRUSA-N N=1NN=NC=1C1=CC=C(C=C1)N1C(N(C(C11CCN(CC1)C([C@@H](C(C)C)NC(C1=C(C=CC(=C1)OC(F)F)F)=O)=O)=O)C)=O Chemical compound N=1NN=NC=1C1=CC=C(C=C1)N1C(N(C(C11CCN(CC1)C([C@@H](C(C)C)NC(C1=C(C=CC(=C1)OC(F)F)F)=O)=O)=O)C)=O ONTHXIMRAUBPSG-OAQYLSRUSA-N 0.000 description 1
- 101150071357 NPP2 gene Proteins 0.000 description 1
- 206010061309 Neoplasm progression Diseases 0.000 description 1
- NPAPBSBEHUJKKT-HSZRJFAPSA-N O1C2=C(NCC1)C=CC(=C2)N1C(N(C(C11CCN(CC1)C([C@@H](C(C)C)NC(C1=C(C=CC(=C1)C(F)(F)F)F)=O)=O)=O)C)=O Chemical compound O1C2=C(NCC1)C=CC(=C2)N1C(N(C(C11CCN(CC1)C([C@@H](C(C)C)NC(C1=C(C=CC(=C1)C(F)(F)F)F)=O)=O)=O)C)=O NPAPBSBEHUJKKT-HSZRJFAPSA-N 0.000 description 1
- DDGLAJYINOCBIE-JOCHJYFZSA-N O1COC2=C1C=CC(=C2)N2C(N(C(C21CCN(CC1)C([C@@H](C(C)C)NC(C1=C(C=CC(=C1)C(F)(F)F)F)=O)=O)=O)C)=O Chemical compound O1COC2=C1C=CC(=C2)N2C(N(C(C21CCN(CC1)C([C@@H](C(C)C)NC(C1=C(C=CC(=C1)C(F)(F)F)F)=O)=O)=O)C)=O DDGLAJYINOCBIE-JOCHJYFZSA-N 0.000 description 1
- LKNXEALWFBTCAW-VQIWEWKSSA-N OC(=O)C(F)(F)F.CN1CN(C2=CC=CC=C2)C2(CCN(CC2)C(=O)[C@H](NC(=O)C2=CC=CC(C)=N2)C2CCCCC2)C1=O Chemical compound OC(=O)C(F)(F)F.CN1CN(C2=CC=CC=C2)C2(CCN(CC2)C(=O)[C@H](NC(=O)C2=CC=CC(C)=N2)C2CCCCC2)C1=O LKNXEALWFBTCAW-VQIWEWKSSA-N 0.000 description 1
- IDRGFNPZDVBSSE-UHFFFAOYSA-N OCCN1CCN(CC1)c1ccc(Nc2ncc3cccc(-c4cccc(NC(=O)C=C)c4)c3n2)c(F)c1F Chemical compound OCCN1CCN(CC1)c1ccc(Nc2ncc3cccc(-c4cccc(NC(=O)C=C)c4)c3n2)c(F)c1F IDRGFNPZDVBSSE-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 1
- 108090001050 Phosphoric Diester Hydrolases Proteins 0.000 description 1
- 102000004861 Phosphoric Diester Hydrolases Human genes 0.000 description 1
- 101100080097 Phytophthora capsici NLP2 gene Proteins 0.000 description 1
- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 108010009413 Pyrophosphatases Proteins 0.000 description 1
- 102000009609 Pyrophosphatases Human genes 0.000 description 1
- 208000012322 Raynaud phenomenon Diseases 0.000 description 1
- 208000033626 Renal failure acute Diseases 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- 101000995838 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) Nucleotide pyrophosphatase Proteins 0.000 description 1
- 206010039491 Sarcoma Diseases 0.000 description 1
- 206010039710 Scleroderma Diseases 0.000 description 1
- 206010050207 Skin fibrosis Diseases 0.000 description 1
- 206010042971 T-cell lymphoma Diseases 0.000 description 1
- 208000027585 T-cell non-Hodgkin lymphoma Diseases 0.000 description 1
- 208000024770 Thyroid neoplasm Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- LXRZVMYMQHNYJB-UNXOBOICSA-N [(1R,2S,4R)-4-[[5-[4-[(1R)-7-chloro-1,2,3,4-tetrahydroisoquinolin-1-yl]-5-methylthiophene-2-carbonyl]pyrimidin-4-yl]amino]-2-hydroxycyclopentyl]methyl sulfamate Chemical compound CC1=C(C=C(S1)C(=O)C1=C(N[C@H]2C[C@H](O)[C@@H](COS(N)(=O)=O)C2)N=CN=C1)[C@@H]1NCCC2=C1C=C(Cl)C=C2 LXRZVMYMQHNYJB-UNXOBOICSA-N 0.000 description 1
- PDKXJKWLFFZPPF-UHFFFAOYSA-N [dimethylamino-(3-oxidotriazolo[4,5-b]pyridin-3-ium-1-yl)methylidene]-dimethylazanium Chemical compound C1=CC=C2N(C(N(C)C)=[N+](C)C)N=[N+]([O-])C2=N1 PDKXJKWLFFZPPF-UHFFFAOYSA-N 0.000 description 1
- CSCPPACGZOOCGX-WFGJKAKNSA-N acetone d6 Chemical compound [2H]C([2H])([2H])C(=O)C([2H])([2H])[2H] CSCPPACGZOOCGX-WFGJKAKNSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 201000011040 acute kidney failure Diseases 0.000 description 1
- YKIOKAURTKXMSB-UHFFFAOYSA-N adams's catalyst Chemical compound O=[Pt]=O YKIOKAURTKXMSB-UHFFFAOYSA-N 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 125000004450 alkenylene group Chemical group 0.000 description 1
- BHELZAPQIKSEDF-UHFFFAOYSA-N allyl bromide Chemical compound BrCC=C BHELZAPQIKSEDF-UHFFFAOYSA-N 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 239000001099 ammonium carbonate Substances 0.000 description 1
- 235000012501 ammonium carbonate Nutrition 0.000 description 1
- 229940035676 analgesics Drugs 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000002917 arthritic effect Effects 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 238000002820 assay format Methods 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- VZOVOHRDLOYBJX-UHFFFAOYSA-N benzyl 4-oxopiperidine-1-carboxylate Chemical compound C1CC(=O)CCN1C(=O)OCC1=CC=CC=C1 VZOVOHRDLOYBJX-UHFFFAOYSA-N 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 238000001574 biopsy Methods 0.000 description 1
- IPWKHHSGDUIRAH-UHFFFAOYSA-N bis(pinacolato)diboron Chemical compound O1C(C)(C)C(C)(C)OB1B1OC(C)(C)C(C)(C)O1 IPWKHHSGDUIRAH-UHFFFAOYSA-N 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 239000000168 bronchodilator agent Substances 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 230000004709 cell invasion Effects 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- DGLFSNZWRYADFC-UHFFFAOYSA-N chembl2334586 Chemical compound C1CCC2=CN=C(N)N=C2C2=C1NC1=CC=C(C#CC(C)(O)C)C=C12 DGLFSNZWRYADFC-UHFFFAOYSA-N 0.000 description 1
- 230000035605 chemotaxis Effects 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 208000020832 chronic kidney disease Diseases 0.000 description 1
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 description 1
- 208000019425 cirrhosis of liver Diseases 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- GBRBMTNGQBKBQE-UHFFFAOYSA-L copper;diiodide Chemical compound I[Cu]I GBRBMTNGQBKBQE-UHFFFAOYSA-L 0.000 description 1
- 229960001334 corticosteroids Drugs 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- HXSNGAHNYZBZTH-UHFFFAOYSA-N cyclopropylmethanamine;hydrochloride Chemical compound Cl.NCC1CC1 HXSNGAHNYZBZTH-UHFFFAOYSA-N 0.000 description 1
- 230000003436 cytoskeletal effect Effects 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 238000001212 derivatisation Methods 0.000 description 1
- 210000004207 dermis Anatomy 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- IEJIGPNLZYLLBP-UHFFFAOYSA-N dimethyl carbonate Chemical compound COC(=O)OC IEJIGPNLZYLLBP-UHFFFAOYSA-N 0.000 description 1
- 210000002889 endothelial cell Anatomy 0.000 description 1
- 210000002919 epithelial cell Anatomy 0.000 description 1
- IEMGWBMVQLVHEY-UHFFFAOYSA-N ethyl 2-(3-amino-6,7-dihydro-5h-cyclopenta[b]pyridin-7-yl)acetate Chemical compound NC1=CN=C2C(CC(=O)OCC)CCC2=C1 IEMGWBMVQLVHEY-UHFFFAOYSA-N 0.000 description 1
- PQJJJMRNHATNKG-UHFFFAOYSA-N ethyl bromoacetate Chemical compound CCOC(=O)CBr PQJJJMRNHATNKG-UHFFFAOYSA-N 0.000 description 1
- VEUUMBGHMNQHGO-UHFFFAOYSA-N ethyl chloroacetate Chemical compound CCOC(=O)CCl VEUUMBGHMNQHGO-UHFFFAOYSA-N 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 210000002950 fibroblast Anatomy 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 238000010363 gene targeting Methods 0.000 description 1
- 208000005017 glioblastoma Diseases 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 201000010536 head and neck cancer Diseases 0.000 description 1
- 238000000589 high-performance liquid chromatography-mass spectrometry Methods 0.000 description 1
- 235000003642 hunger Nutrition 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
- 150000002431 hydrogen Chemical group 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 238000000099 in vitro assay Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 102000006495 integrins Human genes 0.000 description 1
- 108010044426 integrins Proteins 0.000 description 1
- 230000009545 invasion Effects 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000000468 ketone group Chemical group 0.000 description 1
- 231100000518 lethal Toxicity 0.000 description 1
- 230000001665 lethal effect Effects 0.000 description 1
- 210000000265 leukocyte Anatomy 0.000 description 1
- 229940065725 leukotriene receptor antagonists for obstructive airway diseases Drugs 0.000 description 1
- 125000003564 m-cyanobenzyl group Chemical group [H]C1=C([H])C(=C([H])C(C#N)=C1[H])C([H])([H])* 0.000 description 1
- 125000000040 m-tolyl group Chemical group [H]C1=C([H])C(*)=C([H])C(=C1[H])C([H])([H])[H] 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
- 206010061289 metastatic neoplasm Diseases 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- KUGLDBMQKZTXPW-NUBCRITNSA-N methyl (2r)-2-amino-3-methylbutanoate;hydrochloride Chemical compound Cl.COC(=O)[C@H](N)C(C)C KUGLDBMQKZTXPW-NUBCRITNSA-N 0.000 description 1
- BKNZVLSJCYPDLJ-UHFFFAOYSA-N methyl 2-amino-2-(oxan-4-yl)acetate;hydrochloride Chemical compound Cl.COC(=O)C(N)C1CCOCC1 BKNZVLSJCYPDLJ-UHFFFAOYSA-N 0.000 description 1
- WNGSYXVSSXGSPQ-HSZRJFAPSA-N methyl N-[4-[8-[(2R)-2-[[2-fluoro-5-(trifluoromethyl)benzoyl]amino]-3-methylbutanoyl]-3-methyl-4-oxo-1,3,8-triazaspiro[4.5]decan-1-yl]phenyl]carbamate Chemical compound COC(NC1=CC=C(C=C1)N1CN(C(C11CCN(CC1)C([C@@H](C(C)C)NC(C1=C(C=CC(=C1)C(F)(F)F)F)=O)=O)=O)C)=O WNGSYXVSSXGSPQ-HSZRJFAPSA-N 0.000 description 1
- XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical compound COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 230000001617 migratory effect Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- 230000014399 negative regulation of angiogenesis Effects 0.000 description 1
- 230000004770 neurodegeneration Effects 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 239000012285 osmium tetroxide Substances 0.000 description 1
- 229910000489 osmium tetroxide Inorganic materials 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- 125000003544 oxime group Chemical group 0.000 description 1
- 125000006505 p-cyanobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C#N)C([H])([H])* 0.000 description 1
- 201000002528 pancreatic cancer Diseases 0.000 description 1
- 208000008443 pancreatic carcinoma Diseases 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 230000004963 pathophysiological condition Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 229940081066 picolinic acid Drugs 0.000 description 1
- FSDNTQSJGHSJBG-UHFFFAOYSA-N piperidine-4-carbonitrile Chemical compound N#CC1CCNCC1 FSDNTQSJGHSJBG-UHFFFAOYSA-N 0.000 description 1
- LZMJNVRJMFMYQS-UHFFFAOYSA-N poseltinib Chemical compound C1CN(C)CCN1C(C=C1)=CC=C1NC1=NC(OC=2C=C(NC(=O)C=C)C=CC=2)=C(OC=C2)C2=N1 LZMJNVRJMFMYQS-UHFFFAOYSA-N 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 description 1
- 229910000105 potassium hydride Inorganic materials 0.000 description 1
- 230000002206 pro-fibrotic effect Effects 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000000770 proinflammatory effect Effects 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- AOJFQRQNPXYVLM-UHFFFAOYSA-N pyridin-1-ium;chloride Chemical compound [Cl-].C1=CC=[NH+]C=C1 AOJFQRQNPXYVLM-UHFFFAOYSA-N 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000007634 remodeling Methods 0.000 description 1
- 201000002793 renal fibrosis Diseases 0.000 description 1
- 239000013557 residual solvent Substances 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 238000011808 rodent model Methods 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
- XIIOFHFUYBLOLW-UHFFFAOYSA-N selpercatinib Chemical compound OC(COC=1C=C(C=2N(C=1)N=CC=2C#N)C=1C=NC(=CC=1)N1CC2N(C(C1)C2)CC=1C=NC(=CC=1)OC)(C)C XIIOFHFUYBLOLW-UHFFFAOYSA-N 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- XGVXKJKTISMIOW-ZDUSSCGKSA-N simurosertib Chemical compound N1N=CC(C=2SC=3C(=O)NC(=NC=3C=2)[C@H]2N3CCC(CC3)C2)=C1C XGVXKJKTISMIOW-ZDUSSCGKSA-N 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 210000000329 smooth muscle myocyte Anatomy 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000037351 starvation Effects 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000003419 tautomerization reaction Methods 0.000 description 1
- WNZBTQWYOPZLNF-UHFFFAOYSA-N tert-butyl 1-(4-methoxycarbonylphenyl)-2-methyl-4-oxo-1,3,10-triazaspiro[4.5]decane-8-carboxylate Chemical compound C(C)(C)(C)OC(=O)C1CNC2(C(NC(N2C2=CC=C(C=C2)C(=O)OC)C)=O)CC1 WNZBTQWYOPZLNF-UHFFFAOYSA-N 0.000 description 1
- LVYVGVJPTGKRSM-UHFFFAOYSA-N tert-butyl 3-(methylsulfonyloxymethyl)azetidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CC(COS(C)(=O)=O)C1 LVYVGVJPTGKRSM-UHFFFAOYSA-N 0.000 description 1
- VMKIXWAFFVLJCK-UHFFFAOYSA-N tert-butyl 3-oxoazetidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CC(=O)C1 VMKIXWAFFVLJCK-UHFFFAOYSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- INQOMBQAUSQDDS-FIBGUPNXSA-N trideuterio(iodo)methane Chemical compound [2H]C([2H])([2H])I INQOMBQAUSQDDS-FIBGUPNXSA-N 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 230000005751 tumor progression Effects 0.000 description 1
- 210000005166 vasculature Anatomy 0.000 description 1
- 230000007998 vessel formation Effects 0.000 description 1
- GTLDTDOJJJZVBW-UHFFFAOYSA-N zinc cyanide Chemical compound [Zn+2].N#[C-].N#[C-] GTLDTDOJJJZVBW-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/10—Spiro-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/538—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with carbocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/69—Boron compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/04—Antipruritics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/025—Boronic and borinic acid compounds
Definitions
- ATX Autotaxin
- LPC Lysophosphatidylcholine
- LPA Lysophosphatidic Acid
- LPA Low-power plasma phosphatidylcholine
- IPF Idiopathic Pulmonary Fibrosis
- thrombosis thrombosis
- cholestatic pruritus which are caused, mediated and/or propagated by increased LPA levels and/or activation of ATX.
- Fibrotic diseases are chronic, debilitating and often lethal pathologies driven by a dysregulated response to tissue or organ injury. Fibrosis can develop in the liver, kidney, lung, dermis, vasculature, gut and other sites. Fibrosis develops due to action of pathways including growth factors, cytokines, integrin and lipids.
- ATX, LPA, and LPA Receptor (LPAR) pathways have been implicated in fibrotic disease.
- profiling studies show increased levels of ATX, LPA and LPARs in various rodent models of fibrosis and in human patient fluids and biopsy tissue.
- LPA can induce proliferative, survival, and chemotactic responses in transformed cell lines, indicating that LPA may exert pro-inflammatory and pro-fibrotic responses in cells known to be critical in fibrotic disease, including: fibroblasts, smooth muscle cells, macrophages, epithelial and endothelial cells, and leukocytes.
- Gene-targeted mouse models have implicated LPARs in fibrosis pathogenesis.
- Inhibitors of LPARs indicate that antagonism of receptors within this pathway blocked or reversed fibrosis in the lung, liver, kidney and skin in rodents.
- Cell type-specific gene targeting studies have showed that ATX plays a role in the development of lung fibrosis and inflammatory arthritis.
- ATX and LPA have also been implicated in tumor progression and metastasis.
- ATX may be responsible for increased LPA levels in ascites and plasma of ovarian cancer patients since ATX converts LPC to LPA.
- Increased levels of LPA, altered receptor expression and altered responses to LPA may contribute to initiation, progression or outcome of ovarian cancer.
- LPA has also been linked to prostate, breast, melanoma, head and neck, bowel, brain and thyroid cancers.
- LPA has been shown to promote tumor cell survival, proliferation, invasion and migration into neighboring tissues, which can result in the formation of metastases. Additionally, LPA promotes cytoskeletal remodeling that may enhance migratory and invasive properties of cells, which may contribute to cancer metastasis. These biological and pathobiological processes of LPA are initiated through the activation of G-protein coupled receptors.
- Transcriptome analyses of more than 350 normal tissues and more than 1700 malignant tissues demonstrate that ATX is expressed in a variety of carcinomas and sarcomas, underscoring the potential contribution of LPA to metastatic disease.
- LPA levels when treating patients with diseases, such as cancer, lymphocyte homing, chronic inflammation, neuropathic pain, fibrotic diseases, thrombosis, and cholestatic pruritus it is desirable to lower LPA levels. This can be accomplished through inhibition of enzymes involved in LPA biosynthesis, such as ATX.
- ATX is expressed in tumors and affects tumor cell proliferation and invasion into neighboring tissues both of which can lead to the formation of metastases
- ATX is a target for anti-tumor therapy.
- ATX taken with other anti-angiogenetic factors, brings about blood vessel formation.
- Angiogenesis supplies tumors with nutrients during tumor growth. Therefore, inhibition of angiogenesis is a target for anti-tumor therapy, leading to starvation of a tumor.
- ATX has also been implicated in nerve injury-induced neuropathic pain.
- LPA biosynthesis, through ATX, is the source of LPA for LPA1 receptor-mediated neuropathic pain. Therefore, targeted inhibition of ATX-mediated LPA biosynthesis may represent a novel treatment to prevent nerve injury-induced neuropathic pain.
- WO2013061297 WO2012166415, US20120100592, WO2012024620, WO2011116867, WO2011017350, WO2011006569, WO2010115491, WO2010115491, WO2010112124, WO2010112116, WO2010063352, US20100016258, and WO2009151644.
- ATX inhibitors having the potential to reach the clinic and obtain regulatory approval for use in the treatment and/or prophylaxis of physiological and/or pathophysiological conditions, such as cancer, lymphocyte homing, chronic inflammation, neuropathic pain, fibrotic diseases, thrombosis, and cholestatic pruritus which are caused, mediated and/or propagated by increased LPA levels and/or the activation of ATX.
- physiological and/or pathophysiological conditions such as cancer, lymphocyte homing, chronic inflammation, neuropathic pain, fibrotic diseases, thrombosis, and cholestatic pruritus which are caused, mediated and/or propagated by increased LPA levels and/or the activation of ATX.
- the present invention includes certain substituted compounds described herein, their salts, preparations thereof, pharmaceutical compositions and formulations thereof, and methods of treating disease such as cancers therewith.
- the present invention includes compounds of Formula I and pharmaceutically acceptable salts thereof:
- X 1 is selected from C 1-2alkyl , C ⁇ O, NR 3 , or O
- X 2 is selected from C 1-2alkyl , C ⁇ O, NR 3 , or O
- X 3 is selected from C 1-2alkyl , C ⁇ O, NR 3 , O or CR 10 R 11
- R 1 , R 2 , R 2a , R 4 , R 10 and R 11 are each independently optionally substituted
- m and n are each independently selected from 0, 1 or 2. Any of the above can be further substituted.
- Compounds of Formula I inhibit ATX.
- compounds of the present invention are inhibitors of ATX. In some embodiments, compounds of the present invention are selective inhibitors of ATX.
- the present invention includes a method for the treatment of at least one of cancer, lymphocyte homing, chronic inflammation, neuropathic pain, fibrotic diseases, thrombosis, and cholestatic pruritus comprising administering to a subject in need thereof a therapeutically effective amount of a compound or salt of the compound of Formula I that binds to and inhibits ATX providing a reduction in LPA levels.
- Embodiments of the present invention include the compounds herein, pharmaceutically acceptable salts thereof, any physical forms thereof including solvates and hydrates, preparation of the compounds, intermediates, and pharmaceutical compositions and formulations thereof.
- the present invention concerns compounds and salts thereof of Formula I, as shown below and defined herein.
- X 1 and X 2 are each independently selected from one or more of C 1-2alkyl , C ⁇ O, NR 3 , or O;
- X 3 is independently selected from one or more of C 1-2alkyl , C ⁇ O, NR 3 , O, or CR 10 R 11 ;
- n are each independently selected from 0, 1 or 2;
- R 1 is selected from C 0-12 alkyl-, C 3-12 cycloalkyl-C 0-12 alkyl-, C 3-12 heterocycloalkyl-C 0-12 alkyl-, aryl-C 0-12 alkyl-, aryl-C 3-12 cycloalkyl-, aryl-C 3-12 heterocycloalkyl-, heteroaryl-C 0-12 alkyl-, heteroaryl-C 3-12 cycloalkyl-, or heteroaryl-C 3-12 heterocycloalkyl-, any of which is optionally substituted with one or more independent G 1 substituents;
- R 2 is selected from C 0-12 alkyl-, C 3-12 cycloalkyl-C 0-12 alkyl-, C 3-12 heterocycloalkyl-C 0-12 alkyl-, aryl-C 0-12 alkyl-, aryl-C 3-12 cycloalkyl-, aryl-C 3-12 heterocycloalkyl-, heteroaryl-C 0-12 alkyl-, heteroaryl-C 3-12 cycloalkyl-, or heteroaryl-C 3-12 heterocycloalkyl-, any of which is optionally substituted with one or more independent G 2 substituents;
- R 2a is selected from C 0-12 alkyl-, C 3-12 cycloalkyl-C 0-12 alkyl-, C 3-12 heterocycloalkyl-C 0-12 alkyl-, aryl-C 0-12 alkyl-, aryl-C 3-12 cycloalkyl-, aryl-C 3-12 heterocycloalkyl-, heteroaryl-C 0-12 alkyl-, heteroaryl-C 3-12 cycloalkyl-, or heteroaryl-C 3-12 heterocycloalkyl-, any of which is optionally substituted with one or more independent G 2a substituents;
- R 2 and R 2a are each independently a linear structure, or, R 2 and R 2a are taken together with the carbon atom to which they are attached to form a 3-12 membered saturated or unsaturated ring, wherein said ring optionally includes one or more additional heteroatoms selected from O, N, or S(O) m1 ;
- R 3 is selected from C 0-12 alkyl-, C 3-12 cycloalkyl-C 0-12 alkyl-, C 3-12 heterocycloalkyl-C 0-12 alkyl-, aryl-C 0-12 alkyl-, aryl-C 3-12 cycloalkyl-, aryl-C 3-12 heterocycloalkyl-, heteroaryl-C 0-12 alkyl-, heteroaryl-C 3-12 cycloalkyl-, or heteroaryl-C 3-12 heterocycloalkyl-, any of which is optionally substituted with one or more independent G 3 substituents;
- R 4 is selected from C 0-12 alkyl-, C 3-12 cycloalkyl-C 0-12 alkyl-, C 3-12 heterocycloalkyl-C 0-12 alkyl-, aryl-C 0-12 alkyl-, aryl-C 3-12 cycloalkyl-, aryl-C 3-12 heterocycloalkyl-, heteroaryl-C 0-12 alkyl-, heteroaryl-C 3-12 cycloalkyl-, heteroaryl-C 3-12 heterocycloalkyl-, or pyridine-N-oxide, any of which is optionally substituted with one or more independent G 4 substituents;
- G 1 , G 2 , G 2a , G 3 , and G 4 are each independently selected from one or more of H, D, halo, —CN, —CD 3 , —OCD 3 , -oxo-, —CF 3 , —OCF 3 , —OCHF 2 , —NR 5 R 6 , —NO 2 , —B(OH) 2 , —PO(OR 12 ) 2 , —PO(OR 12 )R 13 , —CONR 12 OH, —C 0-12 alkyl, —C 2-12 alkenyl, —C 2-12 alkynyl, C 3-12 cycloalkyl-C 0-12 alkyl-, C 3-12 heterocycloalkyl-C 0-12 alkyl-, aryl-C 0-12 alkyl-, heteroaryl-C 0-12 alkyl-, —OC 0-12 alkyl, —S(O) n1 R 12 ,
- Q 1 is selected from H, D, halo, —CN, —CD 3 , —OCD 3 , -oxo-, —CF 3 , —OCF 3 , —OCHF 2 , —NO 2 , —B(OH) 2 , —PO(OR 17 ) 2 , —PO(OR 17 )R 18 , NR 17 R 18 , —CONR 17 OH, C 0-12 alkyl-, —C 2-12 alkenyl, —C 2-12 alkynyl, aryl-C 0-12 alkyl-, heteroaryl-C 0-12 alkyl-, C 3-12 cycloalkyl-C 0-12 alkyl-, C 3-12 heterocycloalkyl-C 0-12 alkyl-, aryl-C 0-12 cycloalkyl-, heteroaryl-C 3-12 cycloalkyl-, C 3-12 heterocycloalkyl-C 0-12 alkyl-,
- Q 2 is selected from one or more of H, D, halo, —CN, -oxo-, —CD 3 , —OCD 3 , —CF 3 , —OCF 3 , —OCHF 2 , —NO 2 , —B(OH) 2 , —PO(OR 27 ) 2 , —PO(OR 27 )R 28 , —CONR 27 OH, —CONR 27 R 28 C 0-12 alkyl-, —C 2-12 alkenyl, —C 2-12 alkynyl, —OC 0-12 alkyl, aryl-C 0-12 alkyl-, heteroaryl-C 0-12 alkyl-, C 3-12 cycloalkyl-C 0-12 alkyl-, C 3-12 heterocycloalkyl-C 0-12 alkyl-, aryl-C 0-12 cycloalkyl-, heteroaryl-C 3-12 cycloalkyl-, C 3-12 heterocycl
- R 5 , R 6 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , and R 16 are each independently selected from one or more of H, C 1-6 alkyl-, C 3-8 cycloalkyl-C 0-6 alkyl-, C 3-8 heterocycloalkyl-C 0-6 alkyl-, aryl-C 0-6 alkyl-, aryl-C 3-8 cycloalkyl-, aryl-C 3-8 heterocycloalkyl-, heteroaryl-C 1-6 alkyl-, heteroaryl-C 3-8 cycloalkyl- or heteroaryl-C 3-8 heterocycloalkyl-, any of which may be optionally substituted;
- R 17 , R 18 , R 19 , R 20 , R 21 , R 27 , R 28 , R 29 , and R 30 are each independently selected from H, C 1-6 alkyl-, C 3-8 cycloalkyl-C 0-6 alkyl-, C 3-8 heterocycloalkyl-C 0-6 alkyl-, aryl-C 0-6 -alkyl-, aryl-C 3-8 cycloalkyl-, aryl-C 3-8 heterocycloalkyl-, heteroaryl-C 1-6 alkyl-, heteroaryl-C 3-8 cycloalkyl- or heteroaryl-C 3-8 heterocycloalkyl-, any of which may be optionally substituted;
- —NR 5 R 6 and —NR 12 R 13 are each independently a linear structure, or, R 5 and R 6 , or R 12 and R 13 respectively, are taken together with the nitrogen atom to which they are attached to form a 3-12 membered saturated or unsaturated ring, wherein said ring optionally includes one or more additional heteroatoms selected from O, N, or S(O) m2 ;
- —CR 10 R 11 and —CR 14 R 15 are each independently a linear structure, or, R 10 and R 11 , or R 14 and R 15 respectively, are taken together with the carbon atom to which they are attached to form a 3-12 membered saturated or unsaturated ring, wherein said ring optionally includes one or more heteroatoms selected from O, N, or S(O) m3 ;
- R 19 R 20 is a linear structure, or, R 19 and R 20 are taken together with the carbon atom to which they are attached to form a 3-12 membered saturated or unsaturated ring, wherein said ring optionally includes one or more additional heteroatoms selected from O, N, or S(O) m4 ;
- —NR 17 R 18 is a linear structure, or, R 17 and R 18 are taken together with the nitrogen atom to which they are attached to form a 3-12 membered saturated or unsaturated ring, wherein said ring optionally includes one or more additional heteroatoms selected from O, N, or S(O) m5 ;
- CR 29 R 30 is a linear structure, or, R 29 and R 30 are taken together with the carbon atom to which they are attached to form a 3-12 membered saturated or unsaturated ring, wherein said ring optionally includes one or more additional heteroatoms selected from O, N, or S(O) m6 ;
- —NR 27 R 28 is a linear structure, or, R 27 and R 28 are taken together with the nitrogen atom to which they are attached to form a 3-12 membered saturated or unsaturated ring, wherein said ring optionally includes one or more additional heteroatoms selected from O, N, or S(O) m7 ;
- n1, n2, n3, n4, n5 and n6 are each independently selected from 0, 1 or 2;
- R 1 is selected from one of C 3-8 cycloalkyl-C 0-8 alkyl-, C 3-8 heterocycloalkyl-C 0-8 alkyl-, aryl-C 0-8 alkyl-, or heteroaryl-C 0-8 alkyl-;
- G 1 is selected from one of H, halo, —CN, -oxo-, —CF 3 , —OCF 3 , —OCHF 2 , —NR 5 R 6 , —NO 2 , —OC 0-8 alkyl, —S(O) n1 R 12 , —B(OH) 2 , —C 0-8 alkyl, —C 2-8 alkenyl, —C 2-8 alkynyl, C 3-8 cycloalkyl-C 0-8 alkyl-, C 3-8 heterocycloalkyl-C 0-8 alkyl-, aryl-C 0-8 alkyl-, or heteroaryl-C 0-8 -alkyl-.
- G 1 is selected from 0 to 3 of H, halo, —CN, -oxo-, —CF 3 , —OCF 3 , —OCHF 2 , —NR 5 R 6 , —NO 2 , —OC 0-8 alkyl, —S(O) n1 R 12 , —B(OH) 2 , —C 0-8 alkyl, —C 2-8 alkenyl, —C 2-8 alkynyl, C 3-8 cycloalkyl-C 0-8 alkyl-, C 3-8 heterocycloalkyl-C 0-8 alkyl-, aryl-C 0-8 alkyl-, or heteroaryl-C 0-8 alkyl-.
- R 2 is selected from C 0-8 alkyl-, C 3-8 cycloalkyl-C 0-8 alkyl-, or C 3-8 heterocycloalkyl-C 0-8 alkyl-;
- R 2a is C 0-8 alkyl-
- G 2 is selected from one or more of H, halo, —CN, —CD 3 , —OCD 3 , —CF 3 , —OCF 3 , —OCHF 2 , or —OC 0-8 alkyl;
- R 2 and R 2a are each independently a linear structure, or, R 2 and R 2a are taken together with the carbon atom to which they are attached to form a 3-12 membered saturated or unsaturated ring, wherein said ring optionally includes one or more additional heteroatoms selected from O, or N.
- G 2 is selected from 0 to 3 of H, halo, —CN, —CD 3 , —OCD 3 , —CF 3 , —OCF 3 , —OCHF 2 , or —OC 0-8 alkyl.
- R 3 is selected from C 0-8 alkyl-, C 3-8 cycloalkyl-C 0-8 alkyl-, or C 3-8 heterocycloalkyl-C 0-8 alkyl-;
- G 3 is selected from one or more of H, D, halo, —CN, —CD 3 , —OCD 3 , -oxo-, —CF 3 , —OCF 3 , —OCHF 2 , —NR 5 R 6 , —C 0-8 alkyl, —C 2-8 alkenyl, —C 2-8 alkynyl, —C 0-8 alkyl, —S(O) n1 R 12 , —C(O)R 12 , —C(O)NR 12 R 13 , or —C(O)OR 12 .
- G 3 is selected from 0 to 3 of H, D, halo, —CN, —CD 3 , —OCD 3 , -oxo-, —CF 3 , —OCF 3 , —OCHF 2 , —NR 5 R 6 , —C 0-8 alkyl, —C 2-8 alkenyl, —C 2-8 alkynyl, —OC 0-8 alkyl, —S(O) n1 R 12 , —C(O)R 12 , —C(O)NR 12 R 13 , or —C(O)OR 12 .
- R 4 is selected from C 0-8 alkyl-, C 3-8 cycloalkyl-C 3-8 alkyl-, C 3-8 heterocycloalkyl-C 0-8 alkyl-, aryl-C 0-8 alkyl-, heteroaryl-C 0-8 alkyl-, heteroaryl-C 3-8 cycloalkyl-, heteroaryl-C 3-8 heterocycloalkyl-, or pyridine-N-oxide;
- G 4 is selected from one or more of H, D, halo, —CN, —CD 3 , —OCD 3 , -oxo-, —CF 3 , —OCF 3 , —OCHF 2 , —NR 5 R 6 , —NO 2 , —B(OH) 2 , —CONR 12 OH, —C 0-8 alkyl, C 3-8 cycloalkyl-C 0-8 alkyl-, C 3-8 heterocycloalkyl-C 0-8 alkyl-, aryl-C 0-8 alkyl-, heteroaryl-C 0-8 alkyl-, —OC 0-8 alkyl, —S(O) n1 R 12 , —C(O)R 12 , —C(O)NR 12 R 13 , —C(O)—C(O)NR 12 R 13 , —C(O)OR 12 , —C(O)—C(O)OR 12 ,
- G 4 is selected from 0 to 3 of H, D, halo, —CN, —CD 3 , —OCD 3 , -oxo-, —CF 3 , —OCF 3 , —OCHF 2 , —NR 5 R 6 , —NO 2 , —B(OH) 2 , —CONR 12 OH, —C 0-8 alkyl, C 3-8 cycloalkyl-C 0-8 alkyl-, C 3-8 heterocycloalkyl-C 0-8 alkyl-, aryl-C 0-6 -alkyl-, heteroaryl-C 0-8 alkyl-, —OC 0-8 alkyl, —S(O) n R 12 , —C(O)R 12 , —C(O)NR 12 R 13 , —C(O)—C(O)NR 12 R 13 , —C(O)OR 12 , —C(O)—C(O)OR 12
- Q 1 is selected from H, D, halo, —CN, —CD 3 , —OCD 3 , -oxo-, —CF 3 , —OCF 3 , —OCHF 2 , NR 17 R 18 , C 0-8 alkyl-, aryl-C 0-8 alkyl-, heteroaryl-C 0-8 alkyl-, C 3-8 cycloalkyl-C 0-8 alkyl-, C 3-8 heterocycloalkyl-C 0-8 alkyl-, aryl-C 0-8 cycloalkyl-, heteroaryl-C 3-8 cycloalkyl-, C 3-8 heterocycloalkyl-C 3-8 cycloalkyl-, C 3-8 heterocycloalkyl-C 3-8 cycloalkyl-, C 3-8 cycloalkyl-C 3-8 cycloalkyl-, C 1-8 alkyl-C 3-8 heterocycloalkyl-, C 3-8 heterocycl
- R 1 is selected from one of C 3-6 cycloalkyl-C 0-6 alkyl-, C 3-6 heterocycloalkyl-C 0-6 alkyl-, aryl-C 0-6 alkyl-, or heteroaryl-C 0-6 alkyl-;
- G 1 is selected from one of H, halo, —CN, -oxo-, —CF 3 , —OCF 3 , —OCHF 2 , —NR 5 R 6 , —NO 2 , —OC 0-6 alkyl, —S(O) n1 R 12 , —B(OH) 2 , —C 0-6 alkyl, —C 2-6 alkenyl, —C 2-6 alkynyl, C 3-6 cycloalkyl-C 0-6 alkyl-, C 3-6 heterocycloalkyl-C 0-6 alkyl-, aryl-C 0-6 alkyl-, or heteroaryl-C 0-6 alkyl-.
- G 1 is selected from 0 to 2 of H, halo, —CN, -oxo-, —CF 3 , —OCF 3 , —OCHF 2 , —NR 5 R 5 , —NO 2 , —OC 0-6 alkyl, —S(O) n1 R 12 , —B(OH) 2 , —C 0-6 alkyl, —C 2-6 alkenyl, —C 2-6 alkynyl, C 3-6 cycloalkyl-C 0-6 alkyl-, C 3-6 heterocycloalkyl-C 0-6 alkyl-, aryl-C 0-6 alkyl-, or heteroaryl-C 0-6 alkyl-.
- R 2 is selected from C 0-6 alkyl-, C 3-6 cycloalkyl-C 0-6 alkyl-, or C 3-6 heterocycloalkyl-C 0-6 alkyl-;
- R 2a is C 0-6 alkyl-
- G 2 is selected from one or more of H, halo, —CN, —CD 3 , —OCD 3 , —CF 3 , —OCF 3 , —OCHF 2 , or —OC 0-6 alkyl;
- R 2 and R 2a are each independently a linear structure, or, R 2 and R 2a are taken together with the carbon atom to which they are attached to form a 3-12 membered saturated or unsaturated ring, wherein said ring optionally includes one or more additional heteroatoms selected from O, or N.
- R 2 and R 2a are each independently a linear structure, or, R 2 and R 2a are taken together with the carbon atom to which they are attached to form a 4-6 membered saturated or unsaturated ring, wherein said ring optionally includes one or more additional heteroatoms selected from O, or N.
- G 2 is selected from 0 to 2 of H, halo, —CN, —CD 3 , —OCD 3 , —CF 3 , —OCF 3 , —OCHF 2 , or —OC 0-6 alkyl.
- R 3 is selected from C 0-6 alkyl-, C 3-6 cycloalkyl-C 0-6 alkyl-, or C 3-6 heterocycloalkyl-C 0-6 alkyl-;
- G 3 is selected from one or more of H, D, halo, —CN, —CD 3 , —OCD 3 , -oxo-, —CF 3 , —OCF 3 , —OCHF 2 , —NR 5 R 6 , —C 0-6 alkyl, —C 2-6 alkenyl, —C 2-6 alkynyl, —OC 0-6 alkyl, —S(O) n1 R 12 , —C(O)R 12 , —C(O)NR 12 R 13 , or —C(O)OR 12 .
- G 3 is selected from 0 to 2 of H, D, halo, —CN, —CD 3 , —OCD 3 , -oxo-, —CF 3 , —OCF 3 , —OCHF 2 , —NR 5 R 6 , —C 0-6 alkyl, —C 2-6 alkenyl, —C 2-6 alkynyl, —OC 0-6 alkyl, —S(O) n1 R 12 , —C(O)R 12 , —C(O)NR 12 R 13 , or —C(O)OR 12 .
- R 4 is selected from C 0-6 alkyl-, C 3-6 cycloalkyl-C 0-6 alkyl-, C 3-6 heterocycloalkyl-C 0-6 alkyl-, aryl-C 0-6 alkyl-, heteroaryl-C 0-6 alkyl-, heteroaryl-C 3-6 cycloalkyl-, heteroaryl-C 3-6 heterocycloalkyl-, or pyridine-N-oxide;
- G 4 is selected from one or more of H, D, halo, —CN, —CD 3 , —OCD 3 , -oxo-, —CF 3 , —OCF 3 , —OCHF 2 , —NR 5 R 6 , —NO 2 , —B(OH) 2 , —CONR 12 OH, —C 0-6 alkyl, C 3-6 cycloalkyl-C 0-6 alkyl-, C 3-6 heterocycloalkyl-C 0-6 alkyl-, aryl-C 0-6 alkyl-, heteroaryl-C 0-6 alkyl-, —OC 0-6 alkyl, —S(O) n1 R 12 , —C(O)R 12 , —C(O)NR 12 R 13 , —C(O)—C(O)NR 12 R 13 , —C(O)OR 12 , —C(O)—C(O)OR 12 ,
- G 4 is selected from 0 to 2 of H, D, halo, —CN, —CD 3 , —OCD 3 , -oxo-, —CF 3 , —OCF 3 , —OCHF 2 , —NR 5 R 6 , —NO 2 , —B(OH) 2 , —CONR 12 OH, —C 0-6 alkyl, C 3-6 cycloalkyl-C 0-6 alkyl-, C 3-6 heterocycloalkyl-C 0-6 alkyl-aryl-C 0-6 alkyl-, heteroaryl-C 0-6 alkyl-, —OC 0-6 alkyl, —S(O) n1 R 12 , —C(O)R 12 , —C(O)NR 12 R 13 , —C(O)—C(O)NR 12 R 13 , —C(O)OR 12 , —C(O)—C(O)OR 12 , —
- Q 1 is selected from H, D, halo, —CN, —CD 3 , —OCD 3 , -oxo-, —CF 3 , —OCF 3 , —OCHF 2 , NR 17 R 18 , C 0-6 alkyl-, aryl-C 0-6 alkyl-, heteroaryl-C 0-6 alkyl-, C 3-6 cycloalkyl-C 0-6 alkyl-, C 3-6 heterocycloalkyl-C 0-6 alkyl-, aryl-C 0-6 cycloalkyl-, heteroaryl-C 3-6 cycloalkyl-, C 3-6 heterocycloalkyl-C 3-6 cycloalkyl-, C 3-6 heterocycloalkyl-C 3-6 cycloalkyl-, C 3-6 cycloalkyl-C 3-6 cycloalkyl-, C 0-6 alkyl-C 3-6 heterocycloalkyl-, C 3-6 hetero
- R 2 is selected from methyl, ethyl, propyl, isopropyl, or one of the following groups:
- R 2a is selected H, methyl, ethyl, propyl, isopropyl; or
- R 2 and R 2a are taken together with the carbon atom to which they are attached to form one of the following groups:
- R is selected from one of C 6 cycloalkyl-C 0-6 alkyl-, C 6 heterocycloalkyl-C 0-6 alkyl-, 6-membered-aryl-C 0-6 alkyl-, or 6-membered-heteroaryl-C 0-6 alkyl-,
- R 1 wherein the 4-position of R 1 is hydrogen, and wherein R 1 is optionally substituted by one or more G 1 substituents at the 2, 3, 5 and 6 positions.
- —NR 5 R 6 and —NR 12 R 13 are each independently a linear structure, or, R 5 and R 6 , or R 12 and R 13 , respectively, are taken together with the nitrogen atom to which they are attached to form a 4-8 membered saturated or unsaturated ring, wherein said ring optionally includes one or more additional heteroatoms selected from O, N, or S(O) m2 ;
- —CR 10 R 11 and —CR 14 R 15 are each independently a linear structure, or, R 10 and R 11 , or R 14 and R 15 respectively, are taken together with the carbon atom to which they are attached to form a 4-8 membered saturated or unsaturated ring, wherein said ring optionally includes one or more heteroatoms selected from O, N, or S(O) m3 ;
- R 19 R 20 is a linear structure, or, R 19 and R 20 are taken together with the carbon atom to which they are attached to form a 4-8 membered saturated or unsaturated ring, wherein said ring optionally includes one or more additional heteroatoms selected from O, N, or S(O) m4 ;
- —NR 17 R 18 is a linear structure, or, R 17 and R 18 are taken together with the nitrogen atom to which they are attached to form a 4-8 membered saturated or unsaturated ring, wherein said ring optionally includes one or more additional heteroatoms selected from O, N, or S(O) m5 ;
- CR 29 R 30 is a linear structure, or, R 29 and R 30 are taken together with the carbon atom to which they are attached to form a 4-8 membered saturated or unsaturated ring, wherein said ring optionally includes one or more additional heteroatoms selected from O, N, or S(O) m6 ;
- —NR 27 R 28 is a linear structure, or, R 27 and R 28 are taken together with the nitrogen atom to which they are attached to form a 4-8 membered saturated or unsaturated ring, wherein said ring optionally includes one or more additional heteroatoms selected from O, N, or S(O) m7 ;
- m2, m3, m4, m5, m6, and m7 are each independently selected from 0, 1 or 2.
- compounds of the present invention are a subgenus of Formula I, having the Formula Ia:
- X 3 is selected from C ⁇ O, or CR 10 R 11 .
- R 2a is hydrogen.
- R 2 is C 1-12 alkyl-, C 3-12 cycloalkyl-, or C 1-12 heteroalkyl any of which is optionally substituted with one or more independent G 2 substituents (e.g., methyl, ethyl, iso-propyl, sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl).
- R 1 is aryl or heteroaryl, any of which is optionally substituted with one or more independent G 1 substituents.
- R 1 is aryl.
- the 4-position of said aryl is H, and wherein the 2, 3, 5 and 6 positions of said aryl are optionally substituted by one or more G 1 substituents.
- said 2, 3, 5, and 6 positions are optionally substituted with halo (e.g., fluoro, chloro, bromo), C 1-6 alkyl (e.g., methyl, ethyl, CF 3 ), C 1-6 heteroalkyl (e.g., methoxy, trifluoromethoxy), or C 3-6 cycloalkyl (e.g., cyclopropyl).
- halo e.g., fluoro, chloro, bromo
- C 1-6 alkyl e.g., methyl, ethyl, CF 3
- C 1-6 heteroalkyl e.g., methoxy, trifluoromethoxy
- C 3-6 cycloalkyl e.g., cyclopropyl
- R 1 is 3-methyl-phenyl, 3-methyl-4-fluoro-phenyl, 2-fluoro-5-ethyl-phenyl, 2-fluoro-5-trifluoromethyl-phenyl, 3-fluoro-5-methyl-phenyl, 2-fluoro-5-cyclopropyl-phenyl, 2-fluoro-5-chloro-phenyl, 3,5-dichloro-phenyl, 2-fluoro-5-methyl-phenyl, 3-chloro-5-trifluoromethyl-phenyl, 2-fluoro-5-trifluromethoxy-phenyl, 2-fluoro-5-difluoromethoxy-phenyl, 3-fluoro-5-ethyl-phenyl, 3-cyclopropyl, 3-ethyl-phenyl, 2-fluoro-3-methyl-phenyl, or 2-fluoro-5-methoxy-phenyl.
- R 3 is C 1-12 alkyl or C 1-12 heteroalkyl. In certain embodiments of Formula Ia, R 3 is C 1-12 alkyl (e.g., methyl,
- R 3 is C 1-12 heteroalkyl
- R 4 is C 1-12 alkyl (e.g., iso-butyl), C 3-8 cycloalkyl (e.g., cyclopentyl or cyclohexyl), aryl (e.g., phenyl, 4-methoxy-phenyl, 3-fluoro-4-methoxy-phenyl, 4-cyano-phenyl, 3-cyano-phenyl, 3-methoxy-phenyl, 4-trifluoromethoxy-phenyl, 3-chloro-phenyl, 3-bromo-phenyl, 4-deutero-phenyl, 4-trifluoromethyl-phenyl, 4-carboxy-phenyl, 4-chloro-phenyl, 4-fluoro-phenyl, 4-methyl-phenyl, 3,4-dichloro-phenyl, 4-ethoxy-phenyl, 4-trideuteromethoxy-phenyl, 4-carboxymethyl-phenyl, 4-(oxe
- X 3 is C ⁇ O. In other embodiments of Formula Ia, X 3 is CR 10 R 11 wherein R 10 is hydrogen and R 11 is hydrogen or methyl.
- compounds of the present invention are a subgenus of Formula I, having the Formula Ih:
- X 3 is selected from C ⁇ O, or CR 10 R 11 .
- the 4-position of the phenyl ring in Formula Ih is H, and wherein the 2, 3, 5 and 6 positions of the phenyl ring in Formula Ih are optionally substituted by one or more G 1 substituents.
- R 3 is selected from methyl, ethyl, propyl, isopropyl, —(CH 2 ) 1-3 -cyclopropyl, C 3-8 cycloalkyl, —(CH 2 ) 1-3 CN, —(CH 2 ) 1-3 C(O)OH, or —(CH 2 ) 1-3 S(O) 2 Me.
- X 1 is selected from C 1-2alkyl or C ⁇ O;
- X 2 is selected from C 1-2alkyl , NR 3 , or O;
- R 10 and R 11 are each independently equal to H or C 1-6 alkyl
- n are each equal to 1.
- the compounds of Formula I are inhibitors of ATX.
- the compound of Formula I is any one of the compounds described herein (e.g., any one of the compounds described in Examples 1 to 246)
- the present invention includes a pharmaceutical composition comprising the compound or salt of any one of the compounds of Formula I, formulated with or without one or more pharmaceutical carriers.
- the present invention includes a method for the treatment of at least one of cancer, lymphocyte homing, chronic inflammation, neuropathic pain, fibrotic diseases, thrombosis, and cholestatic pruritus mediated at least in part by ATX comprising administering to a subject in need thereof a therapeutically effective amount of a compound or salt of the compound of Formula I.
- the present invention includes a method for the treatment of at least one of cancer, lymphocyte homing, chronic inflammation, neuropathic pain, fibrotic diseases, thrombosis, and cholestatic pruritus comprising administering to a subject in need thereof a therapeutically effective amount of a compound or salt of the compound of Formula I that binds to and inhibits ATX providing a reduction in LPA levels.
- the present invention includes a method of treating fibrosis, inflammation, cancer, angiogenesis, or pain in a mammal comprising administering a therapeutically effective amount of a compound according to Formula I, or a pharmaceutically acceptable salt thereof, to the mammal in need thereof.
- the present invention includes a method of treating lung fibrosis, asthma, chronic obstructive pulmonary disease (COPD), renal fibrosis, acute kidney injury, chronic kidney disease, liver fibrosis, skin fibrosis, fibrosis of the gut, breast cancer, pancreatic cancer, ovarian cancer, prostate cancer, glioblastoma, bone cancer, colon cancer, bowel cancer, head and neck cancer, melanoma, multiple myeloma, chronic lymphocytic leukemia, B cell lymphoma, T cell lymphoma, cancer pain, tumor metastasis, transplant organ rejection, scleroderma, ocular fibrosis, age related macular degeneration (AMD), diabetic retinopathy, collagen vascular disease, atherosclerosis, Raynaud's phenomenom, rheumatoid arthritis, osteoarthritis or neuropathic pain in a mammal comprising administering a therapeutically effective amount of a compound according Formula I
- COPD
- the present invention further includes administering to the mammal one or more additional therapeutically active agents selected from: corticosteroids, immunosuppressants, analgesics, anti-cancer agents, anti-inflammatories, non-steroidal anti-inflammatories, dual cyclooxygenase-1 and -2 inhibitors, cyclooxygenase-2 selective inhibitors, TNF ⁇ blockers, kinase inhibitors, chemokine receptor antagonists, bronchodilators, leukotriene receptor antagonists, leukotriene formation inhibitors, prostaglandin receptor antagonists, prostaglandin formation inhibitors, monoacylglycerol kinase inhibitors, phospholipase A1 inhibitors, phospholipase A2 inhibitors, lysophospholipase D (lysoPLD) inhibitors, autotaxin inhibitors, and LPA receptor antagonists.
- additional therapeutically active agents selected from: corticosteroids, immunosuppressants, analgesics
- compounds are present as a material in substantially pure form.
- compounds are selected from any one of the Examples herein or a pharmaceutically acceptable salt thereof.
- variable definition above includes any subset thereof and the compounds of Formula I include any combination of such variables or variable subsets.
- the present invention includes the compounds and salts thereof, their physical forms, preparation of the compounds, useful intermediates, and pharmaceutical compositions and formulations thereof.
- the compounds of the present invention and the term “compound” in the claims include any pharmaceutically acceptable salts or solvates, and any amorphous or crystal forms, or tautomers, whether or not specifically recited in context.
- the present invention includes all isomers of the compounds.
- Compounds may have one or more asymmetric carbon atoms can exist as two or more stereoisomers.
- a compound of the invention contains an alkenyl or alkenylene group
- geometric cis/trans (or Z/E) isomers are possible.
- the compound contains, for example, a keto or oxime group or an aromatic moiety
- tautomeric isomerism (‘tautomerism’) can occur.
- a single compound may exhibit more than one type of isomerism.
- the present invention includes any stereoisomers, even if not specifically shown, individually as well as mixtures, geometric isomers, and pharmaceutically acceptable salts thereof. Where a compound or stereocenter is described or shown without definitive stereochemistry, it is to be taken to embrace all possible individual isomers, configurations, and mixtures thereof. Thus, a material sample containing a mixture of stereoisomers would be embraced by a recitation of either of the stereoisomers or a recitation without definitive stereochemistry. Also contemplated are any cis/trans isomers or tautomers of the compounds described.
- the present invention includes all stereoisomers, geometric isomers and tautomeric forms of the inventive compounds, including compounds exhibiting more than one type of isomerism, and mixtures of one or more thereof.
- the compound of Formula I of the present invention includes any possible tautomers and pharmaceutically acceptable salts thereof, and mixtures thereof, except where specifically stated otherwise.
- R 1 , R 2 , R 2a , R 3 , R 4 , X 3 , m and n are as previously described for a compound of Formula I.
- R 1 , R 2 , R 2a , R 3 , R 4 , R 10 , R 11 , m and n are as previously described for a compound of Formula I.
- R 1 , R 2 , R 2a , X 1 -X 3 , G 4 , m and n are as previously described for a compound of Formula I and wherein E99 is equal to 0, 1, 2, or 3.
- R 1 , R 2 , R 2a , R 3 , R 4 , m and n are as previously described for a compound of Formula I.
- R 1 , R 2 , R 2a , X 1 -X 3 , G 4 , m and n are as previously described for a compound of Formula I, wherein Y 1 -Y 4 and Z 1 -Z 6 are each independently selected from one or more of C 0-2 alkyl, O, N or S and wherein E99 is equal to 0, 1, 2, or 3.
- R 1 , R 2 , R 2a , R 3 , G 4 , m and n are as previously described for a compound of Formula I, wherein Y 1 -Y 4 and Z 1 -Z 6 are each independently selected from one or more of C 0-2 alkyl, O, N or S and wherein E99 is equal to 0, 1, 2, or 3.
- R 1 , R 2 , R 2a , R 3 , R 10 , R 11 , G 4 , m and n are as previously described for a compound of Formula I, wherein Y 1 -Y 4 and Z 1 -Z 6 are each independently selected from one or more of C 0-2 alkyl, O, N or S and wherein E99 is equal to 0, 1, 2, or 3.
- R 2 , R 2a , R 3 , R 4 , X 3 , G 1 , m and n are as previously described for a compound of Formula I.
- R 2 , R 2a , R 3 , R 4 , R 10 , R 11 , G 1 , m and n are as previously described for a compound of Formula I.
- R 2 , R 2a , X 1 -X 3 , G 1 , G 4 , m and n are as previously described for a compound of Formula I and wherein E99 is equal to 0, 1, 2, or 3.
- R 2 , R 2a , R 3 , R 4 , G 1 , m and n are as previously described for a compound of Formula I.
- R 2 , R 2a , X 1 -X 3 , G 1 , G 4 , m and n are as previously described for a compound of Formula I, wherein Y 1 -Y 4 and Z 1 -Z 6 are each independently selected from one or more of C 0-2 alkyl, O, N or S and wherein E99 is equal to 0, 1, 2, or 3.
- R 2 , R 2a , R 3 , G 1 , G 4 , m and n are as previously described for a compound of Formula I, wherein Y 1 -Y 4 and Z 1 -Z 6 are each independently selected from one or more of C 0-2 alkyl, O, N or S and wherein E99 is equal to 0, 1, 2, or 3.
- R 2 , R 2a , R 3 , R 10 , R 11 , G 1 , G 4 , m and n are as previously described for a compound of Formula I, wherein Y 1 -Y 4 and Z 1 -Z 6 are each independently selected from one or more of C 0-2 alkyl, O, N or S and E99 is equal to 0, 1, 2, or 3.
- Compounds of the present invention include the intermediates, examples, and synthetic methods described herein.
- the compounds of Formula I may be prepared by the methods described below, together with synthetic methods known in the art of organic chemistry, or modifications and derivatizations that are familiar to those of ordinary skill in the art.
- the starting materials used herein are commercially available or may be prepared by routine methods known in the art [such as those methods disclosed in standard reference books such as the Compendium of Organic Synthetic Methods, Vol. I-VI (Wiley-Interscience); or the Comprehensive Organic Transformations, by R. C. Larock (Wiley-Interscience)].
- Preferred methods include, but are not limited to, those described below.
- any of the following synthetic sequences it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This can be achieved by means of conventional protecting groups, such as those described in T. W. Greene, Protective Groups in Organic Chemistry, John Wiley & Sons, 1981; T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Chemistry, John Wiley & Sons, 1991, and T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Chemistry, John Wiley & Sons, 1999, which are hereby incorporated by reference.
- conventional protecting groups such as those described in T. W. Greene, Protective Groups in Organic Chemistry, John Wiley & Sons, 1981; T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Chemistry, John Wiley & Sons, 1991, and T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Chemistry, John Wiley & Sons, 1999
- a compound of Formula II and IIa were reacted under suitable amide coupling conditions.
- HATU in the presence of diisopropylethyl amine (DIPEA) can be used.
- DIPEA diisopropylethyl amine
- Suitable solvents for use in the above process included, but were not limited to, ethers such as THF, glyme, and the like; DMF; DMSO; MeCN; halogenated solvents such as chloroform or DCM.
- Suitable solvents for use in the above process include, but are not limited to, ethers such as THF, glyme, and the like; DMF; DMSO; MeCN; halogenated solvents such as chloroform or DCM.
- mixtures of these solvents may be used, however the preferred solvents were DCM and DMF.
- the above process was carried out at temperatures between about 0° C. and about 100° C. Preferably, the reaction was carried out at or about rt. The above process was preferably carried out at about atmospheric pressure although higher or lower pressures may be used if desired. Substantially equimolar amounts of reactants were preferably used although higher or lower amounts may be used if desired.
- Suitable solvents for use in this process included, but were not limited to, ethers such as THF, glyme, and the like; DMF; DMSO; MeCN; halogenated solvents such as chloroform or DCM; or alcohols or water. If desired, mixtures of these solvents may be used, however the preferred solvent was DCM.
- ethers such as THF, glyme, and the like
- DMF dimethyl sulfate
- MeCN dimethyl methoxymethyl methoxymethyl methoxymethyl methoxymethyl methoxymethyl ether
- halogenated solvents such as chloroform or DCM
- alcohols or water e.glyl alcohols or water.
- mixtures of these solvents may be used, however the preferred solvent was DCM.
- the above process was carried out at temperatures between about ⁇ 20° C. and about 40° C.
- the reaction was carried out between 0° C. and 25° C.
- the above process to produce was preferably carried out at about atmospheric pressure
- Substantially equimolar amounts of compounds of Formula III and IV and base and sub-stoichiometric amounts of DMAP were preferably used although higher or lower amounts may be used if desired.
- other suitable reaction conditions for the conversion of a carboxylic acid derived compound such as compound of Formula II to an amide such as compound of Formula I can be found in Larock, R. C. Comprehensive Organic Transformations, 2nd ed.; Wiley and Sons: New York, 1999, pp 1941-1949.
- Compounds of Formula III and IV as well as IIa are either commercially available, are synthesized by known chemical procedures or are described in detail within.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Organic Chemistry (AREA)
- Epidemiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Immunology (AREA)
- Pulmonology (AREA)
- Dermatology (AREA)
- Rheumatology (AREA)
- Urology & Nephrology (AREA)
- Hematology (AREA)
- Oncology (AREA)
- Pain & Pain Management (AREA)
- Physical Education & Sports Medicine (AREA)
- Neurology (AREA)
- Vascular Medicine (AREA)
- Gastroenterology & Hepatology (AREA)
- Ophthalmology & Optometry (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Transplantation (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Diabetes (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
Description
- This application claims the benefit under 35 U.S.C. 119(e) of U.S. Provisional Patent Application No. 61/975,123 filed on Apr. 4, 2014 and entitled “Substituted Spirocyclic Inhibitors Of Autotaxin And Their Preparation And Use In The Treatment Of LPA-Dependent Or LPA-Mediated Diseases.” The entire contents of the above-referenced application is incorporated herein by reference.
- Autotaxin (ATX) is a secreted enzyme of the ectonucleotide pyro-phosphatase/phosphodiesterase family, and is also known as Ectonucleotide Pyrophosphatase/Phosphodiesterase 2 (ENPP-2 or NPP2). ATX plays a role in driving pathological conditions, including fibrosis, arthritic inflammation, neurodegeneration, neuropathic pain, and cancer. ATX is the fundamental regulator of the conversion of Lysophosphatidylcholine (LPC) to Lysophosphatidic Acid (LPA). LPA is a bioactive lipid that affects migration, proliferation, and survival of various cell types.
- Inhibition of ATX has been shown to reduce LPA levels in pathological settings. Reduction of LPA may provide therapeutic benefits in diseases with unmet medical need, including cancer, lymphocyte homing, chronic inflammation, neuropathic pain, fibrotic diseases such as Idiopathic Pulmonary Fibrosis (IPF), thrombosis, and cholestatic pruritus which are caused, mediated and/or propagated by increased LPA levels and/or activation of ATX.
- Fibrotic diseases are chronic, debilitating and often lethal pathologies driven by a dysregulated response to tissue or organ injury. Fibrosis can develop in the liver, kidney, lung, dermis, vasculature, gut and other sites. Fibrosis develops due to action of pathways including growth factors, cytokines, integrin and lipids.
- ATX, LPA, and LPA Receptor (LPAR) pathways have been implicated in fibrotic disease. For example, profiling studies show increased levels of ATX, LPA and LPARs in various rodent models of fibrosis and in human patient fluids and biopsy tissue. LPA can induce proliferative, survival, and chemotactic responses in transformed cell lines, indicating that LPA may exert pro-inflammatory and pro-fibrotic responses in cells known to be critical in fibrotic disease, including: fibroblasts, smooth muscle cells, macrophages, epithelial and endothelial cells, and leukocytes. Gene-targeted mouse models have implicated LPARs in fibrosis pathogenesis. Inhibitors of LPARs indicate that antagonism of receptors within this pathway blocked or reversed fibrosis in the lung, liver, kidney and skin in rodents. Cell type-specific gene targeting studies have showed that ATX plays a role in the development of lung fibrosis and inflammatory arthritis.
- ATX and LPA have also been implicated in tumor progression and metastasis. ATX may be responsible for increased LPA levels in ascites and plasma of ovarian cancer patients since ATX converts LPC to LPA. Increased levels of LPA, altered receptor expression and altered responses to LPA may contribute to initiation, progression or outcome of ovarian cancer. LPA has also been linked to prostate, breast, melanoma, head and neck, bowel, brain and thyroid cancers.
- LPA has been shown to promote tumor cell survival, proliferation, invasion and migration into neighboring tissues, which can result in the formation of metastases. Additionally, LPA promotes cytoskeletal remodeling that may enhance migratory and invasive properties of cells, which may contribute to cancer metastasis. These biological and pathobiological processes of LPA are initiated through the activation of G-protein coupled receptors.
- Transcriptome analyses of more than 350 normal tissues and more than 1700 malignant tissues demonstrate that ATX is expressed in a variety of carcinomas and sarcomas, underscoring the potential contribution of LPA to metastatic disease.
- Accordingly, when treating patients with diseases, such as cancer, lymphocyte homing, chronic inflammation, neuropathic pain, fibrotic diseases, thrombosis, and cholestatic pruritus it is desirable to lower LPA levels. This can be accomplished through inhibition of enzymes involved in LPA biosynthesis, such as ATX.
- Since ATX is expressed in tumors and affects tumor cell proliferation and invasion into neighboring tissues both of which can lead to the formation of metastases, ATX is a target for anti-tumor therapy. Moreover, in angiogenesis, ATX, taken with other anti-angiogenetic factors, brings about blood vessel formation. Angiogenesis supplies tumors with nutrients during tumor growth. Therefore, inhibition of angiogenesis is a target for anti-tumor therapy, leading to starvation of a tumor.
- ATX has also been implicated in nerve injury-induced neuropathic pain. LPA biosynthesis, through ATX, is the source of LPA for LPA1 receptor-mediated neuropathic pain. Therefore, targeted inhibition of ATX-mediated LPA biosynthesis may represent a novel treatment to prevent nerve injury-induced neuropathic pain.
- Various publications refer to compounds that are capable of inhibiting ATX, including: WO2013061297, WO2012166415, US20120100592, WO2012024620, WO2011116867, WO2011017350, WO2011006569, WO2010115491, WO2010115491, WO2010112124, WO2010112116, WO2010063352, US20100016258, and WO2009151644.
