WO2016112236A1 - Cyclic ureas as inhibitors of rock - Google Patents
Cyclic ureas as inhibitors of rock Download PDFInfo
- Publication number
- WO2016112236A1 WO2016112236A1 PCT/US2016/012560 US2016012560W WO2016112236A1 WO 2016112236 A1 WO2016112236 A1 WO 2016112236A1 US 2016012560 W US2016012560 W US 2016012560W WO 2016112236 A1 WO2016112236 A1 WO 2016112236A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- substituted
- independently selected
- alkyl
- heterocyclyl
- occurrence
- Prior art date
Links
- 239000011435 rock Substances 0.000 title abstract description 39
- 239000003112 inhibitor Substances 0.000 title abstract description 12
- -1 Cyclic ureas Chemical class 0.000 title description 75
- 235000013877 carbamide Nutrition 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 136
- 150000003839 salts Chemical class 0.000 claims abstract description 66
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 17
- 210000002460 smooth muscle Anatomy 0.000 claims abstract description 6
- 230000003176 fibrotic effect Effects 0.000 claims abstract description 5
- 208000027866 inflammatory disease Diseases 0.000 claims abstract description 4
- 230000002981 neuropathic effect Effects 0.000 claims abstract 2
- 230000000771 oncological effect Effects 0.000 claims abstract 2
- 125000000217 alkyl group Chemical group 0.000 claims description 340
- 125000000623 heterocyclic group Chemical group 0.000 claims description 208
- 229910052801 chlorine Inorganic materials 0.000 claims description 203
- 229910052731 fluorine Inorganic materials 0.000 claims description 200
- 229910052794 bromium Inorganic materials 0.000 claims description 197
- 229910052739 hydrogen Inorganic materials 0.000 claims description 143
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 125
- 229910021481 rutherfordium Inorganic materials 0.000 claims description 115
- 125000003342 alkenyl group Chemical group 0.000 claims description 92
- 125000000304 alkynyl group Chemical group 0.000 claims description 91
- 229910052757 nitrogen Inorganic materials 0.000 claims description 91
- 101150063022 CHRD gene Proteins 0.000 claims description 82
- 101100274355 Danio rerio chd gene Proteins 0.000 claims description 82
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 75
- 125000003118 aryl group Chemical group 0.000 claims description 58
- 125000001072 heteroaryl group Chemical group 0.000 claims description 48
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 45
- 238000011282 treatment Methods 0.000 claims description 45
- 125000004452 carbocyclyl group Chemical group 0.000 claims description 44
- 101150105130 RORB gene Proteins 0.000 claims description 43
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 39
- 229910052702 rhenium Inorganic materials 0.000 claims description 36
- 229910052701 rubidium Inorganic materials 0.000 claims description 36
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 34
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 33
- 201000010099 disease Diseases 0.000 claims description 26
- 230000000694 effects Effects 0.000 claims description 16
- 208000024172 Cardiovascular disease Diseases 0.000 claims description 14
- 239000003937 drug carrier Substances 0.000 claims description 12
- 238000011321 prophylaxis Methods 0.000 claims description 12
- 206010020772 Hypertension Diseases 0.000 claims description 10
- 150000004885 piperazines Chemical class 0.000 claims description 9
- 108010041788 rho-Associated Kinases Proteins 0.000 claims description 9
- 102000000568 rho-Associated Kinases Human genes 0.000 claims description 9
- 208000006011 Stroke Diseases 0.000 claims description 8
- 208000035475 disorder Diseases 0.000 claims description 7
- 206010019280 Heart failures Diseases 0.000 claims description 5
- 230000001594 aberrant effect Effects 0.000 claims description 5
- GLUUGHFHXGJENI-UHFFFAOYSA-N diethylenediamine Natural products C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 5
- 206010002383 Angina Pectoris Diseases 0.000 claims description 4
- 201000001320 Atherosclerosis Diseases 0.000 claims description 4
- 208000002815 pulmonary hypertension Diseases 0.000 claims description 4
- 208000029078 coronary artery disease Diseases 0.000 claims description 3
- 239000003085 diluting agent Substances 0.000 claims description 3
- 208000023275 Autoimmune disease Diseases 0.000 claims 1
- 208000031481 Pathologic Constriction Diseases 0.000 claims 1
- 208000018262 Peripheral vascular disease Diseases 0.000 claims 1
- 206010047163 Vasospasm Diseases 0.000 claims 1
- 208000026106 cerebrovascular disease Diseases 0.000 claims 1
- 208000010125 myocardial infarction Diseases 0.000 claims 1
- 208000037804 stenosis Diseases 0.000 claims 1
- 230000036262 stenosis Effects 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 193
- 230000002526 effect on cardiovascular system Effects 0.000 abstract description 4
- 230000001363 autoimmune Effects 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 250
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 230
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 161
- 239000000203 mixture Substances 0.000 description 160
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical class OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 130
- 239000000243 solution Substances 0.000 description 116
- 238000005160 1H NMR spectroscopy Methods 0.000 description 113
- 239000011541 reaction mixture Substances 0.000 description 109
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 103
- 235000019439 ethyl acetate Nutrition 0.000 description 102
- 239000007787 solid Substances 0.000 description 97
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 89
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 74
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 74
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 72
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 70
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 69
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 66
- 239000002904 solvent Substances 0.000 description 66
- 229910052938 sodium sulfate Inorganic materials 0.000 description 64
- 238000004128 high performance liquid chromatography Methods 0.000 description 59
- 239000007832 Na2SO4 Substances 0.000 description 58
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 55
- 235000002639 sodium chloride Nutrition 0.000 description 54
- 239000012267 brine Substances 0.000 description 52
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 52
- 239000000543 intermediate Substances 0.000 description 49
- 238000002360 preparation method Methods 0.000 description 48
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 42
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 42
- 239000012453 solvate Substances 0.000 description 38
- 229910000027 potassium carbonate Inorganic materials 0.000 description 37
- 239000000651 prodrug Substances 0.000 description 35
- 229940002612 prodrug Drugs 0.000 description 35
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 34
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 34
- 238000006243 chemical reaction Methods 0.000 description 34
- 235000011152 sodium sulphate Nutrition 0.000 description 33
- 239000000047 product Substances 0.000 description 31
- 229910000104 sodium hydride Inorganic materials 0.000 description 31
- 239000012044 organic layer Substances 0.000 description 30
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 28
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 28
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 27
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 25
- 239000012391 XPhos Pd G2 Substances 0.000 description 25
- 239000012043 crude product Substances 0.000 description 25
- 238000003818 flash chromatography Methods 0.000 description 25
- 238000002953 preparative HPLC Methods 0.000 description 25
- 238000000746 purification Methods 0.000 description 23
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 22
- 239000000706 filtrate Substances 0.000 description 22
- YAMHXTCMCPHKLN-UHFFFAOYSA-N imidazolidin-2-one Chemical compound O=C1NCCN1 YAMHXTCMCPHKLN-UHFFFAOYSA-N 0.000 description 22
- 235000015320 potassium carbonate Nutrition 0.000 description 22
- IPISOFJLWYBCAV-UHFFFAOYSA-N tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole-1-carboxylate Chemical compound C1=NN(C(=O)OC(C)(C)C)C=C1B1OC(C)(C)C(C)(C)O1 IPISOFJLWYBCAV-UHFFFAOYSA-N 0.000 description 22
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 21
- 239000002585 base Substances 0.000 description 20
- 239000003921 oil Substances 0.000 description 20
- 239000003814 drug Substances 0.000 description 18
- 238000003786 synthesis reaction Methods 0.000 description 18
- 238000004293 19F NMR spectroscopy Methods 0.000 description 17
- 229910052799 carbon Inorganic materials 0.000 description 17
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 17
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 17
- 230000015572 biosynthetic process Effects 0.000 description 16
- 125000004432 carbon atom Chemical group C* 0.000 description 16
- 239000012071 phase Substances 0.000 description 16
- 239000003208 petroleum Substances 0.000 description 15
- 125000001424 substituent group Chemical group 0.000 description 15
- 239000004202 carbamide Substances 0.000 description 14
- 238000010828 elution Methods 0.000 description 14
- 239000002245 particle Substances 0.000 description 14
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 13
- 150000001412 amines Chemical class 0.000 description 13
- 229960004132 diethyl ether Drugs 0.000 description 13
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 13
- 235000017557 sodium bicarbonate Nutrition 0.000 description 13
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 12
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 12
- 229910052796 boron Inorganic materials 0.000 description 12
- 239000006184 cosolvent Substances 0.000 description 12
- 239000012074 organic phase Substances 0.000 description 12
- 125000004429 atom Chemical group 0.000 description 11
- 125000005842 heteroatom Chemical group 0.000 description 11
- 239000007788 liquid Substances 0.000 description 11
- 229920006395 saturated elastomer Polymers 0.000 description 11
- 239000000377 silicon dioxide Substances 0.000 description 11
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 11
- GRRIMVWABNHKBX-UHFFFAOYSA-N (3-methoxyphenyl)methanamine Chemical compound COC1=CC=CC(CN)=C1 GRRIMVWABNHKBX-UHFFFAOYSA-N 0.000 description 10
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 10
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 10
- 229910052681 coesite Inorganic materials 0.000 description 10
- 229910052906 cristobalite Inorganic materials 0.000 description 10
- 229940079593 drug Drugs 0.000 description 10
- 238000001914 filtration Methods 0.000 description 10
- 229910052682 stishovite Inorganic materials 0.000 description 10
- 229910052905 tridymite Inorganic materials 0.000 description 10
- WDFQBORIUYODSI-UHFFFAOYSA-N 4-bromoaniline Chemical compound NC1=CC=C(Br)C=C1 WDFQBORIUYODSI-UHFFFAOYSA-N 0.000 description 9
- 229910052760 oxygen Inorganic materials 0.000 description 9
- 229910052717 sulfur Inorganic materials 0.000 description 9
- CZQIJQFTRGDODI-UHFFFAOYSA-N 1-bromo-4-isocyanatobenzene Chemical compound BrC1=CC=C(N=C=O)C=C1 CZQIJQFTRGDODI-UHFFFAOYSA-N 0.000 description 8
- PHRJTGPFEAUEBC-UHFFFAOYSA-N 1-fluoro-3-(isocyanatomethyl)benzene Chemical compound FC1=CC=CC(CN=C=O)=C1 PHRJTGPFEAUEBC-UHFFFAOYSA-N 0.000 description 8
- 239000002253 acid Substances 0.000 description 8
- 238000003556 assay Methods 0.000 description 8
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical group NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 8
- 150000001721 carbon Chemical group 0.000 description 8
- 238000004587 chromatography analysis Methods 0.000 description 8
- 150000002148 esters Chemical class 0.000 description 8
- 239000012948 isocyanate Substances 0.000 description 8
- 150000002513 isocyanates Chemical class 0.000 description 8
- 238000004519 manufacturing process Methods 0.000 description 8
- 125000002950 monocyclic group Chemical group 0.000 description 8
- 239000002244 precipitate Substances 0.000 description 8
- 230000008569 process Effects 0.000 description 8
- 235000012239 silicon dioxide Nutrition 0.000 description 8
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 7
- 239000005695 Ammonium acetate Substances 0.000 description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 7
- 125000003545 alkoxy group Chemical group 0.000 description 7
- 235000019257 ammonium acetate Nutrition 0.000 description 7
- 229940043376 ammonium acetate Drugs 0.000 description 7
- 239000003795 chemical substances by application Substances 0.000 description 7
- OENICUBCLXKLJQ-UHFFFAOYSA-N ethyl 2,3-dibromopropanoate Chemical compound CCOC(=O)C(Br)CBr OENICUBCLXKLJQ-UHFFFAOYSA-N 0.000 description 7
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 7
- 239000000284 extract Substances 0.000 description 7
- 239000000725 suspension Substances 0.000 description 7
- BAFHKFIYBFCXAU-UHFFFAOYSA-N (2-fluoro-5-methoxyphenyl)methanamine Chemical compound COC1=CC=C(F)C(CN)=C1 BAFHKFIYBFCXAU-UHFFFAOYSA-N 0.000 description 6
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 6
- 101100356682 Caenorhabditis elegans rho-1 gene Proteins 0.000 description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 101150111584 RHOA gene Proteins 0.000 description 6
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
- 238000006069 Suzuki reaction reaction Methods 0.000 description 6
- 230000029936 alkylation Effects 0.000 description 6
- 238000005804 alkylation reaction Methods 0.000 description 6
- 239000012039 electrophile Substances 0.000 description 6
- 125000004438 haloalkoxy group Chemical group 0.000 description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 6
- 239000010410 layer Substances 0.000 description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
- 239000002480 mineral oil Substances 0.000 description 6
- 235000010446 mineral oil Nutrition 0.000 description 6
- 239000012312 sodium hydride Substances 0.000 description 6
- 241000894007 species Species 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 238000004808 supercritical fluid chromatography Methods 0.000 description 6
- QVSVMNXRLWSNGS-UHFFFAOYSA-N (3-fluorophenyl)methanamine Chemical group NCC1=CC=CC(F)=C1 QVSVMNXRLWSNGS-UHFFFAOYSA-N 0.000 description 5
- QWGAJMDRYUIPIT-UHFFFAOYSA-N 1-(isocyanatomethyl)-3-methoxybenzene Chemical group COC1=CC=CC(CN=C=O)=C1 QWGAJMDRYUIPIT-UHFFFAOYSA-N 0.000 description 5
- BCMYXYHEMGPZJN-UHFFFAOYSA-N 1-chloro-2-isocyanatoethane Chemical compound ClCCN=C=O BCMYXYHEMGPZJN-UHFFFAOYSA-N 0.000 description 5
- VCYCTWDKBKJCME-UHFFFAOYSA-N 3-(4-bromophenyl)-4-(hydroxymethyl)-1-[(3-methoxyphenyl)methyl]imidazolidin-2-one Chemical compound BrC1=CC=C(C=C1)N1C(N(CC1CO)CC1=CC(=CC=C1)OC)=O VCYCTWDKBKJCME-UHFFFAOYSA-N 0.000 description 5
- 208000010228 Erectile Dysfunction Diseases 0.000 description 5
- 239000012448 Lithium borohydride Substances 0.000 description 5
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 5
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 5
- 241000700159 Rattus Species 0.000 description 5
- 239000004480 active ingredient Substances 0.000 description 5
- 125000002619 bicyclic group Chemical group 0.000 description 5
- 125000002618 bicyclic heterocycle group Chemical group 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 239000002552 dosage form Substances 0.000 description 5
- FBUCEIBCUAHNFD-UHFFFAOYSA-N ethyl 2-bromo-3-(4-bromoanilino)propanoate Chemical compound BrC(C(=O)OCC)CNC1=CC=C(C=C1)Br FBUCEIBCUAHNFD-UHFFFAOYSA-N 0.000 description 5
- 238000009472 formulation Methods 0.000 description 5
- 125000001188 haloalkyl group Chemical group 0.000 description 5
- 239000001257 hydrogen Substances 0.000 description 5
- 230000007062 hydrolysis Effects 0.000 description 5
- 238000006460 hydrolysis reaction Methods 0.000 description 5
- 201000001881 impotence Diseases 0.000 description 5
- 125000001041 indolyl group Chemical group 0.000 description 5
- 230000005764 inhibitory process Effects 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 231100000252 nontoxic Toxicity 0.000 description 5
- 230000003000 nontoxic effect Effects 0.000 description 5
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 5
- 230000019491 signal transduction Effects 0.000 description 5
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 5
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 5
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 125000004434 sulfur atom Chemical group 0.000 description 5
- 229940124597 therapeutic agent Drugs 0.000 description 5
- 125000001544 thienyl group Chemical group 0.000 description 5
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 5
- CJWGCBRQAHCVHW-SSDOTTSWSA-N (1r)-1-(3-methoxyphenyl)ethanamine Chemical compound COC1=CC=CC([C@@H](C)N)=C1 CJWGCBRQAHCVHW-SSDOTTSWSA-N 0.000 description 4
- ZKSOJQDNSNJIQW-UHFFFAOYSA-N 1-(bromomethyl)-3-methoxybenzene Chemical compound COC1=CC=CC(CBr)=C1 ZKSOJQDNSNJIQW-UHFFFAOYSA-N 0.000 description 4
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 4
- PAQZWJGSJMLPMG-UHFFFAOYSA-N 2,4,6-tripropyl-1,3,5,2$l^{5},4$l^{5},6$l^{5}-trioxatriphosphinane 2,4,6-trioxide Chemical compound CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1 PAQZWJGSJMLPMG-UHFFFAOYSA-N 0.000 description 4
- QSKPIOLLBIHNAC-UHFFFAOYSA-N 2-chloro-acetaldehyde Chemical compound ClCC=O QSKPIOLLBIHNAC-UHFFFAOYSA-N 0.000 description 4
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 4
- CRIXOEJNMCGMFU-UHFFFAOYSA-N BrC1=CC=C(C=C1)NC(=O)NC(CO)(C)C Chemical compound BrC1=CC=C(C=C1)NC(=O)NC(CO)(C)C CRIXOEJNMCGMFU-UHFFFAOYSA-N 0.000 description 4
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 4
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 4
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- 241000124008 Mammalia Species 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 229920002472 Starch Polymers 0.000 description 4
- 239000013543 active substance Substances 0.000 description 4
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 4
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 4
- 125000002527 bicyclic carbocyclic group Chemical group 0.000 description 4
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 4
- YSHOWEKUVWPFNR-UHFFFAOYSA-N burgess reagent Chemical compound CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC YSHOWEKUVWPFNR-UHFFFAOYSA-N 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 238000004296 chiral HPLC Methods 0.000 description 4
- 239000012230 colorless oil Substances 0.000 description 4
- 229910052805 deuterium Inorganic materials 0.000 description 4
- WAFOXBLHEIRCAP-UHFFFAOYSA-N ethyl 2-chloro-3-[(3-methoxyphenyl)methylamino]propanoate Chemical compound ClC(C(=O)OCC)CNCC1=CC(=CC=C1)OC WAFOXBLHEIRCAP-UHFFFAOYSA-N 0.000 description 4
- NGOGFTYYXHNFQH-UHFFFAOYSA-N fasudil Chemical compound C=1C=CC2=CN=CC=C2C=1S(=O)(=O)N1CCCNCC1 NGOGFTYYXHNFQH-UHFFFAOYSA-N 0.000 description 4
- 229960002435 fasudil Drugs 0.000 description 4
- 125000002541 furyl group Chemical group 0.000 description 4
- 125000002883 imidazolyl group Chemical group 0.000 description 4
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 4
- 208000001286 intracranial vasospasm Diseases 0.000 description 4
- 125000000842 isoxazolyl group Chemical group 0.000 description 4
- 208000017169 kidney disease Diseases 0.000 description 4
- 125000001624 naphthyl group Chemical group 0.000 description 4
- 239000012299 nitrogen atmosphere Substances 0.000 description 4
- 125000002971 oxazolyl group Chemical group 0.000 description 4
- 125000004430 oxygen atom Chemical group O* 0.000 description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 4
- 239000004033 plastic Substances 0.000 description 4
- 229920003023 plastic Polymers 0.000 description 4
- 125000003373 pyrazinyl group Chemical group 0.000 description 4
- 125000003226 pyrazolyl group Chemical group 0.000 description 4
- 125000004076 pyridyl group Chemical group 0.000 description 4
- 230000002829 reductive effect Effects 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- 239000008107 starch Substances 0.000 description 4
- 235000019698 starch Nutrition 0.000 description 4
- 239000003826 tablet Substances 0.000 description 4
- 125000003831 tetrazolyl group Chemical group 0.000 description 4
- 125000000335 thiazolyl group Chemical group 0.000 description 4
- 125000004306 triazinyl group Chemical group 0.000 description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 4
- 238000001665 trituration Methods 0.000 description 4
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 3
- XOAWAEJRZAUCBQ-UHFFFAOYSA-N 1-(4-bromophenyl)-4,4-dimethylimidazolidin-2-one Chemical compound BrC1=CC=C(C=C1)N1C(NC(C1)(C)C)=O XOAWAEJRZAUCBQ-UHFFFAOYSA-N 0.000 description 3
- CKPQCRZJUMIZSZ-UHFFFAOYSA-N 1-(5-bromopyridin-2-yl)-3-(2,2-dimethoxyethyl)urea Chemical compound BrC=1C=CC(=NC=1)NC(=O)NCC(OC)OC CKPQCRZJUMIZSZ-UHFFFAOYSA-N 0.000 description 3
- NNBQSRWXJWCBRZ-OAHLLOKOSA-N 1-[(1R)-1-(3-methoxyphenyl)ethyl]-3-[4-(1H-pyrazol-4-yl)phenyl]imidazolidin-2-one Chemical compound N1N=CC(=C1)C1=CC=C(C=C1)N1C(N(CC1)[C@H](C)C1=CC(=CC=C1)OC)=O NNBQSRWXJWCBRZ-OAHLLOKOSA-N 0.000 description 3
- 125000005955 1H-indazolyl group Chemical group 0.000 description 3
- QKWWDTYDYOFRJL-UHFFFAOYSA-N 2,2-dimethoxyethanamine Chemical compound COC(CN)OC QKWWDTYDYOFRJL-UHFFFAOYSA-N 0.000 description 3
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 3
- QGQSOHAZQJREQX-UHFFFAOYSA-N 3-(4-bromophenyl)-1-[(3-methoxyphenyl)methyl]-2-oxoimidazolidine-4-carboxylic acid Chemical compound COC1=CC=CC(CN2CC(N(C2=O)C2=CC=C(Br)C=C2)C(O)=O)=C1 QGQSOHAZQJREQX-UHFFFAOYSA-N 0.000 description 3
- XYNBYRIOJLMJDM-UHFFFAOYSA-N 3-(4-bromophenyl)-1h-imidazol-2-one Chemical compound C1=CC(Br)=CC=C1N1C(=O)NC=C1 XYNBYRIOJLMJDM-UHFFFAOYSA-N 0.000 description 3
- LKJYNYKTZLTHJN-UHFFFAOYSA-N 3-cyclopropylaniline Chemical compound NC1=CC=CC(C2CC2)=C1 LKJYNYKTZLTHJN-UHFFFAOYSA-N 0.000 description 3
- YFLOLCNMBKTBQE-UHFFFAOYSA-N 4-(hydroxymethyl)-1-[(3-methoxyphenyl)methyl]-3-[4-(1H-pyrazol-4-yl)phenyl]imidazolidin-2-one Chemical compound N1N=CC(=C1)C1=CC=C(C=C1)N1C(N(CC1CO)CC1=CC(=CC=C1)OC)=O YFLOLCNMBKTBQE-UHFFFAOYSA-N 0.000 description 3
- IDDDVXIUIXWAGJ-DDSAHXNVSA-N 4-[(1r)-1-aminoethyl]-n-pyridin-4-ylcyclohexane-1-carboxamide;dihydrochloride Chemical compound Cl.Cl.C1CC([C@H](N)C)CCC1C(=O)NC1=CC=NC=C1 IDDDVXIUIXWAGJ-DDSAHXNVSA-N 0.000 description 3
- 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 3
- 206010003225 Arteriospasm coronary Diseases 0.000 description 3
- VAFZZUKCXFHFMN-UHFFFAOYSA-N BrC1=CC=C(C=C1)NC(=O)NCC(OC)OC Chemical compound BrC1=CC=C(C=C1)NC(=O)NCC(OC)OC VAFZZUKCXFHFMN-UHFFFAOYSA-N 0.000 description 3
- IXMVSHLVCSJCQJ-CQSZACIVSA-N BrC1=CC=C(C=C1)NC(=O)N[C@@H](CO[Si](C)(C)C(C)(C)C)CO Chemical compound BrC1=CC=C(C=C1)NC(=O)N[C@@H](CO[Si](C)(C)C(C)(C)C)CO IXMVSHLVCSJCQJ-CQSZACIVSA-N 0.000 description 3
- 208000003890 Coronary Vasospasm Diseases 0.000 description 3
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 3
- 208000010412 Glaucoma Diseases 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 241000282414 Homo sapiens Species 0.000 description 3
- 101000669921 Homo sapiens Rho-associated protein kinase 2 Proteins 0.000 description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 3
- 229910003204 NH2 Inorganic materials 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- 206010028980 Neoplasm Diseases 0.000 description 3
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 3
- 108091000080 Phosphotransferase Proteins 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 206010063837 Reperfusion injury Diseases 0.000 description 3
- 102100039314 Rho-associated protein kinase 2 Human genes 0.000 description 3
- 125000001931 aliphatic group Chemical group 0.000 description 3
- 208000006673 asthma Diseases 0.000 description 3
- 125000005605 benzo group Chemical group 0.000 description 3
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 3
- 239000011230 binding agent Substances 0.000 description 3
- 230000036772 blood pressure Effects 0.000 description 3
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 3
- 201000011510 cancer Diseases 0.000 description 3
- 239000000969 carrier Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 235000008504 concentrate Nutrition 0.000 description 3
- 239000012141 concentrate Substances 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 description 3
- 201000011634 coronary artery vasospasm Diseases 0.000 description 3
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 3
- 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 3
- NLUNLVTVUDIHFE-UHFFFAOYSA-N cyclooctylcyclooctane Chemical compound C1CCCCCCC1C1CCCCCCC1 NLUNLVTVUDIHFE-UHFFFAOYSA-N 0.000 description 3
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 3
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 3
- XXBNIZMWCZGAQO-JTQLQIEISA-N ethyl (2S)-2-[(4-bromophenyl)carbamoylamino]-3-hydroxypropanoate Chemical compound BrC1=CC=C(C=C1)NC(N[C@H](C(=O)OCC)CO)=O XXBNIZMWCZGAQO-JTQLQIEISA-N 0.000 description 3
- RNCZPRFKCVSQFD-UHFFFAOYSA-N ethyl 1-(4-bromophenyl)-3-[(3-methoxyphenyl)methyl]-2-oxoimidazolidine-4-carboxylate Chemical compound BrC1=CC=C(C=C1)N1C(N(C(C1)C(=O)OCC)CC1=CC(=CC=C1)OC)=O RNCZPRFKCVSQFD-UHFFFAOYSA-N 0.000 description 3
- JWTXPITXBAPBLU-UHFFFAOYSA-N ethyl 1-[(3-methoxyphenyl)methyl]aziridine-2-carboxylate Chemical compound COC=1C=C(CN2C(C2)C(=O)OCC)C=CC=1 JWTXPITXBAPBLU-UHFFFAOYSA-N 0.000 description 3
- XQTDJCPVBBMKQC-UHFFFAOYSA-N ethyl 3-(4-bromophenyl)-1-[(3-methoxyphenyl)methyl]-2-oxoimidazolidine-4-carboxylate Chemical compound BrC1=CC=C(C=C1)N1C(N(CC1C(=O)OCC)CC1=CC(=CC=C1)OC)=O XQTDJCPVBBMKQC-UHFFFAOYSA-N 0.000 description 3
- PDFLNJUJXGLBPQ-UHFFFAOYSA-N ethyl 3-[(4-bromophenyl)carbamoyl-[(3-methoxyphenyl)methyl]amino]-2-chloropropanoate Chemical compound BrC1=CC=C(C=C1)NC(N(CC1=CC(=CC=C1)OC)CC(C(=O)OCC)Cl)=O PDFLNJUJXGLBPQ-UHFFFAOYSA-N 0.000 description 3
- 239000008103 glucose Substances 0.000 description 3
- 150000002430 hydrocarbons Chemical group 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 125000002632 imidazolidinyl group Chemical group 0.000 description 3
- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 238000001990 intravenous administration Methods 0.000 description 3