- Accordingly, there remains a need for ATX inhibitors having the potential to reach the clinic and obtain regulatory approval for use in the treatment and/or prophylaxis of physiological and/or pathophysiological conditions, such as cancer, lymphocyte homing, chronic inflammation, neuropathic pain, fibrotic diseases, thrombosis, and cholestatic pruritus which are caused, mediated and/or propagated by increased LPA levels and/or the activation of ATX.
- The present invention includes certain substituted compounds described herein, their salts, preparations thereof, pharmaceutical compositions and formulations thereof, and methods of treating disease such as cancers therewith.
- The present invention includes compounds of Formula I and pharmaceutically acceptable salts thereof:
- wherein X1 is selected from C1-2alkyl, C═O, NR3, or O; X2 is selected from C1-2alkyl, C═O, NR3, or O; X3 is selected from C1-2alkyl, C═O, NR3, O or CR10R11; R1, R2, R2a, R4, R10 and R11 are each independently optionally substituted; and m and n are each independently selected from 0, 1 or 2. Any of the above can be further substituted. Compounds of Formula I inhibit ATX.
- In some embodiments, compounds of the present invention are inhibitors of ATX. In some embodiments, compounds of the present invention are selective inhibitors of ATX.
- In some embodiments, the present invention includes a method for the treatment of at least one of cancer, lymphocyte homing, chronic inflammation, neuropathic pain, fibrotic diseases, thrombosis, and cholestatic pruritus comprising administering to a subject in need thereof a therapeutically effective amount of a compound or salt of the compound of Formula I that binds to and inhibits ATX providing a reduction in LPA levels.
- Embodiments of the present invention include the compounds herein, pharmaceutically acceptable salts thereof, any physical forms thereof including solvates and hydrates, preparation of the compounds, intermediates, and pharmaceutical compositions and formulations thereof.
- In some embodiments, the present invention concerns compounds and salts thereof of Formula I, as shown below and defined herein.
- A compound according to Formula I:
- or a pharmaceutically acceptable salt thereof, wherein:
- X1 and X2 are each independently selected from one or more of C1-2alkyl, C═O, NR3, or O;
- X3 is independently selected from one or more of C1-2alkyl, C═O, NR3, O, or CR10R11;
- m and n are each independently selected from 0, 1 or 2;
- R1 is selected from C0-12alkyl-, C3-12cycloalkyl-C0-12alkyl-, C3-12heterocycloalkyl-C0-12alkyl-, aryl-C0-12alkyl-, aryl-C3-12cycloalkyl-, aryl-C3-12heterocycloalkyl-, heteroaryl-C0-12alkyl-, heteroaryl-C3-12cycloalkyl-, or heteroaryl-C3-12heterocycloalkyl-, any of which is optionally substituted with one or more independent G1 substituents;
- R2 is selected from C0-12alkyl-, C3-12cycloalkyl-C0-12alkyl-, C3-12heterocycloalkyl-C0-12alkyl-, aryl-C0-12alkyl-, aryl-C3-12cycloalkyl-, aryl-C3-12heterocycloalkyl-, heteroaryl-C0-12alkyl-, heteroaryl-C3-12cycloalkyl-, or heteroaryl-C3-12heterocycloalkyl-, any of which is optionally substituted with one or more independent G2 substituents;
- R2a is selected from C0-12alkyl-, C3-12cycloalkyl-C0-12alkyl-, C3-12heterocycloalkyl-C0-12alkyl-, aryl-C0-12alkyl-, aryl-C3-12cycloalkyl-, aryl-C3-12heterocycloalkyl-, heteroaryl-C0-12alkyl-, heteroaryl-C3-12cycloalkyl-, or heteroaryl-C3-12heterocycloalkyl-, any of which is optionally substituted with one or more independent G2a substituents;
- R2 and R2a are each independently a linear structure, or, R2 and R2a are taken together with the carbon atom to which they are attached to form a 3-12 membered saturated or unsaturated ring, wherein said ring optionally includes one or more additional heteroatoms selected from O, N, or S(O)m1;
- R3 is selected from C0-12alkyl-, C3-12cycloalkyl-C0-12alkyl-, C3-12heterocycloalkyl-C0-12alkyl-, aryl-C0-12alkyl-, aryl-C3-12cycloalkyl-, aryl-C3-12heterocycloalkyl-, heteroaryl-C0-12alkyl-, heteroaryl-C3-12cycloalkyl-, or heteroaryl-C3-12heterocycloalkyl-, any of which is optionally substituted with one or more independent G3 substituents;
- R4 is selected from C0-12alkyl-, C3-12cycloalkyl-C0-12alkyl-, C3-12heterocycloalkyl-C0-12alkyl-, aryl-C0-12alkyl-, aryl-C3-12cycloalkyl-, aryl-C3-12heterocycloalkyl-, heteroaryl-C0-12alkyl-, heteroaryl-C3-12cycloalkyl-, heteroaryl-C3-12heterocycloalkyl-, or pyridine-N-oxide, any of which is optionally substituted with one or more independent G4 substituents;
- G1, G2, G2a, G3, and G4 are each independently selected from one or more of H, D, halo, —CN, —CD3, —OCD3, -oxo-, —CF3, —OCF3, —OCHF2, —NR5R6, —NO2, —B(OH)2, —PO(OR12)2, —PO(OR12)R13, —CONR12OH, —C0-12alkyl, —C2-12alkenyl, —C2-12alkynyl, C3-12cycloalkyl-C0-12alkyl-, C3-12heterocycloalkyl-C0-12alkyl-, aryl-C0-12alkyl-, heteroaryl-C0-12alkyl-, —OC0-12alkyl, —S(O)n1R12, —C(O)R12, —C(O)NR12R13, —C(O)—C(O)NR12R13, —C(O)OR12, —C(O)—C(O)OR12, —OC(O)R12, —NR12C(O)R13, —NR12C(O)O R, —NR12S(O)R13, —(CR14R15)C(O)R13, —(CR14R15)C(O)OR12, —(CR14R15)C(O)NR12R13, —(CR14R15)n1S(O)2NR12R13, —(CR14R15)n1 NR12R13, —(CR14R15)n1OR12, —(CR14R15)n1S(O)n3R12, —NR16C(O)NR12R13, —NR16S(O)2NR12R13 or —NR16S(O)NR12R13, any of which is optionally substituted with one or more independent Q1 substituents;
- Q1 is selected from H, D, halo, —CN, —CD3, —OCD3, -oxo-, —CF3, —OCF3, —OCHF2, —NO2, —B(OH)2, —PO(OR17)2, —PO(OR17)R18, NR17R18, —CONR17OH, C0-12alkyl-, —C2-12 alkenyl, —C2-12alkynyl, aryl-C0-12alkyl-, heteroaryl-C0-12alkyl-, C3-12cycloalkyl-C0-12alkyl-, C3-12heterocycloalkyl-C0-12alkyl-, aryl-C0-12cycloalkyl-, heteroaryl-C3-12cycloalkyl-, C3-12heterocycloalkyl-C3-12cycloalkyl-, C3-12cycloalkyl-C3-12 cycloalkyl-, C1-12alkyl-C3-12heterocycloalkyl-, C3-12heterocycloalkyl-C3-12heterocycloalkyl-, aryl-C3-12heterocycloalkyl-, heteroaryl-C3-12heterocycloalkyl-, —OC0-12alkyl, —C(O)—C(O)NR17R18, —C(O)—C(O)OR17, —OC(O)R17, —NR17C(O)R18, —NR17S(O)2R18, —(CR19R20)n3C(O)R17, —(CR19R20)n3C(O)OR17, —(CR19R20)n3C(O)NR17R18, —(CR19R20)n3S(O)2NR17R18, —(CR19R20)n3NR17R18, —(CR19R20)n3OR17, —(CR19R20)n3S(O)n4R17, —NR21C(O)NR17R18, —NR21S(O)2NR17R18 or —NR21S(O)NR17R18, any of which is optionally substituted with one or more independent Q2 substituents;
- Q2 is selected from one or more of H, D, halo, —CN, -oxo-, —CD3, —OCD3, —CF3, —OCF3, —OCHF2, —NO2, —B(OH)2, —PO(OR27)2, —PO(OR27)R28, —CONR27OH, —CONR27R28C0-12alkyl-, —C2-12 alkenyl, —C2-12 alkynyl, —OC0-12alkyl, aryl-C0-12alkyl-, heteroaryl-C0-12alkyl-, C3-12cycloalkyl-C0-12alkyl-, C3-12heterocycloalkyl-C0-12alkyl-, aryl-C0-12cycloalkyl-, heteroaryl-C3-12cycloalkyl-, C3-12heterocycloalkyl-C3-12cycloalkyl-, C3-12cycloalkyl-C3-12cycloalkyl-, C1-12alkyl-C3-12heterocycloalkyl-, C3-12heterocycloalkyl-C3-12heterocycloalkyl-, aryl-C3-12heterocycloalkyl-, heteroaryl-C3-12heterocycloalkyl-, —C(O)—C(O)NR27R28, —C0-12alkylC(O)OR27, —C(O)—C(O)OR27, —OC(O)R27, —NR27C(O)R28, —NR27C(O)OR, —NR27S(O)2R28, —(CR29R30)n5C(O)R27, —(CR29R30)n5C(O)OR27, —(CR29R30)n5C(O)NR27R28, —(CR29R30)n5S(O)2NR27R28, —(CR29R30)n5NR27R28, —(CR29R30)n5OR27, —(CR29R30)n5S(O)n6R27, —NR30C(O)NR27R28, —NR30S(O)2NR27R28 or —NR30S(O)NR27R28 substituents, any of which may be optionally substituted;
- R5, R6, R10, R11, R12, R13, R14, R15, and R16 are each independently selected from one or more of H, C1-6alkyl-, C3-8cycloalkyl-C0-6alkyl-, C3-8heterocycloalkyl-C0-6alkyl-, aryl-C0-6alkyl-, aryl-C3-8cycloalkyl-, aryl-C3-8heterocycloalkyl-, heteroaryl-C1-6 alkyl-, heteroaryl-C3-8cycloalkyl- or heteroaryl-C3-8heterocycloalkyl-, any of which may be optionally substituted;
- R17, R18, R19, R20, R21, R27, R28, R29, and R30 are each independently selected from H, C1-6alkyl-, C3-8cycloalkyl-C0-6alkyl-, C3-8heterocycloalkyl-C0-6alkyl-, aryl-C0-6-alkyl-, aryl-C3-8cycloalkyl-, aryl-C3-8heterocycloalkyl-, heteroaryl-C1-6alkyl-, heteroaryl-C3-8cycloalkyl- or heteroaryl-C3-8heterocycloalkyl-, any of which may be optionally substituted;
- —NR5R6 and —NR12R13 are each independently a linear structure, or, R5 and R6, or R12 and R13 respectively, are taken together with the nitrogen atom to which they are attached to form a 3-12 membered saturated or unsaturated ring, wherein said ring optionally includes one or more additional heteroatoms selected from O, N, or S(O)m2;
- —CR10R11 and —CR14R15 are each independently a linear structure, or, R10 and R11, or R14 and R15 respectively, are taken together with the carbon atom to which they are attached to form a 3-12 membered saturated or unsaturated ring, wherein said ring optionally includes one or more heteroatoms selected from O, N, or S(O)m3;
- —CR19R20 is a linear structure, or, R19 and R20 are taken together with the carbon atom to which they are attached to form a 3-12 membered saturated or unsaturated ring, wherein said ring optionally includes one or more additional heteroatoms selected from O, N, or S(O)m4;
- —NR17R18 is a linear structure, or, R17 and R18 are taken together with the nitrogen atom to which they are attached to form a 3-12 membered saturated or unsaturated ring, wherein said ring optionally includes one or more additional heteroatoms selected from O, N, or S(O)m5;
- —CR29R30 is a linear structure, or, R29 and R30 are taken together with the carbon atom to which they are attached to form a 3-12 membered saturated or unsaturated ring, wherein said ring optionally includes one or more additional heteroatoms selected from O, N, or S(O)m6;
- —NR27R28 is a linear structure, or, R27 and R28 are taken together with the nitrogen atom to which they are attached to form a 3-12 membered saturated or unsaturated ring, wherein said ring optionally includes one or more additional heteroatoms selected from O, N, or S(O)m7;
- wherein m1, m2, m3, m4, m5, m6, m7, n1, n2, n3, n4, n5 and n6 are each independently selected from 0, 1 or 2;
- or a pharmaceutically acceptable salt, solvate or a prodrug thereof.
- In some embodiments of Formula I:
- R1 is selected from one of C3-8cycloalkyl-C0-8alkyl-, C3-8heterocycloalkyl-C0-8alkyl-, aryl-C0-8alkyl-, or heteroaryl-C0-8alkyl-;
- G1 is selected from one of H, halo, —CN, -oxo-, —CF3, —OCF3, —OCHF2, —NR5R6, —NO2, —OC0-8alkyl, —S(O)n1R12, —B(OH)2, —C0-8 alkyl, —C2-8alkenyl, —C2-8alkynyl, C3-8cycloalkyl-C0-8alkyl-, C3-8heterocycloalkyl-C0-8alkyl-, aryl-C0-8alkyl-, or heteroaryl-C0-8-alkyl-.
- In some embodiments of Formula I:
- G1 is selected from 0 to 3 of H, halo, —CN, -oxo-, —CF3, —OCF3, —OCHF2, —NR5R6, —NO2, —OC0-8alkyl, —S(O)n1R12, —B(OH)2, —C0-8alkyl, —C2-8alkenyl, —C2-8alkynyl, C3-8cycloalkyl-C0-8alkyl-, C3-8heterocycloalkyl-C0-8alkyl-, aryl-C0-8alkyl-, or heteroaryl-C0-8alkyl-.
- In some embodiments of Formula I:
- R2 is selected from C0-8alkyl-, C3-8cycloalkyl-C0-8alkyl-, or C3-8heterocycloalkyl-C0-8alkyl-;
- R2a is C0-8alkyl-;
- G2 is selected from one or more of H, halo, —CN, —CD3, —OCD3, —CF3, —OCF3, —OCHF2, or —OC0-8alkyl;
- R2 and R2a are each independently a linear structure, or, R2 and R2a are taken together with the carbon atom to which they are attached to form a 3-12 membered saturated or unsaturated ring, wherein said ring optionally includes one or more additional heteroatoms selected from O, or N.
- In some embodiments of Formula I:
- G2 is selected from 0 to 3 of H, halo, —CN, —CD3, —OCD3, —CF3, —OCF3, —OCHF2, or —OC0-8alkyl.
- In some embodiments of Formula I:
- R3 is selected from C0-8alkyl-, C3-8cycloalkyl-C0-8alkyl-, or C3-8heterocycloalkyl-C0-8alkyl-;
- G3 is selected from one or more of H, D, halo, —CN, —CD3, —OCD3, -oxo-, —CF3, —OCF3, —OCHF2, —NR5R6, —C0-8alkyl, —C2-8alkenyl, —C2-8alkynyl, —C0-8alkyl, —S(O)n1R12, —C(O)R12, —C(O)NR12R13, or —C(O)OR12.
- In some embodiments of Formula I:
- G3 is selected from 0 to 3 of H, D, halo, —CN, —CD3, —OCD3, -oxo-, —CF3, —OCF3, —OCHF2, —NR5R6, —C0-8alkyl, —C2-8alkenyl, —C2-8alkynyl, —OC0-8alkyl, —S(O)n1R12, —C(O)R12, —C(O)NR12R13, or —C(O)OR12.
- In some embodiments of Formula I:
- R4 is selected from C0-8alkyl-, C3-8cycloalkyl-C3-8alkyl-, C3-8heterocycloalkyl-C0-8alkyl-, aryl-C0-8alkyl-, heteroaryl-C0-8alkyl-, heteroaryl-C3-8cycloalkyl-, heteroaryl-C3-8heterocycloalkyl-, or pyridine-N-oxide;
- G4 is selected from one or more of H, D, halo, —CN, —CD3, —OCD3, -oxo-, —CF3, —OCF3, —OCHF2, —NR5R6, —NO2, —B(OH)2, —CONR12OH, —C0-8alkyl, C3-8cycloalkyl-C0-8alkyl-, C3-8heterocycloalkyl-C0-8alkyl-, aryl-C0-8alkyl-, heteroaryl-C0-8alkyl-, —OC0-8alkyl, —S(O)n1R12, —C(O)R12, —C(O)NR12R13, —C(O)—C(O)NR12R13, —C(O)OR12, —C(O)—C(O)OR12, —OC(O)R12, —NR12C(O)R13, —NR12C(O)OR3, —(CR14R15)C(O)R13, —(CR14R15)n1S(O)2NR12R13, —(CR14R15)n1NR12R13, —(CR14R15)n1OR12, —(CR14R15)n1S(O)n2R12, or —NR16C(O)NR12R13.
- In some embodiments of Formula I:
- G4 is selected from 0 to 3 of H, D, halo, —CN, —CD3, —OCD3, -oxo-, —CF3, —OCF3, —OCHF2, —NR5R6, —NO2, —B(OH)2, —CONR12OH, —C0-8alkyl, C3-8cycloalkyl-C0-8alkyl-, C3-8heterocycloalkyl-C0-8alkyl-, aryl-C0-6-alkyl-, heteroaryl-C0-8alkyl-, —OC0-8alkyl, —S(O)nR12, —C(O)R12, —C(O)NR12R13, —C(O)—C(O)NR12R13, —C(O)OR12, —C(O)—C(O)OR12, —OC(O)R12, —NR12C(O)R13, —NR12C(O)OR13 (CR14R15)C(O)R13, —(CR14R15)n1S(O)2NR12R13, —(CR14R15)n1NR12R13, —(CR14R15)n1OR12, —(CR14R15)n1S(O)n2R12, or —NR16C(O)NR12R13.
- In some embodiments of Formula I:
- Q1 is selected from H, D, halo, —CN, —CD3, —OCD3, -oxo-, —CF3, —OCF3, —OCHF2, NR17R18, C0-8alkyl-, aryl-C0-8alkyl-, heteroaryl-C0-8alkyl-, C3-8cycloalkyl-C0-8alkyl-, C3-8heterocycloalkyl-C0-8alkyl-, aryl-C0-8cycloalkyl-, heteroaryl-C3-8cycloalkyl-, C3-8heterocycloalkyl-C3-8cycloalkyl-, C3-8cycloalkyl-C3-8cycloalkyl-, C1-8alkyl-C3-8heterocycloalkyl-, C3-8heterocycloalkyl-C3-8heterocycloalkyl-, aryl-C3-8heterocycloalkyl-, heteroaryl-C3-8heterocycloalkyl-, —OC0-8alkyl, —C(O)—C(O)NR17R18, —C(O)—C(O)OR17, —OC(O)R17, —NR17C(O)R18, —NR17S(O)2R18, —(CR19R20)n3C(O)R17, —(CR19R20)n3C(O)OR17, —(CR19R20)n3C(O)NR17R18, —(CR19R20)n3S(O)2NR17R18, —(CR19R20)n3NR17R18, —(CR19R20)n3OR17, —(CR19R20)n3S(O)n4R17, —NR21C(O)NR17R18, —NR21S(O)2NR17R18, or —NR21S(O)NR17R18.
- In some embodiments of Formula I:
- R1 is selected from one of C3-6cycloalkyl-C0-6alkyl-, C3-6heterocycloalkyl-C0-6alkyl-, aryl-C0-6alkyl-, or heteroaryl-C0-6alkyl-;
- G1 is selected from one of H, halo, —CN, -oxo-, —CF3, —OCF3, —OCHF2, —NR5R6, —NO2, —OC0-6alkyl, —S(O)n1R12, —B(OH)2, —C0-6alkyl, —C2-6alkenyl, —C2-6alkynyl, C3-6cycloalkyl-C0-6alkyl-, C3-6heterocycloalkyl-C0-6alkyl-, aryl-C0-6alkyl-, or heteroaryl-C0-6alkyl-.
- In some embodiments of Formula I:
- G1 is selected from 0 to 2 of H, halo, —CN, -oxo-, —CF3, —OCF3, —OCHF2, —NR5R5, —NO2, —OC0-6alkyl, —S(O)n1R12, —B(OH)2, —C0-6alkyl, —C2-6alkenyl, —C2-6alkynyl, C3-6cycloalkyl-C0-6alkyl-, C3-6heterocycloalkyl-C0-6alkyl-, aryl-C0-6alkyl-, or heteroaryl-C0-6alkyl-.
- In some embodiments of Formula I:
- R2 is selected from C0-6alkyl-, C3-6cycloalkyl-C0-6alkyl-, or C3-6heterocycloalkyl-C0-6alkyl-;
- R2a is C0-6alkyl-;
- G2 is selected from one or more of H, halo, —CN, —CD3, —OCD3, —CF3, —OCF3, —OCHF2, or —OC0-6 alkyl;
- R2 and R2a are each independently a linear structure, or, R2 and R2a are taken together with the carbon atom to which they are attached to form a 3-12 membered saturated or unsaturated ring, wherein said ring optionally includes one or more additional heteroatoms selected from O, or N.
- In some embodiments of Formula I:
- R2 and R2a are each independently a linear structure, or, R2 and R2a are taken together with the carbon atom to which they are attached to form a 4-6 membered saturated or unsaturated ring, wherein said ring optionally includes one or more additional heteroatoms selected from O, or N.
- In some embodiments of Formula I:
- G2 is selected from 0 to 2 of H, halo, —CN, —CD3, —OCD3, —CF3, —OCF3, —OCHF2, or —OC0-6alkyl.
- In some embodiments of Formula I:
- R3 is selected from C0-6alkyl-, C3-6cycloalkyl-C0-6alkyl-, or C3-6heterocycloalkyl-C0-6alkyl-;
- G3 is selected from one or more of H, D, halo, —CN, —CD3, —OCD3, -oxo-, —CF3, —OCF3, —OCHF2, —NR5R6, —C0-6alkyl, —C2-6alkenyl, —C2-6alkynyl, —OC0-6alkyl, —S(O)n1R12, —C(O)R12, —C(O)NR12R13, or —C(O)OR12.
- In some embodiments of Formula I:
- G3 is selected from 0 to 2 of H, D, halo, —CN, —CD3, —OCD3, -oxo-, —CF3, —OCF3, —OCHF2, —NR5R6, —C0-6alkyl, —C2-6alkenyl, —C2-6alkynyl, —OC0-6alkyl, —S(O)n1R12, —C(O)R12, —C(O)NR12R13, or —C(O)OR12.
- In some embodiments of Formula I:
- R4 is selected from C0-6alkyl-, C3-6cycloalkyl-C0-6alkyl-, C3-6heterocycloalkyl-C0-6alkyl-, aryl-C0-6alkyl-, heteroaryl-C0-6alkyl-, heteroaryl-C3-6cycloalkyl-, heteroaryl-C3-6heterocycloalkyl-, or pyridine-N-oxide;
- G4 is selected from one or more of H, D, halo, —CN, —CD3, —OCD3, -oxo-, —CF3, —OCF3, —OCHF2, —NR5R6, —NO2, —B(OH)2, —CONR12OH, —C0-6alkyl, C3-6cycloalkyl-C0-6alkyl-, C3-6heterocycloalkyl-C0-6alkyl-, aryl-C0-6alkyl-, heteroaryl-C0-6alkyl-, —OC0-6alkyl, —S(O)n1R12, —C(O)R12, —C(O)NR12R13, —C(O)—C(O)NR12R13, —C(O)OR12, —C(O)—C(O)OR12, —OC(O)R12, —NR12C(O)R13, —NR12C(O)OR13, —(CR14R15)C(O)R13, —(CR14R15)n1S(O)2NR12R13, —(CR14R15)n1NR12R13, —(CR14R15)n1OR12, —(CR14R15)n1S(O)n2R12, or —NR16C(O)NR12R13.
- In some embodiments of Formula I:
- G4 is selected from 0 to 2 of H, D, halo, —CN, —CD3, —OCD3, -oxo-, —CF3, —OCF3, —OCHF2, —NR5R6, —NO2, —B(OH)2, —CONR12OH, —C0-6alkyl, C3-6cycloalkyl-C0-6alkyl-, C3-6heterocycloalkyl-C0-6alkyl-aryl-C0-6alkyl-, heteroaryl-C0-6alkyl-, —OC0-6alkyl, —S(O)n1R12, —C(O)R12, —C(O)NR12R13, —C(O)—C(O)NR12R13, —C(O)OR12, —C(O)—C(O)OR12, —OC(O)R12, —NR12C(O)R13, —NR12C(O)OR13, —(CR14R15)C(O)R13, —(CR14R15)n1S(O)2NR12R13, —(CR14R15)n1NR12R13, —(CR14R15)n1OR12, —(CR14R15)n1S(O)n2R12, or —NR16C(O)NR12R13.
- In some embodiments of Formula I:
- Q1 is selected from H, D, halo, —CN, —CD3, —OCD3, -oxo-, —CF3, —OCF3, —OCHF2, NR17R18, C0-6alkyl-, aryl-C0-6alkyl-, heteroaryl-C0-6alkyl-, C3-6cycloalkyl-C0-6alkyl-, C3-6heterocycloalkyl-C0-6alkyl-, aryl-C0-6cycloalkyl-, heteroaryl-C3-6cycloalkyl-, C3-6heterocycloalkyl-C3-6cycloalkyl-, C3-6cycloalkyl-C3-6cycloalkyl-, C0-6alkyl-C3-6heterocycloalkyl-, C3-6heterocycloalkyl-C3-6heterocycloalkyl-, aryl-C3-6heterocycloalkyl-, heteroaryl-C3-6heterocycloalkyl-, —OC0-6alkyl, —C(O)—C(O)NR17R18, —C(O)—C(O)OR17, —OC(O)R17, —NR17C(O)R18, —NR17S(O)2R18, —(CR19R20)n3C(O)R17, —(CR19R20)n3C(O)OR17, —(CR19R20)n3C(O)NR17R18, —(CR19R20)n3S(O)2NR17R18, —(CR19R20)n3NR17R18, —(CR19R20)n3OR17, —(CR19R20)n3S(O)n4R17, —NR21C(O)NR17R18, —NR21S(O)2NR17R18, or —NR21S(O)NR17R18.
- In some embodiments of Formula I:
- R2 is selected from methyl, ethyl, propyl, isopropyl, or one of the following groups:
- and R2a is selected H, methyl, ethyl, propyl, isopropyl; or
- R2 and R2a are taken together with the carbon atom to which they are attached to form one of the following groups:
- In some embodiments of Formula I:
- R is selected from one of C6cycloalkyl-C0-6alkyl-, C6heterocycloalkyl-C0-6alkyl-, 6-membered-aryl-C0-6alkyl-, or 6-membered-heteroaryl-C0-6alkyl-,
- wherein the 4-position of R1 is hydrogen, and wherein R1 is optionally substituted by one or more G1 substituents at the 2, 3, 5 and 6 positions.
- In some embodiments of Formula I:
- —NR5R6 and —NR12R13 are each independently a linear structure, or, R5 and R6, or R12 and R13, respectively, are taken together with the nitrogen atom to which they are attached to form a 4-8 membered saturated or unsaturated ring, wherein said ring optionally includes one or more additional heteroatoms selected from O, N, or S(O)m2;
- —CR10R11 and —CR14R15 are each independently a linear structure, or, R10 and R11, or R14 and R15 respectively, are taken together with the carbon atom to which they are attached to form a 4-8 membered saturated or unsaturated ring, wherein said ring optionally includes one or more heteroatoms selected from O, N, or S(O)m3;
- —CR19R20 is a linear structure, or, R19 and R20 are taken together with the carbon atom to which they are attached to form a 4-8 membered saturated or unsaturated ring, wherein said ring optionally includes one or more additional heteroatoms selected from O, N, or S(O)m4;
- —NR17R18 is a linear structure, or, R17 and R18 are taken together with the nitrogen atom to which they are attached to form a 4-8 membered saturated or unsaturated ring, wherein said ring optionally includes one or more additional heteroatoms selected from O, N, or S(O)m5;
- —CR29R30 is a linear structure, or, R29 and R30 are taken together with the carbon atom to which they are attached to form a 4-8 membered saturated or unsaturated ring, wherein said ring optionally includes one or more additional heteroatoms selected from O, N, or S(O)m6;
- —NR27R28 is a linear structure, or, R27 and R28 are taken together with the nitrogen atom to which they are attached to form a 4-8 membered saturated or unsaturated ring, wherein said ring optionally includes one or more additional heteroatoms selected from O, N, or S(O)m7;
- wherein m2, m3, m4, m5, m6, and m7 are each independently selected from 0, 1 or 2.
- In some embodiments of Formula I, compounds of the present invention are a subgenus of Formula I, having the Formula Ia:
- wherein X3 is selected from C═O, or CR10R11.
- In some embodiments of Formula Ia, R2a is hydrogen. In other embodiments of Formula Ia, R2 is C1-12alkyl-, C3-12cycloalkyl-, or C1-12heteroalkyl any of which is optionally substituted with one or more independent G2 substituents (e.g., methyl, ethyl, iso-propyl, sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl). In certain embodiments of Formula Ia, R1 is aryl or heteroaryl, any of which is optionally substituted with one or more independent G1 substituents. In other embodiments, of Formula Ia, R1 is aryl. In certain embodiments of Formula Ia, the 4-position of said aryl is H, and wherein the 2, 3, 5 and 6 positions of said aryl are optionally substituted by one or more G1 substituents. In some embodiments of Formula Ia, said 2, 3, 5, and 6 positions are optionally substituted with halo (e.g., fluoro, chloro, bromo), C1-6alkyl (e.g., methyl, ethyl, CF3), C1-6heteroalkyl (e.g., methoxy, trifluoromethoxy), or C3-6cycloalkyl (e.g., cyclopropyl). In some embodiments, R1 is 3-methyl-phenyl, 3-methyl-4-fluoro-phenyl, 2-fluoro-5-ethyl-phenyl, 2-fluoro-5-trifluoromethyl-phenyl, 3-fluoro-5-methyl-phenyl, 2-fluoro-5-cyclopropyl-phenyl, 2-fluoro-5-chloro-phenyl, 3,5-dichloro-phenyl, 2-fluoro-5-methyl-phenyl, 3-chloro-5-trifluoromethyl-phenyl, 2-fluoro-5-trifluromethoxy-phenyl, 2-fluoro-5-difluoromethoxy-phenyl, 3-fluoro-5-ethyl-phenyl, 3-cyclopropyl, 3-ethyl-phenyl, 2-fluoro-3-methyl-phenyl, or 2-fluoro-5-methoxy-phenyl.
- In other embodiments of Formula Ia, R3 is C1-12alkyl or C1-12heteroalkyl. In certain embodiments of Formula Ia, R3 is C1-12alkyl (e.g., methyl,
- In other embodiments of Formula Ia, R3 is C1-12heteroalkyl
- In some embodiments of Formula Ia, R4 is C1-12alkyl (e.g., iso-butyl), C3-8cycloalkyl (e.g., cyclopentyl or cyclohexyl), aryl (e.g., phenyl, 4-methoxy-phenyl, 3-fluoro-4-methoxy-phenyl, 4-cyano-phenyl, 3-cyano-phenyl, 3-methoxy-phenyl, 4-trifluoromethoxy-phenyl, 3-chloro-phenyl, 3-bromo-phenyl, 4-deutero-phenyl, 4-trifluoromethyl-phenyl, 4-carboxy-phenyl, 4-chloro-phenyl, 4-fluoro-phenyl, 4-methyl-phenyl, 3,4-dichloro-phenyl, 4-ethoxy-phenyl, 4-trideuteromethoxy-phenyl, 4-carboxymethyl-phenyl, 4-(oxetan-3-ylmethoxy)-phenyl,4-(2-hydroxyethoxy)-phenyl, 4-boronic acid-phenyl, 3-methoxy-4-carboxy-phenyl, 3-chloro-4-carboxy-phenyl, 4-carboxamide-phenyl, 4-oxyacetic acid-phenyl, 4-oxyacetamide-phenyl, 4-cyanomethyl-phenyl, 4-(2-dimethylamino-ethoxy)-phenyl, 4-acetamido-phenyl, 4-methyl-sulfnamido-phenyl, 4-methylcarbamate phenyl, benzo[d][1,3] dioxol-5-yl, 2-chloro phenyl, 4 methylsulfonyl-phenyl, 3-methyl-1-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl, 4-(oxetan-3-ylamino)-phenyl, 4-(1H-1,2,4-triazol-3-yl)-phenyl, 4-(2H-tetrazol-5-yl)-phenyl) heteroaryl (e.g. 4-pyridyl, 1-methyl-1H-indazol-5-yl, 2-methyl-2H-indazoyl-5-yl, 1-imidazo[1,2a]pyridine-6-yl, 3-methylimidazo[1,5a]pyridine-6-yl, 1H-pyrrolo[2,3b]pyridine-5-yl, 3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl, 1-methyl-6-oxo-1,6-dihydropyridin-3-yl, 5-benzofuranyl, 2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl, 1H-benzo[d][1,2,3]triazol-5-yl, 1H-indazoyl-5-yl, 1H-indol-5-yl, 3-pyridyl) aryl-C1-6alkyl (e.g., 4-cyanobenzyl, benzyl, 4-fluorobenzyl, 4-methoxybenzyl, 4-chlorobenzyl, 3-cyano-benzyl, 3-chloro-benzyl, 2-fluoro-5-methoxy-benzyl, 2-fluoro-4-methoxy-benzyl, 2-chloro-4-methoxy-benzyl), heteroaryl-C1-6alkyl (e.g., (2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-methyl, (6-methoxypyridin-3-yl)-methyl, (quinoxalin-6-yl)-methyl, (3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)-methyl, (pyrimidin-2-yl)-methyl, (2-methylbenzo[d]oxazol-5-yl)-methyl), or C3-12heterocycloalkyl (e.g., 1-methyl-6-oxo-1,6-dihydropyridin-3-yl) any of which is optionally substituted with one or more independent Q1 substituents.
- In some embodiments of Formula Ia, X3 is C═O. In other embodiments of Formula Ia, X3 is CR10R11 wherein R10 is hydrogen and R11 is hydrogen or methyl.
- In some embodiments of Formula I, compounds of the present invention are a subgenus of Formula I, having the Formula Ih:
- wherein X3 is selected from C═O, or CR10R11.
- In some embodiments of Formula I:
- the 4-position of the phenyl ring in Formula Ih is H, and wherein the 2, 3, 5 and 6 positions of the phenyl ring in Formula Ih are optionally substituted by one or more G1 substituents.
- In some embodiments of Formula I:
- R3 is selected from methyl, ethyl, propyl, isopropyl, —(CH2)1-3-cyclopropyl, C3-8cycloalkyl, —(CH2)1-3CN, —(CH2)1-3C(O)OH, or —(CH2)1-3S(O)2Me.
- In some embodiments of Formula I:
- X1 is selected from C1-2alkyl or C═O;
- X2 is selected from C1-2alkyl, NR3, or O;
- X3 is selected from C═O or CR10R11;
- R10 and R11 are each independently equal to H or C1-6alkyl;
- m and n are each equal to 1.
- In some embodiments, the compounds of Formula I are inhibitors of ATX.
- In some embodiments, the compound of Formula I is any one of the compounds described herein (e.g., any one of the compounds described in Examples 1 to 246)
- In some embodiments, the present invention includes a pharmaceutical composition comprising the compound or salt of any one of the compounds of Formula I, formulated with or without one or more pharmaceutical carriers.
- In some embodiments, the present invention includes a method for the treatment of at least one of cancer, lymphocyte homing, chronic inflammation, neuropathic pain, fibrotic diseases, thrombosis, and cholestatic pruritus mediated at least in part by ATX comprising administering to a subject in need thereof a therapeutically effective amount of a compound or salt of the compound of Formula I.
- In some embodiments, the present invention includes a method for the treatment of at least one of cancer, lymphocyte homing, chronic inflammation, neuropathic pain, fibrotic diseases, thrombosis, and cholestatic pruritus comprising administering to a subject in need thereof a therapeutically effective amount of a compound or salt of the compound of Formula I that binds to and inhibits ATX providing a reduction in LPA levels.
- In some embodiments, the present invention includes a method of treating fibrosis, inflammation, cancer, angiogenesis, or pain in a mammal comprising administering a therapeutically effective amount of a compound according to Formula I, or a pharmaceutically acceptable salt thereof, to the mammal in need thereof.
- In some embodiments, the present invention includes a method of treating lung fibrosis, asthma, chronic obstructive pulmonary disease (COPD), renal fibrosis, acute kidney injury, chronic kidney disease, liver fibrosis, skin fibrosis, fibrosis of the gut, breast cancer, pancreatic cancer, ovarian cancer, prostate cancer, glioblastoma, bone cancer, colon cancer, bowel cancer, head and neck cancer, melanoma, multiple myeloma, chronic lymphocytic leukemia, B cell lymphoma, T cell lymphoma, cancer pain, tumor metastasis, transplant organ rejection, scleroderma, ocular fibrosis, age related macular degeneration (AMD), diabetic retinopathy, collagen vascular disease, atherosclerosis, Raynaud's phenomenom, rheumatoid arthritis, osteoarthritis or neuropathic pain in a mammal comprising administering a therapeutically effective amount of a compound according Formula I, or a pharmaceutically acceptable salt thereof, to the mammal in need thereof.
- In some embodiments, the present invention further includes administering to the mammal one or more additional therapeutically active agents selected from: corticosteroids, immunosuppressants, analgesics, anti-cancer agents, anti-inflammatories, non-steroidal anti-inflammatories, dual cyclooxygenase-1 and -2 inhibitors, cyclooxygenase-2 selective inhibitors, TNFα blockers, kinase inhibitors, chemokine receptor antagonists, bronchodilators, leukotriene receptor antagonists, leukotriene formation inhibitors, prostaglandin receptor antagonists, prostaglandin formation inhibitors, monoacylglycerol kinase inhibitors, phospholipase A1 inhibitors, phospholipase A2 inhibitors, lysophospholipase D (lysoPLD) inhibitors, autotaxin inhibitors, and LPA receptor antagonists.
- In some embodiments of Formula I, compounds are present as a material in substantially pure form.
- In some embodiments of Formula I, compounds are selected from any one of the Examples herein or a pharmaceutically acceptable salt thereof.
- Each variable definition above includes any subset thereof and the compounds of Formula I include any combination of such variables or variable subsets.
- The present invention includes the compounds and salts thereof, their physical forms, preparation of the compounds, useful intermediates, and pharmaceutical compositions and formulations thereof.
- The compounds of the present invention and the term “compound” in the claims include any pharmaceutically acceptable salts or solvates, and any amorphous or crystal forms, or tautomers, whether or not specifically recited in context.
- The present invention includes all isomers of the compounds. Compounds may have one or more asymmetric carbon atoms can exist as two or more stereoisomers. Where a compound of the invention contains an alkenyl or alkenylene group, geometric cis/trans (or Z/E) isomers are possible. Where the compound contains, for example, a keto or oxime group or an aromatic moiety, tautomeric isomerism (‘tautomerism’) can occur. A single compound may exhibit more than one type of isomerism.
- The present invention includes any stereoisomers, even if not specifically shown, individually as well as mixtures, geometric isomers, and pharmaceutically acceptable salts thereof. Where a compound or stereocenter is described or shown without definitive stereochemistry, it is to be taken to embrace all possible individual isomers, configurations, and mixtures thereof. Thus, a material sample containing a mixture of stereoisomers would be embraced by a recitation of either of the stereoisomers or a recitation without definitive stereochemistry. Also contemplated are any cis/trans isomers or tautomers of the compounds described.
- The present invention includes all stereoisomers, geometric isomers and tautomeric forms of the inventive compounds, including compounds exhibiting more than one type of isomerism, and mixtures of one or more thereof. When a tautomer of the compound of Formula I exists, the compound of Formula I of the present invention includes any possible tautomers and pharmaceutically acceptable salts thereof, and mixtures thereof, except where specifically stated otherwise.
- In an embodiment, a compound according to Formula I and above embodiments is provided, wherein the compound of Formula I is represented by the compound of Formula Ia:
- wherein R1, R2, R2a, R3, R4, X3, m and n are as previously described for a compound of Formula I.
- In an embodiment, a compound according to Formula I and above embodiments is provided, wherein the compound of Formula I is represented by the compound of Formula Ib:
- wherein R1, R2, R2a, R3, R4, R10, R11, m and n are as previously described for a compound of Formula I.
- In an embodiment, a compound according to Formula I and above embodiments is provided, wherein the compound of Formula I is represented by the compound of Formula Ic:
- wherein R1, R2, R2a, X1-X3, G4, m and n are as previously described for a compound of Formula I and wherein E99 is equal to 0, 1, 2, or 3.
- In an embodiment, a compound according to Formula I and above embodiments is provided, wherein the compound of Formula I is represented by the compound of Formula Id:
- wherein R1, R2, R2a, R3, R4, m and n are as previously described for a compound of Formula I.
- In an embodiment, a compound according to Formula I and above embodiments is provided, wherein the compound of Formula I is represented by the compound of Formula Ie:
- wherein R1, R2, R2a, X1-X3, G4, m and n are as previously described for a compound of Formula I, wherein Y1-Y4 and Z1-Z6 are each independently selected from one or more of C0-2alkyl, O, N or S and wherein E99 is equal to 0, 1, 2, or 3.
- In an embodiment, a compound according to Formula I and above embodiments is provided, wherein the compound of Formula I is represented by the compound of Formula If:
- wherein R1, R2, R2a, R3, G4, m and n are as previously described for a compound of Formula I, wherein Y1-Y4 and Z1-Z6 are each independently selected from one or more of C0-2alkyl, O, N or S and wherein E99 is equal to 0, 1, 2, or 3.
- In an embodiment, a compound according to Formula I and above embodiments is provided, wherein the compound of Formula I is represented by the compound of Formula Ig:
- wherein R1, R2, R2a, R3, R10, R11, G4, m and n are as previously described for a compound of Formula I, wherein Y1-Y4 and Z1-Z6 are each independently selected from one or more of C0-2alkyl, O, N or S and wherein E99 is equal to 0, 1, 2, or 3.
- In an embodiment, a compound according to Formula I and above embodiments is provided, wherein the compound of Formula I is represented by the compound of Formula Ih:
- wherein R2, R2a, R3, R4, X3, G1, m and n are as previously described for a compound of Formula I.
- In an embodiment, a compound according to Formula I and above embodiments is provided, wherein the compound of Formula I is represented by the compound of Formula Ii:
- wherein R2, R2a, R3, R4, R10, R11, G1, m and n are as previously described for a compound of Formula I.
- In an embodiment, a compound according to Formula I and above embodiments is provided, wherein the compound of Formula I is represented by the compound of Formula Ij:
- wherein R2, R2a, X1-X3, G1, G4, m and n are as previously described for a compound of Formula I and wherein E99 is equal to 0, 1, 2, or 3.
- In an embodiment, a compound according to Formula I and above embodiments is provided, wherein the compound of Formula I is represented by the compound of Formula Ik:
- wherein R2, R2a, R3, R4, G1, m and n are as previously described for a compound of Formula I.
- In an embodiment, a compound according to Formula I and above embodiments is provided, wherein the compound of Formula I is represented by the compound of Formula Il:
- wherein R2, R2a, X1-X3, G1, G4, m and n are as previously described for a compound of Formula I, wherein Y1-Y4 and Z1-Z6 are each independently selected from one or more of C0-2alkyl, O, N or S and wherein E99 is equal to 0, 1, 2, or 3.
- In an embodiment, a compound according to Formula I and above embodiments is provided, wherein the compound of Formula I is represented by the compound of Formula Im:
- wherein R2, R2a, R3, G1, G4, m and n are as previously described for a compound of Formula I, wherein Y1-Y4 and Z1-Z6 are each independently selected from one or more of C0-2alkyl, O, N or S and wherein E99 is equal to 0, 1, 2, or 3.
- In an embodiment, a compound according to Formula I and above embodiments is provided, wherein the compound of Formula I is represented by the compound of Formula In:
- wherein R2, R2a, R3, R10, R11, G1, G4, m and n are as previously described for a compound of Formula I, wherein Y1-Y4 and Z1-Z6 are each independently selected from one or more of C0-2alkyl, O, N or S and E99 is equal to 0, 1, 2, or 3.
- In an embodiment, a compound according to Formula I and above embodiments is provided, wherein the compound of Formula I is represented by the compound of Formula Io:
- wherein R2, R2a, R3, R4, X3, G1 m and n are as previously described for a compound of Formula I.
- The present invention includes the compounds, intermediates, examples and synthetic methods described herein. Compounds of Formula I are prepared according to reaction schemes described herein. Unless otherwise indicated, the substituents in the schemes are defined as above.
- Compounds of the present invention include the intermediates, examples, and synthetic methods described herein.
- The compounds of Formula I may be prepared by the methods described below, together with synthetic methods known in the art of organic chemistry, or modifications and derivatizations that are familiar to those of ordinary skill in the art. The starting materials used herein are commercially available or may be prepared by routine methods known in the art [such as those methods disclosed in standard reference books such as the Compendium of Organic Synthetic Methods, Vol. I-VI (Wiley-Interscience); or the Comprehensive Organic Transformations, by R. C. Larock (Wiley-Interscience)]. Preferred methods include, but are not limited to, those described below.
- During any of the following synthetic sequences it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This can be achieved by means of conventional protecting groups, such as those described in T. W. Greene, Protective Groups in Organic Chemistry, John Wiley & Sons, 1981; T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Chemistry, John Wiley & Sons, 1991, and T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Chemistry, John Wiley & Sons, 1999, which are hereby incorporated by reference.
- Compounds of Formula I, or their pharmaceutically acceptable salts, can be prepared according to the reaction Schemes discussed hereinbelow and the general skill in the art. Unless otherwise indicated, the substituents in the Schemes are defined as above. Isolation and purification of the products is accomplished by standard procedures, which are known to a chemist of ordinary skill.
- When a general or exemplary synthetic procedure is referred to, one skilled in the art can readily determine the appropriate reagents, if not indicated, extrapolating from the general or exemplary procedures. Some of the general procedures are given as examples for preparing specific compounds. One skilled in the art can readily adapt such procedures to the synthesis of other compounds. Representation of an unsubstituted position in structures shown or referred to in the general procedures is for convenience and does not preclude substitution as described elsewhere herein. For specific groups that can be present, either as groups in the general procedures or as optional substituents not shown, refer to the descriptions in the remainder of this document, including the claims, summary and detailed description.
- A general procedure for the synthesis of compounds of Formula I is shown in Scheme 1.
- where R1, R2, R2a, R4, X1, X2, and X3 are as defined previously for compound of Formula I and A1=OH, alkoxy, or a suitable leaving group such as imidazole.
- In a typical preparation, of a compound of Formula I, a compound of Formula II and IIa were reacted under suitable amide coupling conditions. Suitable conditions include but are not limited to treating compounds of Formula II (when A1=OH) and IIa with coupling reagents such as DCC or EDC in conjunction with DMAP, HOBt, HOAt, and the like. Moreover, HATU in the presence of diisopropylethyl amine (DIPEA) can be used. Suitable solvents for use in the above process included, but were not limited to, ethers such as THF, glyme, and the like; DMF; DMSO; MeCN; halogenated solvents such as chloroform or DCM. If desired, mixtures of these solvents were used, however the preferred solvents were DCM and DMF. The above process was carried out at temperatures between about 0° C. and about 100° C. Preferably, the reaction was carried out at about rt. The above process was preferably carried out at or about atmospheric pressure although higher or lower pressures may be used if desired. Substantially equimolar amounts of reactants were preferably used although higher or lower amounts may be used if desired. Additionally, other suitable reaction conditions for the conversion of a carboxylic acid derived compound such as compound of Formula II to an amide such as compound of Formula I can be found in Larock, R. C. Comprehensive Organic Transformations, 2nd ed.; Wiley and Sons: New York, 1999, pp 1941-1949. Compounds of Formula IIa are either commercially available, are synthesized by known chemical procedures or are described in detail within.
- A general procedure for the synthesis of compounds of Formula II is shown in Scheme 2
- where R1, R2, and R2a are as defined previously for compound of Formula I, A1=OH, and A2=OH, alkoxy, or a suitable leaving group such as Cl or imidazole.
- In a typical preparation, of a compound of Formula II, a compound of Formula III and IV were reacted under suitable amide coupling conditions. Suitable conditions include but are not limited to treating compounds of Formula IV (when A1=OH) and compounds of Formula III with coupling reagents such as DCC or EDC in conjunction with DMAP, HOBt. HOAt, and the like. Moreover, HATU in the presence of DIPEA may be used. Suitable solvents for use in the above process include, but are not limited to, ethers such as THF, glyme, and the like; DMF; DMSO; MeCN; halogenated solvents such as chloroform or DCM. If desired, mixtures of these solvents may be used, however the preferred solvents were DCM and DMF. The above process was carried out at temperatures between about 0° C. and about 100° C. Preferably, the reaction was carried out at or about rt. The above process was preferably carried out at about atmospheric pressure although higher or lower pressures may be used if desired. Substantially equimolar amounts of reactants were preferably used although higher or lower amounts may be used if desired. Alternatively, compounds of Formula III and IV (where A2=suitable leaving group such as Cl) were reacted with bases such as NaOH, TEA or DIPEA and the like in conjunction with DMAP and the like. Suitable solvents for use in this process included, but were not limited to, ethers such as THF, glyme, and the like; DMF; DMSO; MeCN; halogenated solvents such as chloroform or DCM; or alcohols or water. If desired, mixtures of these solvents may be used, however the preferred solvent was DCM. The above process was carried out at temperatures between about −20° C. and about 40° C. Preferably, the reaction was carried out between 0° C. and 25° C. The above process to produce was preferably carried out at about atmospheric pressure although higher or lower pressures were used if desired. Substantially equimolar amounts of compounds of Formula III and IV and base and sub-stoichiometric amounts of DMAP were preferably used although higher or lower amounts may be used if desired. Additionally, other suitable reaction conditions for the conversion of a carboxylic acid derived compound such as compound of Formula II to an amide such as compound of Formula I can be found in Larock, R. C. Comprehensive Organic Transformations, 2nd ed.; Wiley and Sons: New York, 1999, pp 1941-1949. Compounds of Formula III and IV as well as IIa are either commercially available, are synthesized by known chemical procedures or are described in detail within.
- A typical preparation of IIa is shown in Scheme 3 wherein, PG=suitable protecting group.
- Another typical preparation of IIa is shown in Scheme 4 wherein, PG=suitable protecting group.
- Another typical preparation of IIa is shown in Scheme 5 wherein, PG=suitable protecting group.
-
- Representative scheme:
-
- To a solution of aniline (0.5 g, 0.005 mol) in acetic acid (20 mL) was added tert-butyl-4-oxopiperidine-1-carboxylate (1.0 g, 0.005 mol). The resulting mixture was cooled to 0° C. and trimethylsilyl cyanide (0.49 g, 0.005 mol) was added. The resulting solution was stirred overnight at room temperature. Saturated aqueous ammonium chloride solution was added (50 mL). The mixture was extracted with ethyl acetate (3×50 mL) and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with dichloromethane:petroleum ether=1:1 to afford tert-butyl-4-cyano-4-(phenylamino)piperidine-1-carboxylate as a white solid (1.3 g, 86%).
- LCMS (ESI): m/z=302.2 [M+H]+.
-
- To a solution of tert-butyl-4-cyano-4-(phenylamino)piperidine-1-carboxylate (0.45 g, 0.0015 mol) in dichloromethane was added chlorosulfonyl isocyanate (0.32 g, 0.00224 mol) at 0° C. After stirring for 30 minutes at 0° C., the reaction was quenched with a 5% aqueous hydrochloric acid solution (2 mL). The solvent was removed under reduced pressure and ethanol (10 mL) was added. The mixture was stirred for 30 minutes at 80° C. The solvent was removed under reduced pressure and the residue was dissolved in tetrahydrofuran (20 mL) and the pH of the mixture was adjusted to pH 8 by addition of a 10% aqueous potassium carbonate solution. Then di-tert-butyl-dicarbonate (0.5 g, 0.00229 mol) in tetrahydrofuran (20 mL) was added. After stirring overnight, the solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography eluting with ethyl acetate:petroleum ether=10:1 to afford tert-butyl-2,4-dioxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate as a white solid (300 mg, 41%).
- LCMS (ESI): m/z=346.2 [M+H]+.
- 1H-NMR (300 MHz, DMSO-d6): δ=1.25 (s, 9H), 1.34-1.51 (m, 2H), 1.95-2.04 (m, 2H), 3.21-3.25 (m, 2H), 3.67-3.78 (m, 2H), 7.19-7.33 (m, 2H), 7.40-7.53 (m, 3H), 10.99-11.2 (s, br, 1H).
-
- To a solution of tert-butyl-2,4-dioxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate (200 mg, 0.000579 mol) in N,N-dimethylformamide (5 mL) was added sodium hydride (23 mg, 60% in oil, 0.0006 mol) at 0° C. After stirring for 15 minutes, iodomethane (83 mg, 0.00057 mol) was added. The resulting mixture was stirred for 15 minutes. The reaction was quenched with ice-water (10 mL). The mixture was extracted with ethyl acetate (3×50 mL) and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with ethyl acetate:petroleum ether=1:3 to afford tert-butyl-3-methyl-2,4-dioxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate as a white solid (140 mg, 67%).
- LCMS (ESI): m/z=360.2 [M+H]+.
- 1H-NMR (300 MHz, DMSO-d6): δ=1.30 (s, 9H), 1.38-1.58 (m, 2H), 1.97-2.04 (m, 2H), 2.89 (s, 3H), 3.21- 3.25 (m, 2H), 3.78-3.82 (m, 2H), 7.26-7.29 (m, 2H), 7.45-7.51 (m, 3H).
-
- A solution of tert-butyl-3-methyl-2,4-dioxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate (140 mg, 0.000389 mol) in hydrochloric acid in dioxane (6.0 M, 10 mL) was stirred for 30 minutes. The precipitate was collected by filtration and dried under reduced pressure to afford 3-methyl-1-phenyl-1,3,8-triazaspiro[4.5]decane-2,4-dione hydrochloride as a white solid (92 mg, 80%).
- LCMS (ESI): m/z=260.1 [M+H]+.
-
- To a solution of (R)-2-amino-2-cyclohexylacetic acid (100 mg, 0.636 mmol) in a 20% aqueous sodium hydroxide solution (2 mL) was added dropwise 3-methylbenzoyl chloride (110 mg, 0.709 mmol) at 0° C. The mixture was stirred for 10 minutes before the reaction was quenched with ice-water (10 mL). The pH of the mixture was adjusted to 1 by addition of a 37% aqueous hydrochloric acid solution. The mixture was extracted with ethyl acetate (3×100 mL). The combined organic layers were dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography eluting with dichloromethane:methanol=20:1 to afford (R)-2-cyclohexyl-2-(3-methylbenzamido)acetic acid as a colorless oil (87 mg, 50%).
- LCMS (ESI): m/z=276.2 [M+H]+.
-
- To a mixture of 3-methyl-1-phenyl-1,3,8-triazaspiro[4.5]decane-2,4-dione hydrochloride (20 mg, 0.000068 mol) and (R)-2-cyclohexyl-2-(3-methylbenzamido) acetic acid (35 mg, 0.000119 mol) in dichloromethane (5 mL) was added 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate (HATU) (146 mg, 0.00038 mol) and N,N-diisopropylethylamine (83 mg, 0.00064 mol). The resulting mixture was stirred for 2 hours at room temperature before the reaction was quenched with ice-water (10 mL). The mixture was extracted with ethyl acetate (3×10 mL) and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by prep-TLC with dichloromethane:methanol=15:1 to afford (R)—N-(1-cyclohexyl-2-(3-methyl-2,4-dioxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-8-yl)-2-oxoethyl)-3-methylbenzamide as a white solid (8.4 mg, 23%).
- LCMS (ESI): m/z=517.2 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=1.04-1.88 (m, 15H), 2.40 (s, 3H), 3.09 (s, 3H), 3.46-3.47 (m, 1H), 3.92-4.51 (m, 3H), 4.83-4.85 (m, 1H), 7.15-7.52 (m, 9H).
- The following 24 compounds were synthesized following the general procedure described above:
-
- 3.5 mg, yield: 9%, white solid.
- LCMS (ESI): m/z=481.2 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=0.72-0.97 (m, 6H), 1.70-2.25 (m, 5H), 3.09 (s, 3H), 3.46-3.47 (m, 1H), 4.51-3.92 (m, 3H), 4.85-4.83 (m, 1H), 7.52-7.15 (m, 9H).
-
- 27 mg, yield: 29%, white solid.
- LCMS (ESI): m/z=495.2 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=0.9-1.05 (m, 6H), 1.69-2.11 (m, 5H), 2.39 (s, 3H), 3.09 (s, 3H), 3.58-4.51 (m, 4H), 4.89-4.91 (m, 1H), 7.05-7.65 (m, 8H).
-
- 12 mg, yield: 13%, white solid.
- LCMS (ESI): m/z=509.2 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=0.81-0.98 (m, 6H), 1.23-1.92 (m, 7H), 2.32 (s, 3H), 3.09 (s, 3H), 3.33-3.47 (m, 1H), 3.92-3.95 (m, 1H), 4.32-4.40 (m, 1H), 4.47-4.50 (m, 1H), 4.97-5.01 (m, 1H), 7.05-7.65 (m, 8H).
-
- 44.3 mg, yield: 47%, white solid.
- LCMS (ESI): m/z=564.2 [M+H]+.
- 1H NMR (400 MHz, CD3OD): δ=0.79-1.01 (m, 6H), 1.24-1.27 (m, 3H), 1.66-1.74 (m, 1H), 1.82-2.24 (m, 4H), 2.67-2.73 (m, 2H), 3.41-3.46 (m, 1H), 3.77 (s, 2H), 3.85-3.93 (m, 2H), 4.2-4.32 (m, 1H), 4.42- 4.56 (m, 1H), 4.62 (s, 2H), 4.84-4.86 (m, 1H), 6.60-7.57 (m, 7H).
-
- 58.0 mg, yield: 29%, white solid.
- LCMS (ESI): m/z=596.9 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=0.82-1.02 (m, 6H), 1.67-2.20 (m, 5H), 3.07 (s, 3H), 3.45-3.51 (m, 1H), 3.84 (s, 2H), 3.92-3.97 (m, 2H), 4.19-4.29 (m, 1H), 4.41-4.53 (m, 1H), 4.84-4.88 (m, 1H), 6.99-8.50 (m, 7H).
-
- 75.8 mg, yield: 44.9%, white solid.
- LCMS (ESI): m/z=573.9 [M+H]+.
- 1H-NMR (400 MHz, CDCl3): δ=0.89-1.05 (m, 6H), 1.74-1.81 (m, 1H), 1.92-2.14 (m, 4H), 3.16 (s, 3H), 3.48-3.53 (m, 1H), 4.00-4.13 (m, 2H), 4.43-4.67 (m, 1H), 4.97-5.03 (m, 1H), 7.27-7.40 (m, 3H), 7.26- 7.73 (m, 1H), 7.70-7.81 (m, 3H), 8.25-8.34 (m, 1H).
-
- 64.7 mg, yield: 31%, white solid.
- LCMS (ESI): m/z=573.9 [M+H]+.
- 1H-NMR (400 MHz, CDCl3): δ=0.89-1.05 (m, 6H), 1.72-1.78 (m, 1H), 1.96-2.12 (m, 4H), 3.16 (s, 3H), 3.48-3.55 (m, 1H), 3.99-4.12 (m, 2H), 4.65-4.68 (m, 1H), 4.92-5.05 (m, 1H), 7.25-7.30 (m, 1H), 7.39- 7.71 (m, 6H), 8.15-8.34 (m, 1H).
-
- 51.0 mg, yield: 30%, white solid.
- LCMS (ESI): m/z=627 [M+H]+.
- 1H NMR (400 MHz, CD3OD): δ=0.80-1.03 (m, 6H), 1.71-2.28 (m, 5H), 3.09-3.19 (m, 6H), 3.48-3.54 (m, 1H), 3.95-4.02 (m, 1H), 4.21-4.55 (m, 2H), 4.84-4.89 (m, 1H), 7.42-8.55 (m, 8H).
-
- 44.0 mg, yield: 29%, white solid.
- LCMS (ESI): m/z=579 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=0.80-1.03 (m, 6H), 1.71-2.28 (m, 5H), 3.09 (s, 3H), 3.46-3.53 (m, 1H), 3.75-3.84 (m, 3H), 3.75-3.99 (m, 1H), 4.18-4.52 ((m, 2H), 4.84-4.88 (m, 1H), 679-8.53 (m, 8H).
-
- 13.9 mg, yield: 20%, white solid.
- LCMS (ESI): m/z=619.7 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=0.80-1.06 (m, 6H), 1.36 (m, 1H), 1.69-1.95 (m, 1H), 2.00-2.23 (m, 3H), 3.08 (s, 3H), 3.29 (s, 2H), 3.43 (s, 1H), 3.49 (m, 1H), 3.92-3.99 (m, 1H), 4.17-4.31 (m, 1H), 4.39-4.53 (m, 1H), 4.84 (m, 1H), 7.00-7.44 (m, 4H), 7.78-8.01 (m, 2H).
-
- 35.8 mg, yield: 26%, white solid.
- LCMS (ESI): m/z=603.2 [M+H]+.
- 1H-NMR (400 MHz, CDCl3): δ=0.79-1.04 (m, 6H), 1.79-2.12 (m, 5H), 3.16 (s, 3H), 3.49-3.59 (m, 1H), 4.02-4.15 (m, 5H), 4.60-4.63 (m, 1H), 4.99-5.03 (m, 1H), 7.12-7.23 (m, 2H), 7.43-7.59 (m, 3H), 7.71- 7.76 (m, 1H), 8.01-8.07 (m, 1H), 8.16-8.31 (m, 1H).
-
- 17.4 mg, yield: 33%, white solid.
- LCMS (ESI): m/z=603.2 [M+H]+.
- 1H-NMR (400 MHz, CDCl3): δ=0.80-1.04 (m, 6H), 1.83-2.13 (m, 5H), 3.16 (s, 3H), 3.49-3.55 (m, 1H), 4.03-4.08 (m, 2H), 4.26-4.31 (m, 3H), 4.60-4.63 (m, 1H), 4.99-5.02 (m, 1H), 7.00-7.23 (m, 2H), 7.42- 7.54 (m, 2H), 7.72-7.84 (m, 2H), 7.96-8.02 (m, 1H), 8.18-8.34 (m, 1H).
-
- 45.6 mg, yield: 26%, white solid.
- LCMS (ESI): m/z=589.2 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=0.85-1.04 (m, 6H), 1.77-2.33 (m, 5H), 3.14 (s, 3H), 3.46-3.55 (m, 1H), 3.93-4.01 (m, 1H), 4.18-4.31 (m, 1H), 4.46-4.59 (m, 1H), 4.70-4.72 (m, 1H), 7.33-7.48 (m, 1H), 7.70- 8.54 (m, 6H), 9.00 (s, 1H).
-
- 73.4 mg, yield: 43%, white solid.
- LCMS (ESI): m/z=626.9 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=0.79-1.02 (m, 6H), 1.65-1.86 (m, 1H), 2.01-2.28 (m, 4H), 3.09 (s, 2H), 3.11 (s, 3H), 3.20 (s, 1H), 3.46-3.53 (m, 1H), 3.93-3.99 (m, 1H), 4.21-4.30 (m, 1H), 4.43-4.55 (m, 1H), 4.80-4.84 (m, 1H), 7.39-7.47 (m, 1H), 7.62-8.10 (m, 6H), 8.42-8.53 (m, 1H).
-
- 128.0 mg, yield: 70%, white solid.
- LCMS (ESI): m/z=553.0 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=1.02-1.06 (m, 6H), 1.89-2.73 (m, 5H), 3.07 (s, 3H), 3.45-3.52 (m, 1H), 3.82-3.94 (m, 3H), 3.82-4.00 (m, 1H), 4.27-4.30 (m, 1H), 4.89-4.52 (m, 1H), 4.85-4.97 (m, 1H), 6.35- 6.47 (m, 1H), 7.43-7.55 (m, 2H), 7.87-7.89 (m, 1H), 7.99-8.05 (m, 1H).
-
- 159.5 mg, yield: 81%, white solid.
- LCMS (ESI): m/z=553.0 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=0.89-1.04 (m, 6H), 1.76-2.15 (m, 5H), 3.06 (s, 3H), 3.32-3.48 (m, 1H), 3.82-4.00 (m, 4H), 4.27-4.31 (m, 1H), 4.52-4.56 (m, 1H), 4.85-4.90 (m, 1H), 7.42-7.51 (m, 2H), 7.75- 7.80 (m, 1H), 7.87-7.90 (m, 1H), 7.99-8.03 (m, 1H).
-
- 16.0 mg, yield: 30%, white solid.
- LCMS (ESI): m/z=563.1 [M+H].
- 1H-NMR (400 MHz, CD3OD): δ=0.86-1.03 (m, 6H), 1.20-1.31 (m, 3H), 1.75-1.78 (m, 1H), 2.07-2.24 (m, 3H), 2.31-2.33 (m, 1H), 2.61-2.66 (m, 2H), 2.59 (s, 2H), 2.87 (s, 1H), 3.13 (s, 3H), 3.47-3.51 (m, 1H), 3.97-4.02 (m, 1H), 4.23-4.31 (m, 1H), 4.47-4.56 (m, 1H), 4.75-4.78 (m, 1H), 6.99-7.05 (m, 2H), 7.21- 7.34 (m, 2H), 7.55-7.99 (m, 2H), 8.50 (m, 1H).
-
- 12.7 mg, yield: 9%, white solid.
- LCMS (ESI): m/z=603.2 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=0.76-1.01 (m, 6H), 1.72-2.30 (m, 5H), 2.84-2.90 (m, 3H), 3.12 (s, 3H), 3.49-3.55 (t, 1H), 3.93-4.01 (t, 1H), 4.16-4.54 (m, 2H), 4.80-4.82 (m, 1H), 7.34-7.51 (m, 2H), 7.70- 8.08 (m, 4H).
-
- 56.3 mg, yield: 32%, white solid.
- LCMS (ESI): m/z=589.2 [M+H]+.
- 1H-NMR (400 MHz, CDCl3): δ=0.79-1.04 (m, 6H), 1.75-2.18 (m, 5H), 3.18 (s, 3H), 3.47-3.53 (t, 1H), 3.98-4.04 (m, 2H), 4.63-4.66 (m, 1H), 4.97-5.02 (m, 1H), 6.55-6.61 (m, 1H), 7.17-7.22 (m, 1H), 7.42- 7.49 (m, 2H), 7.68-7.77 (m, 1H), 7.82-7.85 (m, 1H), 8.05-8.10 (m, 1H), 8.14-8.34 (m, 1H).
-
- 59.9 mg, yield: 27%, white solid.
- LCMS (ESI): m/z=606.2 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=0.84-1.00 (m, 6H), 1.69-2.15 (m, 5H), 305 (s, 3H), 3.23-3.40 (m, 3H), 3.89-3.93 (m, 1H), 4.19-4.23 (m, 3H), 4.43-4.56 (m, 1H), 4.88-4.94 (m, 1H), 6.54-6.65 (m, 3H), 7.40- 7.42 (m, 1H), 7.86-8.03 (m, 2H).
-
- 22.8 mg, yield: 14%, white solid.
- LCMS (ESI): m/z=566.2.2 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=0.89-1.00 (m, 6H), 1.69-2.13 (m, 5H), 3.04 (m, 3H), 3.31-3.48 (m, 1H), 3.88-3.94 (m, 2H), 4.26-4.28 (m, 2H), 4.52-4.55 (m, 2H), 6.50-6.70 (m, 1H), 7.35-7.42 (m, 3H), 7.94- 8.03 (m, 2H).
-
- 34.8 mg, yield: 45%, white solid.
- LCMS (ESI): m/z=580.2 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=0.90-1.04 (m, 6H), 1.70-1.87 (m, 1H), 1.99-2.18 (m, 4H), 3.07 (s, 3H), 3.44-3.60 (m, 4H), 3.90-3.96 (m, 1H), 4.22-4.32 (m, 1H), 4.46-4.58 (m, 1H), 4.84-4.88 (m, 1H), 6.49- 6.62 (m, 1H), 7.36-7.48 (m, 2H), 7.74-8.02 (m, 3H).
-
- 66.1 mg, yield: 30%, white solid.
- LCMS (ESI): m/z=606.2 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=1.14-1.83 (m, 9H), 1.99-2.16 (m, 3H), 2.36-2.40 (m, 1H), 3.07 (s, 3H), 3.44-3.61 (m, 4H), 3.91-3.94 (m, 1H), 4.29-4.38 (m, 1H), 4.47-4.57 (m, 1H), 4.79-4.88 (m, 1H), 6.47- 6.62 (m, 1H), 7.36-7.47 (m, 2H), 7.74-7.98 (m, 3H).
-
- 50.0 mg, yield: 40%, white solid.
- LCMS (ESI): m/z=580.2 [M+H]+.
- 1H-NMR (400 MHz, CDCl3): δ=0.95-1.05 (m, 6H), 1.69-1.73 (m, 1H), 1.82-2.00 (m, 3H), 2.03-2.16 (m, 1H), 3.15 (s, 3H), 3.45-3.52 (m, 1H), 3.87-4.12 (m, 5H), 4.52-4.64 (m, 1H), 4.98-5.09 (m, 1H), 6.78- 6.87 (m, 1H), 7.29-7.36 (m, 1H), 7.36-7.50 (m, 1H), 7.70-7.81 (m, 1H), 7.99-8.10 (m, 1H), 8.25-8.39 (m, 1H).
-
- 12.8 mg, 16% yield, yellow solid.
- LRMS: m/z=616 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=7.94-7.84 (m, 2H), 7.51-7.26 (m, 5H), 4.88-4.80 (m, 1H), 4.58-4.42 (m, 1H), 4.34-4.19 (m, 1H), 4.02-3.89 (m, 1H), 3.55-3.44 (m, 1H), 3.10 (s, 3H), 2.28-1.94 (m, 4H), 1.76- 1.64 (m, 1H), 1.01 (dd, J=11.8, 6.7 Hz, 4H), 0.92 (d, J=6.7 Hz, 1H), 0.79 (d, J=6.7 Hz, 1H).
-
- 30 mg, 28% yield, yellow solid.
- LRMS: m/z=588 [M+H]+.
- 1H-NMR (400 MHz, DMSO-d6): δ=8.72 (dd, J=30.5, 8.8 Hz, 1H), 8.08 (d, J=30.8, 1H), 7.94 (s, 1H), 7.86-7.61 (m, 2H), 7.56-7.34 (m, 2H), 7.18 (dd, J=49.9, 8.6 Hz, 1H), 6.98 (d, J=49.5 Hz, 1H), 4.67 (t, J=8.4 Hz, 1H), 4.44-3.62 (m, 4H), 3.29 (m, 1H), 3.00 (s, 3H), 2.25-2.09 (m, 2H), 1.70-1.48 (m, 2H), 0.89-0.56 (m, 6H).
-
- Representative scheme:
-
- To a solution of 6-aminobenzo[d]oxazol-2(3H)-one (6 g, 0.04 mol) in acetic acid (100 mL) was added tert-butyl-4-oxopiperidine-1-carboxylate (8.83 g, 0.04 mol). The resulting mixture was cooled to 0° C. and trimethylsilyl cyanide (5.99 g, 0.06 mol) was added. The resulting solution was stirred overnight at room temperature. Saturated aqueous ammonium chloride solution was added (50 mL). The mixture was extracted with ethyl acetate (3×100 mL) and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with dichloromethane:methanol=10:1 to afford tert-butyl-4-cyano-4-(2-oxo-2,3-dihydrobenzo[d]oxazol-6-ylamino)piperidine-1-carboxylate as a white solid (10 g, 71%).
- LCMS (ESI): m/z=359.1 [M+H]+.
-
- To a solution of tert-butyl-4-cyano-4-(2-oxo-2,3-dihydrobenzo[d]oxazol-6-ylamino)piperidine-1-carboxylate (1.0 g, 0.0027 mol) in N,N-dimethylformamide (10 mL) was added sodium hydride (0.2 g, 60% in oil, 0.00521 mol) at 0° C. After stirring for 15 minutes, 3-bromoprop-1-ene (0.35 g, 0.0029 mol) was added. The resulting mixture was stirred for 15 minutes at room temperature and the reaction was quenched with ice-water (10 mL). The mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with ethyl acetate:petroleum ether=1:10 to afford tert-butyl-4-(3-allyl-2-oxo 2,3-dihydrobenzo[d]oxazol 6 ylamino) 4 cyanopiperidine 1 carboxylate as a thick oil (600 mg, 58%).
- LCMS (ESI): m/z=399.2 [M+H]+.
-
- To a solution of tert-butyl-4-(3-allyl-2-oxo-2,3-dihydrobenzo[d]oxazol-6-ylamino)-4-cyanopiperidine-1-carboxylate (0.6 g, 0.0015 mol) in dichloromethane (10 mL) was added chlorosulfonyl isocyanate (0.32 g, 0.0023 mol) at 0° C. After stirring for 30 minutes at 0° C. the reaction was quenched with a 5% aqueous hydrochloric acid solution (5 mL). The solvent was removed under reduced pressure and ethanol (10 mL) was added. The mixture was stirred for 30 minutes at 80° C. The solvent was removed under reduced pressure and the residue was dissolved in tetrahydrofuran (20 mL). The pH of the resulting mixture was adjusted to 8 by addition of a 15% aqueous potassium carbonate solution. To the resulting mixture was added di-tert-butyl-dicarbonate (213 g, 0.0015 mol). After stirring overnight, the solvent was removed under reduced pressure and the residue was extracted with ethyl acetate (3×10 mL). The combined organic layers were dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to afford tert-butyl-1-(3-allyl-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate as a yellow oil (400 mg, crude), which was used directly without any further purification.
- LCMS (ESI): m/z=443.2 [M+H]+.
- 1H-NMR (300 MHz, CDCl3): δ=1.46 (s, 9H), 1.73-1.84 (m, 2H), 2.10-2.23 (m, 2H), 3.17-3.30 (m, 2H), 3.92-4.11 (m, 2H), 4.35-4.46 (m, 2H), 5.20-5.34 (m, 2H), 579-6.01 (m, 2H), 6.78-6.93 (m, 3H).
-
- To a solution of tert-butyl-1-(3-allyl-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate (400 mg, crude) in N,N-dimethylformamide (10 mL) was added sodium hydride (138 mg, 60% in oil, 0.00343 mol) at 0° C. After stirring for 15 minutes, iodomethane (220 mg, 0.0015 mol) was added. The resulting mixture was stirred for 15 minutes at room temperature and the reaction was quenched with ice-water (10 mL). The mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with dichloromethane methanol=10:1 to afford tert-butyl-1-(3-allyl-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)-3-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate as a brown solid (240 mg, 35% over two steps).
- LCMS (ESI): m/z=457.2 [M+H]+.
- 1H-NMR (300 MHz, CDCl3): δ=1.40 (s, 9H), 1.67-1.94 (m, 4H), 3.11 (s, 3H), 3.44-3.58 (m, 2H), 3.93-4.08 (m, 2H), 4.44-4.53 (m, 2H), 5.31-5.47 (m, 2H), 5.81-5.94 (m, 1H), 6.90-7.05 (m, 3H).
-
- To a solution of 2-fluoro-5-(trifluoromethyl)benzoic acid (15.0 g, 0.072 mol) in dichloromethane (500 mL) was added sequentially D-valine methyl ester hydrochloride (12.0 g, 0.072 mol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate (HATU) (41 g, 0.11 mol) and N,N-diisopropylethylamine (23.3 g, 0.18 mol). Before quenching with ice-water (50 mL), the reaction was stirred for 1 hour. The mixture was extracted with dichloromethane (3×100 mL). The combined organic layers were dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography eluting with ethyl acetate:petroleum ether=1:5 to afford (R)-methyl-2-(2-fluoro-5-(trifluoromethyl)benzamido)-3-methylbutanoate as a thick oil (18.6 g, 81%)
- LCMS (ESI): m/z=322.1 [M+H]+.
- 1H-NMR (300 MHz, CD3OD): δ=1.05 (dd, J=6.8, 4.3 Hz, 6H), 2.22-2.35 (m, 1H), 3.79 (s, 3H), 4.58 (d, J=6.0 Hz, 1H), 7.46 (t, J=9.4 Hz, 1H), 7.89 (m, 1H), 8.00 (dd, J=6.2, 2.1 Hz, 1H).
-
- To a solution of (R)-methyl-2-(2-fluoro-5-(trifluoromethyl)benzamido)-3-methylbutanoate (18.6 g, 0.058 mol) in tetrahydrofuran (50 mL) was added an aqueous lithium hydroxide solution (44 mL, 2.0 M, 0.088 mol). Before quenching with ice-water (20 mL), the reaction was stirred 1 hour. The pH of the solution was adjusted to 3 by addition of a 5% aqueous hydrochloric acid solution (5%) The mixture was filtered and the filter cake was washed with petroleum ether (30 mL) and dried under reduced pressure to afford (R)-2-(2-fluoro-5-(trifluoromethyl)benzamido)-3-methylbutanoic acid as a white solid (16.7 g, 94%).
- LCMS (ESI): m/z=308.1 [M+H]+.
- 1H-NMR (300 MHz, DMSO): δ=0.95 (dd, J=6.7, 4.7 Hz, 6H), 2.13-2.17 (m, 1H), 4.31-4.35 (m, 1H), 7.52-7.55 (m, 1H), 7.58-7.85 (m, 2H), 12.77 (br, 1H).
-
- A solution of tert-butyl-1-(3-allyl-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)-3-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate (100 mg, 0.228 mmol) in hydrochloric acid in dioxane (6.0 M, 5 mL) was stirred for 30 minutes. The solvent was removed under reduced pressure. To the residue was added dichloromethane (5 mL), (R)-2-(2-fluoro-5-(trifluoromethyl)benzamido)-3-methyl butanoic acid (79 mg, 0.26 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate (HATU) (146 mg, 0.38 mmol) and N,N-diisopropylethylamine (83 mg, 0.64 mmol). The reaction was stirred for 2 hours before it was quenched by addition of with ice-water (10 mL). The mixture was extracted with ethyl acetate (3×10 mL) and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by prep-TLC (dichloromethane:methanol=15:1) to afford (R)—N-(1-(1-(3-allyl-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)-3-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decan-8-yl)-3-methyl-1-oxobutan-2-yl)-2-fluoro-5-(trifluoromethyl)benzamide as a white solid (120 mg, crude), which was used directly without any further purification.
- LCMS (ESI): m/z=646.1 [M+H]+.
-
- To a solution of (R)—N-(1-(1-(3-allyl-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)-3-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decan-8-yl)-3-methyl-1-oxobutan-2-yl)-2-fluoro-5-(trifluoromethyl)benzamide (120 mg, crude) in dioxane/tert-BuOH (1:1) (10 mL) was added a solution of osmium tetroxide in tert-BuOH (0.5 mL, 0.1%) and N-methylmorpholine-N-oxide (170 mg, 1.45 mmol). After stirring for 30 minutes, to the resulting solution was added sodium periodate (300 mg, 1.4 mmol). Before the reaction was quenched by addition of ice-water (10 mL), the mixture was heated at reflux for 1 hour. The solvent was removed under reduced pressure. The residue was extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with dichloromethane:methanol=10:1 to afford (R)-2-fluoro-N-(3-methyl-1-(3-methyl-2,4-dioxo-1-(2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)-1,3,8-triazaspiro[4.5]decan-8-yl)-1-oxobutan-2-yl)-5-(trifluoromethyl)benzamide as a white solid (8.0 mg, 5% over two steps).
- LCMS (ESI): m/z=606.1 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=0.80-1.01 (m, 6H), 1.70-1.91 (m, 2H), 2.05-2.22 (m, 3H), 3.09 (s, 3H), 3.45-3.50 (m, 1H), 3.86-3.93 (m, 1H), 4.16-4.25 (m, 1H), 4.40-4.48 (m, 1H), 4.81-4.85 (m, 1H), 7.02- 7.08 (m, 3H), 7.30-7.37 (m, 1H), 7.79-7.85 (m, 3H), 8.41-8.56 (m, 1H).
- The following 5 compounds were synthesized following the general procedure described above from tert-butyl-1-(3-allyl-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)-3-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate (prepared as described in Example 28-d):
-
- 39.3 mg, yield: 32%, white solid.
- LCMS (ESI): m/z 606.2 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=0.79-1.00 (m, 6H), 1.73-2.16 (m, 5H), 3.08 (s, 3H), 3.44-3.48 (m, 1H), 3.82-3.95 (m, 1H), 4.16-4.24 (m, 1H), 4.39-4.46 (m, 1H), 4.81-4.86 (m, 1H), 6.95-7.05 (m, 2H), 7.15- 7.45 (m, 2H), 7.81-7.85 (m, 2H).
- This compound was prepared following the general procedure described above using 4-allyl-7-amino-2H-benzo[b][1,4]oxazin-3(4H)-one
- 22.5 mg, yield: 13%, white solid.
- LCMS (ESI): m/z=620.2 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=0.83-1.01 (m, 6H), 1.71-1.74 (m, 1H), 1.84-2.10 (m, 4H), 3.07 (s, 3H), 3.45-3.51 (m, 1H), 3.91-3.97 (m, 1H), 4.18-4.24 (m, 1H), 4.39-4.63 (m, 3H), 5.32-5.42 (m, 1H), 6.80- 6.94 (m, 3H), 7.32-7.47 (m, 1H), 7.86-8.48 (m, 2H).
-
- 23.4 mg, yield: 39%, white solid.
- LCMS (ESI): m/z=566.2 [M+H]+.
- 1H-NMR (400 MHz, CDCl3): δ=0.87-1.07 (m, 6H), 1.21-1.23 (m, 3H), 1.25-1.99 (m, 8H, 3H), 2.65 (m, 2H), 3.16 (s, 3H), 3.48-3.50 (m, 1H), 3.92-3.97 (m, 2H), 4.67-4.69 (m, 1H), 5.13-5.07 (m, 1H), 6.87- 7.02 (m, 1H), 6.99-7.05 (m, 2H), 7.29-7.33 (m, 2H), 7.54-7.74 (m, 2H), 9.37 (m, 1H).
-
- 35 mg, 20% yield, white solid.
- LCMS (ESI): m/z=590.1 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=0.69 (d, J=6.8 Hz, 1H), 0.85 (d, J=6.7 Hz, 1H), 0.95-0.99 (m, 4H), 1.75-2.25 (m, 5H), 3.12 (s, 3H), 3.47-3.57 (m, 1H), 3.93-4.02 (m, 1H), 4.20-4.32 (m, 1H), 4.49-4.56 (m, 1H), 4.78-4.84 (m, 1H), 7.16-7.46 (m, 2H), 7.72-8.03 (m, 4H).
-
-
-
- To a mixture of 3-methyl-1-phenyl-1,3,8-triazaspiro[4.5]decane-2,4-dione hydrochloride (prepared as described in Example 1-d) (513 mg, 1.73 mmol) in dichloromethane (30 mL) was added (R)-2-(tert-butoxycarbonylamino)-3-methylbutanoic acid (411 mg, 0.00026 mol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate (HATU) (900 mg, 2.36 mmol) and N,N-diisopropylethylamine (605 mg, 4.6 mmol). The resulting mixture was stirred for 2 hours at room temperature before the reaction was quenched with ice-water. The mixture was extracted with ethyl acetate (3×10 mL) and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with ethyl acetate:petroleum ether=1:5 to afford (R)-tert-butyl-3-methyl-1-(3-methyl-2,4-dioxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-8-yl)-1-oxobutan-2-ylcarbamate as a colorless oil (650 mg, 81%).
- LCMS (ESI): m/z=459.2 [M+H]+.
- 1H-NMR (300 MHz, CDCl3): δ=0.65-0.92 (m, 6H), 1.34 (s, 6H), 1.44 (s, 3H), 1.59-1.94 (m, 4H), 3.11 (s, 3H), 3.34-3.51 (m, 1H), 3.83-3.94 (m, 2H), 4.27-4.44 (m, 1H), 4.49-4.61 (m, 1H), 5.15-5.17 (m, 1H), 7.05-7.19 (m, 2H), 7.40-7.45 (m, 3H).
-
- A solution of tert-butyl-3-methyl-1-(4-nitrophenyl)-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate (458 mg, 1.98 mmol) in hydrochloric acid in dioxane (6.0 M, 10 mL) was stirred for 30 minutes. The precipitate was collected by filtration and dried under reduced pressure to afford (R)-8-(2-amino-3-methylbutanoyl)-3-methyl-1-phenyl-1,3,8-triazaspiro[4.5]decane-2,4-dione hydrochloride as a white solid (250 mg, 46%).
- LCMS (ESI): m/z=359.2 [M+H]+.
-
- To a mixture of (R)-8-(2-amino-3-methylbutanoyl)-3-methyl-1-phenyl-1,3,8-triazaspiro[4.5]decane-2,4-dione hydrochloride (52 mg, 0.132 mmol) in dichloromethane (2 mL) was added 3-(trifluoromethyl)benzoic acid (23 mg, 0.12 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate (HATU) (68 mg, 0.17 mmol) and N,N-diisopropylethylamine (31 mg, 0.24 mmol). The resulting mixture was stirred for 2 hours at room temperature before the reaction was quenched with ice-water (10 mL). The mixture was extracted with ethyl acetate (3×10 mL) and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with ethyl acetate:petroleum ether=1:5 to afford (R)—N-(3-methyl-1-(3-methyl-2,4-dioxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-8-yl)-1-oxobutan-2-yl)-3-(trifluoromethyl)benzamide as a white solid (34.4 mg, 49%).
- LCMS (ESI): m/z=531.2 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=0.92-1.00 (m, 6H), 1.97-2.19 (m, 5H), 3.08 (s, 3H), 3.91-4.48 (m, 4H), 4.77-4.91 (m, 1H), 7.17-7.33 (m, 4H), 7.84-8.07 (m, 4H), 8.12-8.14 (m, 1H).
- The following 18 compounds were synthesized following the general procedure described above:
-
- 31.2 mg, yield: 51%, white solid.
- LCMS (ESI): m/z=509.2 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=0.79-1.09 (m, 6H), 1.17-1.33 (m, 3H), 1.60-2.24 (m, 5H), 2.73 (m, 2H), 3.09 (s, 3H), 3.48 (m, 1H), 3.83-4.04 (m, 1H), 4.24-4.30 (m, 1H), 4.37-4.52 (m, 1H), 4.85-4.89 (m, 1H), 7.10-7.59 (m, 8H).
-
- 33.9 mg, yield: 50%, white solid.
- LCMS (ESI): m/z=531.2, 533.2 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=0.71-0.90 (m, 6H), 1.58-2.30 (m, 5H), 3.09 (s, 3H), 3.48 (m, 1H), 3.84-4.01 (m, 1H), 4.17-4.58 (m, 2H), 4.74 (m, 1H), 7.17-7.84 (m, 8H).
-
- 34.4 mg, yield: 51%, white solid.
- LCMS (ESI): m/z=531.2, 533.2 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=0.71-1.10 (m, 6H), 1.61-2.25 (m, 5H), 3.10 (s, 3H), 3.46-3.49 (m, 1H), 3.81-4.04 (m, 1H), 4.11-4.58 (m, 2H), 4.74-4.77 (m, 1H), 7.12-7.57 (m, 8H).
-
- 19.8 mg, yield: 29%, white solid.
- LCMS (ESI): m/z=525.2 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=1.22-1.31 (m, 6H), 1.66-2.83 (m, 6H), 3.03 (m, 4H), 3.38 (s, 2H), 3.51-4.51 (m, 5H), 5.01-5.17 (m, 1H), 6.73-7.76 (m, 8H).
-
- 36.0 mg, yield: 54%, white solid.
- LCMS (ESI): m/z=525.2 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=1.00-1.19 (m, 6H), 1.66-2.71 (m, 6H), 3.08 (s, 3H), 3.11 (s, 1H), 3.30 (s, 2H), 3.46-4.47 (m, 5H), 5.03-5.11 (m, 1H), 6.69-7.76 (m, 8H).
-
- 10.0 mg, yield: 17%, white solid.
- LCMS (ESI): m/z=509.2 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=0.79-1.09 (m, 6H), 1.26-1.30 (m, 3H), 1.57-2.27 (m, 5H), 2.63-2.75 (m, 2H), 3.09 (s, 3H), 3.42-3.56 (m, 1H), 4.14-4.32 (m, 2H), 4.37-4.53 (m, 1H), 4.82-4.88 (m, 1H), 7.05- 7.61 (m, 8H).
-
- 10.0 mg, yield: 15%, white solid.
- LCMS (ESI): m/z=555.2 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=1.02-1.27 (m, 6H), 1.65-2.05 (m, 4H), 2.66-2.73 (m, 2H), 3.08 (s, 3H), 3.12-3.20 (m, 1H), 3.44-3.47 (m, 1H), 3.52-3.88 (m, 6H), 4.17-4.25 (m, 1H), 4.31-4.49 (m, 1H), 5.06- 5.17 (m, 1H), 6.93-7.20 (m, 5H), 7.39-7.57 (m, 2H).
-
- 12.8 mg, yield: 11%, white solid.
- LCMS (ESI): m/z=539.2 [M+H]f.
- 1H-NMR (400 MHz, CD3OD): δ=0.67-0.98 (m, 6H), 1.12-1.25 (m, 1H), 1.45-1.48 (m, 1H), 1.62-2.15 (m, 5H), 2.41 (s, 3H), 3.07 (s, 3H), 3.47-3.51 (m, 1H), 3.75 (s, 2H), 3.84 (s, 1H), 3.85-4.51 (m, 3H), 4.89-4.91 (m, 1H), 6.84-7.52 (m, 7H).
-
- 34.0 mg, yield: 39%, white solid.
- LCMS (ESI): m/z=521.2 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=0.67-0.98 (m, 10H), 1.65-2.15 (m, 6H), 3.08 (s, 3H), 3.47-3.51 (m, 1H), 3.91-3.94 (m, 1H), 4.23-4.49 (m, 2H), 4.80-4.90 (m, 1H), 7.05-7.51 (m, 8H).
-
- 42.0 mg, yield: 48%, white solid.
- LCMS (ESI): m/z=515.2[M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=0.76-1.01 (m, 6H), 1.65-2.15 (m, 5H), 3.09 (s, 3H), 3.47-3.51 (m, 1H), 3.90-3.95 (m, 1H), 4.17-4.47 (m, 2H), 4.80-4.82 (m, 1H), 7.22-7.75 (m, 8H).
-
- 26.9 mg, yield: 55%, white solid.
- LCMS (ESI) m/z=549.2 [M+H]f.
- 1H-NMR (400 MHz, CD3OD): δ=0.77-1.03 (m, 6H), 1.68-2.22 (m, 5H), 3.09 (s, 3H), 3.46-3.53 (m, 1H), 3.93-3.99 (m, 1H), 4.18-4.30 (m, 1H), 4.40-4.52 (m, 1H), 4.83-4.86 (m, 1H), 7.23-7.53 (m, 6H), 7.85- 8.02 (m, 2H).
-
- 23.0 mg, yield: 36%, white solid.
- LCMS (ESI): m/z=551.2 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=0.68-0.98 (m, 10H), 1.86-2.16 (m, 6H), 3.32 (s, 3H), 3.47-3.51 (m, 1H), 3.75-3.77 (m, 2H), 3.81-3.88 (m, 1H), 3.93-4.49 (m, 3H), 4.84-4.90 (m, 1H), 6.88-7.34 (m, 7H).
-
- 29.5 mg, yield: 50%, white solid.
- LCMS (ESI): m/z=491 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=0.72-0.97 (m, 6H), 1.23-1.28 (m, 3H), 1.60-2.18 (m, 5H), 2.67-2.73 (m, 2H), 3.07 (s, 3H), 3.49-3.52 (m, 1H), 3.90-4.00 (m, 1H), 4.31-4.49 (m, 2H), 4.76-4.88 (m, 1H), 7.16- 7.49 (m, 8H).
-
- 27.6 mg, yield: 45%, white solid.
- LCMS (ESI): m/z=509 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=0.71-0.96 (m, 6H), 1.24 (m, 3H), 1.65-1.68 (m, 1H), 1.91-2.09 (m, 4H), 2.70-2.72 (m, 2H) 3.07 (s, 3H), 3.45-3.47 (m, 1H), 3.90-3.96 (m, 1H), 4.30-4.47 (m, 2H), 4.73 (m, 1H), 7.14-7.50 (m, 9H).
-
- 18.5 mg, yield: 29%, white solid.
- LCMS (ESI): m/z=531 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=0.71-0.96 (m, 6H), 1.63-1.73 (m, 1H), 1.81-2.61 (m, 4H), 3.08 (s, 3H), 3.47 (m, 1H), 3.89 (m, 1H), 4.22-4.51 (m, 2H), 4.71 (m, 1H), 7.18-8.65 (m, 8H.
-
- 27.2 mg, yield: 31%, white solid.
- LCMS (ESI): m/z=567 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=0.70-0.82 (m, 2H), 0.91-1.03 (m, 4H), 1.14-1.32 (m, 2H), 1.60-1.79 (m, 1H), 1.83-2.17 (m, 4H), 2.99-3.11 (m, 3H), 3.13-3.15 (m, 2H), 3.71-4.01 (m, 6H), 4.14 (m, 1H), 4.47- 4.49 (m, 1H), 5.03-5.26 (m, 1H), 6.95-7.01 (m, 1H), 7.02-7.33 (m, 5H), 7.50-7.71 (m, 1H).
-
- 43.7 mg, yield: 68%, white solid.
- LCMS (ESI): m/z=539 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=0.74-1.08 (m, 6H), 1.21-1.38 (m, 3H), 1.60-1.75 (m, 1H), 1.78-2.25 (m, 4H), 2.62-2.80 (m, 2H), 3.08 (s, 3H), 3.41-3.48 (m, 1H), 3.56-3.76 (m, 2H), 3.84-3.93 (m, 1H), 4.18- 4.27 (m, 2H), 4.48-4.86 (m, 2H), 6.90-6.92 (m, 1H), 7.00-7.26 (m, 4H), 7.45 (m, 2H).
-
- 40.0 mg, yield: 47%, white solid.
- LCMS (ESI): m/z=579 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=0.79-1.01 (m, 6H), 1.66-2.17 (m, 5H), 3.06 (s, 3H), 3.49 (m, 1H), 3.75 (s, 2H), 3.85 (s, 1H), 3.94-4.22 (m, 2H), 4.44-4.50 (m, 1H), 4.86-4.94 (m, 1H), 6.90-6.93 (m, 1H), 7.13 (m, 3H), 7.43 (m, 1H), 7.94 (m, 2H).
-
-
-
- To a solution of 1H-indazol-5-amine (25.0 g, 0.19 mol) in acetic acid (300 mL) was added tert-butyl-4-oxopiperidine-1-carboxylate (45.0 g, 0.22 mol). The resulting mixture was cooled to 0° C. and trimethylsilyl cyanide (37.0 g, 0.37 mol) was added. The resulting solution was stirred overnight at room temperature. Saturated aqueous ammonium chloride solution (500 mL) was added. The resulting mixture was filtered and the filter cake was washed with water (3×50 mL) to afford tert-butyl-4-(1H-indazol-5-ylamino)-4-cyanopiperidine-1-carboxylate as a brown solid (60.0 g, 93%).
- LCMS (ESI): m/z=342.1 [M+H]+.
- 1H-NMR (300 MHz, DMSO-d6): δ=1.41 (s, 9H), 1.76-1.85 (m, 2H), 2.20-2.24 (m, 2H), 3.15 (t, J=10.8 Hz, 2H), 3.78-3.82 (m, 2H), 5.74 (s, 1H), 6.95-7.05 (m, 1H), 7.12-7.20 (m, 1H), 7.29-7.42 (m, 1H), 7.92 (s, 1H), 12.8 (br, 1H).
-
- To a solution of tert-butyl-4-(1H-indazol-5-ylamino)-4-cyanopiperidine-1-carboxylate (60.0 g, 0.18 mol) in tetrahydrofuran: water (300 mL, 1:1) was added potassium carbonate (57.0 g, 0.41 mol) and benzyl chloroformate (53.0 g, 0.31 mol) at 0° C. After stirring overnight, the organic layer was isolated and the aqueous was extracted with ethyl acetate (3×100 mL). The combined layers were washed with water (3×50 mL) and brine (3×50 mL). The organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with ethyl acetate:dichloromethane:petroleum ether=1:2:2 to afford benzyl-5-((1-(tert-butoxycarbonyl)-4-cyanopiperidin-4-yl)amino)-1H-indazole-1-carboxylate as a brown solid (60.0 g, 70%).
- LCMS (ESI): m/z=476.1 [M+H]+.
-
- To a solution of benzyl-5-((1-(tert-butoxycarbonyl)-4-cyanopiperidin-4-yl)amino)-1H-indazole-1-carboxylate (10.0 g, 0.021 mol) in dichloromethane (200 mL) was added chlorosulfonyl isocyanate (20 mL, 0.23 mol) at 0° C. After stirring for 30 minutes at 0° C., the reaction was quenched by addition of a 5% aqueous hydrochloric acid solution (100 mL). The solvent was removed under reduced pressure and ethanol (100 mL) was added. The mixture was stirred for 30 minutes at 80° C. The solvent was removed under reduced pressure and the residue was added to tetrahydrofuran (20 mL) and the pH was adjusted to 8 by addition of a 15% aqueous potassium carbonate solution. Then di-tert-butyl-dicarbonate (5.9 g, 0.027 mol) in tetrahydrofuran (100 mL) was added. After stirring overnight, the solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography eluting with dichloromethane:methanol=50:1 to afford benzyl-5-(8-(tert-butoxycarbonyl)-2,4-dioxo-1,3,8-triazaspiro[4.5]decan-1-yl)-1H-indazole-1-carboxylate as a yellow solid (3.0 g, 27%).
- LCMS (ESI): m/z=520.1 [M+H]+.
- 1H-NMR (300 MHz, CDCl3): δ=1.36 (s, 9H), 1.74-1.81 (m, 2H), 1.96-2.00 (m, 2H), 3.43-3.55 (m, 2H), 4.02 (br, 2H), 5.56 (s, 2H), 7.25-7.41 (m, 5H), 7.51-7.57 (m, 3H), 8.21 (s, 1H), 8.29-8.32 (d, 1H, J=9.2 Hz).
-
- To a solution of benzyl-5-(8-(tert-butoxycarbonyl)-2,4-dioxo-1,3,8-triazaspiro[4.5]decan-1-yl)-1H-indazole-1-carboxylate (10.0 g, 0.019 mol) in N,N-dimethylformamide (100 mL) was added potassium carbonate (5.32 g, 0.039 mol) at 0° C. After stirring for 15 minutes, iodomethane (1.58 mL, 0.025 mol) was added. After stirring for 1 hour, the reaction was quenched by addition of ice-water (50 mL). The mixture was extracted with ethyl acetate (3×50 mL) and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with dichloromethane:methanol=40:1 to afford benzyl-5-(8-(tert-butoxycarbonyl)-3-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decan-1-yl)-1H-indazole-1-carboxylate as a white solid (7.5 g, 73%).
- LCMS (ESI): m/z=534.1 [M+H]+.
- 1H NMR (300 MHz, CDCl3): δ=1.35 (s, 9H), 1.72-1.77 (m, 4H), 1.86-1.90 (m, 2H), 3.11 (s, 3H), 3.51 (br, 2H), 3.86-4.10 (m, 2H), 5.55 (s, 2H), 7.29 (dd, 1H, J=8.9 Hz, J=1.9 Hz), 7.40 (m, 3H), 7.53 (m, 3H), 8.20 (d, 1H, J=0.7 Hz), 8.28 (d, 1H, J=8.6 Hz).
-
- A solution of benzyl-5-(8-(tert-butoxycarbonyl)-3-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decan-1-yl)-1H-indazole-1-carboxylate (3.50 g, 0.00657 mol) in hydrochloric acid in dioxane (10 mL, 6.0 M) was stirred 1 hour. The mixture was filtered, and the filter cake was washed with petroleum ether (3×10 mL) to afford benzyl-5-(3-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decan-1-yl)-1H-indazole-1-carboxylate hydrochloride as a white solid (1.98 g, 70%).
- LCMS (ESI): m/z=434.1 [M+H]+.
-
- To a solution of benzyl-5-(3-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decan-1-yl)-1H-indazole-1-carboxylate hydrochloride (5.0 g, 0.011 mol) in dichloromethane (100 mL) was added sequentially (R)-2-(2-fluoro-5-(trifluoromethyl)benzamido)-3-methylbutanoic acid (prepared as described in Example 26-f) (2.9 g, 0.0094 mol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate (HATU) (5.33 g, 0.01406 mol), N,N-diisopropylethylamine (3.0 g, 0.024 mol). The reaction was stirred for 2 hours before quenching with ice-water (10 mL). The mixture was extracted with ethyl acetate (3×50 mL) and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by prep-TLC with dichloromethane:methanol=15:1 to afford (R)-benzyl-5-(8-(2-(2-fluoro-5-(trifluoromethyl)benzamido)-3-methylbutanoyl)-3-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decan-1-yl)-1H-indazole-1-carboxylate as a white solid (5.1 g, 76%).
- LCMS (ESI): m/z=723.0 [M+H]+.
-
- A mixture of (R)-benzyl-5-(8-(2-(2-fluoro-5-(trifluoromethyl)benzamido)-3-methyl butanoyl)-3-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decan-1-yl)-1H-indazole-1-carboxylate (350 mg, 0.48 mmol) and palladium on carbon (50 mg, 5%) in methanol (50 mL) was stirred for 3 hours under a hydrogen atmosphere. The resulting mixture was filtered and the filter cake was washed with methanol (5×10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC (acetonitrile and water, acetonitrile from 5% to 60%) to afford (R)—N-(1-(1-(1H-indazol-5-yl)-3-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decan-8-yl)-3-methyl-1-oxobutan-2-yl)-2-fluoro-5-(trifluoromethyl)benzamide as a white solid (78 mg, 27%).
- LCMS (ESI): m/z=589.2 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=0.67-0.99 (m, 6H), 1.74-2.26 (m, 5H), 3.11 (s, 3H), 3.48-3.54 (m, 1H), 3.94-4.00 (m, 1H), 4.18-4.52 (m, 2H), 4.80-4.84 (m, 1H), 7.16-7.68 (m, 3H), 7.75-7.87 (m, 2H), 7.87- 8.15 (m, 1H), 8.46-8.51 (m, 1H).
- The following 22 compounds were synthesized following the general procedure described above:
-
- 73.2 mg, yield: 30%, white solid.
- LCMS (ESI): m/z=589.0 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=0.79-1.04 (m, 6H), 1.84-2.13 (m, 5H), 3.18 (s, 3H), 3.48-3.54 (m, 1H), 4.02-4.06 (m, 2H), 4.60-4.64 (m, 1H), 4.97-5.01 (m, 1H), 6.91-6.96 (m, 1H), 7.15-7.24 (m, 1H), 7.42- 8.01 (m, 4H), 8.13-8.34 (m, 1H).
-
- 29.7 mg, yield: 37%, white solid.
- LCMS (ESI): m/z=561.2 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=0.63-1.00 (m, 10H), 1.72-2.25 (m, 6H), 3.11 (s, 3H), 3.47-3.53 (m, 1H), 3.93-3.99 (m, 1H), 4.16-4.51 (m, 2H), 4.80-4.82 (m, 1H), 6.89-7.11 (m, 1H), 7.17-7.30 (m, 2H), 7.40- 7.53 (m, 1H), 7.65-7.67 (m, 1H), 7.77-8.03 (m, 1H), 8.10-8.15 (m, 1H).
-
- 29.4 mg, yield: 46%, white solid.
- LCMS (ESI): m/z=549.2 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=0.67-1.04 (m, 6H), 1.18-1.31 (m, 3H), 1.73-2.25 (m, 5H), 2.58-2.70 (m, 2H), 3.10 (s, 3H), 3.47-3.50 (m, 1H), 3.93-3.99 (m, 1H), 4.16-4.51 (m, 2H), 4.81-4.88 (m, 1H), 6.90- 6.94 (m, 1H), 7.09-7.17 (m, 1H), 7.24-7.35 (m, 2H), 7.51-7.56 (m, 1H), 7.65-7.77 (m, 1H), 8.03-8.15 (m, 1H).
-
- 25.2 mg, yield: 39%, white solid.
- LCMS (ESI): m/z=535.2 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=0.66-0.97 (m, 6H), 1.72-2.34 (m, 8H), 3.10 (s, 3H), 3.45-3.54 (m, 1H), 3.92-3.98 (m, 1H), 4.25-4.50 (m, 2H), 4.80-4.82 (m, 1H), 6.86-7.09 (m, 1H), 7.17-7.28 (m, 3H), 7.50- 7.52 (m, 1H), 7.64-7.76 (m, 1H), 8.04-8.15 (m, 1H).
-
- 33.7 mg, yield: 41%, white solid.
- LCMS (ESI): m/z=615.2 [M+H]+.
- 1H-NMR (400 MHz, CDCl3): δ=1.23-1.96 (m, 10H), 2.09-2.23 (m, 2H), 2.34-2.40 (m, 1H), 3.10 (s, 3H), 3.48-3.54 (m, 1H), 3.92-4.00 (m, 1H), 4.30-4.33 (m, 1H), 4.47-4.51 (m, 1H), 4.83-4.84 (m, 1H), 7.14- 7.30 (m, 2H), 7.39-7.52 (m, 1H), 7.66-7.68 (m, 1H), 7.74-7.86 (m, 2H), 7.96-8.15 (m, 1H).
-
- 33.6 mg, yield: 41%, white solid.
- LCMS (ESI): m/z=601.2 [M+H]+.
- 1H-NMR (400 MHz, CDCl3): δ=1.58-1.88 (m, 10H), 2.54-2.77 (m, 1H), 3.18 (s, 3H), 3.48-3.54 (m, 1H), 3.92-4.09 (m, 2H), 4.48-4.61 (m, 1H), 5.09-5.12 (m, 1H), 7.00-7.35 (m, 3H), 7.44-7.62 (m, 2H), 7.71- 7.74 (m, 1H), 7.98-8.08 (m, 1H).
- (This compound was obtained as the des-chloro by-product of Example 57)
- 6.9 mg, yield: 11%, white solid.
- LCMS (ESI): m/z=571.2 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=0.61-0.62 (m, 1H), 0.86-0.88 (m, 1H), 0.94-1.09 (m, 4H), 1.75-2.25 (m, 5H), 3.10 (s, 3H), 3.46-3.53 (m, 1H), 3.92-3.99 (m, 1H), 4.42-4.52 (m, 2H), 4.74-4.78 (m, 1H), 7.15- 7.29 (m, 1H), 7.47-7.51 (m, 1H), 7.58-7.67 (m, 2H), 7.77-7.96 (m, 2H), 8.01-8.18 (m, 2H).
-
- 8.8 mg, yield: 14%, white solid.
- LCMS (ESI): m/z=605.2 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=0.85-0.87 (m, 1H), 0.95-0.99 (m, 4H), 1.06-1.08 (m, 1H), 1.70-1.78 (m, 1H), 1.89-1.99 (m, 1H), 2.07-2.34 (m, 3H), 3.10 (s, 3H), 3.50-3.54 (m, 1H), 3.91-3.99 (m, 1H), 4.23- 4.52 (m, 2H), 4.74-4.77 (m, 1H), 7.14-7.17 (m, 1H), 7.48-7.50 (m, 1H), 7.64-7.65 (m, 1H), 7.77-7.89 (m, 3H), 7.97-7.98 (m, 1H), 8.07-8.15 (m, 1H).
-
- 22.0 mg, yield: 54%, white solid.
- LCMS (ESI): m/z=585.2 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=0.58-1.10 (m, 6H), 1.70-1.89 (m, 3H), 2.10-2.12 (m, 4H), 2.34-2.43 (m, 1H), 3.12 (s, 3H), 3.51-3.54 (m, 1H), 3.98-4.00 (m, 1H), 4.17-4.62 (m, 2H), 4.78-4.82 (m, 1H), 7.17- 7.25 (m, 2H), 7.40-7.44 (m, 1H), 7.50-7.84 (m, 3H), 8.00-8.10 (m, 1H).
-
- 18.4 mg, yield: 28%, white solid.
- LCMS (ESI): m/z=605.2 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=0.67-0.97 (m, 6H), 1.71-2.12 (m, 5H), 3.10 (s, 3H), 3.47-3.50 (m, 1H), 3.91-3.96 (m, 1H), 4.15-4.23 (m, 1H), 4.38-4.48 (m, 1H), 4.81-4.83 (m, 1H), 7.07-7.41 (m, 6H), 8.03- 8.15 (m, 1H).
-
- 22.2 mg, yield: 34%, white solid.
- LCMS (ESI): m/z=551.2 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=0.67-0.68 (m, 1H), 0.80-0.82 (m, 1H), 0.95-0.97 (m, 4H), 1.72-1.79 (m, 1H), 1.88-1.92 (m, 1H), 2.07-2.23 (m, 3H), 3.10 (s, 3H), 3.46-3.52 (m, 1H), 3.76-3.80 (m, 3H), 3.92- 3.98 (m, 1H), 4.15-4.27 (m, 1H), 4.37-4.51 (m, 1H), 4.81-4.83 (m, 1H), 6.90-7.28 (m, 4H), 7.50-7.66 (m, 1H), 7.64-7.76 (m, 1H), 8.03-8.15 (m, 1H).
-
- 3.5 mg, 6.7% yield, white solid.
- LCMS (ESI): m/z=507.2 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=0.67-0.98 (m, 6H), 1.73-1.79 (m, 1H), 1.88-1.91 (m, 1H), 1.95-2.09 (m, 3H), 3.33 (s, 1H), 3.11 (s, 2H), 3.48-3.54 (m, 1H), 3.93-3.96 (m, 1H), 4.16-4.28 (m, 1H), 4.37-4.52 (m, 1H), 4.79-4.88 (m, 1H), 6.63-6.81 (m, 1H), 6.90-7.06 (m, 1H), 7.21-7.32 (m, 2H), 7.48-7.55 (m, 1H), 7.68-7.78 (m, 1H), 8.03-8.15 (m, 1H), 8.26-8.31 (m, 1H).
-
- 41.2 mg, 29% yield, white solid.
- LCMS (ESI): m/z=571.1, 573.1 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=0.63-1.00 (m, 6H), 1.68-2.23 (m, 5H), 3.10 (s, 3H), 3.32-3.51 (m, 1H), 3.92-3.98 (m, 1H), 4.17-4.50 (m, 2H), 4.72-4.77 (m, 1H), 7.14-7.21 (m, 2H), 7.26-7.35 (m, 1H), 7.43- 7.46 (m, 1H), 7.53-7.76 (m, 2H), 8.03-8.15 (m, 1H).
-
- 20.9 mg, 31.3% yield, white solid.
- LCMS (ESI): m/z=539.1 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=0.67-0.98 (m, 6H), 1.72-1.80 (m, 1H), 1.88-1.95 (m, 1H), 2.08-2.24 (m, 3H), 3.10 (s, 1H), 3.46-3.53 (m, 1H), 4.15-4.29 (m, 1H), 4.48-452 (m, 1H), 4.80-4.81 (m, 1H), 4.90- 4.91 (m, 1H), 7.00-7.07 (m, 4H), 7.65-7.74 (m, 1H), 8.03-8.15 (m, 2H).
-
- 2.5 mg, 10.3% yield, white solid.
- LCMS (ESI): m/z=561.3 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=0.58-0.88 (m, 6H), 1.45-1.92 (m, 20H), 3.32 (s, 3H), 3.43-3.53 (m, 1H), 3.85-3.93 (m, 1H), 4.05-4.25 (m, 1H), 4.38-4.55 (m, 1H), 4.84-4.88 (m, 1H), 7.00-7.12 (m, 1H), 7.22- 7.29 (m, 1H), 7.62-7.67 (m, 1H), 8.13-8.14 (m, 1H).
-
- 50 mg, 67% yield, white solid.
- LCMS (ESI): m/z=605.1, 607.1 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=0.99-0.66 (m, 6H), 1.71-1.80 (m, 1H), 2.00-2.28 (m, 4H), 3.12 (s, 3H), 3.48-3.58 (m, 1H), 3.94-4.05 (m, 1H), 4.34-4.54 (m, 2H), 4.74-4.82 (m, 1H), 7.18-7.34 (m, 1H), 7.40- 7.45 (m, 1H), 7.68-7.78 (m, 3H), 8.00-8.16 (m, 1H).
-
- 81.1 mg, 57% yield, white solid.
- LCMS (ESI): m/z=589.2 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=0.67-0.99 (m, 6H), 1.74-2.16 (m, 5H), 3.11 (s, 3H), 3.48-3.55 (m, 1H), 3.94-4.52 (m, 3H), 481-4.89 (m, 1H), 7.16-7.21 (m, 1H), 7.28-7.41 (m, 1H), 7.52-7.54 (m, 1H), 7.66- 7.68 (m, 1H), 7.76-7.87 (m, 2H), 7.99-8.02 (m, 1H).
-
- 14.9 mg, 15% yield, white solid.
- LCMS (ESI): m/z=547.1 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=1.80-2.13 (m, 5H), 3.10 (s, 3H), 3.42-3.61 (m, 1H), 3.83-3.91 (m, 2H), 4.21-4.23 (m, 2H), 4.39-4.49 (m, 1H), 7.20-7.23 (m, 1H), 7.34-7.40 (m, 1H), 7.60-7.63 (m, 1H), 7.71- 7.72 (m, 1H), 7.82-7.83 (m, 1H), 8.09-8.11 (m, 2H).
-
- 36.8 mg, 11% yield, white solid.
- LCMS (ESI): m/z=573.2 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=1.26-1.36 (m, 4H), 1.76-1.84 (m, 2H), 2.10-2.13 (m, 2H), 3.10 (s, 3H), 3.59-3.80 (m, 2H), 4.31-4.35 (m, 2H), 7.15-7.22 (m, 2H), 7.48-7.50 (m, 1H), 7.64-7.65 (m, 1H), 7.76- 7.83 (m, 2H), 8.01 (s, 1H).
-
- 22.2 mg, 14% yield, white solid.
- LCMS (ESI): m/z=561.1 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=1.23-1.37 (m, 3H), 1.78-2.13 (m, 4H), 3.11 (s, 3H), 3.50-3.53 (m, 1H), 3.96-4.08 (m, 2H), 4.46-4.49 (m, 1H), 5.02-5.04 (m, 1H), 7.22-7.29 (m, 1H), 7.41-7.59 (m, 1H), 7.71- 7.78. (m, 1H), 7.86-7.91 (m, 2H), 8.07-8.15 (m, 2H).
-
- 4.8 mg, 6% yield, yellow solid.
- LRMS m/z=588 [M+H]+.
- 1H-NMR (400 MHz, DMSO-d6): δ=8.61 (s, 1H), 8.51 (d, J=8.7 Hz, 1H), 8.27 (d, J=3.7 Hz, 1H), 8.15-8.09 (m, 1H), 7.94 (d, J=1.4 Hz, 1H), 7.71 (t, J=9.0 Hz, 1H), 7.65 (dd, J=8.7, 1.9 Hz, 1H), 4.76 (dd, J=16.3, 6.0 Hz, 2H), 429 (dd, J=28.0, 6.2 Hz, 2H), 3.64-3.44 (m, 2H), 3.28 (m, 2H), 3.01 (s, 3H), 2.21-2.08 (m, 2H), 1.79-1.58 (m, 2H).
-
- 23.8 mg, 14% yield, white solid.
- LCMS (ESI): m/z=597.1 [M+Na]+.
- 1H-NMR (400 MHz, CD3OD): δ=1.47 (s, 6H), 1.68-1.84 (m, 2H), 2.01-2.05 (m, 2H), 3.06 (s, 3H), 3.55-3.87 (br, 2H), 4.39-4.50 (m, 2H), 7.03-7.06 (m, 1H), 7.29-7.42 (m, 2H), 7.53-7.54 (m, 1H), 7.67-7.69 (m, 1H), 7.81-7.84 (m, 1H), 7.93-7.94 (m, 1H).
-
-
-
- To a mixture of cyclopropylmethanamine hydrochloride (500 mg, 47 mmol) in methanol: water (9:1, 50 mL) was added 1-benzylpiperidin-4-one (700 mg, 3.7 mmol) and potassium cyanide (200 mg, 3.0 mmol). The resulting mixture was stirred overnight. The reaction was quenched with aqueous potassium carbonate (10%, 30 mL). The resulting mixture was extracted with ethyl acetate (3×100 mL). The combined organic layers were dried over with anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography eluting with dichloromethane:methanol=10:1 to afford 1-benzyl-4-(cyclopropylmethylamino)piperidine-4-carbonitrile as a yellow oil (450 mg, crude), which was used directly without any further purification.
- LCMS (ESI): m/z=377.2 [M+H]+.
-
- To a solution of 1-benzyl-4-(cyclopropylmethylamino)piperidine-4-carbonitrile (450 mg, crude) in dichloromethane was added chlorosulfonyl isocyanate (300 mg, 2.11 mmol) at 0° C. After stirring for 30 minutes at 0° C., the reaction was quenched with a 5% aqueous hydrochloric acid solution (5 mL). The solvent was removed under reduced pressure and ethanol (10 mL) was added. The mixture was stirred for 30 minutes at 80° C. The solvent was removed under reduced pressure. The residue was dissolved in methanol. After stirring for 5 minutes, 5% palladium on carbon (150 mg, 50% wet with water) was added. The resulting mixture was stirred under a hydrogen atmosphere for 1 hour. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was added to tetrahydrofuran (20 mL) and the pH was adjusted to 8 by addition of aqueous potassium carbonate (15%). Then di-tert-butyl-dicarbonate (300 mg, 1.37 mmol) in tetrahydrofuran (20 mL) was added. After stirring overnight, the solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography eluting with dichloromethane:methanol=10:1 to afford tert-butyl-1-(cyclopropylmethyl)-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate as a yellow oil (200 mg, 13% over two steps).
- LCMS (ESI): m/z=324.2 [M+H]+.
-
- To a solution of tert-butyl-1-(cyclopropylmethyl)-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate (200 mg, 0.61 mmol) in N,N-dimethylformamide (2 mL) was added sodium hydride (50 mg, 60% in oil, 1.30 mmol) at 0° C. After stirring for 15 minutes, iodomethane (100 mg, 0.74 mmol) was added. The resulting mixture was stirred for 15 minutes at room temperature and the reaction was quenched with ice-water (10 mL). The mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by prep-HPLC (acetonitrile and water, acetonitrile from 5% to 50%) to afford tert-butyl-1-(cyclopropylmethyl)-3-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate as a white solid (110 mg, 52%).
- LCMS (ESI): m/z=338.2 [M+H]+.
- 1H-NMR (300 MHz, CDCl3): δ=0.29-0.35 (m, 2H), 0.46-0.57 (m, 2H), 1.45 (s, 9H), 1.56-1.69 (m, 3H), 1.83-1.94 (m, 2H), 2.98 (s, 3H), 3.08 (d, J=6.9 Hz, 2H), 3.37-3.56 (m, 2H), 3.96-4.12 (m, 2H).
-
- A solution of tert-butyl-1-(cyclopropylmethyl)-3-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate (110 mg, 0.35 mmol) in hydrochloric acid in dioxane (6.0 M, 10 mL) was stirred for 30 minutes. The solvent was removed under reduced pressure. To the residue was added dichloromethane (5 mL), (R)-2-(2-fluoro-5-(trifluoromethyl)benzamido)-3-methylbutanoic acid (prepared as described in Example 28-f) (100 mg, 0.34 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate (HATU) (150 mg, 0.39 mmol) and N,N-diisopropylethylamine (150 mg, 1.16 mmol). The resulting mixture was stirred for 2 hours at room temperature before the reaction was quenched with ice-water (5 mL). The mixture was extracted with ethyl acetate (3×10 mL) and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by prep-TLC with dichloromethane:methanol=15:1 to afford (R)—N-(1-(1-(cyclopropylmethyl)-3-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decan-8-yl)-3-methyl-1-oxobutan-2-yl)-2-fluoro-5-(trifluoromethyl)benzamide as a white solid (44.6 mg, 24%).
- LCMS (ESI): m/z=527.2 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=0.29-0.33 (m, 2H), 0.46-0.54 (m, 3H), 1.04-1.11 (m, 6H), 1.75-1.84 (m, 2H), 1.95-2.05 (m, 1H), 2.15-2.19 (m, 1H), 2.35-2.41 (m, 1H), 3.01 (s, 3H), 3.17-3.20 (m, 2H), 3.42- 3.48 (m, 1H), 3.92-3.95 (m, 1H), 4.11-4.33 (m, 1H), 4.57-4.60 (m, 1H), 4.90-4.95 (m, 1H), 7.41-7.48 (m, 1H), 7.91 (s, 1H), 8.04-8.06 (m, 1H), 8.56 (s, 1H).
- The following 5 compounds were synthesized following the general procedure described above:
-
- 137.2 mg, yield: 12%, white solid.
- LCMS (ESI): m/z=513.1 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=0.78-0.91 (m, 4H), 1.03-1.11 (m, 6H), 1.80-1.97 (m, 2H), 2.14-2.48 (m, 4H), 2.97 (s, 3H), 3.46-3.52 (m, 1H), 3.93-3.99 (m, 1H), 4.32-4.34 (m, 1H), 4.57-4.61 (m, 1H), 4.95- 5.01 (m, 1H), 7.45-7.50 (m, 1H), 7.89-7.90 (m, 1H), 8.03-8.05 (m, 1H), 8.60 (m, 1H).
-
- 7.8 mg, yield: 4%, white solid.
- LCMS (ESI): m/z=557.2 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=1.05-1.12 (m, 6H), 1.47-1.57 (m, 2H), 1.75-2.02 (m, 3H), 2.12-2.28 (m, 1H), 2.37-2.68 (m, 3H), 2.96 (s, 3H), 3.50-3.53 (m, 4H), 3.88-4.06 (m, 3H), 4.28-4.36 (m, 1H), 4.54- 4.66 (m, 1H), 4.87-5.00 (m, 1H), 7.47-7.60 (m, 1H), 7.90-7.92 (m, 1H), 7.95-7.89 (m, 1H).
-
- 45.0 mg, yield: 36%, white solid.
- LCMS (ESI): m/z=577.2 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=1.02-1.15 (m, 6H), 1.77-2.23 (m, 8H), 3.00 (s, 3H), 3.41-3.47 (m, 1H), 3.91-3.97 (m, 1H), 4.29-4.32 (m, 1H), 4.49-4.68 (m, 2H), 4.87-4.94 (m, 1H), 7.21-7.50 (m, 5H), 7.88- 8.08 (m, 2H), 8.47-8.59 (m, 1H).
-
- 71.7 mg, yield: 42%, white solid.
- LCMS (ESI): m/z=571.2 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=1.04-1.11 (m, 6H), 1.12-1.14 (m, 1H), 1.27-1.30 (m, 2H), 1.61-1.67 (m, 2H), 1.17-2.08 (m, 5H), 2.37-2.44 (m, 1H), 2.99 (s, 3H), 3.12-3.17 (m, 2H), 3.30-3.46 (m, 2H), 3.90- 3.97 (m, 3H), 4.30-4.33 (m, 1H), 4.58-4.61 (m, 2H), 4.96-4.98 (m, 2H), 7.45-7.50 (m, 1H), 7.09-7.92 (m, 1H), 8.06-8.07 (m, 1H).
-
- 16.0 mg, yield: 14%, white solid.
- LCMS (ESI): m/z=577.2 [M+H].
- 1H-NMR (400 MHz, CD3OD): δ=0.95-1.14 (m, 6H), 1.69 (m, 1H), 1.87 (m, 5H), 2.17 (m, 1H), 2.25-2.43 (m, 1H), 3.04 (s, 3H), 3.37-3.61 (m, 1H), 3.90-4.22 (m, 2H), 4.43 (m, 1H), 4.62 (m, 1H), 5.08 (m, 1H), 7.2-7.61 (m, 7H), 7.72-7.84 (m, 1H), 8.29-8.43 (m, 1H).
-
-
-
- To a solution of 4-methoxyaniline (2 g, 16 mmol) in acetic acid (20 mL) was added tert-butyl-4-oxopiperidine-1-carboxylate (3.5 g, 17.5 mmol). The resulting mixture was cooled to 0° C. and trimethylsilyl cyanide (1.9 g, 19 mmol) was added. The solution was stirred overnight at room temperature. Saturated aqueous ammonium chloride solution was added (50 mL). The mixture was extracted with ethyl acetate (3×50 mL) and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with dichloromethane: petroleum ether=1:1 to afford tert-butyl-4-cyano-4-(4-methoxyphenylamino)piperidine-1-carboxylate as a white solid (5.0 g, 86%).
- LCMS (ESI): m/z=332.2 [M+H]+.
- 1H-NMR (300 MHz, DMSO-d6): δ=1.40 (s, 9H), 1.65-1.89 (m, 2H), 2.06-2.19 (m, 2H), 3.01-3.21 (m, 2H) 3.68 (s, 3H), 3.72-3.88 (m, 2H), 5.50 (s, 1H), 6.80 (d, J=9 Hz, 2H), 6.90 (d, J=9 Hz, 2H).
-
- To a solution of tert-butyl-4-cyano-4-(4-methoxyphenyl amino)piperidine-1-carboxylate (2.0 g, 6 mmol) in dichloromethane was added chlorosulfonyl isocyanate (2.3 g, 16 mmol) at 0° C. After stirring for 30 minutes at 0° C., the reaction was quenched with a 5% aqueous hydrochloric acid solution (2 mL). The solvent was removed under reduced pressure and ethanol (10 mL) was added. The mixture was stirred for 30 minutes at 80° C. The solvent was removed under reduced pressure and the residue was dissolved in tetrahydrofuran (20 mL) and the pH of the mixture was adjusted to pH 8 by addition of a 10% aqueous potassium carbonate solution. Then di-tert-butyl-dicarbonate (2.5 g, 11 mmol) in tetrahydrofuran (20 mL) was added. After stirring overnight, the solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography eluting with ethyl acetate:petroleum ether=10:1 to afford tert-butyl-1-(4-methoxyphenyl)-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate as a white solid (1.02 g, 45%).
- LCMS (ESI): m/z=376.2 [M+H]+.
-
- To a solution of tert-butyl-1-(4-methoxyphenyl)-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate (1.0 mg, 2.6 mmol) in N,N-dimethylformamide (10 mL) was added sodium hydride (0.2 g, 60% in oil, 5.2 mmol) at 0° C. After stirring for 15 minutes, iodomethane (0.37 g, 6 mmol) was added. The resulting mixture was stirred for 15 minutes. The reaction was quenched with ice-water (10 mL). The mixture was extracted with ethyl acetate (3×50 mL) and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with ethyl acetate:petroleum ether=1:3 to afford tert-butyl-1-(4-methoxyphenyl)-3-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate as a white solid (140 mg, 67%).
- LCMS (ESI): m/z=390.2 [M+H]+.
- 1H-NMR (300 MHz, CDCl3): δ=1.39 (s, 9H), 1.62-1.86 (m, 4H), 3.09 (s, 3H), 3.39-3.56 (m, 2H), 3.86 (s, 3H), 3.89-4.00 (m, 2H), 3.78-3.82 (m, 2H), 6.94 (d, J=9 Hz, 2H), 7.07 (d, J=9 Hz, 2H).
-
- To a solution of tert-butyl-1-(4-methoxyphenyl)-3-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate (1.0 g, 2.5 mmol) in dichloromethane (50 mL) was added boron tribromide (4 g, 15 mmol) at 0° C. After stirring overnight, the reaction was quenched by addition of ice-water (5 mL). To the mixture were added benzyl chloroformate (1.56 g, 3.6 mmol) and a 10% aqueous sodium hydroxide solution (12 mL). The mixture was stirred for 2 hours. The organic layer was separated and discarded. The pH of the aqueous layer was adjusted to 2 by addition of 10% aqueous hydrochloric acid solution. The resulting mixture was extracted with dichloromethane (3×50 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was washed with ethyl acetate (30 mL) to afford benzyl-1-(4-hydroxyphenyl)-3-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate as a white solid (620 mg, 59%)
- LCMS (ESI): m/z=410.1 [M+H]f.
-
- To a solution of benzyl-1-(4-hydroxyphenyl)-3-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate (150 mg, 0.367 mmol) in N,N-dimethylformamide (15 mL) was added potassium hydride (50 mg, 1.25 mmol) at 0° C. After stirring for 30 minutes at 0° C., to the resulting solution was added tert-butyl-3-((methylsulfonyloxy)methyl)azetidine-1-carboxylate (243 mg, 0.917 mmol). The resulting mixture was stirred overnight before the reaction was quenched by addition of ice-water (10 mL). The mixture was extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by prep-TLC (dichloromethane:methanol=20:1) to afford benzyl-1-(4-((1-(tert-butoxycarbonyl)azetidin-3-yl)methoxy)phenyl)-3-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate as a colorless oil (130 mg, 71%).
- LCMS (ESI): m/z=579.2 [M+H]+.
-
- To a solution of benzyl-1-(4-((1-(tert-butoxycarbonyl)azetidin-3-yl)methoxy)phenyl)-3-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate (130 mg, 0.225 mmol) in methanol (10 mL) was added 5% palladium on carbon (70 mg). The resulting mixture was stirred for 1 hour under a hydrogen atmosphere. The catalyst was removed by filtration and the solvent was removed under reduced pressure to afford tert-butyl-3-((4-(3-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decan-1-yl)phenoxy)methyl)azetidine-1-carboxylate as a white solid (31 mg, 100%).
- LCMS (ESI): m/z=445.2 [M+H]+.
-
- To a solution of tert-butyl-3-((4-(3-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decan-1-yl) phenoxy)methyl)azetidine-1-carboxylate (107 mg, 0.240 mmol) in dichloromethane (10 mL) was added (R)-2-(2-fluoro-5-(trifluoromethyl)benzamido)-3-methylbutanoic acid (prepared as described in Example 28-f) (80 mg, 0.247 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate (HATU) (128 mg, 0.337 mmol) and N,N-diisopropylethylamine (44 mg, 0.337 mmol).
- The resulting mixture was stirred for 2 hours at room temperature before the reaction was quenched with ice-water (10 mL). The mixture was extracted with ethyl acetate (3×10 mL) and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by prep-TLC with dichloromethane:methanol=15:1 to afford (R)-tert-butyl-3-((4-(8-(2-(2-fluoro-5-(trifluoromethyl)benzamido)-3-methylbutanoyl)-3-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decan-1-yl)phenoxy)methyl)azetidine-1-carboxylate as a white solid (80 mg, crude), which was used directly without any further purification.