- 208000028867 ischemia Diseases 0.000 description 3
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 3
- 239000000314 lubricant Substances 0.000 description 3
- 235000019359 magnesium stearate Nutrition 0.000 description 3
- NXPHGHWWQRMDIA-UHFFFAOYSA-M magnesium;carbanide;bromide Chemical compound [CH3-].[Mg+2].[Br-] NXPHGHWWQRMDIA-UHFFFAOYSA-M 0.000 description 3
- MYWUZJCMWCOHBA-VIFPVBQESA-N methamphetamine Chemical compound CN[C@@H](C)CC1=CC=CC=C1 MYWUZJCMWCOHBA-VIFPVBQESA-N 0.000 description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 3
- 150000007522 mineralic acids Chemical class 0.000 description 3
- 125000002757 morpholinyl group Chemical group 0.000 description 3
- 230000003287 optical effect Effects 0.000 description 3
- 125000001715 oxadiazolyl group Chemical group 0.000 description 3
- 125000000160 oxazolidinyl group Chemical group 0.000 description 3
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 3
- 239000000123 paper Substances 0.000 description 3
- PUBVIAHPSLGSFN-UHFFFAOYSA-N phenyl n-(5-bromopyridin-2-yl)carbamate Chemical compound N1=CC(Br)=CC=C1NC(=O)OC1=CC=CC=C1 PUBVIAHPSLGSFN-UHFFFAOYSA-N 0.000 description 3
- 102000020233 phosphotransferase Human genes 0.000 description 3
- 125000004193 piperazinyl group Chemical group 0.000 description 3
- 125000003386 piperidinyl group Chemical group 0.000 description 3
- 125000003367 polycyclic group Polymers 0.000 description 3
- 239000002243 precursor Substances 0.000 description 3
- 125000006239 protecting group Chemical group 0.000 description 3
- 125000000714 pyrimidinyl group Chemical group 0.000 description 3
- 125000000168 pyrrolyl group Chemical group 0.000 description 3
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 3
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 238000006722 reduction reaction Methods 0.000 description 3
- 230000001105 regulatory effect Effects 0.000 description 3
- 239000012279 sodium borohydride Substances 0.000 description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 description 3
- 235000000346 sugar Nutrition 0.000 description 3
- KIGIRYPHYKALIK-UHFFFAOYSA-N tert-butyl N-(3-cyclopropylphenyl)carbamate Chemical compound C1(CC1)C=1C=C(C=CC=1)NC(OC(C)(C)C)=O KIGIRYPHYKALIK-UHFFFAOYSA-N 0.000 description 3
- CWPBIJUKARSYKD-UHFFFAOYSA-N tert-butyl N-(4-bromo-3-cyclopropylphenyl)carbamate Chemical compound BrC1=C(C=C(C=C1)NC(OC(C)(C)C)=O)C1CC1 CWPBIJUKARSYKD-UHFFFAOYSA-N 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 3
- CXWXQJXEFPUFDZ-UHFFFAOYSA-N tetralin Chemical compound C1=CC=C2CCCCC2=C1 CXWXQJXEFPUFDZ-UHFFFAOYSA-N 0.000 description 3
- 238000002560 therapeutic procedure Methods 0.000 description 3
- 230000009466 transformation Effects 0.000 description 3
- 238000000844 transformation Methods 0.000 description 3
- 125000001425 triazolyl group Chemical group 0.000 description 3
- LRFWYBZWRQWZIM-UHFFFAOYSA-N (2-fluorophenyl)methanamine Chemical group NCC1=CC=CC=C1F LRFWYBZWRQWZIM-UHFFFAOYSA-N 0.000 description 2
- VAVHMEQFYYBAPR-ITWZMISCSA-N (e,3r,5s)-7-[4-(4-fluorophenyl)-1-phenyl-2-propan-2-ylpyrrol-3-yl]-3,5-dihydroxyhept-6-enoic acid Chemical compound CC(C)C1=C(\C=C\[C@@H](O)C[C@@H](O)CC(O)=O)C(C=2C=CC(F)=CC=2)=CN1C1=CC=CC=C1 VAVHMEQFYYBAPR-ITWZMISCSA-N 0.000 description 2
- 125000004514 1,2,4-thiadiazolyl group Chemical group 0.000 description 2
- BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 description 2
- TZFCICDGDYSTCO-CYBMUJFWSA-N 1-(4-bromophenyl)-1-(2-chloroethyl)-3-[(1R)-1-(3-methoxyphenyl)ethyl]urea Chemical compound BrC1=CC=C(C=C1)N(C(=O)N[C@H](C)C1=CC(=CC=C1)OC)CCCl TZFCICDGDYSTCO-CYBMUJFWSA-N 0.000 description 2
- WEBSBVNASIARDC-UHFFFAOYSA-N 1-(4-bromophenyl)-3-(2-chloroethyl)urea Chemical compound ClCCNC(=O)NC1=CC=C(Br)C=C1 WEBSBVNASIARDC-UHFFFAOYSA-N 0.000 description 2
- HZGFMAINEPFALC-UHFFFAOYSA-N 1-(5-bromo-4-fluoropyridin-2-yl)-3-(2-chloroethyl)urea Chemical compound BrC=1C(=CC(=NC=1)NC(=O)NCCCl)F HZGFMAINEPFALC-UHFFFAOYSA-N 0.000 description 2
- MLBLLDLHRJCOIB-UHFFFAOYSA-N 1-(5-bromo-4-fluoropyridin-2-yl)imidazolidin-2-one Chemical compound BrC=1C(=CC(=NC=1)N1C(NCC1)=O)F MLBLLDLHRJCOIB-UHFFFAOYSA-N 0.000 description 2
- NMJLMTJOGLHZFG-UHFFFAOYSA-N 1-(5-bromo-6-methoxypyridin-2-yl)-3-(2-chloroethyl)urea Chemical compound BrC=1C=CC(=NC=1OC)NC(=O)NCCCl NMJLMTJOGLHZFG-UHFFFAOYSA-N 0.000 description 2
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 2
- DFPYXQYWILNVAU-UHFFFAOYSA-N 1-hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1.C1=CC=C2N(O)N=NC2=C1 DFPYXQYWILNVAU-UHFFFAOYSA-N 0.000 description 2
- BPXKZEMBEZGUAH-UHFFFAOYSA-N 2-(chloromethoxy)ethyl-trimethylsilane Chemical compound C[Si](C)(C)CCOCCl BPXKZEMBEZGUAH-UHFFFAOYSA-N 0.000 description 2
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 2
- HACRKYQRZABURO-UHFFFAOYSA-N 2-phenylethyl isocyanate Chemical compound O=C=NCCC1=CC=CC=C1 HACRKYQRZABURO-UHFFFAOYSA-N 0.000 description 2
- VSCBATMPTLKTOV-UHFFFAOYSA-N 2-tert-butylimino-n,n-diethyl-1,3-dimethyl-1,3,2$l^{5}-diazaphosphinan-2-amine Chemical compound CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C VSCBATMPTLKTOV-UHFFFAOYSA-N 0.000 description 2
- XJEJLZQJTWXQAB-UHFFFAOYSA-N 3-(5-bromopyridin-2-yl)-1H-imidazol-2-one Chemical compound BrC=1C=CC(=NC=1)N1C(NC=C1)=O XJEJLZQJTWXQAB-UHFFFAOYSA-N 0.000 description 2
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 2
- NDCFPYSZIBBKFT-UHFFFAOYSA-N 4-(hydroxymethyl)-3-[(3-methoxyphenyl)methyl]-1-[4-(1H-pyrazol-4-yl)phenyl]imidazolidin-2-one Chemical compound N1N=CC(=C1)C1=CC=C(C=C1)N1C(N(C(C1)CO)CC1=CC(=CC=C1)OC)=O NDCFPYSZIBBKFT-UHFFFAOYSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- WRFYIYOXJWKONR-UHFFFAOYSA-N 4-bromo-2-methoxyaniline Chemical compound COC1=CC(Br)=CC=C1N WRFYIYOXJWKONR-UHFFFAOYSA-N 0.000 description 2
- UVDWSNIVPGNZFL-UHFFFAOYSA-N 4-bromo-3-cyclopropylaniline Chemical compound NC1=CC=C(Br)C(C2CC2)=C1 UVDWSNIVPGNZFL-UHFFFAOYSA-N 0.000 description 2
- RUTNWXBHRAIQSP-UHFFFAOYSA-N 4-bromo-3-methoxyaniline Chemical compound COC1=CC(N)=CC=C1Br RUTNWXBHRAIQSP-UHFFFAOYSA-N 0.000 description 2
- NTZTWGPSRYUWFM-UHFFFAOYSA-N 4-bromo-N-(2-chloroethyl)-3-methoxyaniline Chemical compound BrC1=C(C=C(NCCCl)C=C1)OC NTZTWGPSRYUWFM-UHFFFAOYSA-N 0.000 description 2
- XIXFJFPXOWYEJY-UHFFFAOYSA-N 4-bromo-n-(2-chloroethyl)aniline Chemical compound ClCCNC1=CC=C(Br)C=C1 XIXFJFPXOWYEJY-UHFFFAOYSA-N 0.000 description 2
- FLDSMVTWEZKONL-AWEZNQCLSA-N 5,5-dimethyl-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-1,4,7,8-tetrahydrooxepino[4,5-c]pyrazole-3-carboxamide Chemical compound CC1(CC2=C(NN=C2C(=O)N[C@@H]2C(N(C3=C(OC2)C=CC=C3)C)=O)CCO1)C FLDSMVTWEZKONL-AWEZNQCLSA-N 0.000 description 2
- ZMGMDXCADSRNCX-UHFFFAOYSA-N 5,6-dihydroxy-1,3-diazepan-2-one Chemical class OC1CNC(=O)NCC1O ZMGMDXCADSRNCX-UHFFFAOYSA-N 0.000 description 2
- 208000024827 Alzheimer disease Diseases 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- UMYTZPUJKKRUDX-CYBMUJFWSA-N BrC1=CC=C(C=C1)N1C(N[C@H](C1)CO[Si](C)(C)C(C)(C)C)=O Chemical compound BrC1=CC=C(C=C1)N1C(N[C@H](C1)CO[Si](C)(C)C(C)(C)C)=O UMYTZPUJKKRUDX-CYBMUJFWSA-N 0.000 description 2
- PSZZAFOZOHZNPU-HNNXBMFYSA-N BrC1=CC=C(C=C1)NC(N[C@H](C(=O)OCC)CO[Si](C)(C)C(C)(C)C)=O Chemical compound BrC1=CC=C(C=C1)NC(N[C@H](C(=O)OCC)CO[Si](C)(C)C(C)(C)C)=O PSZZAFOZOHZNPU-HNNXBMFYSA-N 0.000 description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 2
- 201000000057 Coronary Stenosis Diseases 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N Formic acid Chemical compound OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 239000007818 Grignard reagent Substances 0.000 description 2
- 239000007995 HEPES buffer Substances 0.000 description 2
- 208000022559 Inflammatory bowel disease Diseases 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- GSCCALZHGUWNJW-UHFFFAOYSA-N N-Cyclohexyl-N-methylcyclohexanamine Chemical compound C1CCCCC1N(C)C1CCCCC1 GSCCALZHGUWNJW-UHFFFAOYSA-N 0.000 description 2
- 150000001204 N-oxides Chemical class 0.000 description 2
- 208000012902 Nervous system disease Diseases 0.000 description 2
- 208000025966 Neurological disease Diseases 0.000 description 2
- YNPNZTXNASCQKK-UHFFFAOYSA-N Phenanthrene Natural products C1=CC=C2C3=CC=CC=C3C=CC2=C1 YNPNZTXNASCQKK-UHFFFAOYSA-N 0.000 description 2
- BHHGXPLMPWCGHP-UHFFFAOYSA-N Phenethylamine Chemical group NCCC1=CC=CC=C1 BHHGXPLMPWCGHP-UHFFFAOYSA-N 0.000 description 2
- 102000010780 Platelet-Derived Growth Factor Human genes 0.000 description 2
- 108010038512 Platelet-Derived Growth Factor Proteins 0.000 description 2
- 229920000954 Polyglycolide Polymers 0.000 description 2
- 239000004793 Polystyrene Substances 0.000 description 2
- 201000004681 Psoriasis Diseases 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- 239000005864 Sulphur Substances 0.000 description 2
- 229910021626 Tin(II) chloride Inorganic materials 0.000 description 2
- DGEZNRSVGBDHLK-UHFFFAOYSA-N [1,10]phenanthroline Chemical compound C1=CN=C2C3=NC=CC=C3C=CC2=C1 DGEZNRSVGBDHLK-UHFFFAOYSA-N 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 description 2
- 125000004450 alkenylene group Chemical group 0.000 description 2
- 125000002947 alkylene group Chemical group 0.000 description 2
- 125000004419 alkynylene group Chemical group 0.000 description 2
- 238000010640 amide synthesis reaction Methods 0.000 description 2
- 235000019270 ammonium chloride Nutrition 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 239000012298 atmosphere Substances 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 125000004604 benzisothiazolyl group Chemical group S1N=C(C2=C1C=CC=C2)* 0.000 description 2
- 125000004603 benzisoxazolyl group Chemical group O1N=C(C2=C1C=CC=C2)* 0.000 description 2
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 2
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 2
- 125000004935 benzoxazolinyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 2
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 2
- 125000005512 benztetrazolyl group Chemical group 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 description 2
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 2
- 125000000609 carbazolyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3NC12)* 0.000 description 2
- 125000002837 carbocyclic group Chemical group 0.000 description 2
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- 239000011111 cardboard Substances 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- 230000012292 cell migration Effects 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 125000003016 chromanyl group Chemical group O1C(CCC2=CC=CC=C12)* 0.000 description 2
- 239000007891 compressed tablet Substances 0.000 description 2
- 230000008602 contraction Effects 0.000 description 2
- 229920001577 copolymer Polymers 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- 125000001162 cycloheptenyl group Chemical group C1(=CCCCCC1)* 0.000 description 2
- DEZRYPDIMOWBDS-UHFFFAOYSA-N dcm dichloromethane Chemical compound ClCCl.ClCCl DEZRYPDIMOWBDS-UHFFFAOYSA-N 0.000 description 2
- 230000034994 death Effects 0.000 description 2
- 231100000517 death Toxicity 0.000 description 2
- NNBZCPXTIHJBJL-UHFFFAOYSA-N decalin Chemical compound C1CCCC2CCCCC21 NNBZCPXTIHJBJL-UHFFFAOYSA-N 0.000 description 2
- 230000005595 deprotonation Effects 0.000 description 2
- 238000010537 deprotonation reaction Methods 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 2
- GKCXXDSWWDWUHS-BYPYZUCNSA-N ethyl (2s)-2-amino-3-hydroxypropanoate Chemical compound CCOC(=O)[C@@H](N)CO GKCXXDSWWDWUHS-BYPYZUCNSA-N 0.000 description 2
- HFIJJDZJYSFOIM-UHFFFAOYSA-N ethyl 2-chloro-3-[(3-fluorophenyl)methylamino]propanoate Chemical compound ClC(C(=O)OCC)CNCC1=CC(=CC=C1)F HFIJJDZJYSFOIM-UHFFFAOYSA-N 0.000 description 2
- 125000001153 fluoro group Chemical group F* 0.000 description 2
- 235000003599 food sweetener Nutrition 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 239000003292 glue Substances 0.000 description 2
- 150000004795 grignard reagents Chemical class 0.000 description 2
- 229940093915 gynecological organic acid Drugs 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 230000035874 hyperreactivity Effects 0.000 description 2
- 230000001631 hypertensive effect Effects 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 238000001361 intraarterial administration Methods 0.000 description 2
- 238000011835 investigation Methods 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 125000004936 isatinoyl group Chemical group N1(C(=O)C(=O)C2=CC=CC=C12)C(=O)* 0.000 description 2
- YDNLNVZZTACNJX-UHFFFAOYSA-N isocyanatomethylbenzene Chemical group O=C=NCC1=CC=CC=C1 YDNLNVZZTACNJX-UHFFFAOYSA-N 0.000 description 2
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- 125000001786 isothiazolyl group Chemical group 0.000 description 2
- 125000000468 ketone group Chemical group 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 239000002502 liposome Substances 0.000 description 2
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 2
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- 238000004949 mass spectrometry Methods 0.000 description 2
- 230000001404 mediated effect Effects 0.000 description 2
- DOYKYXMRPXMHLZ-UHFFFAOYSA-N methyl 3-amino-3-(3-methoxyphenyl)propanoate Chemical group COC(=O)CC(N)C1=CC=CC(OC)=C1 DOYKYXMRPXMHLZ-UHFFFAOYSA-N 0.000 description 2
- 229920000609 methyl cellulose Polymers 0.000 description 2
- 239000001923 methylcellulose Substances 0.000 description 2
- 235000010981 methylcellulose Nutrition 0.000 description 2
- 201000006417 multiple sclerosis Diseases 0.000 description 2
- 230000008692 neointimal formation Effects 0.000 description 2
- 208000004296 neuralgia Diseases 0.000 description 2
- 208000021722 neuropathic pain Diseases 0.000 description 2
- 125000004930 octahydroisoquinolinyl group Chemical group C1(NCCC2CCCC=C12)* 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 235000005985 organic acids Nutrition 0.000 description 2
- 125000004095 oxindolyl group Chemical group N1(C(CC2=CC=CC=C12)=O)* 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- LXCFILQKKLGQFO-UHFFFAOYSA-N p-hydroxybenzoic acid methyl ester Natural products COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 2
- LXNAVEXFUKBNMK-UHFFFAOYSA-N palladium(II) acetate Substances [Pd].CC(O)=O.CC(O)=O LXNAVEXFUKBNMK-UHFFFAOYSA-N 0.000 description 2
- 238000007911 parenteral administration Methods 0.000 description 2
- 239000003182 parenteral nutrition solution Substances 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 2
- 229920000747 poly(lactic acid) Polymers 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 239000004633 polyglycolic acid Substances 0.000 description 2
- 239000004626 polylactic acid Substances 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- 235000011056 potassium acetate Nutrition 0.000 description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 238000011324 primary prophylaxis Methods 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 2
- 125000002098 pyridazinyl group Chemical group 0.000 description 2
- 238000006268 reductive amination reaction Methods 0.000 description 2
- 208000037803 restenosis Diseases 0.000 description 2
- 238000004007 reversed phase HPLC Methods 0.000 description 2
- 230000002441 reversible effect Effects 0.000 description 2
- 206010039073 rheumatoid arthritis Diseases 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 235000010265 sodium sulphite Nutrition 0.000 description 2
- 208000020431 spinal cord injury Diseases 0.000 description 2
- 150000003413 spiro compounds Chemical class 0.000 description 2
- 238000011699 spontaneously hypertensive rat Methods 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 235000011150 stannous chloride Nutrition 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 238000013268 sustained release Methods 0.000 description 2
- 239000012730 sustained-release form Substances 0.000 description 2
- 239000003765 sweetening agent Substances 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- NSNJTAGQKCBELZ-UHFFFAOYSA-N tert-butyl 4-[4-[5-(hydroxymethyl)-3-[(3-methoxyphenyl)methyl]-2-oxoimidazolidin-1-yl]phenyl]pyrazole-1-carboxylate Chemical compound OCC1CN(C(N1C1=CC=C(C=C1)C=1C=NN(C=1)C(=O)OC(C)(C)C)=O)CC1=CC(=CC=C1)OC NSNJTAGQKCBELZ-UHFFFAOYSA-N 0.000 description 2
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 description 2
- 125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 description 2
- 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 125000004525 thiadiazinyl group Chemical group S1NN=C(C=C1)* 0.000 description 2
- 125000001113 thiadiazolyl group Chemical group 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- AXZWODMDQAVCJE-UHFFFAOYSA-L tin(II) chloride (anhydrous) Chemical compound [Cl-].[Cl-].[Sn+2] AXZWODMDQAVCJE-UHFFFAOYSA-L 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- FAQYAMRNWDIXMY-UHFFFAOYSA-N trichloroborane Chemical compound ClB(Cl)Cl FAQYAMRNWDIXMY-UHFFFAOYSA-N 0.000 description 2
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 2
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 2
- ONDSBJMLAHVLMI-UHFFFAOYSA-N trimethylsilyldiazomethane Chemical compound C[Si](C)(C)[CH-][N+]#N ONDSBJMLAHVLMI-UHFFFAOYSA-N 0.000 description 2
- 229910000404 tripotassium phosphate Inorganic materials 0.000 description 2
- 235000019798 tripotassium phosphate Nutrition 0.000 description 2
- 239000002691 unilamellar liposome Substances 0.000 description 2
- 239000003981 vehicle Substances 0.000 description 2
- 239000003039 volatile agent Substances 0.000 description 2
- 239000003643 water by type Substances 0.000 description 2
- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 description 1
- XFQNWPYGEGCIMF-HCUGAJCMSA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].[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.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 XFQNWPYGEGCIMF-HCUGAJCMSA-N 0.000 description 1
- XGPXBCKGQLCHDW-ZCTOJWETSA-M (1z,5z)-cycloocta-1,5-diene;(2s,5s)-1-[2-[(2s,5s)-2,5-diethylphospholan-1-yl]phenyl]-2,5-diethylphospholane;rhodium;trifluoromethanesulfonate Chemical compound [Rh].C\1C\C=C/CC\C=C/1.[O-]S(=O)(=O)C(F)(F)F.CC[C@H]1CC[C@H](CC)P1C1=CC=CC=C1P1[C@@H](CC)CC[C@@H]1CC XGPXBCKGQLCHDW-ZCTOJWETSA-M 0.000 description 1
- PQCUDKMMPTXMAL-UHFFFAOYSA-N (2,6-difluorophenyl)methanamine Chemical group NCC1=C(F)C=CC=C1F PQCUDKMMPTXMAL-UHFFFAOYSA-N 0.000 description 1
- KDDNKZCVYQDGKE-UHFFFAOYSA-N (2-chlorophenyl)methanamine Chemical group NCC1=CC=CC=C1Cl KDDNKZCVYQDGKE-UHFFFAOYSA-N 0.000 description 1
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- GVVCHDNSTMEUCS-MUGJNUQGSA-N (2s,5s)-1-[2-[(2s,5s)-2,5-diethylphospholan-1-yl]phenyl]-2,5-diethylphospholane Chemical compound CC[C@H]1CC[C@H](CC)P1C1=CC=CC=C1P1[C@@H](CC)CC[C@@H]1CC GVVCHDNSTMEUCS-MUGJNUQGSA-N 0.000 description 1
- CUKWUWBLQQDQAC-VEQWQPCFSA-N (3s)-3-amino-4-[[(2s)-1-[[(2s)-1-[[(2s)-1-[[(2s,3s)-1-[[(2s)-1-[(2s)-2-[[(1s)-1-carboxyethyl]carbamoyl]pyrrolidin-1-yl]-3-(1h-imidazol-5-yl)-1-oxopropan-2-yl]amino]-3-methyl-1-oxopentan-2-yl]amino]-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]amino]-3-methyl-1-ox Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C)C(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@@H](N)CC(O)=O)C(C)C)C1=CC=C(O)C=C1 CUKWUWBLQQDQAC-VEQWQPCFSA-N 0.000 description 1
- SQBOSZXDOHQFAA-SEVDZJIVSA-N (4r,5r,6r,7r)-1,3-dibenzyl-5,6-dihydroxy-4,7-bis(phenoxymethyl)-1,3-diazepan-2-one Chemical compound C([C@@H]1[C@@H](O)[C@@H]([C@H](N(CC=2C=CC=CC=2)C(=O)N1CC=1C=CC=CC=1)COC=1C=CC=CC=1)O)OC1=CC=CC=C1 SQBOSZXDOHQFAA-SEVDZJIVSA-N 0.000 description 1
- KZKRPYCBSZIQKN-REOHCLBHSA-N (4s)-2-oxoimidazolidine-4-carboxylic acid Chemical compound OC(=O)[C@@H]1CNC(=O)N1 KZKRPYCBSZIQKN-REOHCLBHSA-N 0.000 description 1
- SERVOTWJOQLFFE-QMMMGPOBSA-N (5S)-3-(4-bromophenyl)-5-(hydroxymethyl)imidazolidine-2,4-dione Chemical compound BrC1=CC=C(C=C1)N1C(N[C@H](C1=O)CO)=O SERVOTWJOQLFFE-QMMMGPOBSA-N 0.000 description 1
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 description 1
- FDKXTQMXEQVLRF-ZHACJKMWSA-N (E)-dacarbazine Chemical compound CN(C)\N=N\c1[nH]cnc1C(N)=O FDKXTQMXEQVLRF-ZHACJKMWSA-N 0.000 description 1
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 1
- 125000004605 1,2,3,4-tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 description 1
- 125000004607 1,2,3,4-tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000004502 1,2,3-oxadiazolyl group Chemical group 0.000 description 1
- 125000004511 1,2,3-thiadiazolyl group Chemical group 0.000 description 1
- 125000001399 1,2,3-triazolyl group Chemical group N1N=NC(=C1)* 0.000 description 1
- 125000004504 1,2,4-oxadiazolyl group Chemical group 0.000 description 1
- 125000001376 1,2,4-triazolyl group Chemical group N1N=C(N=C1)* 0.000 description 1
- 125000004506 1,2,5-oxadiazolyl group Chemical group 0.000 description 1
- 125000004517 1,2,5-thiadiazolyl group Chemical group 0.000 description 1
- 125000001781 1,3,4-oxadiazolyl group Chemical group 0.000 description 1
- 125000004520 1,3,4-thiadiazolyl group Chemical group 0.000 description 1
- LVEYOSJUKRVCCF-UHFFFAOYSA-N 1,3-Bis(diphenylphosphino)propane Substances C=1C=CC=CC=1P(C=1C=CC=CC=1)CCCP(C=1C=CC=CC=1)C1=CC=CC=C1 LVEYOSJUKRVCCF-UHFFFAOYSA-N 0.000 description 1
- RUKVGXGTVPPWDD-UHFFFAOYSA-N 1,3-bis(2,4,6-trimethylphenyl)imidazolidine Chemical group CC1=CC(C)=CC(C)=C1N1CN(C=2C(=CC(C)=CC=2C)C)CC1 RUKVGXGTVPPWDD-UHFFFAOYSA-N 0.000 description 1
- UIIJKBSUGZNVQN-UHFFFAOYSA-N 1-(2-bromoethyl)-2-methoxybenzene Chemical compound COC1=CC=CC=C1CCBr UIIJKBSUGZNVQN-UHFFFAOYSA-N 0.000 description 1
- COGKCVIZDSDFHI-UHFFFAOYSA-N 1-(2-phenylethyl)-3-[4-(1H-pyrazol-4-yl)phenyl]imidazolidin-2-one Chemical compound N1N=CC(=C1)C1=CC=C(C=C1)N1C(N(CC1)CCC1=CC=CC=C1)=O COGKCVIZDSDFHI-UHFFFAOYSA-N 0.000 description 1
- DGGRDUPQQAZJQY-UHFFFAOYSA-N 1-(4-bromo-2-methoxyphenyl)-1-(2-chloroethyl)-3-[(3-fluorophenyl)methyl]urea Chemical compound BrC1=CC(=C(C=C1)N(C(=O)NCC1=CC(=CC=C1)F)CCCl)OC DGGRDUPQQAZJQY-UHFFFAOYSA-N 0.000 description 1
- ZFRQKSSARXFRCG-UHFFFAOYSA-N 1-(4-bromo-3-ethylphenyl)-1-(2-chloroethyl)-3-[(3-methoxyphenyl)methyl]urea Chemical compound BrC1=C(C=C(C=C1)N(C(=O)NCC1=CC(=CC=C1)OC)CCCl)CC ZFRQKSSARXFRCG-UHFFFAOYSA-N 0.000 description 1
- AEQLCUFHTKMUCJ-UHFFFAOYSA-N 1-(4-bromo-3-ethylphenyl)-3-[(3-methoxyphenyl)methyl]imidazolidin-2-one Chemical compound BrC1=C(C=C(C=C1)N1C(N(CC1)CC1=CC(=CC=C1)OC)=O)CC AEQLCUFHTKMUCJ-UHFFFAOYSA-N 0.000 description 1
- IZPRJISEQYKMHD-UHFFFAOYSA-N 1-(4-bromo-3-methoxyphenyl)-1-(2-chloroethyl)-3-[(3-fluorophenyl)methyl]urea Chemical compound BrC1=C(C=C(C=C1)N(C(=O)NCC1=CC(=CC=C1)F)CCCl)OC IZPRJISEQYKMHD-UHFFFAOYSA-N 0.000 description 1
- XSVLKZQXPUILGI-UHFFFAOYSA-N 1-(4-bromo-3-methoxyphenyl)-3-[(2-fluoro-5-methoxyphenyl)methyl]imidazolidin-2-one Chemical compound BrC1=C(C=C(C=C1)N1C(N(CC1)CC1=C(C=CC(=C1)OC)F)=O)OC XSVLKZQXPUILGI-UHFFFAOYSA-N 0.000 description 1
- OOUCBNBSUFSKRS-UHFFFAOYSA-N 1-(4-bromo-3-methoxyphenyl)-3-[3-hydroxy-1-(3-methoxyphenyl)propyl]imidazolidin-2-one Chemical compound BrC1=C(C=C(C=C1)N1C(N(CC1)C(CCO)C1=CC(=CC=C1)OC)=O)OC OOUCBNBSUFSKRS-UHFFFAOYSA-N 0.000 description 1
- PFKFBFMSSQETNP-UHFFFAOYSA-N 1-(4-bromo-3-methoxyphenyl)imidazolidine-2,4-dione Chemical compound C1=C(Br)C(OC)=CC(N2C(NC(=O)C2)=O)=C1 PFKFBFMSSQETNP-UHFFFAOYSA-N 0.000 description 1
- ZAJXQINKXUAWJJ-UHFFFAOYSA-N 1-(4-bromophenyl)-1-(2-chloroethyl)-3-(2-phenylethyl)urea Chemical compound BrC1=CC=C(C=C1)N(C(=O)NCCC1=CC=CC=C1)CCCl ZAJXQINKXUAWJJ-UHFFFAOYSA-N 0.000 description 1
- PWNKYCIDSZTIOF-UHFFFAOYSA-N 1-(4-bromophenyl)-3-(2-phenylethyl)imidazolidin-2-one Chemical compound BrC1=CC=C(C=C1)N1C(N(CC1)CCC1=CC=CC=C1)=O PWNKYCIDSZTIOF-UHFFFAOYSA-N 0.000 description 1
- PVYONXVJSUIHAF-CYBMUJFWSA-N 1-(4-bromophenyl)-3-[(1R)-1-(3-methoxyphenyl)ethyl]imidazolidin-2-one Chemical compound BrC1=CC=C(C=C1)N1C(N(CC1)[C@H](C)C1=CC(=CC=C1)OC)=O PVYONXVJSUIHAF-CYBMUJFWSA-N 0.000 description 1
- PXKIBFIJNCCZEX-UHFFFAOYSA-N 1-(4-bromophenyl)-3-[(2-fluoro-3-methoxyphenyl)methyl]imidazolidin-2-one Chemical compound BrC1=CC=C(C=C1)N1C(N(CC1)CC1=C(C(=CC=C1)OC)F)=O PXKIBFIJNCCZEX-UHFFFAOYSA-N 0.000 description 1
- WRXPWZKUFYCYKU-UHFFFAOYSA-N 1-(4-bromophenyl)-3-[(3-methoxyphenyl)methyl]imidazolidin-2-one Chemical compound BrC1=CC=C(C=C1)N1C(N(CC1)CC1=CC(=CC=C1)OC)=O WRXPWZKUFYCYKU-UHFFFAOYSA-N 0.000 description 1
- QMJUROHCICDVFF-UHFFFAOYSA-N 1-(4-bromophenyl)-3-[2-(2-methoxyphenyl)ethyl]imidazol-2-one Chemical compound BrC1=CC=C(C=C1)N1C(N(C=C1)CCC1=C(C=CC=C1)OC)=O QMJUROHCICDVFF-UHFFFAOYSA-N 0.000 description 1
- IQYIOVFMXOWYEQ-UHFFFAOYSA-N 1-(4-bromophenyl)imidazolidin-2-one Chemical compound C1=CC(Br)=CC=C1N1C(=O)NCC1 IQYIOVFMXOWYEQ-UHFFFAOYSA-N 0.000 description 1
- UZPHQWVNBDGGCU-UHFFFAOYSA-N 1-(5-bromo-4-methylpyridin-2-yl)-3-(2-chloroethyl)urea Chemical compound BrC=1C(=CC(=NC=1)NC(=O)NCCCl)C UZPHQWVNBDGGCU-UHFFFAOYSA-N 0.000 description 1
- QXPLHQMBJXUDBM-UHFFFAOYSA-N 1-(5-bromo-6-methoxypyridin-2-yl)imidazolidin-2-one Chemical compound BrC=1C=CC(=NC=1OC)N1C(NCC1)=O QXPLHQMBJXUDBM-UHFFFAOYSA-N 0.000 description 1
- AFJSFTQVPPXCRQ-UHFFFAOYSA-N 1-(bromomethyl)-2-fluoro-3-methoxybenzene Chemical compound COC1=CC=CC(CBr)=C1F AFJSFTQVPPXCRQ-UHFFFAOYSA-N 0.000 description 1
- XTEIMRMVNBUQSJ-OAHLLOKOSA-N 1-[(1R)-1-(3-methoxyphenyl)ethyl]-3-[2-methoxy-4-(1H-pyrazol-4-yl)phenyl]imidazolidin-2-one Chemical compound COC1=C(C=CC(=C1)C=1C=NNC=1)N1C(N(CC1)[C@H](C)C1=CC(=CC=C1)OC)=O XTEIMRMVNBUQSJ-OAHLLOKOSA-N 0.000 description 1
- LXEYNVHQNOXMQK-UHFFFAOYSA-N 1-[(2,6-difluorophenyl)methyl]-3-[3-methoxy-4-(1H-pyrazol-4-yl)phenyl]imidazolidin-2-one Chemical compound FC1=C(CN2C(N(CC2)C2=CC(=C(C=C2)C=2C=NNC=2)OC)=O)C(=CC=C1)F LXEYNVHQNOXMQK-UHFFFAOYSA-N 0.000 description 1
- HHWDCAKVSSSKCZ-UHFFFAOYSA-N 1-[(2-fluoro-5-methoxyphenyl)methyl]-3-[3-methoxy-4-(1H-pyrazol-4-yl)phenyl]imidazolidin-2-one Chemical compound FC1=C(CN2C(N(CC2)C2=CC(=C(C=C2)C=2C=NNC=2)OC)=O)C=C(C=C1)OC HHWDCAKVSSSKCZ-UHFFFAOYSA-N 0.000 description 1
- JVEFMTIWWVNIRU-UHFFFAOYSA-N 1-[(3-fluorophenyl)methyl]-2-oxo-3-[4-(1H-pyrazol-4-yl)phenyl]imidazolidine-4-carboxylic acid Chemical compound N1N=CC(=C1)C1=CC=C(C=C1)N1C(N(CC1C(=O)O)CC1=CC(=CC=C1)F)=O JVEFMTIWWVNIRU-UHFFFAOYSA-N 0.000 description 1
- HFJHECSDPULPIU-UHFFFAOYSA-N 1-[(3-fluorophenyl)methyl]-3-[2-methoxy-4-(1H-pyrazol-4-yl)phenyl]imidazolidin-2-one Chemical compound FC=1C=C(CN2C(N(CC2)C2=C(C=C(C=C2)C=2C=NNC=2)OC)=O)C=CC=1 HFJHECSDPULPIU-UHFFFAOYSA-N 0.000 description 1
- WGEUAXKQYVSRHY-UHFFFAOYSA-N 1-[(3-fluorophenyl)methyl]-3-[3-methoxy-4-(1H-pyrazol-4-yl)phenyl]imidazolidin-2-one Chemical compound COC1=C(C=CC(=C1)N1CCN(CC2=CC(F)=CC=C2)C1=O)C1=CNN=C1 WGEUAXKQYVSRHY-UHFFFAOYSA-N 0.000 description 1
- MUKLZKCIRDTYCM-UHFFFAOYSA-N 1-[(3-fluorophenyl)methyl]-4-(hydroxymethyl)-3-[4-(1H-pyrazol-4-yl)phenyl]imidazolidin-2-one Chemical compound N1N=CC(=C1)C1=CC=C(C=C1)N1C(N(CC1CO)CC1=CC(=CC=C1)F)=O MUKLZKCIRDTYCM-UHFFFAOYSA-N 0.000 description 1
- IWXDJTRBIGVMEG-UHFFFAOYSA-N 1-[(3-methoxyphenyl)methyl]-2-oxo-3-[4-(1H-pyrazol-4-yl)phenyl]imidazolidine-4-carboxylic acid Chemical compound N1N=CC(=C1)C1=CC=C(C=C1)N1C(N(CC1C(=O)O)CC1=CC(=CC=C1)OC)=O IWXDJTRBIGVMEG-UHFFFAOYSA-N 0.000 description 1
- BMEJPAZHWTWBKT-UHFFFAOYSA-N 1-[(3-methoxyphenyl)methyl]-3-[4-(1H-pyrazol-4-yl)phenyl]imidazolidine-2,4-dione Chemical compound N1N=CC(=C1)C1=CC=C(C=C1)N1C(N(CC1=O)CC1=CC(=CC=C1)OC)=O BMEJPAZHWTWBKT-UHFFFAOYSA-N 0.000 description 1
- QISMYKJVOCVFLG-UHFFFAOYSA-N 1-[(3-methoxyphenyl)methyl]-3-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl]imidazolidin-2-one Chemical compound N1C=CC=2C1=NC=CC=2C1=CC=C(C=C1)N1C(N(CC1)CC1=CC(=CC=C1)OC)=O QISMYKJVOCVFLG-UHFFFAOYSA-N 0.000 description 1
- XAQWJBMIHYQAMU-UHFFFAOYSA-N 1-[(3-methoxyphenyl)methyl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)phenyl]imidazolidin-2-one Chemical compound N1=CN=C(C2=C1NC=C2)C1=CC=C(C=C1)N1C(N(CC1)CC1=CC(=CC=C1)OC)=O XAQWJBMIHYQAMU-UHFFFAOYSA-N 0.000 description 1
- WJASCAQGZUNIRX-UHFFFAOYSA-N 1-[2-(2-fluorophenyl)ethyl]-3-[2-methoxy-4-(1H-pyrazol-4-yl)phenyl]imidazolidin-2-one Chemical compound FC1=C(CCN2C(N(CC2)C2=C(C=C(C=C2)C=2C=NNC=2)OC)=O)C=CC=C1 WJASCAQGZUNIRX-UHFFFAOYSA-N 0.000 description 1
- XGCROCOIBGNQTI-UHFFFAOYSA-N 1-[2-(4-fluorophenyl)ethyl]-3-[3-methoxy-4-(1H-pyrazol-4-yl)phenyl]imidazolidin-2-one Chemical compound FC1=CC=C(CCN2C(N(CC2)C2=CC(=C(C=C2)C=2C=NNC=2)OC)=O)C=C1 XGCROCOIBGNQTI-UHFFFAOYSA-N 0.000 description 1
- HYEOCFWCWKJHQY-MRXNPFEDSA-N 1-[3-ethyl-4-(1H-pyrazol-4-yl)phenyl]-3-[(1R)-1-(3-methoxyphenyl)ethyl]imidazolidin-2-one Chemical compound C(C)C=1C=C(C=CC=1C=1C=NNC=1)N1C(N(CC1)[C@H](C)C1=CC(=CC=C1)OC)=O HYEOCFWCWKJHQY-MRXNPFEDSA-N 0.000 description 1
- WYJMOUGDPGZMCS-UHFFFAOYSA-N 1-[3-ethyl-4-(1H-pyrazol-4-yl)phenyl]-3-[2-(3-methoxyphenyl)ethyl]imidazolidin-2-one Chemical compound C(C)C=1C=C(C=CC=1C=1C=NNC=1)N1C(N(CC1)CCC1=CC(=CC=C1)OC)=O WYJMOUGDPGZMCS-UHFFFAOYSA-N 0.000 description 1
- HEJCJVHXTDWFJO-UHFFFAOYSA-N 1-[3-hydroxy-1-(3-methoxyphenyl)-3-methylbutyl]-3-[3-methoxy-4-(1H-pyrazol-4-yl)phenyl]imidazolidin-2-one Chemical compound OC(CC(C1=CC(=CC=C1)OC)N1C(N(CC1)C1=CC(=C(C=C1)C=1C=NNC=1)OC)=O)(C)C HEJCJVHXTDWFJO-UHFFFAOYSA-N 0.000 description 1
- WZBRLPCQUOXSNO-UHFFFAOYSA-N 1-[3-hydroxy-1-(3-methoxyphenyl)propyl]-3-[3-methoxy-4-(1H-pyrazol-4-yl)phenyl]imidazolidin-2-one Chemical compound OCCC(C1=CC(=CC=C1)OC)N1C(N(CC1)C1=CC(=C(C=C1)C=1C=NNC=1)OC)=O WZBRLPCQUOXSNO-UHFFFAOYSA-N 0.000 description 1
- FNAYFJWFINCCCN-UHFFFAOYSA-N 1-[3-methoxy-4-(1H-pyrazol-4-yl)phenyl]-3-[[2-(1H-pyrazol-4-yl)phenyl]methyl]imidazolidin-2-one Chemical compound N1N=CC(=C1)C1=C(CN2C(N(CC2)C2=CC(=C(C=C2)C=2C=NNC=2)OC)=O)C=CC=C1 FNAYFJWFINCCCN-UHFFFAOYSA-N 0.000 description 1
- PYALLCMXWCFOCX-UHFFFAOYSA-N 1-[4-(2-aminopyridin-4-yl)phenyl]-3-[(3-methoxyphenyl)methyl]imidazolidin-2-one Chemical compound NC1=NC=CC(=C1)C1=CC=C(C=C1)N1C(N(CC1)CC1=CC(=CC=C1)OC)=O PYALLCMXWCFOCX-UHFFFAOYSA-N 0.000 description 1
- NXMVPMHQRPARFQ-UHFFFAOYSA-N 1-[4-(2-aminopyrimidin-4-yl)phenyl]-3-[(3-methoxyphenyl)methyl]imidazolidin-2-one Chemical compound NC1=NC=CC(=N1)C1=CC=C(C=C1)N1C(N(CC1)CC1=CC(=CC=C1)OC)=O NXMVPMHQRPARFQ-UHFFFAOYSA-N 0.000 description 1
- UFARZHULZNJGDE-UHFFFAOYSA-N 1-benzyl-3-[2-methoxy-4-(1H-pyrazol-4-yl)phenyl]imidazolidin-2-one Chemical compound C(C1=CC=CC=C1)N1C(N(CC1)C1=C(C=C(C=C1)C=1C=NNC=1)OC)=O UFARZHULZNJGDE-UHFFFAOYSA-N 0.000 description 1
- CZCPSFBOZOSXND-UHFFFAOYSA-N 1-benzyl-3-[3-ethyl-4-(1H-pyrazol-4-yl)phenyl]imidazolidin-2-one Chemical compound C(C1=CC=CC=C1)N1C(N(CC1)C1=CC(=C(C=C1)C=1C=NNC=1)CC)=O CZCPSFBOZOSXND-UHFFFAOYSA-N 0.000 description 1
- MICMHFIQSAMEJG-UHFFFAOYSA-N 1-bromopyrrolidine-2,5-dione Chemical compound BrN1C(=O)CCC1=O.BrN1C(=O)CCC1=O MICMHFIQSAMEJG-UHFFFAOYSA-N 0.000 description 1
- FDCHHLBMDMJXGM-UHFFFAOYSA-N 1-fluoro-4-(2-isocyanatoethyl)benzene Chemical group FC1=CC=C(CCN=C=O)C=C1 FDCHHLBMDMJXGM-UHFFFAOYSA-N 0.000 description 1
- 125000006432 1-methyl cyclopropyl group Chemical group [H]C([H])([H])C1(*)C([H])([H])C1([H])[H] 0.000 description 1
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 1
- 125000006017 1-propenyl group Chemical group 0.000 description 1
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 1
- IEQAICDLOKRSRL-UHFFFAOYSA-N 2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-(2-dodecoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethanol Chemical compound CCCCCCCCCCCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCO IEQAICDLOKRSRL-UHFFFAOYSA-N 0.000 description 1
- 125000005273 2-acetoxybenzoic acid group Chemical group 0.000 description 1
- MLONYBFKXHEPCD-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol Chemical compound OCC(N)(CO)CO.OCC(N)(CO)CO MLONYBFKXHEPCD-UHFFFAOYSA-N 0.000 description 1
- 125000004974 2-butenyl group Chemical group C(C=CC)* 0.000 description 1
- 125000006040 2-hexenyl group Chemical group 0.000 description 1
- 125000006022 2-methyl-2-propenyl group Chemical group 0.000 description 1
- 125000006024 2-pentenyl group Chemical group 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- CAAMSDWKXXPUJR-UHFFFAOYSA-N 3,5-dihydro-4H-imidazol-4-one Chemical compound O=C1CNC=N1 CAAMSDWKXXPUJR-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
- LRSUMZGSORKIJR-UHFFFAOYSA-N 3-(4-bromophenyl)-1-[(3-methoxyphenyl)methyl]imidazolidine-2,4-dione Chemical compound BrC1=CC=C(C=C1)N1C(N(CC1=O)CC1=CC(=CC=C1)OC)=O LRSUMZGSORKIJR-UHFFFAOYSA-N 0.000 description 1
- KEVZSEIFNDIJIH-UHFFFAOYSA-N 3-(4-bromophenyl)-5-(hydroxymethyl)-1-[(3-methoxyphenyl)methyl]imidazolidine-2,4-dione Chemical compound BrC1=CC=C(C=C1)N1C(N(C(C1=O)CO)CC1=CC(=CC=C1)OC)=O KEVZSEIFNDIJIH-UHFFFAOYSA-N 0.000 description 1
- FPFDMHRKTCRRBC-UHFFFAOYSA-N 3-(4-bromophenyl)imidazolidine-2,4-dione Chemical compound C1=CC(Br)=CC=C1N1C(=O)NCC1=O FPFDMHRKTCRRBC-UHFFFAOYSA-N 0.000 description 1
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 1
- OWOQDSHISJTONB-UHFFFAOYSA-N 3-[3-(4-bromo-3-methoxyphenyl)-2-oxoimidazolidin-1-yl]-3-(3-methoxyphenyl)propanoic acid Chemical compound BrC1=C(C=C(C=C1)N1C(N(CC1)C(CC(=O)O)C1=CC(=CC=C1)OC)=O)OC OWOQDSHISJTONB-UHFFFAOYSA-N 0.000 description 1
- BNXVBSPMYKOITQ-UHFFFAOYSA-N 3-benzyl-1-(4-bromo-3-methoxyphenyl)imidazolidine-2,4-dione Chemical compound C(C1=CC=CC=C1)N1C(N(CC1=O)C1=CC(=C(C=C1)Br)OC)=O BNXVBSPMYKOITQ-UHFFFAOYSA-N 0.000 description 1
- PYXRSVHHYDHINP-UHFFFAOYSA-N 3-benzyl-1-[3-methoxy-4-(1H-pyrazol-4-yl)phenyl]imidazolidine-2,4-dione Chemical compound C(C1=CC=CC=C1)N1C(N(CC1=O)C1=CC(=C(C=C1)C=1C=NNC=1)OC)=O PYXRSVHHYDHINP-UHFFFAOYSA-N 0.000 description 1
- NDWIDQDXARXUKA-UHFFFAOYSA-N 3-benzyl-4-(hydroxymethyl)-1-[3-methoxy-4-(1H-pyrazol-4-yl)phenyl]imidazolidin-2-one Chemical compound C(C1=CC=CC=C1)N1C(N(CC1CO)C1=CC(=C(C=C1)C=1C=NNC=1)OC)=O NDWIDQDXARXUKA-UHFFFAOYSA-N 0.000 description 1
- DHYHYLGCQVVLOQ-UHFFFAOYSA-N 3-bromoaniline Chemical compound NC1=CC=CC(Br)=C1 DHYHYLGCQVVLOQ-UHFFFAOYSA-N 0.000 description 1
- 125000004975 3-butenyl group Chemical group C(CC=C)* 0.000 description 1
- 125000006041 3-hexenyl group Chemical group 0.000 description 1
- 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 0.000 description 1
- VUHMKNHUHMYLFV-UHFFFAOYSA-N 4-(2-hydroxypropan-2-yl)-3-[(3-methoxyphenyl)methyl]-1-[4-(1H-pyrazol-4-yl)phenyl]imidazolidin-2-one Chemical compound N1N=CC(=C1)C1=CC=C(C=C1)N1C(N(C(C1)C(C)(C)O)CC1=CC(=CC=C1)OC)=O VUHMKNHUHMYLFV-UHFFFAOYSA-N 0.000 description 1
- TVOJIBGZFYMWDT-UHFFFAOYSA-N 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1h-pyrazole Chemical compound O1C(C)(C)C(C)(C)OB1C1=CNN=C1 TVOJIBGZFYMWDT-UHFFFAOYSA-N 0.000 description 1
- KWQNNOZROOJVJB-UHFFFAOYSA-N 4-bromo-3-ethylaniline Chemical compound CCC1=CC(N)=CC=C1Br KWQNNOZROOJVJB-UHFFFAOYSA-N 0.000 description 1
- MAQAEXGARJHNTD-UHFFFAOYSA-N 4-bromo-N-(2-chloroethyl)-2-methoxyaniline Chemical compound BrC1=CC(=C(NCCCl)C=C1)OC MAQAEXGARJHNTD-UHFFFAOYSA-N 0.000 description 1
- RQMWVVBHJMUJNZ-UHFFFAOYSA-N 4-chloropyridin-2-amine Chemical compound NC1=CC(Cl)=CC=N1 RQMWVVBHJMUJNZ-UHFFFAOYSA-N 0.000 description 1
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- 125000006042 4-hexenyl group Chemical group 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
- 125000003119 4-methyl-3-pentenyl group Chemical group [H]\C(=C(/C([H])([H])[H])C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000005986 4-piperidonyl group Chemical group 0.000 description 1
- 125000002471 4H-quinolizinyl group Chemical group C=1(C=CCN2C=CC=CC12)* 0.000 description 1
- 125000004608 5,6,7,8-tetrahydroquinolinyl group Chemical group N1=C(C=CC=2CCCCC12)* 0.000 description 1
- GGHBRLQYBZMEPV-UHFFFAOYSA-N 5-bromo-4-fluoropyridin-2-amine Chemical compound NC1=CC(F)=C(Br)C=N1 GGHBRLQYBZMEPV-UHFFFAOYSA-N 0.000 description 1
- JDNCMHOKWINDKI-UHFFFAOYSA-N 5-bromo-4-methylpyridin-2-amine Chemical compound CC1=CC(N)=NC=C1Br JDNCMHOKWINDKI-UHFFFAOYSA-N 0.000 description 1
- STTFWVSVDMLUCF-UHFFFAOYSA-N 5-bromo-6-methoxypyridin-2-amine Chemical compound COC1=NC(N)=CC=C1Br STTFWVSVDMLUCF-UHFFFAOYSA-N 0.000 description 1
- WGOLHUGPTDEKCF-UHFFFAOYSA-N 5-bromopyridin-2-amine Chemical compound NC1=CC=C(Br)C=N1 WGOLHUGPTDEKCF-UHFFFAOYSA-N 0.000 description 1
- 125000006043 5-hexenyl group Chemical group 0.000 description 1
- 125000006163 5-membered heteroaryl group Chemical group 0.000 description 1
- 239000005541 ACE inhibitor Substances 0.000 description 1
- 102100023818 ADP-ribosylation factor 3 Human genes 0.000 description 1
- OZAIFHULBGXAKX-VAWYXSNFSA-N AIBN Substances N#CC(C)(C)\N=N\C(C)(C)C#N OZAIFHULBGXAKX-VAWYXSNFSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 102000007469 Actins Human genes 0.000 description 1
- 108010085238 Actins Proteins 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- DHMQDGOQFOQNFH-UHFFFAOYSA-M Aminoacetate Chemical compound NCC([O-])=O DHMQDGOQFOQNFH-UHFFFAOYSA-M 0.000 description 1
- 229920000856 Amylose Polymers 0.000 description 1
- 102400000345 Angiotensin-2 Human genes 0.000 description 1
- 101800000733 Angiotensin-2 Proteins 0.000 description 1
- 102000015427 Angiotensins Human genes 0.000 description 1
- 108010064733 Angiotensins Proteins 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 229910015845 BBr3 Inorganic materials 0.000 description 1
- 229910015844 BCl3 Inorganic materials 0.000 description 1
- GUBGYTABKSRVRQ-DCSYEGIMSA-N Beta-Lactose Chemical compound OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-DCSYEGIMSA-N 0.000 description 1
- KAEYSBNPPDKJSI-OAQYLSRUSA-N BrC1=CC=C(C=C1)N1C(N([C@H](C1)CO[Si](C)(C)C(C)(C)C)CC1=CC(=CC=C1)OC)=O Chemical compound BrC1=CC=C(C=C1)N1C(N([C@H](C1)CO[Si](C)(C)C(C)(C)C)CC1=CC(=CC=C1)OC)=O KAEYSBNPPDKJSI-OAQYLSRUSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- 102100021943 C-C motif chemokine 2 Human genes 0.000 description 1
- 101710155857 C-C motif chemokine 2 Proteins 0.000 description 1
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 description 1
- BNQQJIRZGZUKEJ-UHFFFAOYSA-N COC=1C=C(CN2C(N(CC2)C2=CC=C(C=C2)B2OC(C(O2)(C)C)(C)C)=O)C=CC=1 Chemical compound COC=1C=C(CN2C(N(CC2)C2=CC=C(C=C2)B2OC(C(O2)(C)C)(C)C)=O)C=CC=1 BNQQJIRZGZUKEJ-UHFFFAOYSA-N 0.000 description 1
- 229940127291 Calcium channel antagonist Drugs 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 206010007559 Cardiac failure congestive Diseases 0.000 description 1
- 229930186147 Cephalosporin Natural products 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 108020004635 Complementary DNA Proteins 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 238000006646 Dess-Martin oxidation reaction Methods 0.000 description 1
- DYHSDKLCOJIUFX-UHFFFAOYSA-N Di-tert-butyl dicarbonate Substances CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 1
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 1
- 102400000686 Endothelin-1 Human genes 0.000 description 1
- 101800004490 Endothelin-1 Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- OTMSDBZUPAUEDD-UHFFFAOYSA-N Ethane Chemical compound CC OTMSDBZUPAUEDD-UHFFFAOYSA-N 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- 108091006027 G proteins Proteins 0.000 description 1
- 102000030782 GTP binding Human genes 0.000 description 1
- 108091000058 GTP-Binding Proteins 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 239000007821 HATU Substances 0.000 description 1
- 229910004373 HOAc Inorganic materials 0.000 description 1
- 101000684275 Homo sapiens ADP-ribosylation factor 3 Proteins 0.000 description 1
- 101001000061 Homo sapiens Protein phosphatase 1 regulatory subunit 12A Proteins 0.000 description 1
- 101001130437 Homo sapiens Ras-related protein Rap-2b Proteins 0.000 description 1
- 101000669917 Homo sapiens Rho-associated protein kinase 1 Proteins 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 206010061216 Infarction Diseases 0.000 description 1
- 102000003777 Interleukin-1 beta Human genes 0.000 description 1
- 108090000193 Interleukin-1 beta Proteins 0.000 description 1
- 229930194542 Keto Natural products 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 1
- 229920001410 Microfiber Polymers 0.000 description 1
- 108010037801 Myosin-Light-Chain Phosphatase Proteins 0.000 description 1
- 102000011131 Myosin-Light-Chain Phosphatase Human genes 0.000 description 1
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 1
- 208000008457 Neurologic Manifestations Diseases 0.000 description 1
- REYJJPSVUYRZGE-UHFFFAOYSA-N Octadecylamine Chemical compound CCCCCCCCCCCCCCCCCCN REYJJPSVUYRZGE-UHFFFAOYSA-N 0.000 description 1
- 229910019213 POCl3 Inorganic materials 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 108090000608 Phosphoric Monoester Hydrolases Proteins 0.000 description 1
- 102000004160 Phosphoric Monoester Hydrolases Human genes 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 229920001710 Polyorthoester Polymers 0.000 description 1
- 102000001708 Protein Isoforms Human genes 0.000 description 1
- 108010029485 Protein Isoforms Proteins 0.000 description 1
- 102000009516 Protein Serine-Threonine Kinases Human genes 0.000 description 1
- 108010009341 Protein Serine-Threonine Kinases Proteins 0.000 description 1
- 102100036547 Protein phosphatase 1 regulatory subunit 12A Human genes 0.000 description 1
- 208000001647 Renal Insufficiency Diseases 0.000 description 1
- 208000002200 Respiratory Hypersensitivity Diseases 0.000 description 1
- 102100039313 Rho-associated protein kinase 1 Human genes 0.000 description 1
- 102100027609 Rho-related GTP-binding protein RhoD Human genes 0.000 description 1
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 1
- 229940124639 Selective inhibitor Drugs 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- BCKXLBQYZLBQEK-KVVVOXFISA-M Sodium oleate Chemical compound [Na+].CCCCCCCC\C=C/CCCCCCCC([O-])=O BCKXLBQYZLBQEK-KVVVOXFISA-M 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 101100054666 Streptomyces halstedii sch3 gene Proteins 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 1
- 206010047295 Ventricular hypertrophy Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- WGOBPPNNYVSJTE-HSZRJFAPSA-N [(2r)-1-diphenylphosphanylpropan-2-yl]-diphenylphosphane Chemical compound C([C@@H](C)P(C=1C=CC=CC=1)C=1C=CC=CC=1)P(C=1C=CC=CC=1)C1=CC=CC=C1 WGOBPPNNYVSJTE-HSZRJFAPSA-N 0.000 description 1
- CKUAXEQHGKSLHN-UHFFFAOYSA-N [C].[N] Chemical group [C].[N] CKUAXEQHGKSLHN-UHFFFAOYSA-N 0.000 description 1
- 159000000021 acetate salts Chemical class 0.000 description 1
- 125000000641 acridinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3C=C12)* 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 235000010419 agar Nutrition 0.000 description 1
- 208000037883 airway inflammation Diseases 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 125000004414 alkyl thio group Chemical group 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- CBTVGIZVANVGBH-UHFFFAOYSA-N aminomethyl propanol Chemical compound CC(C)(N)CO CBTVGIZVANVGBH-UHFFFAOYSA-N 0.000 description 1
- XKMRRTOUMJRJIA-UHFFFAOYSA-N ammonia nh3 Chemical compound N.N XKMRRTOUMJRJIA-UHFFFAOYSA-N 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 229950006323 angiotensin ii Drugs 0.000 description 1
- 229940044094 angiotensin-converting-enzyme inhibitor Drugs 0.000 description 1
- 125000002178 anthracenyl group Chemical group C1(=CC=CC2=CC3=CC=CC=C3C=C12)* 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000003064 anti-oxidating effect Effects 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 125000002393 azetidinyl group Chemical group 0.000 description 1
- 125000004931 azocinyl group Chemical group N1=C(C=CC=CC=C1)* 0.000 description 1
- 239000000440 bentonite Substances 0.000 description 1
- 229910000278 bentonite Inorganic materials 0.000 description 1
- 235000012216 bentonite Nutrition 0.000 description 1
- SVPXDRXYRYOSEX-UHFFFAOYSA-N bentoquatam Chemical compound O.O=[Si]=O.O=[Al]O[Al]=O SVPXDRXYRYOSEX-UHFFFAOYSA-N 0.000 description 1
- 229960000686 benzalkonium chloride Drugs 0.000 description 1
- 125000004618 benzofuryl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid group Chemical group C(C1=CC=CC=C1)(=O)O WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- WGNZRLMOMHJUSP-UHFFFAOYSA-N benzotriazol-1-yloxy(tripyrrolidin-1-yl)phosphanium Chemical compound C1CCCN1[P+](N1CCCC1)(N1CCCC1)ON1C2=CC=CC=C2N=N1 WGNZRLMOMHJUSP-UHFFFAOYSA-N 0.000 description 1
- RROBIDXNTUAHFW-UHFFFAOYSA-N benzotriazol-1-yloxy-tris(dimethylamino)phosphanium Chemical compound C1=CC=C2N(O[P+](N(C)C)(N(C)C)N(C)C)N=NC2=C1 RROBIDXNTUAHFW-UHFFFAOYSA-N 0.000 description 1
- 125000003354 benzotriazolyl group Chemical group N1N=NC2=C1C=CC=C2* 0.000 description 1
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 1
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 1
- FCDPQMAOJARMTG-UHFFFAOYSA-M benzylidene-[1,3-bis(2,4,6-trimethylphenyl)imidazolidin-2-ylidene]-dichlororuthenium;tricyclohexylphosphanium Chemical compound C1CCCCC1[PH+](C1CCCCC1)C1CCCCC1.CC1=CC(C)=CC(C)=C1N(CCN1C=2C(=CC(C)=CC=2C)C)C1=[Ru](Cl)(Cl)=CC1=CC=CC=C1 FCDPQMAOJARMTG-UHFFFAOYSA-M 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- 239000002876 beta blocker Substances 0.000 description 1
- 229940097320 beta blocking agent Drugs 0.000 description 1
- 239000012867 bioactive agent Substances 0.000 description 1
- 229920002988 biodegradable polymer Polymers 0.000 description 1
- 239000004621 biodegradable polymer Substances 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 229920001400 block copolymer Polymers 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- MCQRPQCQMGVWIQ-UHFFFAOYSA-N boron;methylsulfanylmethane Chemical compound [B].CSC MCQRPQCQMGVWIQ-UHFFFAOYSA-N 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 125000000480 butynyl group Chemical group [*]C#CC([H])([H])C([H])([H])[H] 0.000 description 1
- 239000000480 calcium channel blocker Substances 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 235000011132 calcium sulphate Nutrition 0.000 description 1
- 125000004623 carbolinyl group Chemical group 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 150000001735 carboxylic acids Chemical group 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 230000021164 cell adhesion Effects 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 230000005754 cellular signaling Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 229940124587 cephalosporin Drugs 0.000 description 1
- 150000001780 cephalosporins Chemical class 0.000 description 1
- ARQRPTNYUOLOGH-UHFFFAOYSA-N chcl3 chloroform Chemical compound ClC(Cl)Cl.ClC(Cl)Cl ARQRPTNYUOLOGH-UHFFFAOYSA-N 0.000 description 1
- 125000003636 chemical group Chemical group 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 230000035605 chemotaxis Effects 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 229960004926 chlorobutanol Drugs 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 125000004230 chromenyl group Chemical group O1C(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000000259 cinnolinyl group Chemical group N1=NC(=CC2=CC=CC=C12)* 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000004040 coloring Methods 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 239000002299 complementary DNA Substances 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 125000001047 cyclobutenyl group Chemical group C1(=CCC1)* 0.000 description 1
- XSYZCZPCBXYQTE-UHFFFAOYSA-N cyclodecylcyclodecane Chemical compound C1CCCCCCCCC1C1CCCCCCCCC1 XSYZCZPCBXYQTE-UHFFFAOYSA-N 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000522 cyclooctenyl group Chemical group C1(=CCCCCCC1)* 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- SNRCKKQHDUIRIY-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloromethane;dichloropalladium;iron(2+) Chemical compound [Fe+2].ClCCl.Cl[Pd]Cl.C1=C[CH-]C(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.C1=C[CH-]C(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 SNRCKKQHDUIRIY-UHFFFAOYSA-L 0.000 description 1
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 description 1
- WLVKDFJTYKELLQ-UHFFFAOYSA-N cyclopropylboronic acid Chemical compound OB(O)C1CC1 WLVKDFJTYKELLQ-UHFFFAOYSA-N 0.000 description 1
- 230000021953 cytokinesis Effects 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 125000004856 decahydroquinolinyl group Chemical group N1(CCCC2CCCCC12)* 0.000 description 1
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000007933 dermal patch Substances 0.000 description 1
- NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 description 1
- 150000001975 deuterium Chemical group 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 1
- 229940038472 dicalcium phosphate Drugs 0.000 description 1
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 1
- 125000003963 dichloro group Chemical group Cl* 0.000 description 1
- ASWXNYNXAOQCCD-UHFFFAOYSA-N dichloro(triphenyl)-$l^{5}-phosphane Chemical compound C=1C=CC=CC=1P(Cl)(C=1C=CC=CC=1)(Cl)C1=CC=CC=C1 ASWXNYNXAOQCCD-UHFFFAOYSA-N 0.000 description 1
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 1
- 102000038379 digestive enzymes Human genes 0.000 description 1
- 108091007734 digestive enzymes Proteins 0.000 description 1
- BGRWYRAHAFMIBJ-UHFFFAOYSA-N diisopropylcarbodiimide Natural products CC(C)NC(=O)NC(C)C BGRWYRAHAFMIBJ-UHFFFAOYSA-N 0.000 description 1
- UXGNZZKBCMGWAZ-UHFFFAOYSA-N dimethylformamide dmf Chemical compound CN(C)C=O.CN(C)C=O UXGNZZKBCMGWAZ-UHFFFAOYSA-N 0.000 description 1
- 239000002934 diuretic Substances 0.000 description 1
- 229940030606 diuretics Drugs 0.000 description 1
- UZZWBUYVTBPQIV-UHFFFAOYSA-N dme dimethoxyethane Chemical compound COCCOC.COCCOC UZZWBUYVTBPQIV-UHFFFAOYSA-N 0.000 description 1
- CETRZFQIITUQQL-UHFFFAOYSA-N dmso dimethylsulfoxide Chemical compound CS(C)=O.CS(C)=O CETRZFQIITUQQL-UHFFFAOYSA-N 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 238000009510 drug design Methods 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 239000003596 drug target Substances 0.000 description 1
- 239000012636 effector Substances 0.000 description 1
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 230000002124 endocrine Effects 0.000 description 1
- OLAMWIPURJGSKE-UHFFFAOYSA-N et2o diethylether Chemical compound CCOCC.CCOCC OLAMWIPURJGSKE-UHFFFAOYSA-N 0.000 description 1
- OCLXJTCGWSSVOE-UHFFFAOYSA-N ethanol etoh Chemical compound CCO.CCO OCLXJTCGWSSVOE-UHFFFAOYSA-N 0.000 description 1
- SRCZQMGIVIYBBJ-UHFFFAOYSA-N ethoxyethane;ethyl acetate Chemical compound CCOCC.CCOC(C)=O SRCZQMGIVIYBBJ-UHFFFAOYSA-N 0.000 description 1
- NRFKMJQVWJLUDU-UHFFFAOYSA-N ethyl 1-benzyl-2-oxo-3-[4-(1H-pyrazol-4-yl)phenyl]imidazolidine-4-carboxylate Chemical compound N1N=CC(=C1)C1=CC=C(C=C1)N1C(N(CC1C(=O)OCC)CC1=CC=CC=C1)=O NRFKMJQVWJLUDU-UHFFFAOYSA-N 0.000 description 1
- QEULPJZBADJNAU-UHFFFAOYSA-N ethyl 1-benzyl-3-(4-bromophenyl)-2-oxoimidazolidine-4-carboxylate Chemical compound C(C1=CC=CC=C1)N1C(N(C(C1)C(=O)OCC)C1=CC=C(C=C1)Br)=O QEULPJZBADJNAU-UHFFFAOYSA-N 0.000 description 1
- NTNZTEQNFHNYBC-UHFFFAOYSA-N ethyl 2-aminoacetate Chemical compound CCOC(=O)CN NTNZTEQNFHNYBC-UHFFFAOYSA-N 0.000 description 1
- AMLWQSYZUFWMJI-UHFFFAOYSA-N ethyl 3-(benzylamino)-2-chloropropanoate Chemical compound C(C1=CC=CC=C1)NCC(C(=O)OCC)Cl AMLWQSYZUFWMJI-UHFFFAOYSA-N 0.000 description 1
- OJGRWMKNEOUTSP-UHFFFAOYSA-N ethyl 3-[(4-bromophenyl)carbamoyl-[(3-fluorophenyl)methyl]amino]-2-chloropropanoate Chemical compound BrC1=CC=C(C=C1)NC(N(CC1=CC(=CC=C1)F)CC(C(=O)OCC)Cl)=O OJGRWMKNEOUTSP-UHFFFAOYSA-N 0.000 description 1
- DBPFRRFGLYGEJI-UHFFFAOYSA-N ethyl glyoxylate Chemical compound CCOC(=O)C=O DBPFRRFGLYGEJI-UHFFFAOYSA-N 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- OJCSPXHYDFONPU-UHFFFAOYSA-N etoac etoac Chemical compound CCOC(C)=O.CCOC(C)=O OJCSPXHYDFONPU-UHFFFAOYSA-N 0.000 description 1
- 210000001105 femoral artery Anatomy 0.000 description 1
- 230000004761 fibrosis Effects 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 description 1
- 125000003709 fluoroalkyl group Chemical group 0.000 description 1
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 description 1
- 239000011888 foil Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 125000003838 furazanyl group Chemical group 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 235000001727 glucose Nutrition 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 125000004995 haloalkylthio group Chemical group 0.000 description 1
- 125000001475 halogen functional group Chemical group 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 125000005283 haloketone group Chemical group 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 208000019622 heart disease Diseases 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000006343 heptafluoro propyl group Chemical group 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000005980 hexynyl group Chemical group 0.000 description 1
- 238000004896 high resolution mass spectrometry Methods 0.000 description 1
- WJRBRSLFGCUECM-UHFFFAOYSA-N hydantoin Chemical compound O=C1CNC(=O)N1 WJRBRSLFGCUECM-UHFFFAOYSA-N 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 239000000017 hydrogel Substances 0.000 description 1