- LCMS (ESI): m/z=734.1 [M+H]+.
-
- To a solution of (R)-tert-butyl-3-((4-(8-(2-(2-fluoro-5-(trifluoromethyl)benzamido)-3-methylbutanoyl)-3-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decan-1-yl)phenoxy)methyl)azetidine-1-carboxylate (80 mg, crude) in dichloromethane (10 mL) was added trifluoroacetic acid (2 mL). The resulting mixture was stirred for 2 hours. The solvents were removed under reduced pressure and the residue was purified by prep HPLC (acetonitrile and water, acetonitrile from 30% to 70%) to afford (R)—N-(1-(1-(1-(4-(azetidin-3-ylmethoxy)phenyl)-3-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decan-8-yl)-3-methyl-1-oxobutan-2-yl)-2-fluoro-5-(trifluoromethyl)benzamide trifluoroacetic acid salt as a white solid (48 mg, 26% over two steps).
- LCMS (ESI): m/z=634.0 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=0.82-1.01 (m, 6H), 1.67-2.11 (m, 5H), 3.09 (s, 3H), 3.38-3.51 (m, 2H), 3.97-4.44 (m, 9H), 4.83-4.90 (m, 1H), 7.18-8.50 (m, 8H).
- The following 4 compounds were synthesized following the general procedure described above:
-
- 60.3 mg, yield: 25%, white solid.
- LCMS (ESI): m/z=604 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=0.79-1.01 (m, 6H), 1.77-2.12 (m, 5H), 3.09 (s, 3H), 3.31-3.33 (m, 1H), 3.95-4.51 (m, 3H), 4.85-4.97 (m, 2H), 5.07 (s, 1H), 7.06-7.46 (m, 5H), 7.87-8.01 (m, 2H), 8.50-8.53 (m, 1H).
-
- 43.0 mg, yield: 51%, white solid.
- LCMS (ESI): m/z=635 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=0.82-1.02 (m, 6H), 1.31-2.20 (m, 6H), 3.08 (s, 3H), 3.41-3.53 (m, 2H), 3.92-3.98 (m, 1H), 4.12-4.64 (m, 6H), 485-492 (m, 2H), 6.96-8.51 (m, 8H).
-
- 45.0 mg, yield: 19%, white solid.
- LCMS (ESI): m/z=609.2 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=0.80-1.01 (m, 6H), 1.67-1.88 (m, 2H), 2.05-2.18 (m, 3H), 3.08 (s, 3H), 3.49-3.51 (m, 1H), 3.86-4.05 (m, 4H), 4.11-4.16 (m, 1H), 4.22-4.28 (m, 1H), 4.45 (m, 1H), 4.86-5.01 (m, 1H), 6.94-7.00 (m, 1H), 7.06-7.22 (m, 3H), 7.44-7.49 (m, 1H), 7.94-8.03 (m, 2H).
-
- 15.9 mg, yield: 20%, white solid.
- LCMS (ESI): m/z=635.7 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=0.80-1.01 (m, 6H), 1.66-1.83 (m, 1H), 2.04-2.17 (m, 4H), 2.99 (s, 4H), 3.02 (s, 2H), 3.12 (s, 3H), 3.50-3.54 (m, 1H), 3.56-3.63 (m, 2H), 3.99-4.02 (m, 1H), 4.21-4.25 (m, 1H), 4.34-4.50 (m, 3H), 4.82-4.90 (m, 1H), 7.06-7.12 (m, 2H), 7.22-7.29 (m, 2H), 7.41-7.47 (m, 1H), 7.88- 8.02 (m, 2H).
-
-
-
- To a solution of 4-nitroaniline (5 g, 0.036 mol) in acetic acid (80 mL) was added tert-butyl-4-oxopiperidine-1-carboxylate (7.93 g, 0.0399 mol). The resulting mixture was cooled to 0° C. and trimethylsilyl cyanide (4.3 g, 0.043 mol) was added. The resulting solution was stirred overnight at room temperature. To the solution was added saturated aqueous ammonium chloride solution (50 mL). The mixture was filtered and the filter cake was recrystallized from ethyl acetate to afford tert-butyl-4-cyano-4-(4-nitrophenylamino)piperidine-1-carboxylate as a white solid (4 g, 32%).
- LCMS (ESI): m/z=347.2 [M+H]+.
-
- To a solution of tert-butyl-4-cyano-4-(4-nitrophenylamino)piperidine-1-carboxylate (3.8 g, 0.0109 mol) in dichloromethane was added chlorosulfonyl isocyanate (3.8 g, 0.026 mol) at 0° C. After stirring for 30 minutes at 0° C., the reaction was quenched with a 5% aqueous hydrochloric acid solution (5 mL). The solvent was removed under reduced pressure and ethanol (20 mL) was added. The mixture was stirred for 30 minutes at 80° C. The solvent was removed under reduced pressure and the residue was added to dichloromethane (20 mL). To the resulting suspensions was added sequentially triethylamine (4.4 g, 0.044 mol), di-tert-butyl-dicarbonate (2.39 g, 0.011 mol). After stirring overnight, the solvent was removed and the residue was recrystallized from ethyl acetate:petroleum ether=1:2 to afford tert-butyl-1-(4-nitrophenyl)-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate as a yellow oil (2.2 g, 52%).
- LCMS (ESI): m/z=391.2 [M+H]+.
-
- To a solution of tert-butyl-1-(4-nitrophenyl)-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate (2.2 g, 5.64 mmol) in N,N-dimethylformamide (15 mL) was added sodium hydride (0.237 g, 60% in oil, 6.2 mmol) at 0° C. After stirring for 15 minutes, iodomethane (961 mg, 6.77 mmol) was added. The resulting mixture was stirred for 15 minutes at room temperature and the reaction was quenched with ice-water (10 mL). The mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate petroleum ether=1:2 to afford tert-butyl-3-methyl-1-(4-nitrophenyl)-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate as a yellow solid (1.66 g, 70%).
- LCMS (ESI): m/z=405.1 [M+H].
-
- A solution of tert-butyl-3-methyl-1-(4-nitrophenyl)-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate (800 mg, 1.98 mmol) in hydrochloric acid in dioxane (6.0 M, 10 mL) was stirred for 30 minutes. The precipitate was collected by filtration and dried under reduced pressure to afford 3-methyl-1-(4-nitrophenyl)-1,3,8-triazaspiro[4.5]decane-2,4-dione hydrochloride as a white solid (700 mg, some residual solvent), which was used directly without further purification.
- LCMS (ESI): m/z=305.1 [M+H]+.
-
- To a solution of 3-methyl-1-(4-nitrophenyl)-1,3,8-triazaspiro[4.5]decane-2,4-dione hydrochloride (700 mg, 2.05 mmol) in dichloromethane (10 mL) was added sodium carbonate (652 mg, 6.5 mmol) and water (10 mL). To the mixture was added benzyl chloroformate (350 mg, 2.05 mmol) dropwise. The resulting mixture was stirred for 1 hour at room temperature and the reaction was quenched with ice-water (10 mL). The mixture was extracted with dichloromethane (3×50 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate:petroleum ether=1:2 to afford benzyl-3-methyl-1-(4-nitrophenyl)-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate as a yellow solid (810 mg, 90%).
- LCMS (ESI): m/z=439.1 [M+H]+.
-
- To a solution of benzyl-3-methyl-1-(4-nitrophenyl)-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate (100 mg, 0.28 mmol) in ethanol (10 mL) was added Raney-Ni (0.1 g, 50% in ethanol). After heating to 5000, to the resulting mixture hydrazine (0.1 g, 2.5 mmol) was added dropwise. Before removing the Raney-Ni by filtration, the reaction mixture was stirred at 50° C. for 30 minutes. The solvent was removed under reduced pressure and the residue was used directly without further purification.
-
- To a solution of tert-butyl-3-oxoazetidine-1-carboxylate (59 mg, 0.343 mmol) and benzyl-1-(4-aminophenyl)-3-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate (140 mg, 0.68 mmol) in dichloromethane (30 mL) was added titaniumisopropoxide (178 mg, 0.68 mmol). The resulting mixture was heated at reflux overnight. After cooling to room temperature, to the resulting solution was added sodium triacetoxyborohydride (210 mg, 1.0 mmol). The reaction was stirred for 2 hours. The reaction was quenched with an aqueous sodium hydroxide solution (1.0 M, 10 mL). The mixture was extracted with ethyl acetate (3×10 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by prep-TLC (ethyl acetate: petroleum ether=1:1) to afford benzyl-1-(4-(1-(tert-butoxycarbonyl)azetidin-3-ylamino)phenyl)-3-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate as a white solid (30 mg, 15%).
-
- To a solution of benzyl-1-(4-(1-(tert-butoxycarbonyl)azetidin-3-ylamino)phenyl)-3-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate (120 mg, 0.213 mmol) in methanol (10 mL) was added 5% palladium on carbon (10 mg, 50% wet with water). The resulting mixture was stirred under a hydrogen atmosphere for 1 hour. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure to afford tert-butyl-3-(4-(3-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decan-1-yl)phenylamino)azetidine-1-carboxylate as a thick oil (90 mg, crude), which was used directly without any further purification.
-
- To a solution of tert-butyl-3-(4-(3-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decan-1-yl) phenylamino)azetidine-1-carboxylate (90 mg, 0.21 mmol) in dichloromethane (5 mL) was added sequentially (R)-2-(2-fluoro-5-(trifluoromethyl)benzamido)-3-methylbutanoic acid (prepared as described in Example 28-f) (65 mg, 0.21 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate (HATU) (260 mg, 0.68 mmol) and N,N-diisopropylethylamine (180 mg, 1.36 mmol). The resulting mixture was stirred for 2 hours at room temperature before the reaction was quenched with ice-water. The mixture was extracted with ethyl acetate (3×10 mL) and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by prep-TLC with dichloromethane:methanol=15:1 to afford (R)-tert-butyl-3-(4-(8-(2-(2-fluoro-5-(trifluoromethyl)benzamido)-3-methylbutanoyl)-3-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decan-1-yl)phenylamino)azetidine-1-carboxylate as a white solid (50 mg, 33%).
- LCMS (ESI): m/z=719.0 [M+H]+.
-
- To a solution of (R)-tert-butyl-3-(4-(8-(2-(2-fluoro-5-(trifluoromethyl)benzamido)-3-methylbutanoyl)-3-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decan-1-yl)phenylamino)azetidine-1-carboxylate (50 mg, 0.21 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (2 mL) at 0° C. The reaction was stirred 3 hours at room temperature. The solvent was removed under reduced pressure and the residue was purified by prep-HPLC (acetonitrile and water, acetonitrile from 30% to 60%) to afford (R)—N-(1-(1-(4-(azetidin-3-ylamino)phenyl)-3-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decan-8-yl)-3-methyl-1-oxobutan-2-yl)-2-fluoro-5-(trifluoromethyl)benzamide trifluoroacetic acid salt as a white solid (17.8 mg, 35%).
- LCMS (ESI): m/z=619.0 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=0.80-1.01 (m, 6H), 1.68-2.03 (m, 6H), 3.07 (s, 3H), 3.45-3.52 (m, 1H), 3.93-4.46 (m, 7H), 4.83-4.85 (m, 1H), 6.58-6.69 (m, 2H), 7.01-7.07 (m, 2H), 7.41-7.46 (m, 1H), 7.87- 8.00 (m, 2H), 8.48-8.53 (m, 1H).
- The following compound was synthesized following the general procedure described above:
-
- 32.6 mg, yield: 43%, white solid
- LCMS (ESI): m/z=620.0 [M+H]+.
- 1H-NMR (400 MHz, CDCl3): δ=0.80-1.01 (m, 6H), 1.67-2.03 (m, 5H), 3.06 (s, 3H), 3.42-3.48 (m, 1H), 3.94-4.53 (m, 7H), 4.88-5.01 (m, 2H), 6.47-6.62 (m, 2H), 6.93-7.01 (m, 2H), 7.41-7.46 (m, 1H), 7.86- 7.95 (m, 2H).
-
-
-
- A mixture of benzyl-4-oxopiperidine-1-carboxylate (11.7 g, 50 mmol), potassium cyanide (4.87 g, 75 mmol) and ammonium carbonate (24 g, 250 mmol) in ethanol (100 mL), was placed in a stainless steel bomb and heated at 110° C. overnight. The reaction mixture was poured into ice-water (300 mL) and the resulting mixture was filtered. The pH of the mixture in water (100 mL) was adjusted to 2 by addition of an aqueous hydrochloric acid solution (6.0 M). The mixture was filtered and the filter cake was recrystallized from methanol: diethyl ether=1:1 to afford benzyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate as a white solid (10.0 g, 66%).
- LCMS (ESI): m/z=304.1 [M+H]+.
- 1H-NMR (300 MHz, DMSO-dG): δ=1.43-1.56 (m, 2H), 1.63-1.85 (m, 2H), 2.45-2.60 (m, 2H), 3.33 (s, 2H), 3.88 (dd, J=9.7, 4.0 Hz, 2H), 5.09 (s, 2H), 7.20-7.53 (m, 5H), 8.54 (s, 1H), 10.66 (s, 1H).
-
- To a solution of benzyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate (3.03 g, 10 mmol) in N,N-dimethylformamide (20 mL), was added potassium carbonate (2.76 g, 20 mmol). After stirring for 15 minutes, iodomethane (1.42 g, 10 mmol) was added. Before quenching with ice-water (10 mL), the resulting mixture was stirred at room temperature overnight. The mixture was extracted with dichloromethane (3×150 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with dichloromethane:methanol=50:1) to afford benzyl-3-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate as a white solid (1.0 g, 32%).
- LCMS (ESI): m/z=318.1 [M+H].
- 1H-NMR (300 MHz, CDCl3): δ=1.57 (m, 2H), 1.70-1.85 (m, 2H), 2.84 (s, 3H), 3.24 (s, 2H), 3.84-3.90 (m, 2H), 5.10 (s, 2H), 7.29-7.45 (m, 5H), 8.81 (s, 1H).
-
- To a solution of benzyl-3-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate (110 mg, 0.347 mmol) in N,N-dimethylformamide (5 mL), was added cesium carbonate (452 mg, 1.39 mmol), and 4-(bromomethyl)benzonitrile (136 mg, 0.69 mmol). The resulting mixture was stirred at 80° C. for 4 hours, before the reaction was quenched with ice-water (10 mL). The mixture was extracted with dichloromethane (3×50 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting (ethyl acetate:petroleum ether=1:2) to afford benzyl-1-(4-cyanobenzyl)-3-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate as a white solid (130 mg, 86%).
- LCMS (ESI) m/z=433.1 [M+H]+.
- 1H-NMR (300 MHz, CDCl3): δ=1.70 (m, 4H), 3.07 (s, 3H), 3.52 (s, 2H), 4.11 (dd, J=14.3 Hz, J=7.1 Hz, 2H), 4.48 (s, 2H), 5.11 (s, 2H), 7.33-7.42 (m, 2H), 7.55-7.66 (m, 2H).
-
- To a solution of benzyl-1-(4-cyanobenzyl)-3-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate (130 mg, 0.3 mmol) in dichloromethane (1 mL) was added hydrobromic acid (2 mL, 38% in acetic acid) at 0° C. Then the reaction was warmed to room temperature and stirred for 2 hours. The solvent was removed under reduced pressure to afford 4-((3-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decan-1-yl)methyl)benzonitrile hydrobromide as a white solid (100 mg, crude), which was used directly without any further purification.
- LCMS (ESI): m/z=299.2 [M+H]+.
-
- To the mixture of 4-((3-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decan-1-yl)methyl)benzonitrile hydrobromide (100 mg, crude) was added dichloromethane (5 mL), (R)-2-(2-fluoro-5-(trifluoromethyl)benzamido)-3-methylbutanoic acid (prepared as described in Example 28-f) (81 mg, 0.26 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate (HATU) (146 mg, 0.38 mmol) and N,N-diisopropylethylamine (83 mg, 0.64 mmol). The resulting mixture was stirred for 2 hours at room temperature before the reaction was quenched with ice-water. The mixture was extracted with dichloromethane (3×10 mL) and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by prep-TLC with dichloromethane:methanol=15:1 to afford (R)—N-(1-(1-(4-cyanobenzyl)-3-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decan-8-yl)-3-methyl-1-oxobutan-2-yl)-2-fluoro-5-(trifluoromethyl)benzamide as a white solid (56 mg, 41%).
- LCMS (ESI): m/z=588.0 [M+H].
- 1H-NMR (400 MHz, CD3OD): δ=0.89-0.96 (m, 6H), 1.62-2.22 (m, 5H), 2.95 (s, 3H), 3.25-3.31 (m, 1H), 3.75-3.82 (m, 1H), 4.13-4.16 (m, 1H), 4.39-4.54 (m, 3H), 4.74-4.79 (m, 1H), 7.34-7.62 (m, 5H), 7.79- 7.95 (m, 2H), 8.35-8.44 (m, 1H).
- The following 38 compounds were synthesized following the general procedure described above:
-
- 140.8 mg, yield: 57%, white solid.
- LCMS (ESI): m/z=562.9 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=1.00-1.06 (m, 6H), 1.65-1.87 (m, 3H), 2.05-2.17 (m, 1H), 2.30-2.38 (m, 1H), 3.07 (s, 3H), 3.32-3.33 (m, 2H), 3.37-3.44 (m, 1H), 3.87-3.93 (m, 1H), 4.12-4.27 (m, 1H), 4.45- 4.72 (m, 2H), 7.21-7.33 (m, 5H), 7.42-7.51 (m, 1H), 7.87-8.10 (m, 2H), 8.50 (m, 1H).
-
- 100.0 mg, yield: 45%, white solid.
- LCMS (ESI): m/z=581.1[M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=1.01-1.07 (m, 6H), 1.66-1.89 (m, 3H), 2.12-2.39 (m, 2H), 3.06 (s, 3H), 3.36-3.44 (m, 1H), 3.87-3.93 (m, 1H), 4.11-4.32 (m, 1H), 4.48-4.65 (m, 3H), 4.85-4.90 (m, 1H), 6.95- 7.10 (m, 2H), 7.37-7.47 (m, 3H), 7.91-8.06 (m, 2H), 8.53 (s, 1H).
-
- 48.5 mg, yield: 40%, white solid.
- LCMS (ESI): m/z=593.2 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=1.01-1.06 (m, 6H), 1.60-2.38 (m, 5H), 3.32-3.39 (m, 2H), 3.79-3.84 (m, 3H), 3.89-3.93 (m, 1H), 4.11-4.26 (m, 1H), 4.42-4.66 (m, 2H), 6.77-6.90 (m, 2H), 7.24-7.26 (m, 2H), 7.41-7.53 (m, 1H), 7.44-7.51 (m, 1H), 7.87-7.90 (m, 1H), 8.10-8.12 (m, 1H).
-
- 27.9 mg, yield: 14%, white solid.
- LCMS (ESI): m/z=577.2 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=1.02-1.15 (m, 6H), 1.67-2.18 (m, 5H), 3.00 (s, 3H), 3.07 (s, 3H), 3.41-3.47 (m, 1H), 3.91-3.97 (m, 1H), 4.29-4.32 (m, 1H), 4.49-4.68 (m, 2H), 4.87-4.94 (m, 1H), 7.21-7.50 (m, 5H), 7.88-8.08 (m, 2H), 8.47-8.59 (m, 1H).
-
- 37.5 mg, yield: 40%, white solid.
- LCMS (ESI): m/z=641.2 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=0.99-1.07 (m, 6H), 1.75-2.32 (m, 5H), 3.13-3.17 (m, 6H), 3.87-3.93 (m, 1H), 4.25-4.28 (m, 1H), 4.51-4.54 (m, 1H), 4.75-4.65 (m, 2H), 4.84-4.90 (m, 2H), 7.65-7.61 (m, 3H), 8.06-8.08 (m, 3H), 8.47-8.59 (m, 1H).
-
- 52.3 mg, yield: 20%, white solid.
- LCMS (ESI): m/z=594.2 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=1.01-1.07 (m, 6H), 1.83-2.15 (m, 5H), 2.65-2.94 (m, 1H), 3.08 (s, 3H), 3.33-3.44 (m, 1H), 3.94-3.97 (m, 4H), 4.25-4.27 (m, 1H), 4.55-4.64 (m, 2H), 4.84-4.88 (m, 1H), 6.96- 7.11 (m, 2H), 7.45-7.47 (m, 1H), 7.91-8.10 (m, 3H).
-
- 41.6 mg, yield: 43%, white solid.
- LCMS (ESI): m/z=578.2 [M+H]f.
- 1H-NMR (400 MHz, CD3OD): δ=1.02-1.08 (m, 6H), 1.86-2.24 (m, 5H), 2.73 (s, 3H), 3.09 (s, 3H), 3.43-3.47 (m, 1H), 3.90-3.96 (m, 1H), 4.26-4.30 (m, 1H), 4.57-4.60 (m, 1H), 4.79-4.84 (m, 3H), 7.45-7.48 (m, 1H), 7.87-8.02 (m, 4H), 8.58-8.65 (m, 1H).
-
- 38.8 mg, yield: 22%, white solid.
- LCMS (ESI): m/z=621.0 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=1.02-1.07 (m, 6H), 1.61-1.77 (m, 3H), 2.11-2.35 (m, 2H), 3.05 (s, 3H), 3.32-3.37 (m, 2H), 3.87-3.89 (m, 1H), 4.15-4.40 (m, 4H), 4.38-4.49 (m, 3H), 4.87-4.91 (m, 1H), 6.67- 6.80 (m, 3H), 7.43-7.49 (m, 1H), 7.89-8.12 (m, 2H).
-
- 61.5 mg, yield: 32%, white solid.
- LCMS (ESI): m/z=594.2 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=1.03-1.08 (m, 6H), 1.71-1.94 (m, 3H), 2.13-2.18 (m, 1H), 2.34-2.42 (m, 1H), 3.04 (s, 3H), 3.37-3.46 (m, 1H), 3.88-3.94 (m, 4H), 4.18-4.30 (m, 1H), 4.50-4.65 (m, 3H), 4.80 (s, 1H), 6.84-6.87 (m, 1H), 7.43-7.51 (m, 1H), 7.74-8.55 (m, 5H).
-
- 2.9 mg, yield: 7%, white solid.
- LCMS (ESI): m/z=603.2 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=0.92-1.05 (m, 6H), 1.65-2.42 (m, 5H), 3.09 (s, 3H), 3.33-3.44 (m, 2H), 3.85-4.48 (m, 2H), 4.62-4.79 (m, 2H), 4.80-4.81 (m, 1H), 7.40-7.58 (m, 3H), 7.74-7.75 (m, 1H), 7.23- 8.54 (m, 3H).
-
- 51.0 mg, yield: 47%, white solid.
- LCMS (ESI): m/z=597.2 [M+H]+.
- 1H-NMR (400 MHz, CD3OD) δ=1.02-1.07 (m, 6H), 1.67-2.33 (m, 5H), 3.06 (s, 3H), 3.33-3.41 (m, 1H), 3.90-4.21 (m, 2H), 4.52-4.60 (m, 2H), 4.64-4.87 (m, 2H), 7.24-7.47 (m, 5H), 7.91-8.09 (m, 2H).
-
- 25.0 mg, yield: 20%, white solid.
- LCMS (ESI): m/z=615.2 [M+H].
- 1H-NMR (400 MHz, CD3OD): δ=1.00-1.06 (m, 6H), 1.75-2.38 (m, 5H), 3.11 (s, 3H), 3.42-3.43 (m, 1H), 3.91-4.50 (m, 3H), 4.87-4.79 (m, 2H), 4.90-5.00 (m, 1H), 7.38-7.52 (m, 1H), 7.82-7.94 (m, 2H), 7.98- 8.15 (m, 3H), 8.82-8.96 (m, 2H).
-
- 28.0 mg, yield: 18%, white solid.
- LCMS (ESI): m/z=588.2 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=1.01-1.06 (m, 6H), 1.83-2.34 (m, 5H), 3.06 (s, 3H), 3.33-3.43 (m, 1H), 3.90-4.25 (m, 2H), 4.63-4.50 (m, 3H), 4.84-4.86 (m, 1H), 7.47-7.70 (m, 5H), 7.89-8.08 (m, 2H), 8.52 (s, 1H).
-
- 26.3 mg, yield: 16%, white solid.
- LCMS (ESI): m/z=603.2 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=1.03-1.08 (m, 6H), 1.83-2.03 (m, 3H), 2.12-2.19 (m, 1H), 2.33-2.40 (m, 1H), 3.08 (s, 3H), 3.42-3.49 (m, 1H), 3.89-3.96 (m, 1H), 4.24-4.28 (m, 1H), 4.57-4.60 (m, 1H), 4.69- 4.84 (m, 3H), 7.46-7.51 (m, 1H), 7.87-8.21 (m, 6H), 8.30-8.62 (m, 1H).
-
- 22.9 mg, yield: 19%, white solid.
- LCMS (ESI): m/z=641.0 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=1.02-1.07 (m, 6H), 1.74-1.91 (m, 4H), 2.28-2.35 (m, 1H), 3.07-3.14 (m, 6H), 3.43-3.49 (m, 1H), 3.87-3.94 (m, 1H), 4.11-4.28 (m, 2H), 4.51-4.55 (m, 1H), 4.64-4.78 (m, 2H), 7.45-7.57 (m, 2H), 7.62-7.72 (m, 2H), 7.83-8.09 (m, 3H).
-
- 13.6 mg, yield: 8%, white solid.
- LCMS (ESI): m/z=597.1 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=1.02-1.07 (m, 6H), 1.67-1.85 (m, 3H), 2.05-2.15 (m, 1H), 2.34-2.38 (m, 1H), 3.06 (s, 3H), 3.38-4.44 (m, 1H), 3.86-4.28 (m, 3H), 4.50-4.54 (m, 1H), 4.61-4.71 (m, 1H), 4.86- 4.90 (m, 1H), 7.23-7.50 (m, 5H), 7.89-8.02 (m, 1H), 8.09-8.11 (m, 1H), 8.50 (br, 1H).
-
- 36.0 mg, yield: 15%, white solid.
- LCMS (ESI): m/z=634.2 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=0.92-1.06 (m, 6H), 1.68-2.37 (m, 5H), 3.06 (s, 3H), 3.28 (s, 3H), 3.30-3.36 (m, 2H), 3.86-4.24 (m, 1H), 4.62-4.70 (m, 3H), 4.85-4.87 (m, 1H), 7.06-7.16 (m, 3H), 7.41-7.46 (m, 1H), 7.99-8.09 (m, 2H).
-
- 7.2 mg, yield: 6%, white solid.
- LCMS (ESI): m/z=617.2 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=1.02 (m, 6H), 1.31-2.16 (m, 5H), 2.88 (m, 4H), 3.08 (s, 3H), 3.42-4.25 (m, 4H), 4.49-4.75 (m, 2H), 7.47-7.74 (m, 4H), 7.91-8.05 (m, 2H).
-
- 21.4 mg, yield: 18%, white solid.
- LCMS (ESI): m/z=611.2 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=1.01-1.04 (m, 6H), 1.71-1.93 (m, 3H), 2.08-2.15 (m, 2H), 3.06 (s, 3H), 3.36-3.43 (m, 1H), 3.71-3.77 (m, 3H), 3.88-3.91 (m, 1H), 4.17-4.27 (m, 1H), 4.48-4.57 (m, 3H), 4.84- 4.94 (m, 1H), 6.77-7.01 (m, 3H), 7.43-7.46 (m, 1H), 7.50-8.85 (m, 2H).
-
- 22.5 mg, yield: 5.3%, white solid.
- LCMS (ESI): m/z=610.7 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=1.01-1.06 (m, 6H), 1.68-1.84 (m, 3H), 2.10-2.28 (m, 2H), 3.03 (s, 3H), 3.36-3.45 (m, 1H), 3.75-3.80 (m, 3H), 3.86-3.90 (m, 1H), 4.16-4.30 (m, 1H), 4.48-4.65 (m, 3H), 4.89- 4.95 (m, 1H), 6.54-6.76 (m, 2H), 7.26-7.50 (m, 2H), 7.87-7.92 (m, 1H), 8.02-8.12 (m, 1H), 8.49-8.51 (s, 1H).
-
- 49.2 mg, yield: 34%, white solid.
- LCMS (ESI): m/z=613.2 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=0.30-0.63 (m, 4H), 1.11-1.27 (m, 1H), 1.70-1.85 (m, 3H), 2.15-2.21 (m, 1H), 3.14 (s, 3H), 3.41-3.48 (m, 1H), 3.89-3.99 (m, 2H), 4.57-4.90 (m, 4H), 7.24-7.32 (m, 1H), 7.75- 7.77 (m, 3H), 7.96-8.14 (m, 2H), 8.40-8.41 (m, 1H), 8.82-8.88 (m, 2H).
-
- 69.1 mg, yield: 26%, white solid.
- LCMS (ESI): m/z=627.2 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=1.73-2.17 (m, 10H), 2.62-2.77 (m, 1H), 3.15 (s, 3H), 3.38-3.49 (m, 1H), 3.89-4.04 (m, 2H), 4.54-4.58 (m, 1H), 4.65-4.95 (m, 2H), 5.05-5.12 (m, 1H), 7.29-7.33 (m, 1H), 7.51- 7.58 (m, 1H), 7.73-7.79 (m, 2H), 7.98 (s, 1H), 8.08-8.16 (m, 1H), 8.33-8.43 (m, 1H), 8.82-8.89 (m, 2H).
-
- 16.6 mg, yield: 12%, white solid.
- LCMS (ESI): m/z=565.1 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=1.01-1.08 (m, 6H), 1.75-2.36 (m, 5H), 3.05 (s, 3H), 3.42-3.49 (m, 1H), 3.88-3.96 (m, 1H), 4.18-4.27 (m, 1H), 4.46-4.55 (m, 1H), 4.65-4.77 (m, 2H), 4.86-4.89 (m, 1H), 7.33- 7.48 (m, 2H), 7.83-8.04 (m, 2H), 8.69-8.77 (m, 2H).
-
- 91.5 mg, yield: 55%, white solid.
- LCMS (ESI): m/z=641.2 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=1.21-1.80 (m, 9H), 1.85-1.95 (m, 3H), 2.30-2.43 (m, 2H), 3.10 (s, 3H), 3.40-3.46 (m, 1H), 3.88-3.95 (m, 1H), 4.17-4.34 (m, 2H), 4.91-5.02 (m, 1H), 7.40-7.45 (m, 1H), 7.85- 7.89 (m, 2H), 7.97-8.13 (m, 3H), 8.85-8.90 (m, 2H).
-
- 13.7 mg, yield: 5%, white solid.
- LCMS (ESI): m/z=589.2 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=1.03-1.08 (m, 6H), 1.78-1.96 (m, 3H), 2.10-2.21 (m, 1H), 2.27-2.35 (m, 1H), 3.05 (s, 3H), 3.32-3.43 (m, 1H), 3.88-3.94 (m, 1H), 4.19-4.29 (m, 1H), 4.34-4.58 (m, 1H), 4.67- 4.73 (m, 2H), 4.83-4.85 (m, 1H, contained in solvent signal), 7.43-7.50 (m, 1H), 7.80-7.78 (m, 1H), 7.85-7.92 (m, 1H), 7.98-8.08 (m, 2H), 8.51-8.55 (m, 1H), 8.71-8.73 (m, 1H).
-
- 53.7 mg, yield: 18%, white solid.
- LCMS (ESI): m/z=618.2 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=0.98-1.06 (m, 6H), 1.84-1.97 (m, 3H), 2.12-2.16 (m, 1H), 2.26-2.34 (m, 1H), 2.60 (s, 3H), 3.08 (s, 3H), 3.41-3.48 (m, 1H), 3.89-3.96 (m, 1H), 4.19-4.28 (m, 1H), 4.51-4.58 (m, 1H), 4.75-4.80 (m, 2H), 4.84-4.86 (m, 1H, contained in solvent signal), 7.27-7.36 (m, 1H), 7.43-7.48 (m, 1H), 7.71-7.76 (m, 1H), 7.88-7.91 (m, 1H), 8.77-8.71 (m, 1H), 8.06-8.01 (m, 1H).
-
- 2.5 mg, yield: 6%, white solid.
- LCMS (ESI): m/z=567.2 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=1.04-1.09 (m, 6H), 1.69-1.76 (m, 2H), 1.95-2.03 (m, 1H), 2.14-2.21 (m, 1H), 2.47-2.99 (m, 1H), 3.03 (s, 3H), 3.40-3.46 (m, 1H), 3.81 (s, 3H), 3.86-3.93 (m, 1H), 4.26-4.58 (m, 3H), 4.86-4.95 (m, 2H), 7.46-7.51 (m, 2H), 7.60-7.64 (m, 1H), 7.91 (m, 1H), 8.03-8.11 (m, 1H), 8.55 (m, 1H).
-
- 55.0 mg, yield: 28%, white solid.
- LCMS (ESI): m/z=618.0 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=0.94-1.10 (m, 6H), 1.67-1.90 (m, 3H), 2.08-2.40 (m, 2H), 2.59-2.71 (m, 3H), 3.08 (s, 3H), 3.33-3.42 (m, 1H), 3.92-4.26 (m, 3H), 4.48-4.71 (m, 3H), 7.37-7.61 (m, 4H), 7.85- 8.06 (m, 2H).
-
- 40.0 mg, yield: 22%, white solid.
- LCMS (ESI): m/z=584.2 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=1.05 (m, 6H), 1.76-2.01 (m, 3H), 2.17-2.19 (m, 2H), 2.39-2.41 (m, 3H), 3.05 (s, 3H), 3.44-3.92 (m, 2H), 4.28-4.57 (m, 2H), 4.85-4.87 (m, 2H), 4.91-5.01 (m, 1H), 7.12-7.15 (m, 1H), 7.46-7.52 (m, 1H), 7.85-8.07 (m, 2H).
-
- 11.5 mg, yield: 11%, white solid.
- LCMS (ESI): m/z=544.1 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=0.90-1.03 (m, 6H), 1.65-2.34 (m, 5H), 2.59-2.64 (m, 3H), 3.05 (s, 3H), 3.32-3.40 (m, 1H), 3.85-3.90 (m, 1H), 4.14-4.23 (m, 1H), 4.46-4.68 (m, 1H), 4.72-4.78 (m, 2H), 4.81- 4.86 (m, 1H), 7.33-7.42 (m, 1H), 7.46-7.51 (m, 2H), 8.20-8.25 (m, 1H), 7.78-7.80 (m, 2H).
-
- 38.5 mg, yield: 25%, white solid.
- LCMS (ESI): m/z=627.1 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=1.00-1.04 (m, 6H), 1.73-1.82 (m, 3H), 2.05-2.14 (m, 2H), 3.06 (s, 3H), 3.32-3.39 (m, 1H), 3.75-3.81 (m, 3H), 3.87-3.90 (m, 1H), 4.22-4.28 (m, 2H), 4.46-4.59 (m, 2H), 4.91- 4.93 (m, 1H), 6.78-6.88 (m, 2H), 7.39-7.90 (m, 2H), 8.02-8.04 (m, 1H), 8.10-8.12 (m, 1H).
-
- 50.0 mg, yield: 27%, white solid.
- LCMS (ESI): m/z=594.2 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=1.07-1.09 (m, 6H), 1.69-2.08 (m, 3H), 2.16-2.42 (m, 2H), 3.04 (s, 3H), 3.52-3.91 (m, 6H), 4.31-4.37 (m, 2H), 4.40-4.66 (m, 1H), 4.86-4.90 (m, 1H), 6.53-6.55 (m, 1H), 7.49- 7.78 (m, 3H), 7.86-7.95 (m, 1H), 8.11-8.13 (m, 1H).
-
- 40.0 mg, yield: 32%, white solid.
- LCMS (ESI): m/z=584.2 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=1.04-1.16 (m, 6H), 1.77-2.38 (m, 8H), 2.99-3.01 (m, 4H), 3.42-3.56 (m, 4H), 3.76-4.09 (m, 4H), 4.21-4.32 (m, 1H), 4.55-4.62 (m, 1H), 4.89-5.00 (m, 1H), 7.45-7.50 (m, 1H), 7.89-7.91 (m, 1H), 8.05-8.06 (m, 1H).
-
- 70 mg, 75% yield, white solid.
- LCMS (ESI): m/z=487.1 [M+H]+.
- 1H-NMR (400 MHz, CDCl3): δ=1.01-1.11 (m, 6H), 1.69-2.19 (m, 5H), 2.85-2.89 (m, 3H), 3.06 (s, 3H), 3.44-3.52 (m, 1H), 3.96-4.13 (m, 2H), 4.67-4.71 (m, 1H), 5.09-5.12 (m, 1H), 7.29-7.34 (m, 1H), 7.52- 7.57 (m, 1H), 7.77-7.80 (m, 1H), 8.35-8.37 (m, 1H).
-
- 62 mg, 45% yield, white solid.
- LCMS (ESI): m/z=501.2 [M+H]+.
- 1H-NMR (400 MHz, CDCl3): δ=1.02-1.12 (m, 6H), 1.21-1.29 (m, 3H), 1.73-1.91 (m, 3H), 2.01-2.19 (m, 2H), 3.05 (s, 3H), 3.26-3.32 (m, 2H), 3.46-3.53 (m, 1H), 4.00-4.12 (m, 2H), 4.67-4.69 (m, 1H), 5.09- 5.15 (m, 1H), 7.29-7.35 (m, 1H), 7.53-7.58 (m, 1H), 7.78-7.79 (m, 1H), 8.35-8.36 (m, 1H).
-
- 97 mg, 37% yield, white solid.
- LCMS (ESI): m/z=543.2 [M+H]+.
- 1H-NMR (400 MHz, CDCl3): δ=0.91-1.12 (m, 12H), 1.50-1.95 (m, 6H), 2.03-2.18 (m, 2H), 3.15 (s, 3H), 3.18-3.22 (m, 2H), 3.43-3.51 (m, 1H), 3.97-4.10 (m, 2H), 4.67-4.70 (m, 1H), 5.08-5.14 (m, 1H), 7.29- 7.34 (m, 1H), 7.46-7.51 (m, 1H), 7.75-7.79 (m, 1H), 8.36-8.37 (m, 1H).
-
- 36 mg, 18% yield, white solid.
- LCMS (ESI): m/z=541.2 [M+H]+.
- 1H-NMR (400 MHz, CDCl3): δ=0.94-1.16 (m, 6H), 1.47-1.60 (m, 2H), 1.67-1.98 (m, 7H), 2.06-2.23 (m, 4H), 3.02 (s, 3H), 3.36-0.350 (m, 2H), 3.96-4.06 (m, 2H), 4.66-4.69 (m, 1H), 5.09-5.15 (m, 1H), 7.29-7.35 (m, 1H), 7.47-7.58 (m, 1H), 7.76-7.83 (m, 1H), 8.33-8.40 (m, 1H).
-
- 58 mg, 35% yield, white solid.
- LCMS (ESI): m/z=473.1 [M+H]+.
- 1H-NMR (400 MHz, CDCl3): δ=1.00-1.09 (m, 6H), 1.70-1.91 (m, 2H), 1.89-2.14 (m, 3H), 3.04 (s, 3H), 3.35-3.60 (m, 1H), 3.75-3.78 (m, 1H), 4.07-4.11 (m, 1H), 4.12-4.41 (m, 1H), 5.07-5.16 (m, 1H), 7.05 (s, 1H), 7.29-7.37 (m, 1H), 7.58-7.62 (m, 1H), 7.76-7.80 (m, 1H), 8.31-8.36 (m, 1H).
-
-
-
- To a solution of benzyl-1-(4-aminophenyl)-3-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate (prepared as described in Example 86-f) (150 mg, 0.37 mmol) in dichloromethane (15 mL) was added triethylamine (92 mg, 0.92 mmol). The resulting mixture was cooled to 00° C. and methyl chloroformate (42 mg, 0.44 mmol) was added. The resulting mixture was stirred for 1 hour. After quenching by addition of ice-water (10 mL), the resulting mixture was extracted with dichloromethane (3×10 mL) and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with dichloromethane:methanol=20:1 to afford benzyl-1-(4-(methoxycarbonylamino)phenyl)-3-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate as a white solid (95 mg, 51%).
- LCMS (ESI): m/z=467.2 [M+H]+.
-
- To a solution of benzyl-1-(4-(methoxycarbonylamino)phenyl)-3-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate (95 mg, 0.20 mmol) in ethanol (15 mL) was added 5% palladium on carbon (15 mg). After stirring for 3 hours, the mixture was filtered. The filtrate was concentrated under reduced pressure to afford methyl-4-(3-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decan-1-yl)phenylcarbamate as a white solid (55 mg, 82%).
- LCMS (ESI): m/z=333.2 [M+H]+.
-
- To a solution of methyl-4-(3-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decan-1-yl)phenylcarbamate (55 mg, 0.17 mmol) in dichloromethane (5 mL) was added sequentially (R)-2-(2-fluoro-5-(trifluoromethyl)benzamido)-3-methylbutanoic acid (prepared as described in Example 28-f) (51 mg, 0.17 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate (HATU) (90 mg, 0.23 mmol) and N,N-diisopropylethylamine (32 mg, 0.23 mmol). The reaction was stirred for 2 hours at room temperature before quenching with ice-water (5 mL). The mixture was extracted with ethyl acetate (3×10 mL) and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by prep-TLC with dichloromethane:methanol=15:1 to afford (R)-methyl-4-(8-(2-(2-fluoro-5-(trifluoromethyl)benzamido)-3-methylbutanoyl)-3-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decan-1-yl)phenylcarbamate as a white solid (16 mg, 15%).
- LCMS (ESI): m/z=622.1 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=0.82-1.09 (m, 6H), 1.58-2.47 (m, 5H), 3.08 (s, 3H), 3.43-3.54 (m, 1H), 3.76-3.77 (m, 3H), 3.91-4.01 (m, 1H), 4.16-4.53 (m, 3H), 711-7.18 (m, 1H), 718-723 (m, 1H), 7.40-747 (m, 2H), 7.58-7.61 (m, 1H), 7.87-8.00 (m, 2H).
- The following compound was synthesized following the general procedure described above:
-
- 44.2 mg, yield: 22%, white solid
- LCMS (ESI): m/z=632.1 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=0.72-1.05 (m, 10H), 1.66-2.27 (m, 6H), 3.08 (s, 3H), 3.46-3.59 (m, 1H), 3.90-3.54 (m, 3H), 4.83-4.87 (m, 1H), 7.09-7.32 (m, 2H), 7.34-7.52 (m, 1H), 7.59-7.74 (m, 2H), 7.81- 8.05 (m, 2H).
-
-
-
- To a solution of tert-butyl-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate (920 mg, 2.78 mmol) in N,N-dimethylformamide (10 mL) was added sodium hydride (138 mg, 60% in oil, 3.34 mmol) at 0° C. After stirring for 15 minutes, iodomethane (789 mg, 5.56 mmol) was added. The resulting mixture was stirred for 15 minutes at room temperature and the reaction was quenched with ice-water (10 mL). The mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with ethyl acetate:petroleum ether=1:3 to afford tert-butyl-3-methyl-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate as a white solid (900 mg, 93%).
- LCMS (ESI): m/z=346.4 [M+H]+.
- 1H-NMR (300 MHz, CDCl3): δ=1.51, (s, 9H), 1.54-1.67 (m, 2H), 2.56-2.57 (m, 2H), 3.01 (s, 3H), 3.50-3.64 (m, 2H), 3.96-4.12 (m, 2H), 4.69-4.75 (m, 2H), 6.72-6.77 (m, 2H), 6.83-6.87 (m, 1H), 7.22-7.25 (m, 1H), 7.27-7.28 (m, 1H).
-
- To a solution of tert-Butyl-3-methyl-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate (300 mg, 1.89 mmol) in methanol (50 mL) was added dropwise acetyl chloride (1.49 g, 18.87 mmol). The resulting mixture was stirred for 2 hours. The precipitate was collected by filtration and dried under reduced pressure to afford 3-methyl-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one hydrochloride as a white solid (173 mg, 70%).
- LCMS (ESI): m/z=246.4 [M+H]+.
-
- To a suspension of methyl-2-amino-2-(tetrahydro-2H-pyran-4-yl)acetate hydrochloride (210 mg, 1.0 mmol) in dichloromethane (20 mL) was added triethylamine (303 mg, 3.0 mmol). To the mixture was added dropwise a solution of 3-methylbenzoyl chloride (170 mg, 1.1 mmol) in dichloromethane (5 mL) at 0° C. The mixture was stirred for 1 hour before the reaction was quenched with ice-water (10 mL). The organic layer was collected and the aqueous layer was extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography eluting with ethyl acetate:petroleum ether=1:1 to afford methyl-2-(3-methylbenzamido)-2-(tetrahydro-2H-pyran-4-yl)acetate as a colorless oil (200 mg, 68%).
- LCMS (ESI): m/z=292.1 [M+H]+.
- 1H-NMR (300 MHz, CDCl3): δ=1.45-1.71 (m, 4H), 2.10-2.25 (m, 1H), 2.41 (s, 3H), 3.31-3.46 (m, 2H), 3.80 (s, 3H), 3.91-4.06 (m, 2H), 4.83-4.94 (m, 1H), 6.61-6.75 (m, 1H), 7.31-7.34 (m, 2H), 7.51-7.68 (m, 2H).
-
- To a solution of methyl-2-(3-methylbenzamido)-2-(tetrahydro-2H-pyran-4-yl)acetate (200 mg, 0.68 mmol) in methanol (10 mL) was added a 10% aqueous sodium hydroxide solution (5 mL). The reaction was heated at reflux for 2 hours before it was cooled to room temperature. The pH of the mixture was adjusted to 2 by addition of a 10% aqueous hydrochloric acid solution. The resulting mixture was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure to afford 2-(3-methylbenzamido)-2-(tetrahydro-2H-pyran-4-yl)acetic acid as a thick oil (180 mg, crude), which used directly in the next step without further purification.
- LCMS (ESI): m/z=278.1 [M+H]+.
-
- To a solution of 3-methyl-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one hydrochloride (106 mg, 0.379 mmol) in dichloromethane (10 mL) was added sequentially 2-(3-methylbenzamido)-2-(tetrahydro-2H-pyran-4-yl)acetic acid (70 mg, 0.25 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate (HATU) (144 mg, 0.38 mmol) and N,N-diisopropylethylamine (98 mg, 0.75 mmol). The reaction was stirred for 2 hours before it was quenched by addition of with ice-water (10 mL). The mixture was extracted with ethyl acetate (3×10 mL) and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by prep-TLC with ethyl acetate:petroleum ether=1:1 to afford 3-methyl-N-(2-(3-methyl-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-8-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)benzamide as a white solid (50 mg, 39%).
- LCMS (ESI): m/z=505.2 [M+H]+.
- 3-Methyl-N-(2-(3-methyl-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-8-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)benzamide was separated by chiral-HPLC (column: CHIRALPAK* (Daicel) IB (250 mm×20 mm, 5 μm). Mobile phase: hexane: ethanol (0.1% FA)=70:30, flow rate: 20 mL/min) to afford two isomers. Their confirmations were tentatively assigned as drawn.
-
- Retention time: 7.481 minutes, ee=97.1%.
- LCMS (ESI): m/z=505.2 [M+H]+.
- 1H-NMR (400 MHz, CDCl3): δ=1.54-1.90 (m, 7H), 2.42-2.66 (m, 5H), 3.05 (s, 3H), 3.36-3.45 (m, 2H), 3.54-3.64 (m, 2H), 3.97-4.14 (m, 4H), 4.54-4.66 (m, 1H), 4.71-4.76 (m, 2H), 5.17-5.23 (m, 1H), 6.98- 7.24 (m, 5H), 7.62-7.66 (m, 4H).
-
- Retention time: 14.04 minutes, ee=95%
- LCMS (ESI): m/z=505.2 [M+H]+.
- 1H-NMR (400 MHz, CDCl3): δ=1.54-1.90 (m, 7H), 2.42-2.66 (m, 5H), 3.05 (s, 3H), 3.36-3.45 (m, 2H), 3.54-3.64 (m, 2H), 3.97-4.14 (m, 4H), 4.54-4.66 (m, 1H), 4.71-4.76 (m, 2H), 5.17-5.23 (m, 1H), 6.98- 7.24 (m, 5H), 7.62-7.66 (m, 4H).
- The following compound was synthesized following the general procedure described above using chiral amino acid.
-
- 14.6 mg, yield: 20%, white solid.
- LCMS (ESI): m/z=504.2 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=1.0-1.44 (m, 5H), 1.51-2.00 (m, 8H), 2.41-2.76 (m, 5H), 3.02 (s, 3H), 3.50-3.55 (m, 1H), 3.96-4.01 (m, 1H), 4.19-4.39 (m, 1H), 4.48-4.50 (m, 1H), 4.75 (m, 2H), 5.07 (m, 1H), 6.56-6.73 (m, 2H), 6.80-7.00 (m, 2H), 7.26-7.35 (m, 1H), 7.53-7.55 (m, 1H), 7.77-8.01 (m, 2H).
- The following compound was synthesized following the general procedure described for Example 236.
-
- 26.4 mg, yield: 58%, white solid.
- LCMS (ESI): m/z=464.2 [M+H]+.
- 1H-NMR (400 MHz, CDCl3): δ=1.00-1.04 (m, 6H), 1.75-1.87 (m, 2H), 2.25-2.39 (two singlets, 3H), 2.45-2.54 (m, 3H), 2.86-2.96 (two singlets, 3H), 3.05 (s, 3H), 3.52-4.75 (m, 6H), 5.26-5.28 (m, 1H), 6.75-7.27 (m, 9H).
-
-
-
- To a mixture of 3-methyl-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one hydrochloride (prepared as described in Example 129-b) (296 mg, 0.47 mmol) in dichloromethane (30 mL) was added (2R,3S)-2-(tert-butoxycarbonylamino)-3-methoxybutanoic acid (100 mg, 0.43 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate (HATU) (243 mg, 0.64 mmol) and N,N-diisopropylethylamine (139 mg, 1.07 mmol). The reaction was stirred for 2 hours before it was quenched with ice-water (5 mL). The mixture was extracted with ethyl acetate (3×10 mL) and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with ethyl acetate:petroleum ether=1:5 to afford tert-butyl-(2R,3S)-3-methoxy-1-(3-methyl-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-8-yl)-1-oxobutan-2-ylcarbamate as a colorless oil (197 mg, 100%).
- LCMS (ESI): m/z=461.2 [M+H].
- 1H-NMR (400 MHz, CDCl3): δ=0.83-1.12 (m, 3H), 1.38 (s, 6H), 1.45 (s, 3H), 1.59-1.64 (m, 4H), 2.83 (s, 3H), 3.06 (s, 1H), 3.14 (s, 2H), 3.34 (s, 2H), 3.30-3.57 (m, 2H), 3.83-4.01 (m, 2H), 4.51-4.75 (m, 2H), 5.47-5.59 (m, 1H), 7.13-7.20 (m, 2H), 7.40-7.52 (m, 3H).
-
- A solution of tert-butyl-(2R,3S)-3-methoxy-1-(3-methyl-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-8-yl)-1-oxobutan-2-ylcarbamate (197 mg, 0.43 mmol) in hydrochloric acid in dioxane (6.0 M, 10 mL) was stirred for 30 minutes. The precipitate was collected by filtration and dried under reduced pressure to afford 8-((2R,3S)-2-amino-3-methoxybutanoyl)-3-methyl-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one hydrochloride as a white solid (120 mg, 60%).
- LCMS (ESI): m/z=361.2 [M+H]+.
-
- To a mixture of 8-((2R,3S)-2-amino-3-methoxybutanoyl)-3-methyl-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one hydrochloride (52 mg, 0.135 mmol) in dichloromethane (10 mL) was added 5-ethyl-2-fluorobenzoic acid (24 mg, 0.144 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate (HATU) (75 mg, 0.196 mmol) and N,N-diisopropylethylamine (51 mg, 0.39 mmol). The resulting mixture was stirred for 2 hours at room temperature before the reaction was quenched with ice-water (10 mL). The mixture was extracted with ethyl acetate (3×10 mL) and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with ethyl acetate:petroleum ether=1:5 to afford 5-ethyl-2-fluoro-N-((2R,3S)-3-methoxy-1-(3-methyl-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-yl)-1-oxobutan-2-yl)benzamide as a colorless oil (11.2 mg, 15%).
- 11.2 mg, yield: 15%, white solid
- LCMS (ESI): m/z=511.2 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=1.22-1.31 (m, 6H), 1.66-2.83 (m, 6H), 3.03 (s, 3H), 3.11 (s, 3H), 3.83 (s, 3H), 3.38-4.78 (m, 7H), 5.17-5.3 (m, 1H), 6.73-7.76 (m, 8H).
- The following 3 compounds were synthesized following the general procedure described above:
-
- 10.1 mg, yield: 9%, white solid
- LCMS (ESI): m/z=479 [M+H]+.
- 1H-NMR (400 MHz, CDCl3): δ=1.22-1.27 (m, 3H), 1.70-1.83 (m, 2H), 2.43 (s, 3H), 2.56-2.66 (m, 1H), 2.80-2.94 (m, 1H), 3.06 (s, 3H), 3.41 (s, 3H), 3.46-4.22 (m, 4H), 4.45-4.84 (m, 3H), 5.08-5.51 (m, 1H), 6.85-6.90 (m, 3H), 7.22-7.24 (m, 1H), 7.38-7.50 (m, 3H), 7.67-7.69 (m, 2H).
-
- 9.0 mg, yield: 14%, white solid
- LCMS (ESI): m/z=493.2 [M+H]+.
- 1H-NMR (400 MHz, CDCl3): δ=1.22-1.26 (m, 6H), 1.66-1.85 (m, 2H), 2.45-2.79 (m, 4H), 2.98 (s, 3H), 3.42 (s, 3H), 3.53-3.64 (m, 1H), 4.03-4.36 (m, 2H), 4.42-4.77 (m, 7H), 5.18-5.29 (m, 1H), 6.69-7.76 (m, 9H).
-
- 8.0 mg, yield: 12%, white solid
- LCMS (ESI): m/z=511.2 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=1.14-1.37 (m, 6H), 1.75-1.81 (m, 2H), 2.50-2.59 (m, 1H), 2.63-2.86 (m, 3H), 3.03 (s, 3H), 3.50 (s, 3H), 3.52-3.59 (m, 1H), 3.74-4.10 (m, 2H), 4.34-4.49 (m, 2H), 4.74-4.77 (m, 2H), 5.21-5.26 (m, 1H), 7.24-7.80 (m, 8H).
- The following 8 compounds were synthesized following the general procedure described above using D-Valine:
-
- 5.0 mg, yield: 7%, white solid
- LCMS (ESI): m/z=464.2 [M+H]+.
- 1H-NMR (400 MHz, CDCl3): δ=1.02-1.09 (m, 5H), 1.24-1.28 (m, 1H), 1.75-2.24 (m, 4H), 2.98-3.06 (m, 6H), 3.51-3.54 (m, 1H), 3.94-4.12 (m, 2H), 4.57-4.62 (m, 1H), 4.72-4.77 (m, 2H), 5.20-5.24 (m, 1H), 5.35-5.45 (m, 1H), 6.75-6.77 (m, 1H), 6.84-6.88 (m, 1H), 7.17-7.19 (m, 1H), 7.35-7.37 (m, 2H), 7.82-7.95 (m, 2H), 8.73-8.75 (m, 1H).
-
- 10.0 mg, yield: 16%, white solid
- LCMS (ESI): m/z=477.2 [M+H]+.
- 1H-NMR (400 MHz, CDCl3): δ=1.01-1.14 (m, 6H), 1.25-1.29 (m, 3H), 1.74-1.83 (m, 2H), 2.16-2.18 (m, 1H), 2.68-2.71 (m, 4H), 3.02 (s, 3H), 3.52-3.56 (m, 1H), 3.99-4.08 (m, 2H), 4.54-4.71 (m, 3H), 5.09- 5.15 (m, 1H), 6.67-7.24 (m, 6H), 7.34-7.36 (m, 2H), 7.62-7.67 (m, 2H).
-
- 20.0 mg, yield: 32%, white solid
- LCMS (ESI): m/z=481.2 [M+H]+.
- 1H-NMR (400 MHz, CDCl3): δ=0.98-1.04 (m, 6H), 1.83-1.97 (m, 2H), 2.03-2.23 (m, 1H), 2.46-2.61 (m, 5H), 3.02 (s, 3H), 3.52-3.57 (m, 1H), 4.03-4.06 (m, 2H), 4.57-4.71 (m, 3H), 5.04-5.08 (m, 1H), 6.69- 7.13 (m, 6H), 7.65-7.70 (m, 2H).
-
- 13.0 mg, yield: 19%, white solid
- LCMS (ESI): m/z=481.2 [M+H]+.
- 1H-NMR (400 MHz, CDCl3): δ=0.97-1.06 (m, 6H), 1.74-1.79 (m, 2H), 1.81-1.83 (m, 1H), 2.40-2.59 (m, 5H), 3.03 (s, 3H), 3.53-3.56 (m, 1H), 4.02-4.05 (m, 2H), 4.57-4.71 (m, 3H), 5.09-5.18 (m, 1H), 6.70- 7.39 (m, 8H).
-
- 13.0 mg, yield: 11%, white solid
- LCMS (ESI): m/z=481.2 [M+H]+.
- 1H-NMR (400 MHz, CDCl3): δ=0.97-1.06 (m, 6H), 1.74-1.79 (m, 2H), 1.81-1.83 (m, 1H), 2.13 (s, 3H), 2.34-2.50 (m, 2H), 3.02 (s, 3H), 3.50-3.54 (m, 1H), 4.03-4.08 (m, 2H), 4.54-4.71 (m, 3H), 5.09-5.18 (m, 1H), 6.67-7.14 (m, 7H), 7.43-7.46 (m, 1H), 7.79-7.80 (m, 1H).
-
- 21.0 mg, yield: 29%, white solid
- LCMS (ESI): m/z=489.2 [M+H].
- 1H-NMR (400 MHz, CDCl3): δ=0.73-1.10 (m, 10H), 1.78-1.95 (m, 2H), 2.12-2.15 (m, 1H), 2.60-2.64 (m, 3H), 3.02 (s, 3H), 3.51-3.55 (m, 1H), 4.04-4.07 (m, 2H), 4.59-4.70 (m, 3H), 5.08-5.10 (m, 1H), 6.65- 7.99 (m, 9H).
-
- 9.9 mg, yield 15%, white solid
- LCMS (ESI): m/z=509.2 [M+H]+.
- 1H-NMR (400 MHz, CDCl3): δ=1.02-1.09 (m, 6H), 1.69-2.77 (m, 5H), 3.02 (s, 3H), 3.52-4.34 (m, 4H), 4.74-4.77 (m, 2H), 4.89-4.93 (m, 1H), 6.70-6.78 (m, 2H), 6.86-6.88 (m, 1H), 7.03-7.25 (m, 2H), 7.93- 7.96 (m, 2H), 8.09-8.11 (m, 1H).
-
- 42.0 mg, yield: 33%, white solid
- LCMS (ESI): m/z=495 [M+H]+.
- 1H-NMR (400 MHz, CDCl3): δ=0.94-1.16 (m, 6H), 1.18-1.38 (m, 3H), 1.60-1.93 (m, 2H), 2.13-2.34 (m, 1H), 2.37-2.62 (m, 1H), 2.62-2.76 (m, 2H), 2.81 (m, 1H), 3.08 (s, 3H), 3.43-3.63 (m, 1H), 3.91-4.10 (m, 1H), 4.20-4.38 (m, 1H), 4.43-4.60 (m, 1H), 4.65-4.76 (m, 2H), 4.96-5.09 (m, 1H), 6.70-6.89 (m, 3H), 7.01-7.32 (m, 3H), 7.34-7.53 (m, 1H), 7.57-7.71 (m, 1H).
-
-
-
- To a solution of tert-butyl-1-(4-cyanophenyl)-3-methyl-4-oxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate (prepared as described in Example 179-e) (190 mg, 0.15 mmol) in methanol (15 mL) was added an aqueous sodium hydroxide solution (6 mL, 1.0 M). After stirring for 15 minutes, to the resulting solution was added a 30% aqueous hydrogen peroxide (6 mL) dropwise. The resulting mixture was stirred overnight. The solvent was removed under reduced pressure and the residue was diluted with water (40 mL) and ethyl acetate (40 mL). The organic layer was collected and dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with dichloromethane:methanol=200:1 to afford tert-butyl-1-(4-carbamoylphenyl)-3-methyl-4-oxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate as a white solid (160 mg, 80%).
- LCMS (ESI): m/z=389.1 [M+H]+.
-
- A solution of tert-butyl-1-(4-carbamoylphenyl)-3-methyl-4-oxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate (160 mg, 0.41 mmol) in hydrochloric acid in dioxane (6.0 M, 10 mL) was stirred for 30 minutes. The precipitate was collected by filtration and dried under reduced pressure to afford 4-(3-methyl-4-oxo-1,3,8-triazaspiro[4.5]decan-1-yl)benzamide hydrochloride as a white solid (120 mg, 90%).
- LCMS (ESI): m/z=289.1 [M+H]+.
-
- To a solution of 2-fluoro-3-methylbenzoic acid (1.54 g, 10 mmol) in dichloromethane (50 mL) was added sequentially D-valine methyl ester hydrochloride (1.71 g, 10.2 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate (HATU) (4.2 g, 11.0 mmol) and N,N-diisopropylethylamine (3.9 g, 30 mmol). Before quenching with ice-water (50 mL), the reaction was stirred for 2 hours. The mixture was extracted with dichloromethane (3×100 mL) The combined organic layers were dried over sodium sulfate and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography eluting with ethyl acetate:petroleum ether=1:4 to afford (R)-methyl-2-(2-fluoro-3-methylbenzamido)-3-methylbutanoate as a thick oil (3.5 g, crude), which was used directly without further purification.
- LCMS (ESI): m/z=268.2 [M+H]+.
-
- To a solution of (R)-methyl-2-(2-fluoro-3-methylbenzamido)-3-methylbutanoate (3.9 g, crude) in methanol (30 mL) was added an aqueous lithium hydroxide solution (20 mL, 2.0 M, 0.044 mol). Before quenching with ice-water (20 mL), the reaction was stirred for 1 hour. The pH of the solution was adjusted to 3 by addition of a 5% aqueous hydrochloric acid solution. The mixture was filtered and the filter cake was washed with petroleum ether (30 mL) and dried under reduced pressure to afford (R)-2-(2-fluoro-3-methylbenzamido)-3-methylbutanoic acid as a thick oil (2.40 g, 94% over two steps).
- LCMS (ESI): m/z=254.1 [M+H]+.
- 1H-NMR (300 MHz, CDCl3): δ=1.05 (t, J=7.8 Hz, 6H), 2.32 (s, 3H), 2.34-2.44 (m, 1H), 4.78-4.82 (m, 1H), 7.06-7.13 (m, 1H), 7.27-7.35 (m, 1H), 7.79-7.91 (m, 1H).
-
- To a mixture of 4-(3-methyl-4-oxo-1,3,8-triazaspiro[4.5]decan-1-yl)benzamide hydrochloride (100 mg, 0.3 mmol) in dichloromethane (5 mL) was added (R)-2-(2-fluoro-3-methylbenzamido)-3-methylbutanoic acid (94 mg, 0.34 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate (HATU) (177 mg, 0.46 mmol) and N,N-diisopropylethylamine (80 mg, 0.62 mmol). The resulting mixture was stirred for 2 hours at room temperature before the reaction was quenched with ice-water (10 mL). The mixture was extracted with ethyl acetate (3×10 mL) and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by prep-TLC with dichloromethane:methanol=15:1 to afford (R)—N-(1-(1-(4-carbamoylphenyl)-3-methyl-4-oxo-1,3,8-triazaspiro[4.5]decan-8-yl)-3-methyl-1-oxobutan-2-yl)-2-fluoro-3-methylbenzamide as a white solid (11.8 mg, 7.3%).
- LCMS (ESI): m/z=524.2 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=0.96-1.25 (m, 6H), 1.68-1.96 (m, 2H), 2.18-2.26 (m, 4H), 2.70-2.71 (m, 1H), 2.89-2.92 (m, 1H), 3.04 (s, 3H), 3.56-3.58 (m, 1H), 3.99-4.03 (m, 1H), 4.37-4.39 (m, 1H), 4.54- 4.58 (m, 1H), 4.79-4.82 (m, 2H), 4.95-5.16 (m, 1H), 6.74-6.80 (m, 2H), 7.14-7.17 (m, 1H), 7.38-7.40 (m, 1H), 7.47-7.81 (m, 3H).
- The following compound was synthesized following the general procedure described above:
-
- 24.2 mg, yield: 17%, white solid.
- LCMS (ESI): m/z=524.0 [M+H]+.
- 1H-NMR (400 MHz, CDCl3): δ=0.94-1.19 (m, 6H), 1.69-1.86 (m, 2H), 2.17-2.26 (m, 1H), 2.33 (s, 3H), 2.54-2.69 (m, 1H), 2.75-2.87 (m, 1H), 3.07 (s, 3H), 3.49-3.65 (m, 1H), 4.04-4.19 (m, 2H), 4.60-4.67 (m, 1H), 4.78 (s, 2H), 5.01-5.24 (m, 1H), 6.19-6.34 (m, 2H), 6.92-7.00 (m, 1H), 7.09-7.22 (m, 3H), 7.35 (s, 1H), 7.50-7.63 (m, 1H), 7.70-7.85 (m, 1H).