- 150000004680 hydrogen peroxides Chemical class 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- UWYVPFMHMJIBHE-OWOJBTEDSA-N hydroxymaleic acid group Chemical group O/C(/C(=O)O)=C/C(=O)O UWYVPFMHMJIBHE-OWOJBTEDSA-N 0.000 description 1
- 230000004047 hyperresponsiveness Effects 0.000 description 1
- 238000013299 hypertensive rat model Methods 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- 125000002636 imidazolinyl group Chemical group 0.000 description 1
- 210000002865 immune cell Anatomy 0.000 description 1
- 238000000099 in vitro assay Methods 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 125000004926 indolenyl group Chemical group 0.000 description 1
- 125000003406 indolizinyl group Chemical group C=1(C=CN2C=CC=CC12)* 0.000 description 1
- 230000007574 infarction Effects 0.000 description 1
- 208000030603 inherited susceptibility to asthma Diseases 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- SYJRVVFAAIUVDH-UHFFFAOYSA-N ipa isopropanol Chemical compound CC(C)O.CC(C)O SYJRVVFAAIUVDH-UHFFFAOYSA-N 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 125000001977 isobenzofuranyl group Chemical group C=1(OC=C2C=CC=CC12)* 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
- 125000003384 isochromanyl group Chemical group C1(OCCC2=CC=CC=C12)* 0.000 description 1
- 125000005438 isoindazolyl group Chemical group 0.000 description 1
- 125000004594 isoindolinyl group Chemical group C1(NCC2=CC=CC=C12)* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000005956 isoquinolyl group Chemical group 0.000 description 1
- 201000006370 kidney failure Diseases 0.000 description 1
- 230000003907 kidney function Effects 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 239000008297 liquid dosage form Substances 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 230000003908 liver function Effects 0.000 description 1
- 238000011866 long-term treatment Methods 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 238000002483 medication Methods 0.000 description 1
- COTNUBDHGSIOTA-UHFFFAOYSA-N meoh methanol Chemical compound OC.OC COTNUBDHGSIOTA-UHFFFAOYSA-N 0.000 description 1
- IBIKHMZPHNKTHM-RDTXWAMCSA-N merck compound 25 Chemical compound C1C[C@@H](C(O)=O)[C@H](O)CN1C(C1=C(F)C=CC=C11)=NN1C(=O)C1=C(Cl)C=CC=C1C1CC1 IBIKHMZPHNKTHM-RDTXWAMCSA-N 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- LULAYUGMBFYYEX-UHFFFAOYSA-N metachloroperbenzoic acid Natural products OC(=O)C1=CC=CC(Cl)=C1 LULAYUGMBFYYEX-UHFFFAOYSA-N 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- SCQXGTAVEQAZKX-UHFFFAOYSA-N methyl 3-[3-(4-bromo-3-methoxyphenyl)-2-oxoimidazolidin-1-yl]-3-(3-methoxyphenyl)propanoate Chemical compound BrC1=C(C=C(C=C1)N1C(N(CC1)C(CC(=O)OC)C1=CC(=CC=C1)OC)=O)OC SCQXGTAVEQAZKX-UHFFFAOYSA-N 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 229960002216 methylparaben Drugs 0.000 description 1
- 239000003658 microfiber Substances 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 210000001616 monocyte Anatomy 0.000 description 1
- PEECTLLHENGOKU-UHFFFAOYSA-N n,n-dimethylpyridin-4-amine Chemical compound CN(C)C1=CC=NC=C1.CN(C)C1=CC=NC=C1 PEECTLLHENGOKU-UHFFFAOYSA-N 0.000 description 1
- GVOISEJVFFIGQE-YCZSINBZSA-N n-[(1r,2s,5r)-5-[methyl(propan-2-yl)amino]-2-[(3s)-2-oxo-3-[[6-(trifluoromethyl)quinazolin-4-yl]amino]pyrrolidin-1-yl]cyclohexyl]acetamide Chemical compound CC(=O)N[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1C(=O)[C@@H](NC=2C3=CC(=CC=C3N=CN=2)C(F)(F)F)CC1 GVOISEJVFFIGQE-YCZSINBZSA-N 0.000 description 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
- RCSBCWXPGSPJNF-UHFFFAOYSA-N n-[4-[5-[3-chloro-4-(trifluoromethoxy)phenyl]-1,3,4-oxadiazol-2-yl]butyl]-4-(1,8-naphthyridin-2-yl)butanamide Chemical compound C1=C(Cl)C(OC(F)(F)F)=CC=C1C(O1)=NN=C1CCCCNC(=O)CCCC1=CC=C(C=CC=N2)C2=N1 RCSBCWXPGSPJNF-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003506 n-propoxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000007971 neurological deficit Effects 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 239000012457 nonaqueous media Substances 0.000 description 1
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002868 norbornyl group Chemical group C12(CCC(CC1)C2)* 0.000 description 1
- SFLSHLFXELFNJZ-UHFFFAOYSA-N norepinephrine Natural products NCC(O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-UHFFFAOYSA-N 0.000 description 1
- 229960002748 norepinephrine Drugs 0.000 description 1
- 238000005016 nuclear Overhauser enhanced spectroscopy Methods 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 229940126701 oral medication Drugs 0.000 description 1
- 239000007935 oral tablet Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- MUJIDPITZJWBSW-UHFFFAOYSA-N palladium(2+) Chemical compound [Pd+2] MUJIDPITZJWBSW-UHFFFAOYSA-N 0.000 description 1
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
- 125000001312 palmitoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 125000005981 pentynyl group Chemical group 0.000 description 1
- 239000002304 perfume Substances 0.000 description 1
- 208000030613 peripheral artery disease Diseases 0.000 description 1
- 239000008024 pharmaceutical diluent Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 125000004934 phenanthridinyl group Chemical group C1(=CC=CC2=NC=C3C=CC=CC3=C12)* 0.000 description 1
- 125000004625 phenanthrolinyl group Chemical group N1=C(C=CC2=CC=C3C=CC=NC3=C12)* 0.000 description 1
- 125000001791 phenazinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3N=C12)* 0.000 description 1
- 229940117803 phenethylamine Drugs 0.000 description 1
- 125000001484 phenothiazinyl group Chemical group C1(=CC=CC=2SC3=CC=CC=C3NC12)* 0.000 description 1
- 125000005954 phenoxathiinyl group Chemical group 0.000 description 1
- 125000001644 phenoxazinyl group Chemical group C1(=CC=CC=2OC3=CC=CC=C3NC12)* 0.000 description 1
- AHWALFGBDFAJAI-UHFFFAOYSA-N phenyl carbonochloridate Chemical compound ClC(=O)OC1=CC=CC=C1 AHWALFGBDFAJAI-UHFFFAOYSA-N 0.000 description 1
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 1
- 125000001639 phenylmethylene group Chemical group [H]C(=*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 150000008105 phosphatidylcholines Chemical class 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 125000001557 phthalyl group Chemical group C(=O)(O)C1=C(C(=O)*)C=CC=C1 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 125000004928 piperidonyl group Chemical group 0.000 description 1
- 229960005235 piperonyl butoxide Drugs 0.000 description 1
- 125000004591 piperonyl group Chemical group C(C1=CC=2OCOC2C=C1)* 0.000 description 1
- LYKMMUBOEFYJQG-UHFFFAOYSA-N piperoxan Chemical compound C1OC2=CC=CC=C2OC1CN1CCCCC1 LYKMMUBOEFYJQG-UHFFFAOYSA-N 0.000 description 1
- 229920001610 polycaprolactone Polymers 0.000 description 1
- 125000005575 polycyclic aromatic hydrocarbon group Chemical group 0.000 description 1
- 229920000656 polylysine Polymers 0.000 description 1
- 229920006324 polyoxymethylene Polymers 0.000 description 1
- 229920002223 polystyrene Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000012041 precatalyst Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- 229960003415 propylparaben Drugs 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 210000001243 pseudopodia Anatomy 0.000 description 1
- 125000001042 pteridinyl group Chemical group N1=C(N=CC2=NC=CN=C12)* 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 1
- 125000002755 pyrazolinyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000001422 pyrrolinyl group Chemical group 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 125000004621 quinuclidinyl group Chemical group N12C(CC(CC1)CC2)* 0.000 description 1
- 238000011552 rat model Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000007634 remodeling Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000004366 reverse phase liquid chromatography Methods 0.000 description 1
- 125000006413 ring segment Chemical group 0.000 description 1
- 229910052707 ruthenium Inorganic materials 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 239000008299 semisolid dosage form Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229940076279 serotonin Drugs 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 230000016160 smooth muscle contraction Effects 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- RYYKJJJTJZKILX-UHFFFAOYSA-M sodium octadecanoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC([O-])=O RYYKJJJTJZKILX-UHFFFAOYSA-M 0.000 description 1
- WGRULTCAYDOGQK-UHFFFAOYSA-M sodium;sodium;hydroxide Chemical compound [OH-].[Na].[Na+] WGRULTCAYDOGQK-UHFFFAOYSA-M 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 238000007614 solvation Methods 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- VNFWTIYUKDMAOP-UHFFFAOYSA-N sphos Chemical compound COC1=CC=CC(OC)=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 VNFWTIYUKDMAOP-UHFFFAOYSA-N 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- YQRMLCCOGRDYLW-UHFFFAOYSA-N tert-butyl 4-[2-methoxy-4-[3-[3-methoxy-1-(3-methoxyphenyl)-3-oxopropyl]-2-oxoimidazolidin-1-yl]phenyl]pyrazole-1-carboxylate Chemical compound COC1=C(C=CC(=C1)N1C(N(CC1)C(CC(=O)OC)C1=CC(=CC=C1)OC)=O)C=1C=NN(C=1)C(=O)OC(C)(C)C YQRMLCCOGRDYLW-UHFFFAOYSA-N 0.000 description 1
- BFRDYMOJBOOXNG-UHFFFAOYSA-N tert-butyl 4-[4-(3-benzyl-5-ethoxycarbonyl-2-oxoimidazolidin-1-yl)phenyl]pyrazole-1-carboxylate Chemical compound C(C1=CC=CC=C1)N1C(N(C(C1)C(=O)OCC)C1=CC=C(C=C1)C=1C=NN(C=1)C(=O)OC(C)(C)C)=O BFRDYMOJBOOXNG-UHFFFAOYSA-N 0.000 description 1
- SIJXZJOHGFLPSZ-UHFFFAOYSA-N tert-butyl 4-[4-[4-ethoxycarbonyl-3-[(3-methoxyphenyl)methyl]-2-oxoimidazolidin-1-yl]phenyl]pyrazole-1-carboxylate Chemical compound C(C)OC(=O)C1N(C(N(C1)C1=CC=C(C=C1)C=1C=NN(C=1)C(=O)OC(C)(C)C)=O)CC1=CC(=CC=C1)OC SIJXZJOHGFLPSZ-UHFFFAOYSA-N 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- UEUXEKPTXMALOB-UHFFFAOYSA-J tetrasodium;2-[2-[bis(carboxylatomethyl)amino]ethyl-(carboxylatomethyl)amino]acetate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O UEUXEKPTXMALOB-UHFFFAOYSA-J 0.000 description 1
- PHCBRBWANGJMHS-UHFFFAOYSA-J tetrasodium;disulfate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O PHCBRBWANGJMHS-UHFFFAOYSA-J 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- 125000004627 thianthrenyl group Chemical group C1(=CC=CC=2SC3=CC=CC=C3SC12)* 0.000 description 1
- 125000005309 thioalkoxy group Chemical group 0.000 description 1
- 125000005403 thiohaloalkoxy group Chemical group 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 230000037317 transdermal delivery Effects 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
- 125000006168 tricyclic group Chemical group 0.000 description 1
- WLPUWLXVBWGYMZ-UHFFFAOYSA-N tricyclohexylphosphine Chemical compound C1CCCCC1P(C1CCCCC1)C1CCCCC1 WLPUWLXVBWGYMZ-UHFFFAOYSA-N 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 150000003672 ureas Chemical class 0.000 description 1
- 210000005166 vasculature Anatomy 0.000 description 1
- 230000002227 vasoactive effect Effects 0.000 description 1
- PXXNTAGJWPJAGM-UHFFFAOYSA-N vertaline Natural products C1C2C=3C=C(OC)C(OC)=CC=3OC(C=C3)=CC=C3CCC(=O)OC1CC1N2CCCC1 PXXNTAGJWPJAGM-UHFFFAOYSA-N 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
- 125000001834 xanthenyl group Chemical group C1=CC=CC=2OC3=CC=CC=C3C(C12)* 0.000 description 1
- 229930195724 β-lactose Natural products 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/42—Oxazoles
- A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- 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
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Definitions
- the present invention relates to novel cyclic urea derivatives, compositions containing them, and methods of using them, for example, for the treatment or prophylaxis of disorders associated with aberrant Rho kinase activity.
- Rho-Kinase is a member of the serine-threonine protein kinase family. ROCK exists in two isoforms, ROCK1 and ROCK2 (Ishizaki, T. et al., EMBO J., 15:1885-1893 (1996)). ROCK has been identified as an effector molecule of RhoA, a small GTP-binding protein (G protein) that plays a key role in multiple cellular signaling pathways. ROCK and RhoA are ubiquitously expressed across tissues. The RhoA/ROCK signaling pathway is involved in a number of cellular functions, such as ACTIN® organization, cell adhesion, cell migration, and cytokinesis (Riento, K. et al., Nat.
- RhoA Upon activation of its receptor, RhoA is activated, and, in turn, it activates ROCK. Activated ROCK phosphorylates the myosin-binding subunit of myosin light chain phosphatase, which inhibits activity of the phosphatase and leads to contraction. Contraction of the smooth muscle in the vasculature increases blood pressure, leading to hypertension.
- Rho A/ROCK signaling pathway plays an important role in signal transduction initiated by several vasoactive factors, for example, angiotensin II (Yamakawa, T. et al., Hypertension, 35:313-318 (2000)), urotension II (Sauzeau, V. et al., Circ. Res., 88:1102-1104 (2001)), endothelin-1 (Tangkijvanich, P. et al., Hepatology, 33:74-80 (2001)), serotonin (Shimokawa, H., Jpn. Circ. J., 64:1-12 (2000)), norepinephrine (Martinez, M.C.
- PDGF platelet-derived growth factor
- ROCK inhibitors fasudil (Asano, T. et al., J. Pharmacol. Exp. Ther., 241:1033-1040 (1987)) or Y-27632 (Uehata, M. et al., Nature, 389:990-994 (1997)) further illustrate the link between ROCK and cardiovascular disease.
- ROCK expression and activity have been shown to be elevated in spontaneously hypertensive rats, suggesting a link to the development of hypertension in these animals (Mukai, Y. et al., FASEB J., 15:1062-1064 (2001)).
- the ROCK inhibitor Y-27632 (Uehata, M.
- ROCK inhibitor Y-27632 also inhibited neointimal formation in rats (Sawada, N. et al., Circulation, 101:2030-2033 (2000)).
- ROCK inhibitor would be useful in treating other cardiovascular diseases.
- fasudil was shown to reduce both the infarct size and neurologic deficit (Toshima, Y., Stroke, 31:2245-2250 (2000)).
- the ROCK inhibitor Y-27632 was shown to improve ventricular hypertrophy, fibrosis and function in a model of congestive heart failure in Dahl salt- sensitive rats (Kobayashi, N. et al., Cardiovasc. Res., 55:757-767 (2002)).
- ROCK cardiovascular disease 2019
- coronary vasospasm Shiokawa, H. et al., Cardiovasc. Res., 43:1029-1039 (1999)
- cerebral vasospasm Sato, M. et al., Circ. Res., 87:195-200 (2000)
- ischemia/reperfusion injury Yada, T. et al., J. Am. Coll. Cardiol., 45:599-607 (2005)
- pulmonary hypertension Fukumoto, Y. et al., Heart, 91:391-392 (2005)
- angina Shiokawa, H. et al., J. Cardiovasc.
- RhoA/ROCK signaling pathway allows formation of multiple competing lamellipodia that disrupt the productive migration of monocytes (Worthylake, R.A. et al., J. Biol. Chem., 278:13578- 13584 (2003)). It has also been reported that small molecule inhibitors of Rho Kinase are capable of inhibiting MCP-1 mediated chemotaxis in vitro (Iijima, H., Bioorg. Med. Chem., 15:1022-1033 (2007)). Due to the dependence of immune cell migration upon the RhoA/ROCK signaling pathway one would anticipate inhibition of Rho Kinase should also provide benefit for diseases such as rheumatoid arthritis, psoriasis, and inflammatory bowel disease.
- ROCK inhibitors may also be useful in other diseases involving smooth muscle hyper-reactivity, including asthma and glaucoma (Shimokawa, H. et al., Arterioscler. Thromb. Vase. Biol., 25:1767-1775 (2005)).
- Rho- kinase has been indicated as a drug target for the treatment of various other diseases, including airway inflammation and hyperresponsiveness (Henry, P.J. et al., Pulm.
- CVD cardiovascular diseases
- ROCK inhibitors Although there are many reports of ROCK inhibitors under investigation (see, for example, US 2008/0275062 A1), fasudil is the only marketed ROCK inhibitor at this time. An i.v. formulation was approved in Japan for treatment of cerebral vasospasm. There remains a need for new therapeutics, including ROCK inhibitors, for the treatment of cardiovascular diseases, cancer, neurological diseases, renal diseases, fibrotic diseases, bronchial asthma, erectile dysfunction, and glaucoma. SUMMARY OF THE INVENTION
- the present invention provides novel cyclic urea derivatives including stereoisomers, tautomers, pharmaceutically acceptable salts, or solvates thereof, which are useful as selective inhibitors of Rho kinases.
- the present invention also provides processes and intermediates for making the compounds of the present invention.
- the present invention also provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier and at least one of the compounds of the present invention or stereoisomers, tautomers, pharmaceutically acceptable salts, or solvates thereof.
- the compounds of the invention may be used in the treatment and/or prophylaxis of conditions associated with aberrant ROCK activity.
- the compounds of the present invention may be used in therapy.
- the compounds of the present invention may be used for the manufacture of a medicament for the treatment and/or prophylaxis of a condition associated with aberrant ROCK activity.
- the present invention is directed to a method of treating a cardiovascular or related disease which method comprises administering to a patient in need of such treatment a compound of the present invention as described above.
- diseases include, for example, hypertension, atherosclerosis, restenosis, stroke, heart failure, renal failure, coronary artery disease, peripheral artery disease, coronary vasospasm, cerebral vasospasm, ischemia/reperfusion injury, pulmonary hypertension, angina, erectile dysfunction and renal disease.
- the present invention is directed to a method of treating diseases involving smooth muscle hyper reactivity including asthma, erectile dysfunction and glaucoma, which method comprises administering to a patient in need of such treatment a compound of the present invention as described above.
- the present invention is directed to a method of treating diseases mediated at least partially by Rho kinase including fibrotic diseases, oncology, spinal- cord injury, Alzheimer's disease, multiple sclerosis, stroke, neuropathic pain, rheumatoid arthritis, psoriasis and inflammatory bowel disease, which method comprises
- the present invention is directed at pharmaceutical compositions comprising the above-mentioned compounds, processes for preparing the above-mentioned compounds and intermediates used in these processes.
- the compounds of the invention can be used alone, in combination with other compounds of the present invention, or in combination with one or more, preferably one to two other agent(s).
- the present invention provides, inter alia, compounds of Formula (I): (I) or stereoisomers, enantiomers, diastereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein
- Ring A is independently selected from
- J1, J2, J3, and J4 are independently selected from N and CR3; provided one of J1, J2, J3, and J4 is N and no more than two of J1, J2, J3, and J4 are N;
- K is independently selected from N and CR1;
- R1 is independently selected from H, F, Cl, Br, OH, CN, NRaRa, ⁇ OC1 ⁇ 4 alkyl substituted with 0 ⁇ 3 R e , and C 1 ⁇ 4 alkyl substituted with 0 ⁇ 3 R e ;
- R4 is independently selected from H, F, Cl, Br, OH, CN, OC1 ⁇ 4 alkyl substituted with 0 ⁇ 3 R e , NR a R a , and C 1 ⁇ 4 alkyl substituted with 0 ⁇ 3 R e ;
- R6 and R7 are independently selected from H, C1 ⁇ 4alkyl substituted with 0 ⁇ 4 Re,
- R8 is independently selected from C3 ⁇ 6 cycloalkyl, heterocyclyl, aryl and heteroaryl, each substituted with 0 ⁇ 5 R 9 ;
- R a is independently selected from H, C 1 ⁇ 6 alkyl substituted with 0 ⁇ 5 Re, C2 ⁇ 6 alkenyl substituted with 0 ⁇ 5 Re, C2 ⁇ 6 alkynyl substituted with 0 ⁇ 5 Re, ⁇ (CH 2 ) r ⁇ C 3 ⁇ 10 carbocyclyl substituted with 0 ⁇ 5 R e , and ⁇ (CH 2 ) r ⁇ heterocyclyl substituted with 0 ⁇ 5 Re; or Ra and Ra together with the nitrogen atom to which they are both attached form a heterocyclic ring substituted with 0 ⁇ 5 R e ;
- Rb at each occurrence, is independently selected from H, C1 ⁇ 6 alkyl substituted with 0 ⁇ 5 Re, C2 ⁇ 6 alkenyl substituted with 0 ⁇ 5 Re, C2 ⁇ 6 alkynyl substituted with 0 ⁇ 5 Re, ⁇ (CH2)r ⁇ C3 ⁇ 10carbocyclyl substituted with 0 ⁇ 5 Re, and ⁇ (CH2)r ⁇ heterocyclyl substituted with 0 ⁇ 5 R e ;
- Rc at each occurrence, is independently selected from C1 ⁇ 6 alkyl substituted with 0 ⁇ 5 Re, C 2 ⁇ 6 alkenyl substituted with 0 ⁇ 5 R e , C 2 ⁇ 6 alkynyl substituted with 0 ⁇ 5 R e,
- R d at each occurrence, is independently selected from H and C 1 ⁇ 4 alkyl substituted with 0 ⁇ 5 Re;
- Rf at each occurrence, is independently selected from H, F, Cl, Br, CN, OH, C1 ⁇ 5alkyl, C3 ⁇ 6 cycloalkyl, and phenyl, or Rf and Rf together with the nitrogen atom to which they are both attached form a heterocyclic ring optionally substituted with C1 ⁇ 4alkyl;
- n is independently selected from 1, 2, and 3;
- p at each occurrence, is independently selected from zero, 1, and 2;
- the present invention provides compounds of Formula (I) or stereoisomers, enantiomers, diastereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein
- Ring A is independently selected from
- J 1 , J 2 , J 3 , and J 4 are independently selected from N and CH; provided no more than two of J1, J2, J3, and J4 are N;
- K is independently selected from N and CH;
- R1 is independently selected from H, F, Cl, Br, OH, CN, NRaRa, ⁇ OC1 ⁇ 4 alkyl substituted with 0 ⁇ 3 R e , and C 1 ⁇ 4 alkyl substituted with 0 ⁇ 3 R e ;
- R4 is independently selected from H, F, Cl, Br, OH, CN, OC1 ⁇ 4 alkyl substituted with 0 ⁇ 3 R e , NR a R a , and C 1 ⁇ 4 alkyl substituted with 0 ⁇ 3 R e ;
- R6 and R7 are independently selected from H, C1 ⁇ 4alkyl substituted with 0 ⁇ 4 Re,
- R 8 is independently selected from aryl and heteroaryl, each substituted with 0 ⁇ 5 R 9 ;
- Ra at each occurrence, is independently selected from H, C1 ⁇ 6 alkyl substituted with 0 ⁇ 5 R e , C 2 ⁇ 6 alkenyl substituted with 0 ⁇ 5 R e , C 2 ⁇ 6 alkynyl substituted with 0 ⁇ 5 R e , ⁇ (CH2)r ⁇ C3 ⁇ 10carbocyclyl substituted with 0 ⁇ 5 Re, and ⁇ (CH2)r ⁇ heterocyclyl substituted with 0 ⁇ 5 R e ; or R a and R a together with the nitrogen atom to which they are both attached form a heterocyclic ring substituted with 0 ⁇ 5 Re;
- R b at each occurrence, is independently selected from H, C 1 ⁇ 6 alkyl substituted with 0 ⁇ 5 Re, C2 ⁇ 6 alkenyl substituted with 0 ⁇ 5 Re, C2 ⁇ 6 alkynyl substituted with 0 ⁇ 5 Re, ⁇ (CH 2 ) r ⁇ C 3 ⁇ 10 carbocyclyl substituted with 0 ⁇ 5 R e , and ⁇ (CH 2 ) r ⁇ heterocyclyl substituted with 0 ⁇ 5 Re;
- R c at each occurrence, is independently selected from C 1 ⁇ 6 alkyl substituted with 0 ⁇ 5 R e , C2 ⁇ 6alkenyl substituted with 0 ⁇ 5 Re, C2 ⁇ 6alkynyl substituted with 0 ⁇ 5 Re,
- Rd at each occurrence, is independently selected from H and C1 ⁇ 4alkyl substituted with 0 ⁇ 5 R e ;
- Rf at each occurrence, is independently selected from H, F, Cl, Br, CN, OH, C1 ⁇ 5alkyl, C 3 ⁇ 6 cycloalkyl, and phenyl, or R f and R f together with the nitrogen atom to which they are both attached form a heterocyclic ring optionally substituted with C 1 ⁇ 4 alkyl;
- n is independently selected from 1, 2, and 3;
- p at each occurrence, is independently selected from zero, 1, and 2;
- r at each occurrence, is independently selected from zero, 1, 2, 3, and 4;
- R9 is not a substituted piperazine
- the present invention provides compounds of Formula (I) or stereoisomers, enantiomers, diastereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein
- R 1 is independently selected from H, F, Cl, Br, OH, CN, NR a R a , ⁇ OC 1 ⁇ 4 alkyl substituted with 0 ⁇ 3 Re, and C1 ⁇ 4 alkyl substituted with 0 ⁇ 3 Re;
- R4 is independently selected from H, F, Cl, Br, OH, CN, and C1 ⁇ 4 alkyl substituted with 0 ⁇ 3 R e ;
- R6 and R7 are independently selected from H, C1 ⁇ 4alkyl substituted with 0 ⁇ 4 Re,
- R8 is independently selected from
- the present invention provides compounds of Formula (I) or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein R1 is independently selected from H, F, Cl, Br, OH, CN, NRaRa, ⁇ OC1 ⁇ 4 alkyl substituted with 0 ⁇ 3 R e , and C 1 ⁇ 4 alkyl substituted with 0 ⁇ 3 R e ;
- R4 is independently selected from H, F, Cl, Br, OH, CN, and C1 ⁇ 4 alkyl substituted with 0 ⁇ 3 Re;
- R6 and R7 are independently selected from H, C1 ⁇ 4alkyl substituted with 0 ⁇ 4 Re,
- R8 is independently selected from
- Ring A is inde endentl selected from
- R 1 is independently selected from H, F, Cl, Br, CN, NR a R a , and C 1 ⁇ 4 alkyl substituted with 0 ⁇ 4 Re;
- R 2 is independently selected from H, F, Cl, Br, OH, CN, NR a R a , and C 1 ⁇ 4 alkyl substituted with 0 ⁇ 4 Re;
- R3 is independently selected from H, F, Cl, Br, CN, C1 ⁇ 4 alkyl substituted with 0 ⁇ 3 Re, ⁇ (CH 2 ) r OR b , and ⁇ C 3 ⁇ 6 cycloalkyl;
- R4 is independently selected from H, F, Cl, Br, OH, CN, OC1 ⁇ 4 alkyl substituted with 0 ⁇ 3 R e , and C 1 ⁇ 4 alkyl substituted with 0 ⁇ 3 R e ;
- R6 and R7 are independently selected from H, C1 ⁇ 4alkyl substituted with 0 ⁇ 4 Re,
- R9 is independently selected from F, Cl, Br, C1 ⁇ 4 alkyl, nitro, ⁇ (CH2)rS(O)pRc,
- R a is independently selected from H, C 1 ⁇ 6 alkyl substituted with 0 ⁇ 5 Re, C2 ⁇ 6 alkenyl substituted with 0 ⁇ 5 Re, C2 ⁇ 6 alkynyl substituted with 0 ⁇ 5 Re, ⁇ (CH 2 ) r ⁇ C 3 ⁇ 10 cycloalkyl substituted with 0 ⁇ 5 R e , ⁇ (CH 2 ) r ⁇ aryl substituted with 0 ⁇ 5 Re, and ⁇ (CH2)r ⁇ heterocyclyl substituted with 0 ⁇ 5 Re; or Ra and Ra together with the nitrogen atom to which they are both attached form a heterocyclic ring substituted with 0 ⁇ 5 Re;
- R b at each occurrence, is independently selected from H, C 1 ⁇ 6 alkyl substituted with 0 ⁇ 5 Re, C2 ⁇ 6 alkenyl substituted with 0 ⁇ 5 Re, C2 ⁇ 6 alkynyl substituted with 0 ⁇ 5 Re, ⁇ (CH2)r ⁇ C3 ⁇ 10carbocyclyl substituted with 0 ⁇ 5 Re, and ⁇ (CH2)r ⁇ heterocyclyl substituted with 0 ⁇ 5 Re;
- Rc at each occurrence, is independently selected from C1 ⁇ 6 alkyl substituted with 0 ⁇ 5 Re, C 2 ⁇ 6 alkenyl substituted with 0 ⁇ 5 R e , C 2 ⁇ 6 alkynyl substituted with 0 ⁇ 5 R e ,
- R f at each occurrence, is independently selected from H, F, Cl, Br, CN, OH, C 1 ⁇ 5 alkyl, C3 ⁇ 6 cycloalkyl, and phenyl, or Rf and Rf together with the nitrogen atom to which they are both attached form a heterocyclic ring optionally substituted with C1 ⁇ 4alkyl;
- n is independently selected from 1, 2, and 3;
- p at each occurrence, is independently selected from zero, 1, and 2;
- r at each occurrence, is independently selected from zero, 1, 2, 3, and 4.