-
-
-
- A solution of tert-butyl-1-(4-bromophenyl)-3-methyl-4-oxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate (prepared as described in Example 179-d) (250 mg, 0.00041 mol) in hydrochloric acid in dioxane (6.0 M, 10 mL) was stirred for 30 minutes. The precipitate was collected by filtration and dried under reduced pressure to afford 1-(4-bromophenyl)-3-methyl-1,3,8-triazaspiro[4.5]decan-4-one hydrochloride as a white solid (180 mg, 85%).
- LCMS (ESI): m/z=324.1, 326.1 [M+H]+.
-
- To a mixture of 1-(4-bromophenyl)-3-methyl-1,3,8-triazaspiro[4.5]decan-4-one hydrochloride (167 mg, 0.465 mmol) in dichloromethane (10 mL) was added (R)-2-(2-fluoro-3-methylbenzamido)-3-methylbutanoic acid (prepared as described in Example 145-d) (140 mg, 0.511 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate (HATU) (292 mg, 0.767 mmol) and N,N-diisopropylethylamine (150 mg, 1.16 mmol). The resulting mixture was stirred for 2 hours before the reaction was quenched with ice-water (10 mL). The mixture was extracted with ethyl acetate (3×10 mL) and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with ethyl acetate:petroleum ether=1:5 to afford (R)—N-(1-(1-(4-Bromophenyl)-3-methyl-4-oxo-1,3,8-triazaspiro[4.5]decan-8-yl)-3-methyl-1-oxobutan-2-yl)-2-fluoro-3-methylbenzamide as a colorless oil (220 mg, 85%).
- LCMS (ESI): m/z=559.2, 561.2 [M+H]+.
-
- To a solution of (R)—N-(1-(1-(4-bromophenyl)-3-methyl-4-oxo-1,3,8-triazaspiro[4.5]decan-8-yl)-3-methyl-1-oxobutan-2-yl)-2-fluoro-3-methylbenzamide (220 mg, 0.39 mmol) in DMSO (10 mL) was added sequentially bis(pinacolato)diboron (300 mg, 1.18 mmol), tris(dibenzylideneacetone)dipalladium (36 mg, 0.039 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) (46 mg, 0.047 mmol) and potassium acetate (78 mg, 0.788 mmol) under an argon atmosphere. The reaction mixture was stirred at 130° C. for 2 hours. After quenching with ice-water (5 mL), the reaction mixture was extracted with ethyl acetate (3×15 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. To the residue were added ethanol (3 mL) and an aqueous hydrochloric acid solution (3 mL, 1.0 M). The resulting mixture was stirred overnight. The solvents were removed under reduced pressure. The residue was purified by prep-HPLC (acetonitrile and water, acetonitrile from 5% to 75%) to afford (R)-4-(8-(2-(2-fluoro-3-methylbenzamido)-3-methylbutanoyl)-3-methyl-4-oxo-1,3,8-triazaspiro[4.5]decan-1-yl)phenylboronic acid as a brown oil (14 mg, 7%).
- LCMS (ESI): m/z=525.2 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=1.03-1.19 (m, 6H), 1.71-1.82 (m, 2H), 2.20-2.40 (m, 4H), 2.63-2.78 (m, 1H), 2.92-2.96 (m, 1H), 3.04 (s, 3H), 3.48-3.62 (m, 1H), 4.00-4.03 (m, 1H), 4.29-4.65 (m, 2H), 4.78- 4.86 (m, 2H), 4.94-5.03 (m, 1H), 6.72-6.76 (m, 2H), 7.04-7.26 (m, 1H), 7.32-7.63 (m, 2H), 7.82-7.85 (m, 2H).
- The following compound was synthesized following the general procedure described above:
-
- 2.0 mg, yield: 8%, white solid.
- LCMS (ESI): m/z=525.2 [M+H]+.
- 1H-NMR (400 MHz, CDCl3): δ=0.94-1.16 (m, 6H), 1.61-1.95 (m, 3H), 2.09-2.35 (m, 3H), 2.47-2.90 (m, 2H), 2.93-3.16 (m, 3H), 3.55-3.60 (m, 1H), 3.95-4.19 (m, 2H), 4.46-4.84 (m, 3H), 4.98-5.20 (m, 1H), 6.63-7.19 (m, 4H), 7.34-7.85 (m, 3H).
-
-
-
- To a solution of methyl-4-aminobenzoate (16.46 g, 0.109 mol) in acetic acid (160 mL) was added tert-butyl-4-oxopiperidine-1-carboxylate (23.8 g, 0.12 mol). The resulting mixture was cooled to 0° C. and trimethylsilyl cyanide (12.95 g, 0.131 mol) was added. The resulting solution was stirred overnight at room temperature. Saturated aqueous ammonium chloride solution was added (200 mL). After stirring at room temperature for 10 minutes, the mixture was filtered. The filter cake was dried under reduced pressure to afford tert-butyl-4-cyano-4-(4-(methoxycarbonyl)phenylamino)piperidine-1-carboxylate as a white solid (39.1 g, 100%).
- LCMS (ESI): m/z=360.2 [M+H]+.
-
- To a solution of tert-butyl-4-cyano-4-(4-(methoxycarbonyl)phenylamino)piperidine-1-carboxylate (20.0 g, 0.0557 mol) in methanol (300 mL) was added an aqueous sodium hydroxide solution (100 mL, 1.0 M). After stirring for 15 minutes, to the resulting solution was added a 30% aqueous hydrogen peroxide solution (8 mL) dropwise. After stirring overnight, the resulting mixture was filtered. The filter cake was washed with water (3×100 mL) and dried under reduced pressure to afford tert-butyl-4-carbamoyl-4-(4-(methoxycarbonyl)phenylamino)piperidine-1-carboxylate as a white solid (18.0 g, 79%).
- LCMS (ESI): m/z=378.2 [M+H]+.
- 1H-NMR (400 MHz, DMSO-d6): δ=1.39 (s, 9H), 1.82-1.92 (m, 4H), 3.14-3.17 (m, 2H), 3.61-3.64 (m, 2H), 3.78 (s, 3H), 6.57 (s, 1H), 6.62-6.70 (m, 2H), 7.15 (s, 1H), 7.41 (s, 1H), 7.62-7.77 (m, 2H).
-
- To a solution of tert-butyl-4-carbamoyl-4-(4-(methoxycarbonyl)phenylamino)piperidine-1-carboxylate (20.0 g, 0.053 mol) in triethyl orthoformate (200 mL) was added acetic acid (1 mL, cat.). The resulting mixture was stirred at 150° C. for 30 hours. The solvent was removed under reduced pressure. The residue was dissolved in methanol (200 mL). To the resulting solution was added sodium borohydride (2.62 g, 0.069 mol) at 0° C. The resulting mixture was stirred for 30 minutes. The solvent was removed under reduced pressure and the residue was diluted with water (200 mL) and ethyl acetate (150 mL). The organic layer was collected and the aqueous layer was extracted with ethyl acetate (3×100 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with dichloromethane:methanol=100:1 to afford tert-butyl-1-(4-(methoxycarbonyl)phenyl)-4-oxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate as a white solid (10 g, 48%).
- LCMS (ESI): m/z=390.2 [M+H]+.
- 1H-NMR (400 MHz, DMSO-d6): δ=1.40 (s, 9H), 1.72-1.75 (m, 2H), 2.47-2.50 (m, 2H), 3.35-3.42 (m, 2H), 3.78 (s, 3H), 3.97-4.01 (m, 2H), 4.70 (s, 3H), 6.68 (d, J=8.8 Hz, 2H), 7.75 (d, J=8.8 Hz, 2H), 8.94 (s, 1H).
-
- To a solution of tert-butyl-1-(4-(methoxycarbonyl)phenyl)-4-oxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate (1.0 g, 0.00258 mol) in N,N-dimethylformamide (10 mL) was added sodium hydride (180 mg, 60% in oil, 0.00437 mol) at 0° C. After stirring for 15 minutes, iodomethane (0.55 g, 0.00386 mol) was added. The resulting mixture was stirred for 15 minutes at room temperature and the reaction was quenched with ice-water (10 mL). The mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with ethyl acetate:petroleum ether=1.1 to afford tert-butyl-1-(4-(methoxycarbonyl)phenyl)-3-methyl-4-oxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate as a white solid (0.95 g, 94%).
- LCMS (ESI): m/z=404.2 [M+H]+.
-
- To a solution of tert-butyl-1-(4-(methoxycarbonyl)phenyl)-3-methyl-4-oxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate (1.0 g, 0.00248 mol) in methanol (10 mL) was added a 15% aqueous sodium hydroxide solution (15 mL). The reaction was heated at reflux for 1 hour before cooling to room temperature. The pH of the resulting solution was adjusted to 1 by addition of 10% aqueous hydrochloric acid solution. The mixture was filtered and the filter cake was washed with water (10 mL) and then dried under reduced pressure to afford 4-(8-(tert-butoxycarbonyl)-3-methyl-4-oxo-1,3,8-triazaspiro[4.5]decan-1-yl)benzoic acid as a white solid (0.92 g, 94%).
- LCMS (ESI): m/z=390.2 [M+H]+.
-
- To a solution of 4-(8-(tert-butoxycarbonyl)-3-methyl-4-oxo-1,3,8-triazaspiro[4.5]decan-1-yl)benzoic acid (0.92 g, 0.00236 mol) in N,N-dimethylformamide (10 mL) was added potassium carbonate (0.51 g, 0.00372 mol) and benzyl bromide (0.55 g, 0.00322 mol). Before the reaction was quenched by addition of ice-water (10 mL), the mixture was heated for 2 hours at 50° C. The mixture was extracted with ethyl acetate (3×30 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with ethyl acetate:petroleum ether=1:1 to afford tert-butyl-1-(4-(benzyloxycarbonyl)phenyl)-3-methyl-4-oxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate as a white solid (0.9 g, 81%).
- LCMS (ESI): m/z=480.2 [M+H]+.
- 1H-NMR (300 MHz, CDCl3): δ=1.53 (s, 9H), 1.62-1.65 (m, 2H), 2.57-2.79 (m, 2H), 3.03 (s, 3H), 3.66-4.49 (m, 2H), 4.05-4.16 (m, 2H), 4.74 (s, 2H), 5.33 (s, 2H), 6.65 (d, J=9.1 Hz, 2H), 7.30-7.48 (m, 5H), 7.75 (d, J=9.1 Hz, 2H).
-
- A solution of tert-butyl-1-(4-(benzyloxycarbonyl)phenyl)-3-methyl-4-oxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate (0.9 g, 0.00187 mol) in hydrochloric acid in dioxane (6.0 M, 20 mL) was stirred for 30 minutes. The precipitate was collected by filtration and dried under reduced pressure to afford benzyl-4-(3-methyl-4-oxo-1,3,8-triazaspiro[4.5]decan-1-yl)benzoate hydrochloride as a white solid (0.92 g, 80%).
- LCMS (ESI): m/z=380.2 [M+H]+.
-
- To a mixture of benzyl-4-(3-methyl-4-oxo-1,3,8-triazaspiro[4.5]decan-1-yl)benzoate hydrochloride (120 mg, 0.28 mmol) in dichloromethane (5 mL) was added sequentially (R)-2-(2-fluoro-5-(trifluoromethyl)benzamido)-3-methylbutanoic acid (prepared as described in Example 28-f) (99 mg, 0.32 mmol), (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate (HATU) (190 mg, 0.50 mmol) and N,N-diisopropylethylamine (150 mg, 1.164 mmol). The resulting mixture was stirred for 2 hours at room temperature before the reaction was quenched by addition of with ice-water (5 mL). The mixture was extracted with ethyl acetate (3×10 mL) and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by prep-TLC with dichloromethane:methanol=15:1 to afford (R)-benzyl-4-(8-(2-(2-fluoro-5-(trifluoromethyl)benzamido)-3-methylbutanoyl)-3-methyl-4-oxo-1,3,8-triazaspiro[4.5]decan-1-yl)benzoate as a thick oil (112 mg, crude).
- LCMS (ESI): m/z=669.2 [M+H]+.
-
- To a solution of ((R)-benzyl-4-(8-(2-(2-fluoro-5-(trifluoromethyl)benzamido)-3-methylbutanoyl)-3-methyl-4-oxo-1,3,8-triazaspiro[4.5]decan-1-yl)benzoate (112 mg, 80% purity, 0.134 mmol) in methanol (15 mL) was added 5% palladium on carbon (50 mg, 50% wet with water). The mixture was stirred under a hydrogen atmosphere for 40 minutes. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC (acetonitrile and water, acetonitrile from 20% to 60%) to afford (R)-4-(8-(2-(2-fluoro-5-(trifluoromethyl)benzamido)-3-methylbutanoyl)-3-methy-4-oxo-1,3,8-triazaspiro[4.5]decan-1-yl)benzoic acid as a white solid (64 mg, 38% over two steps).
- LCMS (ESI): m/z=579.2 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=1.05-1.28 (m, 6H), 1.68-1.91 (m, 2H), 2.19-2.35 (m, 1H), 2.36-2.82 (m, 1H), 2.88-3.00 (m, 1H), 3.04 (s, 3H), 3.50-3.63 (m, 1H), 3.92-4.01 (m, 1H), 4.03-4.10 (m, 1H), 4.29- 4.48 (m, 1H), 4.50-4.66 (m, 2H), 4.93-5.18 (m, 1H), 6.74-6.79 (m, 2H), 6.79-7.49 (m, 1H), 7.70-7.72 (m, 1H), 7.88-7.89 (m, 1H), 8.02-8.05 (m, 1H).
- The following 18 compounds were synthesized following the general procedure described above:
-
- 12.0 mg, yield: 28%, white solid.
- LCMS (ESI): m/z=525.2 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=0.86-1.25 (m, 6H), 1.60-1.94 (m, 2H), 2.16-2.43 (m, 4H), 2.60-2.85 (m, 1H), 2.85-3.00 (m, 1H), 3.07 (s, 3H), 3.54-3.60 (m, 2H), 4.04-4.36 (m, 2H), 4.60-4.85 (m, 2H), 5.10- 5.25 (m, 1H), 6.66-6.71 (m, 2H), 7.00-7.20 (m, 1H), 7.29-7.33 (m, 1H), 7.53-7.73 (m, 1H), 7.73-8.08 (m, 3H).
-
- 54.9 mg, yield: 27%, white solid.
- LCMS (ESI): m/z=609.2 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=1.08-1.17 (m, 6H), 1.76-1.88 (m, 2H), 2.22-2.94 (m, 1H), 2.71-2.88 (m, 2H), 3.05 (s, 3H), 3.55-3.60 (m, 1H), 3.85 (s, 3H), 4.02-4.07 (m, 1H), 4.38-4.40 (m, 1H), 4.56-4.58 (m, 1H), 4.71-4.82 (m, 2H), 5.02-5.05 (m, 1H), 6.20-6.27 (m, 1H), 6.43-6.45 (m, 1H), 7.46-7.50 (m, 1H), 7.57-7.78 (m, 1H), 7.89 (m, 1H), 8.03-8.04 (m, 1H), 8.63-8.68 (m, 1H).
-
- 24.0 mg, yield: 31%, white solid.
- LCMS (ESI): m/z=539.2 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=1.03-1.34 (m, 9H), 1.64-1.90 (m, 2H), 2.15-2.28 (m, 1H), 2.61-2.74 (m, 3H), 2.84-2.98 (m, 1H), 3.03 (s, 3H), 3.46-3.61 (m, 1H), 3.95-4.11 (m, 1H), 4.31-4.42 (m, 1H), 4.54- 4.65 (m, 1H), 4.13-4.84 (m, 2H), 4.96-4.98 (m, 1H), 6.52-6.79 (m, 1H), 7.10-7.19 (m, 1H), 7.31-7.40 (m, 1H), 7.61-7.65 (m, 1H), 7.74-7.90 (m, 2H).
-
- 23.5 mg, yield: 49%, white solid.
- LCMS (ESI): m/z=551.2 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=0.55-0.73 (m, 2H), 0.89-1.00 (m, 2H), 1.03-1.04 (m, 3H), 1.09-1.14 (m, 4H), 1.71-1.74 (m, 1H), 1.80-1.84 (m, 1H), 1.91-2.02 (m, 1H), 2.20-2.33 (m, 1H), 2.67-2.83 (m, 1H), 2.92-3.00 (m, 1H), 3.04 (s, 3H), 3.52-3.59 (m, 1H), 3.99-4.05 (m, 1H), 4.33-4.43 (m, 1H), 4.54-4.63 (m, 1H), 4.81-4.83 (m, 1H), 4.97-5.05 (m, 1H), 6.76-6.80 (m, 2H), 7.09-7.29 (m, 2H), 7.46-7.50 (m, 1H), 7.74- 7.90 (m, 2H), 8.24-8.32 (m, 1H).
-
- 13.0 mg, yield: 12%, white solid.
- LCMS (ESI): m/z=613.0 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=1.05-1.20 (m, 6H), 1.4-1.88 (m, 2H), 2.22-2.29 (m, 1H), 2.63-2.70 (m, 1H), 2.89-2.94 (m, 1H), 3.04 (s, 3H), 3.53-3.60 (m, 1H), 4.01-4.08 (m, 1H), 4.39-4.42 (m, 1H), 4.57- 4.59 (m, 1H), 4.80-4.84 (m, 2H), 5.05-5.10 (m, 1H), 6.68-6.72 (m, 1H), 6.79-6.82 (m, 1H), 7.44-7.49 (m, 1H), 7.65-7.67 (m, 1H), 7.88-7.90 (m, 1H), 8.05-8.07 (m, 1H), 8.58-8.67 (m, 1H).
-
- 36.5 mg, yield: 33%, white solid.
- LCMS (ESI): m/z=619.2 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=0.35-0.38 (m, 2H), 0.63-0.67 (m, 2H), 1.05-1.12 (m, 7H), 1.71-1.92 (m, 2H), 2.23-2.27 (m, 1H), 2.69-2.80 (m, 1H), 2.93-3.00 (m, 1H), 3.31-3.33 (m, 2H), 3.52-3.59 (m, 1H), 3.99-4.07 (m, 1H), 4.33-4.42 (m, 1H), 4.56-460 (m, 1H), 4.94-5.05 (m, 4H), 6.79-6.81 (m, 2H), 7.45-7.47 (m, 1H), 7.73-7.89 (m, 3H), 8.03-8.06 (m, 1H), 8.55-8.67 (m, 1H).
-
- 29.0 mg, yield: 35%, white solid.
- LCMS (ESI): m/z=605.2 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=1.32-1.40 (m, 1H), 1.45-1.58 (m, 1H), 1.65-1.81 (m, 6H), 1.93-1.95 (m, 1H), 2.50-2.56 (m, 1H), 2.67-2.76 (m, 2H), 2.95-3.01 (m, 1H), 3.04 (s, 3H), 3.51-3.60 (m, 1H), 4.00- 4.08 (m, 1H), 4.39-4.50 (m, 1H), 4.56-4.59 (m, 1H), 4.83-4.88 (m, 2H, 1H contained in solvent signal), 5.04-5.07 (m, 1H), 6.74-6.83 (m, 2H), 7.43-7.48 (m, 1H), 7.69-7.71 (m, 1H), 7.86-8.06 (m, 3H).
-
- 23.1 mg, yield: 9%, white solid.
- LCMS (ESI): m/z=578.2 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=1.05-1.20 (m, 6H), 1.73-1.85 (m, 2H), 2.25-2.28 (m, 1H), 2.69-2.73 (m, 1H), 2.95-2.98 (m, 1H), 3.05 (s, 3H), 3.54-3.61 (m, 1H), 4.04-4.05 (m, 1H), 4.35-4.38 (m, 1H), 4.46- 4.49 (m, 1H), 4.56-4.58 (m, 2H), 4.99-5.06 (m, 1H), 6.78-6.81 (m, 2H), 7.46-7.51 (m, 1H), 7.63-7.65 (m, 1H), 7.80-7.82 (m, 1H), 7.88-7.89 (m, 1H), 8.04-8.05 (m, 1H).
-
- 25.0 mg, yield: 32%, white solid.
- LCMS (ESI): m/z=593.2 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=0.99-1.16 (m, 6H), 1.78-1.80 (m, 2H), 2.22-2.30 (m, 1H), 2.36-2.39 (m, 2H), 2.44-2.59 (m, 2H), 2.63-2.72 (m, 1H), 3.03 (s, 3H), 3.58-3.65 (m, 1H), 3.94-4.10 (m, 1H), 4.31- 4.35 (m, 1H), 4.44-4.49 (m, 1H), 4.73-4.78 (m, 2H), 4.98-5.03 (m, 1H), 6.91-7.02 (m, 2H), 7.21 (m, 1H), 7.39-7.51 (m, 1H), 7.84-8.09 (m, 2H).
-
- 4.1 mg, yield: 6%, white solid.
- LCMS (ESI): m/z=593.2 [M+H]+.
- 1H-NMR (400 MHz, CDCl3): δ=1.06-1.15 (m, 6H), 1.21-1.23 (m, 2H), 1.27-1.29 (m, 1H), 1.66-1.70 (m, 1H), 1.82-1.85 (m, 1H), 2.70-2.74 (m, 1H), 2.87-2.91 (m, 1H), 3.07 (s, 3H), 3.54-3.57 (m, 1H), 4.12- 4.17 (m, 1H), 4.29-4.32 (m, 1H), 4.66-4.69 (m, 1H), 476-4.85 (m, 2H), 5.22-5.32 (m, 1H), 6.59-6.73 (m, 2H), 7.28-7.52 (m, 1H), 7.68-7.98 (m, 4H), 8.33-8.39 (m, 1H).
-
- 18.5 mg, yield 30%, white solid.
- LCMS (ESI): m/z=595.1 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=1.03-1.20 (m, 6H), 1.69-1.90 (m, 2H), 2.27-2.35 (m, 1H), 2.64-2.73 (m, 1H), 2.94-2.99 (m, 1H), 3.04 (s, 3H), 3.51-3.58 (m, 1H), 3.99-4.06 (m, 1H), 4.43-4.60 (m, 2H), 4.80- 4.84 (m, 3H, 1H contained in solvent signal), 6.70-6.80 (m, 2H), 7.58-7.61 (m, 2H), 7.87-7.90 (m, 1H), 8.13-8.17 (m, 2H), 8.82-8.99 (m, 1H).
-
- 15.0 mg, yield: 35%, white solid.
- LCMS (ESI): m/z=575.2 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=1.13-1.15 (m, 6H), 1.69-1.80 (m, 2H), 2.22-2.35 (m, 1H), 2.50-2.54 (m, 3H), 2.67-2.84 (m, 1H), 3.00-3.13 (m, 4H), 3.54-3.58 (m, 1H), 4.06-4.11 (m, 1H), 4.39-4.43 (m, 1H), 4.54-4.67 (m, 1H), 4.84-4.92 (m, 2H): 4.94-5.05 (m, 1H), 6.80-6.83 (m, 2H), 7.48-7.53 (m, 1H), 7.64-7.67 (m, 1H), 7.71-7.81 (m, 2H), 7.89-8.00 (m, 1H).
-
- 10.6 mg, yield: 15%, white solid.
- LCMS (ESI): m/z=595.2 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=1.75-1.88 (m, 6H), 1.75-1.78 (m, 2H), 2.25-2.36 (m, 2H), 2.90-2.92 (m, 1H), 3.10 (s, 3H), 3.55-3.59 (m, 1H), 4.01-4.03 (m, 1H), 4.31-4.35 (m, 2H), 4.83-4.85 (m, 1H), 4.96- 5.00 (m, 2H), 6.75-6.80 (m, 1H), 7.36-7.90 (m, 5H), 8.56-8.61 (m, 1H).
-
- 27.5 mg, yield: 26%, white solid.
- LCMS (ESI): m/z=541.2 [M+H]+.
- 1H-NMR (400 MHz, CDCl3): δ=1.08-1.27 (m, 6H), 1.68-1.78 (m, 2H), 2.21-2.24 (m, 1H), 2.27-2.77 (m, 1H), 2.88-2.93 (m, 1H), 3.06 (s, 3H), 3.50-3.57 (m, 1H), 3.78-3.82 (m, 3H), 4.03-4.22 (m, 2H), 4.69- 4.80 (m, 3H), 5.07-5.21 (m, 1H), 6.50-6.69 (m, 2H), 6.95-7.12 (m, 2H), 7.53-7.84 (m, 2H), 7.94-7.96 (m, 2H).
-
- 29.9 mg, yield: 54%, white solid.
- LCMS (ESI): m/z=551.2 [M+H]+.
- 1H-NMR (400 MHz, CDCl3): δ=0.90-1.03 (m, 6H), 1.72-1.97 (m, 16H), 2.15-2.21 (m, 1H), 2.68-2.83 (m, 3H), 3.04 (s, 3H), 3.50-3.56 (m, 1H), 4.00-4.94 (m, 1H), 4.24-4.26 (m, 1H), 4.52-4.54 (m, 1H), 4.73- 4.75 (m, 1H), 4.84-4.86 (m, 2H), 6.77-6.79 (m, 2H), 7.85-7.95 (m, 2H).
-
- 36.0 mg, yield: 51%, white solid.
- LCMS (ESI): m/z=577.2 [M+H]+.
- 1H-NMR (400 MHz, CDCl3): δ=1.04-1.15 (m, 6H), 1.72-1.81 (m, 2H), 2.24-2.29 (m, 1H), 2.67-2.94 (m, 2H), 3.04 (s, 3H), 3.52-3.59 (m, 1H), 4.03-4.06 (m, 1H), 4.32-4.34 (m, 1H), 4.55-4.58 (m, 1H), 4.86- 4.91 (m, 1H), 4.97-5.05 (m, 2H), 6.75-6.77 (m, 2H), 6.85-6.94 (m, 1H), 7.28-7.31 (m, 1H), 7.52-7.55 (m, 1H), 7.72-7.79 (m, 1H), 7.88-7.90 (m, 1H), 8.39-8.46 (m, 1H).
-
- 19.9 mg, 77% yield, white solid.
- LCMS (ESI): m/z=591.1 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=0.79-1.01 (m, 6H), 1.71-2.19 (m, 5H), 3.09 (s, 3H), 3.46-3.52 (m, 1H), 3.89-4.04 (m, 1H), 4.15-4.56 (m, 2H), 4.79-4.84 (m, 1H), 6.66-7.00 (m, 1H), 7.21-7.49 (m, 5H), 8.02- 8.17 (m, 2H).
-
- 57.4 mg, 66% yield, white solid.
- LCMS (ESI): m/z=609.2 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=0.80-1.01 (m, 6H), 1.70-2.27 (m, 5H), 3.10 (s, 3H), 3.46-3.54 (m, 1H), 3.91-3.99 (m, 1H), 4.26-4.58 (m, 2H), 4.78-4.83 (m, 1H), 7.26-7.65 (m, 5H), 8.04-8.16 (m, 2H).
-
-
-
- To a solution of 4-methoxyaniline (50 g, 0.040 mol) in acetic acid (30 mL) was added tert-butyl-4-oxopiperidine-1-carboxylate (8.8 g, 0.044 mol). The resulting mixture was cooled to 0° C. and trimethylsilyl cyanide (4.36 g, 0.040 mol) was added. The solution was stirred overnight. Saturated aqueous ammonium chloride solution was added (50 mL). The mixture was filtered, the filter cake was washed with water (3×10 mL) and dried under reduced pressure to afford tert-butyl-4-cyano-4-(4-methoxyphenylamino)piperidine-1-carboxylate as a white solid (12.1 g, 93%).
- LCMS (ESI): m/z=332.1 [M+H]+.
-
- To a solution of tert-butyl-4-cyano-4-(4-methoxyphenylamino)piperidine-1-carboxylate (3.0 g, 9.06 mmol) in methanol (16 mL) was added an aqueous sodium hydroxide solution (10 mL, 1.0 M). After stirring for 15 minutes, to the resulting solution was added a 30% aqueous hydrogen peroxide solution (10 mL) dropwise. The resulting mixture was stirred overnight and filtered. The white solid was washed with water (3×10 mL) and dried under reduced pressure to afford tert-butyl-4-carbamoyl-4-(4-methoxyphenylamino)piperidine-1-carboxylate as a white solid (2.8 g, crude), which was used directly without any further purification.
- LCMS (ESI): m/z=350.2 [M+H]+.
-
- To a solution of tert-butyl-4-carbamoyl-4-(4-methoxyphenylamino)piperidine-1-carboxylate (450 mg, 1.3 mmol) in triethyl orthoformate (4 mL) was added acetic acid (2 drops, cat.). The mixture was heated at 140° C. for 30 minutes in a microwave reactor. The solvent was removed under reduced pressure and the residue was dissolved in methanol (10 mL). To the resulting solution was added sodium borohydride (100 mg, 2.6 mmol) at 0° C. The resulting mixture was stirred for 30 minutes. The solvent was removed under reduced pressure and the residue was diluted with water (10 mL) and ethyl acetate (15 mL). The organic layer was collected and the aqueous layer was extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with dichloromethane:methanol=200:1 to afford tert-butyl-1-(4-methoxyphenyl)-4-oxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate as a white solid (220 mg, 48%).
- LCMS (ESI): m/z=362.2 [M+H]+.
-
- To a solution of tert-butyl-1-(4-methoxyphenyl)-4-oxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate (240 mg, 0.66 mmol) in N,N-dimethylformamide (5 mL) was added sodium hydride (82 mg, 60% in oil, 2.04 mmol) at 0° C. After stirring for 15 minutes, iodomethane (600 mg, 4.2 mmol) was added. The resulting mixture was stirred for 1 hour. The reaction was quenched with ice-water (10 mL) and the mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with dichloromethane:methanol=15:1 to afford tert-butyl-1-(4-methoxyphenyl)-3-methyl-4-oxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate as a yellow oil (232 mg, 93%).
- LCMS (ESI): m/z=376.1 [M+H]*.
-
- To a solution of tert-butyl 1-(4-methoxyphenyl)-3-methyl-4-oxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate (160 mg, 0.42 mmol) in dichloromethane (15 mL) was added boron tribromide (500 mg, 2.0 mmol) at 0° C. After stirring overnight, the reaction was quenched by addition of ice-water (5 mL). To the mixture was added di-tert-butyl-dicarbonate (300 mg, 1.37 mmol) and potassium carbonate (1 g, 7.24 mmol). The mixture was stirred for 2 hours. The organic layer was isolated and the aqueous layer was extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with dichloromethane methanol=40:1 to afford tert-butyl-1-(4-hydroxyphenyl)-3-methyl-4-oxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate as a colorless oil (110 mg, 72%).
- LCMS (ESI): m/z=362.1 [M+H]+.
-
- To a solution of tert-butyl-1-(4-hydroxyphenyl)-3-methyl-4-oxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate (50 mg, 0.14 mmol) in N,N-dimethylformamide (15 mL) was added potassium carbonate (38 mg, 0.28 mmol) and ethyl-2-bromoacetate (50 mg, 0.14 mmol). The resulting mixture was stirred overnight. After quenching with ice-water (10 mL), the mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by prep-TLC with ethyl acetate:petroleum ether=1:1 to afford tert-butyl-1-(4-(2-ethoxy-2-oxoethoxy)phenyl)-3-methyl-4-oxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate as a colorless oil (40 mg, 65%).
- LCMS (ESI): m/z=448.2 [M+H]+.
-
- A solution of tert-butyl-1-(4-(2-ethoxy-2-oxoethoxy)phenyl)-3-methyl-4-oxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate (40 mg, 0.089 mmol) in hydrochloric acid in dioxane (6.0 M, 10 mL) was stirred for 30 minutes. The precipitate was collected by filtration and dried under reduced pressure to afford ethyl-2-(4-(3-methyl-4-oxo-1,3,8-triazaspiro[4.5]decan-1-yl)phenoxy)acetate hydrochloride as a white solid (31 mg, 100%).
- LCMS (ESI): m/z=348.2 [M+H]+.
-
- To a solution of 5-ethyl-2-fluorobenzoic acid (1.00 g, 5.95 mmol) in dichloromethane (50 mL) was added sequentially D-valine methyl ester hydrochloride (1.2 g, 7.18 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate (HATU) (3.4 g, 8.94 mmol) and N,N-diisopropylethylamine (1.9 g, 14.7 mmol). Before quenching with ice-water (50 mL), the reaction was stirred for 2 hours. The mixture was extracted with dichloromethane (3×100 mL). The combined organic layers were dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography eluting with ethyl acetate:petroleum ether=1:4 to afford (R)-methyl-2-(5-ethyl-2-fluorobenzamido)-3-methylbutanoate as a thick oil (1.6 g, 95%).
- LCMS (ESI): m/z=282.2 [M+H]+.
-
- To a solution of (R)-methyl-2-(5-ethyl-2-fluorobenzamido)-3-methylbutanoate (1.6 g, crude) in tetrahydrofuran (20 mL) was added an aqueous lithium hydroxide solution (240 mg in 10 mL of water, 17.8 mmol). Before quenching with ice-water (20 mL), the reaction was stirred for 1 hour. The pH of the solution was adjusted to 3 by addition of a 9% aqueous hydrochloric acid solution. The mixture was filtered and the filter cake was washed with petroleum ether (30 mL) and dried under reduced pressure to afford (R)-2-(5-ethyl-2-fluorobenzamido)-3-methylbutanoic acid as a white solid (1.3 g, 94% over two steps).
- LCMS (ESI): m/z=268.1 [M+H]+.
- 1H-NMR (300 MHz, CDCl3): δ=1.05 (dd, J=8.6, 6.9 Hz, 6H), 1.23 (t, J=7.6 Hz, 3H), 2.31-2.45 (m, 1H), 2.65 (q, J=7.8 Hz, 2H), 7.01-7.07 (m, 1H), 7.16-7.33 (m, 2H), 7.85-7.93 (m, 1H).
-
- To a mixture of ethyl-2-(4-(3-methyl-4-oxo-1,3,8-triazaspiro[4.5]decan-1-yl)phenoxy)acetate hydrochloride (31 mg, 0.089 mmol) in dichloromethane (5 mL) was added sequentially (R)-2-(5-ethyl-2-fluorobenzamido)-3-methylbutanoic acid (24 mg, 0.089 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate (HATU) (51 mg, 0.13 mmol) and N,N-diisopropylethylamine (29 mg, 0.22 mmol). The resulting mixture was stirred for 2 hours at room temperature before the reaction was quenched with ice-water The mixture was extracted with ethyl acetate (3×10 mL) and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by prep-TLC with dichloromethane:methanol=15:1 to afford (R)-ethyl-2-(4-(8-(2-(5-ethyl-2-fluorobenzamido)-3-methyl butanoyl)-3-methyl-4-oxo-1,3,8-triazaspiro[4.5]decan-1-yl)phenoxy)acetate as a colorless oil (20 mg, 37%).
- LCMS (ESI): m/z=597.1 [M+H]+.
-
- To a solution of (R)-ethyl-2-(4-(8-(2-(5-ethyl-2-fluorobenzamido)-3-methylbutanoyl)-3-methyl-4-oxo-1,3,8-triazaspiro[4.5]decan-1-yl)phenoxy)acetate (20 mg, 0.03 mmol) in tetrahydrofuran (2 mL) was added an aqueous lithium hydroxide solution (2 mL, 2.0 M). The resulting mixture was stirred overnight. The pH of the reaction mixture was adjusted to 3 by addition of an aqueous hydrochloric acid solution (2.0 M). The resulting mixture was extracted with ethyl acetate (3×10 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by prep-HPLC (acetonitrile and water, acetonitrile from 30% to 70%) to afford (R)-2-(4-(8-(2-(5-ethyl-2-fluorobenzamido)-3-methylbutanoyl)-3-methyl-4-oxo-1,3,8-triazaspiro[4.5]decan-1-yl)phenoxy)acetic acid as a white solid (7.0 mg, 39%).
- LCMS (ESI): m/z=569.2 [M+H]+.
- 1H-NMR (400 MHz, CDCl3): δ=0.99-1.04 (m, 9H), 1.73-2.14 (m, 5H), 2.65-2.67 (m, 2H), 3.02 (s, 3H), 3.57-3.60 (m, 1H), 4.02-4.04 (m, 2H), 4.45-4.66 (m, 5H), 5.06-5.10 (m, 1H), 6.75-7.80 (m, 8H).
- The following 3 compounds were synthesized following the general procedure described above:
-
- 11.0 mg, yield: 17%, white solid.
- LCMS (ESI): m/z=568.2 [M+H]+.
- 1H-NMR (400 MHz, CDCl3): δ=0 98-1.05 (m, 6H), 1.23-1.27 (m, 3H), 1.73-1.89 (m, 2H), 2.09-2.27 (m, 3H), 2.64-2.71 (m, 2H), 3.03 (s, 3H), 3.53-3.59 (m, 1H), 4.03-4.06 (m, 2H), 4.39-4.89 (m, 3H), 4.63- 4.69 (m, 2H), 5.08-5.15 (m, 1H), 6.14-6.17 (m, 1H), 6.57-6.61 (m, 1H), 6.77-6.85 (m, 4H), 7.02-7.08 (m, 1H), 7.28-7.32 (m, 1H), 7.51-7.56 (m, 1H), 7.84-7.85 (m, 1H).
-
- 2.0 mg, yield: 4%, white solid.
- LCMS (ESI): m/z=550 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=0.98-1.00 (m, 6H), 1.24-1.32 (m, 3H), 1.67-1.84 (m, 3H), 2.01-2.21 (m, 4H), 2.47-2.52 (m, 1H), 2.65-2.73 (m, 2H), 3.02 (s, 3H), 3.55-3.65 (m, 2H), 3.95-4.04 (m, 1H), 4.36- 4.48 (m, 1H), 4.73-4.75 (m, 2H), 4.79-4.82 (m, 1H), 4.97-5.01 (m, 1H), 6.83-6.89 (m, 3H), 7.03-7.05 (m, 1H), 7.11-7.20 (m, 4H), 7.39-7.44 (m, 1H), 7.58-7.61 (m, 1H), 8.18-8.25 (m, 1H).
-
- 20.8 mg, yield: 24%, white solid.
- LCMS (ESI): m/z=621.8 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=0.98-1.06 (m, 6H), 1.75-2.21 (m, 4H), 2.48-2.53 (m, 1H), 2.98 (s, 4H), 3.00 (s, 3H), 3.02 (s, 2H), 3.57-3.61 (m, 3H), 3.93-4.11 (m, 1H), 4.22-4.26 (m, 3H), 4.33-4.40 (m, 1H), 4.69-4.72 (m, 2H), 4.94-4.98 (m, 1H), 6.89-7.06 (m, 4H), 7.47-7.53 (m, 1H), 7.92-7.98 (m, 1H), 8.02- 8.06 (m, 1H).
-
-
-
- To a solution of tert-butyl-1-(4-aminophenyl)-3-methyl-4-oxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate (prepared as described in Example 218-d) (150 mg, 0.41 mmol) in dichloromethane (15 mL) was added triethylamine (92 mg, 0.92 mmol). The resulting mixture was cooled to 0° C. and acetyl chloride (42 mg, 0.54 mmol) was added. The reaction was stirred for 30 minutes. After the reaction was quenched by addition of ice-water (10 mL), the mixture was extracted with dichloromethane (3×10 mL) and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with ethyl acetate:petroleum ether=1:3 to afford tert-butyl-1-(4-acetamidophenyl)-3-methyl-4-oxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate as a white solid (95 mg, 51%).
- LCMS (ESI): m/z=403.2 [M+H]+.
-
- To a solution of tert-butyl-1-(4-acetamidophenyl)-3-methyl-4-oxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate (100 mg, 0.248 mmol) in dioxane (2 mL) was added hydrochloric acid in dioxane (4 mL, 6.0 M). The resulting mixture was stirred for 6 hours. The precipitate was collected by filtration and dried under reduced pressure to afford N-(4-(3-methyl-4-oxo-1,3,8-triazaspiro[4.5]decan-1-yl)phenyl)acetamide hydrochloride as a white solid (80 mg, 95%).
- LCMS (ESI): m/z=303.2 [M+H]+.
-
- To a solution of N-(4-(3-methyl-4-oxo-1,3,8-triazaspiro[4.5]decan-1-yl)phenyl)acetamide hydrochloride (69 mg, 0.206 mmol) in dichloromethane (5 mL) was added sequentially (R)-2-(5-ethyl-2-fluorobenzamido)-3-methylbutanoic acid (prepared as described in Example 168-i) (50 mg, 0.187 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate (HATU) (142 mg, 0.374 mmol) and N,N-diisopropylethylamine (48 mg, 0.374 mmol). The reaction was stirred for 2 hours at room temperature before quenching with ice-water (5 mL). The mixture was extracted with ethyl acetate (3×10 mL) and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by prep-TLC with dichloromethane:methanol=15:1 to afford (R)—N-(1-(1-(4-acetamidophenyl)-3-methyl-4-oxo-1,3,8-triazaspiro[4.5]decan-8-yl)-3-methyl-1-oxobutan-2-yl)-5-ethyl-2-fluorobenzamide as a white solid (16 mg, 16%).
- LCMS (ESI): m/z=552.2 [M+H]+.
- 1H-NMR (400 MHz, CDCl3): δ=1.02-1.07 (m, 6H), 1.20-1.27 (m, 3H), 1.71-1.92 (m, 2H), 2.08-2.11 (m, 3H), 2.17-2.45 (m, 2H), 2.57-2.72 (m, 3H), 3.02 (s, 3H), 3.51-3.58 (m, 1H), 3.95-4.05 (m, 1H), 4.18- 4.31 (m, 1H), 4.40-4.48 (m, 1H), 4.73-4.75 (m, 2H), 4.95-4.99 (m, 1H), 6.79-7.62 (m, 8H).
- The following 3 compounds were synthesized following the general procedure described above:
-
- 10.6 mg, yield: 10%, white solid.
- LCMS (ESI): m/z=588.2 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=1.03-1.08 (m, 6H), 1.22-1.27 (m, 3H), 1.71-1.92 (m, 2H), 2.18-2.53 (m, 2H), 2.66-2.78 (m, 3H), 2.82-2.91 (m, 3H), 3.03 (s, 3H), 3.51-3.58 (m, 1H), 3.95-4.05 (m, 1H), 4.22- 4.33 (m, 1H), 4.44-4.51 (m, 1H), 4.75-4.76 (m, 2H), 4.95-4.99 (m, 1H), 6.81-8.31 (m, 8H).
-
- 24.6 mg, yield: 22%, white solid.
- LCMS (ESI): m/z=628.2 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=1.04-1.09 (m, 6H), 1.72-1.93 (m, 2H), 2.19-2.24 (m, 1H), 2.33-2.49 (m, 1H), 2.68-2.76 (m, 1H), 2.76-2.91 (m, 3H), 3.03 (s, 3H), 3.54-3.60 (m, 1H), 3.97-4.12 (m, 1H), 4.22- 4.31 (m, 1H), 4.43-4.51 (m, 1H), 4.74-4.76 (m, 2H), 4.94-5.02 (m, 1H), 6.81-6.91 (m, 2H), 7.07-7.21 (m, 2H), 7.39-7.52 (m, 1H), 7.85-7.95 (m, 1H), 8.04-8.06 (m, 1H), 8.55-8.63 (m, 1H).
-
- 58.4 mg, yield: 27%, white solid.
- LCMS (ESI) m/z=607.8 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=1.01-1.05 (m, 6H), 1.68-1.87 (m, 2H), 2.14-2.51 (m, 3H), 2.98 (s, 3H), 3.50-3.56 (m, 1H), 3.70-3.73 (m, 3H), 3.92-4.42 (m, 3H), 4.68-4.71 (m, 2H), 4.95-4.99 (m, 1H), 6.80- 6.87 (m, 2H), 7.19-7.44 (m, 3H), 7.86-7.77 (m, 1H), 8.02-8.04 (m, 1H).
-
-
-
- To a solution of tert-butyl-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate (150 mg, 0.453 mmol) in N,N-dimethylformamide (20 mL) was added sodium hydride (20 mg, 60% in oil, 0.5 mmol) at 0° C. After stirring for 30 minutes, ethyl-2-chloroacetate (67 mg, 0.543 mmol) was added. The reaction was stirred overnight, before quenching with ice-water (10 mL). The resulting mixture was filtered to afford tert-butyl-3-(2-ethoxy-2-oxoethyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate as a white solid (164 mg, 87%).
- LCMS (ESI): m/z=418.2 [M+H]+.
-
- To a solution of tert-butyl-3-(2-ethoxy-2-oxoethyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate (80 mg, 0.192 mmol) in dioxane (2 mL) was added hydrochloric acid in dioxane (4 mL, 6.0 M). The resulting mixture was stirred for 6 hours. The precipitate was collected by filtration and dried under reduced pressure to afford ethyl 2-(4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)acetate hydrochloride as a white solid (65 mg, 97%).
- LCMS (ESI): m/z=318.2 [M+H]+.
-
- To a solution of 3-fluoro-5-methylbenzoic acid (1.0 g, 6.49 mmol) in dichloromethane (30 mL) was added sequentially D-valine methyl ester hydrochloride (1.2 g, 7.14 mmol), 1-[bis(dimethylamino)methylene]-11H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate (HATU) (3.7 g, 9.74 mmol) and N,N-diisopropylethylamine (2.5 g, 19.48 mmol). Before quenching with ice-water (50 mL), the reaction was stirred for 2 hours. The mixture was extracted with dichloromethane (3×100 mL). The combined organic layers were dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography eluting with ethyl acetate:petroleum ether=1:4 to afford (R)-methyl-2-(3-fluoro-5-methylbenzamido)-3-methylbutanoate as a thick oil (0.6 g, 35%).
- LCMS (ESI): m/z=268.2 [M+H]+.
-
- To a solution of (R)-methyl-2-(3-fluoro-5-methylbenzamido)-3-methylbutanoate (1.64 g, 6.14 mmol) in tetrahydrofuran (30 mL) was added an aqueous lithium hydroxide solution (0.73 g in 20 mL of water, 30.7 mmol). Before quenching with ice-water (20 mL), the reaction was stirred for 1 hour. The pH of the solution was adjusted to 3 by addition of a 5% aqueous hydrochloric acid solution. The mixture was filtered and the filter cake was washed with petroleum ether (30 mL) and dried under reduced pressure to afford (R)-2-(3-fluoro-5-methylbenzamido)-3-methylbutanoic acid as a thick oil (0.8 g, 53%).
- LCMS (ESI): m/z=254.1 [M+H]+.
-
- To a mixture of ethyl-2-(4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)acetate hydrochloride (65 mg, 0.184 mmol) in dichloromethane (5 mL) was added sequentially (R)-2-(3-fluoro-5-methylbenzamido)-3-methylbutanoic acid (60 mg, 0.224 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate (HATU) (140 mg, 0.368 mmol) and N,N-diisopropylethylamine (120 mg, 0.920 mmol). The reaction was stirred for 2 hours at room temperature before quenching with ice-water (5 mL). The mixture was extracted with ethyl acetate (3×10 mL) and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by prep-TLC with ethyl acetate:petroleum ether=15:1 to afford (R)-ethyl-2-(8-(2-(3-fluoro-5-methylbenzamido)-3 methylbutanoyl)-4-oxo 1 phenyl 1,3,8 triazaspiro[4.5]decan 3 yl)acetate as a white solid (20 mg, 20%).
- LCMS (ESI): m/z=553.2 [M+H]+.
-
- To a solution of (R)-ethyl-2-(8-(2-(3-fluoro-5-methylbenzamido)-3-methylbutanoyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)acetate (20 mg, 0.036 mmol) in tetrahydrofuran:water=1:1 (10 mL) was added lithium hydroxide (156 mg, 6.5 mmol). The resulting mixture was stirred overnight. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL) The pH of the aqueous layer was adjusted to 1 by addition of a 5% aqueous hydrochloric acid solution. The resulting mixture was extracted with ethyl acetate (3×10 mL). The combined organic layers were dried over anhydrous sodium sulfate and dried under reduced pressure. The residue was purified by prep-HPLC to afford (R)-2-(8-(2-(3-fluoro-5-methylbenzamido)-3-methyl butanoyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)acetic acid as a white solid (2.7 mg, 15%).
- LCMS (ESI): m/z=525.0 [M+H]+.
- 1H-NMR (400 MHz, CDCl3): δ=0.99-1.05 (m, 6H), 1.24-1.28 (m, 1H), 1.77-1.87 (m, 2H), 2.16-2.26 (m, 1H), 2.43-2.44 (m, 3H), 2.55-2.67 (m, 3H), 3.50-3.60 (m, 1H), 3.98-4.13 (m, 3H), 4.33-4.66 (m, 4H), 5.22-5.30 (m, 1H), 6.68-7.45 (m, 7H).
- The following 2 compounds were synthesized following the general procedure described above:
-
- 35.0 mg, yield: 29%, white solid.
- LCMS (ESI): m/z=587.2 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=0.99-1.09 (m, 6H), 1.74-1.87 (m, 2H), 2.16-2.23 (m, 3H), 2.35 (s, 3H), 2.49-2.74 (m, 2H), 3.02 (s, 3H), 3.19-3.24 (m, 2H), 3.50-3.98 (m, 3H), 4.01-4.02 (m, 1H), 4.32-4.35 (m, 1H), 4.47-4.51 (m, 1H), 4.73-4.81 (m, 2H), 4.97-5.00 (m, 1H), 6.71-7.52 (m, 8H).
-
- 58.3 mg, yield: 60%, white solid.
- LCMS (ESI): m/z=520.2 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=1.03-1.08 (m, 6H), 1.22-1.27 (m, 3H), 1.73-1.95 (m, 2H), 2.16-2.53 (m, 2H), 2.65-2.77 (m, 3H), 3.47-3.57 (m, 1H), 3.93-4.05 (m, 1H), 4.21-4.53 (m, 2H), 4.57-4.58 (m, 2H), 4.84-4.86 (m, 2H), 4.97-4.99 (m, 1H), 6.75-7.62 (m, 8H).
-
-
-
- To a solution of 4-bromoaniline (4.17 g, 0.024 mol) in acetic acid (100 mL) was added tert-butyl-4-oxopiperidine-1-carboxylate (5 g, 0.025 mol). The resulting mixture was cooled to 0° C. and trimethylsilyl cyanide (2.71 g, 0.027 mol) was added. The resulting solution was stirred overnight. Saturated aqueous ammonium chloride solution was added (50 mL). The mixture was filtered, the filter cake was washed with water (3×10 mL) and dried under reduced pressure to afford tert-butyl-4-(4-bromophenylamino)-4-cyanopiperidine-1-carboxylate as a white solid (9.0 g, 98%).
- LCMS (ESI): m/z=380.1, 383.1 [M+H]+.
- 1H-NMR (400 MHz, DMSO-d6): δ=1.41 (s, 9H), 1.65-1.85 (m, 2H), 2.28 (d, J=13.6 Hz, 2H), 3.10-3.16 (m, 2H), 3.76 (d, J=14.3 Hz, 2H), 6.34 (s, 1H), 6.74-6.91 (m, 2H), 7.27-7.43 (m, 2H).
-
- To a solution of tert-butyl-4-(4-bromophenylamino)-4-cyanopiperidine-1-carboxylate (4.0 g, 0.011 mol) in methanol (300 mL) was added an aqueous sodium hydroxide solution (36 mL, 1.0 M). After stirring for 15 minutes, to the resulting solution was added a 30% aqueous hydrogen peroxide solution (29 mL) dropwise. The resulting mixture was stirred overnight and filtered. The precipitate was washed with water (3×100 mL) and dried under reduced pressure to afford tert-butyl-4-(4-bromophenylamino)-4-carbamoylpiperidine-1-carboxylate as a white solid (3.6 g, 85%).
- LCMS (ESI): m/z=398.2, 400.2 [M+H]+.
- 1H-NMR (300 MHz, DMSO-d0): δ=1.39 (s, 9H), 1.59-1.98 (m, 4H), 3.12-3.16 (m, 2H), 3.54-360 (m, 2H), 5.92 (s, 1H), 6.53 (d, J=8.9 Hz, 2H), 7.12 (s, 1H), 7.21 (d, J=8.9 Hz, 2H), 7.33 (s, 1H).
-
- To a solution of tert-butyl-4-(4-bromophenylamino)-4-carbamoylpiperidine-1-carboxylate (0.6 g, 0.0015 mol) in triethyl orthoformate (200 mL) was added acetic acid (1 drop, cat.). The resulting mixture was heated at 170° C. for 30 minutes in a microwave reactor. The solvent was removed under reduced pressure. The residue was dissolved in methanol (200 mL) and to the resulting solution was added sodium borohydride (2.62 g, 0.069 mol) at 0° C. The resulting mixture was stirred for 30 minutes. The solvent was removed under reduced pressure and the residue was diluted with water (200 mL) and ethyl acetate (150 mL). The organic layer was collected and the aqueous layer was extracted with ethyl acetate (3×100 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with dichloromethane:methanol=200:1 to afford tert-butyl-1-(4-bromophenyl)-4-oxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate as a white solid (210 mg, 33%).
- LCMS (ESI): m/z=410.1, 413.1 [M+H]+.
-
- To a solution of tert-butyl-1-(4-bromophenyl)-4-oxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate (210 mg, 0.51 mmol) in N,N-dimethylformamide (3 mL) was added sodium hydride (41 mg, 60% in oil, 1.02 mmol) at 0° C. After stirring for 15 minutes, iodomethane (145 mg, 1.02 mmol) was added. The resulting mixture was stirred for 1 hour. The reaction was quenched with ice-water (10 mL) and the mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with dichloromethane:methanol=15:1 to afford tert-butyl-1-(4-bromophenyl)-3-methyl-4-oxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate as a white solid (210 mg, 97%).
- LCMS (ESI): m/z=424.1, 426.1 [M+H]+.
-
- To a solution of tert-butyl-1-(4-bromophenyl)-3-methyl-4-oxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate (100 mg, 0.24 mmol) in N,N-dimethylformamide was added sequentially zinc cyanide (135 mg, 1.18 mmol), tris(dibenzylideneacetone)dipalladium (22 mg, 0.024 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) (27 mg, 0.047 mmol) under an argon atmosphere. The reaction mixture was stirred overnight at 130° C. After quenching with ice-water (5 mL), the reaction mixture was extracted with ethyl acetate (3×15 mL) The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with ethyl acetate:petroleum ether=1:1 to afford tert-butyl-1-(4-cyanophenyl)-3-methyl-4-oxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate as a brown oil (50 mg, crude), which was used directly without any further purification.
- LCMS (ESI): m/z=371.2 [M+H]+.
-
- A solution of tert-butyl-1-(4-cyanophenyl)-3-methyl-4-oxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate (60 mg, 0.16 mmol) in hydrochloric acid in dioxane (6.0 M, 10 mL) was stirred for 30 minutes. The precipitate was collected by filtration and dried under reduced pressure to afford 4-(3-methyl-4-oxo-1,3,8-triazaspiro[4.5]decan-1-yl)benzonitrile hydrochloride as a white solid (60 mg, crude), which was used directly without any further purification.
- LCMS (ESI): m/z=271.1 [M+H]+.
-
- To a mixture of 4-(3-methyl-4-oxo-1,3,8-triazaspiro[4.5]decan-1-yl)benzonitrile hydrochloride (55 mg, 0.203 mmol) in dichloromethane (5 mL) was added (R)-2-(2-fluoro-3-methylbenzamido)-3-methylbutanoic acid (prepared as described in Example 145-d) (61 mg, 0.223 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate (HATU) (116 mg, 0.304 mmol) and N,N-diisopropylethylamine (53 mg, 0.406 mmol). The resulting mixture was stirred for 2 hours at room temperature before the reaction was quenched with ice-water. The mixture was extracted with ethyl acetate (3×10 mL) and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by prep-TLC with dichloromethane:methanol=15:1 to afford (R)—N-(1-(1-(4-cyanophenyl)-3-methyl-4-oxo-1,3,8-triazaspiro[4.5]decan-8-yl)-3-methyl-1-oxobutan-2-yl)-2-fluoro-3-methylbenzamide as a white solid (19 mg, 18%).
- LCMS (ESI): m/z=506.2 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=1.03-1.19 (m, 6H), 1.7-1.82 (m, 2H), 2.20-2.40 (m, 4H), 2.69-2.69-2.73 (m, 2H), 2.81-2.85 (m, 2H), 3.04 (s, 3H), 3.50-3.53 (m, 1H), 3.98-4.03 (m, 1H), 4.36-4.39 (m, 1H), 4.54-4.59 (m, 1H), 4.79-4.85 (m, 2H), 4.94-4.99 (m, 2H), 6.25-6.78 (m, 2H), 7.14-7.29 (m, 3H), 7.45-7.55 (m, 2H).
- The following 12 compounds were synthesized following the general procedure described above:
-
- 9.2 mg, 8% yield, white solid.
- LCMS (ESI): m/z=488.0 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=1.18-1.03 (m, 6H), 1.80-1.65 (m, 2H), 2.20-2.15 (m, 1H), 2.44 (d, J=4.9 Hz, 3H), 2.60-55 (m, 1H), 2.80-2.78 (m, 1H), 3.08 (s, 3H), 3.63-3.50 (m, 2H), 4.20-4.04 (m, 2H), 4.74-4.62 (m, 2H), 5.18-5.03 (m, 1H), 7.15-6.60 (m, 4H), 7.44-7.30 (m, 2H), 7.67 (d, J=9.2 Hz, 2H).
-
- 45.1 mg, 47% yield, white solid.
- LCMS (ESI): m/z=538.1 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=0.81-1.02 (m, 6H), 1.65-2.21 (m, 5H), 3.08 (s, 3H), 3.46-3.51 (m, 1H), 3.91-3.98 (m, 1H), 4.19-4.30 (m, 1H), 4.41-4.52 (m, 1H), 4.82-4.85 (m, 1H), 7.22-7.54 (m, 5H), 7.88- 8.01 (m, 2H), 8.48-8.49 (m, 1H).
-
- 47.9 mg, 44% yield, white solid.
- LCMS (ESI): m/z=567.1 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=0.80-1.02 (m, 6H), 1.65-2.00 (m, 2H), 2.03-2.21 (m, 3H), 3.08 (s, 3H), 3.45-3.52 (m, 1H), 3.92-3.98 (m, 1H), 4.19-4.30 (m, 1H), 4.41-4.53 (m, 1H), 4.82-4.88 (m, 1H), 7.10- 7.14 (m, 1H), 7.23-7.28 (m, 2H), 7.33-7.47 (m, 2H), 7.87-8.01 (m, 2H).
-
- 29.5 mg, 27% yield: 27%, white solid.
- LCMS (ESI): m/z=617.1 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=0.83-1.02 (m, 6H), 1.65-1.86 (m, 1H), 1.94-2.22 (m, 4H), 3.08 (s, 3H), 3.32-3.51 (m, 1H), 3.91-3.97 (m, 1H), 4.21-4.31 (m, 1H), 4.43-4.55 (m, 1H), 4.82-4.87 (m, 1H), 7.19- 7.27 (m, 1H), 7.38-7.50 (m, 1H), 7.59-7.68 (m, 2H), 7.87-8.02 (m, 2H), 8.47-8.54 (m, 1H).
-
- 34 mg, 35% yield, white solid.
- LCMS (ESI) m/7=563.2 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=0.78-0.99 (m, 6H), 1.65-2.18 (m, 5H), 2.30-2.41 (m, 3H), 3.08 (s, 3H), 3.44-3.52 (m, 1H), 3.90-3.99 (m, 1H), 4.16-4.50 (m, 2H), 4.84-4.88 (m, 1H), 7.08-7.46 (m, 5H), 7.88- 8.02 (m, 2H), 8.43-8.52 (m, 1H).
-
- 6 mg, 15% yield, white solid.
- LCMS (ESI): m/z=588.2 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=0.77-0.83 (m, 2H), 0.89-0.95 (m, 2H), 1.03 (d, J=6.8 Hz, 2H), 1.83-1.98 (m, 3H), 2.07-2.12 (m, 2H), 3.17 (s, 3H), 3.49-3.55 (m, 1H), 3.97-4.01 (m, 1H), 4.46-4.61 (m, 1.5H), 4.99-5.02 (m, 1H), 5.37 (s, 0.5H), 6.55-6.61 (m, 1H), 6.90-6.97 (m, 1H), 7.21-7.28 (m, 1H), 7.41-7.48 (m, 3H), 7.70-7.73 (m, 1H), 8.22 (d, J=4.9 Hz, 1H), 8.32-8.39 (m, 1H).
-
- 172 mg, 52% yield, white solid.
- LCMS (ESI): m/z=617.2 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=0.87-1.05 (m, 6H), 1.75-1.80 (m, 1H), 1.91-2.12 (m, 4H), 3.15 (s, 3H), 3.45-3.53 (m, 1H), 3.99-4.07 (m, 2H), 4.63-4.66 (m, 1H), 5.00-5.03 (m, 1H), 7.24-7.43 (m, 4H), 7.67- 7.78 (m, 3H), 8.27-8.36 (m, 1H).
-
- 120 mg, 79% yield, white solid.
- LCMS (ESI): m/z=583.1 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=0.87-1.05 (m, 6H), 1.77-1.80 (m, 1H), 1.91-2.12 (m, 4H), 3.15 (s, 3H), 3.46-3.53 (m, 1H), 3.98-4.04 (m, 2H), 4.63-4.66 (m, 1H), 4.98-5.01 (m, 1H), 7.05-7.11 (m, 1H), 7.17- 7.29 (m, 2H), 7.35-7.46 (m, 3H), 7.75-7.78 (m, 1H), 8.25-8.36 (m, 1H).
-
- 98 mg, 71% yield, white solid.
- LCMS (ESI): m/z=550.1 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=1.00-1.16 (m, 6H), 1.78-1.92 (m, 2H), 2.18-2.24 (m, 1H), 3.07-3.24 (m, 4H), 3.40-3.52 (m, 2H), 3.98-4.14 (m, 2H), 4.62-4.71 (m, 1H), 5.15-5.20 (m, 1H), 7.01-7.10 (m, 1H), 7.28-7.35 (m, 1H), 7.53-7.60 (m, 1H), 7.68-7.81 (m, 2H), 7.98-8.26 (m, 2H), 8.35-8.39 (m, 1H).
-
- 150 mg, 49% yield, white solid.
- LCMS (ESI): m/z=550.1 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=0.88-1.06 (m, 6H), 1.70-1.81 (m, 1H), 1.99-2.23 (m, 4H), 3.18 (s, 3H), 3.48-3.54 (m, 1H), 4.00-4.15 (m, 2H), 4.59-4.70 (m, 1H), 4.86-5.05 (m, 1H), 7.31-7.42 (m, 1H), 7.69- 7.78 (m, 2H), 7.85-7.92 (m, 1H), 8.13-8.35 (m, 1H), 8.70-8.77 (m, 1H), 9.31 (s, 1H).
-
- 25 mg, 47% yield, white solid.
- LCMS (ESI): m/z=550.1 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=0.75-1.03 (m, 6H), 1.66-2.21 (m, 5H), 3.09 (s, 3H), 3.44-3.53 (m, 1H), 3.91-4.01 (m, 1H), 4.15-4.32 (m, 1H), 4.37-4.54 (m, 1H), 4.83-4.86 (m, 1H), 7.22-7.32 (m 2H), 7.37- 7.53 (m 3H), 7.84-8.03 (m 2H).
-
- 102.6 mg, 35% yield, white solid.
- LCMS (ESI): m/z=593.1 [M+H]+.
- 1H-NMR (300 MHz, DMSO-d6): δ=0.92-1.11 (m, 6H), 1.70-178 (m, 2H), 2.07-2.11 (m, 3H), 3.03-3.12 (m, 5H), 4.13-4.17 (m, 2H), 4.76 (t, 1H), 6.04-6.10 (m, 2H), 6.87-6.71 (m, 3H), 7.50-7.68 (m, 1H), 8.01-7.74 (m, 2H), 8.34 (d, 1H).
-
-
-
- To a solution of 3-chloroaniline (2.0 g, 0.015 mol) in acetic acid (20 mL) was added tert-butyl-4-oxopiperidine-1-carboxylate (3.4 g, 0.016 mol). The resulting mixture was cooled to 0° C. and trimethylsilyl cyanide (1.86 g, 0.017 mol) was added. The solution was stirred overnight. Saturated aqueous ammonium chloride was added (50 mL). The mixture was filtered, the filter cake was washed with water (3×10 mL) and dried under reduced pressure to afford tert-butyl-4-(3-chlorophenylamino)-4-cyanopiperidine-1-carboxylate as a white solid (5.0 g, 100%).
- LCMS (ESI): m/z=336.1, 338.1 [M+H]+.
- 1H-NMR (400 MHz, DMSO-d6): δ=1.41 (s, 9H), 1.64-1.85 (m, 2H), 2.29-2.32 (m, 2H), 3.15-3.17 (m, 2H), 3.77-3.85 (m, 2H), 6.46 (s, 1H), 6.72-6.94 (m, 3H), 7.21-7.29 (m, 1H).
-
- To a solution of tert-butyl-4-(3-chlorophenylamino)-4-cyanopiperidine-1-carboxylate (1.0 g, 2.97 mmol) in methanol (16 mL) was added an aqueous sodium hydroxide solution (10 mL, 1.0 M). After stirring for 15 minutes, to the resulting solution was added a 30% aqueous hydrogen peroxide solution (7 mL) dropwise. The resulting mixture was stirred overnight and filtered. The white solid was washed with water (3×10 mL) and dried under reduced pressure to afford tert-butyl-4-carbamoyl-4-(3-chlorophenylamino)piperidine-1-carboxylate as a white solid (1.0 g, crude), which was used directly without any further purification.
- LCMS (ESI): m/z=354.1, 356.1 [M+H]+.
-
- To a solution of tert-butyl-4-carbamoyl-4-(3-chlorophenylamino)piperidine-1-carboxylate (450 mg, 1.2 mmol) in triethyl orthoformate (4 mL) was added acetic acid (2 drops, cat.). The mixture was heated at 140° C. for 30 minutes in a microwave reactor. The solvent was removed under reduced pressure and the residue was dissolved in methanol (10 mL). To the resulting solution was added sodium borohydride (100 mg, 2.6 mmol) at 0° C. The resulting mixture was stirred for 30 minutes. The solvent was removed under reduced pressure and the residue was diluted with water (10 mL) and ethyl acetate (15 mL). The organic layer was collected and the aqueous layer was extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with dichloromethane:methanol=200.1 to afford tert-butyl-1-(3-chlorophenyl)-4-oxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate as a white solid (120 mg, 25%).
- LCMS (ESI): m/z=366.1, 368.1 [M+H]+.
- 1H-NMR (300 MHz, CDCl3): δ=1.51 (s, 9H), 1.61-1.76 (m, 2H), 2.47-2.66 (m, 2H), 3.51-3.62 (m, 2H), 3.99-4.16 (m, 2H), 4.73 (s, 2H), 6.57-6.72 (m, 2H), 6.77-6.87 (m, 1H), 7.06-7.21 (m, 1H).
-
- To a solution of tert-butyl-1-(3-chlorophenyl)-4-oxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate (120 mg, 0.33 mmol) in N,N-dimethylformamide (3 mL) was added sodium hydride (41 mg, 60% in oil, 1.02 mmol) at 0° C. After stirring for 15 minutes, iodomethane (233 mg, 1.64 mmol) was added. The resulting mixture was stirred for 1 hour. The reaction was quenched with ice-water (10 mL) and the mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with dichloromethane:methanol=15:1 to afford tert-butyl-1-(3-chlorophenyl)-3-methyl-4-oxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate as a yellow oil (120 mg, 96%).
- LCMS (ESI): m/z=380.1, 382.1 [M+H]+.
-
- A solution of tert-butyl-1-(3-chlorophenyl)-3-methyl-4-oxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate (120 mg, 0.13 mmol) in hydrochloric acid in dioxane (6.0 M, 10 mL) was stirred for 30 minutes. The precipitate was collected by filtration and dried under reduced pressure to afford 1-(3-chlorophenyl)-3-methyl-1,3,8-triazaspiro[4.5]decan-4-one hydrochloride as a white solid (80 mg, 80%).
- LCMS (ESI): m/z=280.1, 282.1 [M+H]+.
-
- To a suspension of (R)-methyl-2-amino-3-methylbutanoate hydrochloride (2.9 g, 17 mmol) in dichloromethane (30 mL) was added N,N-diisopropylethylamine (5.6 g, 40 mmol). To the resulting mixture was added dropwise a solution of 3-methylbenzoyl chloride (3.2 g, 20.6 mmol) in dichloromethane (5 mL) at 0° C. The mixture was stirred for 1 hour before the reaction was quenched with ice-water (10 mL). The organic layer was collected and the aqueous layer was extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography eluting with ethyl acetate:petroleum ether=1:10 to afford (R)-methyl-3-methyl-2-(3-methylbenzamido)butanoate as a yellow oil (3.3 g, 78%).
- LCMS (ESI): m/z=250.1 [M+H]+.
- 1H-NMR (300 MHz, CDCl3): δ=1.01 (t, J=7.2 Hz, 6H), 2.19-2.36 (m, 1H), 2.42 (s, 3H), 3.79 (s, 3H), 4.59-4.83 (m, 1H), 6.55-6.66 (m, 1H), 7.30-7.38 (m, 2H), 7.56-7.66 (m, 2H).
-
- To a solution of (R)-methyl-3-methyl-2-(3-methylbenzamido)butanoate (1.5 g, 6 mmol) in tetrahydrofuran (12 mL) was added an aqueous lithium hydroxide solution (8 mL, 2.0 M, 0.016 mol). Before quenching with ice-water (20 mL), the reaction was stirred for 1 hour. The pH of the solution was adjusted to 3 by addition of a 5% aqueous hydrochloric acid solution. The mixture was filtered and the filter cake was washed with petroleum ether (30 mL) and dried under reduced pressure to afford (R)-3-methyl-2-(3-methyl benzamido)butanoic acid as a thick oil (1.1 g, 77%).
- LCMS (ESI): m/z=236.1 [M+H]+.
-
- To a mixture of 1-(3-chlorophenyl)-3-methyl-1,3,8-triazaspiro[4.5]decan-4-one hydrochloride (45 mg, 0.14 mmol) in dichloromethane (5 mL) was added (R)-3-methyl-2-(3-methylbenzamido)butanoic acid (37 mg, 0.16 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate (HATU) (81 mg, 0.21 mmol) and N,N-diisopropylethylamine (46 mg, 0.35 mmol). The resulting mixture was stirred for 2 hours at room temperature before the reaction was quenched with ice-water (5 mL). The mixture was extracted with ethyl acetate (3×10 mL) and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by prep-TLC with dichloromethane:methanol=15:1 to afford (R)—N-(1-(1-(3-chlorophenyl)-3-methyl-4-oxo-1,3,8-triazaspiro[4.5]decan-8-yl)-3-methyl-1-oxobutan-2-yl)-3-methylbenzamide as a white solid (2.1 mg, 3%).
- LCMS (ESI): m/z=497.0, 499.0 [M+H]+.
- 1H-NMR (400 MHz, CDCl3): δ=0.97-1.15 (m, 6H), 1.64-2.22 (m, 5H), 2.44 (s, 3H), 2.49-2.75 (m, 1H), 3.03 (s, 3H), 3.50-3.65 (m, 1H), 4.10-4.20 (m, 1H), 4.58-4.73 (m, 3H), 5.25-5.50 (m, 1H), 6.92-7.15 (m, 3H), 7.34-7.36 (m, 3H), 7.49-7.70 (m, 2H).
- The following 16 compounds were synthesized following the general procedure described above:
-
- 8.7 mg, yield: 16%, white solid.
- LCMS (ESI): m/z=496 [M+H]+.
- 1H-NMR (400 MHz, CDCl3): δ=0.89-1.22 (m, 6H), 1.61-1.88 (m, 2H), 2.01-2.27 (m, 1H), 2.30-2.77 (m, 5H), 3.15 (s, 3H), 3.43-3.71 (m, 1H), 3.96-4.23 (m, 2H), 4.50-4.83 (m, 3H), 4.97-5.22 (m, 1H), 6.50- 6.76 (m, 2H), 6.91-7.12 (m, 2H), 7.13-7.25 (m, 1H), 7.32-7.46 (m, 2H), 7.58-7.72 (m, 2H).
-
- 3.0 mg, yield: 5%, white solid.
- LCMS (ESI): m/z=542.2 [M+H]+.
- 1H-NMR (400 MHz, CDCl3): δ=0.99-1.16 (m, 6H), 1.63-1.88 (m, 2H), 2.15-2.22 (m, 1H), 2.44 (s, 3H), 2.48-2.82 (m, 2H), 3.05 (s, 3H), 3.55-3.60 (m, 1H), 3.89-4.24 (m, 2H), 4.60-4.71 (m, 3H), 5.00-5.25 (m, 1H), 6.58-6.75 (m, 1H), 6.80-6.96 (m, 1H), 6.96-7.20 (m, 2H), 7.36-7.44 (m, 2H), 7.54-7.77 (m, 2H).
-
- 6.6 mg, yield: 14%, white solid.
- LCMS (ESI): m/z=464 [M+H]+.
- 1H-NMR (400 MHz, CDCl3): δ=1.08-1.13 (m, 6H), 1.66-2.00 (m, 2H), 2.14-2.24 (m, 1H), 2.43-2.50 (m, 4H), 2.90-3.05 (m, 1H), 3.10 (s, 3H), 3.53-3.64 (m, 1H), 4.03-4.36 (m, 2H), 4.56-4.98 (m, 4H), 7.07- 7.11 (m, 1H), 7.32-7.44 (m, 3H), 7.60-7.65 (m, 2H), 7.96-8.04 (m, 2H), 8.30-8.40 (m, 1H).
-
- 20.0 mg, yield: 23%, white solid.
- LCMS (ESI): m/z=497.2, 499.2 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=0.78-1.08 (m, 6H), 1.49-2.31 (m, 5H), 2.43 (s, 3H), 2.97 (s, 3H), 3.46-4.23 (m, 4H), 4.62-4.77 (m, 2H), 4.79-4.87 (m, 1H), 7.13-7.72 (m, 8H).
-
- 23.0 mg, yield: 29%, white solid.
- LCMS (ESI): m/z=493.2 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=0.89-1.04 (m, 6H), 1.65-2.09 (m, 3H), 2.13-2.31 (m, 2H), 2.42 (s, 3H), 2.99 (s, 3H), 3.45-3.61 (m, 1H), 3.63 (s, 2H), 3.79 (s, 1H), 3.87-4.44 (m, 3H), 4.69-4.71 (m, 2H), 4.91-5.04 (m, 1H), 6.64-6.69 (m, 1H), 6.80-7.06 (m, 3H), 7.32-7.46 (m, 2H), 7.67-7.88 (m, 2H).
-
- 13.0 mg, yield: 17%, white solid.
- LCMS (ESI): m/z=493.2 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=0.93-1.16 (m, 6H), 1.61-2.01 (m, 2H), 1.97-2.20 (m, 1H), 2.24 (s, 3H), 2.48-2.80 (m, 2H), 3.02 (s, 3H), 3.47-3.57 (m, 3H), 3.59 (s, 1H), 3.78 (s, 1H), 3.84-4.60 (m, 3H), 4.75 (m, 1H), 4.90 (m, 1H), 6.21-6.53 (m, 3H), 6.88-7.13 (m, 1H), 7.38 (m, 2H), 7.58-7.74 (m, 2H).
-
- 3.2 mg, yield: 4%, white solid.
- LCMS (ESI): m/z=542.2 [M+H]+.
- 1H-NMR (400 MHz, CDCl3): δ=1.01-1.14 (m, 6H), 1.66-1.78 (m, 2H), 2.32-2.33 (m, 1H), 2.54-2.63 (m, 4H), 2.72-2.75 (m, 1H), 3.01 (s, 3H), 3.48-4.52 (m, 4H), 4.71-4.73 (m, 2H), 4.92-4.95 (m, 1H), 6.57- 6.74 (m, 2H), 7.00-7.03 (m, 2H), 7.33-7.46 (m, 2H), 7.69-7.73 (m, 2H).
-
- 19.2 mg, yield: 17%, white solid.
- LCMS (ESI): m/z=573 [M+H]+.
- 1H-NMR (400 MHz, CDCl3): δ=1.02-1.12 (m, 9H), 1.69-1.70 (m, 1H), 1.80-1.89 (m, 1H), 2.65-2.70 (m, 5H), 2.94 (s, 3H), 3.07 (s, 3H), 3.53-3.60 (m, 1H), 4.08-4.18 (m, 2H), 4.68 (m, 1H), 4.78-4.89 (m, 2H), 5.01-5.21 (m, 1H), 6.74-7.92 (m, 8H).
-
- 20.0 mg, yield: 34%, white solid.
- LCMS (ESI): m/z=526.2 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=0.84-1.10 (m, 6H), 1.18-1.32 (m, 3H), 1.54-1.75 (m, 1H), 1.77-2.01 (m, 3H), 2.13-2.22 (m, 1H), 2.62-2.77 (m, 2H), 3.09 (s, 3H), 3.48-3.57 (m, 3H), 3.56-3.62 (m, 1H), 3.90- 4.07 (m, 1H), 4.15-4.59 (m, 1H), 4.36-4.44 (m, 1H), 4.56-4.61 (m, 2H), 4.87-4.92 (m, 1H), 6.47-6.63 (m, 1H), 7.13-7.21 (m, 1H), 7.40-7.43 (m, 1H), 7.47-7.70 (m, 3H).
-
- 65.3 mg, yield: 47%, white solid.
- LCMS (ESI): m/z=525.0 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=0.88-1.13 (m, 6H), 1.18-1.36 (m, 3H), 1.71-1.92 (m, 2H), 1.93-2.38 (m, 3H), 2.68 (m, 2H), 3.00-3.05 (m, 3H), 3.65 (m, 3H), 3.79 (m, 1H), 3.91-4.09 (m, 1H), 4.20-4.25 (m, 1H), 4.35-4.41 (m, 1H), 4.62-4.76 (m, 2H), 4.94-5.01 (m, 1H), 6.72-6.88 (m, 1H), 6.91-6.98 (m, 2H), 7.13- 7.21 (m, 2H), 7.34-7.47 (m, 1H), 7.547.66 (m, 1H).
-
- 10.0 mg, yield: 19%, white solid.
- LCMS (ESI): m/z=566.0 [M+H]+.
- 1H-NMR (400 MHz, CDCl3): δ=0.99-1.06 (m, 6H), 1.22-1.27 (m, 3H), 1.76-1.88 (m, 2H), 2.11-2.37 (m, 3H), 2.65-2.69 (m, 2H), 3.04 (s, 3H), 3.32 (s, 2H), 3.39 (s, 1H), 3.54-3.59 (m, 1H), 4.05-4.07 (m, 2H), 4.53-4.57 (m, 1H), 4.53-4.72 (m, 2H), 5.07-5.10 (m, 1H), 6.41-6.45 (m, 1H), 6.57-6.59 (m, 1H), 6.97- 6.99 (m, 1H), 7.04-7.07 (m, 1H), 7.26-7.73 (m, 1H), 7.47-7.49 (m, 1H), 7.77-7.79 (m, 1H).
-
- 24.7 mg, yield: 27%, white solid.
- LCMS (ESI): m/z=566.2 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=0.91-1.04 (m, 6H), 1.62-2.18 (m, 5H), 2.97 (s, 3H), 3.52-3.64 (m, 4H), 3.99-4.37 (m, 3H), 4.59-4.63 (m, 2H), 4.87 (m, 1H), 6.48-6.58 (m, 1H), 7.42-7.60 (m 3H), 7.97-8.03 (m, 2H).
-
- 9.3 mg, yield: 6%, white solid.
- LCMS (ESI): m/z=613.2 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=1.06-1.19 (m, 6H), 1.74-1.95 (m, 2H), 2.20-2.33 (m, 1H), 2.66-2.87 (m, 1H), 2.97-3.14 (m, 7H), 3.50-3.61 (m, 1H), 4.02-4.15 (m, 1H), 4.37-4.39 (m, 1H), 4.57-4.60 (m, 1H), 4.83-4.85 (m, 2H, contained in solvent signal), 4.95-5.05 (m, 1H), 6.88-6.94 (m, 2H), 7.45-7.52 (m, 1H), 7.62-7.78 (m, 2H), 7.90-8.09 (m, 2H).
-
- 6.1 mg, yield: 7%, white solid.
- LCMS (ESI): m/z=575.2 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=1.08-1.14 (m, 6H), 1.82-1.94 (m, 2H), 2.17-2.22 (m, 1H), 2.47-2.50 (m, 1H), 2.88-2.91 (m, 1H), 3.07 (s, 3H), 3.56-3.62 (m, 1H), 4.05-4.12 (m, 1H), 4.33-4.36 (m, 1H), 4.61- 4.63 (m, 1H), 4.83-4.87 (m, 3H), 7.48-7.52 (m, 1H), 7.72-7.88 (m, 4H), 8.07-8.09 (m, 2H), 8.35 (m, 1H), 8.74-8.75 (m, 1H).
-
- 59.2 mg, yield: 40%, white solid.
- LCMS (ESI): m/z=582.2 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=0.88-1.06 (m, 6H), 1.56-1.69 (m, 1H), 1.83-1.97 (m, 3H), 2.19-2.21 (m, 1H), 2.97 (s, 3H), 3.51 (s, 3H), 3.55-3.58 (m, 1H), 3.99-4.35 (m, 3H), 4.59-4.63 (m, 2H), 4.80-4.82 (m, 1H), 6.46-6.58 (m, 1H), 7.52-7.66 (m, 2H), 7.92-7.94 (m, 1H), 8.08-8.14 (m, 2H).
-
- 53.3 mg, yield: 31%, white solid.
- 1H-NMR (400 MHz, CD3OD): δ=1.31-1.72 (m, 8H), 1.85-1.91 (m, 4H), 2.35-2.39 (m, 1H), 2.96 (s, 3H), 3.50 (s, 3H), 3.52-3.59 (m, 1H), 3.96-3.99 (m, 1H), 4.19-4.36 (m, 2H), 4.59-4.63 (m, 2H), 4.92-4.95 (m, 1H), 6.46-6.58 (m, 1H), 7.42-7.46 (m, 1H), 7.52-7.67 (m, 2H), 7.87-8.00 (m, 2H).
-
-
-
- To a solution of tert-butyl-4-carbamoyl-4-(4-methoxyphenylamino)piperidine-1-carboxylate (prepared as described in Example 168-b) (300 mg, 0.85 mmol) in triethyl orthoacetate (5 mL) was added acetic acid (1 drop, cat.). The resulting mixture was heated at 170° C. for 30 minutes in a microwave reactor. The solvent was removed under reduced pressure and the residue was dissolved in methanol (10 mL). To the resulting solution was added sodium borohydride (50 mg, 0.069 mol) at 0° C. The mixture was stirred for 30 minutes. The solvent was removed under reduced pressure and the residue was diluted with water (10 mL) and ethyl acetate (10 mL). The organic layer was collected and the aqueous layer was extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with dichloromethane:methanol=100:1 to afford tert-butyl-1-(4-methoxyphenyl)-2-methyl-4-oxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate as a white solid (120 mg, 38%).
- LCMS (ESI): m/z=376.2 [M+H]+.
- 1H-NMR (300 MHz, CDCl3): δ=1.19 (d, J=5.3 Hz, 3H), 1.38 (s, 9H), 1.59-1.85 (m, 4H), 3.25-3.27 (m, 1H), 3.80-3.88 (m, 6H), 5.00-5.19 (m, 1H), 6.85 (d, J=8.9 Hz, 2H), 7.05 (d, J=8.9 Hz, 2H).
-
- To a solution of tert-butyl-1-(4-methoxyphenyl)-2-methyl-4-oxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate (120 mg, 0.32 mmol) in N,N-dimethylformamide (10 mL) was added sodium hydride (20 mg, 60% in oil, 0.52 mmol) at 0° C. After stirring for 15 minutes, iodomethane (282 mg, 1.9 mmol) was added. The resulting mixture was stirred for 15 minutes at room temperature and the reaction was quenched with ice-water (10 mL). The mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with ethyl acetate:petroleum ether=1:1 to afford tert-butyl-1-(4-methoxyphenyl)-2,3-dimethyl-4-oxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate as a white solid (80 mg, 66%).
- LCMS (ESI): m/z=390.2 [M+H]+.
-
- A solution of tert-butyl-1-(4-methoxyphenyl)-2,3-dimethyl-4-oxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate (80 mg, 0.2 mmol) in hydrochloric acid in dioxane (6.0 M, 10 mL) was stirred for 30 minutes. The solvent was removed under reduced pressure to afford 1-(4-methoxyphenyl)-2,3-dimethyl-1,3,8-triazaspiro[4.5]decane-4-one hydrochloride as a white solid (60 mg, 90%).
- LCMS (ESI): m/z=290.2 [M+H]+.
-
- To a mixture of 1-(4-methoxyphenyl)-2,3-dimethyl-1,3,8-triazaspiro[4.5]decane-4-one hydrochloride (60 mg, 0.18 mmol) in dichloromethane (5 mL) was added sequentially (R)-2-(2-fluoro-5-(trifluoromethyl)benzamido)-3-methylbutanoic acid (prepared as described in Example 28-f) (60 mg, 0.19 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate (HATU) (120 mg, 0.31 mmol) and N,N-diisopropylethylamine (270 mg, 2.0 mmol). The reaction was stirred for 2 hours before the reaction was quenched by addition of ice-water (10 mL). The mixture was extracted with ethyl acetate (3×10 mL) and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by prep-TLC with dichloromethane:methanol=15:1 to afford 2-fluoro-N-((2R)-1-(1-(4-methoxyphenyl)-2,3-dimethyl-4-oxo-1,3,8-triazaspiro[4.5]decan-8-yl)-3-methyl-1-oxobutan-2-yl)-5-(trifluoromethyl)benzamide (6.5 mg, 5.9%).
- LCMS (ESI): m/z=579.2 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=0.72-1.01 (m, 6H), 1.18-1.22 (m, 3H), 1.31-1.52 (m, 1H), 1.78-2.22 (m, 4H), 2.93 (s, 3H), 3.68-3.73 (m, 3H), 3.81-3.82 (m, 1H), 3.97-4.38 (m, 2H), 4.79-4.93 (m, 2H), 5.07- 5.12 (m, 1H), 6.76-8.45 (m, 8H).
-
-
-
- To a solution of tert-butyl-4-carbamoyl-4-(4-(methoxycarbonyl)phenylamino)piperidine-1-carboxylate (prepared as described in Example 149-b) (500 mg, 0.00136 mmol) in triethyl orthoacetate (5 mL) was added acetic acid (1 drop, cat.). The resulting mixture was heated at 170° C. for 30 minutes in a microwave reactor. The solvent was removed under reduced pressure and the residue was dissolved in methanol (10 mL). To the resulting solution was added sodium borohydride (100 mg, 0.0026 mol) at 000. The mixture was stirred for 30 minutes. The solvent was removed under reduced pressure and the residue was diluted with water (10 mL) and ethyl acetate (10 mL). The organic layer was collected and the aqueous layer was extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with dichloromethane:methanol=100:1 to afford tert-butyl-1-(4-(methoxycarbonyl)phenyl)-2-methyl-4-oxo-1,3,6-triazaspiro[4.5]decane-8-carboxylate as a white solid (223 mg, 41%).
- LCMS (ESI): m/z=404.2 [M+H]+
-
- To a solution of tert-butyl-1-(4-(methoxycarbonyl)phenyl)-2-methyl-4-oxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate (500 mg, 1.23 mmol) in N,N-dimethylformamide (10 mL) was added sodium hydride (52 mg, 60% in oil, 1.46 mmol) at 0° C. After stirring for 15 minutes, iodomethane (0.55 g, 3.87 mmol) was added. The resulting mixture was stirred for 15 minutes at room temperature and the reaction was quenched with ice-water (10 mL). The mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with ethyl acetate:petroleum ether=1:1 to afford tert-butyl 1-(4-(methoxycarbonyl)phenyl)-2,3-dimethyl-4-oxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate as a white solid (432 mg, 83%).
- LCMS (ESI): m/z=418.2 [M+H]+.
-
- To a solution of tert-butyl-1-(4-(methoxycarbonyl)phenyl)-2,3-dimethyl-4-oxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate (430 mg, 1.02 mmol) in methanol (10 mL) was added a 15% aqueous sodium hydroxide solution (15 mL). The reaction was heated at reflux for 1 hour before cooling to room temperature. The pH of the resulting solution was adjusted to 1 by addition of 10% aqueous hydrochloric acid solution. The mixture was filtered and the filter cake was washed with water (10 mL) and then dried under reduced pressure to afford 4-(8-(tert-butoxycarbonyl)-2,3-dimethyl-4-oxo-1,3,8-triazaspiro[4.5]decan-1-yl)benzoic acid as a white solid (370 mg, 89%).
- LCMS (ESI): m/z=404.1 [M+H]+.
-
- To a solution of 4-(8-(tert-butoxycarbonyl)-2,3-dimethyl-4-oxo-1,3,8-triazaspiro[4.5]decan-1-yl)benzoic acid (370 mg, 0.91 mmol) in N,N-dimethylformamide (10 mL) was added potassium carbonate (490 mg, 3.5 mmol) and benzyl bromide (320 mg, 1.7 mmol). Before the reaction was quenched by addition of ice-water (10 mL), the mixture was heated for 2 hours at 50° C. The mixture was extracted with ethyl acetate (3×30 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with ethyl acetate:petroleum ether=1:1 to afford tert-butyl-1-(4-(benzyloxycarbonyl)phenyl)-2,3-dimethyl 4 oxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate as a white solid (391 mg, 89%).
- LCMS (ESI): m/z=494.2 [M+H]+.
-
- A solution of tert-butyl-1-(4-(benzyloxycarbonyl)phenyl)-2,3-dimethyl-4-oxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate (391 mg, 0.79 mmol) in hydrochloric acid in dioxane (6.0 M, 20 mL) was stirred for 30 minutes. The precipitate was collected by filtration and dried under reduced pressure to afford benzyl-4-(2,3-dimethyl-4-oxo-1,3,8-triazaspiro[4.5]decan-1-yl)benzoate hydrochloride as a white solid (312 mg, 92%).
- LCMS (ESI): m/z=394.2 [M+H]+.
-
- To a mixture of benzyl-4-(2,3-dimethyl-4-oxo-1,3,8-triazaspiro[4.5]decan-1-yl)benzoate hydrochloride (312 mg, 0.73 mmol) in dichloromethane (5 mL) was added sequentially (R)-2-(5-ethyl-2-fluorobenzamido)-3-methylbutanoic acid (prepared as described in Example 168-i) (195 mg, 0.73 mmol), (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluoro phosphate (HATU) (277 mg, 1.10 mmol) and N,N-diisopropylethylamine (230 mg, 1.78 mmol). The resulting mixture was stirred for 2 hours at room temperature before the reaction was quenched by addition of with ice-water (5 mL). The mixture was extracted with ethyl acetate (3×10 mL) and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by prep-TLC with dichloromethane:methanol=15:1 to afford benzyl-4-(8-((R)-2-(5-ethyl-2-fluorobenzamido)-3-methylbutanoyl)-2,3-dimethyl-4-oxo-1,3,8-triazaspiro[4.5]decan-1-yl)benzoate as a thick oil (251 mg, crude), which was used directly without further purification.
- LCMS (ESI): m/z=644.2 [M+H]+.
-
- To a solution of benzyl-4-(8-((R)-2-(5-ethyl-2-fluorobenzamido)-3-methylbutanoyl)-2,3-dimethyl-4-oxo-1,3,8-triazaspiro[4.5]decan-1-yl)benzoate (251 mg, crude) in methanol (15 mL) was added 5% palladium on carbon (50 mg, 50% wet with water). The mixture was stirred under a hydrogen atmosphere for 40 minutes. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC (acetonitrile and water, acetonitrile from 20% to 60%) to afford (4-(8-((R)-2-(5-ethyl-2-fluorobenzamido)-3-methyl butanoyl)-2-methyl-4-oxo-1,3,8-triazaspiro[4.5]decan-1-yl)benzoic acid as a white solid (126 mg, 32% over two steps).
- LCMS (ESI): m/z=553.1 [M+H]+.
-
- 4-((R)-8-((R)-2-(5-Ethyl-2-fluorobenzamido)-3-methylbutanoyl)-2,3-dimethyl-4-oxo-1,3,8-triazaspiro[4.5]decan-1-yl)benzoic acid (126 mg) was separated by chiral prep-HPLC (column: CHIRALPAK* (Daicel) IA (250 mm×20 mm, 5 μm). Mobile phase=hexane:ethanol (0.2% EDA-0.2% FA)=1:1, flow rate: 20 mL/min) to afford as a white solid (31.7 mg, 32%). The conformation was tentatively assigned.
- LCMS (ESI): m/z=553.1 [M+H]+.
- Chiral HPLC: (CHIRALPAK*IB (205 mm×4.6 mm, 5 μm). Mobile phase=hexane: ethanol (0.2% FA-0.2% DEA)=1:1, retention time: 6.78 minutes), ee=96.1%.
- 1H-NMR (400 MHz, CD3OD): δ=1.00-1.13 (m, 6H), 1.17-1.32 (m, 4H), 1.43-1.45 (m, 3H), 1.60-1.85 (m, 2H), 2.23-2.35 (m, 1H), 2.65-2.83 (m, 4H), 3.01 (s, 3H), 3.53-3.59 (m, 1H), 4.00-4.05 (m, 1H), 4.34- 4.39 (m, 1H), 4.54-4.71 (m, 1H), 5.40-5.59 (m, 1H), 6.88-7.00 (m, 2H), 7.12-7.19 (m, 1H), 7.35-7.50 (m, 1H), 7.58-7.77 (m, 1H), 7.82-8.01 (m, 2H).
-
- 4-((S)-8-((R)-2-(5-Ethyl-2-fluorobenzamido)-3-methylbutanoyl)-2,3-dimethyl-4-oxo-1,3,8-triazaspiro[4.5]decan-1-yl)benzoic acid (126 mg) was separated by chiral prep-HPLC (column CHIRALPAK* (Daicel) IA (250 mm×20 mm, 5 μm). Mobile phase=hexane: ethanol (0.2% EDA-0.2% FA)=1:1, flow rate: 20 mL/min) to afford as a white solid (31.4 mg, 31%). The conformation was tentatively assigned.
- LCMS (ESI): m/z=553.0 [M+H]+.
- Chiral HPLC: (CHIRALPAK*IB (205 mm×4.6 mm, 5 μm). Mobile phase=hexane: ethanol (0.2% FA-0.2% DEA)=1:1, retention time: 10.578 minutes, ee=97%.
- 1H-NMR (400 MHz, CD3OD): δ=1.03-1.11 (m, 6H), 1.18-1.33 (m, 4H), 1.46-1.49 (m, 3H), 1.54-1.94 (m, 2H), 2.22-2.65 (m, 4H), 2.99 (s, 3H), 3.06-3.08 (m, 1H), 3.57-3.59 (m, 1H), 4.03-4.10 (m, 1H), 4.37- 4.44 (m, 1H), 4.52-4.59 (m, 1H), 5.42-5.59 (m, 1H), 6.92-7.00 (m, 2H), 7.17-7.19 (m, 1H), 7.39-7.42 (m, 1H), 7.58-7.77 (m, 1H), 7.82-8.01 (m, 2H).
- The following 2 compounds were synthesized following the general procedure described above:
-
- 35.6 mg, yield: 23%, white solid.
- LCMS (ESI): m/z=593 [M+H]+.
- Chiral HPLC: (CHIRALPAK*IB (205 mm×4.6 mm, 5 μm). Mobile phase=hexane: ethanol (0.2% FA-0.2% DEA) 1:1, retention time: 6.31 minutes, ee=95.1%.
- 1H-NMR (400 MHz, CD3OD): δ=0.99-1.15 (m, 6H), 1.32-1.45 (m, 4H), 1.63-1.87 (m, 2H), 2.26-2.65 (m, 2H), 2.79-2.81 (m, 1H), 2.99 (s, 3H), 3.54-3.59 (m, 1H), 4.06-4.09 (m, 2H), 4.34-4.55 (m, 1H), 5.41- 5.59 (m, 1H), 6.89-6.99 (m, 2H), 7.45-7.59 (m, 1H), 7.83-7.99 (m, 3H), 8.02-8.05 (m, 1H).
-
- 35.7 mg, yield: 24%, white solid.
- LCMS (ESI): m/z=593.0 [M+H]+.
- Chiral HPLC: (CHIRALPAK*IB (205 mm×4.6 mm, 5 μm). Mobile phase=hexane: ethanol (0.2% FA-0.2% DEA)=1:1, retention time: 12.7 minutes, ee=97%.
- 1H-NMR (400 MHz, CD3OD): δ=1.04-1.16 (m, 6H), 1.32-1.35 (m, 2H), 1.45-1.74 (m, 4H), 1.95-2.10 (m, 1H), 2.24-2.35 (m, 1H), 2.61-2.81 (m, 1H), 3.04 (s, 3H), 3.59-3.67 (m, 1H), 4.02-4.37 (m, 2H), 4.53- 4.61 (m, 1H), 5.42-5.53 (m, 1H), 6.92-7.01 (m, 2H), 7.48-7.67 (m, 1H), 7.81-7.88 (m, 3H), 8.01-8.07 (m, 1H).
-
-
-
- To a solution of tert-butyl-4-(1H-indazol 5 ylamino)-4-cyanopiperidine-1-carboxylate (prepared as described in Example 52-a) (1.0 g, 2.92 mmol) in N,N-dimethylformamide (10 mL) was added sodium hydride (0.175 g, 60% in oil, 4.39 mmol) at 0° C. After stirring for 15 minutes at 0° C., 2-(trimethylsilyl) ethoxymethyl chloride (0.54 g, 3.22 mmol) was added. After stirring for 2 hours, the reaction was quenched by addition of ice-water (20 mL). The mixture was extracted with dichloromethane (3×20 mL). The combined organic layers were washed with brine and dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with dichloromethane:methanol=100:1 to afford tert-butyl-4-cyano-4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-5-ylamino)piperidine-1-carboxylate as a white solid (280 mg, 21%).
- LCMS (ESI): m/z=472.2 [M+H]+.
- 1H-NMR (300 MHz, DMSO-d6): δ=0.01-0.02 (m, 9H), 0.8-0.87 (m, 2H), 1.44-1.45 (m, 9H), 1.82-1.87 (m, 2H), 2.29-2.33 (m, 2H), 3.18-3.25 (m, 2H), 3.49-3.57 (m, 2H), 3.78-3.82 (m, 2H), 5.59-5.70 (m, 2H), 5.95 (s, 1H), 6.94-6.98 (m, 2H), 7.51-7.54 (m, 1H), 8.26 (s, 1H).
-
- To a solution of tert-butyl-4-cyano-4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-5-ylamino) piperidine-1-carboxylate (600 mg, 1.73 mmol) in methanol (5 mL) was added an aqueous sodium hydroxide solution (6.67 mL, 1.0 M). After stirring for 15 minutes, to the resulting solution was added a 30% aqueous hydrogen peroxide solution (5.07 mL) dropwise. After stirring overnight, the reaction was quenched with ice-water (50 mL) and the mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine and dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with dichloromethane:methanol=100:1 to afford tert-butyl-4-carbamoyl-4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-5-ylamino)piperidine-1-carboxylate as a white solid (500 mg, 80%).
- LCMS (ESI): m/z=490.2 [M+H]+.
-
- To a solution of tert-butyl-4-carbamoyl-4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-5-ylamino)piperidine-1-carboxylate (300 mg, 0.613 mmol) in triethyl orthoformate (2 mL) was added acetic acid (1 drop, cat.). The resulting mixture was stirred for 30 minutes at 130° C. in a microwave reactor. The solvent was removed under reduced pressure and the residue was dissolved in methanol (10 mL). To the solution was added sodium borohydride (100 mg, 2.63 mmol) at 0° C. The resulting mixture was stirred for 30 minutes. The solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography eluting with dichloromethane:methanol=100:1 to afford tert-butyl-4-oxo-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-5-yl)-1,3,8-triazaspiro[4.5]decane-8-carboxylate as a white solid (100 mg, 32%).
- LCMS (ESI): m/z=502.2 [M+H]+.
-
- To a solution of tert-butyl-4-oxo-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-5-yl)-1,3,8-triazaspiro[4.5]decane-8-carboxylate (200 mg, 0.40 mmol) in N,N-dimethylformamide (5 mL) was added sodium hydride (48 mg, 1.2 mol) at 0° C. After stirring for 15 minutes, iodomethane (283 mg, 2.0 mmol) was added. After stirring for 1 hour, the reaction was quenched by addition of ice-water (10 mL). The mixture was extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with dichloromethane:methanol=100:1 to afford tert-butyl-3-methyl-4-oxo-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-5-yl)-1,3,8-triazaspiro[4.5]decane-8-carboxylate as a white solid (180 mg, 87%).
- LCMS (ESI): m/z=516.2 [M+H]+.
- 1H-NMR (300 MHz, CDCl3) δ=0.01-0.03 (m, 9H), 0.86-0.95 (m, 2H), 1.44 (s, 9H), 1.69-1.74 (m, 2H), 2.12-2.16 (m, 2H), 2.99 (s, 3H), 3.57-3.62 (m, 4H), 3.82-3.94 (m, 2H), 4.68 (s, 2H), 5.27-5.66 (m, 2H), 7.00-7.08 (m, 2H), 7.61-7.64 (m, 1H), 7.88-7.98 (m, 1H).
-
- A solution of tert-butyl-3-methyl-4-oxo-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-5-yl)-1,3,8-triazaspiro[4.5]decane-8-carboxylate (180 mg, 0.35 mmol) in hydrochloric acid in dioxane (6.0 M, 20 mL) was stirred for 30 minutes. The precipitate was collected by filtration and dried under reduced pressure to afford 1-(1H-indazol-5-yl)-3-methyl-1,3,8-triazaspiro[4.5]decan-4-one hydrochloride as a white solid (115 mg, crude), which was used directly without any further purification.
- LCMS (ESI): m/z=285.2 [M+H]+.
-
- To a mixture of 1-(1H-indazol-5-yl)-3-methyl-1,3,8-triazaspiro[4.5]decan-4-one hydrochloride (115 mg, crude) in dichloromethane (10 mL) was added sequentially (R)-2-(2-fluoro-5-(trifluoromethyl)benzamido)-3-methylbutanoic acid (prepared as described in Example 28-f) (129 mg, 0.34 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate (HATU) (198 mg, 0.52 mmol), N,N-diisopropylethylamine (109 mg, 0.85 mmol). The reaction was stirred for 2 hours before quenching with ice-water (10 mL). The mixture was extracted with dichloromethane (3×10 mL) and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by prep-TLC with dichloromethane:methanol=20:1 to afford (R)—N-(1-(1-(1H-indazol-5-yl)-3-methyl-4-oxo-1,3,8-triazaspiro[4.5]decan-8-yl)-3-methyl-1-oxobutan-2-yl)-2-fluoro-5-(trifluoromethyl)benzamide as a white solid (35 mg, 32%).
- LCMS (ESI): m/z=575.2 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=0.85-1.06 (m, 6H), 1.82-2.19 (m, 5H), 3.02 (s, 3H), 3.56-3.66 (m, 1H), 3.94-4.34 (m, 3H), 4.75-4.78 (m, 2H), 4.98-5.01 (m, 1H), 7.17-7.53 (m, 4H), 7.80-7.93 (m, 2H), 8.01- 8.21 (m, 1H).
- The following 2 compounds were synthesized following the general procedure described above:
-
- 9.5 mg, yield: 10%, white solid.
- LCMS (ESI): m/z=535.0 [M+H]+.
- 1H-NMR (400 MHz, CDCl3): δ=0.94-1.05 (m, 6H), 1.19-1.26 (m, 3H), 1.85-2.11 (m, 5H), 2.61-2.67 (m, 2H), 3.05 (s, 3H), 3.58-3.63 (m, 1H), 3.98-4.05 (m, 2H), 4.27-4.46 (m, 1H), 4.71-4.76 (m, 2H), 5.10 (s, 1H), 7.00-7.12 (m, 2H), 7.28-7.30 (m, 1H), 7.33-7.79 (m, 2H), 7.94-8.02 (m, 2H).
-
- 18.8 mg, yield: 16%, white solid.
- LCMS (ESI): m/z=535.0 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=1.07-1.11 (m, 6H), 1.17-1.22 (m, 3H), 1.79-1.98 (m, 2H), 2.21-2.31 (m, 1H), 2.44-2.68 (m, 3H), 2.81-2.89 (m, 1H), 3.06-3.07 (m, 3H), 3.52-3.65 (m, 1H), 4.00-4.07 (m, 1H), 4.24-4.36 (m, 1H), 4.46-4.57 (m, 1H), 4.85-4.87 (m, 2H) 4.93-4.97 (m, 1H), 7.06-9.22 (m, 7H).
-
-
-
- To a solution of aniline (10 g, 107 mmol) in tetrahydrofuran (800 mL) was added sodium hydroxide (22 g, 537 mmol) at 0° C. After stirring for 10 minutes at 0° C., to the resulting solution was added tert-butyl-4-oxopiperidine-1-carboxylate (42 g, 55 mmol). The resulting suspension was stirred for 20 minutes at 0° C. To the suspension was added chloroform (64 g, 537 mmol). The reaction was stirred overnight before quenching with water (100 mL). The resulting mixture was extracted with ethyl acetate (100 mL). The pH of the aqueous layer was adjusted to 3 by addition of a 5% aqueous hydrochloric acid solution and extracted with ethyl acetate (3×100 mL). The combined organic layers were dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure to afford 1-(tert-butoxycarbonyl)-4-(phenylamino)piperidine-4-carboxylic acid as a yellow solid (18 g, 52%).
- LCMS (ESI): m/z=321.2 [M+H]+.
- 1H-NMR (300 MHz, DMSO-d6): 0=1.39 (s, 9H), 1.82-1.95 (m, 4H), 3.16-3.26 (m, 2H), 3.57-3.61 (m, 2H), 6.52-6.56 (m, 3H), 7.02-7.07 (m, 2H).
-
- To a solution of 1-(tert-butoxycarbonyl)-4-(phenylamino)piperidine-4-carboxylic acid (2 g, 6.25 mmol) in tetrahydrofuran (10 mL) was added lithium aluminum hydride (4 mL, 2.4 M in tetrahydrofuran, 9.6 mmol). Before quenching by sequential addition of ice-water (4 mL), 15% aqueous sodium hydroxide solution (12 mL) and water (4 mL), the reaction was stirred for 2 hours. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with ethyl acetate:petroleum ether=1:3 to afford tert-butyl-4-(hydroxymethyl)-4-(phenylamino)piperidine-1-carboxylate as a yellow oil (580 mg, 30%).
- LCMS (ESI): m/z=307.1 [M+H]+.
-
- To a solution of tert-butyl-4-(hydroxymethyl)-4-(phenylamino)piperidine-1-carboxylate (250 mg, 0.817 mmol) in acetonitrile (5 mL) was added pyridinium chloride (118 mg, 1.01 mmol) and 1,1′-carbonyldiimidazole (265 mg, 1.63 mmol). Before quenching by addition of ice-water (4 mL), the reaction was stirred for 2 hours at 70° C. The mixture was extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with ethyl acetate:petroleum ether=1:5 to afford the crude product. The crude product was washed with petroleum ether (3×5 mL) to afford tert-butyl-2-oxo-1-phenyl-3-oxa-1,8-diazaspiro[4.5]decane-8-carboxylate as a white solid (170 mg, 62%).
- LCMS (ESI): m/z=333.2 [M+H]+.
-
- A solution of tert-butyl-2-oxo-1-phenyl-3-oxa-1,8-diazaspiro[4.5]decane-8-carboxylate (70 mg, 0.21 mmol) in hydrochloric acid in dioxane (6.0 M, 10 mL) was stirred for 30 minutes. The precipitate was collected by filtration and dried. The crude product was used directly without further purification.
- LCMS (ESI): m/z=233.2 [M+H]+.
-
- To a suspension of 1-phenyl-3-oxa-1,8-diazaspiro[4.5]decan-2-one hydrochloride (45 mg, crude) and (R)-3-methyl-2-(3-methylbenzamido)butanoic acid (prepared as described in Example 192-g) (65 mg, 0.274 mmol) in dichloromethane (5 mL) was added 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate (HATU) (111 mg, 0.316 mmol) and N,N-diisopropylethylamine (82 mg, 0.633 mmol). The resulting mixture was stirred for 2 hours at room temperature before the reaction was quenched with ice-water (10 mL). The mixture was extracted with ethyl acetate (3×10 mL) and the combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by prep-TLC with dichloromethane:methanol=15:1 to afford (R)-3-methyl-N-(3-methyl-1-oxo-1-(2-oxo-1-phenyl-3-oxa-1,8-diazaspiro[4.5]decan-8-yl)butan-2-yl)benzamide as a white solid (13 mg, 13% over two steps).
- LCMS (ESI): m/z=450.2 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=0.74-0.96 (m, 6H), 1.11-1.28 (m, 1H), 1.46-1.86 (m, 1H), 1.89-2.30 (m, 3H), 2.37-2.42 (m, 3H), 2.68-2.90 (m, 2H), 3.15-3.31 (m, 1H), 4.35-4.39 (m, 1H), 4.59-4.91 (m, 3H), 6.99-7.68 (m, 9H).
-
-
-
- To a solution of tert-butyl-4-cyano-4-(4-nitrophenylamino)piperidine-1-carboxylate (prepared as described in Example 86-a) (9.0 g, 0.0261 mol) in methanol (100 mL) was added an aqueous sodium hydroxide solution (100 mL, 1.0 M). After stirring for 15 minutes, a 30% aqueous hydrogen peroxide solution (76 mL) was added dropwise. After stirring overnight, the resulting mixture was filtered. The filter cake was washed with water (3×100 mL) and dried under reduced pressure to afford tert-butyl-4-carbamoyl-4-(4-nitrophenylamino)piperidine-1-carboxylate as a white solid (5.2 g, 55%).
- LCMS (ESI): m/z=365.2 [M+H]+.
-
- To a solution of ter-butyl-4-carbamoyl-4-(4-nitrophenylamino)piperidine-1-carboxylate (2.0 g, 0.0055 mol) in triethyl orthoformate (20 mL) was added acetic acid (1 mL, cat.). The resulting mixture was stirred at 140° C. for 30 minutes in a microwave reactor. The solvent was removed under reduced pressure and the residue was dissolved in methanol (30 mL). To the resulting solution was added sodium borohydride (0.5 g, 0.0132 mol) at 0° C. and the mixture was stirred for 30 minutes. The solvent was removed under reduced pressure and the residue was treated with water (20 mL) and ethyl acetate (50 mL). The organic layer was collected and the aqueous layer was extracted with ethyl acetate (3×10 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with dichloromethane:methanol=100:1 to afford tert-butyl-1-(4-nitrophenyl)-4-oxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate as a white solid (1.2 g, 61%).
- LCMS (ESI): m/z=377.4 [M+H]+.
-
- To a solution of tert-butyl-1-(4-nitrophenyl)-4-oxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate (1.2 g, 0.00319 mol) in N,N-dimethylformamide (10 mL) was added sodium hydride (320 mg, 60% in oil, 0.00798 mol) at 0° C. After stirring for 15 minutes, iodomethane (2.27 g, 0.01598 mol) was added. The resulting mixture was stirred for 60 minutes at room temperature and the reaction was quenched with ice-water (10 mL). The mixture was extracted with ethyl acetate (3×15 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with ethyl acetate:petroleum ether=1:1 to afford tert-butyl-3-methyl-1-(4-nitrophenyl)-4-oxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate as a yellow solid (1.0 g, 81%).
- LCMS (ESI): m/z=391.2 [M+H]+.
- 1H-NMR (400 MHz, CDCl3): δ=1.55 (s, 9H), 1.67-1.74 (m, 2H), 2.56-2.74 (m, 2H), 3.05 (s, 3H), 3.51-3.65 (m, 2H), 4.06-4.16 (m, 2H), 4.79-4.83 (m, 2H), 6.64-6.67 (m, 2H), 8.11-8.14 (m, 2H).
-
- To a solution of tert-butyl-3-methyl-1-(4-nitrophenyl)-4-oxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate (500 mg, 1.281 mmol) in ethanol (10 mL) was added Raney-Ni (0.1 g, 50% in ethanol). After heating to 50° C., hydrazine (1.0 mL) was added dropwise to the resulting suspension. Before removing the Raney-Ni by filtration, the reaction mixture was stirred at room temperature for 30 minutes. The solvent was removed under reduced pressure and the residue was used directly without further purification.
- LCMS (ESI): m/z=361.2 [M+H]+.
-
- To a solution of oxetan-3-one (99 mg, 1.39 mmol) and tert-butyl-1-(4-aminophenyl)-3-methyl-4-oxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate (100 mg, 0.28 mmol) in 1,2-dichloroethane (30 mL) was added acetic acid (1 drop) at room temperature. After two hours, to the solution was added sodium triacetoxyborohydride (294 mg, 1.39 mmol) at room temperature. The mixture was stirred overnight at room temperature. The reaction was quenched with water (10 mL) and the mixture was extracted with dichloromethane (3×10 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by prep-TLC with dichloromethane:methanol=20:1 to afford tert-butyl-3-methyl-1-(4-(oxetan-3-ylamino)phenyl)-4-oxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate as a white solid (50 mg, 42%).
- LCMS (ESI): m/z=416.2 [M+H]+.
-
- To a solution of tert-butyl-3-methyl-1-(4-(oxetan-3-ylamino)phenyl)-4-oxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate (55 mg, 0.13 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (1 mL) at room temperature. The reaction was stirred for 30 minutes at room temperature. The solvent was removed under reduced pressure and water (5 mL) was added to the residue. The pH of the suspension was adjusted to 11 by addition of a 10% aqueous sodium carbonate solution. The mixture was extracted with ethyl acetate (3×10 mL) and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford 3-methyl-1-(4-(oxetan-3-ylamino)phenyl)-1,3,8-triazaspiro[4.5]decan-4-one as the crude product (45 mg, crude) which was used directly without further purification.
-
- To a solution of 3-methyl-1-(4-(oxetan-3-ylamino)phenyl)-1,3,8-triazaspiro[4.5]decan-4-one (45 mg, 0.14 mmol) in dichloromethane (5 mL) was added sequentially (R)-2-(2-fluoro-5-(trifluoromethyl)benzamido)-3-methylbutanoic acid (prepared as described in Example 28-f) (44 mg, 0.14 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate (HATU) (81 mg, 0.21 mmol) and N,N-diisopropylethylamine (46 mg, 0.36 mmol). The resulting mixture was stirred for one hour at room temperature before the reaction was quenched with ice-water. The mixture was extracted with dichloromethane (3×10 mL) and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by prep-TLC with petroleum ether: ethyl acetate=1:2 to afford (R)-2-fluoro-N-(3-methyl-1-(3-methyl-1-(4-(oxetan-3-ylamino)phenyl)-4-oxo-1,3,8-triazaspiro[4.5]decan-8-yl)-1-oxobutan-2-yl)-5-(trifluoromethyl)benzamide as a white solid (11.5 mg, 13% over two steps).
- LCMS (ESI): m/z=606.2 [M+H]+.
- 1H-NMR (400 MHz, CDCl3): δ=0.88-1.04 (m, 6H), 1.76-2.15 (m, 5H), 3.01 (s, 3H), 3.55-3.60 (m, 2H), 3.92-4.08 (m, 2H), 4.40-4.43 (m, 1H), 4.55-4.65 (m, 5H), 4.94-5.09 (m, 2H), 6.54-6.63 (m, 2H), 6.85- 6.87 (m, 2H), 7.26-7.34 (m, 1H), 7.51-7.60 (m, 1H), 7.76-7.77 (m, 1H), 8.34-8.36 (m, 1H).
-
-
-
- To a solution of 3-(benzyloxy)cyclobutanecarboxylic acid (0.5 g, 2.4 mmol) in tetrahydrofuran (10 mL) was added lithium aluminum hydride (2 mL, 2.4 M in tetrahydrofuran) at 0° C. dropwise. The reaction was stirred overnight at room temperature. After quenching with water (0.2 mL), a 15% aqueous sodium hydroxide solution (0.6 mL) and water (0.2 mL) were added sequentially. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with ethyl acetate:petroleum ether=1:5 to afford (3-(benzyloxy)cyclobutyl)methanol as a colorless oil (420 mg, 90%).
- 1H-NMR (300 MHz, CDCl3): δ=1.68-2.48 (m, 5H), 2.62-3.57 (m, 2H), 3.88-4.17 (m, 1H), 4.40 (m, 2H), 7.24-7.33 (m, 5H).
-
- To a solution of (3-(benzyloxy)cyclobutyl)methanol (200 mg, 1.04 mmol) in dichloromethane (10 mL) was added N,N-diisopropylethylamine (201 mg, 1.56 mmol) and methanesulfonyl chloride (142 mg, 1.25 mmol). The reaction was stirred for 0.5 h at room temperature. Then the reaction was quenched with water (10 mL) and extracted with ethyl acetate (3×10 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude (3-(benzyloxy)cyclobutyl)methyl-methanesulfonate (270 mg, crude), which was used directly without further purification.
-
- To a solution of benzyl-3-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate (prepared as described in Example 88-b) (1.5 g, 4.7 mmol) in methanol (50 mL) was added 5% palladium on carbon (0.2 g). The reaction was stirred overnight at room temperature under a hydrogen atmosphere. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure. To the residue was added sequentially dichloromethane (50 mL), triethylamine (0.56 g, 5.6 mmol), di-tert-butyl dicarbonate (1.2 g, 5.6 mmol). The mixture was stirred for 3 hours before the reaction was quenched with a cold 5% aqueous hydrochloric acid solution (10 mL). The organic layer was collected and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. To the residue was added ethyl acetate:petroleum ether=1:3 (10 mL) and the mixture was stirred at 0° C. for 1 hour. The precipitate was collected by filtration and dried under reduced pressure to afford tert-butyl-3-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate as a white solid (1.23 g, 92%).
- LCMS (ESI): m/z=284.2 [M+H]+.
-
- To a solution of (3-(benzyloxy)cyclobutyl)methyl-methanesulfonate (270 mg, crude) in N,N-dimethylformamide (5 mL) was added tert-butyl-3-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate (283 mg, 1.0 mmol) and cesium carbonate (650 mg, 2.0 mmol). Before quenching by addition of ice-water (20 mL), the mixture was stirred at 80° C. overnight. The mixture was extracted with ethyl acetate (3×10 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with ethyl acetate:petroleum ether=1:5 to afford tert-butyl-1-((3-(benzyloxy)cyclobutyl)methyl)-3-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate as a white solid (290 mg, 63%).
- LCMS (ESI): m/z=458.2 [M+H]+.
- 1H-NMR (300 MHz, CDCl3): δ=1.46 (s, 9H), 1.54-2.68 (m, 8H), 3.01 (s, 3H), 3.31-3.19 (m, 2H), 4.30-3.40 (m, 6H), 4.41-4.39 (m, 2H), 7.33-7.25 (m, 5H).
-
- To a solution of tert-butyl-1-((3-(benzyloxy)cyclobutyl)methyl)-3-methyl-2,4-dioxo-1,3,8-triazaspiro [4.5]decane-8-carboxylate (290 mg, 0.63 mmol) in methanol (10 mL) was added 5% palladium on carbon (30 mg, 50% wet with water). The reaction was stirred overnight at room temperature under a hydrogen atmosphere. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure to afford crude tert-butyl-1-((3-hydroxycyclobutyl)methyl)-3-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate (220 mg, crude), which was used directly without further purification.
- LCMS (ESI): m/z=368.2 [M+H]+.
-
- To a solution of tert-butyl-1-((3-hydroxycyclobutyl)methyl)-3-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate (220 mg, crude) in N,N-dimethylformamide (5 mL) was added sodium hydride (50 mg, 1.2 mmol) at room temperature. After stirring for 15 minutes, iodomethane (425 mg, 3.0 mmol) was added. The resulting mixture was stirred overnight and the reaction was quenched with ice-water (10 mL). The mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with ethyl acetate:petroleum ether=1:3 to afford tert-Butyl-1-((3-methoxycyclobutyl)methyl)-3-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate as a white solid (150 mg, crude), which was used directly without further purification.
- LCMS (ESI): m/z=382.2 [M+H]+.
-
- A solution of tert-butyl-3-methyl-1-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate (150 mg, crude) in hydrochloric acid in dioxane (6.0 M, 10 mL) was stirred for 30 minutes. The solvent was removed under reduced pressure. To the residue was added dichloromethane (5 mL), (R)-2-(2-fluoro-5-(trifluoromethyl)benzamido)-3-methylbutanoic acid (prepared as described in Example 28-f) (121 mg, 0.39 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate (HATU) (224 mg, 0.59 mmol) and N,N-diisopropylethylamine (127 mg, 0.98 mmol). The resulting mixture was stirred for 2 hours at room temperature before the reaction was quenched with ice-water. The mixture was extracted with ethyl acetate (3×10 mL) and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by prep-TLC with dichloromethane:methanol=15:1 to afford (R)-2-fluoro-N-(1-(1-((3-methoxycyclobutyl)methyl)-3-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decan-8-yl)-3-methyl-1-oxobutan-2-yl)-5-(trifluoromethyl)benzamide as a white solid (65.7 mg, 29.5% over three steps).
- LCMS (ESI): m/z=571.2 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=0.98-1.23 (m, 6H), 1.51-2.78 (m, 10H), 2.99 (d, J=2.8 Hz, 3H), 3.09-3.27 (m, 3H), 327-4.10 (m, 6H), 4.29 (t, J=13.0 Hz, 1H), 4.59 (d, J=11.0 Hz, 1H), 4.99 (d, J=7.1 Hz, 1H), 7.48 (t, J=9.4 Hz, 1H), 7.84-7.95 (m, 1H), 7.98-8.18 (m, 1H).
-
-
-
- To a solution of tert-Butyl-1-(4-(methoxycarbonyl)phenyl)-4-oxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate (prepared as described in Example 149-c) (1000 mg, 2.57 mmol) in N,N-dimethylformamide (10 mL) was added sodium hydride (138 mg, 607% in oil, 3.34 mmol) at 0° C. After stirring for 15 minutes, iodomethane (550 mg, 3.86 mmol) was added. The resulting mixture was stirred for 15 minutes before the reaction was quenched with ice-water (10 mL). The mixture was extracted with ethyl acetate (3×10 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure and the residue was purified by silica gel column chromatography eluting with ethyl acetate:petroleum ether=1:2 to afford tert-butyl-1-(4-(methoxycarbonyl)phenyl)-3-methy-4-oxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate as a white solid (1000 mg, 96%).
- LCMS (ESI): m/z=404.2 [M+H]+.
-
- To a solution of tert-butyl-1-(4-(methoxycarbonyl)phenyl)-3-methyl-4-oxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate (1000 mg, 0.94 mmol) in methanol (20 mL) was added a 15% aqueous sodium hydroxide solution (15 mL). The reaction was heated at reflux for 30 minutes before cooling to room temperature. The pH of the resulting solution was adjusted to 3-4 by addition of 10% aqueous hydrochloric acid solution. The suspension was filtered. The filter cake was washed with petroleum ether (15 mL) and dried under reduced pressure to afford 4-(8-(tert-butoxycarbonyl)-3-methyl-4-oxo-1,3,8-triazaspiro[4.5]decan-1-yl)benzoic acid as a white solid (910 mg, 86%).
- LCMS (ESI): m/z=390.4 [M+H]+.
-
- To a solution of 4-(8-(tert-butoxycarbonyl)-3-methyl-4-oxo-1,3,8-triazaspiro[4.5]decan-1-yl)benzoic acid (910 mg 2.34 mmol) in dichloromethane (15 mL) was added sequentially ammonium chloride (751 mg, 14.03 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate (HATU) (1.73 g, 3.51 mmol) and N,N-diisopropylethylamine (1.51 g, 11.69 mmol). The resulting mixture was stirred for 2 hours before the reaction was quenched with ice water (10 mL). The mixture was extracted with dichloromethane (3×15 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with dichloromethane:methanol=20:1 to afford tert-butyl-1-(4-carbamoylphenyl)-3-methyl-4-oxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate as a white solid (850 mg, 94%).
- LCMS (ESI): m/z=389.2 [M+H]+.
-
- A solution of tert-butyl-1-(4-carbamoylphenyl)-3-methyl-4-oxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate (400 mg 1.03 mmol) in N,N-dimethylformamide/N,N-dimethylacetamide (1:1, 10 mL) was stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography eluting with ethyl acetate:petroleum ether=1:3 to afford (E)-tert-butyl-1-(4-(((dimethylamino)methylene)carbamoyl)phenyl)-3-methyl-4-oxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate as a yellow solid (290 mg, 85%).
- LCMS (ESI): m/z=444.3 [M+H]+.
-
- To a solution of (E)-tert-butyl-1-(4-(((dimethylamino)methylene)carbamoyl)phenyl)-3-methyl-4-oxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate (290 mg, 0.65 mmol) in ethanol (20 mL) was added hydrazine hydrate (0.3 mL, 80% in water). The reaction was stirred at room temperature overnight. Then the solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography eluting with dichloromethane:methanol=20:1 to afford tert-butyl-1-(4-(1H-1,2,4-triazol-3-yl)phenyl)-3-methyl-4-oxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate as a thick oil (210 mg, 77%).
- LCMS (ESI): m/z=413.4 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=1.52 (s, 9H), 1.61-1.65 (m, 2H), 2.55-2.73 (m, 2H), 3.01 (m, 3H), 3.48-3.68 (m, 2H), 3.95-4.21 (m, 2H), 4.65-4.73 (m, 2H), 6.71-6.75 (m, 2H), 7.88-7.89 (m, 2H), 8.13 (s, 1H).
-
- A solution of tert-butyl-1-(4-(1H-1,2,4-triazol-3-yl)phenyl)-3-methyl-4-oxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate (110 mg, 0.26 mmol) in hydrochloric acid in dioxane (6.0 M, 10 mL) was stirred for 30 minutes. The precipitate was collected by filtration and dried under reduced pressure to afford 1-(4-(1H-1,2,4-triazol-3-yl)phenyl)-3-methyl-1,3,8-triazaspiro[4.5]decan-4-one hydrochloride as a white solid (90 mg, 95%).
- LCMS (ESI): m/z=313.4 [M+H]+.
-
- To a suspension of 1-(4-(1H-1,2,4-triazol-3-yl)phenyl)-3-methyl-1,3,8-triazaspiro[4.5]decan-4-one hydrochloride (90 mg, 0.26 mmol) in dichloromethane (5 mL) was added (R)-2-(2-fluoro-5-(trifluoromethyl)benzamido)-3-methylbutanoic acid (prepared as described in Example 28-f) (82 mg, 0.26 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate (HATU) (153 mg, 0.40 mmol) and N,N-diisopropylethylamine (104 mg, 0.80 mmol). The resulting mixture was stirred for 2 hours at room temperature before the reaction was quenched with ice-water (10 mL). The mixture was extracted with ethyl acetate (3×10 mL) and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by prep-TLC with dichloromethane:methanol=15:1 to afford (R)—N-(1-(1-(4-(1H-1,2,4-triazol-3-yl)phenyl)-3-methyl-4-oxo-1,3,8-triazaspiro[4.5]decan-8-yl)-3-methyl-1-oxobutan-2-yl)-2-fluoro-5-(trifluoromethyl)benzamide as a white solid (55 mg, 35%).
- LCMS (ESI): m/z=602.2 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=1.06-1.20 (m, 6H), 1.76-1.94 (m, 2H), 2.212.32 (m, 1H), 2.64-2.76 (m, 1H), 2.87-3.01 (m, 1H), 3.05 (s, 3H), 3.54-3.58 (m, 1H), 3.99-4.14 (m, 1H), 4.32-4.39 (m, 1H), 4.57- 4.60 (m, 1H), 4.85-4.87 (m, 2H), 4.97-4.99 (m, 1H), 6.94-6.97 (m, 2H), 7.44-7.50 (m, 1H), 7.71-7.91 (m, 3H), 8.05-8.06 (m, 1H), 8.81-8.88 (m, 1H).
-
-
-
- A solution of tert-butyl-1-(4-(methoxycarbonyl)phenyl)-3-methy-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate (prepared as described in Example 223-c) (120 mg, 0.28 mmol) in hydrochloric acid in dioxane (6.0 M, 10 mL) was stirred for 30 minutes. The precipitate was collected by filtration and dried under reduced pressure to afford 4-(3-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decan-1-yl)benzoic acid hydrochloride as a white solid (100 mg, 97%).
- LCMS (ESI): m/z=317.1 [M+H]+.
-
- To a solution of 4-(3-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decan-1-yl)benzoic acid hydrochloride (2) (100 mg, 0.28 mmol) in dichloromethane (5 mL) was added (R)-2-(2-fluoro-5-(trifluoromethyl)benzamido)-3-methylbutanoic acid (prepared as described in Example 28-f) (89 mg, 0.28 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate (HATU) (165 mg, 0.43 mmol) and N,N-diisopropylethylamine (114 mg, 0.86 mmol). The resulting mixture was stirred for 2 hours at room temperature before the reaction was quenched with ice-water (10 mL). The mixture was extracted with ethyl acetate (3×10 mL) and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by prep-HPLC (Gradient: 95% water, 5% acetonitrile, 30-50 min gradient to 25% water, 85% acetonitrile) to afford (R)-methyl-4-(8-(2-(2-fluoro-5-(trifluoromethyl)benzamido)-3-methylbutanoyl)-3-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decan-1-yl)benzoate as a white solid (46.1 mg, 27%).
- LCMS (ESI): m/z=607.2 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=0.81-1.00 (m, 6H), 1.71-1.86 (m, 1H), 1.96-2.22 (m, 4H), 3.11 (s, 3H), 3.49-3.53 (m, 1H), 3.91-3.93 (m, 3H), 3.95-3.97 (m, 1H), 4.15-4.26 (m, 1H), 4.43-4.55 (m, 1H), 4.85- 4.87 (m, 1H), 7.33-7.42 (m, 3H), 7.77-7.94 (m, 2H), 8.02-8.07 (m, 2H), 8.13-8.30 (m, 1H).