- the present invention provides compounds of Formula (II) or stereoisomers, enantiomers, diastereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein
- Ring A is independently selected from
- K is independently selected from N and CH;
- R 1 is independently selected from H, F, Cl, Br, CN, NR a R a , and C 1 ⁇ 4 alkyl substituted with 0 ⁇ 4 Re;
- R 2 is independently selected from H, F, Cl, Br, OH, CN, NR a R a , and C 1 ⁇ 4 alkyl substituted with 0 ⁇ 4 Re;
- R 3 is independently selected from H, F, Cl, Br, CN, C 1 ⁇ 4 alkyl substituted with 0 ⁇ 3 R e , and ⁇ (CH2)rORb;
- R4 is independently selected from H, F, Cl, Br, OH, CN, OC1 ⁇ 4 alkyl substituted with 0 ⁇ 3 Re, and C1 ⁇ 4 alkyl substituted with 0 ⁇ 3 Re;
- R6 and R7 are independently selected from H, C1 ⁇ 4alkyl substituted with 0 ⁇ 4 Re,
- R9 is independently selected from F, Cl, Br, C1 ⁇ 4 alkyl, nitro, ⁇ (CH2)rS(O)pRc,
- Ra at each occurrence, is independently selected from H, C1 ⁇ 6 alkyl substituted with 0 ⁇ 5 R e , C 2 ⁇ 6 alkenyl substituted with 0 ⁇ 5 R e , C 2 ⁇ 6 alkynyl substituted with 0 ⁇ 5 R e , ⁇ (CH2)r ⁇ C3 ⁇ 10cycloalkyl substituted with 0 ⁇ 5 Re, ⁇ (CH2)r ⁇ aryl substituted with 0 ⁇ 5 R e , and ⁇ (CH 2 ) r ⁇ heterocyclyl substituted with 0 ⁇ 5 R e ; or R a and R a together with the nitrogen atom to which they are both attached form a heterocyclic ring substituted with 0 ⁇ 5 R e ; Rb, at each occurrence, is independently selected from H, C1 ⁇ 6 alkyl substituted with 0 ⁇ 5 R e , C 2 ⁇ 6 alkenyl substituted with 0 ⁇ 5 R e , C 2 ⁇ 6 alkynyl substituted with
- Rc at each occurrence, is independently selected from C1 ⁇ 6 alkyl substituted with 0 ⁇ 5 Re, C 2 ⁇ 6 alkenyl substituted with 0 ⁇ 5 R e , C 2 ⁇ 6 alkynyl substituted with 0 ⁇ 5 R e ,
- Rf at each occurrence, is independently selected from H, F, Cl, Br, CN, OH, C1 ⁇ 5 alkyl, C3 ⁇ 6 cycloalkyl, and phenyl, or Rf and Rf together with the nitrogen atom to which they are both attached form a heterocyclic ring optionally substituted with C 1 ⁇ 4 alkyl;
- n is independently selected from 1, 2, and 3;
- p at each occurrence, is independently selected from zero, 1, and 2;
- r at each occurrence, is independently selected from zero, 1, 2, 3, and 4;
- the present invention provides compounds of Formula (II) or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein
- R3 is independently selected from F, Cl, Br, CN, C1 ⁇ 4 alkyl substituted with 0 ⁇ 3 Re,
- R4 is independently selected from H, F, Cl, Br, OH, CN, and C1 ⁇ 4 alkyl substituted with 0 ⁇ 3 Re;
- R 6 and R 7 together with the carbon atom to which they are both attached form a cycloalkyl substituted with 0 ⁇ 5 Re; alternatively, when n is 2 or 3, two adjacent R 6 groups may form a cycloalkyl substituted with 0 ⁇ 5 R e and two R 7 groups are both hydrogen;
- R 9 is independently selected from F, Cl, Br, CN, C 1 ⁇ 4 alkyl, ⁇ (CHR d ) r S(O) p R c ,
- Ra at each occurrence, is independently selected from H, CN, C1 ⁇ 6 alkyl substituted with 0 ⁇ 5 R e , C 2 ⁇ 6 alkenyl substituted with 0 ⁇ 5 R e , C 2 ⁇ 6 alkynyl substituted with 0 ⁇ 5 R e , ⁇ (CH2)r ⁇ C3 ⁇ 10carbocyclyl substituted with 0 ⁇ 5 Re, and ⁇ (CH2)r ⁇ heterocyclyl substituted with 0 ⁇ 5 R e ; or R a and R a together with the nitrogen atom to which they are both attached form a heterocyclic ring substituted with 0 ⁇ 5 Re;
- R b at each occurrence, is independently selected from H, C 1 ⁇ 6 alkyl substituted with 0 ⁇ 5 Re, C2 ⁇ 6 alkenyl substituted with 0 ⁇ 5 Re, C2 ⁇ 6 alkynyl substituted with 0 ⁇ 5 Re, ⁇ (CH 2 ) r ⁇ C 3 ⁇ 10 carbocyclyl substituted with 0 ⁇ 5 R e , and ⁇ (CH 2 ) r ⁇ heterocyclyl substituted with 0 ⁇ 5 Re;
- R c at each occurrence, is independently selected from C 1 ⁇ 6 alkyl substituted with 0 ⁇ 5 R e , C2 ⁇ 6alkenyl substituted with 0 ⁇ 5 Re, C2 ⁇ 6alkynyl substituted with 0 ⁇ 5 Re,
- Rd at each occurrence, is independently selected from H and C1 ⁇ 4alkyl substituted with 0 ⁇ 5 R e ;
- Rf at each occurrence, is independently selected from H, F, Cl, NH2, OH, OC1 ⁇ 5alkyl, C 1 ⁇ 5 alkyl, C 3 ⁇ 6 cycloalkyl, and phenyl, or R f and R f together with the nitrogen atom to which they are both attached form a heterocyclic ring optionally substituted with C 1 ⁇ 4 alkyl;
- p at each occurrence, is independently selected from zero, 1, and 2;
- r at each occurrence, is independently selected from zero, 1, 2, 3, and 4;
- Ring A is inde endentl selected from
- R1 is independently selected from H, F, Cl, Br, CN, NRaRa, and C1 ⁇ 4alkyl substituted with 0 ⁇ 4 R e ;
- R2 is independently selected from H, F, Cl, Br, OH, CN, NRaRa, and C1 ⁇ 4alkyl substituted with 0 ⁇ 4 R e ;
- R3 is independently selected from H, F, Cl, Br, CN, C1 ⁇ 4 alkyl substituted with 0 ⁇ 3 Re, ⁇ (CH 2 ) r OR b , and ⁇ C 3 ⁇ 6 cycloalkyl;
- R4 is independently selected from H, F, Cl, Br, OH, CN, OC1 ⁇ 4 alkyl substituted with 0 ⁇ 3 R e , and C 1 ⁇ 4 alkyl substituted with 0 ⁇ 3 R e ;
- R9 is independently selected from F, Cl, Br, C1 ⁇ 4 alkyl, nitro, ⁇ (CH2)rS(O)pRc,
- R a at each occurrence, is independently selected from H, C1 ⁇ 6 alkyl substituted with 0 ⁇ 5 Re, C2 ⁇ 6 alkenyl substituted with 0 ⁇ 5 Re, C2 ⁇ 6 alkynyl substituted with 0 ⁇ 5 Re,
- R b at each occurrence, is independently selected from H, C 1 ⁇ 6 alkyl substituted with 0 ⁇ 5 Re, C2 ⁇ 6 alkenyl substituted with 0 ⁇ 5 Re, C2 ⁇ 6 alkynyl substituted with 0 ⁇ 5 Re, ⁇ (CH 2 ) r ⁇ C 3 ⁇ 10 carbocyclyl substituted with 0 ⁇ 5 R e , and ⁇ (CH 2 ) r ⁇ heterocyclyl substituted with 0 ⁇ 5 Re;
- R c at each occurrence, is independently selected from C 1 ⁇ 6 alkyl substituted with 0 ⁇ 5 R e , C2 ⁇ 6alkenyl substituted with 0 ⁇ 5 Re, C2 ⁇ 6alkynyl substituted with 0 ⁇ 5 Re,
- Rf at each occurrence, is independently selected from H, F, Cl, Br, CN, OH, C1 ⁇ 5 alkyl, C 3 ⁇ 6 cycloalkyl, and phenyl, or R f and R f together with the nitrogen atom to which they are both attached form a heterocyclic ring optionally substituted with C1 ⁇ 4alkyl;
- n is independently selected from 1, 2, and 3; p, at each occurrence, is independently selected from zero, 1, and 2; and r, at each occurrence, is independently selected from zero, 1, 2, 3, and 4; and
- R 9 is not a substituted piperazine; 5 (2) when n is 3, R8 is not ; and
- R1 is independently selected from H, F, Cl, Br, CN, NRaRa, and C1 ⁇ 4alkyl substituted with 0 ⁇ 4 R e ;
- R3 is independently selected from H, F, Cl, Br, CN, C1 ⁇ 4 alkyl substituted with 0 ⁇ 3 Re, and ⁇ (CH 2 ) r OR b ;
- R4 is independently selected from H, F, Cl, Br, OH, CN, OC1 ⁇ 4 alkyl substituted with 0 ⁇ 3 R e , and C 1 ⁇ 4 alkyl substituted with 0 ⁇ 3 R e ;
- R9 is independently selected from F, Cl, Br, C1 ⁇ 4 alkyl, nitro, ⁇ (CH2)rS(O)pRc,
- Ra at each occurrence, is independently selected from H, C1 ⁇ 6 alkyl substituted with 0 ⁇ 5 R e , C 2 ⁇ 6 alkenyl substituted with 0 ⁇ 5 R e , C 2 ⁇ 6 alkynyl substituted with 0 ⁇ 5 R e , ⁇ (CH2)r ⁇ C3 ⁇ 10cycloalkyl substituted with 0 ⁇ 5 Re, ⁇ (CH2)r ⁇ aryl substituted with 0 ⁇ 5 R e , and ⁇ (CH 2 ) r ⁇ heterocyclyl substituted with 0 ⁇ 5 R e ; or R a and R a together with the nitrogen atom to which they are both attached form a heterocyclic ring substituted with 0 ⁇ 5 Re;
- Rb at each occurrence, is independently selected from H, C1 ⁇ 6 alkyl substituted with 0 ⁇ 5 Re, C2 ⁇ 6 alkenyl substituted with 0 ⁇ 5 Re, C2 ⁇ 6 alkynyl substituted with 0 ⁇ 5 Re, ⁇ (CH 2 ) r ⁇ C 3 ⁇ 10 carbocyclyl substituted with 0 ⁇ 5 R e , and ⁇ (CH 2 ) r ⁇ heterocyclyl substituted with 0 ⁇ 5 Re;
- R c at each occurrence, is independently selected from C 1 ⁇ 6 alkyl substituted with 0 ⁇ 5 R e , C2 ⁇ 6alkenyl substituted with 0 ⁇ 5 Re, C2 ⁇ 6alkynyl substituted with 0 ⁇ 5 Re,
- Rf at each occurrence, is independently selected from H, F, Cl, Br, CN, OH, C1 ⁇ 5 alkyl, C 3 ⁇ 6 cycloalkyl, and phenyl, or R f and R f together with the nitrogen atom to which they are both attached form a heterocyclic ring optionally substituted with C 1 ⁇ 4 alkyl;
- n is independently selected from 1 and 2;
- p at each occurrence, is independently selected from zero, 1, and 2;
- r at each occurrence, is independently selected from zero, 1, 2, 3, and 4.
- the present invention provides compounds of Formula (III) or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein
- R 1 is independently selected from H
- R3 is independently selected from H, F, Cl, C1 ⁇ 4 alkyl, and -OC1 ⁇ 3 alkyl;
- R 9 is independently selected from F, Cl, C 1 ⁇ 4 alkyl substituted with 0 ⁇ 3 R e , ⁇ OR b , and heterocyclyl substituted with 0 ⁇ 3 Re;
- Rb at each occurrence, is independently selected from H, C1 ⁇ 6 alkyl substituted with 0 ⁇ 5 Re, ⁇ (CH2)r ⁇ C3 ⁇ 10carbocyclyl substituted with 0 ⁇ 5 Re, and ⁇ (CH2)r ⁇ heterocyclyl substituted with 0 ⁇ 5 Re;
- n is independently selected from 1 and 2;
- r at each occurrence, is independently selected from zero, 1, 2, and 3;
- R1 is independently selected from H, F, Cl, Br, CN, NRaRa, and C1 ⁇ 4alkyl substituted with 0 ⁇ 4 R e ;
- R2 is independently selected from H and C1 ⁇ 4alkyl substituted with 0 ⁇ 4 Re;
- R 3 is independently selected from H, F, Cl, Br, CN, C 1 ⁇ 4 alkyl substituted with 0 ⁇ 3 R e, ⁇ (CH2)rORb, and ⁇ C3 ⁇ 6 cycloalkyl;
- R4 is independently selected from H, F, Cl, Br, OH, CN, OC1 ⁇ 4 alkyl substituted with 0 ⁇ 3 R e , and C 1 ⁇ 4 alkyl substituted with 0 ⁇ 3 R e ;
- R6 is independently selected from H, C1 ⁇ 4alkyl substituted with 0 ⁇ 4 Re, ⁇ CH2ORb,
- R 7 is independently selected from H and C 1 ⁇ 4 alkyl
- R9 is independently selected from F, Cl, Br, C1 ⁇ 4 alkyl, nitro, ⁇ (CH2)rS(O)pRc,
- R a is independently selected from H, C 1 ⁇ 6 alkyl substituted with 0 ⁇ 5 Re, C2 ⁇ 6 alkenyl substituted with 0 ⁇ 5 Re, C2 ⁇ 6 alkynyl substituted with 0 ⁇ 5 Re, ⁇ (CH 2 ) r ⁇ C 3 ⁇ 10 cycloalkyl substituted with 0 ⁇ 5 R e , ⁇ (CH 2 ) r ⁇ aryl substituted with 0 ⁇ 5 Re, and ⁇ (CH2)r ⁇ heterocyclyl substituted with 0 ⁇ 5 Re; or Ra and Ra together with the nitrogen atom to which they are both attached form a heterocyclic ring substituted with 0 ⁇ 5 Re;
- R b at each occurrence, is independently selected from H, C 1 ⁇ 6 alkyl substituted with 0 ⁇ 5 Re, C2 ⁇ 6 alkenyl substituted with 0 ⁇ 5 Re, C2 ⁇ 6 alkynyl substituted with 0 ⁇ 5 Re, ⁇ (CH 2 ) r ⁇ C 3 ⁇ 10 carbocyclyl substituted with 0 ⁇ 5 R e , and ⁇ (CH 2 ) r ⁇ heterocyclyl substituted with 0 ⁇ 5 Re;
- R c at each occurrence, is independently selected from C 1 ⁇ 6 alkyl substituted with 0 ⁇ 5 R e , C2 ⁇ 6alkenyl substituted with 0 ⁇ 5 Re, C2 ⁇ 6alkynyl substituted with 0 ⁇ 5 Re,
- Rf at each occurrence, is independently selected from H, F, Cl, Br, CN, OH, C1 ⁇ 5 alkyl, C 3 ⁇ 6 cycloalkyl, and phenyl, or R f and R f together with the nitrogen atom to which they are both attached form a heterocyclic ring optionally substituted with C 1 ⁇ 4 alkyl;
- n is independently selected from 1 and 2;
- p at each occurrence, is independently selected from zero, 1, and 2;
- R 1 is independently selected from F, Cl, Br, CN, NR a R a , and C 1 ⁇ 4 alkyl substituted with 0 ⁇ 4 Re;
- R3 is independently selected from H, CN, C1 ⁇ 4 alkyl, -OC1 ⁇ 3 alkyl, and C3 ⁇ 6 cycloalkyl;
- R 7 is independently selected from H and C 1 ⁇ 4 alkyl
- R9 is independently selected from F, Cl, C1 ⁇ 4 alkyl substituted with 0 ⁇ 3 Re, ⁇ ORb, and heterocyclyl substituted with 0 ⁇ 3 R e ;
- Ra at each occurrence, is independently selected from H, C1 ⁇ 6 alkyl substituted with 0 ⁇ 5 R e , ⁇ (CH 2 ) r ⁇ C 3 ⁇ 6 cycloalkyl substituted with 0 ⁇ 5 R e , ⁇ (CH 2 ) r ⁇ aryl substituted with 0 ⁇ 5 Re, and ⁇ (CH2)r ⁇ heterocyclyl substituted with 0 ⁇ 5 Re;
- R b at each occurrence, is independently selected from H, C 1 ⁇ 6 alkyl substituted with 0 ⁇ 5 Re, ⁇ (CH2)r ⁇ C3 ⁇ 10carbocyclyl substituted with 0 ⁇ 5 Re, and ⁇ (CH2)r ⁇ heterocyclyl substituted with 0 ⁇ 5 R e ;
- n is independently selected from 1 and 2;
- r at each occurrence, is independently selected from zero, 1, 2, and 3.
- r at each occurrence, is independently selected from zero, 1, 2, and 3.
- K is independently selected from N and CH;
- R1 is independently selected from H, F, Cl, Br, CN, NRaRa, and C1 ⁇ 4alkyl substituted with 0 ⁇ 4 R e ;
- R3 is independently selected from H, CN, C1 ⁇ 4 alkyl substituted with 0 ⁇ 3 Re, and ⁇ ORb;
- R a at each occurrence, is independently selected from H, C 1 ⁇ 6 alkyl substituted with 0 ⁇ 5 Re, ⁇ (CH2)r ⁇ C3 ⁇ 6cycloalkyl substituted with 0 ⁇ 5 Re, ⁇ (CH2)r ⁇ aryl substituted with 0 ⁇ 5 R e , and ⁇ (CH 2 ) r ⁇ heterocyclyl substituted with 0 ⁇ 5 R e ; or R a and R a together with the nitrogen atom to which they are both attached form a heterocyclic ring substituted with 0 ⁇ 5 R e ;
- Rb at each occurrence, is independently selected from H, C1 ⁇ 6 alkyl substituted with 0 ⁇ 5 R e , C 2 ⁇ 6 alkenyl substituted with 0 ⁇ 5 R e , C 2 ⁇ 6 alkynyl substituted with 0 ⁇ 5 R e , ⁇ (CH2)r ⁇ C3 ⁇ 10carbocyclyl substituted with 0 ⁇ 5 Re, and ⁇ (CH2)r ⁇ heterocyclyl substituted with 0 ⁇ 5 R e ;
- Rc at each occurrence, is independently selected from C1 ⁇ 6 alkyl substituted with 0 ⁇ 5 Re, C 2 ⁇ 6 alkenyl substituted with 0 ⁇ 5 R e , C 2 ⁇ 6 alkynyl substituted with 0 ⁇ 5 R e ,
- R f at each occurrence, is independently selected from H, F, Cl, Br, CN, OH, C 1 ⁇ 5 alkyl, C3 ⁇ 6 cycloalkyl, and phenyl, or Rf and Rf together with the nitrogen atom to which they are both attached form a heterocyclic ring optionally substituted with C1 ⁇ 4alkyl;
- n is independently selected from 1 and 2;
- p at each occurrence, is independently selected from zero, 1, and 2;
- r at each occurrence, is independently selected from zero, 1, 2, 3, and 4.
- r at each occurrence, is independently selected from zero, 1, 2, 3, and 4.
- R 1 is independently selected from H and CF 3 ;
- R3 is independently selected from H, CN, C1 ⁇ 4 alkyl, ⁇ OC1 ⁇ 3 alkyl, and ⁇ C3 ⁇ 6 cycloalkyl;
- R 7 is independently selected from H and C 1 ⁇ 4 alkyl
- R9 is independently selected from F, Cl, C1 ⁇ 4 alkyl substituted with 0 ⁇ 3 Re, ⁇ ORb, and heterocyclyl substituted with 0 ⁇ 3 R e ;
- R10, and R11 are independently selected from H, C1 ⁇ 4alkyl substituted with 0 ⁇ 4 Re;
- R 10 and R 11 are not all H
- Ra at each occurrence, is independently selected from H, C1 ⁇ 6 alkyl substituted with 0 ⁇ 5 R e , ⁇ (CH 2 ) r ⁇ C 3 ⁇ 6 cycloalkyl substituted with 0 ⁇ 5 R e , ⁇ (CH 2 ) r ⁇ aryl substituted with 0 ⁇ 5 Re, and ⁇ (CH2)r ⁇ heterocyclyl substituted with 0 ⁇ 5 Re;
- R b at each occurrence, is independently selected from H, C 1 ⁇ 6 alkyl substituted with 0 ⁇ 5 Re, ⁇ (CH2)r ⁇ C3 ⁇ 10carbocyclyl substituted with 0 ⁇ 5 Re, and ⁇ (CH2)r ⁇ heterocyclyl substituted with 0 ⁇ 5 R e ;
- n is independently selected from 1 and 2;
- R1 is independently selected from H, F, Cl, Br, CN, NRaRa, and C1 ⁇ 4alkyl substituted with 0 ⁇ 4 R e ;
- R3 is independently selected from H, CN, C1 ⁇ 4 alkyl substituted with 0 ⁇ 3 Re, and ⁇ ORb;
- Ra at each occurrence, is independently selected from H, C1 ⁇ 6 alkyl substituted with 0 ⁇ 5 R e , ⁇ (CH 2 ) r ⁇ C 3 ⁇ 6 cycloalkyl substituted with 0 ⁇ 5 R e , ⁇ (CH 2 ) r ⁇ aryl substituted with 0 ⁇ 5 Re, and ⁇ (CH2)r ⁇ heterocyclyl substituted with 0 ⁇ 5 Re; or Ra and Ra together with the nitrogen atom to which they are both attached form a heterocyclic ring substituted with 0 ⁇ 5 Re;
- R b at each occurrence, is independently selected from H, C 1 ⁇ 6 alkyl substituted with 0 ⁇ 5 Re, C2 ⁇ 6 alkenyl substituted with 0 ⁇ 5 Re, C2 ⁇ 6 alkynyl substituted with 0 ⁇ 5 Re, ⁇ (CH 2 ) r ⁇ C 3 ⁇ 10 carbocyclyl substituted with 0 ⁇ 5 R e , and ⁇ (CH 2 ) r ⁇ heterocyclyl substituted with 0 ⁇ 5 Re;
- Rc at each occurrence, is independently selected from C1 ⁇ 6 alkyl substituted with 0 ⁇ 5 Re, C2 ⁇ 6alkenyl substituted with 0 ⁇ 5 Re, C2 ⁇ 6alkynyl substituted with 0 ⁇ 5 Re,
- R f at each occurrence, is independently selected from H, F, Cl, Br, CN, OH, C 1 ⁇ 5 alkyl, C3 ⁇ 6 cycloalkyl, and phenyl, or Rf and Rf together with the nitrogen atom to which they are both attached form a heterocyclic ring optionally substituted with C1 ⁇ 4alkyl;
- n is independently selected from 1 and 2;
- p at each occurrence, is independently selected from zero, 1, and 2;
- R1 is independently selected from H, F, Cl, Br, CN, NRaRa, and C1 ⁇ 4alkyl substituted with 0 ⁇ 4 R e ;
- R3 is independently selected from H, CN, C1 ⁇ 4 alkyl substituted with 0 ⁇ 3 Re, and ⁇ ORb;
- R a at each occurrence, is independently selected from H, C 1 ⁇ 6 alkyl substituted with 0 ⁇ 5 Re, ⁇ (CH2)r ⁇ C3 ⁇ 6cycloalkyl substituted with 0 ⁇ 5 Re, ⁇ (CH2)r ⁇ aryl substituted with 0 ⁇ 5 R e , and ⁇ (CH 2 ) r ⁇ heterocyclyl substituted with 0 ⁇ 5 R e ; or R a and R a together with the nitrogen atom to which they are both attached form a heterocyclic ring substituted with 0 ⁇ 5 R e ;
- Rb at each occurrence, is independently selected from H, C1 ⁇ 6 alkyl substituted with 0 ⁇ 5 R e , C 2 ⁇ 6 alkenyl substituted with 0 ⁇ 5 R e , C 2 ⁇ 6 alkynyl substituted with 0 ⁇ 5 R e , ⁇ (CH2)r ⁇ C3 ⁇ 10carbocyclyl substituted with 0 ⁇ 5 Re, and ⁇ (CH2)r ⁇ heterocyclyl substituted with 0 ⁇ 5 R e ;
- Rc at each occurrence, is independently selected from C1 ⁇ 6 alkyl substituted with 0 ⁇ 5 Re, C 2 ⁇ 6 alkenyl substituted with 0 ⁇ 5 R e , C 2 ⁇ 6 alkynyl substituted with 0 ⁇ 5 R e,
- Rf at each occurrence, is independently selected from H, F, Cl, Br, CN, OH, C1 ⁇ 5 alkyl, C 3 ⁇ 6 cycloalkyl, and phenyl, or R f and R f together with the nitrogen atom to which they are both attached form a heterocyclic ring optionally substituted with C 1 ⁇ 4 alkyl;
- n is independently selected from 1 and 2;
- p at each occurrence, is independently selected from zero, 1, and 2;
- r at each occurrence, is independently selected from zero, 1, 2, 3, and 4.
- r at each occurrence, is independently selected from zero, 1, 2, 3, and 4.
- K is independently selected from N and CH;
- R 1 is independently selected from H, F, Cl, Br, CN, NR a R a , and C 1 ⁇ 4 alkyl substituted with 0 ⁇ 4 Re;
- R 3 is independently selected from H, CN, C 1 ⁇ 4 alkyl substituted with 0 ⁇ 3 R e , and ⁇ OR b ;
- Ra at each occurrence, is independently selected from H, C1 ⁇ 6 alkyl substituted with 0 ⁇ 5 R e , ⁇ (CH 2 ) r ⁇ C 3 ⁇ 6 cycloalkyl substituted with 0 ⁇ 5 R e , ⁇ (CH 2 ) r ⁇ aryl substituted with 0 ⁇ 5 Re, and ⁇ (CH2)r ⁇ heterocyclyl substituted with 0 ⁇ 5 Re; or Ra and Ra together with the nitrogen atom to which they are both attached form a heterocyclic ring substituted with 0 ⁇ 5 Re;
- Rb at each occurrence, is independently selected from H, C1 ⁇ 6 alkyl substituted with 0 ⁇ 5 R e , C 2 ⁇ 6 alkenyl substituted with 0 ⁇ 5 R e , C 2 ⁇ 6 alkynyl substituted with 0 ⁇ 5 R e , ⁇ (CH2)r ⁇ C3 ⁇ 10carbocyclyl substituted with 0 ⁇ 5 Re, and ⁇ (CH2)r ⁇ hetero
- Rc at each occurrence, is independently selected from C1 ⁇ 6 alkyl substituted with 0 ⁇ 5 Re, C 2 ⁇ 6 alkenyl substituted with 0 ⁇ 5 R e , C 2 ⁇ 6 alkynyl substituted with 0 ⁇ 5 R e ,
- Rf at each occurrence, is independently selected from H, F, Cl, Br, CN, OH, C1 ⁇ 5 alkyl, C3 ⁇ 6 cycloalkyl, and phenyl, or Rf and Rf together with the nitrogen atom to which they are both attached form a heterocyclic ring optionally substituted with C 1 ⁇ 4 alkyl;
- n is independently selected from 1 and 2;
- p at each occurrence, is independently selected from zero, 1, and 2;
- K is independently selected from N and CH;
- R1 is independently selected from H, F, Cl, Br, CN, NRaRa, and C1 ⁇ 4alkyl substituted with 0 ⁇ 4 Re;
- R3 is independently selected from H, CN, C1 ⁇ 4 alkyl substituted with 0 ⁇ 3 Re, and ⁇ ORb;
- R a is independently selected from H, C 1 ⁇ 6 alkyl substituted with 0 ⁇ 5 Re, ⁇ (CH2)r ⁇ C3 ⁇ 6cycloalkyl substituted with 0 ⁇ 5 Re, ⁇ (CH2)r ⁇ aryl substituted with 0 ⁇ 5 Re, and ⁇ (CH2)r ⁇ heterocyclyl substituted with 0 ⁇ 5 Re; or Ra and Ra together with the nitrogen atom to which they are both attached form a heterocyclic ring substituted with 0 ⁇ 5 Re;
- R b at each occurrence, is independently selected from H, C 1 ⁇ 6 alkyl substituted with 0 ⁇ 5 Re, C2 ⁇ 6 alkenyl substituted with 0 ⁇ 5 Re, C2 ⁇ 6 alkynyl substituted with 0 ⁇ 5 Re, ⁇ (CH 2 ) r ⁇ C 3 ⁇ 10 carbocyclyl substituted with 0 ⁇ 5 R e , and ⁇ (CH 2 ) r ⁇ heterocyclyl substituted with 0 ⁇ 5 Re;
- R c at each occurrence, is independently selected from C 1 ⁇ 6 alkyl substituted with 0 ⁇ 5 R e , C2 ⁇ 6alkenyl substituted with 0 ⁇ 5 Re, C2 ⁇ 6alkynyl substituted with 0 ⁇ 5 Re,
- Rf at each occurrence, is independently selected from H, F, Cl, Br, CN, OH, C1 ⁇ 5 alkyl, C 3 ⁇ 6 cycloalkyl, and phenyl, or R f and R f together with the nitrogen atom to which they are both attached form a heterocyclic ring optionally substituted with C 1 ⁇ 4 alkyl;
- n is independently selected from 1 and 2;
- p at each occurrence, is independently selected from zero, 1, and 2;
- r at each occurrence, is independently selected from zero, 1, 2, 3, and 4.
- r at each occurrence, is independently selected from zero, 1, 2, 3, and 4.