- The following compound was synthesized following the general procedure described above:
-
- 10.6 mg, 48% yield, white solid.
- LCMS (ESI): m/z=564.7 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=0.64-0.73 (m, 2H), 0.80-0.90 (m, 2H), 0.94-1.05 (m, 6H), 1.64-1.79 (m, 1H), 1.81-1.91 (m, 1H), 1.91-2.02 (m, 1H), 2.05-2.25 (m, 2H), 3.10 (d, 3H), 3.49-3.50 (m, 1H), 3.75 (m, 1H), 3.94-4.30 (m, 2H), 4.39-4.51 (m, 1H), 4.77-4.87 (m, 1H), 6.99-7.14 (m, 1H), 7.19-7.27 (m, 1H), 7.29-7.37 (m, 2H), 7.43 (dd, 1H), 8.08 (dd, 2H).
-
-
-
- To a solution of methyl-4-aminobenzoate (16.46 g, 0.109 mol) in acetic acid (160 mL) was added tert-butyl-4-oxopiperidine-1-carboxylate (23.8 g, 0.12 mol). The resulting mixture was cooled to 0° C. and trimethylsilyl cyanide (12.95 g, 0.131 mol) was added. The resulting solution was stirred overnight at room temperature. Saturated aqueous ammonium chloride solution was added (200 mL). After stirring at room temperature for 10 minutes, the suspension was filtered. The filter cake was dried under reduced pressure to afford tert-butyl-4-cyano-4-(4-(methoxycarbonyl)phenylamino)piperidine-1-carboxylate as a white solid (39.1 g, 100%).
- LCMS (ESI): m/z=360.2 [M+H]+.
- 1H-NMR (300 MHz, DMSO-d6) b=2.18-2.28 (m, 4H), 2.96-3.25 (m, 4H), 4.25-4.35 (m, 2H), 6.48-6.68 (m, 3H), 7.04-7.18 (m, 2H), 7.40-7.50 (m, 3H), 7.56-7.73 (m, 2H).
-
- To a solution of tert-butyl-4-cyano-4-(4-(methoxycarbonyl)phenylamino)piperidine-1-carboxylate (6.0 g 16.7 mmol) in dichloromethane (70 mL) was added chlorosulfonyl isocyanate (4.0 g 28.4 mmol) at 0° C. After stirring for 30 minutes at 0° C., the reaction was quenched with a 5% aqueous hydrochloric acid solution (20 mL). The solvent was removed under reduced pressure and ethanol (35 mL) was added. The suspension was stirred 30 minutes at 80° C. The solvent was removed under reduced pressure and the residue was added to tetrahydrofuran (50 mL) and the pH of the suspension was adjusted to pH 8 by addition of a 10% aqueous potassium carbonate solution. Then di-tert-butyl dicarbonate (6.20 g, 28.4 mmol) in tetrahydrofuran (50 mL) was added. After stirring overnight, the solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography eluting with ethyl acetate:petroleum ether=10:1 to afford tert-butyl-1-(4-(methoxycarbonyl)phenyl)-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate as a white solid (4.0 g, 60%).
- LCMS (ESI): m/z=404.4 [M+H]+.
-
- To a solution of tert-butyl-1-(4-(methoxycarbonyl)phenyl)-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate (3.45 g, 8.56 mmol) in N,N-dimethylformamide (40 mL) was added sodium hydride (685 mg, 60% in oil, 17.2 mmol) at 0° C., After stirring for 15 minutes, iodomethane (1.83 g, 12.84 mmol) was added. The resulting mixture was stirred for 15 minutes. The reaction was quenched with ice-water (20 mL) and the mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with ethyl acetate:petroleum ether=1-3 to afford tert-butyl-1-(4-(methoxycarbonyl)phenyl)-3-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate as a white solid (3.0 g, 84%). LCMS (ESI): m/z=418.2 [M+H]+.
-
- To a solution of tert-butyl-1-(4-(methoxycarbonyl)phenyl)-3-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate (1300 mg, 3.12 mmol) in methanol (30 mL) was added a 15% aqueous sodium hydroxide solution (15 mL). The reaction was heated at reflux for 30 minutes before cooling to room temperature. The pH of the resulting solution was adjusted to 3-4 by addition of 10% aqueous hydrochloric acid solution. The suspension was filtered. The filter cake was washed with petroleum ether and dried under reduced pressure to afford 4-(8-(tert-butoxycarbonyl)-3-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decan-1-yl)benzoic acid as a white solid (1150 mg, 892%).
- LCMS (ESI): m/z=404.4 [M+H]+.
-
- To a solution of 4-(8-(tert-butoxycarbonyl)-3-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decan-1-yl)benzoic acid (400 mg, 0.99 mmol) in N,N-dimethylformamide (6 mL) was added potassium carbonate (274 mg, 1.99 mmol) and benzyl bromide (177 mg, 1.29 mmol). Before the reaction was quenched by addition of ice-water (10 mL), the resulting suspension was heated for 2 hours at 50° C. The mixture was extracted with ethyl acetate (3×30 mL) and then the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with ethyl acetate:petroleum ether=1:2 to afford tert-butyl-1-(4-((benzyloxy)carbonyl)phenyl)-3-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate as a white solid (500 mg, 91%).
- LCMS (ESI): m/z=493.4 [M+H]+.
- 1H-NMR (300 MHz, DMSO-d6): δ=1.41 (s, 2H), 1.62-1.86 (m, 4H), 3.13 (s, 3H), 3.53-3.68 (m, 2H), 4.03- 4.13 (m, 2H), 5.41 (s, 2H), 7.26-7.29 (m, 2H), 7.37-7.42 (m, 5H), 8.17-8.19 (m, 2H).
-
- A solution of tert-butyl-1-(4-((benzyloxy)carbonyl)phenyl)-3-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate (120 mg, 0.24 mmol) in hydrochloric acid in dioxane (6.0 M, 10 mL) was stirred for 30 minutes. The precipitate was collected by filtration and dried under reduced pressure to afford benzyl 4-(3-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decan-1-yl)benzoate hydrochloride as a white solid (110 mg, 98%).
- LCMS (ESI): m/z=393.4 [M+H]+.
-
- To a suspension of benzyl 4-(3-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decan-1-yl)benzoate hydrochloride (90 mg, 0.26 mmol) in dichloromethane (5 mL) was added (R)-2-(2-fluoro-5-(trifluoromethyl)benzamido)-3 methylbutanoic acid (prepared as described in Example 28-f) (82 mg, 0.26 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate (HATU) (153 mg, 0.40 mmol) and N,N-diisopropylethylamine (104 mg, 0.80 mmol). The resulting mixture was stirred for 2 hours at room temperature before the reaction was quenched with ice-water (10 mL). The mixture was extracted with ethyl acetate (3×10 mL) and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by prep-TLC with ethyl acetate:petroleum ether=2:1 to afford (R)-benzyl-4-(8-(2-(2-fluoro-5-(trifluoromethyl)benzamido)-3-methylbutanoyl)-3-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decan-1-yl)benzoate as a white solid (150 mg, 91%).
- LCMS (ESI): m/z=393.4 [M+H]+.
-
- A suspension of (R)-benzyl-4-(8-(2-(2-fluoro-5-(trifluoromethyl)benzamido)-3-methylbutanoyl)-3-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decan-1-yl)benzoate (150 mg, 0.22 mmol) and 5% palladium on carbon (10 mg) in methanol (40 mL) was stirred for 30 minutes under a hydrogen atmosphere. The mixture was filtered and the filter cake was washed with methanol (5×10 mL). The filtrate was concentrated under reduced pressure and the residue was purified by prep-HPLC (Gradient: 95% water, 5% acetonitrile, 30-50 min gradient to 25% water, 85% acetonitrile) to afford (R)-4-(8-(2-(2-fluoro-5-(trifluoromethyl)benzamido)-3-methylbutanoyl)-3-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decan-1-yl)benzoic acid as a white solid (55.5 mg, 61%).
- LCMS (ESI): m/z=593.1 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=0.80-1.01 (m, 6H), 1.70-1.86 (m, 1H), 1.88-2.24 (m, 4H), 3.10 (s, 3H), 3.47-3.54 (m, 1H), 3.93-3.99 (m, 1H), 4.20-4.31 (m, 1H), 4.43-4.59 (m, 1H), 4.83-4.87 (m, 1H), 7.34- 7.46 (m, 3H), 7.85-7.88 (m, 2H), 8.00-8.16 (m, 2H).
-
-
-
- To a solution of tert-butyl-1-(4-(methoxycarbonyl)phenyl)-3-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate (prepared as described in Example 223-c) (1300 mg, 3.12 mmol) in methanol (25 mL) was added a 15% aqueous sodium hydroxide solution (7 mL). The reaction was heated at reflux for 30 minutes before cooling to room temperature. The pH of the resulting solution was adjusted to 3-4 by addition of 10% aqueous hydrochloric acid solution. The suspension was filtered. The filter cake was washed with water (10 mL) and dried under reduced pressure to afford 4-(8-(tert-butoxycarbonyl)-3-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decan-1-yl)benzoic acid as a white solid (1150 mg, 92%).
- LCMS (ESI): m/z=404.4 [M+H]+.
-
- To a solution of 4-(8-(tert-butoxycarbonyl)-3-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decan-1-yl)benzoic acid (1000 mg 2.48 mmol) in N,N-dimethylformamide (15 mL) was added ammonium chloride (1350 mg, 25.31 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate (HATU) (2400 mg, 6.33 mmol) and N,N-diisopropylethylamine (2180 mg, 16.87 mmol). The resulting mixture was stirred at room temperature for 24 hours before the reaction was quenched with ice water (15 mL). The organic layer were extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with dichloromethane:methanol=20:1 to afford tert-butyl-1-(4-carbamoylphenyl)-3-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate as a white solid (850 mg, 85%).
- LCMS (ESI): m/z=403.4 [M+H]+.
-
- To a solution of tert-butyl-1-(4-carbamoylphenyl)-3-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate (850 mg 2.11 mmol) in dichloromethane (20 mL) was added pyridine (1500 mg 18.98 mmol) and trifluoroacetic anhydride (2120 mg 10.09 mmol). The resulting mixture was stirred at room temperature for 3 hours before the reaction was quenched with saturated aqueous sodium carbonate solution (20 mL). The mixture was extracted with dichloromethane (3×15 mL) The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with ethyl acetate:petroleum ether=1:1 to afford tert-butyl-1-(4-cyanophenyl)-3-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate as a brown solid (600 mg, 74%).
- LCMS (ESI): m/z=385.4 [M+H]+.
-
- To a solution of tert-butyl-1-(4-cyanophenyl)-3-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate (50 mg 0.13 mmol) in N,N-dimethylformamide (3 mL), was added sodium azide (51 mg 0.078 mmol), ammonium chloride (42 mg 0.78 mmol), copper iodide (10 mg, cat.), and the mixture was heated at reflux for 2 days. After the reaction was quenched with ice water (10 mL), the mixture was extracted with ethyl acetate (3×15 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with dichloromethane:methanol=15:1 to afford tert-butyl-1-(4-(2H-tetrazol-5-yl)phenyl)-3-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate as a thick oil (30 mg, 54%).
- LCMS (ESI): m/z=428.3 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=1.38 (s, 9H), 1.76-1.78 (m, 2H), 1.79-1.81 (m, 2H), 2.88 (s, 3H), 3.32-3.54 (m, 2H), 3.98-4.01 (m, 2H), 7.36-7.38 (m, 2H), 8.17-8.19 (m, 2H).
-
- A solution of tert-butyl-1-(4-(2H-tetrazol-5-yl)phenyl)-3-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate (30 mg, 0.07 mmol) in hydrochloric acid in dioxane (6.0 M, 10 mL) was stirred for 30 minutes. The mixture was concentrated under reduced pressure to afford 1-(4-(2H-tetrazol-5-yl)phenyl)-3-methyl-1,3,8-triazaspiro[4.5]decane-2,4-dione hydrochloride as a white solid (30 mg, crude), which was used directly without any further purification.
- LCMS (ESI): m/z=328.3 [M+H]+.
-
- To a suspension of 1-(4-(2H-tetrazol-5-yl)phenyl)-3-methyl-1,3,8-triazaspiro[4.5]decane-2,4-dione hydrochloride (30 mg, crude) in dichloromethane (5 mL) was added (R)-2-(2-fluoro-5-(trifluoromethyl)benzamido)-3-methylbutanoic acid (prepared as described in Example 28-f) (22 mg, 0.07 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate (HATU) (40 mg, 0.11 mmol) and N,N-diisopropylethylamine (28 mg, 0.21 mmol). The resulting mixture was stirred for 2 hours at room temperature before the reaction was quenched with ice-water (10 mL). The mixture was extracted with ethyl acetate (3×10 mL) and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by prep-TLC with dichloromethane:methanol=10:1 to afford (R)—N-(1-(1-(4-(2H-tetrazol-5-yl)phenyl)-3-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decan-8-yl)-3-methyl-1-oxobutan-2-yl)-2-fluoro-5-(trifluoromethyl)benzamide as a white solid (2.7 mg, 9%).
- LCMS (ESI): m/z=617.2 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=0.78-0.92 (m, 2H), 0.97-1.02 (m, 4H), 1.37-1.41 (m, 1H), 1.75-1.83 (m, 1H), 1.98-2.24 (m, 3H), 3.12 (s, 3H), 3.48-3.55 (m, 2H), 3.94-4.01 (m, 1H), 4.21-4.57 (m, 1H), 4.80- 4.84 (m, 1H), 7.22-7.58 (m, 3H), 7.71-8.01 (m, 2H), 8.05-8.20 (m, 2H).
- The following 2 compounds were synthesized following the general procedure described above:
-
- 23.6 mg, 19% yield, white solid.
- LCMS (ESI): m/z=633.2 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=0.79-1.00 (m, 6H), 1.75-2.25 (m, 5H), 3.11 (s, 3H), 3.45-3.54 (m, 1H), 3.92-4.03 (m, 1H), 4.21-4.31 (m, 1H), 4.44-4.60 (m, 1H), 4.81-4.87 (m, 1H), 7.14-7.60 (m, 5H), 8.06- 8.20 (m, 2H).
-
- 22.4 mg, 20% yield, white solid.
- LCMS (ESI): m/z=615.2 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=0.79-1.01 (m, 6H), 1.71-2.17 (m, 5H), 3.11 (s, 3H), 3.47-3.54 (m, 1H), 3.93-4.00 (m, 1H), 4.20-4.55 (m, 2H), 4.81-4.86 (m, 1H), 6.56-6.93 (m, 1H), 7.03-7.57 (m, 5H), 8.06- 8.18 (m, 2H).
-
-
-
- To a solution of tert-butyl-1-(4-carbamoylphenyl)-3-methyl-4-oxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate (prepared as described in Example 145, or alternatively, as described in Example 220) (320 mg 0.83 mmol) in dichloromethane (50 mL), was added pyridine (652 mg 8.25 mmol), then trifluoroacetic anhydride (866 mg 4.12 mmol). The resulting mixture was stirred at room temperature for 3 hours before the reaction was quenched with a saturated aqueous sodium carbonate solution (15 mL). The mixture was extracted with dichloromethane (3×15 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with ethyl acetate:petroleum ether=1:1 to afford tert-butyl-1-(4-cyanophenyl)-3-methyl-4-oxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate as a thick oil (207 mg, 68%).
- LCMS (ESI): m/z=371.4 [M+H]+.
-
- To a solution of tert-butyl-1-(4-cyanophenyl)-3-methyl-4-oxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate (90 mg 0.24 mmol) in toluene (10 mL) was added tributyltin azide (243 mg, 0.73 mmol). The mixture was heated at reflux for 24 hours before the reaction was quenched with ice water (10 mL). The pH of the resulting solution was adjusted to 5-6 by addition of 10% aqueous hydrochloric acid solution. The mixture was extracted with ethyl acetate (3×15 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with dichloromethane:methanol=10:1 to afford tert-butyl-1-(4-(2H-tetrazol-5-yl)phenyl)-3-methyl-4-oxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate (70 mg, 70%).
- LCMS (ESI): m/z=414.3 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=1.54 (s, 9H), 1.65-1.68 (m, 2H), 2.61-2.74 (m, 2H), 3.04 (s, 3H), 3.53-3.73 (m, 2H), 4.04-4.20 (m, 2H), 4.69-4.75 (m, 2H), 6.73-6.76 (m, 2H), 7.95-7.98 (m, 2H).
-
- A solution of tert-butyl-1-(4-(2H-tetrazol-5-yl)phenyl)-3-methyl-4-oxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate (70 mg, 0.17 mmol) in hydrochloric acid in dioxane (6.0 M, 10 mL) was stirred for 30 minutes. The precipitate was collected by filtration and dried under reduced pressure to afford 1-(4-(2H-tetrazol-5-yl)phenyl)-3-methyl-1,3,8-triazaspiro[4.5]decan-4-one hydrochloride as a white solid (58 mg, 98%).
- LCMS (ESI): m/z=314.3 [M+H]+.
-
- To a suspension of 1-(4-(2H-tetrazol-5-yl)phenyl)-3-methyl-1,3,8-triazaspiro[4.5]decan-4-one hydrochloride (58 mg, 0.16 mmol) in dichloromethane (5 mL) was added (R)-2-(2-fluoro-5-(trifluoromethyl)benzamido)-3-methylbutanoic acid (prepared as described in Example 28-f) (63 mg, 0.20 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide-hexafluorophosphate (HATU) (97 mg, 0.25 mmol) and N,N-diisopropylethylamine (67 mg, 0.51 mmol). The resulting mixture was stirred for 2 hours at room temperature before the reaction was quenched with ice-water (10 mL). The mixture was extracted with ethyl acetate (3×10 mL) and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by prep-TLC with dichloromethane:methanol=10:1 to afford (R)—N-(1-(1-(4-(2H-tetrazol-5-yl)phenyl)-3-methyl-4-oxo-1,3,8-triazaspiro[4.5]decan-8-yl)-3-methyl-1-oxobutan-2-yl)-2-fluoro-5-(trifluoromethyl)benzamide as a white solid (10.5 mg, 11%).
- LCMS (ESI): m/z=603.2 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=1.06-1.33 (m, 6H), 1.73-1.96 (m, 2H), 2.17-2.37 (m, 1H), 2.70-2.81 (m, 1H), 2.90-2.99 (m, 1H), 3.09-3.15 (m, 1H), 3.06 (s, 3H), 3.46-3.65 (m, 1H), 4.02-4.07 (m, 1H), 4.29- 4.39 (m, 1H), 4.52-4.64 (m, 1H), 4.99-5.01 (m, 2H), 6.91-6.93 (m, 2H), 7.45-7.50 (m, 1H), 7.68-7.78 (m, 2H), 7.90-8.07 (m, 2H).
-
-
-
- To a suspension of benzyl-5-(3-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decan-1-yl)-1H-indazole-1-carboxylate hydrochloride (prepared as described in Example 52-e) (2.80 g, crude) in dichloromethane (100 mL) was added sequentially (R)-2-(tert-butoxycarbonylamino)-3-methylbutanoic acid (1.54 g, 7.10 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate (HATU) (3.68 g, 9.70 mmol) and N,N-diisopropylethylamine (2.09 g, 16.16 mmol). The resulting mixture was stirred for 2 hours at room temperature before the reaction was quenched with ice-water. The mixture was extracted with dichloromethane (3×50 mL) and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with ethyl acetate:petroleum ether=1:1 to afford (R)-benzyl-5-(8-(2-(tert-butoxycarbonylamino)-3-methylbutanoyl)-3-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decan-1-yl)-1H-indazole-1-carboxylate as a white solid (2.20 g, 54%).
- LCMS (ESI): m/z=655.2 [M+Na]+.
- 1H-NMR (300 MHz, CDCl3): δ=0.59-1.35 (m, 15H), 1.67-2.13 (m, 5H), 3.08 (s, 3H), 3.34-3.46 (m, 1H), 3.80-3.88 (m, 1H), 4.09-4.14 (m, 2H), 4.69-4.51 (m, 1H), 5.55 (s, 2H), 6.43-6.62 (m, 1H), 7.38-7.42 (m, 4H), 7.54-7.59 (m, 2H), 7.69-7.79 (m, 1H), 8.18-8.31 (m, 2H).
-
- A solution of (R)-benzyl-5-(8-(2-(tert-butoxycarbonylamino)-3-methylbutanoyl)-3-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decan-1-yl)-1H-indazole-1-carboxylate (2.20 mg, 3.48 mmol) in hydrochloric acid in dioxane (6.0 M, 10 mL) was stirred for 30 minutes. The precipitate was collected by filtration and dried under reduced pressure to afford (R)-benzyl-5-(8-(2-amino-3-methylbutanoyl)-3-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decan-1-yl)-1H-indazole-1-carboxylate hydrochloride as a white solid (2.00 g, crude), which was used directly without any further purification.
- LCMS (ESI): m/z=533.2 [M+H]+
-
- To a mixture of (R)-benzyl-5-(8-(2-amino-3-methylbutanoyl)-3-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decan-1-yl)-1H-indazole-1-carboxylate hydrochloride (100 mg, crude) in dichloromethane (10 mL) was added sequentially picolinic acid (23 mg, 0.19 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate (HATU) (106 g, 0.28 mmol) and N,N-diisopropylethylamine (61 g, 0.47 mmol). The resulting mixture was stirred for 2 hours at room temperature before the reaction was quenched with ice-water. The mixture was extracted with dichloromethane (3×10 mL) and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by prep-TLC with dichloromethane:methanol=15:1 to afford (R)-benzyl-5-(3-methyl-8-(3-methyl-2-(picolinamido)butanoyl)-2,4-dioxo-1,3,8-triazaspiro[4.5]decan-1-yl)-1H-indazole-1-carboxylate as a thick oil (100 mg, 83%).
- LCMS (ESI): m/z=638.1 [M+H]+.
-
- A mixture of (R)-benzyl-5-(3-methyl-8-(3-methyl-2-(picolinamido)butanoyl)-2,4-dioxo-1,3,8-triazaspiro[4.5]decan-1-yl)-1H-indazole-1-carboxylate (100 mg, 0.16 mmol) and 5% palladium on carbon (50 mg) in methanol (10 mL) was stirred for 1 hour under a hydrogen atmosphere. The mixture was filtered and the filter cake was washed with methanol (5×10 mL). The filtrate was concentrated under reduced pressure and the residue was purified by prep-HPLC (Gradient: 95% water, 5% acetonitrile, 30-50 min gradient to 25% water, 85% acetonitrile) to afford (R)—N-(1-(1-(1H-indazol-5-yl)-3-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decan-8-yl)-3-methyl-1-oxobutan-2-yl)picolinamide as a white solid (27.6 mg, 29%).
- LCMS (ESI): m/z=504.2 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=0.70-0.94 (m, 6H), 1.71-2.24 (m, 5H), 3.10 (s, 3H), 3.47-3.53 (m, 1H), 3.90-3.98 (m, 1H), 4.13-4.25 (m, 1H), 4.39-4.51 (m, 1H), 4.80-4.82 (m, 1H), 7.12-7.28 (m, 1H), 7.45- 8.15 (m, 6H), 8.45-8.62 (m, 1H).
- The following 8 compounds were synthesized following the procedure described above:
-
- 59.8 mg, yield 63%, white solid.
- LCMS (ESI): m/z=504.2 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=0.63-1.02 (m, 6H), 1.06-1.22 (m, 1H), 1.92-2.28 (m, 4H), 3.11 (s, 3H), 3.47-3.52 (m, 1H), 3.91-3.99 (m, 1H), 4.22-4.51 (m, 2H), 4.69-4.80 (m, 1H), 7.17-7.29 (m, 1H), 7.52- 7.78 (m, 3H), 8.05-8.15 (m, 2H), 8.60-9.10 (m, 3H).
-
- 33.8 mg, yield: 36%, white solid.
- LCMS (ESI): m/z=509.2 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=0.56-0.89 (m, 6H), 1.31-1.41 (m, 7H), 1.54-1.79 (m, 5H), 1.95-2.27 (m, 4H), 3.10 (s, 3H), 3.43-3.54 (m, 1H), 3.86-3.92 (m, 1H), 4.08-4.53 (m, 3H), 7.19-7.26 (m, 1H), 7.62- 7.74 (m, 2H), 8.10-8.18 (m, 1H).
-
- 29.8 mg, yield: 31%, yellow solid.
- LCMS (ESI): m/z=504.2 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=0.63-0.98 (m, 6H), 1.72-2.24 (m, 5H), 3.11 (s, 3H), 3.46-3.53 (m, 1H), 3.91-3.97 (m, 1H), 4.22-4.52 (m, 2H), 4.71-4.77 (m, 1H), 7.18-7.29 (m, 1H), 7.53-8.14 (m, 5H), 8.66- 8.82 (m, 2H).
-
- 33.8 mg, yield: 35%, white solid.
- LCMS (ESI): m/z=483.2 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=0.57-0.75 (m, 1H), 0.85-0.88 (m, 10H), 1.18-1.33 (m, 4H), 1.71-2.21 (m, 5H), 3.10 (s, 3H), 3.43-3.49 (m, 1H), 3.80-3.92 (m, 1H), 4.07-4.50 (m, 2H), 4.56-4.59 (m, 1H), 7.09- 7.28 (m, 1H), 7.61-7.77 (m, 2H), 8.11-8.14 (m, 1H).
-
- 63.6 mg, yield: 67%, white solid.
- LCMS (ESI): m/z=503.2 [M-+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=0.61-0.99 (m, 6H), 1.73-2.17 (m, 5H), 3.10 (s, 3H), 3.46-3.52 (m, 1H), 3.90-3.97 (m, 1H), 4.22-4.53 (m, 2H), 4.72-4.74 (m, 1H), 7.13-7.81 (m, 8H), 8.03-8.15 (m, 1H).
-
- 31.5 mg, yield: 35%, white solid.
- LCMS (ESI): m/z=510.2 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=0.69-0.98 (m, 6H), 1.70-2.23 (m, 5H), 3.10 (s, 3H), 3.46-3.53 (m, 1H), 3.91-3.98 (m, 1H), 4.12-4.24 (m, 1H), 4.39-4.51 (m, 1H), 4.73-4.78 (m, 1H), 7.14-7.29 (m, 1H), 7.49- 7.51 (m, 1H), 7.64-7.67 (m, 1H), 7.76-7.81 (m, 2H), 7.86-7.96 (m, 1H), 8.06-8.15 (m, 1H).
-
- 30.5 mg, yield: 34%, white solid.
- LCMS (ESI): m/z=578.1 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=0.69-0.98 (m, 6H), 1.72-2.10 (m, 5H), 3.10 (s, 3H), 3.47-3.53 (m, 1H), 3.89-3.98 (m, 1H), 4.13-4.26 (m, 1H), 4.40-4.52 (m, 1H), 4.73-4.79 (m, 1H), 7.17-7.29 (m, 1H), 7.54- 7.77 (m, 2H), 8.06-8.15 (m, 1H), 8.34-8.53 (m, 2H).
-
- 66.1 mg, yield: 67%, white solid.
- LCMS (ESI): m/z=603.2 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=0.57-0.95 (m, 6H), 1.62-1.93 (m, 2H), 2.05-2.40 (m, 3H), 2.50 (s, 2H), 2.80 (s, 1H), 3.11 (s, 3H), 3.49-3.55 (m, 1H), 3.89-3.95 (m, 1H), 4.30-4.55 (m, 2H), 5.11-5.25 (m, 1H), 6.96-8.15 (m, 7H).
-
-
-
- To a solution of tert-butyl-1-(4-(methoxycarbonyl)phenyl)-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate (prepared as described in Example 223-b) (600 mg, 1.49 mmol) in N,N-dimethylformamide (10 mL) was added sodium hydride (90 mg, 60% in oil, 2.23 mmol) at 0° C. After stirring for 15 minutes, 1,2-dibromoethane (2800 mg, 14.88 mmol) was added. The resulting mixture was stirred overnight before the reaction was quenched with ice-water (10 mL). The mixture was extracted with ethyl acetate (3×15 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with ethyl acetate:petroleum ether=1:2 to afford tert-butyl-3-(2-bromoethyl)-1-(4-(methoxycarbonyl)phenyl)-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate as a white solid (480 mg, 65%).
- LCMS (ESI): m/z=510.1 [M+H]+.
-
- To a solution of tert-butyl-3-(2-bromoethyl)-1-(4-(methoxycarbonyl)phenyl)-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate (480 mg, 0.94 mmol) in ethanol (20 mL) was added a 40% aqueous dimethylamine solution (10 mL) and the reaction was stirred overnight. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography eluting with dichloromethane:methanol=20:1 to afford tert-butyl-3-(2-(dimethylamino)ethyl)-1-(4-(methoxycarbonyl)phenyl)-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate as a thick oil (310 mg, 67%).
- LCMS (ESI): m/z=475.5 [M+H]+.
- 1H-NMR (400 MHz, CDCl3): δ=1.36 (s, 9H), 1.39-1.45 (m, 2H), 1.65-1.92 (m, 4H), 2.31 (s, 6H), 2.63-2.71 (m, 2H), 3.40-3.58 (m, 2H), 3.88 (s, 3H), 3.90-4.11 (m, 2H), 7.25-7.27 (m, 2H), 8.06-8.09 (m, 2H).
-
- A solution of tert-butyl-3-(2-(dimethylamino)ethyl)-1-(4-(methoxycarbonyl)phenyl)-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate (310 mg, 0.65 mmol) in hydrochloric acid in dioxane (6.0 M, 10 mL) was stirred for 30 minutes. The precipitate was collected by filtration and dried under reduced pressure to afford methyl 4 (3 (2 (dimethylamino)ethyl)-2,4-dioxo-1,3,8-triazaspiro[4.5]decan-1-yl)benzoate hydrochloride as a white solid (300 mg, crude), which was used directly without any further purification.
- LCMS (ESI): m/z=313.4 [M+H]+.
-
- To a mixture of methyl-4-(3-(2-(dimethylamino)ethyl)-2,4-dioxo-1,3,8-triazaspiro[4.5]decan-1-yl)benzoate hydrochloride (300 mg, crude) in dichloromethane (10 mL) was added (R)-2-(2-fluoro-5-(trifluoromethyl)benzamido)-3-methylbutanoic acid (prepared as described in Example 28-f) (201 mg, 0.65 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate (HATU) (372 mg, 0.98 mmol) and N,N diisopropylethylamine (295 mg, 2.28 mmol). The resulting mixture was stirred for 2 hours at room temperature before the reaction was quenched with ice-water (10 mL). The mixture was extracted with ethyl acetate (3×10 mL) and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by prep-TLC with dichloromethane:methanol=10:1 to afford (R)-methyl-4-(3-(2-(dimethylamino)ethyl)-8-(2-(2-fluoro-5-(trifluoromethyl)benzamido)-3-methylbutanoyl)-2,4-dioxo-1,3,8-triazaspiro[4.5]decan-1-yl)benzoate as a white solid (390 mg, 93%).
- LCMS (ESI): m/z=313.4 [M+H]+.
-
- To a solution of (R)-methyl-4-(3-(2-(dimethylamino)ethyl)-8-(2-(2-fluoro-5-(trifluoromethyl)benzamido)-3-methylbutanoyl)-2,4-dioxo-1,3,8-triazaspiro[4.5]decan-1-yl)benzoate (390 mg, 0.59 mmol) in methanol (20 mL) was added a 15% aqueous sodium hydroxide solution (15 mL). The reaction was heated at reflux for 5 minutes before cooling to room temperature. The pH of the resulting solution was adjusted to 5-6 by addition of 10% aqueous hydrochloric acid. The solvent was removed under reduced pressure. To the residue was added Methanol (50 mL), the resulting solid was removed by filtration. The filtrate concentrated under reduced pressure and the residue was purified by prep-HPLC (Gradient: 95% water, 5% acetonitrile, 30-50 min gradient to 25% water, 85% acetonitrile) to afford (R)-4-(3-(2-(dimethylamino)ethyl)-8-(2-(2-fluoro-5-(trifluoromethyl)benzamido)-3-methylbutanoyl)-2,4-dioxo-1,3,8-triazaspiro[4.5]decan-1-yl)benzoic acid trifluoroacetic acid salt as a white solid (16.6 mg, 5%).
- LCMS (ESI): m/z=650.2 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=0.79-1.03 (m, 6H), 1.71-2.34 (m, 5H), 3.04 (s, 6H), 3.47-3.54 (m, 3H), 3.87-4.05 (m, 3H), 4.20-4.37 (m, 1H), 4.41-4.60 (m, 1H), 4.82-4.86 (m, 1H), 7.36-7.48 (m, 3H), 7.85- 8.10 (m, 4H).
-
-
-
- To a solution of tert-butyl-1-(4-(methoxycarbonyl)phenyl)-4-oxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate (prepared as described in Example 149-c) (600 mg, 1.54 mmol) in N,N-dimethylformamide (10 mL) was added sodium hydride (93 mg, 60% in oil, 2.31 mmol) at 0° C. After stirring for 15 minutes, 1,2-dibromoethane (2900 mg, 15.43 mmol) was added. The resulting mixture was stirred overnight before the reaction was quenched with ice-water (10 mL). The mixture was extracted with ethyl acetate (3×15 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with ethyl acetate:petroleum ether=1:1 to afford tert-butyl-3-(2-bromoethyl)-1-(4-(methoxycarbonyl)phenyl)-4-oxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate as a white solid (540 mg, 70%).
- LCMS (ESI): m/z=496.1 [M+H]+.
-
- To a solution of tert-butyl-3-(2-bromoethyl)-1-(4-(methoxycarbonyl)phenyl)-4-oxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate (540 mg, 1.09 mmol) in ethanol (20 mL) was added a 40% aqueous dimethylamine solution (10 mL) and the reaction was stirred overnight. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography eluting with dichloromethane:methanol=20:1 to afford tert-butyl-3-(2-(dimethylamino)ethyl)-1-(4-(methoxycarbonyl)phenyl)-4-oxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate as a thick oil (340 mg, 69%).
- LCMS (ESI): m/z=460.0 [M+H]+.
- 1H-NMR (300 MHz, CDCl3): δ=1.50 (s, 9H), 1.56-1.61 (m, 2H), 2.23 (s, 6H), 2.48-2.52 (m, 2H), 2.64-2.75 (m, 2H), 2.49-3.52 (m, 4H), 3.85 (s, 3H), 3.96-4.20 (m, 2H), 4.69-4.79 (m, 2H), 6.59-6.62 (m, 2H), 7.82-7.85 (m, 2H).
-
- A solution of tert-butyl-3-(2-(dimethylamino)ethyl)-1-(4-(methoxycarbonyl)phenyl)-4-oxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate (340 mg, 0.74 mmol) in hydrochloric acid in dioxane (6.0 M, 10 mL) was stirred for 30 minutes. The precipitate was collected by filtration and dried under reduced pressure to afford methyl 4-(3-(2-(dimethylamino)ethyl)-4-oxo-1,3,8-triazaspiro[4.5]decan-1-yl)benzoate hydrochloride as a white solid (300 mg, crude), which was used directly without any further purification.
- LCMS (ESI): m/z=396.4 [M+H]+.
-
- To a suspension of methyl-4-(3-(2-(dimethylamino)ethyl)-4-oxo-1,3,8-triazaspiro[4.5]decan-1-yl)benzoate hydrochloride (300 mg, crude) in dichloromethane (10 mL) was added (R)-2-(2-fluoro-5-(trifluoromethyl)benzamido)-3-methylbutanoic acid (prepared as described in Example 28-f) (227 mg, 0.74 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate (HATU) (421 mg, 1.11 mmol) and N,N-diisopropylethylamine (333 mg, 2.58 mmol). The resulting mixture was stirred for 2 hours at room temperature before the reaction was quenched with ice-water (10 mL). The mixture was extracted with ethyl acetate (3×10 mL) and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by prep-TLC with dichloromethane:methanol=10:1 to afford (R)-methyl-4-(3-(2-(dimethylamino)ethyl)-8-(2-(2-fluoro-5-(trifluoromethyl)benzamido)-3-methylbutanoyl)-4-oxo-1,3,8-triazaspiro[4.5]decan-1-yl)benzoate as a white solid (280 mg, 60%).
- LCMS (ESI): m/z=650.0 [M+H]+.
-
- To a solution of (R)-methyl-4-(3-(2-(dimethylamino)ethyl)-8-(2-(2-fluoro-5-(trifluoromethyl)benzamido)-3-methylbutanoyl)-4-oxo-1,3,8-triazaspiro[4.5]decan-1-yl)benzoate (280 mg, 0.43 mmol) in tetrahydrofuran (20 mL) was added an aqueous lithium hydroxide solution (2 mL, 1.0 M). The reaction was refluxed for 2 days before cooling to room temperature. The pH of the resulting solution was adjusted to 3-4 by addition of 10% aqueous hydrochloric acid solution. The solvent was removed in reduced pressure. To the residue was added Methanol (50 mL), the resulting solid was removed by filtration. The filtrate was concentrated under reduced pressure and the residue was purified by prep-HPLC (Gradient: 95% water, 5% acetonitrile, 30-50 min gradient to 25% water, 85% acetonitrile) to afford (R)-4-(3-(2-(dimethylamino)ethyl)-8-(2-(2-fluoro-5-(trifluoromethyl)benzamido)-3-methylbutanoyl)-4-oxo-1,3,8-triazaspiro[4.5]decan-1-yl)benzoic acid trifluoroacetic acid salt as a white solid (25.2 mg, 9%).
- LCMS (ESI): m/z=636.2 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=0.91-1.19 (m, 6H), 1.71-2.06 (m, 2H), 2.18-2.35 (m, 1H), 2.79-3.04 (m, 2H), 3.32 (s, 6H), 3.37-3.47 (m, 4H), 3.89-4.12 (m, 3H), 4.31-4.60 (m, 2H), 4.96-5.09 (m, 2H), 6.77- 6.91 (m, 2H), 7.38-7.52 (m, 1H), 7.71-8.04 (m, 4H).
-
-
-
- To a solution of 2-methoxypyridin-4-amine (15 g, 12 mmol) in acetic acid (50 mL) was added tert-butyl-4-oxopiperidine-1-carboxylate (26.6 g, 13 mmol). The resulting mixture was cooled to 0° C. and trimethylsilyl cyanide (17.8 g, 18 mmol) was added. The solution was stirred overnight at room temperature. Saturated aqueous ammonium chloride solution was added (50 mL). The mixture was extracted with ethyl acetate (3×50 mL) and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with dichloromethane: petroleum ether=1:1 to afford tert-butyl-4-cyano-4-(2-methoxypyridin-4-ylamino)piperidine-1-carboxylate as a white solid (15 g, 37%).
- LCMS (ESI): m/z=333.1 [M+H]+.
-
- To a suspension of tert-butyl-4-cyano-4-(2-methoxypyridin-4-ylamino)piperidine-1-carboxylate (2 g, 6.0 mmol) in methanol was added sodium hydroxide (0.48 g, 12 mmol). To the resulting mixture was added dropwise hydrogen peroxide (30%, 20 mL) over 30 minutes. After stirring at room temperature for an additional 1 hour, the reaction was quenched by addition of ice-water (20 mL). The mixture was extracted with ethyl acetate (3×20 mL). The combined organic layer was washed with brine (10 mL) and dried over anhydrous sodium sulfate. The residue was purified by silica gel column chromatography eluting with dichloromethane:methanol=5:1 to afford tert-butyl 4-carbamoyl-4-(2-methoxypyridin-4-ylamino) piperidine-1-carboxylate as a yellow solid (1.9 g, 90%).
- LCMS (ESI): m/z=351.2 [M+H]+.
-
- To a solution of tert-butyl-4-carbamoyl-4-(2-methoxypyridin-4-ylamino)piperidine-1-carboxylate (1.9 g, 5.4 mmol) in dimethyl carbonate (20 mL) was added 1,1′-carbonyldiimdazole (2.6 g, 16 mmol) and sodium hydride (0.4 g, 11 mmol). The resulting mixture was heated at 50° C. for 3 hours before the reaction was quenched by addition of ice-water (10 mL). The resulting mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (10 mL) and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to afford tert-butyl-1-(2-methoxypyridin-4-yl)-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate as a white solid (2 g, crude), which was used directly without any further purification.
- LCMS (ESI): m/z=377.1 [M+H]+.
-
- To a solution of tert-butyl-1-(2-methoxypyridin-4-yl)-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate (2 g, crude) in N,N-dimethylformamide (30 mL) was added sodium hydride (0.426 g, 60% in oil, 10.4 mmol) at 00° C. After stirring for 15 minutes, iodomethane (1130 mg, 7.98 mmol) was added. The resulting mixture was stirred for 15 minutes at room temperature and the reaction was quenched with ice-water (10 mL). The mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with dichloromethane:methanol=50:1 to afford tert-butyl-1-(2-methoxypyridin-4-yl)-3-methyl-2,4-dioxo-1,3,8-triazaspiro [4.5]decane-8-carboxylate as a yellow solid (2 g, 94% over two steps).
- LCMS (ESI): m/z=391.1 [M+H]+.
-
- A solution of tert-butyl-1-(2-methoxypyridin-4-yl)-3-methyl-2,4-dioxo-1,3,8-triazaspiro [4.5]decane-8-carboxylate (2 g, 5 mmol) was heated at 130° C. in a microwave reactor for 30 minutes. The solvent was removed under reduced pressure. The residue was dissolved in tetrahydrofuran (20 mL). To the resulting mixture was added aqueous sodium hydroxide (2.0 M, 5.1 mL, 10 mmol) and di-tert-butyl-dicarbonate (1.3 g, 6 mmol). The resulting mixture was stirred for 1 hour before it was poured into ice-water (10 mL). The resulting mixture was extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with ethyl acetate:petroleum ether=4:1 to afford tert-butyl-1-(2-hydroxypyridin-4-yl)-3-methyl-2,4-dioxo-1,3,8 triazaspiro [4.5]decane 8 carboxylate as a white solid (250 mg, 13%).
- LCMS (ESI): m/z=377.1 [M+H]+.
-
- To a solution of tert-butyl-1-(2-hydroxypyridin-4-yl)-3-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate (200 mg, 0.53 mmol) in dichloromethane (5 mL) was added 1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide (228 mg, 0.64 mmol), triethylamine (107 mg, 1.0 mmol) and N,N-dimethylpyridin-4-amine (65 mg, 0.53 mmol) at room temperature. The resulting mixture was stirred for 3 hours before it was diluted with dichloromethane (20 mL). The mixture was washed with brine (20 mL) and dried over anhydrous sodium sulfate. The residue was purified by silica gel column chromatography eluting with ethyl acetate:petroleum ether=3:2 to afford tert-butyl-3-methyl-2,4-dioxo-1-(2-(trifluoromethylsulfonyloxy)pyridin-4-yl)-1,3,8-triazaspiro[4.5]decane-8-carboxylate (250 mg, 92%) as a white solid.
- LCMS (ESI): m/z=509.1 [M+H]+.
-
- To a solution of tert-butyl-3-methyl-2,4-dioxo-1-(2-(trifluoromethylsulfonyloxy)pyridin-4-yl)-1,3,8-triazaspiro[4.5]decane-8-carboxylate (250 mg, 0.49 mmol) in N,N-dimethylformamide (30 mL) was added triethylsilane (114 mg, 0.98 mmol) and 1,1-bis(diphenylphosphino)ferrocene-palladium(II) dichloromethane complex (201 mg, 0.24 mmol). The resulting mixture was stirred under a nitrogen atmosphere for 3 hours. The reaction was quenched by addition of ice-water (20 mL) and the extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with ethyl acetate to afford tert-butyl-3-methyl-2,4-dioxo-1-(pyridin-4-yl)-1,3,8-triazaspiro[4.5]decane-8-carboxylate (155 mg, 87%) as a white solid.
- LCMS (ESI): m/z=361.2 [M+H]+.
-
- A solution of tert-butyl-3-methyl-2,4-dioxo-1-(pyridin-4-yl)-1,3,8-triazaspiro[4.5]decane-8-carboxylate (155 mg, 0.43 mmol) in hydrochloric acid in dioxane (6.0 M, 20 mL) was stirred for 30 minutes. The precipitate was collected by filtration and dried under reduced pressure to afford 3-methyl-1-(pyridin-4-yl)-1,3,8-triazaspiro[4.5]decane-2,4-dione hydrochloride as a white solid (142 mg, 100%).
- LCMS (ESI): m/z=261.1 [M+H]+.
-
- To a mixture of 3-methyl-1-(pyridin-4-yl)-1,3,8-triazaspiro[4.5]decane-2,4-dione hydrochloride (150 mg, 0.45 mmol) in dichloromethane (5 mL) was added sequentially (R)-2-(2-fluoro-5-(trifluoromethyl)benzamido)-3-methylbutanoic acid (prepared as described in Example 28-f) (240 mg, 0.32 mmol), (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate (HATU) (443 mg, 1.17 mmol) and N,N-diisopropylethylamine (252 mg, 1.95 mmol). The resulting mixture was stirred for 2 hours at room temperature before the reaction was quenched by addition of with ice-water (5 mL). The mixture was extracted with ethyl acetate (3×10 mL) and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by prep-HPLC (acetonitrile and water, acetonitrile from 5% to 80%) to afford (R)-2-fluoro-N-(3-methyl-1-(3-methyl-2,4-dioxo-1-(pyridin-4-yl)-1,3,8-triazaspiro[4.5]decan-8-yl)-1-oxobutan-2-yl)-5-(trifluoromethyl)benzamide as white solid (110 mg, 26%).
- LCMS (ESI): m/z=550.1 [M+H]+.
- 1H-NMR (400 MHz, CDCl3): δ=1.09 (m, 6H), 1.97 (m, 2H), 2.35 (m, 2H), 2.98 (m, 1H), 3.23 (s, 3H), 3.53 (t, J=12.0 Hz, 1H), 4.08 (t, J=12.9 Hz, 1H), 4.29 (m, 1H), 4.83 (m, 2H), 7.34 (m, 2H), 7.86 (m, 1H), 8.27 (m, 2H), 8.68 (m, 2H), 10.84 (s, 1H).
-
- To a solution of (R)-2-fluoro-N-(3-methyl-1-(3-methyl-2,4-dioxo-1-(pyridin-4-yl)-1,3,8-triazaspiro [4.5]decan-8-yl)-1-oxobutan-2-yl)-5-(trifluoromethyl)benzamide (prepared as described in Example 239) (83 mg, 0.15 mmol) in chloroform (5 mL) was added m-chloroperbenzoic acid (53 mg, 0.3 mmol). The resulting mixture was stirred overnight. The solvent was removed under reduced pressure and the residue was purified by prep-HPLC (acetonitrile and water, acetonitrile from 5% to 80%) to afford (R)-4-(8-(2-(2-fluoro-5-(trifluoromethyl)benzamido)-3-methylbutanoyl)-3-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decan-1-yl)pyridine 1-oxide as a white solid (70 mg, 82%).
- LCMS (ESI): m/z=566.1 [M+H]+.
- 1H-NMR (400 MHz, CDCl3): δ=1.07-1.10 (m, 6H), 1.89-2.26 (m, 4H), 2.67 (s, 1H), 3.19 (s, 3H), 3.51 (t, J=12.5 Hz, 1H), 4.06-4.20 (m, 2H), 4.75-4.88 (m, 2H), 7.29-7.52 (m, 3H), 7.82 (s, 2H), 8.29-8.40 (m, 3H).
-
-
-
- To a solution of tert-butyl-1-(4-methoxyphenyl)-3-methyl-2,4-dioxo-1,3,8-triazaspiro [4.5]decane-8-carboxylate (prepared as described in Example 168-d) (1.2 g, 3.08 mmol) in acetic acid (15 mL) was added platinum dioxide (50 mg, cat.). The mixture was stirred under a hydrogen atmosphere for 4 hours. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by a gel silica column chromatography eluting with petroleum ether: ethyl acetate 5:1 to afford tert-butyl-1-(4-methoxycyclohexyl)-3-methyl-2,4-dioxo-1,3:8-triazaspiro[4.5]decane-8-carboxylate as white solid (250 mg, 20%) and tert-butyl 1-cyclohexyl-3-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate (150 mg, 12%) as a white solid.
- LCMS (ESI): m/z=396.1 (Example 241-a) and 366.1 (Example 241-a′) [M+H]+.
-
- A solution of tert-butyl 1-(4-methoxycyclohexyl)-3-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate (250 mg, 0.63 mmol) In hydrochloric acid in dioxane (6.0 M, 20 mL) was stirred for 30 minutes. The precipitate was collected by filtration and dried under reduced pressure to afford 1-(4-methoxycyclohexyl)-3-methy-1,3,8-triazaspiro[4.5]decane-2,4-dione hydrochloride) as a white solid (170 mg, 85%).
- LCMS (ESI): m/z=296.1 [M+H]+.
-
- To a mixture of 1-(4-methoxycyclohexyl)-3-methyl-1,3,8-triazaspiro [4.5]decane-2,4-dione hydrochloride) (70 mg, 0.17 mmol) in dichloromethane (5 mL) was added sequentially (R)-2-(2-fluoro-5-(trifluoromethyl)benzamido)-3-methyl-butanoic acid (prepared as described in Example 28-f) (57 mg, 0.19 mmol), (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate (HATU) (96 mg, 0.25 mmol) and N,N-diisopropylethylamine (150 mg, 1.164 mmol). The resulting mixture was stirred for 2 hours at room temperature before the reaction was quenched by addition of with ice-water (5 mL). The mixture was extracted with ethyl acetate (3×10 mL) and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by prep-TLC with dichloromethane:methanol=15:1 to afford (R)-2-fluoro-N-(1-(1-(4-methoxycyclohexyl)-3-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decan-8-yl)-3-methyl-1-oxobutan-2-yl)-5-(trifluoromethyl)benzamide (14.6 mg, 15%) as a white solid.
- LCMS (ESI): m/z=585.2 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=1.050-1.111 (m, 6H), 1.307-1.439 (m, 5H), 1.713-2.292 (m, 6H), 2.292-2.680 (m, 3H), 2.952 (s, 3H), 3.069-3.204 (m, 1H), 3.321-3.33 (m, 3H), 3.368-3.502 (m, 2H), 3.840-4.016 (m, 1H), 4.211-4.02 (m, 1H), 4.518-4.658 (m, 1H), 7.422-7.535 (m, 1H), 7.861-7.943 (m, 1H), 8.006-8.132 (m, 1H).
-
-
-
- A solution of tert-butyl-1-cyclohexyl-3-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate (prepared as described in Example 241) (150 mg, 0.41 mmol) in hydrochloric acid in dioxane (6.0 M, 20 mL) was stirred for 30 minutes. The precipitate was collected by filtration and dried under reduced pressure to afford 1-cyclohexyl-3-methyl-1,3,8-triazaspiro[4.5]decane-2,4-dione hydrochloride (90 mg, 73%) as a white solid.
- LCMS (ESI): m/z=266.1 [M+H]+.
-
- To a mixture of 1-cyclohexyl-3-methyl-1,3,8-triazaspiro[4.5]decane-2,4-dione hydrochloride (90 mg, 0.29 mmol) in dichloromethane (5 mL) was added sequentially (R)-2-(2-fluoro-5-(trifluoromethyl)benzamido)-3-methylbutanoic acid (prepared as described in Example 28-f) (98 mg, 0.32 mmol), (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate (HATU) (165 mg, 0.43 mmol) and N,N-diisopropylethylamine (110 mg, 0.89 mmol). The resulting mixture was stirred for 2 hours at room temperature before the reaction was quenched by addition of with ice-water (5 mL). The mixture was extracted with ethyl acetate (3×10 mL) and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by prep-TLC with dichloromethane:methanol=15:1 to afford (R)—N-(1-(1-cyclohexyl-3-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decan-8-yl)-3-methyl-1-oxobutan-2-yl)-2-fluoro-5-(trifluoromethyl)benzamide as a white solid (34.3 mg, 21%).
- LCMS (ESI): m/z=555.2 [M+H]+.
- 1H-NMR (400 MHz, CDCl3): δ=1.035-1.121 (m, 6H), 1.225-1.279 (m, 3H), 1.514-1.893 (m, 8H), 2.159-2.287 (m, 4H), 2.675-2.902 (m, 1H), 3.013 (s, 3H), 3.384-3.534 (m, 1H), 4.003-4.051 (m, 2H), 4.658-4.688 (m, 1H), 4.929-5.192 (m, 1H), 7.285-7.350 (m, 1H), 7.482-7.509 (m, 1H), 7.785-7.803 (m, 1H), 8.389-8.406 (m, 1H).
-
-
-
- To a solution of tert-butyl-1-(4-methoxyphenyl)-3-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate (prepared as described in Example 81-c) (0.6 g, 1.54 mmol) in anhydrous dichloromethane (30 mL) was added boron tribromide (3 mL, 1.0 M in dichloromethane) dropwise at 0° C. Then the solution was stirred at room temperature for 12 hours before the reaction was quenched with water. The aqueous layer was extracted with dichloromethane (30 mL), the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford tert-butyl-1-(4-hydroxyphenyl)-3-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate as a yellow solid (390 mg, 65%).
- LCMS (ESI): m/z=376.2 [M+H]+.
-
- To a solution of tert-butyl-1-(4-hydroxyphenyl)-3-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate (0.375 g, 1 mmol) in acetone (30 mL) was added potassium carbonate (0.278 g, 2 mmol) and iodomethane-d3 (0.29 g, 2 mmol), then the resulting mixture was stirred at 60° C. for 6 hours. Then the mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography eluting with ethyl acetate:petroleum=1:2 to afford tert-butyl-1-(4-methoxy-d3-phenyl)-3-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate as a white solid (210 mg, 54%).
- LCMS (ESI): m/z=393.2 [M+H]+.
-
- Hydrogen chloride gas was bubbled into a stirring solution of tert-butyl-1-(4-methoxy-d3-phenyl)-3-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate (0.21 g, 0.54 mmol) in ethyl acetate (10 mL) for 0.5 hours. Then the mixture was concentrated under reduced pressure to afford 3-methyl-1-(4-methoxy-d3-phenyl)-1,3,8-triazaspiro[4.5]decane-2,4-dione hydrochloride as a white solid (0.17 g, 100%).
- LCMS (ESI): m/z=293.2 [M+H]+.
-
- To a solution of 3-methyl-1-(4-methoxy-d3-phenyl)-1,3,8-triazaspiro[4.5]decane-2,4-dione hydrochloride (0.17 g, 0.53 mmol), (R)-2-(2-fluoro-5-(trifluoromethyl)benzamido)-3-methylbutanoic acid (0.196 g, 0.64 mmol) (prepared as described in Example 28-f) and triethylamine (0.16 g, 1.6 mmol) in dichloromethane (20 mL) was added 1-ethyl-3-(3-dimethyllaminopropyl)carbodiimide hydrochloride (EDCl) (0.153 g, 0.8 mmol) and 1-hydroxbenzotriazole (HOBT) (0.108 g, 0.8 mmol), then the resulting mixture was stirred at room temperature for 4 hours before the reaction was quenched with water (20 mL). The aqueous layer was extracted with ethyl acetate (3×20 mL), the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with dichloromethane:methanol=70:1 to afford (R)—N-(3-methyl-1-(3-methyl-2,4-dioxo-1-(4-methoxy-d3-phenyl)-1,3,8-triazaspiro[4.5]decan-8-yl)-1-oxobutan-2-yl)-3-(trifluoromethyl)-5-fluorobenzamide as a white solid (0.1 g, 33%).
- LCMS (ESI): m/z=582.2 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=8.05-7.85 (m, 2H), 7.44 (dd, J=20.0, 11.1 Hz, 1H), 7.22 (d, J=8.8 Hz, 1H), 7.13 (d, J=8.8 Hz, 1H), 7.04 (d, J=8.8 Hz, 1H), 6.91 (d, J=88 Hz, 1H), 4.85 (s, 1H), 4.45 (dd, J=35.0, 13.1 Hz, 1H), 4.23 (dd, J=30.7, 14.0 Hz, 1H), 3.95 (t, J=13.1 Hz, 1H), 3.49 (dd, J=14.4, 11.6 Hz, 1H), 3.08 (s, 3H), 2.22-1.99 (m, 3H), 1.96-1.81 (m, 1H), 1.71 (td, J=13.1, 4.8 Hz, 1H), 1.05-0.73 (m, 6H).
- The following compound was synthesized following the procedure described above:
-
- 17 mg, 23% yield, white solid.
- LCMS (ESI): m/z=593.2 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=8.02-7.90 (m, 2H), 7.47-7.37 (m, 1H), 7.20 (d, J=8.8 Hz, 1H), 7.11 (d, J=8.8 Hz, 1H), 7.03 (d, J=8.8 Hz, 1H), 6.89 (d, J=8.8 Hz, 1H), 4.49 (d, J=13.4 Hz, 1H), 4.27 (d, J=13.9 Hz, 1H), 4.12 (d, J=7.1 Hz, 2H), 4.10-3.90 (m, 3H), 3.49 (t, J=12.8 Hz, 1H), 3.08 (s, 3H), 2.25-2.05 (m, 2H), 1.94 (m, 1H), 1.71 (m, 1H), 1.44-1.30 (m, 4H), 1.27 (dd, J=16.9, 9.8 Hz, 3H), 1.07-0.76 (m, 7H).
-
-
-
- A solution of 2-amino-4-nitrophenol (600 mg, 3.9 mmol) in trimethyl orthoformate (30 mL) was stirred at reflux for 12 hours. The reaction mixture was slowly poured into ice-cold water (100 mL) and extracted with ethyl acetate (100 mL). The organic layer was concentrated under reduced pressure and the residue was purified by silica gel column chromatography eluting with dichloromethane:methanol=30:1 to afford 5-nitrobenzo[d]oxazole as a white solid (530 mg, 83%).
- LCMS (ESI): m/z=164.0 [M+H]+.
-
- To a solution of 5-nitrobenzo[d]oxazole (530 mg, 3.23 mmol) in methanol (30 mL) was added palladium on carbon (100 mg, dry, 5%). The mixture was stirred under a hydrogen gas atmosphere at room temperature for 12 hours. The catalyst was removed by filtration and the filtrate was concentrated to dryness under reduced pressure to afford benzo[d]oxazol-5-amine as a yellow solid (430 mg, 100%).
- LCMS (ESI): m/z=134.1 [M+H]+.
-
- A mixture of benzo[d]oxazol-5-amine (430 mg, 3.2 mmol) and tert-butyl-4-oxopiperidine-1-carboxylate (637 mg, 3.2 mmol) in acetic acid (10 mL) was stirred at 0° C. for 15 minutes, then trimethylsilyl cyanide (317 mg, 3.2 mmol) was added. The reaction mixture was stirred for 4 hours at room temperature. Then the mixture was slowly poured into concentrated aqueous ammonium hydroxide solution (30 mL) and extracted with ethyl acetate (50 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure and the residue was purified by silica gel column chromatography eluting with dichloromethane:methanol=40:1 to afford tert-butyl-4-(benzo[d]oxazol-5-ylamino)-4-cyanopiperidine-1-carboxylate as a white solid (500 mg, 46%).
- LCMS (ESI): m/z=342.2 [M+H]+.
-
- To a solution of tert-butyl-4-(benzo[d]oxazol-5-ylamino)-4-cyanopiperidine-1-carboxylate (500 mg, 1.5 mmol) in dichloromethane (30 mL) was added chlorosulfonyl isocyanate (0.31 mL, 1.65 mmol) dropwise over 15 minutes at 0° C. The mixture was stirred for 1 hour at room temperature and then concentrated under reduced pressure. The residue was dissolved in 1.0 M aqueous hydrochloric acid solution (20 mL) and stirred at reflux for 1 hour. Then the pH of the solution was adjusted to pH 9 by addition of solid potassium carbonate. To the solution was added di-tert-butyl dicarbonate (360 mg, 1.65 mmol) and the reaction mixture was stirred for 12 hours. The mixture was extracted with dichloromethane/methanol=10:1 (60 mL), the organic layer was dried over anhydrous sodium sulfate and concentrated to dryness to afford tert-butyl-1-(3-amino-4-hydroxyphenyl)-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate as a brownish solid (crude, 500 mg, 88%).
- LCMS (ESI): m/z=376.2 [M+H]+.
-
- To a solution of tert-butyl-1-(3-amino-4-hydroxyphenyl)-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate (500 mg, 1.3 mmol) and ammonium chloride (53 mg, 0.15 mmol) in ethanol (30 mL) was added trimethyl orthoformate (5 mL) Then the mixture was stirred for 12 hours at 60° C. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography eluting with dichloromethane:methanol=20:1 to afford tert-butyl-1-(benzo[d]oxazol-5-yl)-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate as a white solid (470 mg, 94%).
- LCMS (ESI): m/z=386.2 [M+H]+.
-
- To a mixture of tert-butyl-1-(benzo[d]oxazol-5-yl)-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate (470 mg, 1.2 mmol) and potassium carbonate (337 mg, 2.4 mmol) in N,N-dimethylformamide (10 mL) was added iodomethane (190 mg, 1.34 mmol) and then the mixture was stirred for 1 hour at room temperature. The mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography eluting with dichloromethane:methanol=20:1 to afford tert-butyl-1-(benzo[d]oxazol-5-yl)-3-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate as a white solid (347 mg, 72%).
- LCMS (ESI): m/z=400.2 [M+H]+.
-
- tert-Butyl-1-(benzo[d]oxazol-5-yl)-3-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate (347 mg, 0.87 mmol) was dissolved in a solution of hydrochloric acid in ethyl acetate (2.0 M, 10 mL). The mixture was stirred for 4 hours at room temperature before it was concentrated under reduced pressure to afford crude 1-(benzo[d]oxazol-5-yl)-3-methyl-1,3,8-triazaspiro[4.5]decane-2,4-dione hydrochloride as a white solid (247 mg, 95%), which was used directly in the next step without further purification.
- LCMS (ESI): m/z=300.1 [M+H]+.
-
- To a mixture of 1-(benzo[d]oxazol-5-yl)-3-methyl-1,3,8-triazaspiro[4.5]decane-2,4-dione hydrochloride (247 mg, 0.82 mmol), (R)-2-(2-fluoro-5-(trifluoromethyl)benzamido)-3-methylbutanoic acid (252 mg, 0.82 mmol) (prepared as described in Example 28-f), 1-ethyl-3-(3-dimethyllaminopropyl)carbodiimide hydrochloride (250 mg, 1.3 mmol), and N-hydroxybenzotriazole (176 mg, 1.3 mmol) in dichloromethane (20 mL) was added triethylamine (0.5 mL) at room temperature. The mixture was stirred at room temperature for 5 hours, before it was washed with water (30 mL). The organic layer was concentrated to dryness under reduced pressure and the residue was purified by silica gel column chromatography eluting with dichloromethane:methanol:ammonium hydroxide=20:1:0.1 to afford (R)—N-(1-(1-(benzo[d]oxazol-5-yl)-3-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decan-8-yl)-3-methyl-1-oxobutan-2-yl)-2-fluoro-5-(trifluoromethyl)benzamide as a yellow solid (16.6 mg, 3.4%).
- LCMS (ESI): m/z=589.2 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=8.55 (s, 1H), 8.06-7.74 (m, 3H), 7.73-7.66 (m, 1H), 7.43 (dd, J=18.7, 9.0 Hz, 1H), 7.37-7.28 (m, 1H), 4.86-4.78 (m, 1H), 4.58-4.37 (m, 1H), 4.34-4.15 (m, 1H), 3.97 (t, J=12.0 Hz, 1H), 3.51 (t, J=12.0 Hz, 1H), 3.12 (s, 3H), 2.32-1.87 (m, 4H), 1.83-1.67 (m, 1H), 0.99 (t, J=6.2 Hz, 4H), 0.87 (d, J=6.7 Hz, 1H), 0.73 (d, J=6.7 Hz, 1H).
- The following compound was synthesized following the procedure described above:
-
- 40 mg, 36% yield, white solid.
- LCMS (ESI): m/z=603.2 [M+H]+.
- 1H-NMR (400 MHz, CD3OD): δ=7.92-7.82 (m, 1H), 7.74 (dd, J=24.9, 7.4 Hz, 1H), 7.63-7.41 (m, 2H), 7.33 (t, J=9.5 Hz, 1H), 7.22 (dd, J=8.6, 1.9 Hz, 1H), 4.83 (d, J=7.8 Hz, 1H), 4.47 (dd, J=43.4, 13.8 Hz, 1H), 4.24 (dd, J=29.4, 12.7 Hz, 1H), 3.96 (t, J=13.3 Hz, 1H), 3.51 (t, J=13.8 Hz, 1H), 3.11 (s, 3H), 2.66 (d, J=26.8 Hz, 3H), 2.27-2.08 (m, 2H), 2.06-1.96 (m, 1H), 1.80-1.60 (m, 1H), 1.00-0.71 (m, 6H).
- Unless otherwise noted, all solvents, chemicals, and reagents were obtained commercially and used without purification. The 1H-NMR spectra were obtained in CDCl3, DMSO-d6, CD3OD, or acetone-d6 at 25° C. at 300 MHz or 400 MHz on an OXFORD (Varian) with chemical shift (δ, ppm) reported relative to TMS as an internal standard. HPLC-MS chromatograms and spectra were obtained with an Agilent 1200-6110 system. Prep-HPLC instruments were Gilson GX-281 (Gilson) and P230 Preparative Gradient System (Gradient: 95% water, 5% acetonitrile, 30-50 min gradient to 25% water, 75% acetonitrile). The microwave instrument was a CEM Discover SP.