- Ring A is inde endentl selected from
- K is independently selected from N and CR 1 ;
- R1 is independently selected from H, F, Cl, Br, CN, NRaRa, and C1 ⁇ 4alkyl substituted with 0 ⁇ 4 R e ;
- R2 is independently selected from H, F, Cl, Br, OH, CN, NRaRa, and C1 ⁇ 4alkyl substituted with 0 ⁇ 4 R e ;
- R4 is independently selected from H, F, Cl, Br, OH, CN, OC1 ⁇ 4 alkyl substituted with 0 ⁇ 3 R e , and C 1 ⁇ 4 alkyl substituted with 0 ⁇ 3 R e ;
- R6 and R7 are independently selected from H, C1 ⁇ 4alkyl substituted with 0 ⁇ 4 Re,
- R 8 is independently selected from
- R9 is independently selected from F, Cl, Br, C1 ⁇ 4 alkyl, nitro, ⁇ (CH2)rS(O)pRc,
- Ra at each occurrence, is independently selected from H, C1 ⁇ 6 alkyl substituted with 0 ⁇ 5 R e , C 2 ⁇ 6 alkenyl substituted with 0 ⁇ 5 R e , C 2 ⁇ 6 alkynyl substituted with 0 ⁇ 5 R e , ⁇ (CH2)r ⁇ C3 ⁇ 10cycloalkyl substituted with 0 ⁇ 5 Re, ⁇ (CH2)r ⁇ aryl substituted with 0 ⁇ 5 R e , and ⁇ (CH 2 ) r ⁇ heterocyclyl substituted with 0 ⁇ 5 R e ; or R a and R a together with the nitrogen atom to which they are both attached form a heterocyclic ring substituted with 0 ⁇ 5 R e ;
- Rb at each occurrence, is independently selected from H, C1 ⁇ 6 alkyl substituted with 0 ⁇ 5 Re, C2 ⁇ 6 alkenyl substituted with 0 ⁇ 5 Re, C2 ⁇ 6 alkynyl substituted with 0 ⁇ 5 Re, ⁇ (CH2)r ⁇ C3 ⁇ 10carbocyclyl substituted with 0 ⁇ 5 Re, and ⁇ (CH2)r ⁇ heterocyclyl substituted with 0 ⁇ 5 Re;
- R c at each occurrence, is independently selected from C 1 ⁇ 6 alkyl substituted with 0 ⁇ 5 R e , C2 ⁇ 6alkenyl substituted with 0 ⁇ 5 Re, C2 ⁇ 6alkynyl substituted with 0 ⁇ 5 Re,
- Rf at each occurrence, is independently selected from H, F, Cl, Br, CN, OH, C1 ⁇ 5 alkyl, C 3 ⁇ 6 cycloalkyl, and phenyl, or R f and R f together with the nitrogen atom to which they are both attached form a heterocyclic ring optionally substituted with C 1 ⁇ 4 alkyl;
- n is independently selected from 1, 2, and 3; p, at each occurrence, is independently selected from zero, 1, and 2; and
- Ring A is inde endentl selected from
- K is independently selected from N and CR 1 ;
- R1 is independently selected from H, F, Cl, Br, CN, NRaRa, and C1 ⁇ 4alkyl substituted with 0 ⁇ 4 R e ;
- R2 is independently selected from H, F, Cl, Br, OH, CN, NRaRa, and C1 ⁇ 4alkyl substituted with 0 ⁇ 4 R e ;
- R4 is independently selected from H, F, Cl, Br, OH, CN, OC1 ⁇ 4 alkyl substituted with 0 ⁇ 3 R e , and C 1 ⁇ 4 alkyl substituted with 0 ⁇ 3 R e ;
- R 6 and R 7 are independently selected from H, C 1 ⁇ 4 alkyl substituted with 0 ⁇ 4 R e ,
- R 9 is independently selected from F, Cl, Br, C 1 ⁇ 4 alkyl, nitro, ⁇ (CH 2 ) r S(O) p R c ,
- R a is independently selected from H, C 1 ⁇ 6 alkyl substituted with 0 ⁇ 5 Re, C2 ⁇ 6 alkenyl substituted with 0 ⁇ 5 Re, C2 ⁇ 6 alkynyl substituted with 0 ⁇ 5 Re, ⁇ (CH 2 ) r ⁇ C 3 ⁇ 10 cycloalkyl substituted with 0 ⁇ 5 R e , ⁇ (CH 2 ) r ⁇ aryl substituted with 0 ⁇ 5 Re, and ⁇ (CH2)r ⁇ heterocyclyl substituted with 0 ⁇ 5 Re; or Ra and Ra together with the nitrogen atom to which they are both attached form a heterocyclic ring substituted with 0 ⁇ 5 Re;
- R b at each occurrence, is independently selected from H, C 1 ⁇ 6 alkyl substituted with 0 ⁇ 5 Re, C2 ⁇ 6 alkenyl substituted with 0 ⁇ 5 Re, C2 ⁇ 6 alkynyl substituted with 0 ⁇ 5 Re, ⁇ (CH 2 ) r ⁇ C 3 ⁇ 10 carbocyclyl substituted with 0 ⁇ 5 R e , and ⁇ (CH 2 ) r ⁇ heterocyclyl substituted with 0 ⁇ 5 Re;
- Rc at each occurrence, is independently selected from C1 ⁇ 6 alkyl substituted with 0 ⁇ 5 Re, C2 ⁇ 6alkenyl substituted with 0 ⁇ 5 Re, C2 ⁇ 6alkynyl substituted with 0 ⁇ 5 Re,
- Rf at each occurrence, is independently selected from H, F, Cl, Br, CN, OH, C1 ⁇ 5 alkyl, C 3 ⁇ 6 cycloalkyl, and phenyl, or R f and R f together with the nitrogen atom to which they are both attached form a heterocyclic ring optionally substituted with C 1 ⁇ 4 alkyl;
- n is independently selected from 1, 2, and 3;
- p at each occurrence, is independently selected from zero, 1, and 2;
- Ring A is independently selected from
- K is independently selected from N and CR1;
- R1 is independently selected from H, F, Cl, Br, CN, NRaRa, and C1 ⁇ 4alkyl substituted with 0 ⁇ 4 R e ;
- R2 is independently selected from H, F, Cl, Br, OH, CN, NRaRa, and C1 ⁇ 4alkyl substituted with 0 ⁇ 4 R e ;
- R4 is independently selected from H, F, Cl, Br, OH, CN, OC1 ⁇ 4 alkyl substituted with 0 ⁇ 3 R e , and C 1 ⁇ 4 alkyl substituted with 0 ⁇ 3 R e ;
- R6 and R7 are independently selected from H, C1 ⁇ 4alkyl substituted with 0 ⁇ 4 Re,
- R8 is independently selected from
- R 9 is independently selected from F, Cl, Br, C 1 ⁇ 4 alkyl, nitro, ⁇ (CH 2 ) r S(O) p R c ,
- R a is independently selected from H, C 1 ⁇ 6 alkyl substituted with 0 ⁇ 5 Re, C2 ⁇ 6 alkenyl substituted with 0 ⁇ 5 Re, C2 ⁇ 6 alkynyl substituted with 0 ⁇ 5 Re, ⁇ (CH 2 ) r ⁇ C 3 ⁇ 10 cycloalkyl substituted with 0 ⁇ 5 R e , ⁇ (CH 2 ) r ⁇ aryl substituted with 0 ⁇ 5 Re, and ⁇ (CH2)r ⁇ heterocyclyl substituted with 0 ⁇ 5 Re; or Ra and Ra together with the nitrogen atom to which they are both attached form a heterocyclic ring substituted with 0 ⁇ 5 Re;
- Rb at each occurrence, is independently selected from H, C1 ⁇ 6 alkyl substituted with 0 ⁇ 5 Re, C2 ⁇ 6 alkenyl substituted with 0 ⁇ 5 Re, C2 ⁇ 6 alkynyl substituted with 0 ⁇ 5 Re, ⁇ (CH2)r ⁇ C3 ⁇ 10carbocyclyl substituted with 0 ⁇ 5 Re, and ⁇ (CH2)r ⁇ heterocyclyl substituted with 0 ⁇ 5 R e ;
- Rc at each occurrence, is independently selected from C1 ⁇ 6 alkyl substituted with 0 ⁇ 5 Re, C 2 ⁇ 6 alkenyl substituted with 0 ⁇ 5 R e , C 2 ⁇ 6 alkynyl substituted with 0 ⁇ 5 R e ,
- R f at each occurrence, is independently selected from H, F, Cl, Br, CN, OH, C 1 ⁇ 5 alkyl, C3 ⁇ 6 cycloalkyl, and phenyl, or Rf and Rf together with the nitrogen atom to which they are both attached form a heterocyclic ring optionally substituted with C1 ⁇ 4alkyl;
- n is independently selected from 1, 2, and 3;
- p at each occurrence, is independently selected from zero, 1, and 2;
- Ring A is independently selected from
- K is independently selected from N and CR1;
- R 1 is independently selected from H, F, Cl, Br, CN, NR a R a , and C 1 ⁇ 4 alkyl substituted with 0 ⁇ 4 Re;
- R 2 is independently selected from H, F, Cl, Br, OH, CN, NR a R a , and C 1 ⁇ 4 alkyl substituted with 0 ⁇ 4 Re;
- R4 is independently selected from H, F, Cl, Br, OH, CN, OC1 ⁇ 4 alkyl substituted with 0 ⁇ 3 R e , and C 1 ⁇ 4 alkyl substituted with 0 ⁇ 3 R e ;
- R6 and R7 are independently selected from H, C1 ⁇ 4alkyl substituted with 0 ⁇ 4 Re,
- R8 is independently selected from
- R 9 is independently selected from F, Cl, Br, C 1 ⁇ 4 alkyl, nitro, ⁇ (CH 2 ) r S(O) p R c ,
- R a is independently selected from H, C 1 ⁇ 6 alkyl substituted with 0 ⁇ 5 Re, C2 ⁇ 6 alkenyl substituted with 0 ⁇ 5 Re, C2 ⁇ 6 alkynyl substituted with 0 ⁇ 5 Re, ⁇ (CH2)r ⁇ C3 ⁇ 10cycloalkyl substituted with 0 ⁇ 5 Re, ⁇ (CH2)r ⁇ aryl substituted with 0 ⁇ 5 Re, and ⁇ (CH2)r ⁇ heterocyclyl substituted with 0 ⁇ 5 Re; or Ra and Ra together with the nitrogen atom to which they are both attached form a heterocyclic ring substituted with 0 ⁇ 5 R e ;
- Rb at each occurrence, is independently selected from H, C1 ⁇ 6 alkyl substituted with 0 ⁇ 5 R e , C 2 ⁇ 6 alkenyl substituted with 0 ⁇ 5 R e , C 2 ⁇ 6 alkynyl substituted with 0 ⁇ 5 R e , ⁇ (CH2)r ⁇ C3 ⁇ 10carbocyclyl substituted with 0 ⁇ 5 Re, and ⁇ (CH2)r ⁇ heterocyclyl substituted with 0 ⁇ 5 R e ;
- Rc at each occurrence, is independently selected from C1 ⁇ 6 alkyl substituted with 0 ⁇ 5 Re, C 2 ⁇ 6 alkenyl substituted with 0 ⁇ 5 R e , C 2 ⁇ 6 alkynyl substituted with 0 ⁇ 5 R e ,
- R f at each occurrence, is independently selected from H, F, Cl, Br, CN, OH, C 1 ⁇ 5 alkyl, C3 ⁇ 6 cycloalkyl, and phenyl, or Rf and Rf together with the nitrogen atom to which they are both attached form a heterocyclic ring optionally substituted with C1 ⁇ 4alkyl;
- n is independently selected from 1, 2, and 3;
- p at each occurrence, is independently selected from zero, 1, and 2;
- r at each occurrence, is independently selected from zero, 1, 2, 3, and 4.
- r at each occurrence, is independently selected from zero, 1, 2, 3, and 4.
- R1 is independently selected from H, F, Cl, Br, CN, NRaRa, and C1 ⁇ 4alkyl substituted with 0 ⁇ 4 R e ;
- R2 is independently selected from H and C1 ⁇ 4alkyl substituted with 0 ⁇ 4 Re;
- R 3 is independently selected from H, F, Cl, Br, CN, C 1 ⁇ 4 alkyl substituted with 0 ⁇ 3 R e, ⁇ (CH2)rORb, and ⁇ C3 ⁇ 6 cycloalkyl;
- R 4 is independently selected from H, F, Cl, Br, OH, CN, OC 1 ⁇ 4 alkyl substituted with 0 ⁇ 3 Re, and C1 ⁇ 4 alkyl substituted with 0 ⁇ 3 Re;
- R7 is independently selected from H and C1 ⁇ 4alkyl; provided R6 and R7 are not both H; when R 7 is C 1 ⁇ 4 alkyl, R 6 is not H;
- R9 is independently selected from F, Cl, Br, C1 ⁇ 4 alkyl, nitro, ⁇ (CH2)rS(O)pRc,
- R a is independently selected from H, C 1 ⁇ 6 alkyl substituted with 0 ⁇ 5 Re, C2 ⁇ 6 alkenyl substituted with 0 ⁇ 5 Re, C2 ⁇ 6 alkynyl substituted with 0 ⁇ 5 Re, ⁇ (CH 2 ) r ⁇ C 3 ⁇ 10 cycloalkyl substituted with 0 ⁇ 5 R e , ⁇ (CH 2 ) r ⁇ aryl substituted with 0 ⁇ 5 Re, and ⁇ (CH2)r ⁇ heterocyclyl substituted with 0 ⁇ 5 Re; or Ra and Ra together with the nitrogen atom to which they are both attached form a heterocyclic ring substituted with 0 ⁇ 5 Re;
- R b at each occurrence, is independently selected from H, C 1 ⁇ 6 alkyl substituted with 0 ⁇ 5 Re, C2 ⁇ 6 alkenyl substituted with 0 ⁇ 5 Re, C2 ⁇ 6 alkynyl substituted with 0 ⁇ 5 Re, ⁇ (CH 2 ) r ⁇ C 3 ⁇ 10 carbocyclyl substituted with 0 ⁇ 5 R e , and ⁇ (CH 2 ) r ⁇ heterocyclyl substituted with 0 ⁇ 5 Re;
- R c at each occurrence, is independently selected from C 1 ⁇ 6 alkyl substituted with 0 ⁇ 5 R e , C2 ⁇ 6alkenyl substituted with 0 ⁇ 5 Re, C2 ⁇ 6alkynyl substituted with 0 ⁇ 5 Re,
- Rf at each occurrence, is independently selected from H, F, Cl, Br, CN, OH, C1 ⁇ 5 alkyl, C 3 ⁇ 6 cycloalkyl, and phenyl, or R f and R f together with the nitrogen atom to which they are both attached form a heterocyclic ring optionally substituted with C 1 ⁇ 4 alkyl;
- n is independently selected from 1 and 2;
- p at each occurrence, is independently selected from zero, 1, and 2;
- r at each occurrence, is independently selected from zero, 1, 2, 3, and 4.
- r at each occurrence, is independently selected from zero, 1, 2, 3, and 4.
- R1 is independently selected from F, Cl, Br, CN, NRaRa, and C1 ⁇ 4alkyl substituted with 0 ⁇ 4 Re;
- R3 is independently selected from H, CN, C1 ⁇ 4 alkyl substituted with 0 ⁇ 3 Re, and ⁇ ORb;
- Ra at each occurrence, is independently selected from H, C1 ⁇ 6 alkyl substituted with 0 ⁇ 5 R e , ⁇ (CH 2 ) r ⁇ C 3 ⁇ 6 cycloalkyl substituted with 0 ⁇ 5 R e , ⁇ (CH 2 ) r ⁇ aryl substituted with 0 ⁇ 5 Re, and ⁇ (CH2)r ⁇ heterocyclyl substituted with 0 ⁇ 5 Re; or Ra and Ra together with the nitrogen atom to which they are both attached form a heterocyclic ring substituted with 0 ⁇ 5 R e ;
- Rb at each occurrence, is independently selected from H, C1 ⁇ 6 alkyl substituted with 0 ⁇ 5 R e , C 2 ⁇ 6 alkenyl substituted with 0 ⁇ 5 R e , C 2 ⁇ 6 alkynyl substituted with 0 ⁇ 5 R e , ⁇ (CH2)r ⁇ C3 ⁇ 10carbocyclyl substituted with 0 ⁇ 5 Re, and ⁇ (CH2)r ⁇ heterocyclyl substituted with 0 ⁇ 5 R e ;
- Rc at each occurrence, is independently selected from C1 ⁇ 6 alkyl substituted with 0 ⁇ 5 Re, C 2 ⁇ 6 alkenyl substituted with 0 ⁇ 5 R e , C 2 ⁇ 6 alkynyl substituted with 0 ⁇ 5 R e,
- Rf at each occurrence, is independently selected from H, F, Cl, Br, CN, OH, C1 ⁇ 5 alkyl, C 3 ⁇ 6 cycloalkyl, and phenyl, or R f and R f together with the nitrogen atom to which they are both attached form a heterocyclic ring optionally substituted with C 1 ⁇ 4 alkyl;
- n is independently selected from 1 and 2;
- p at each occurrence, is independently selected from zero, 1, and 2;
- r at each occurrence, is independently selected from zero, 1, 2, 3, and 4.
- r at each occurrence, is independently selected from zero, 1, 2, 3, and 4.
- Ring A is independently selected from
- J 1 , J 2 , J 3 , and J 4 are independently selected from N and CR 3 ;
- K is independently selected from N and CR1;
- R 1 is independently selected from H, F, Cl, Br, OH, CN, NR a R a , ⁇ OC 1 ⁇ 4 alkyl substituted with 0 ⁇ 3 Re, and C1 ⁇ 4 alkyl substituted with 0 ⁇ 3 Re;
- R 4 is independently selected from H, F, Cl, Br, OH, CN, OC 1 ⁇ 4 alkyl substituted with 0 ⁇ 3 Re, NRaRa, and C1 ⁇ 4 alkyl substituted with 0 ⁇ 3 Re;
- R 6 and R 7 are independently selected from H, C 1 ⁇ 4 alkyl substituted with 0 ⁇ 4 R e ,
- R 8 is independently selected from C 3 ⁇ 6 cycloalkyl, heterocyclyl, aryl and heteroaryl, each substituted with 0 ⁇ 5 R9;
- R a is independently selected from H, C 1 ⁇ 6 alkyl substituted with 0 ⁇ 5 Re, C2 ⁇ 6 alkenyl substituted with 0 ⁇ 5 Re, C2 ⁇ 6 alkynyl substituted with 0 ⁇ 5 Re, ⁇ (CH 2 ) r ⁇ C 3 ⁇ 10 carbocyclyl substituted with 0 ⁇ 5 R e , and ⁇ (CH 2 ) r ⁇ heterocyclyl substituted with 0 ⁇ 5 Re; or Ra and Ra together with the nitrogen atom to which they are both attached form a heterocyclic ring substituted with 0 ⁇ 5 R e ;
- Rb at each occurrence, is independently selected from H, C1 ⁇ 6 alkyl substituted with 0 ⁇ 5 R e , C 2 ⁇ 6 alkenyl substituted with 0 ⁇ 5 R e , C 2 ⁇ 6 alkynyl substituted with 0 ⁇ 5 R e , ⁇ (CH2)r ⁇ C3 ⁇ 10carbocyclyl substituted with 0 ⁇ 5 Re, and ⁇ (CH2)r ⁇ heterocyclyl substituted with 0 ⁇ 5 R e ;
- Rc at each occurrence, is independently selected from C1 ⁇ 6 alkyl substituted with 0 ⁇ 5 Re, C 2 ⁇ 6 alkenyl substituted with 0 ⁇ 5 R e , C 2 ⁇ 6 alkynyl substituted with 0 ⁇ 5 R e,
- R d at each occurrence, is independently selected from H and C 1 ⁇ 4 alkyl substituted with 0 ⁇ 5 Re;
- Rf at each occurrence, is independently selected from H, F, Cl, Br, CN, OH, C1 ⁇ 5alkyl, C 3 ⁇ 6 cycloalkyl, and phenyl, or R f and R f together with the nitrogen atom to which they are both attached form a heterocyclic ring optionally substituted with C 1 ⁇ 4 alkyl;
- n is independently selected from 1, 2, and 3;
- p at each occurrence, is independently selected from zero, 1, and 2;
- r at each occurrence, is independently selected from zero, 1, 2, 3, and 4;
- R 9 is not a substituted piperazine.
- the present invention provides a compound selected from any subset list of compounds exemplified in the present application.
- the compounds of the present invention have ROCK IC50 values ⁇ 10 ⁇ M.
- the compounds of the present invention have ROCK IC 50 values ⁇ 1 ⁇ M.
- the compounds of the present invention have ROCK IC 50 values ⁇ 0.1 ⁇ M.
- the compounds of the present invention have ROCK IC50 values ⁇ 0.05 ⁇ M.
- the compounds of the present invention have ROCK IC50 values ⁇ 0.01 ⁇ M. II. OTHER EMBODIMENTS OF THE INVENTION
- the present invention provides a composition comprising at least one of the compounds of the present invention or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or a solvate thereof.
- the present invention provides a pharmaceutical composition, comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present invention or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or a solvate thereof.
- the present invention provides a process for making a compound of the present invention.
- the present invention provides an intermediate for making a compound of the present invention.
- the present invention provides a pharmaceutical composition further comprising additional therapeutic agent(s).
- the present invention provides a method for the treatment and/or prophylaxis of a condition associated with aberrant ROCK activity comprising administering to a patient in need of such treatment and/or prophylaxis a therapeutically effective amount of at least one of the compounds of the present invention or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or a solvate thereof.
- the term "patient” encompasses all mammalian species.
- treating cover the treatment of a disease-state in a mammal, particularly in a human, and include: (a) inhibiting the disease-state, i.e., arresting it development; and/or (b) relieving the disease-state, i.e., causing regression of the disease state.
- prophylaxis is the protective treatment of a disease state to reduce and/or minimize the risk and/or reduction in the risk of recurrence of a disease state by administering to a patient a therapeutically effective amount of at least one of the compounds of the present invention or a or a stereoisomer, a tautomer, a
- Patients may be selected for prophylaxis therapy based on factors that are known to increase risk of suffering a clinical disease state compared to the general population.
- prophylaxis treatment conditions of the clinical disease state may or may not be presented yet.
- "Prophylaxis" treatment can be divided into (a) primary prophylaxis and (b) secondary prophylaxis.
- Primary prophylaxis is defined as treatment to reduce or minimize the risk of a disease state in a patient that has not yet presented with a clinical disease state
- secondary prophylaxis is defined as minimizing or reducing the risk of a recurrence or second occurrence of the same or similar clinical disease state.
- prevention cover the preventive treatment of a subclinical disease-state in a mammal, particularly in a human, aimed at reducing the probability of the occurrence of a clinical disease-state.
- Patients are selected for preventative therapy based on factors that are known to increase risk of suffering a clinical disease state compared to the general population.
- Optically active forms may be prepared by resolution of racemic forms or by synthesis from optically active starting materials. All processes used to prepare compounds of the present invention and intermediates made therein are considered to be part of the present invention. When enantiomeric or diastereomeric products are prepared, they may be separated by conventional methods, for example, by chromatography or fractional crystallization. Depending on the process conditions the end products of the present invention are obtained either in free (neutral) or salt form. Both the free form and the salts of these end products are within the scope of the invention. If so desired, one form of a compound may be converted into another form.
- a free base or acid may be converted into a salt; a salt may be converted into the free compound or another salt; a mixture of isomeric compounds of the present invention may be separated into the individual isomers.
- Compounds of the present invention, free form and salts thereof, may exist in multiple tautomeric forms, in which hydrogen atoms are transposed to other parts of the molecules and the chemical bonds between the atoms of the molecules are consequently rearranged. It should be understood that all tautomeric forms, insofar as they may exist, are included within the invention.
- stereoisomer refers to isomers of identical constitution that differ in the arrangement of their atoms in space. Enantiomers and diastereomers are examples of stereoisomers.
- enantiomer refers to one of a pair of molecular species that are mirror images of each other and are not superimposable.
- diastereomer refers to stereoisomers that are not mirror images.
- racemate or “racemic mixture” refers to a composition composed of equimolar quantities of two enantiomeric species, wherein the composition is devoid of optical activity.
- R and S represent the configuration of substituents around a chiral carbon atom(s).
- the isomeric descriptors “R” and “S” are used as described herein for indicating atom configuration(s) relative to a core molecule and are intended to be used as defined in the literature (IUPAC Recommendations 1996, Pure and Applied Chemistry, 68:2193-2222 (1996)).
- chiral refers to the structural characteristic of a molecule that makes it impossible to superimpose it on its mirror image.
- homochiral refers to a state of enantiomeric purity.
- optical activity refers to the degree to which a homochiral molecule or nonracemic mixture of chiral molecules rotates a plane of polarized light.
- alkyl or “alkylene” is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms.
- C 1 to C 10 alkyl or “C 1 ⁇ 10 alkyl” (or alkylene) is intended to include C1, C2, C3, C4, C5, C6, C7, C8, C9, and C10 alkyl groups.
- C 1 to C 6 alkyl or “C 1 ⁇ C 6 alkyl” denotes alkyl having 1 to 6 carbon atoms.
- Alkyl group can be unsubstituted or substituted with at least one hydrogen being replaced by another chemical group.
- Example alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, t- butyl), and pentyl (e.g., n-pentyl, isopentyl, neopentyl).
- Alkenyl or “alkenylene” is intended to include hydrocarbon chains of either straight or branched configuration having the specified number of carbon atoms and one or more, preferably one to two, carbon-carbon double bonds that may occur in any stable point along the chain.
- C 2 to C 6 alkenyl or “C 2 ⁇ 6 alkenyl” (or alkenylene), is intended to include C2, C3, C4, C5, and C6 alkenyl groups.
- alkenyl include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2- propenyl, and 4-methyl-3-pentenyl.
- Alkynyl or “alkynylene” is intended to include hydrocarbon chains of either straight or branched configuration having one or more, preferably one to three, carbon- carbon triple bonds that may occur in any stable point along the chain.
- C2 to C6 alkynyl or “C2 ⁇ 6 alkynyl” (or alkynylene) is intended to include C2, C3, C4, C5, and C6 alkynyl groups; such as ethynyl, propynyl, butynyl, pentynyl, and hexynyl.
- alkoxy refers to an -O-alkyl group.
- C1 to C6 alkoxy or “C 1 ⁇ 6 alkoxy” (or alkyloxy) is intended to include C 1 , C 2 , C 3 , C 4 , C 5 , and C 6 alkoxy groups.
- Example alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), and t-butoxy.
- alkylthio or “thioalkoxy” represents an alkyl group as defined above with the indicated number of carbon atoms attached through a sulphur bridge; for example, methyl-S- and ethyl-S-.
- Halo or halogen includes fluoro (F), chloro (Cl), bromo (Br), and iodo (I).
- Haloalkyl is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more halogens.
- haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoropropyl, and heptachloropropyl.
- haloalkyl also include "fluoroalkyl” that is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more fluorine atoms.
- Haloalkoxy or "haloalkyloxy” represents a haloalkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge.
- C1 to C6 haloalkoxy or “C1 ⁇ 6 haloalkoxy”
- C1 ⁇ 6 haloalkoxy is intended to include C1, C2, C3, C 4 , C 5 , and C 6 haloalkoxy groups.
- Examples of haloalkoxy include, but are not limited to, trifluoromethoxy, 2,2,2-trifluoroethoxy, and pentafluorothoxy.
- haloalkylthio or “thiohaloalkoxy” represents a haloalkyl group as defined above with the indicated number of carbon atoms attached through a sulphur bridge; for example, trifluoromethyl- S-, and pentafluoroethyl-S-.
- cycloalkyl refers to cyclized alkyl groups, including mono-, bi- or poly-cyclic ring systems.
- C 3 to C 7 cycloalkyl or “C 3 ⁇ 7 cycloalkyl” is intended to include C3, C4, C5, C6, and C7 cycloalkyl groups.
- Example cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and norbornyl.
- Branched cycloalkyl groups such as 1-methylcyclopropyl and 2-methylcyclopropyl are included in the definition of "cycloalkyl".
- carbocycle As used herein, “carbocycle”, “carbocyclyl” or “carbocyclic residue” is intended to mean any stable 3-, 4-, 5-, 6-, 7-, or 8-membered monocyclic or bicyclic or 7-, 8-, 9-, 10-, 11-, 12-, or 13-membered bicyclic or tricyclic hydrocarbon ring, any of which may be saturated, partially unsaturated, unsaturated or aromatic.
- carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptenyl, cycloheptyl, cycloheptenyl, adamantyl, cyclooctyl, cyclooctenyl, cyclooctadienyl, [3.3.0]bicyclooctane,
- carbocycles are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, and indanyl.
- carbocyclyl When the term “carbocyclyl” is used, it is intended to include “aryl”.
- a bridged ring occurs when one or more carbon atoms link two non-adjacent carbon atoms.
- Preferred bridges are one or two carbon atoms. It is noted that a bridge always converts a monocyclic ring into a tricyclic ring. When a ring is bridged, the substituents recited for the ring may also be present on the bridge.
- bicyclic carbocyclyl or "bicyclic carbocyclic group” is intended to mean a stable 9- or 10-membered carbocyclic ring system that contains two fused rings and consists of carbon atoms. Of the two fused rings, one ring is a benzo ring fused to a second ring; and the second ring is a 5- or 6-membered carbon ring which is saturated, partially unsaturated, or unsaturated.
- the bicyclic carbocyclic group may be attached to its pendant group at any carbon atom which results in a stable structure.
- the bicyclic carbocyclic group described herein may be substituted on any carbon if the resulting compound is stable. Examples of a bicyclic carbocyclic group are, but not limited to, naphthyl, 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, and indanyl.
- Aryl groups refer to monocyclic or polycyclic aromatic hydrocarbons, including, for example, phenyl, naphthyl, and phenanthranyl. Aryl moieties are well known and described, for example, in Lewis, R.J., ed., Hawley's Condensed Chemical Dictionary, 13th Edition, John Wiley & Sons, Inc., New York (1997). "C 6 or C 10 aryl” or “C6 ⁇ 10 aryl” refers to phenyl and naphthyl.
- heterocycle As used herein, the term “heterocycle”, “heterocyclyl”, or “heterocyclic ring” is intended to mean a stable 3-, 4-, 5-, 6-, or 7-membered monocyclic or bicyclic or 7-, 8-, 9-, 10-, 11-, 12-, 13-, or 14-membered polycyclic heterocyclic ring that is saturated, partially unsaturated, or fully unsaturated, and that contains carbon atoms and 1, 2, 3 or 4 heteroatoms independently selected from the group consisting of N, O and S; and including any polycyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring.
- the nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., N ⁇ O and S(O)p, wherein p is 0, 1 or 2).
- the nitrogen atom may be substituted or unsubstituted (i.e., N or NR wherein R is H or another substituent, if defined).
- the heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure.
- the heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable.
- a nitrogen in the heterocycle may optionally be quaternized. It is preferred that when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another. It is preferred that the total number of S and O atoms in the heterocycle is not more than 1.
- heterocycle it is intended to include heteroaryl.
- Bridged rings are also included in the definition of heterocycle.
- a bridged ring occurs when one or more atoms (i.e., C, O, N, or S) link two non-adjacent carbon or nitrogen atoms.
- Examples of bridged rings include, but are not limited to, one carbon atom, two carbon atoms, one nitrogen atom, two nitrogen atoms, and a carbon-nitrogen group. It is noted that a bridge always converts a monocyclic ring into a tricyclic ring. When a ring is bridged, the substituents recited for the ring may also be present on the bridge.
- heterocycles include, but are not limited to, acridinyl, azetidinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl, benztriazolyl, benztetrazolyl,
- Examples of 5- to 10-membered heterocycles include, but are not limited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl, piperazinyl, piperidinyl, imidazolyl, imidazolidinyl, indolyl, tetrazolyl, isoxazolyl, morpholinyl, oxazolyl, oxadiazolyl, oxazolidinyl, tetrahydrofuranyl, thiadiazinyl, thiadiazolyl, thiazolyl, triazinyl, triazolyl, benzimidazolyl, 1H-indazolyl, benzofuranyl, benzothiofuranyl, benztetrazolyl, benzotriazolyl, benzisoxazolyl, benzoxazolyl, oxindolyl, benzoxazolinyl, benz
- Examples of 5- to 6-membered heterocycles include, but are not limited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl, piperazinyl, piperidinyl, imidazolyl, imidazolidinyl, indolyl, tetrazolyl, isoxazolyl, morpholinyl, oxazolyl, oxadiazolyl, oxazolidinyl, tetrahydrofuranyl, thiadiazinyl, thiadiazolyl, thiazolyl, triazinyl, and triazolyl. Also included are fused ring and spiro compounds containing, for example, the above heterocycles.
- bicyclic heterocycle or "bicyclic heterocyclic group” is intended to mean a stable 9- or 10-membered heterocyclic ring system which contains two fused rings and consists of carbon atoms and 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, O and S.
- one ring is a 5- or 6-membered monocyclic aromatic ring comprising a 5-membered heteroaryl ring, a 6- membered heteroaryl ring or a benzo ring, each fused to a second ring.
- the second ring is a 5- or 6-membered monocyclic ring which is saturated, partially unsaturated, or unsaturated, and comprises a 5-membered heterocycle, a 6-membered heterocycle or a carbocycle (provided the first ring is not benzo when the second ring is a carbocycle).
- the bicyclic heterocyclic group may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure.
- the bicyclic heterocyclic group described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. It is preferred that when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another. It is preferred that the total number of S and O atoms in the heterocycle is not more than 1.
- bicyclic heterocyclic group examples include quinolinyl, isoquinolinyl, phthalazinyl, quinazolinyl, indolyl, isoindolyl, indolinyl, 1H-indazolyl, benzimidazolyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, 5,6,7,8- tetrahydro-quinolinyl, 2,3-dihydro-benzofuranyl, chromanyl, 1,2,3,4-tetrahydro- quinoxalinyl, and 1,2,3,4-tetrahydro-quinazolinyl.
- aromatic heterocyclic group refers to substituted and unsubstituted aromatic 5- or 6-membered monocyclic groups, 9- or 10- membered bicyclic groups, and 11- to 14-membered tricyclic groups which have at least one heteroatom (O, S or N) in at least one of the rings, said heteroatom-containing ring preferably having 1, 2, or 3 heteroatoms selected from O, S, and N.
- Each ring of the heteroaryl group containing a heteroatom can contain one or two oxygen or sulfur atoms and/or from one to four nitrogen atoms provided that the total number of heteroatoms in each ring is four or less and each ring has at least one carbon atom.
- Heteroaryl groups can be substituted or unsubstituted.
- the nitrogen atom may be substituted or unsubstituted (i.e., N or NR wherein R is H or another substituent, if defined).
- the nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., N ⁇ O and S(O)p) and the nitrogen atoms may optionally be quaternized.
- Heteroaryl groups which are bicyclic or tricyclic must include at least one fully aromatic ring but the other fused ring or rings may be aromatic or non-aromatic.
- the heteroaryl group may be attached at any available nitrogen or carbon atom of any ring.
- the heteroaryl ring system may contain zero, one, two or three substituents.
- Heteroaryl groups include, without limitation, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrroyl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, purinyl, carbazolyl, benzimidazolyl, indolinyl, benzodioxolanyl, and benzodioxane.
- counterion is used to represent a negatively charged species such as chloride, bromide, hydroxide, acetate, and sulfate.
- a dotted ring When a dotted ring is used within a ring structure, this indicates that the ring structure may be saturated, partially saturated or unsaturated.
- substituted means that at least one hydrogen atom is replaced with a non-hydrogen group, provided that normal valencies are maintained and that the substitution results in a stable compound.
- 2 hydrogens on the atom are replaced.
- Keto substituents are not present on aromatic moieties.
- nitrogen atoms e.g., amines
- these may be converted to N-oxides by treatment with an oxidizing agent (e.g., mCPBA and/or hydrogen peroxides) to afford other compounds of this invention.
- an oxidizing agent e.g., mCPBA and/or hydrogen peroxides
- shown and claimed nitrogen atoms are considered to cover both the shown nitrogen and its N-oxide (N ⁇ O) derivative.
- any variable occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence.
- a group is shown to be substituted with 0-3 R groups, then said group may optionally be substituted with up to three R groups, and at each occurrence R is selected independently from the definition of R.
- R is selected independently from the definition of R.
- substituents and/or variables are permissible only if such combinations result in stable compounds.
- pharmaceutically acceptable refers to those compounds, materials, compositions, and/or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, and/or other problem or complication, commensurate with a reasonable benefit/risk ratio.
- pharmaceutically acceptable salts refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic groups such as amines; and alkali or organic salts of acidic groups such as carboxylic acids.
- the pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
- such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic,
- the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound that contains a basic or acidic moiety by conventional chemical methods.
- such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.
- Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 18th Edition, Mack Publishing Company, Easton, PA (1990), the disclosure of which is hereby incorporated by reference.
- compounds of formula I may have prodrug forms. Any compound that will be converted in vivo to provide the bioactive agent (i.e., a compound of formula I) is a prodrug within the scope and spirit of the invention.
- a prodrug within the scope and spirit of the invention.
- Various forms of prodrugs are well known in the art. For examples of such prodrug derivatives, see:
- Parenteral administration may be used where the ester per se is active, or in those instances where hydrolysis occurs in the blood. Examples of physiologically
- hydrolyzable esters of compounds of formula I include C 1 ⁇ 6 alkyl, C 1 ⁇ 6 alkylbenzyl, 4- methoxybenzyl, indanyl, phthalyl, methoxymethyl, C1 ⁇ 6 alkanoyloxy-C1 ⁇ 6alkyl (e.g., acetoxymethyl, pivaloyloxymethyl or propionyloxymethyl), C1 ⁇ 6alkoxycarbonyloxy- C1 ⁇ 6alkyl (e.g., methoxycarbonyl-oxymethyl or ethoxycarbonyloxymethyl,
- esters used, for example, in the penicillin and cephalosporin arts.
- esters may be prepared by conventional techniques known in the art.
- prodrugs Preparation of prodrugs is well known in the art and described in, for example, King, F.D., ed., Medicinal Chemistry: Principles and Practice, The Royal Society of Chemistry, Cambridge, UK (1994); Testa, B. et al., Hydrolysis in Drug and Prodrug Metabolism. Chemistry, Biochemistry and Enzymology, VCHA and Wiley-VCH, Zurich, Switzerland (2003); Wermuth, C.G., ed., The Practice of Medicinal Chemistry, Academic Press, San Diego, CA (1999).
- the present invention is intended to include all isotopes of atoms occurring in the present compounds.
- Isotopes include those atoms having the same atomic number but different mass numbers.
- isotopes of hydrogen include deuterium and tritium.
- Deuterium has one proton and one neutron in its nucleus and that has twice the mass of ordinary hydrogen.
- Deuterium can be represented by symbols such as " 2 H” or "D”.
- Isotopes of carbon include 13 C and 14 C.
- Isotopically-labeled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopically-labeled reagent in place of the non-labeled reagent otherwise employed. Such compounds have a variety of potential uses, e.g., as standards and reagents in determining the ability of a potential
- “Stable compound” and “stable structure” are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent. It is preferred that compounds of the present invention do not contain a N-halo, S(O)2H, or S(O)H group.
- solvate means a physical association of a compound of this invention with one or more solvent molecules, whether organic or inorganic. This physical association includes hydrogen bonding. In certain instances the solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid.
- the solvent molecules in the solvate may be present in a regular arrangement and/or a non-ordered arrangement.
- the solvate may comprise either a stoichiometric or nonstoichiometric amount of the solvent molecules.
- “Solvate” encompasses both solution-phase and isolable solvates. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Methods of solvation are generally known in the art.
- TRIS tris (hydroxymethyl) aminomethane The compounds of the present invention can be prepared in a number of ways known to one skilled in the art of organic synthesis. IV. BIOLOGY
- the effectiveness of compounds of the present invention as ROCK inhibitors can be determined in a 30 ⁇ L assay containing 20 mM HEPES, pH 7.5, 20 mM MgCl2, 0.015% Brij-35, 4 mM DTT, 5 ⁇ M ATP and 1.5 ⁇ M peptide substrate (FITC-AHA- AKRRRLSSLRA-OH).
- Compounds were dissolved in DMSO so that the final concentration of DMSO was ⁇ 2%, and the reaction was initiated with Rho kinase variants. After incubation, the reaction was terminated by the addition of EDTA and the phosphorylated and non-phosphorylated peptides separated using a LABCHIP® 3000 Reader (Caliper Life Sciences).
- Controls consisted of assays that did not contain compound, and backgrounds consisted of assays that contained enzyme and substrate but had EDTA from the beginning of the reaction to inhibit kinase activity.
- Compounds were tested in dose-response format, and the inhibition of kinase activity was calculated at each concentration of compound. The inhibition data were fit using a curve-fitting program to determine the IC50; i.e., the concentration of compound required to inhibit 50% of kinase activity.
- the compounds of this invention can be administered in such oral dosage forms as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. They may also be administered in intravenous (bolus or infusion), intraperitoneal, subcutaneous, or intramuscular form, all using dosage forms well known to those of ordinary skill in the pharmaceutical arts. They can be administered alone, but generally will be administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.
- composition means a composition comprising a compound of the invention in combination with at least one additional pharmaceutically acceptable carrier.
- a “pharmaceutically acceptable carrier” refers to media generally accepted in the art for the delivery of biologically active agents to animals, in particular, mammals, including, i.e., adjuvant, excipient or vehicle, such as diluents, preserving agents, fillers, flow regulating agents, disintegrating agents, wetting agents, emulsifying agents, suspending agents, sweetening agents, flavoring agents, perfuming agents, antibacterial agents, antifungal agents, lubricating agents and dispensing agents, depending on the nature of the mode of administration and dosage forms.
- Pharmaceutically acceptable carriers are formulated according to a number of factors well within the purview of those of ordinary skill in the art. These include, without limitation: the type and nature of the active agent being formulated; the patient to which the agent- containing composition is to be administered; the intended route of administration of the composition; and the therapeutic indication being targeted. Pharmaceutically acceptable carriers include both aqueous and non-aqueous liquid media, as well as a variety of solid and semi-solid dosage forms. Such carriers can include a number of different ingredients and additives in addition to the active agent, such additional ingredients being included in the formulation for a variety of reasons, e.g., stabilization of the active agent, binders, etc., well known to those of ordinary skill in the art. Descriptions of suitable
- the dosage regimen for the compounds of the present invention will, of course, vary depending upon known factors, such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration; the species, age, sex, health, medical condition, and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment; the frequency of treatment; the route of administration, the renal and hepatic function of the patient, and the effect desired.
- a physician or veterinarian can determine and prescribe the effective amount of the drug required to prevent, counter, or arrest the progress of the disorder.
- the daily oral dosage of each active ingredient when used for the indicated effects, will range between about 0.001 to about 1000 mg/kg of body weight, preferably between about 0.01 to about 100 mg/kg of body weight per day, and most preferably between about 0.1 to about 20 mg/kg/day.
- the most preferred doses will range from about 0.001 to about 10 mg/kg/minute during a constant rate infusion.
- Compounds of this invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three, or four times daily.
- Compounds of this invention can also be administered by parenteral
- administration e.g., intra-venous, intra-arterial, intramuscularly, or subcutaneously.
- intra-venous or intra-arterial the dose can be given continuously or intermittent.
- formulation can be developed for intramuscularly and subcutaneous delivery that ensure a gradual release of the active pharmaceutical ingredient.
- Compounds of this invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using transdermal skin patches.
- suitable intranasal vehicles or via transdermal routes, using transdermal skin patches.
- the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.
- the compounds are typically administered in admixture with suitable pharmaceutical diluents, excipients, or carriers (collectively referred to herein as pharmaceutical carriers) suitably selected with respect to the intended form of administration, e.g., oral tablets, capsules, elixirs, and syrups, and consistent with conventional pharmaceutical practices.
- suitable pharmaceutical diluents, excipients, or carriers suitably selected with respect to the intended form of administration, e.g., oral tablets, capsules, elixirs, and syrups, and consistent with conventional pharmaceutical practices.
- the active drug component can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like; for oral administration in liquid form, the oral drug components can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like.
- suitable binders, lubricants, disintegrating agents, and coloring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate,
- Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like.
- Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.
- the compounds of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles.
- Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines.
- Compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers.
- Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol,
- the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, and crosslinked or amphipathic block copolymers of hydrogels.
- biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, and crosslinked or amphipathic block copolymers of hydrogels.
- Dosage forms suitable for administration may contain from about 1 milligram to about 1000 milligrams of active ingredient per dosage unit.
- the active ingredient will ordinarily be present in an amount of about 0.1-95% by weight based on the total weight of the composition.
- Gelatin capsules may contain the active ingredient and powdered carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like.
- powdered carriers such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like.
- Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract.
- Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance.
- parenteral solutions In general, water, a suitable oil, saline, aqueous dextrose (glucose), and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions.
- Solutions for parenteral administration preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffer substances.
- Antioxidizing agents such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or combined, are suitable stabilizing agents.
- citric acid and its salts and sodium EDTA are also used.
- parenteral solutions can contain preservatives, such as benzalkonium chloride, methyl-or propyl-paraben, and
- each component may be administered at the same time or sequentially in any order at different points in time. Thus, each component may be administered separately but sufficiently closely in time so as to provide the desired therapeutic effect.
- the compounds of the present invention are also useful as standard or reference compounds, for example, as a quality standard or control, in tests or assays involving the inhibition of ROCK.
- Such compounds may be provided in a commercial kit, for example, for use in pharmaceutical research involving ROCK.
- a compound of the present invention could be used as a reference in an assay to compare its known activity to a compound with an unknown activity. This would ensure the experimentor that the assay was being performed properly and provide a basis for comparison, especially if the test compound was a derivative of the reference compound.
- compounds according to the present invention could be used to test their effectiveness.
- the present invention also encompasses an article of manufacture.
- article of manufacture is intended to include, but not be limited to, kits and packages.
- the article of manufacture of the present invention comprises: (a) a first container; (b) a pharmaceutical composition located within the first container, wherein the composition, comprises: a first therapeutic agent, comprising: a compound of the present invention or a pharmaceutically acceptable salt form thereof; and, (c) a package insert stating that the pharmaceutical composition can be used for the treatment of a cardiovascular and/or inflammatory disorder (as defined previously).
- the package insert states that the pharmaceutical composition can be used in combination (as defined previously) with a second therapeutic agent to treat cardiovascular and/or inflammatory disorder.
- the article of manufacture can further comprise: (d) a second container, wherein components (a) and (b) are located within the second container and component (c) is located within or outside of the second container.
- Located within the first and second containers means that the respective container holds the item within its boundaries.
- the first container is a receptacle used to hold a pharmaceutical composition. This container can be for manufacturing, storing, shipping, and/or individual/bulk selling.
- First container is intended to cover a bottle, jar, vial, flask, syringe, tube (e.g., for a cream preparation), or any other container used to manufacture, hold, store, or distribute a pharmaceutical product.
- the second container is one used to hold the first container and, optionally, the package insert.
- the second container include, but are not limited to, boxes (e.g., cardboard or plastic), crates, cartons, bags (e.g., paper or plastic bags), pouches, and sacks.
- the package insert can be physically attached to the outside of the first container via tape, glue, staple, or another method of attachment, or it can rest inside the second container without any physical means of attachment to the first container.
- the package insert is located on the outside of the second container. When located on the outside of the second container, it is preferable that the package insert is physically attached via tape, glue, staple, or another method of attachment. Alternatively, it can be adjacent to or touching the outside of the second container without being physically attached.
- the package insert is a label, tag, marker, etc. that recites information relating to the pharmaceutical composition located within the first container.
- the information recited will usually be determined by the regulatory agency governing the area in which the article of manufacture is to be sold (e.g., the United States Food and Drug
- the package insert specifically recites the indications for which the pharmaceutical composition has been approved.
- the package insert may be made of any material on which a person can read information contained therein or thereon.
- the package insert is a printable material (e.g., paper, plastic, cardboard, foil, adhesive-backed paper or plastic, etc.) on which the desired information has been formed (e.g., printed or applied).
- the compounds of the present invention may be synthesized by methods available to those skilled in the art of organic chemistry (Maffrand, J.P. et al., Heterocycles, 16(1):35-37 (1981)).
- General synthetic schemes for preparing compounds of the present invention are described below. These schemes are illustrative and are not meant to limit the possible techniques one skilled in the art may use to prepare the compounds disclosed herein. Different methods to prepare the compounds of the present invention will be evident to those skilled in the art. Additionally, the various steps in the synthesis may be performed in an alternate sequence in order to give the desired compound or compounds.
- Examples of compounds of the present invention prepared by methods described in the general schemes are given in the intermediates and examples section set out hereinafter.
- Preparation of homochiral examples may be carried out by techniques known to one skilled in the art.
- homochiral compounds may be prepared by separation of racemic products by chiral phase preparative HPLC.
- the example compounds may be prepared by methods known to give enantiomerically enriched products. These include, but are not limited to, the incorporation of chiral auxiliary functionalities into racemic intermediates which serve to control the diastereoselectivity of transformations, providing enantio-enriched products upon cleavage of the chiral auxiliary.
- the compounds of the present invention can be prepared in a number of ways known to one skilled in the art of organic synthesis.
- the compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or by variations thereon as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below.
- the reactions are performed in a solvent or solvent mixture appropriate to the reagents and materials employed and suitable for the transformations being effected. It will be understood by those skilled in the art of organic synthesis that the functionality present on the molecule should be consistent with the transformations proposed. This will sometimes require a judgment to modify the order of the synthetic steps or to select one particular process scheme over another in order to obtain a desired compound of the invention.
- Scheme 1 shows the synthesis of compound 1f from amine 1a.
- Reductive amination with an appropriate haloaldehyde or haloketone affords amine 1b.
- Urea formation to afford 1c is accomplished by reaction with an isocyanate or treatment with triphosgene, followed by an amine.
- Cyclization of 1c with a base such as NaH affords the cyclic urea 1d.
- This intermediate can be directly coupled with an aryl or heteroaryl boronic acid using Pd-catalysis to afford 1f.
- 1d can be converted to the boronic acid/ester 1e via a Suzuki/Miyaura coupling and subsequently to the compound 1f via coupling with the appropriate aryl or heteroaryl halide using Pd-catalysis.
- Scheme 2 shows the preparation of compounds of the generic structure 2d.
- Compound 1a is alkylated with a dihaloester to afford 2a, which can be treated with an isocyanate or triphosgene, followed by an amine (H 2 NR ⁇ ), to afford a urea, which either spontaneously cyclizes or cyclizes with heat or optional treatment with base such as NaH or K 2 CO 3 , to afford 2b.2b is optionally further functionalized by deprotonation with a base such as LiHMDS or LDA, followed by treatment with an electrophile R ⁇ X to afford 2c.
- a base such as LiHMDS or LDA
- ester moiety is optionally further functionalized by reduction with a base such as LiBH4, alkylation by treatment with an alkylmetal species such as a Grignard reagent, or by hydrolysis and amide formation with the resultant acid to afford 2c. Suzuki coupling affords 2d.
- Scheme 3 shows the synthesis of compounds of the generic structure 3d.
- Reaction of R ⁇ NH 2 with a dihaloester affords 3a.
- Reaction of 3a with an isocyanate (related to 1a), or triphosgene, followed by treatment with amine 1a affords a urea, which either cyclizes spontaneously or with heat or optional treatment with base such as NaH or K 2 CO 3 , to afford 3b.
- 3b is optionally further functionalized by deprotonation with a base such as LiHMDS or LDA, followed by treatment with an electrophile R ⁇ X to afford 3c.
- ester moiety is optionally further functionalized by reduction with a base such as LiBH4, alkylation by treatment with an alkylmetal species such as a Grignard reagent, or by hydrolysis and amide formation with the resultant acid to afford 3c. Suzuki coupling affords 3d.
- a base such as LiBH4, alkylation by treatment with an alkylmetal species such as a Grignard reagent, or by hydrolysis and amide formation with the resultant acid to afford 3c. Suzuki coupling affords 3d.
- Scheme 4 shows the synthesis of imidazolone 4f, beginning from isocyanate 4a, which is either commercially available or can be prepared from the amine precursor via treatment with phosgene and base, such as TEA.
- Treatment of 4a with amine 4b affords urea 4c.
- Cyclization is accomplished by treatment with acid such as HCl to afford 4d.
- Alkylation of 4d by treatment with a base such as NaH or K2CO3 and an electrophile affords 4e.
- Suzuki coupling affords 4f.
- Scheme 5 shows the synthesis of imidazodinedione 5d, beginning from isocyanate 4a, which is either commercially available or can be prepared from the amine precursor via treatment with phosgene and base, such as TEA.
- Treatment of 4a with aminoester 5a affords a urea, which either cyclizes spontaneously or with heat or optional treatment with base such as NaH or K2CO3, to afford imidazolidinonedione 5b.
- Alkylation by treatment with a base such as NaH or K 2 CO 3 and an electrophile affords 5c. Suzuki coupling affords 5d.
- Scheme 6 shows the synthesis of imidazolidinedione 6e, beginning with amine 1a, which is subjected to reductive amination with 6a using a reducing agent such as
- Scheme 7 shows the synthesis of generic compound 7e, beginning from amine 1a.
- Treatment with isocyanate 7a which is either commercially available or can be prepared from the amine precursor via treatment with phosgene and base, such as TEA, affords urea 7b.
- Treatment with a base such as NaH or K2CO3 affords the cyclized product 7c.
- Alkylation by treatment with a base such as NaH or K 2 CO 3 and an electrophile affords 7d.
- Suzuki coupling affords 7e. Purification of intermediates and final products was carried out via either normal or reverse phase chromatography.
- A H 2 O/ACN/TFA 90:10:0.1.
- B ACN/H2O/TFA 90:10:0.1 (or) Waters XBridge C18, 19 ⁇ 200 mm, 5- ⁇ m particles; Guard Column: Waters XBridge C18, 19 ⁇ 10 mm, 5- ⁇ m particles; Solvent A: water with 20-mM ammonium acetate; Solvent B: 95:5 acetonitrile:water with 20-mM ammonium acetate; Gradient: 25-65% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min.
- Method B XBridge Phenyl column (3.5 ⁇ m C18, 3.0 ⁇ 150 mm). Gradient elution (1.0 mL/min) from 10-100% Solvent B over 12 min and then 100% Solvent B for 3 min was used.
- Solvent A is 95% water, 5% acetonitrile, 0.05% TFA and Solvent B is 5% water, 95% acetonitrile, 0.05% TFA, UV 220 nm.
- Method C Ascentis Express C18, 2.1 ⁇ 50 mm, 2.7- ⁇ m particles; Solvent A: 95% water, 5% acetonitrile, 0.05% TFA; Solvent B: 95% acetonitrile, 5% water, 0.1% TFA; Temperature: 50 oC; Gradient: 0-100% B over 4 minutes, then a 1-minute hold at 100% B; Flow: 1.1 mL/min.
- Method D Ascentis Express C18, 2.1 ⁇ 50 mm, 2.7- ⁇ m particles; Solvent A: 95% water, 5% acetonitrile with 10 mM ammonium acetate; Solvent B: 95% acetonitrile, 5% water with 10 mM ammonium acetate; Temperature: 50 oC; Gradient: 0-100% B over 4 minutes, then a 1-minute hold at 100% B; Flow: 1.1 mL/min.
- Method E Ascentis Express C18, 2.1 ⁇ 50 mm, 2.7- ⁇ m particles; Solvent A: 95% water, 5% acetonitrile, 0.05% TFA; Solvent B: 95% acetonitrile, 5% water, 0.1% TFA; Temperature: 50 oC; Gradient: 0-100% B over 3 minutes, then a 1-minute hold at 100% B; Flow: 1.1 mL/min.
- Method F Ascentis Express C18, 2.1 ⁇ 50 mm, 2.7- ⁇ m particles; Solvent A: 95% water, 5% acetonitrile with 10 mM ammonium acetate; Solvent B: 95% acetonitrile, 5% water with 10 mM ammonium acetate; Temperature: 50 oC; Gradient: 0-100% B over 3 minutes, then a 1-minute hold at 100% B; Flow: 1.1 mL/min.
- Method G SunFire C18 column (3.5 ⁇ m C18, 3.0 ⁇ 150 mm). Gradient elution (1.0 mL/min) from 10-100% Solvent B over 25 min and then 100% Solvent B for 5 min was used. Solvent A is 95% water, 5% acetonitrile, 0.05% TFA and Solvent B is 5% water, 95% acetonitrile, 0.05% TFA, UV 220 nm.
- Method H XBridge Phenyl column (3.5 ⁇ m C18, 3.0 ⁇ 150 mm). Gradient elution (1.0 mL/min) from 10-100% Solvent B over 25 min and then 100% Solvent B for 5 min was used. Solvent A is 95% water, 5% acetonitrile, 0.05% TFA and Solvent B is 5% water, 95% acetonitrile, 0.05% TFA, UV 220 nm.
- Method I SunFire C18 column (3.5 ⁇ m, 4.6 ⁇ 150 mm). Gradient elution (1.0 mL/min) from 10-100% Solvent B over 12 min and then 100% Solvent B for 3 min was used. Solvent A is 95% water, 5% acetonitrile, 0.05% TFA and Solvent B is 5% water, 95% acetonitrile, 0.05% TFA, UV 220 nm.
- Method J XBridge Phenyl column (3.5 ⁇ m, 4.6 ⁇ 150 mm). Gradient elution (1.0 mL/min) from 10-100% Solvent B over 12 min and then 100% Solvent B for 3 min was used.
- Solvent A is 95% water, 5% acetonitrile, 0.05% TFA and Solvent B is 5% water, 95% acetonitrile, 0.05% TFA, UV 220 nm.
- Method K SunFire C18 column (3.5 ⁇ m, 4.6 ⁇ 150 mm). Gradient elution (1.0 mL/min) from 10-100% Solvent B over 25 min and then 100% Solvent B for 5 min was used. Solvent A is 95% water, 5% acetonitrile, 0.05% TFA and Solvent B is 5% water, 95% acetonitrile, 0.05% TFA, UV 220 nm.
- Method L XBridge Phenyl column (3.5 ⁇ m, 4.6 ⁇ 150 mm). Gradient elution (1.0 mL/min) from 10-100% Solvent B over 25 min and then 100% Solvent B for 5 min was used.
- Solvent A is 95% water, 5% acetonitrile, 0.05% TFA and Solvent B is 5% water, 95% acetonitrile, 0.05% TFA, UV 220 nm.
- Method M SunFire C18 column (3.5 ⁇ m, 4.6 ⁇ 150 mm). Gradient elution (1.0 mL/min) from 10-100% Solvent B over 18 min and then 100% Solvent B for 5 min was used. Solvent A is 95% water, 5% acetonitrile, 0.05% TFA and Solvent B is 5% water, 95% acetonitrile, 0.05% TFA, UV 220 nm.
- Method N XBridge Phenyl column (3.5 ⁇ m, 4.6 ⁇ 150 mm). Gradient elution (1.0 mL/min) from 10-100% Solvent B over 18 min and then 100% Solvent B for 5 min was used. Solvent A is 95% water, 5% acetonitrile, 0.05% TFA and Solvent B is 5% water, 95% acetonitrile, 0.05% TFA, UV 220 nm. SFC and Chiral Purity Methods
- Method I CHIRALPAK® AD-H, 250 ⁇ 4.6 mm, 5.0- ⁇ m particles; CO 2 : 60%, Co-solvent: 40% ⁇ 0.2%DEA in IPA:A CN(1:1) ⁇ , Total Flow: 4.0g/min, Back Pressure: 100bars, Temperature: 25 oC, UV: 218 nm.
- Method II CHIRALPAK® OD-H, 250 ⁇ 4.6 mm, 5.0- ⁇ m particles; CO2: 60%, Co-solvent: 40% ⁇ 0.2% DEA in IPA:A CN(1:1) ⁇ , Total Flow: 4.0g/min, Back Pressure: 104 bars, Temperature: 24.9 oC, UV: 287 nm.
- Method III CHIRALPAK® OJ-H, 250 ⁇ 4.6 mm, 5.0- ⁇ m particles; CO2: 60%, Co-solvent: 30% (0.3% DEA in methanol), Total Flow: 4.0g/min, Back Pressure: 101 bars, Temperature: 23.6 oC, UV: 272 nm.
- Method IV CHIRALPAK® AS-H, 250 ⁇ 4.6 mm, 5.0- ⁇ m particles; CO 2 : 60%, Co-solvent: 40% (0.3% DEA in methanol), Total Flow: 4.0g/min, Back Pressure: 102 bars, Temperature: 25.4 oC, UV: 272 nm.
- Method V CHIRALCEL® OJ-H, 250 ⁇ 4.6 mm, 5.0- ⁇ m particles; CO2: 60%, Co-solvent: 40% (0.2% DEA in methanol), Total Flow: 4.0g/min, Back Pressure: 102 bars, Temperature: 24.6 oC, UV: 272 nm.
- Method VII CHIRALCEL® AS-H, 250 ⁇ 4.6 mm, 5.0- ⁇ m particles; CO2: 60%, Co-solvent: 40% (0.2% DEA in methanol), Total Flow: 4.0 g/min, Back Pressure: 101 bars, Temperature: 24.4 oC, UV: 270 nm.
- Method VIII CHIRALPAK® IC, 250 ⁇ 4.6 mm, 5.0- ⁇ m particles; CO2: 60%, Co-solvent: 40% (0.2% DEA in methanol), Total Flow: 4.0 g/min, Back Pressure: 101 bars, Temperature: 24.4 oC, UV: 270 nm.
- Method IX Column: CHIRALPAK® IF (250 ⁇ 4.6mm), 5 ⁇ , Mobile Phase: 0.2% DEA in ethanol, Flow:1.0ml/min.
- Method X Column: Lux Amylose 2 (250 ⁇ 4.6mm), 5 ⁇ , Mobile Phase: 0.2% DEA in n-hexane:ethanol:5:95, Flow:1.0ml/min.
- Method XI Column: CHIRALCEL® OD-H (250 ⁇ 4.6mm), 5 ⁇ , Mobile Phase: 0.2% DEA in n-hexane:ethanol:70:30, Flow:1.0ml/min.
- Example 1A 0.220 g, 0.576 mmol
- THF THF
- 95% NaH 0.029 g, 1.15 mmol
- reaction mixture was stirred at rt 1.5 h.
- the reaction mixture was cooled to 0 oC and diluted with water.
- the resultant precipitate was collected by filtration, then was washed with diethyl ether and dried under vacuum to obtain 0.18 g (90% yield) of Example 1B as a white solid.
- Example 1B To a solution of Example 1B (0.100 g, 0.290 mmol), tert-butyl 4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (0.128 g, 0.434 mmol) in DMF (3 mL) and water (0.3 mL), was added K 2 CO 3 (0.120 g, 0.869 mmol). The resulting reaction mixture was degassed using N2 gas for 5 min.2nd generation XPhos precatalyst (0.046 g, 0.058 mmol) was added to the reaction, which was degassed again. The mixture was then heated to 90 oC for 2 h.
- Example 6A To a solution of Example 6A (0.350 g, 0.842 mmol) in THF (5 mL) at 0 oC, was added NaH (0.043 g, 1.68 mmol). The reaction mixture was stirred at rt for 1.5 h. The reaction mixture was cooled to 0 oC and diluted with water. The resultant solid mass was collected by filtration, washed with diethyl ether and dried to obtain 0.285 g (89% yield) as a white solid.
- Example 6B To a solution of Example 6B (0.070 g, 0.185 mmol), tert-butyl 4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (0.081 g, 0.280 mmol) in DMF (3 mL) and water (0.3 mL), was added K2CO3 (0.077 g, 0.55 mmol). The resulting reaction mixture was degassed using N 2 for 5 min.2nd generation XPhos precatalyst (0.029 g, 0.037 mmol) was added to the reaction, which was degassed again. The mixture was then heated to 90 oC for 8 h.
- Example 8 Example 8
- Example 7 According to the procedure for the preparation of Example 6, substituting 1- fluoro-4-(2-isocyanatoethyl)benzene for 1-fluoro-3-(isocyanatomethyl)benzene afforded Example 7.
- Example 9A 400 mg, 0.962 mmol
- THF 10 mL
- NaH 77 mg, 1.9 mmol
- the reaction was quenched with cold water and was extracted with ethyl acetate.
- the combined ethyl acetate layers were washed with brine, dried (Na2SO4) and concentrated.
- the residue was washed with 10% diethyl ether in petroleum ether (3 ⁇ 5 mL), then dried to afford 220 mg of Example 9B as a gummy solid that was used in the following step without purification.
- Example 9B To a solution of Example 9B (100 mg, 0.264 mmol) in DMF (2 mL), was added tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (155 mg, 0.527 mmol), K 2 CO 3 (109 mg, 0.791 mmol) and water (0.5 mL). The mixture was purged with nitrogen for 5 min, and then 2nd generation XPhos precatalyst (12.5 mg, 0.016 mmol) was added. The mixture was heated at 100 oC overnight.
- Example 11 Example 10
- Example 13 Example 13
- Example 13A (R)-1-(4-Bromo-3-methoxyphenyl)-1-(2-chloroethyl)-3-(1-(3- methox hen l eth l urea
- Example 13A (R)-1-(4-Bromo-3-methoxyphenyl)-3-(1-(3-methoxyphenyl)ethyl) i
- Example 13A To a solution of Example 13A (0.330 g, 0.747 mmol) in THF (5 mL) at 0 oC, was added NaH (0.038 g, 1.49 mmol), and the reaction mixture was stirred at rt for 2 h. The reaction mixture was cooled to 0 oC, diluted with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na 2 SO 4 and concentrated to obtain 0.285 g (94%) of Example 13B as a burgundy oil.
- Example 13B To a solution of Example 13B (0.070 g, 0.17 mmol), tert-butyl 4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (0.076 g, 0.26 mmol) in DMF (3 mL) and water (0.3 mL), was added K 2 CO 3 (0.072 g, 0.52 mmol). The reaction mixture was degassed using N2 for 5 min.2nd generation XPhos precatalyst (0.027 g, 0.035 mmol) was added, then the reaction mixture was degassed again. The mixture was heated to 90 oC for 4 h.