- The efficacy of the Examples described herein, as inhibitors of ATX are demonstrated and confirmed by pharmacological in vitro assays. The following assays and their respective methods are carried out with the compounds according to the present invention. Activity possessed by the compounds may be demonstrated in vivo. Those skilled in the art will appreciate that a variety of assay formats may be used to determine the activity of the compounds of this invention.
- 100 mM Tris-HCl, pH=9
-
-
Working Enzyme Source Stock conc conc. Final conc. Autotaxin X-Chem 4.6 μM 20 nM 5 nM LPC Sigma L5254 8 mM in assay buffer 400 μM 100 μM Choline Oxidase Sigma C5896 50 U/mL in water 0.8 U/mL 0.1 U/mL HRP Sigma P8375 1000 U/mL in water 8 U/mL 1 U/mL Ampliflu Red Sigma 90101 100 mM in DMSO 400 μM 50 μM - Highest final concentration is 10 M for HA130 (Echelon, B-0701) and 30 M for test compounds. Prepare a 1 mM stock of HA130 and a 3 mM stock of each compound in 100% DMSO. Perform a 1:3 serial dilution in DMSO (transfer 5 l of compound to 10 l of DMSO). Add 240 l of buffer to generate a top working concentration of 40 M (HA130) and 120 M (test compound) in 4% DMSO.
-
- Ampliflu Red—Prepare a stock of 5 mM from 100 mM in 100% DMSO. Further dilute to a working concentration of 400 μM in buffer (8% DMSO)
- Together with compound this yields a 2% DMSO final concentration.
- Choline Oxidase/HRP—0.8 U/mL CO and 8 U/mL HRP.
- Add 5 l of ATX and 5 l of compound in a 384 well plate (Corning 3676). Incubate for 10 mins at RT. Add 5 l of LPC and incubate for 1 hr on the plate shaker. Prepare the CO/HRP and AR immediately prior to use. Add 2.5 l of CO/HRP and follow with 2.5 l AR Note order of addition, CO/HRP mix before AR. Read fluorescence intensity (ex/em: 530/590 nm) kinetically for 30 min at RT on the Tecan M1000.
-
TABLE 1 IC50 ATX Activity Values For Examples 1-246 IC50 (nM) Examples ≥1000 2, 11, 15, 16, 17, 19, 22, 34, 35, 36, 38, 53, 61, 65, 67, 68, 69, 70, 71, 72, 73. 74, 75, 78, 80, 81, 85, 86, 87, 93, 106, 111, 113, 114, 115, 117, 121, 122, 123, 126, 130, 132, 137, 143, 146, 148, 158, 159, 164, 180, 195, 217, 219, 228, 229, 230, 231, 232, 233, 234, 235, 236, 240, 241. ≥500 3, 9, 23, 29, 30, 33, 46, 47, 63, 66, 76, 77, 79, 82, 92, ≤1000 95, 102, 103, 120, 127, 128, 129, 145, 161, 176, 188, 189. ≥0 1, 4, 5,6, 7, 8, 10, 12, 13, 14, 18, 20, 21, 24, 25, 26, 27, ≤500 28, 31, 32, 37, 39, 40, 41, 42, 43, 44, 45, 48, 49, 50, 51, 52, 54, 55, 56, 57, 58, 59, 60, 62, 64, 83, 84, 88, 89, 90, 91, 94, 96, 97, 98, 99, 100, 101, 104, 105, 107, 108, 109, 110, 112, 116, 118, 119, 124, 125, 131, 133, 134, 135, 136, 138, 139, 140, 141, 142, 144, 147, 149, 150, 151, 152, 153, 154, 155, 156, 157, 160, 162, 163, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 177, 178, 179, 181, 182, 183, 184, 185, 186, 187, 190, 191, 192, 193, 194, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 218, 220, 221, 222, 223, 224, 225, 226, 227, 237, 238, 239, 242, 243, 244, 245, 246. - An inhibitor of autotaxin is expected to show beneficial effects in human diseases by inhibiting autotaxin in human plasma and tissues as well as in animal models used to recapitulate such human diseases where the disease is caused, mediated and/or propagated by increased LPA levels and/or the activation of ATX. Such diseases which have been reported in the literature include but are not limited to: chronic inflammation, chronic obstructive pulmonary disease (COPD), arthritis, fibrosis, thrombosis, cholestatic pruritus, septic shock, inflammatory bowel disease, asthma, LPS induced lung inflammation, neuropathic pain, atherosclerosis and cardiovascular disease, multiple sclerosis, bone development and cancer. Literature references which describe human diseases where the disease is caused, mediated and/or propagated by increased LPA levels and/or the activation of ATX, autotaxin and LPA and inhibition thereof in in vitro models and animal models used to mimic human diseases caused, mediated and/or propagated by increased LPA levels and/or the activation of ATX include: J Lipid Res. 2014 Mar. 18; 55(7):1192-1214, Cancer Res 2009; 69 (13), 5441; The Journal of Pharmacology and Experimental Therapeutics, 2010, 334 (1), 310; PLOS ONE, 2014, 9 (4), e93230; Biochem. Soc. Trans. 2014, 42, 125; FASEB J. 2014, 28(6), 2655; Arthritis Rheum, 2011, 63(5), 1405; Cell Cycle, 2009, 8 (22), 3695; Mol Carcinog, 2009, 48(9), 801; Clin Cancer Res. 2013 19(23), 6461; Annu Rev Pharmacol Toxicol. 2010, 50, 157; Mol Cancer Ther 208, 7(10), 3352; Front Oncol. 2013, 3, 236; Biomol Ther (Seoul). 2015, 23(1), 1; Osteoarthritis Cartilage 2015, 23(2), 308; Biochim Biophys Acta. 2015, 1851(1), 61; J Lipid Res. 2014, 55(7), 1192; FEBS Lett. 2014, 588(16), 2712; Future Med Chem. 2013, (16), 1935; Biochim Biophys Acta. 2014, 1841(1), 88; Biochim Biophys Acta. 2013, 1831(1), 42; Am J Respir Cell Mol Biol. 2012, 47(5), 563; Am J Respir Cell Mol Biol. 2012, 47(5), 566; Acta Diabetol. 2013, 50(3), 363; Clin Chim Acta. 2012, 413(23-24), 1817; Clin Chim Acta. 2011, 412(13-14), 1201; Life Sci. 2007, 81(12), 1009; Mol Pain 2011, 7, 33; Mol Pain 2010, 6, 78; Biochimie. 2010, 92(6), 698; J Pharmacol Exp Ther. 2010, 333(2), 540; Mol Pain. 2009, 5, 64; Neuroscience 2008, 152(2), 296; Mol Pain 2008, 4, 6; J Neuroimmunol. 2014, 273(1-2), 120; PLoS One. 2013, 8(7), e70941; Nat Rev Rheumatol. 2012, 8(6), 307; J Exp Med. 2012, 209(5), 925; Curr Opin Investig Drugs 2010, 11(5), 515; Atherosclerosis. 2013, 229(1), 192; J Biol Chem. 2009, 284(11), 7385; Curr Drug Targets 2008, 9(8), 698; Gastroenterology 2010, 139(3), 1008; Lab Invest. 2013, 93(5), 508; J Immunol. 2014, 192(3), 851; Am J Respir Crit Care Med. 2013, 188(8), 889; Am J Respir Crit Care Med. 2013, 188(8), 928; Cell Metab. 2011, 13(5), 592; Exp Cell Res. 2014 Nov. 25. pii: S0014-4827(14)00506-0; Biochem J. 2014, 463(1), 157; Biochim Biophys Acta. 2013, 1831(1), 74; Hepatology 2012, 56(4), 1391; Biochem Soc Trans. 2012, 40(1), 31; Enzyme Res. 2011, 2011:194857.
- The present invention includes pharmaceutical compositions comprising a compound or pharmaceutically acceptable salt thereof of the invention, which is formulated for a desired mode of administration with or without one or more pharmaceutically acceptable and useful carriers.
- The compounds can also be included in pharmaceutical compositions in combination with one or more other therapeutically active compounds.
- The pharmaceutical compositions of the invention comprise a compound of the invention (or a pharmaceutically acceptable salt thereof) as an active ingredient, optional pharmaceutically acceptable carrier(s) and optionally other therapeutic ingredients or adjuvants. The compositions include compositions suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered. The pharmaceutical compositions can be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.
- Compounds of the invention can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier can take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous). Thus, the pharmaceutical compositions of the invention can be presented as discrete units suitable for oral administration such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient. Further, the compositions can be presented as a powder, as granules, as a solution, as a suspension in an aqueous liquid, as a non-aqueous liquid, as an oil-in-water emulsion, or as a water-in-oil liquid emulsion. In addition to the common dosage forms set out above, the compound represented by Formula I, or a pharmaceutically acceptable salt thereof, can also be administered by controlled release means and/or delivery devices. The compositions can be prepared by any of the methods of pharmacy. In general, such methods include a step of bringing into association the active ingredient with the carrier that constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both. The product can then be conveniently shaped into the desired presentation.
- The pharmaceutical carrier employed can be, for example, a solid, liquid, or gas. Examples of solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid. Examples of liquid carriers are sugar syrup, peanut oil, olive oil, and water. Examples of gaseous carriers include carbon dioxide and nitrogen.
- A tablet containing the composition of this invention can be prepared by compression or molding, optionally with one or more accessory ingredients or adjuvants. Compressed tablets can be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent.
- Molded tablets can be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent. Each tablet preferably contains from about 0.05 mg to about 5 g of the active ingredient and each cachet or capsule preferably containing from about 0.05 mg to about 5 g of the active ingredient.
- A formulation intended for the oral administration to humans may contain from about 0.5 mg to about 5 g of active agent, compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95 percent of the total composition. Unit dosage forms will generally contain between from about 1 mg to about 2 g of the active ingredient, typically 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, or 1000 mg.
- Compounds of the invention can be provided for formulation at high purity, for example at least about 90%, 95%, or 98% pure by weight.
- Pharmaceutical compositions of the invention suitable for parenteral administration may be prepared as solutions or suspensions of the active compounds in water. A suitable surfactant can be included such as, for example, hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Further, a preservative can be included to prevent the detrimental growth of microorganisms.
- Pharmaceutical compositions of the invention suitable for injectable use include sterile aqueous solutions or dispersions. Furthermore, the compositions can be in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions. In all cases, the final injectable form must be sterile and must be effectively fluid for easy syringability. The pharmaceutical compositions must be stable under the conditions of manufacture and storage; thus, preferably should be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof.
- Pharmaceutical compositions of the invention can be in a form suitable for topical use such as, for example, an aerosol, cream, ointment, lotion, dusting powder, or the like. Further, the compositions can be in a form suitable for use in transdermal devices. These formulations may be prepared, utilizing a compound represented by Formula I of this invention, or a pharmaceutically acceptable salt thereof, via conventional processing methods. As an example, a cream or ointment is prepared by admixing hydrophilic material and water, together with about 5 wt % to about 10 wt % of the compound, to produce a cream or ointment having a desired consistency.
- Pharmaceutical compositions of this invention can be in a form suitable for rectal administration wherein the carrier is a solid. It is preferable that the mixture forms unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art. The suppositories may be conveniently formed by first admixing the composition with the softened or melted carrier(s) followed by chilling and shaping in molds.
- In addition to the aforementioned carrier ingredients, the pharmaceutical formulations described above may include, as appropriate, one or more additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including anti-oxidants) and the like. Furthermore, other adjuvants can be included to render the formulation isotonic with the blood of the intended recipient.
- Compositions containing a compound described by Formula I, or pharmaceutically acceptable salts thereof, may also be prepared in powder or liquid concentrate form.
- Compounds of the present invention inhibit the activity of ATX in animals, including humans, and are useful in the treatment and/or prevention of various diseases and conditions such as cancer, lymphocyte homing and inflammation, neuropathic pain, fibrotic diseases, thrombosis, and cholestatic pruritus which are caused, mediated and/or propagated by increased LPA levels and/or the activation of ATX. In particular, compounds of the invention, and compositions thereof, are inhibitors of ATX, and are useful in treating conditions modulated, at least in part, by ATX.
- In some embodiments, the invention includes a method of treating cancer comprising administering to a mammal in need thereof a therapeutically effective amount of a compound or salt of the invention.
- In some embodiments, the invention includes a method of treating a cancer mediated at least in part by ATX comprising administering to a mammal in need thereof a therapeutically effective amount of a compound or salt of Formula I.
- In some embodiments, the invention includes a method of treating or a method of manufacturing a medicament for treating a cancer, such as those described herein, which is mediated at least in part by ATX, comprising administering to a mammal in need thereof a therapeutically effective amount of a compound or salt of the invention.
- In some embodiments, the invention includes a method of treating lymphocyte homing and inflammation comprising administering to a mammal in need thereof a therapeutically effective amount of a compound or salt of the invention.
- In some embodiments, the invention includes a method of treating lymphocyte homing and inflammation mediated at least in part by ATX comprising administering to a mammal in need thereof a therapeutically effective amount of a compound or salt of Formula I.
- In some embodiments, the invention includes a method of treating or a method of manufacturing a medicament for treating lymphocyte homing and inflammation, such as those described herein, which is mediated at least in part by ATX, comprising administering to a mammal in need thereof a therapeutically effective amount of a compound or salt of the invention.
- In some embodiments, the invention includes a method of treating neuropathic pain comprising administering to a mammal in need thereof a therapeutically effective amount of a compound or salt of the invention.
- In some embodiments, the invention includes a method of treating neuropathic pain mediated at least in part by ATX comprising administering to a mammal in need thereof a therapeutically effective amount of a compound or salt of Formula I.
- In some embodiments, the invention includes a method of treating or a method of manufacturing a medicament for treating neuropathic pain, such as those described herein, which is mediated at least in part by ATX, comprising administering to a mammal in need thereof a therapeutically effective amount of a compound or salt of the invention.
- In some embodiments, the invention includes a method of treating fibrotic diseases comprising administering to a mammal in need thereof a therapeutically effective amount of a compound or salt of the invention.
- In some embodiments, the invention includes a method of treating fibrotic diseases mediated at least in part by ATX comprising administering to a mammal in need thereof a therapeutically effective amount of a compound or salt of Formula I.
- In some embodiments, the invention includes a method of treating or a method of manufacturing a medicament for treating a fibrotic disease, such as those described herein, which is mediated at least in part by ATX, comprising administering to a mammal in need thereof a therapeutically effective amount of a compound or salt of the invention.
- In some embodiments, the invention includes a method of treating thrombosis comprising administering to a mammal in need thereof a therapeutically effective amount of a compound or salt of the invention.
- In some embodiments, the invention includes a method of treating thrombosis mediated at least in part by ATX comprising administering to a mammal in need thereof a therapeutically effective amount of a compound or salt of Formula I.
- In some embodiments, the invention includes a method of treating or a method of manufacturing a medicament for treating thrombosis, such as those described herein, which is mediated at least in part by ATX, comprising administering to a mammal in need thereof a therapeutically effective amount of a compound or salt of the invention.
- In some embodiments, the invention includes a method of treating cholestatic pruritus comprising administering to a mammal in need thereof a therapeutically effective amount of a compound or salt of the invention.
- In some embodiments, the invention includes a method of treating cholestatic pruritus mediated at least in part by ATX comprising administering to a mammal in need thereof a therapeutically effective amount of a compound or salt of Formula I.
- In some embodiments, the invention includes a method of treating or a method of manufacturing a medicament for cholestatic pruritus, such as those described herein, which is mediated at least in part by ATX, comprising administering to a mammal in need thereof a therapeutically effective amount of a compound or salt of the invention.
- The compounds of Formula I of the invention are useful in the treatment of a variety of cancers, including, but not limited to, solid tumors, sarcoma, fibrosarcoma, osteoma, melanoma, retinoblastoma, rhabdomyosarcoma, glioblastoma, neuroblastoma, teratocarcinoma, hematopoietic malignancy, and malignant ascites. More specifically, the cancers include, but not limited to, lung cancer, bladder cancer, pancreatic cancer, kidney cancer, gastric cancer, breast cancer, colon cancer, prostate cancer (including bone metastases), hepatocellular carcinoma, ovarian cancer, esophageal squamous cell carcinoma, melanoma, an anaplastic large cell lymphoma, an inflammatory myofibroblastic tumor, and a glioblastoma.
- In some embodiments, the above methods are used to treat one or more of bladder, colorectal, non-small cell lung, breast, or pancreatic cancer. In some embodiments, the above methods are used to treat one or more of ovarian, gastric, head and neck, prostate, hepatocellular, renal, glioma, or sarcoma cancer.
- In some embodiments, the invention includes a method, including the above methods, wherein the compound is used to inhibit cellular epithelial to mesenchymal transition (EMT).
- In some embodiments, the method further comprises administering at least on additional active agent. In some embodiments, the invention includes a method of treating cancer comprising administering to a mammal in need thereof a therapeutically effective amount of a compound or salt of the invention, wherein at least one additional active anti-cancer agent is used as part of the method.
- In some embodiments, the invention includes a method of treating the disease described herein mediated at least in part by ATX comprising administering to a mammal in need thereof a therapeutically effective regimen comprising a compound or salt of Formula I and at least one additional active agent.
- Generally, dosage levels on the order of from about 0.01 mg/kg to about 150 mg/kg of body weight per day are useful in the treatment of the above-indicated conditions, or alternatively about 0.5 mg to about 7 g per patient per day. For example, inflammation, cancer, psoriasis, allergy/asthma, disease and conditions of the immune system, disease and conditions of the Central Nervous System (CNS), may be effectively treated by the administration of from about 0.01 to 50 mg of the compound per kilogram of body weight per day, or alternatively about 0.5 mg to about 3.5 g per patient per day.
- It is understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy.
- Except where otherwise indicated, the following general conventions and definitions apply. Unless otherwise indicated herein, language and terms are to be given their broadest reasonable interpretation as understood by the skilled artisan. Any examples given are nonlimiting.
- Any section headings or subheadings herein are for the reader's convenience and/or formal compliance and are non-limiting.
- A recitation of a compound herein is open to and embraces any material or composition containing the recited compound (e.g., a composition containing a racemic mixture, tautomers, epimers, stereoisomers, impure mixtures, etc.). In that a salt, solvate, or hydrate, polymorph, or other complex of a compound includes the compound itself, a recitation of a compound embraces materials containing such forms. Isotopically labeled compounds are also encompassed except where specifically excluded. For example, hydrogen is not limited to hydrogen containing zero neutrons. For example, deuterium is referred to herein as “D” and means a hydrogen atom having one neutron.
- The term “active agent” of the present invention means a compound of the invention in any salt, polymorph, crystal, solvate, or hydrated form.
- The term “pharmaceutically acceptable salt(s)” is known in the art and includes salts of acidic or basic groups which can be present in the compounds and prepared or resulting from pharmaceutically acceptable bases or acids.
- The term “substituted” and substitutions contained in formulas herein refer to the replacement of one or more hydrogen radicals in a given structure with a specified radical, or, if not specified, to the replacement with any chemically feasible radical. When more than one position in a given structure can be substituted with more than one substituent selected from specified groups, the substituents can be either the same or different at every position (independently selected) unless otherwise indicated. In some cases, two positions in a given structure can be substituted with one shared substituent. It is understood that chemically impossible or highly unstable configurations are not desired or intended, as the skilled artisan would appreciate.
- In descriptions and claims where subject matter (e.g., substitution at a given molecular position) is recited as being selected from a group of possibilities, the recitation is specifically intended to include any subset of the recited group. In the case of multiple variable positions or substituents, any combination of group or variable subsets is also contemplated.
- Unless indicated otherwise, a substituent, diradical or other group referred to herein can be bonded through any suitable position to a referenced subject molecule. For example, the term “indolyl” includes 1-indolyl, 2-indolyl, 3-indolyl, etc.
- The convention for describing the carbon content of certain moieties is “(Ca-b)” or “Ca-Cb” meaning that the moiety can contain any number of from “a” to “b” carbon atoms. C0alkyl means a single covalent chemical bond when it is a connecting moiety, and a hydrogen when it is a terminal moiety. Similarly, “x-y” can indicate a moiety containing from x to y atoms, e.g., 5-6heterocycloalkyl means a heterocycloalkyl having either five or six ring members. “Cx-y” may be used to define number of carbons in a group. For example, “C0-12alkyl” means alkyl having 0-12 carbons, wherein C0alkyl means a single covalent chemical bond when a linking group and means hydrogen when a terminal group.
- The term “absent,” as used herein to describe a structural variable (e.g., “—R— is absent”) means that diradical R has no atoms, and merely represents a bond between other adjoining atoms, unless otherwise indicated.
- Unless otherwise indicated (such as by a connecting “-”), the connections of compound name moieties are at the rightmost recited moiety. That is, the substituent name starts with a terminal moiety, continues with any bridging moieties, and ends with the connecting moiety. For example, “heteroarylthioC1-4alkyl is a heteroaryl group connected through a thio sulfur to a C1-4 alkyl, which alkyl connects to the chemical species bearing the substituent.
- The term “aliphatic” means any hydrocarbon moiety, and can contain linear, branched, and cyclic parts, and can be saturated or unsaturated.
- The term “alkyl” means any saturated hydrocarbon group that is straight-chain or branched. Examples of alkyl groups include methyl, ethyl, propyl, 2-propyl, n-butyl, iso-butyl, tert-butyl, pentyl, and the like.
- The term “alkenyl” means any ethylenically unsaturated straight-chain or branched hydrocarbon group. Representative examples include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl, and the like.
- The term “alkynyl” means any acetylenically unsaturated straight-chain or branched hydrocarbon group. Representative examples include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2-, or 3-butynyl, and the like.
- The term “alkoxy” means —O-alkyl, —O-alkenyl, or —O-alkynyl. “Haloalkoxy” means an —O-(haloalkyl) group. Representative examples include, but are not limited to, trifluoromethoxy, tribromomethoxy, and the like.
- “Haloalkyl” means an alkyl, preferably lower alkyl, that is substituted with one or more same or different halo atoms.
- “Hydroxyalkyl” means an alkyl, preferably lower alkyl, that is substituted with one, two, or three hydroxy groups; e.g., hydroxymethyl, 1 or 2-hydroxyethyl, 1,2-, 1,3-, or 2,3-dihydroxypropyl, and the like.
- The term “alkanoyl” means —C(O)-alkyl, —C(O)-alkenyl, or —C(O)-alkynyl.
- “Alkylthio” means an —S-(alkyl) or an —S-(unsubstituted cycloalkyl) group. Representative examples include, but are not limited to, methylthio, ethylthio, propylthio, butylthio, cyclopropylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio, and the like.
- The term “cyclic” means any ring system with or without heteroatoms (N, O, or S(O)02), and which can be saturated, partially saturated, or unsaturated. Ring systems can be bridged and can include fused rings. The size of ring systems may be described using terminology such as “x-ycyclic,” which means a cyclic ring system that can have from x to y ring atoms. For example, the term “9-10carbocyclic” means a 5,6 or 6,6 fused bicyclic carbocyclic ring system which can be saturated, unsaturated or aromatic. It also means a phenyl fused to one 5 or 6 membered saturated or unsaturated carbocyclic group. Nonlimiting examples of such groups include naphthyl, 1,2,3,4 tetrahydronaphthyl, indenyl, indanyl, and the like.
- The term “carbocyclic” means a cyclic ring moiety containing only carbon atoms in the ring(s) without regard to aromaticity. A 3-10 membered carbocyclic means chemically feasible monocyclic and fused bicyclic carbocyclics having from 3 to 10 ring atoms. Similarly, a 4-6 membered carbocyclic means monocyclic carbocyclic ring moieties having 4 to 6 ring carbons, and a 9-10 membered carbocyclic means fused bicyclic carbocyclic ring moieties having 9 to 10 ring carbons.
- The term “cycloalkyl” means a non-aromatic 3-12 carbon mono-cyclic, bicyclic, or polycyclic aliphatic ring moiety. Cycloalkyl can be bicycloalkyl, polycycloalkyl, bridged, or spiroalkyl. One or more of the rings may contain one or more double bonds but none of the rings has a completely conjugated pi-electron system. Examples, without limitation, of cycloalkyl groups are cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, cyclohexadiene, adamantane, cycloheptane, cycloheptatriene, and the like.
- The term “unsaturated carbocyclic” means any cycloalkyl containing at least one double or triple bond. The term “cycloalkenyl” means a cycloalkyl having at least one double bond in the ring moiety.
- The terms “bicycloalkyl” and “polycycloalkyl” mean a structure consisting of two or more cycloalkyl moieties that have two or more atoms in common. If the cycloalkyl moieties have exactly two atoms in common they are said to be “fused”. Examples include, but are not limited to, bicyclo[3.1.0]hexyl, perhydronaphthyl, and the like. If the cycloalkyl moieties have more than two atoms in common they are said to be “bridged”. Examples include, but are not limited to, bicyclo[2.2.1]heptyl (“norbornyl”), bicyclo[2.2.2]octyl, and the like.
- The term “spiroalkyl” means a structure consisting of two cycloalkyl moieties that have exactly one atom in common. Examples include, but are not limited to, spiro[4.5]decyl, spiro[2.3]hexyl, and the like.
- The term “aromatic” means a planar ring moieties containing 4n+2 pi electrons, wherein n is an integer.
- The term “aryl” means aromatic moieties containing only carbon atoms in its ring system. Non-limiting examples include phenyl, naphthyl, and anthracenyl. The terms “aryl-alkyl” or “arylalkyl” or “aralkyl” refer to any alkyl that forms a bridging portion with a terminal aryl.
- “Aralkyl” means alkyl that is substituted with an aryl group as defined above, e.g., —CH2 phenyl, —(CH2)2phenyl, —(CH2)3 phenyl, CH3CH(CH3)CH2phenyl, and the like and derivatives thereof.
- The term “heterocyclic” means a cyclic ring moiety containing at least one heteroatom (N, O, or S(O)0-2), including heteroaryl, heterocycloalkyl, including unsaturated heterocyclic rings.
- The term “heterocycloalkyl” means a non-aromatic monocyclic, bicyclic, or polycyclic heterocyclic ring moiety of 3 to 12 ring atoms containing at least one ring having one or more heteroatoms. The rings may also have one or more double bonds. However, the rings do not have a completely conjugated pi-electron system. Examples, without limitation, of heterocycloalkyl rings include azetidine, oxetane, tetrahydrofuran, tetrahydropyran, oxepane, oxocane, thietane, thiazolidine, oxazolidine, oxazetidine, pyrazolidine, isoxazolidine, isothiazolidine, tetrahydrothiophene, tetrahydrothiopyran, thiepane, thiocane, azetidine, pyrrolidine, piperidine, N-methylpiperidine, azepane, 1,4-diazapane, azocane, [1,3]dioxane, oxazolidine, piperazine, homopiperazine, morpholine, thiomorpholine, 1,2,3,6-tetrahydropyridine and the like. Other examples of heterocycloalkyl rings include the oxidized forms of the sulfur-containing rings. Thus, tetrahydrothiophene-1-oxide, tetrahydrothiophene-1,1-dioxide, thiomorpholine-1-oxide, thiomorpholine-1,1-dioxide, tetrahydrothiopyran-1-oxide, tetrahydrothiopyran-1,1-dioxide, thiazolidine-1-oxide, and thiazolidine-1,1-dioxide are also considered to be heterocycloalkyl rings. The term “heterocycloalkyl” also includes fused ring systems and can include a carbocyclic ring that is partially or fully unsaturated, such as a benzene ring, to form benzofused heterocycloalkyl rings. For example, 3,4-dihydro-1,4-benzodioxine, tetrahydroquinoline, tetrahydroisoquinoline and the like. The term “heterocycloalkyl” also includes heterobicycloalkyl, heteropolycycloalkyl, or heterospiroalkyl, which are bicycloalkyl, polycycloalkyl, or spiroalkyl, in which one or more carbon atom(s) are replaced by one or more heteroatoms selected from O, N, and S. For example, 2-oxa-spiro[3.3]heptane, 2,7-diaza-spiro[4.5]decane, 6-oxa-2-thia-spiro[3.4]octane, octahydropyrrolo[1,2-a]pyrazine, 7-aza-bicyclo[2.2.1]heptane, 2-oxa-bicyclo[2.2.2]octane, and the like, are such heterocycloalkyls.
- Examples of saturated heterocyclic groups include, but are not limited to oxiranyl, thiaranyl, aziridinyl, oxetanyl, thiatanyl, azetidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, 1,4-dioxanyl, 1,4-oxathianyl, morpholinyl, 1,4-dithianyl, piperazinyl, 1,4-azathianyl, oxepanyl, thiepanyl, azepanyl, 1,4-dioxepanyl, 1,4-oxathiepanyl, 1,4-oxaazepanyl, 1,4-dithiepanyl, 1,4-thieazepanyl, 1,4-diazepanyl.
- Non-aryl heterocyclic groups include saturated and unsaturated systems and can include groups having only 4 atoms in their ring system. The heterocyclic groups include benzo-fused ring systems and ring systems substituted with one or more oxo moieties. Recitation of ring sulfur is understood to include the sulfide, sulfoxide or sulfone where feasible. The heterocyclic groups also include partially unsaturated or fully saturated 4-10 membered ring systems, e.g., single rings of 4 to 8 atoms in size and bicyclic ring systems, including aromatic 6-membered aryl or heteroaryl rings fused to a non-aromatic ring. Also included are 4-6 membered ring systems (“4-6 membered heterocyclic”), which include 5-6 membered heteroaryls, and include groups such as azetidinyl and piperidinyl. Heterocyclics can be heteroatom-attached where such is possible. For instance, a group derived from pyrrole can be pyrrol-1-yl (N-attached) or pyrrol-3-yl (C-attached). Other heterocyclics include imidazo(4,5-b)pyridin-3-yl and benzoimidazol-1-yl.
- Examples of heterocyclic groups include pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thioxanyl, piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, 3H-indolyl, quinolizinyl, and the like.
- The term “unsaturated heterocyclic” means a heterocycloalkyl containing at least one unsaturated bond. The term “heterobicycloalkyl” means a bicycloalkyl structure in which at least one carbon atom is replaced with a heteroatom. The term “heterospiroalkyl” means a spiroalkyl structure in which at least one carbon atom is replaced with a heteroatom.
- Examples of partially unsaturated heteroalicyclic groups include, but are not limited to: 3,4-dihydro-2H-pyranyl, 5,6-dihydro-2H-pyranyl, 2H-pyranyl, 1,2,3,4-tetrahydropyridinyl, and 1,2,5,6-tetrahydropyridinyl.
- The terms “heteroaryl” or “hetaryl” mean a monocyclic, bicyclic, or polycyclic aromatic heterocyclic ring moiety containing 5-12 atoms. Examples of such heteroaryl rings include, but are not limited to, furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl. The terms “heteroaryl” also include heteroaryl rings with fused carbocyclic ring systems that are partially or fully unsaturated, such as a benzene ring, to form a benzofused heteroaryl. For example, benzimidazole, benzoxazole, benzothiazole, benzofuran, quinoline, isoquinoline, quinoxaline, indazole, imidazo[1,2-a]pyridine, 3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl, 2-methyl-2H-indazol-5-yl, 3-methylimidazo[1,5-a]pyridine, 2-methyl-1H-benzo[d]imidazole, 1H-pyrrolo[2,3-b]pyridine, 3,4-Dihydro-2H-benzo[b][1,4]oxazine, 2-oxo-2,3-dihydrobenzo[d]oxazole, 3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine, 2,3-Dihydrobenzo[b][1,4]dioxine, 2-methyl-[1,2,4]triazolo[1,5-a]pyridine, and the like. Furthermore, the terms “heteroaryl” include fused 5-6, 5-5, 6-6 ring systems, optionally possessing one nitrogen atom at a ring junction. Examples of such hetaryl rings include, but are not limited to, pyrrolopyrimidinyl, imidazo[1,2-a]pyridinyl, imidazo[2,1-b]thiazolyl, imidazo[4,5-b]pyridine, pyrrolo[2,1-f][1,2,4]triazinyl, and the like. Heteroaryl groups may be attached to other groups through their carbon atoms or the heteroatom(s), if applicable. For example, pyrrole may be connected at the nitrogen atom or at any of the carbon atoms.
- Heteroaryls include, e.g., 5 and 6 membered monocyclics such as pyrazinyl and pyridinyl, and 9 and 10 membered fused bicyclic ring moieties, such as quinolinyl. Other examples of heteroaryl include quinolin-4-yl, 7-methoxy-quinolin-4-yl, pyridin-4-yl, pyridin-3-yl, and pyridin-2-yl. Other examples of heteroaryl include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furanyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, furopyridinyl, and the like. Examples of 5-6 membered heteroaryls include, thiophenyl, isoxazolyl, 1,2,3-triazolyl, 1,2,3-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-triazolyl, 1,3,4-oxadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-oxadiazolyl, 1,2,5-thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,2,4 oxadiazolyl, 1,2,5-triazinyl, 1,3,5-triazinyl, 6-oxo-1,6-dihydropyridine, and the like.
- “Heteroaralkyl” group means alkyl, preferably lower alkyl, that is substituted with a heteroaryl group; e.g., —CH2 pyridinyl, —(CH2)2pyrimidinyl, —(CH2)3imidazolyl, and the like, and derivatives thereof.
- A pharmaceutically acceptable heteroaryl is one that is sufficiently stable to be attached to a compound of the invention, formulated into a pharmaceutical composition and subsequently administered to a patient in need thereof.
- Examples of monocyclic heteroaryl groups include, but are not limited to: pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, 1,2,3-triazolyl, 1,3,4-triazolyl, 1-oxa-2,3-diazolyl, 1-oxa-2,4-diazolyl, 1-oxa-2,5-diazolyl, 1-oxa-3,4-diazolyl, 1-thia-2,3-diazolyl, 1-thia-2,4-diazolyl, 1-thia-2,5-diazolyl, 1-thia-3,4-diazolyl tetrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl.
- Examples of fused ring heteroaryl groups include, but are not limited to: benzoduranyl, benzothiophenyl, indolyl, benzimidazolyl, indazolyl, benzotriazolyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-c]pyridinyl, pyrrolo[3,2-b]pyridinyl, imidazo[4,5-b]pyridinyl, imidazo[4,5-c]pyridinyl, pyrazolo[4,3-d]pyridinyl, pyrazolo[4,3-c]pyridinyl, pyrazolo[3,4-c]pyridinyl, pyrazolo[3,4-b]pyridinyl, isoindolyl, indazolyl, purinyl, indolinyl, imidazo[1,2-a]pyridinyl, imidazo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyridinyl, pyrrolo[1,2-b]pyridazinyl, imidazo[1,2-c]pyrimidinyl, quinolinyl, isoquinolinyl, cinnolinyl, azaquinazoline, quinoxalinyl, phthalazinyl, 1,6-naphthyridinyl, 1,7-naphthyridinyl, 1,8-naphthyridinyl, 1,5-naphthyridinyl, 2,6-naphthyridinyl, 2,7-naphthyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[4,3-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrido[2,3-d]pyrimidinyl, pyrido[2,3-b]pyrazinyl, pyrido[3,4-b]pyrazinyl, pyrimido[5,4-d]pyrimidinyl, pyrimido[2,3-b]pyrazinyl, pyrimido[4,5-d]pyrimidinyl.
- “Arylthio” means an —S-aryl or an —S-heteroaryl group, as defined herein. Representative examples include, but are not limited to, phenylthio, pyridinylthio, furanylthio, thienylthio, pyrimidinylthio, and the like and derivatives thereof.
- The term “9-10 membered heterocyclic” means a fused 5,6 or 6,6 bicyclic heterocyclic ring moiety, which can be saturated, unsaturated or aromatic. The term “9-10 membered fused bicyclic heterocyclic” also means a phenyl fused to one 5 or 6 membered heterocyclic group. Examples include benzofuranyl, benzothiophenyl, indolyl, benzoxazolyl, 3H-imidazo[4,5-c]pyridin-yl, dihydrophthazinyl, 1H-imidazo[4,5-c]pyridin-1-yl, imidazo[4,5-b]pyridyl, 1,3 benzo[1,3]dioxolyl, 2H-chromanyl, isochromanyl, 5-oxo-2,3 dihydro-5H-[1,3]thiazolo[3,2-a]pyrimidyl, 1,3-benzothiazolyl, 1,4,5,6 tetrahydropyridazyl, 1,2,3,4,7,8hexahydropteridinyl, 2-thioxo-2,3,6,9-tetrahydro-1H-purin-8-yl, 3,7-dihydro-1H-purin-8-yl, 3,4-dihydropyrimidin-1-yl, 2,3-dihydro-1,4-benzodioxinyl, benzo[1,3]dioxolyl, 2H-chromenyl, chromanyl, 3,4-dihydrophthalazinyl, 2,3-dihydro-1H-indolyl, 1,3-dihydro-2H-isoindol-2-yl, 2,4,7-trioxo-1,2,3,4,7,8-hexahydropteridin-yl, thieno[3,2-d]pyrimidinyl, 4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-yl, 1,3-dimethyl-6-oxo-2-thioxo-2,3,6,9-tetrahydro-1H-purinyl, 1,2-dihydroisoquinolinyl, 2-oxo-1,3-benzoxazolyl, 2,3-dihydro-5H-1,3-thiazolo-[3,2-a]pyrimidinyl, 5,6,7,8-tetrahydro-quinazolinyl, 4-oxochromanyl, 1,3-benzothiazolyl, benzimidazolyl, benzotriazolyl, purinyl, furylpyridyl, thiophenylpyrimidyl, thiophenylpyridyl, pyrrolylpiridyl, oxazolylpyridyl, thiazolylpiridyl, 3,4-dihydropyrimidin-1-yl imidazolylpyridyl, quinoliyl, isoquinolinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pyrazolyl[3,4]pyridine, 1,2-dihydroisoquinolinyl, cinnolinyl, 2,3-dihydro-benzo[1,4]dioxin4-yl, 4,5,6,7-tetrahydro-benzo[b]-thiophenyl-2-yl, 1,8-naphthyridinyl, 1,5-napthyridinyl, 1,6-naphthyridinyl, 1,7-napthyridinyl, 3,4-dihydro-2H-1,4-benzothiazine, 4,8-dihydroxy-quinolinyl, 1-oxo-1,2-dihydro-isoquinolinyl, 4-phenyl-[1,2,3]thiadiazolyl, and the like.
- The term “aryloxy” means an —O-aryl or an —O-heteroaryl group, as defined herein. Representative examples include, but are not limited to, phenoxy, pyridinyloxy, furanyloxy, thienyloxy, pyrimidinyloxy, pyrazinyloxy, and the like, and derivatives thereof.
- The term “oxo” means a compound containing a carbonyl group. One in the art understands that an “oxo” requires a second bond from the atom to which the oxo is attached.
- The term “halo” or “halogen” means fluoro, chloro, bromo, or iodo.
- “Acyl” means a —C(O)R group, where R can be selected from the nonlimiting group of hydrogen or optionally substituted lower alkyl, trihalomethyl, unsubstituted cycloalkyl, aryl, or other suitable substituent.
- “Thioacyl” or “thiocarbonyl” means a —C(S)R″ group, with R as defined above.
- The term “protecting group” means a suitable chemical group that can be attached to a functional group and removed at a later stage to reveal the intact functional group. Examples of suitable protecting groups for various functional groups are described in T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2d Ed., John Wiley and Sons (1991 and later editions); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed. Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995). The term “hydroxy protecting group”, as used herein, unless otherwise indicated, includes Ac, CBZ, and various hydroxy protecting groups familiar to those skilled in the art including the groups referred to in Greene.
- The term “linear structure” means a moiety having substituents that do not cyclize to form a ring system. A representative example includes, but is not limited to, a compound including —NR5R6 where any atoms of “R5” and any atoms of “R6” do not connect to form a ring.
- As used herein, the term “pharmaceutically acceptable salt” means those salts which retain the biological effectiveness and properties of the parent compound and do not present insurmountable safety or toxicity issues.
- The term “pharmaceutical composition” means an active compound in any form suitable for effective administration to a subject, e.g., a mixture of the compound and at least one pharmaceutically acceptable carrier.
- As used herein, a “physiologically/pharmaceutically acceptable carrier” means a carrier or diluent that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound.
- A “pharmaceutically acceptable excipient” means an inert substance added to a pharmaceutical composition to further facilitate administration of a compound. Examples, without limitation, of excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycols.
- The term “substituted” and substitutions contained in formulas herein refer to the replacement of one or more hydrogen radicals in a given structure with a specified radical, or, if not specified, to the replacement with any chemically feasible radical. When more than one position in a given structure can be substituted with more than one substituent selected from specified groups, the substituents can be either the same or different at every position (independently selected) unless otherwise indicated. In some cases, two positions in a given structure can be substituted with one shared substituent. It is understood that chemically impossible or highly unstable configurations are not desired or intended, as the skilled artisan would appreciate.
- The terms “treat,” “treatment,” and “treating” means reversing, alleviating, or inhibiting the progress of the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition. “Preventing” means partially or completing treating before the disorder or condition occurs.
- “Therapeutically effective amount” means that amount of the compound being administered which will relieve to some extent one or more of the symptoms of the disorder being treated, or result in inhibition of the progress or at least partial reversal of the condition.
- NMR Nuclear magnetic resonance
MDP(S) Mass-directed HPLC purification (system)
LC/MS Liquid chromatography mass spectrometry
LDA Lithium diisopropylamide
tert-BuOH tert-Butanol
AcOH Acetic acid - EtOAc Ethyl acetate
- Boc tert-Butyloxycarbonyl
- PS-DIEA Polymer-supported diisopropylethylamine
PS-PPh3-Pd Polymer-supported Pd(PPh3)4
LAH Lithium aluminum hydride
EDC 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide
HATU: 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate - SEM-Cl 2-(Trimethylsilyl)ethoxymethyl chloride
TBTU O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate
TEMPO 2,2,6,6-Tetramethylpiperidine-1 oxyl
TFA (A) Trifluoroacetic acid (anhydride)
TLC Thin layer chromatography
TMSCN Trimethylsilyl cyanide - RT, R.T., r.t., r.t or rt Room temperature
tR Retention time
Claims (19)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US16/256,429 US20190225611A1 (en) | 2014-04-04 | 2019-04-12 | Substituted spirocyclic inhibitors of autotaxin |
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201461975123P | 2014-04-04 | 2014-04-04 | |
PCT/US2015/024338 WO2015154023A1 (en) | 2014-04-04 | 2015-04-03 | Substituted spirocydic inhibitors of autotaxin |
US201615300762A | 2016-09-29 | 2016-09-29 | |
US15/896,905 US10233182B2 (en) | 2014-04-04 | 2018-02-14 | Substituted spirocyclic inhibitors of autotaxin |
US16/256,429 US20190225611A1 (en) | 2014-04-04 | 2019-04-12 | Substituted spirocyclic inhibitors of autotaxin |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US15/896,905 Continuation US10233182B2 (en) | 2014-04-04 | 2018-02-14 | Substituted spirocyclic inhibitors of autotaxin |
Publications (1)
Publication Number | Publication Date |
---|---|
US20190225611A1 true US20190225611A1 (en) | 2019-07-25 |
Family
ID=54241341
Family Applications (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US15/300,762 Expired - Fee Related US10011601B2 (en) | 2014-04-04 | 2015-04-03 | Substituted spirocyclic inhibitors of autotaxin |
US15/896,905 Expired - Fee Related US10233182B2 (en) | 2014-04-04 | 2018-02-14 | Substituted spirocyclic inhibitors of autotaxin |
US16/256,429 Abandoned US20190225611A1 (en) | 2014-04-04 | 2019-04-12 | Substituted spirocyclic inhibitors of autotaxin |
Family Applications Before (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US15/300,762 Expired - Fee Related US10011601B2 (en) | 2014-04-04 | 2015-04-03 | Substituted spirocyclic inhibitors of autotaxin |
US15/896,905 Expired - Fee Related US10233182B2 (en) | 2014-04-04 | 2018-02-14 | Substituted spirocyclic inhibitors of autotaxin |
Country Status (21)
Country | Link |
---|---|
US (3) | US10011601B2 (en) |
EP (1) | EP3125895A4 (en) |
JP (2) | JP6616821B2 (en) |
KR (1) | KR20160133004A (en) |
CN (1) | CN107106559A (en) |
AP (1) | AP2016009496A0 (en) |
AU (2) | AU2015240519B2 (en) |
CA (1) | CA2943874A1 (en) |
CL (1) | CL2016002516A1 (en) |
CR (1) | CR20160496A (en) |
CU (1) | CU24442B1 (en) |
DO (1) | DOP2016000270A (en) |
EA (1) | EA201691840A1 (en) |
EC (1) | ECSP16084293A (en) |
IL (1) | IL248050A0 (en) |
MD (1) | MD20160116A2 (en) |
MX (1) | MX2016013049A (en) |
PE (1) | PE20170206A1 (en) |
PH (1) | PH12016501922A1 (en) |
SG (1) | SG11201607920RA (en) |
WO (1) | WO2015154023A1 (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US11274101B2 (en) | 2017-09-29 | 2022-03-15 | Takeda Pharmaceutical Company Limited | Heterocyclic compound |
Families Citing this family (25)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU2013276617B9 (en) | 2012-06-13 | 2018-03-29 | F. Hoffmann-La Roche Ag | New diazaspirocycloalkane and azaspirocycloalkane |
SI2900669T1 (en) | 2012-09-25 | 2019-12-31 | F. Hoffmann-La Roche Ag | Hexahydropyrrolo(3,4-c)pyrrole derivatives and related compounds as autotaxin (atx) inhibitors and as inhibitors of the lysophosphatidic acid (lpa) production for treating e.g. renal diseases |
AR095079A1 (en) | 2013-03-12 | 2015-09-16 | Hoffmann La Roche | DERIVATIVES OF OCTAHIDRO-PIRROLO [3,4-C] -PIRROL AND PIRIDINA-FENILO |
MY187449A (en) | 2013-11-26 | 2021-09-22 | Hoffmann La Roche | New octahydro-cyclobuta [1,2-c;3,4-c']dipyrrol-2-yl |
PE20161223A1 (en) | 2014-03-26 | 2016-11-12 | Hoffmann La Roche | [1,4] DIAZEPINE CONDENSED COMPOUNDS AS INHIBITORS OF THE PRODUCTION OF AUTOTAXIN (ATX) AND LYSOPHOSPHATIDIC ACID (LPA) |
DK3122750T3 (en) | 2014-03-26 | 2019-11-04 | Hoffmann La Roche | Bicyclic compounds such as autotaxin (ATX) and lysophosphatidic acid (LPA) production inhibitors |
SG11201607920RA (en) | 2014-04-04 | 2016-10-28 | X Rx Inc | Substituted spirocyclic inhibitors of autotaxin |
MA41898A (en) | 2015-04-10 | 2018-02-13 | Hoffmann La Roche | BICYCLIC QUINAZOLINONE DERIVATIVES |
JP6886967B2 (en) | 2015-09-04 | 2021-06-16 | エフ.ホフマン−ラ ロシュ アーゲーF. Hoffmann−La Roche Aktiengesellschaft | Phenoxymethyl derivative |
JP6876685B2 (en) | 2015-09-24 | 2021-05-26 | エフ.ホフマン−ラ ロシュ アーゲーF. Hoffmann−La Roche Aktiengesellschaft | Bicyclic compounds as ATX inhibitors |
CN107614505B (en) | 2015-09-24 | 2021-05-07 | 豪夫迈·罗氏有限公司 | Novel bicyclic compounds as dual ATX/CA inhibitors |
BR112018006024A2 (en) | 2015-09-24 | 2020-05-12 | F. Hoffmann-La Roche Ag | BICYCLIC COMPOUNDS AS ATX INHIBITORS |
MA42923A (en) | 2015-09-24 | 2021-04-28 | Hoffmann La Roche | BICYCLIC COMPOUNDS AS MIXED ATX / CA INHIBITORS |
AU2017228371A1 (en) | 2016-03-04 | 2018-09-13 | Gilead Sciences, Inc. | Compositions and combinations of autotaxin inhibitors |
JOP20190107A1 (en) * | 2016-11-16 | 2019-05-09 | Lundbeck La Jolla Research Center Inc | Magl inhibitors |
CN108456208B (en) * | 2017-02-22 | 2021-04-16 | 广州市恒诺康医药科技有限公司 | Aza spiro compound and preparation method and application thereof |
RU2019132254A (en) | 2017-03-16 | 2021-04-16 | Ф. Хоффманн-Ля Рош Аг | HETEROCYCLIC COMPOUNDS SUITABLE AS DUAL ATX / CA INHIBITORS |
WO2018167113A1 (en) | 2017-03-16 | 2018-09-20 | F. Hoffmann-La Roche Ag | New bicyclic compounds as atx inhibitors |
US10961242B2 (en) | 2017-05-17 | 2021-03-30 | Legochem Biosciences, Inc. | Compounds as autotaxin inhibitors and pharmaceutical compositions comprising the same |
KR101798840B1 (en) | 2017-05-17 | 2017-11-17 | 주식회사 레고켐 바이오사이언스 | Novel Compounds as Autotaxin Inhibitors and Pharmaceutical Compositions Comprising the Same |
WO2020051230A1 (en) * | 2018-09-04 | 2020-03-12 | X-Rx, Inc. | Amorphous pharmaceutical compositions and uses thereof |
TW202229255A (en) | 2020-11-13 | 2022-08-01 | 丹麥商H 朗德貝克公司 | A magl inhibitor |
CN112675308B (en) * | 2020-12-09 | 2023-05-05 | 中国人民解放军军事科学院军事医学研究院 | Application of substances for inhibiting ENPP2 gene and/or protein expression in preparation of medicines for treating multiple myeloma |
CN116806150A (en) * | 2021-01-05 | 2023-09-26 | 载度思生命科学有限公司 | Novel autotaxin inhibitors |
WO2024073658A1 (en) * | 2022-09-30 | 2024-04-04 | Genentech, Inc. | Hydantoin modulators of cholesterol biosynthesis and their use for promoting remyelination |
Family Cites Families (44)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5877182A (en) | 1996-09-13 | 1999-03-02 | Merck & Co., Inc. | Piperidines promote release of growth hormone |
BR9808502A (en) | 1997-05-08 | 2000-05-23 | Smithkline Beecham Corp | Protease inhibitors |
GB0030303D0 (en) | 2000-12-13 | 2001-01-24 | Lilly Co Eli | Compounds |
WO2002079146A2 (en) | 2001-03-02 | 2002-10-10 | Bristol-Myers Squibb Company | Compounds useful as modulators of melanocortin receptors and pharmaceutical compositions comprising same |
HUP0600103A2 (en) * | 2001-03-02 | 2006-06-28 | Bristol Myers Squibb Co | Co-administration of melanocortin receptor agonist and phosphodiesterase inhibitor for treatment of cyclic-amp associated disorders |
HUP0402338A3 (en) * | 2001-10-01 | 2008-10-28 | Bristol Myers Squibb Co | Spiro-hydantoin compounds, their use as anti-inflammatory agents, pharmaceutical compositions containing them and intermediates for preparing them |
US20040192674A1 (en) | 2003-02-14 | 2004-09-30 | Marquis Robert W. | Cathepsin L inhibitors |
WO2004076418A1 (en) | 2003-02-28 | 2004-09-10 | Galderma Research & Development, S.N.C. | Ligands that modulate lxr-type receptors |
US7576175B2 (en) * | 2004-05-27 | 2009-08-18 | The Regents Of The University Of California | Alpha-4 beta-1 integrin ligands for imaging and therapy |
WO2006137465A1 (en) | 2005-06-24 | 2006-12-28 | Shionogi & Co., Ltd. | Nitrogenated heterocyclic derivative |
US7601844B2 (en) | 2006-01-27 | 2009-10-13 | Bristol-Myers Squibb Company | Piperidinyl derivatives as modulators of chemokine receptor activity |
US8329159B2 (en) * | 2006-08-11 | 2012-12-11 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US8906859B2 (en) * | 2006-11-10 | 2014-12-09 | Cera Therapeutics, Inc. | Uses of kappa opioid synthetic peptide amides |
CA2669917A1 (en) | 2006-11-17 | 2008-05-22 | Dawn M. George | Aminopyrrolidines as chemokine receptor antagonists |
US8378100B2 (en) | 2008-01-09 | 2013-02-19 | University Of Virginia Patent Foundation | Phosphonate derivatives as autotaxin inhibitors |
KR20100134680A (en) | 2008-03-20 | 2010-12-23 | 포레스트 래보러토리즈 홀딩스 리미티드 | Novel piperidine derivatives as inhibitors of stearoyl-coa desaturase |
WO2009151644A2 (en) | 2008-06-13 | 2009-12-17 | Yale University | Small molecule inhibitors of autotaxin methods of use |
WO2010037081A1 (en) * | 2008-09-29 | 2010-04-01 | Palatin Technologies, Inc. | Melanocortin receptor-specific spiro-piperidine compounds |
CA2745041C (en) | 2008-12-01 | 2017-08-22 | Kai Schiemann | 2, 5-diamino-substituted pyrido [4, 3-d] pyrimidines as autotaxin inhibitors against cancer |
KR20120027177A (en) | 2009-04-02 | 2012-03-21 | 메르크 파텐트 게엠베하 | Piperidine and piperazine derivatives as autotaxin inhibitors |
EP2414327B1 (en) | 2009-04-02 | 2014-11-19 | Merck Patent GmbH | Heterocyclic compounds as autotaxin inhibitors |
CA2757415C (en) | 2009-04-02 | 2018-02-06 | Merck Patent Gmbh | Autotaxin inhibitors |
SG171708A1 (en) * | 2009-06-11 | 2011-07-28 | Abbott Lab | Anti-viral compounds to treat hcv infection |
DE102009033392A1 (en) | 2009-07-16 | 2011-01-20 | Merck Patent Gmbh | Heterocyclic compounds as autotaxine inhibitors II |
EP2462128B1 (en) | 2009-08-04 | 2016-09-21 | Amira Pharmaceuticals, Inc. | Compounds as lysophosphatidic acid receptor antagonists |
KR101184115B1 (en) | 2009-08-31 | 2012-09-18 | 일동제약주식회사 | New peptide deformylase inhibitor compounds and the manufacturing process thereof |
US8497371B2 (en) | 2009-10-26 | 2013-07-30 | University Of Memphis Research Foundation | Pipemidic acid derivative autotaxin inhibitors |
US8518945B2 (en) | 2010-03-22 | 2013-08-27 | Hoffmann-La Roche Inc. | Pyrrolopyrazine kinase inhibitors |
CA2794211A1 (en) | 2010-03-26 | 2011-09-29 | Wolfgang Staehle | Benzonaphthyridinamines as autotaxin inhibitors |
JP2011219368A (en) | 2010-04-02 | 2011-11-04 | Daiichi Sankyo Co Ltd | N-salicyl amino acid derivative |
CN103201262B (en) | 2010-08-20 | 2016-06-01 | 艾米拉医药股份有限公司 | Autotaxin inhibitors and application thereof |
WO2012166415A1 (en) | 2011-05-27 | 2012-12-06 | Amira Pharmaceuticals, Inc. | Heterocyclic autotaxin inhibitors and uses thereof |
US8546416B2 (en) * | 2011-05-27 | 2013-10-01 | Novartis Ag | 3-spirocyclic piperidine derivatives as ghrelin receptor agonists |
US9273011B2 (en) | 2011-10-28 | 2016-03-01 | Inhibitaxin Limited | Substituted pyridazines for the treatment of pain |
AU2013276617B9 (en) | 2012-06-13 | 2018-03-29 | F. Hoffmann-La Roche Ag | New diazaspirocycloalkane and azaspirocycloalkane |
AR095079A1 (en) | 2013-03-12 | 2015-09-16 | Hoffmann La Roche | DERIVATIVES OF OCTAHIDRO-PIRROLO [3,4-C] -PIRROL AND PIRIDINA-FENILO |
TW201500356A (en) | 2013-04-12 | 2015-01-01 | Lilly Co Eli | Dihydropyrido pyrimidine compounds |
US20160168119A1 (en) | 2013-07-18 | 2016-06-16 | Novartis Ag | Autotaxin inhibitors |
AU2014291711B2 (en) | 2013-07-18 | 2017-02-02 | Novartis Ag | Autotaxin inhibitors comprising a heteroaromatic ring-benzyl-amide-cycle core |
WO2015042052A1 (en) | 2013-09-17 | 2015-03-26 | Pharmakea, Inc. | Heterocyclic vinyl autotaxin inhibitor compounds |
EP3046905A4 (en) | 2013-09-17 | 2017-03-22 | Pharmakea Inc. | Vinyl autotaxin inhibitor compounds |
EP3049405A4 (en) | 2013-09-26 | 2017-03-08 | Pharmakea Inc. | Autotaxin inhibitor compounds |
SG11201607920RA (en) | 2014-04-04 | 2016-10-28 | X Rx Inc | Substituted spirocyclic inhibitors of autotaxin |
WO2015175171A1 (en) | 2014-04-23 | 2015-11-19 | X-Rx Discovery, Inc. | Substituted n-(2-(amino)-2-oxoethyl)benzamide inhibitors of autotaxin and their preparation and use in the treatment of lpa-dependent or lpa-mediated diseases |
-
2015
- 2015-04-03 SG SG11201607920RA patent/SG11201607920RA/en unknown
- 2015-04-03 JP JP2017503794A patent/JP6616821B2/en not_active Expired - Fee Related
- 2015-04-03 KR KR1020167030589A patent/KR20160133004A/en unknown
- 2015-04-03 MD MDA20160116A patent/MD20160116A2/en not_active Application Discontinuation
- 2015-04-03 AP AP2016009496A patent/AP2016009496A0/en unknown
- 2015-04-03 EP EP15773254.6A patent/EP3125895A4/en not_active Withdrawn
- 2015-04-03 CU CU2016000150A patent/CU24442B1/en unknown
- 2015-04-03 AU AU2015240519A patent/AU2015240519B2/en not_active Ceased
- 2015-04-03 WO PCT/US2015/024338 patent/WO2015154023A1/en active Application Filing
- 2015-04-03 CR CR20160496A patent/CR20160496A/en unknown
- 2015-04-03 CN CN201580028170.3A patent/CN107106559A/en active Pending
- 2015-04-03 CA CA2943874A patent/CA2943874A1/en not_active Abandoned
- 2015-04-03 US US15/300,762 patent/US10011601B2/en not_active Expired - Fee Related
- 2015-04-03 MX MX2016013049A patent/MX2016013049A/en unknown
- 2015-04-03 EA EA201691840A patent/EA201691840A1/en unknown
- 2015-04-03 PE PE2016001885A patent/PE20170206A1/en unknown
-
2016
- 2016-09-26 IL IL248050A patent/IL248050A0/en unknown
- 2016-09-28 PH PH12016501922A patent/PH12016501922A1/en unknown
- 2016-10-03 DO DO2016000270A patent/DOP2016000270A/en unknown
- 2016-10-04 CL CL2016002516A patent/CL2016002516A1/en unknown
- 2016-10-26 EC ECIEPI201684293A patent/ECSP16084293A/en unknown
-
2018
- 2018-02-14 US US15/896,905 patent/US10233182B2/en not_active Expired - Fee Related
-
2019
- 2019-04-12 US US16/256,429 patent/US20190225611A1/en not_active Abandoned
- 2019-11-08 JP JP2019203023A patent/JP2020040960A/en active Pending
- 2019-11-15 AU AU2019264641A patent/AU2019264641A1/en not_active Abandoned
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US11274101B2 (en) | 2017-09-29 | 2022-03-15 | Takeda Pharmaceutical Company Limited | Heterocyclic compound |
Also Published As
Publication number | Publication date |
---|---|
JP2017513932A (en) | 2017-06-01 |
US20170166568A1 (en) | 2017-06-15 |
WO2015154023A1 (en) | 2015-10-08 |
MX2016013049A (en) | 2017-04-27 |
AP2016009496A0 (en) | 2016-10-31 |
CU24442B1 (en) | 2019-09-04 |
CL2016002516A1 (en) | 2017-05-12 |
US10011601B2 (en) | 2018-07-03 |
IL248050A0 (en) | 2016-11-30 |
KR20160133004A (en) | 2016-11-21 |
SG11201607920RA (en) | 2016-10-28 |
EA201691840A1 (en) | 2017-03-31 |
PE20170206A1 (en) | 2017-04-09 |
AU2019264641A1 (en) | 2019-12-05 |
CA2943874A1 (en) | 2015-10-08 |
JP6616821B2 (en) | 2019-12-04 |
CR20160496A (en) | 2017-01-02 |
CN107106559A (en) | 2017-08-29 |
JP2020040960A (en) | 2020-03-19 |
AU2015240519B2 (en) | 2019-08-15 |
EP3125895A1 (en) | 2017-02-08 |
CU20160150A7 (en) | 2017-02-02 |
DOP2016000270A (en) | 2016-12-15 |
AU2015240519A1 (en) | 2016-10-20 |
ECSP16084293A (en) | 2017-01-31 |
US10233182B2 (en) | 2019-03-19 |
EP3125895A4 (en) | 2017-08-30 |
US20180282332A1 (en) | 2018-10-04 |
MD20160116A2 (en) | 2017-04-30 |
PH12016501922A1 (en) | 2016-12-19 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US10233182B2 (en) | Substituted spirocyclic inhibitors of autotaxin | |
JP5816678B2 (en) | Condensed derivatives as PI3Kδ inhibitors | |
CA2894298C (en) | Substituted dihydroisoquinolinone compounds | |
AU2021203734A1 (en) | 5-chloro-2-difluoromethoxyphenyl pyrazolopyrimidine compounds which are JAK inhibitors | |
JP6592008B2 (en) | Substituted N- (2-amino) -2-oxoethylbenzamide inhibitors of autotaxin and their preparation and use in the treatment of LPA-dependent or LPA-mediated diseases | |
US12005054B2 (en) | Piperidinyl-3-(aryloxy)propanamides and propanoates | |
JP7035055B2 (en) | N- (Pyridine-2-yl) Pyridine-Sulfonamide Derivatives and Their Use in the Treatment of Diseases | |
UA114323C2 (en) | NAMPT INHIBITORS | |
JP6322275B2 (en) | N- (2-cyanoheterocyclyl) pyrazolopyridone as Janus kinase inhibitor | |
US11905294B2 (en) | Imidazo[1,5-a]pyrazine derivatives as PI3Kδ inhibitors | |
AU2022214618A1 (en) | Cdk2 inhibitors and methods of using the same | |
TW202122382A (en) | Hydantoin derivative | |
JP2023509495A (en) | RORγt INHIBITOR, PRODUCTION METHOD AND USE THEREOF | |
OA18996A (en) | Substituted Spirocyclic Inhibitors of Autotaxin | |
WO2024086094A1 (en) | Alkylamine-containing small molecule degraders of bcl6 | |
NZ787918A (en) | Pyridopyrimdinone CDK2/4/6 inhibitors | |
US20240092761A1 (en) | Quinazoline compounds and methods of use | |
EA040339B1 (en) | IMIDAZO[1,5-а]PYRAZINE DERIVATIVES AS PI3Kδ INHIBITORS |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AS | Assignment |
Owner name: PPD DEVELOPMENT, LP, TEXAS Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:BABISS, LEE;REEL/FRAME:049539/0758 Effective date: 20150729 Owner name: X-RX, INC., MASSACHUSETTS Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:MULVIHILL, MARK J.;REEL/FRAME:049539/0890 Effective date: 20150812 Owner name: X-CHEM, INC., MASSACHUSETTS Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:CLARK, MATTHEW A.;KEEFE, ANTHONY D.;ZHANG, YING;REEL/FRAME:049539/0776 Effective date: 20150731 Owner name: X-RX, INC., MASSACHUSETTS Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:X-CHEM, INC.;REEL/FRAME:049540/0053 Effective date: 20150803 Owner name: X-RX, INC., MASSACHUSETTS Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:PPD DEVELOPMENT, LP;REEL/FRAME:049539/0984 Effective date: 20150730 Owner name: X-RX, INC., MASSACHUSETTS Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:BIODURO, LLC;REEL/FRAME:049540/0115 Effective date: 20150804 Owner name: X-RX, INC., MASSACHUSETTS Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:PHARMACEUTICAL PRODUCT DEVELOPMENT, LLC;REEL/FRAME:049539/0938 Effective date: 20150731 Owner name: BIODURO, LLC, CALIFORNIA Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:NI, HAIHONG;RUEBSAM, FRANK;WANG, CE;AND OTHERS;SIGNING DATES FROM 20150729 TO 20150804;REEL/FRAME:049539/0857 Owner name: PHARMACEUTICAL PRODUCT DEVELOPMENT, LLC, NORTH CAR Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:RENZETTI, LOUIS;REEL/FRAME:049539/0727 Effective date: 20150729 |
|
STPP | Information on status: patent application and granting procedure in general |
Free format text: AWAITING TC RESP, ISSUE FEE PAYMENT RECEIVED |
|
STPP | Information on status: patent application and granting procedure in general |
Free format text: PUBLICATIONS -- ISSUE FEE PAYMENT VERIFIED |
|
STCB | Information on status: application discontinuation |
Free format text: ABANDONMENT FOR FAILURE TO CORRECT DRAWINGS/OATH/NONPUB REQUEST |