- Example 13 was purified by preparative HPLC to afford 14 mg (21%) of Example 13 as a pale yellow solid.
- Example 15A Trichlorometh l 4-bromo-3-methox hen l 2-chloroeth l carbamate
- Example 15A 1-(4-Bromo-3-methoxyphenyl)-1-(2-chloroethyl)-3-(2-fluoro-5- methox benz l urea
- Example 15B 1-(4-Bromo-3-methoxyphenyl)-3-(2-fluoro-5-methoxybenzyl) imidazolidin-2-one
- Example 15B To a solution of Example 15B (0.110 g, 0.247 mmol) in THF (5 mL) at 0 oC, was added NaH (0.012 g, 0.49 mmol). The reaction mixture was stirred at rt for 8 h. The reaction mixture was cooled to 0 oC, diluted with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by flash chromatography (gradient elution 0-20% EtOAc/Hex) to afford 0.11 g (98% yield) of Example 15C as a pale yellow solid.
- Example 15C To a solution of Example 15C (0.100 g, 0.24 mmol) and tert-butyl 4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (0.108 g, 0.367 mmol) in DMF (3 mL) and water (0.3 mL), was added K 2 CO 3 (0.101 g, 0.733 mmol). The resulting reaction mixture was degassed with N2 for 5 min, then 2nd generation XPhos precatalyst (0.038 g, 0.049 mmol) was added. The reaction was degassed again, then was heated to 90 oC for 6 h.
- Example 16 According to the procedure for the preparation of Example 15, substituting (2,6- difluorophenyl)methanamine for (2-fluoro-5-methoxyphenyl)methanamine afforded Example 16.
- Example 15 According to the procedure for the preparation of Example 15, substituting (2- fluorophenyl)methanamine for (2-fluoro-5-methoxyphenyl)methanamine afforded Example 17.
- Example 18 According to the procedure for the preparation of Example 15, substituting benzylamine for (2-fluoro-5-methoxyphenyl)methanamine afforded Example 18.
- Example 19 According to the procedure for the preparation of Example 15, substituting methyl 3-amino-3-(3-methoxyphenyl)propanoate, HCl for (2-fluoro-5-methoxyphenyl) methanamine afforded Example 19.
- Example 20A Methyl 3-(3-(4-bromo-3-methoxyphenyl)-3-(2-chloroethyl)ureido)-3-(3- methox hen l ro anoate
- Example 15A a solution of Example 15A (0.700 g, 1.64 mmol) in 1 mL CHCl3. The mixture was stirred for 6 h, then was diluted with water, acidified with 5% HCl, and extracted with DCM. The organic layer was dried over Na2SO4 and concentrated to obtain 1.80 g of Example 20A as a yellow oil that was used without further purification.
- Example 20C 3-(3-(4-Bromo-3-methoxyphenyl)-2-oxoimidazolidin-1-yl)-3-(3- methoxyphenyl)propanoic acid
- Example 20A To a solution of Example 20A (1.40 g, 2.80 mmol) in THF (5 mL) at 0 oC, was added NaH (0.142 g, 5.60 mmol). The reaction mixture was stirred at rt for 2 h. The reaction mixture was cooled to 0 oC, then was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by flash chromatography (0-20% EtOAc/Hex) to afford 0.30 g of Example 20B as a colorless oil.
- Example 20C tert-Butyl 4-(2-methoxy-4-(3-(3-methoxy-1-(3-methoxyphenyl)-3- oxopropyl)-2-oxoimidazolidin-1-yl)phenyl)-1H-pyrazole-1-carboxylate
- Example 20B 0.030 g, 0.065 mmol
- tert-butyl 4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate 0.029 g, 0.097 mmol
- K2CO3 0.027 g, 0.19 mmol
- the reaction mixture was degassed with N 2 for 5 min, then 2nd generation XPhos precatalyst (10.2 mg, 0.013 mmol) was added.
- the reaction was degassed again, then was then heated to 90 oC for 6 h.
- Example 20D was used as is in the following step. MS(ESI) m/z: 551.7 (M+H) + . Exam le 20
- Example 20D To a solution of Example 20D (0.030 g, 0.054 mmol) in MeOH, was added NaBH4 (0.021 g, 0.545 mmol). The reaction mixture was stirred at rt overnight. The methanol was evaporated, and the mixture was partitioned between ethyl acetate and water. The organic layer was dried over Na 2 SO 4 and concentrated. The residue was purified by preparative HPLC to afford 5 mg (20% yield) of Example 20.
- Example 21A 1-(4-Bromo-3-methoxyphenyl)-3-(3-hydroxy-1-(3-methoxyphenyl)propyl) imidazolidin-2-one
- Example 20C To a solution of Example 20C (0.140 g, 0.312 mmol) in THF (2 mL) at 0 oC, was added borane-methyl sulfide complex (0.311 mL, 3.12 mmol), dropwise. The reaction mixture was stirred at 50 oC for 1.5 h, then was concentrated. The residue was treated with 6 N HCl in MeOH (2 mL) at rt for 30 min. The mixture was diluted with water and was extracted with methylene chloride (3 ⁇ 40 mL). The combined extracts were dried over sodium sulfate, filtered and concentrated. The product was purified by flash chromatography to afford 0.030 g (22% yield) of Example 21A as a white solid. MS(ESI) m/z: 435.6 (M+H) + . Exam le 21
- Example 21A 0.030 g, 0.069 mmol
- tert-butyl 4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate 0.030 g, 0.103 mmol
- K2CO3 0.029 g, 0.207 mmol
- the reaction mixture was degassed with N 2 for 5 min, then 2nd generation XPhos precatalyst (10.8 mg, 0.014 mmol) was added to the reaction.
- the reaction mixture was degassed again, then was heated to 90 oC for 6 h.
- Example 22A 1-(3-Hydroxy-1-(3-methoxyphenyl)-3-methylbutyl)-3-(3-methoxy-4-(1H-pyrazol-4- yl)phenyl)imidazolidin-2-one
- Example 22A 1-(4-Bromo-3-methoxyphenyl)-3-(3-hydroxy-1-(3-methoxyphenyl)-3- meth lbut l imidazolidin-2-one
- Example 20B 0.070 g, 0.151 mmol
- THF 2 mL
- 3M methylmagnesium bromide 0.201 mL, 0.604 mmol
- the reaction mixture was stirred at rt for 2 h.
- the mixture was diluted with water, then was extracted with ethyl acetate (3 ⁇ 20 mL).
- the combined extracts were dried over sodium sulfate and concentrated to afford 0.080 g of Example 22A, which was used in the following step without further purification.
- Example 22A 0.070 g, 0.15 mmol
- tert-butyl 4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate 0.067 g, 0.23 mmol
- K2CO3 0.063 g, 0.45 mmol
- the reaction mixture was degassed with N 2 for 5 min, then 2nd generation XPhos precatalyst (0.024 g, 0.030 mmol) was added.
- the reaction mixture was degassed again, then was heated at 90 oC for 6 h.
- Example 23A was purified by flash chromatography (gradient elution: 0-15% EtOAc/Hex) to afford 4.50 g of Example 23A as a yellow oil.
- Example 23B 1-(4-Bromo-3-ethylphenyl)-1-(2-chloroethyl)-3-(3-methoxybenzyl)urea
- Example 23A To a solution of Example 23A (0.300 g, 1.14 mmol) in CHCl3 (5 mL) at 0 oC, was added TEA (0.478 mL, 3.43 mmol) followed by bis(trichloromethyl)carbonate (0.407 g, 1.37 mmol). The mixture was stirred at 0 oC for 2 h, then (3-methoxyphenyl)
- Example 23B 1-(4-Bromo-3-ethylphenyl)-3-(3-methoxybenzyl)imidazolidin-2-one
- Example 23B To a solution of Example 23B (0.400 g, 0.507 mmol) in THF (5 mL) at 0 oC, was added NaH (0.026 g, 1.02 mmol). The reaction mixture was stirred at rt for 2 h, then was cooled to 0 oC and diluted with water. The mixture was extracted with ethyl acetate (3 ⁇ 30 mL). The organic layer was washed with brine, dried over Na 2 SO 4 and concentrated to an oil, which was washed with 10% diethyl ether in n-hexane to afford 0.230 g of Example 23C as a yellow oil, which was used as is without further purification.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Epidemiology (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Immunology (AREA)
- Hospice & Palliative Care (AREA)
- Vascular Medicine (AREA)
- Urology & Nephrology (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Transplantation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Plural Heterocyclic Compounds (AREA)
Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
ES16703378T ES2815681T3 (es) | 2015-01-09 | 2016-01-08 | Ureas cíclicas como inhibidores de ROCK |
JP2017536259A JP6779214B2 (ja) | 2015-01-09 | 2016-01-08 | Rock阻害剤としての環状ウレア |
EP16703378.6A EP3242873B1 (en) | 2015-01-09 | 2016-01-08 | Cyclic ureas as inhibitors of rock |
CN201680012270.1A CN107406426B (zh) | 2015-01-09 | 2016-01-08 | 作为rock抑制剂的环状脲类 |
US15/541,725 US10123993B2 (en) | 2015-01-09 | 2016-01-08 | Cyclic ureas as inhibitors of rock |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201562101434P | 2015-01-09 | 2015-01-09 | |
US62/101,434 | 2015-01-09 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2016112236A1 true WO2016112236A1 (en) | 2016-07-14 |
Family
ID=55310909
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2016/012560 WO2016112236A1 (en) | 2015-01-09 | 2016-01-08 | Cyclic ureas as inhibitors of rock |
Country Status (8)
Cited By (15)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2017046739A1 (en) * | 2015-09-15 | 2017-03-23 | Glaxosmithkline Intellectual Property (No.2) Limited | Imidazolidinone derivatives as inhibitors of perk |
WO2017123860A1 (en) | 2016-01-13 | 2017-07-20 | Bristol-Myers Squibb Company | Spiroheptane salicylamides and related compounds as inhibitors of rock |
WO2017205709A1 (en) * | 2016-05-27 | 2017-11-30 | Bristol-Myers Squibb Company | Triazolones and tetrazolones as inhibitors of rock |
WO2018009627A1 (en) | 2016-07-07 | 2018-01-11 | Bristol-Myers Squibb Company | Spiro-fused cyclic ureas as inhibitors of rock |
WO2018009622A1 (en) * | 2016-07-07 | 2018-01-11 | Bristol-Myers Squibb Company | Lactam, cyclic urea and carbamate, and triazolone derivatives as potent and selective rock inhibitors |
WO2018102325A1 (en) * | 2016-11-30 | 2018-06-07 | Bristol-Myers Squibb Company | Tricyclic rho kinase inhibitors |
US10112929B2 (en) | 2015-03-09 | 2018-10-30 | Bristol-Myers Squibb Company | Lactams as inhibitors of rock |
US10123993B2 (en) | 2015-01-09 | 2018-11-13 | Bristol-Myers Squibb Company | Cyclic ureas as inhibitors of rock |
WO2019014308A1 (en) | 2017-07-12 | 2019-01-17 | Bristol-Myers Squibb Company | 5-CHAIN AND BICYCLIC HETEROCYCLIC AMIDES AS ROCK INHIBITORS |
WO2019014304A1 (en) | 2017-07-12 | 2019-01-17 | Bristol-Myers Squibb Company | SPIROHEPTANYL HYDANTOIDS AS ROCK INHIBITORS |
WO2019014300A1 (en) | 2017-07-12 | 2019-01-17 | Bristol-Myers Squibb Company | PHENYLACETAMIDES AS ROCK INHIBITORS |
WO2019014303A1 (en) | 2017-07-12 | 2019-01-17 | Bristol-Myers Squibb Company | 5-OR 6,6-CHANNEL BICYCLIC CHAINS AND AMINOHETEROCYCLIC AMINOHETEROCYCLIC INHIBITORS FOR THE TREATMENT OF CARDIAC INSUFFICIENCY |
WO2019089868A1 (en) * | 2017-11-03 | 2019-05-09 | Bristol-Myers Squibb Company | Diazaspiro rock inhibitors |
US10696674B2 (en) | 2016-07-07 | 2020-06-30 | Bristol-Myers Squibb Company | Spirolactams as inhibitors of ROCK |
WO2023085369A1 (ja) | 2021-11-11 | 2023-05-19 | 学校法人同志社 | 角膜内皮細胞の凍結保存製剤およびその製造法 |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU2019387370A1 (en) | 2018-11-30 | 2021-06-10 | Nuvation Bio Inc. | Pyrrole and pyrazole compounds and methods of use thereof |
CN112759550A (zh) * | 2019-11-04 | 2021-05-07 | 上海科技大学 | 一种平滑受体拮抗剂 |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20080275062A1 (en) | 2004-01-30 | 2008-11-06 | David Harold Drewry | Chemical Compounds |
WO2014134388A1 (en) * | 2013-02-28 | 2014-09-04 | Bristol-Myers Squibb Company | Phenylpyrazole derivatives as potent rock1 and rock2 inhibitors |
WO2014134391A1 (en) * | 2013-02-28 | 2014-09-04 | Bristol-Myers Squibb Company | Phenylpyrazole derivatives as potent rock1 and rock2 inhibitors |
WO2015107053A1 (en) * | 2014-01-20 | 2015-07-23 | F. Hoffmann-La Roche Ag | N-phenyl-lactam derivatives capable of stimulating neurogenesis and their use in the treatment of neurological disorders |
Family Cites Families (18)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH07183769A (ja) * | 1993-12-22 | 1995-07-21 | Fuji Electric Co Ltd | ラッチ回路 |
WO2006048727A1 (en) * | 2004-11-02 | 2006-05-11 | Pfizer Products Inc. | Piperazinylphenalkyl lactam/amine ligands for the 5ht1b receptor |
EP1922306A2 (en) * | 2005-09-02 | 2008-05-21 | Astellas Pharma Inc. | Amide derivatives as rock inhibitors |
WO2009078991A1 (en) * | 2007-12-17 | 2009-06-25 | Peshina William F | Oval cage coupler for filter cages |
WO2009078992A1 (en) * | 2007-12-17 | 2009-06-25 | Amgen Inc. | Linear tricyclic compounds as p38 kinase inhibitors |
WO2010036316A1 (en) * | 2008-09-24 | 2010-04-01 | Yangbo Feng | Urea and carbamate compounds and analogs as kinase inhibitors |
WO2012054367A1 (en) * | 2010-10-19 | 2012-04-26 | Boehringer Ingelheim International Gmbh | Rho kinase inhibitors |
JP6488239B2 (ja) | 2013-01-18 | 2019-03-20 | ブリストル−マイヤーズ スクイブ カンパニーBristol−Myers Squibb Company | Rock阻害剤としてのフタラジノンおよびイソキノリノン |
WO2014145022A1 (en) | 2013-03-15 | 2014-09-18 | President And Fellows Of Harvard College | Hybrid necroptosis inhibitors |
ES2633987T3 (es) | 2013-07-02 | 2017-09-26 | Bristol-Myers Squibb Company | Derivados de pirido-carboxamidas tricíclicas como inhibidores de ROCK |
CN105518005B (zh) | 2013-07-02 | 2018-07-20 | 百时美施贵宝公司 | 作为rock抑制剂的三环吡啶-甲酰胺衍生物 |
EP3027629B1 (en) | 2013-07-31 | 2017-06-14 | UDC Ireland Limited | Luminescent diazabenzimidazole carbene metal complexes |
US9682960B2 (en) | 2013-12-19 | 2017-06-20 | Endorecherche, Inc. | Non-steroidal antiandrogens and selective androgen receptor modulators with a pyridyl moiety |
US9902702B2 (en) | 2014-07-15 | 2018-02-27 | Bristol-Myers Squibb Company | Spirocycloheptanes as inhibitors of rock |
EP3183248B1 (en) | 2014-08-21 | 2020-11-11 | Bristol-Myers Squibb Company | Tied-back benzamide derivatives as potent rock inhibitors |
AR103990A1 (es) | 2015-01-09 | 2017-06-21 | Bristol Myers Squibb Co | Ureas cíclicas como inhibidoras de rock |
WO2016144936A1 (en) | 2015-03-09 | 2016-09-15 | Bristol-Myers Squibb Company | Lactams as inhibitors of rock |
UY37073A (es) | 2016-01-13 | 2017-07-31 | Bristol-Myers Squibb Company Una Corporación Del Estado De Delaware | Salicilamidas espiroheptanos y compuestos relacionados como inhibidores de rock, y las composiciones que los contienen |
-
2016
- 2016-01-08 AR ARP160100053A patent/AR103990A1/es unknown
- 2016-01-08 JP JP2017536259A patent/JP6779214B2/ja active Active
- 2016-01-08 TW TW105100631A patent/TW201630899A/zh unknown
- 2016-01-08 EP EP16703378.6A patent/EP3242873B1/en active Active
- 2016-01-08 WO PCT/US2016/012560 patent/WO2016112236A1/en active Application Filing
- 2016-01-08 CN CN201680012270.1A patent/CN107406426B/zh active Active
- 2016-01-08 US US15/541,725 patent/US10123993B2/en active Active
- 2016-01-08 ES ES16703378T patent/ES2815681T3/es active Active
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20080275062A1 (en) | 2004-01-30 | 2008-11-06 | David Harold Drewry | Chemical Compounds |
WO2014134388A1 (en) * | 2013-02-28 | 2014-09-04 | Bristol-Myers Squibb Company | Phenylpyrazole derivatives as potent rock1 and rock2 inhibitors |
WO2014134391A1 (en) * | 2013-02-28 | 2014-09-04 | Bristol-Myers Squibb Company | Phenylpyrazole derivatives as potent rock1 and rock2 inhibitors |
WO2015107053A1 (en) * | 2014-01-20 | 2015-07-23 | F. Hoffmann-La Roche Ag | N-phenyl-lactam derivatives capable of stimulating neurogenesis and their use in the treatment of neurological disorders |
Non-Patent Citations (51)
Title |
---|
"Design of Prodrugs", 1985, ELSEVIER |
"Hawley's Condensed Chemical Dictionary", 1997, JOHN WILEY & SONS, INC. |
"Medicinal Chemistry: Principles and Practice", 1994, THE ROYAL SOCIETY OF CHEMISTRY |
"Methods in Enzymology", vol. 112, 1985, ACADEMIC PRESS, pages: 309 - 396 |
"Remington's Pharmaceutical Sciences", 1990 |
"Remington's Pharmaceutical Sciences", 1990, MACK PUBLISHING COMPANY |
"The Practice of Medicinal Chemistry", 1999, ACADEMIC PRESS |
ASANO, T. ET AL., J. PHARMACOL. EXP. THER., vol. 241, 1987, pages 1033 - 1040 |
BUNDGAARD, H. ET AL., J. PHARM. SCI., vol. 77, 1988, pages 285 |
BUNDGAARD, H. ET AL.: "A Textbook of Drug Design and Development", 1991, HARWOOD ACADEMIC PUBLISHERS, article "Design and Application of Prodrugs", pages: 113 - 191 |
BUNDGAARD, H., ADV. DRUG DELIV. REV., vol. 8, 1992, pages 1 - 38 |
CIRCULATION, vol. 125, 2012, pages E2 - E220 |
ETO, Y. ET AL., AM. J. PHYSIOL. HEART CIRC. PHYSIOL., vol. 278, 2000, pages H1744 - H1750 |
FUKUMOTO, Y. ET AL., HEART, vol. 91, 2005, pages 391 - 392 |
GONZALEZ-CADAVID, N.F. ET AL., ENDOCRINE, vol. 23, 2004, pages 167 - 176 |
GREENE ET AL.: "Protective Groups in Organic Synthesis", 2006, WILEY-INTERSCIENCE |
HENRY, P.J. ET AL., PULM. PHARMACOL. THER., vol. 18, 2005, pages 67 - 74 |
IIJIMA, H., BIOORG. MED. CHEM., vol. 15, 2007, pages 1022 - 1033 |
ISHIZAKI, T. ET AL., EMBO J., vol. 15, 1996, pages 1885 - 1893 |
IUPAC RECOMMENDATIONS, 1996 |
JIANG, C. ET AL., INT. J. MOL. SCI., vol. 13, 2012, pages 8293 - 8307 |
KAKEYA, N. ET AL., CHEM. PHARM. BULL., vol. 32, 1984, pages 692 |
KISHI, H. ET AL., J. BIOCHEM., vol. 128, 2000, pages 719 - 722 |
KOBAYASHI, N. ET AL., CARDIOVASC. RES., vol. 55, 2002, pages 757 - 767 |
LEPLEY, D. ET AL., CANCER RES., vol. 65, 2005, pages 3788 - 3795 |
MAFFRAND, J.P. ET AL., HETEROCYCLES, vol. 16, no. 1, 1981, pages 35 - 37 |
MARTINEZ, M.C. ET AL., AM. J. PHYSIOL., vol. 279, 2000, pages H1228 - H1238 |
MUELLER, B.K. ET AL., NAT. REV. DRUG DISC., vol. 4, 2005, pages 387 - 398 |
MUKAI, Y. ET AL., FASEB J., vol. 15, 2001, pages 1062 - 1064 |
PURE AND APPLIED CHEMISTRY, vol. 68, 1996, pages 2193 - 2222 |
RATTAN, R. ET AL., J. NEUROSCI. RES., vol. 83, 2006, pages 243 - 255 |
RIENTO, K. ET AL., NAT. REV. MOL. CELL BIOL., vol. 4, 2003, pages 446 - 456 |
SATO, M. ET AL., CIRC. RES., vol. 87, 2000, pages 195 - 200 |
SATOH, S. ET AL., EUR. J. PHARMACOL., vol. 455, 2002, pages 169 - 174 |
SAUZEAU, V. ET AL., CIRC. RES., vol. 88, 2001, pages 1102 - 1104 |
SAWADA, N. ET AL., CIRCULATION, vol. 101, 2000, pages 2030 - 2033 |
SHIMOKAWA, H. ET AL., ARTERIOSCLER. THROMB. VASE. BIOL., vol. 25, 2005, pages 1767 - 1775 |
SHIMOKAWA, H. ET AL., CARDIOVASC. RES., vol. 43, 1999, pages 1029 - 1039 |
SHIMOKAWA, H. ET AL., CARDIOVASC. RES., vol. 51, 2001, pages 169 - 177 |
SHIMOKAWA, H. ET AL., J. CARDIOVASC. PHARMACOL., vol. 39, 2002, pages 319 - 327 |
SHIMOKAWA, H., JPN. CIRC. J., vol. 64, 2000, pages 1 - 12 |
SOMLYO, A.P., NATURE, vol. 389, 1997, pages 908 - 911 |
SUN, X. ET AL., J. NEUROIMMUNOL., vol. 180, 2006, pages 126 - 134 |
TANGKIJVANICH, P. ET AL., HEPATOLOGY, vol. 33, 2001, pages 74 - 80 |
TESTA, B. ET AL.: "Hydrolysis in Drug and Prodrug Metabolism. Chemistry, Biochemistry and Enzymology", 2003, VCHA AND WILEY-VCH |
TOSHIMA, Y., STROKE, vol. 31, 2000, pages 2245 - 2250 |
UEHATA, M. ET AL., NATURE, vol. 389, 1997, pages 990 - 994 |
WORTHYLAKE, R.A. ET AL., J. BIOL. CHEM., vol. 278, 2003, pages 13578 - 13584 |
YADA, T. ET AL., J. AM. COLL. CARDIOL., vol. 45, 2005, pages 599 - 607 |
YAMAKAWA, T. ET AL., HYPERTENSION, vol. 35, 2000, pages 313 - 318 |
ZHOU, L. ET AL., AM. J. NEPHROL., vol. 34, 2011, pages 468 - 475 |
Cited By (36)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10123993B2 (en) | 2015-01-09 | 2018-11-13 | Bristol-Myers Squibb Company | Cyclic ureas as inhibitors of rock |
US10112929B2 (en) | 2015-03-09 | 2018-10-30 | Bristol-Myers Squibb Company | Lactams as inhibitors of rock |
WO2017046739A1 (en) * | 2015-09-15 | 2017-03-23 | Glaxosmithkline Intellectual Property (No.2) Limited | Imidazolidinone derivatives as inhibitors of perk |
WO2017123860A1 (en) | 2016-01-13 | 2017-07-20 | Bristol-Myers Squibb Company | Spiroheptane salicylamides and related compounds as inhibitors of rock |
US10611776B2 (en) | 2016-01-13 | 2020-04-07 | Bristol-Myers Squibb Company | Spiroheptane salicylamides and related compounds as inhibitors of rock |
US10829501B2 (en) | 2016-01-13 | 2020-11-10 | Bristol-Myers Squibb Company | Spiroheptane salicylamides and related compounds as inhibitors of ROCK |
EP3954681A1 (en) | 2016-01-13 | 2022-02-16 | Bristol-Myers Squibb Company | Spiroheptane salicylamides and related compounds as inhibitors of rock |
US10562887B2 (en) | 2016-05-27 | 2020-02-18 | Bristol-Myers Squibb Company | Triazolones and tetrazolones as inhibitors of ROCK |
WO2017205709A1 (en) * | 2016-05-27 | 2017-11-30 | Bristol-Myers Squibb Company | Triazolones and tetrazolones as inhibitors of rock |
KR102473481B1 (ko) | 2016-07-07 | 2022-12-01 | 브리스톨-마이어스 스큅 컴퍼니 | 강력하고 선택적인 rock 억제제로서의 락탐, 시클릭 우레아 및 카르바메이트, 및 트리아졸론 유도체 |
WO2018009622A1 (en) * | 2016-07-07 | 2018-01-11 | Bristol-Myers Squibb Company | Lactam, cyclic urea and carbamate, and triazolone derivatives as potent and selective rock inhibitors |
KR20190025960A (ko) * | 2016-07-07 | 2019-03-12 | 브리스톨-마이어스 스큅 컴퍼니 | 강력하고 선택적인 rock 억제제로서의 락탐, 시클릭 우레아 및 카르바메이트, 및 트리아졸론 유도체 |
WO2018009627A1 (en) | 2016-07-07 | 2018-01-11 | Bristol-Myers Squibb Company | Spiro-fused cyclic ureas as inhibitors of rock |
US10730858B2 (en) | 2016-07-07 | 2020-08-04 | Bristol-Myers Squibb Company | Lactam, cyclic urea and carbamate, and triazolone derivatives as potent and selective rock inhibitors |
US10787450B2 (en) | 2016-07-07 | 2020-09-29 | Bristol-Myers Squibb Company | Spiro-fused cyclic ureas as inhibitors of rock |
US10696674B2 (en) | 2016-07-07 | 2020-06-30 | Bristol-Myers Squibb Company | Spirolactams as inhibitors of ROCK |
JP7191826B2 (ja) | 2016-11-30 | 2022-12-19 | ブリストル-マイヤーズ スクイブ カンパニー | 三環式rhoキナーゼ阻害剤 |
WO2018102325A1 (en) * | 2016-11-30 | 2018-06-07 | Bristol-Myers Squibb Company | Tricyclic rho kinase inhibitors |
JP2020500869A (ja) * | 2016-11-30 | 2020-01-16 | ブリストル−マイヤーズ スクイブ カンパニーBristol−Myers Squibb Company | 三環式rhoキナーゼ阻害剤 |
US10654860B2 (en) | 2016-11-30 | 2020-05-19 | Bristol-Myers Squibb Company | Tricyclic rho kinase inhibitors |
US11299488B2 (en) | 2017-07-12 | 2022-04-12 | Bristol-Myers Squibb Company | Five membered-aminoheterocycle and 5,6-or 6,6-membered bicyclic aminoheterocyclic inhibitors of rock for the treatment of heart failure |
WO2019014300A1 (en) | 2017-07-12 | 2019-01-17 | Bristol-Myers Squibb Company | PHENYLACETAMIDES AS ROCK INHIBITORS |
US11673886B2 (en) | 2017-07-12 | 2023-06-13 | Bristol-Myers Squibb Company | 5-membered and bicyclic heterocyclic amides as inhibitors of ROCK |
WO2019014308A1 (en) | 2017-07-12 | 2019-01-17 | Bristol-Myers Squibb Company | 5-CHAIN AND BICYCLIC HETEROCYCLIC AMIDES AS ROCK INHIBITORS |
US11078197B2 (en) | 2017-07-12 | 2021-08-03 | Bristol-Myers Squibb Company | 5-membered and bicyclic heterocyclic amides as inhibitors of rock |
WO2019014304A1 (en) | 2017-07-12 | 2019-01-17 | Bristol-Myers Squibb Company | SPIROHEPTANYL HYDANTOIDS AS ROCK INHIBITORS |
WO2019014303A1 (en) | 2017-07-12 | 2019-01-17 | Bristol-Myers Squibb Company | 5-OR 6,6-CHANNEL BICYCLIC CHAINS AND AMINOHETEROCYCLIC AMINOHETEROCYCLIC INHIBITORS FOR THE TREATMENT OF CARDIAC INSUFFICIENCY |
US11447487B2 (en) | 2017-07-12 | 2022-09-20 | Bristol-Myers Squibb Company | Spiroheptanyl hydantoins as rock inhibitors |
US11306081B2 (en) | 2017-07-12 | 2022-04-19 | Bristol-Myers Squibb Company | Phenylacetamides as inhibitors of rock |
CN111278825A (zh) * | 2017-11-03 | 2020-06-12 | 百时美施贵宝公司 | 二氮杂螺rock抑制剂 |
JP7163385B2 (ja) | 2017-11-03 | 2022-10-31 | ブリストル-マイヤーズ スクイブ カンパニー | ジアザスピロrock阻害剤 |
US11192891B2 (en) | 2017-11-03 | 2021-12-07 | Bristol-Myers Squibb Company | Diazaspiro ROCK inhibitors |
JP2021501782A (ja) * | 2017-11-03 | 2021-01-21 | ブリストル−マイヤーズ スクイブ カンパニーBristol−Myers Squibb Company | ジアザスピロrock阻害剤 |
CN111278825B (zh) * | 2017-11-03 | 2023-05-02 | 百时美施贵宝公司 | 二氮杂螺rock抑制剂 |
WO2019089868A1 (en) * | 2017-11-03 | 2019-05-09 | Bristol-Myers Squibb Company | Diazaspiro rock inhibitors |
WO2023085369A1 (ja) | 2021-11-11 | 2023-05-19 | 学校法人同志社 | 角膜内皮細胞の凍結保存製剤およびその製造法 |
Also Published As
Publication number | Publication date |
---|---|
JP2018501285A (ja) | 2018-01-18 |
US20180000788A1 (en) | 2018-01-04 |
TW201630899A (zh) | 2016-09-01 |
ES2815681T3 (es) | 2021-03-30 |
EP3242873A1 (en) | 2017-11-15 |
AR103990A1 (es) | 2017-06-21 |
US10123993B2 (en) | 2018-11-13 |
CN107406426A (zh) | 2017-11-28 |
CN107406426B (zh) | 2020-11-20 |
EP3242873B1 (en) | 2020-07-22 |
JP6779214B2 (ja) | 2020-11-04 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
WO2016112236A1 (en) | Cyclic ureas as inhibitors of rock | |
US10787450B2 (en) | Spiro-fused cyclic ureas as inhibitors of rock | |
ES2814325T3 (es) | Derivados de lactama, urea cíclica y carbamato y de triazolona como inhibidores potentes y selectivos de ROCK | |
US10112929B2 (en) | Lactams as inhibitors of rock | |
EP2961745B1 (en) | Phenylpyrazole derivatives as potent rock1 and rock2 inhibitors | |
US10696674B2 (en) | Spirolactams as inhibitors of ROCK | |
EP2945943B1 (en) | Phthalazinones and isoquinolinones as rock inhibitors | |
US9828345B2 (en) | Phenylpyrazole derivatives as potent ROCK1 and ROCK2 inhibitors | |
ES2838573T3 (es) | Derivados de benzamida ligados como inhibidores potentes de ROCK | |
WO2017205709A1 (en) | Triazolones and tetrazolones as inhibitors of rock | |
ES2937039T3 (es) | Inhibidores diazaespiro de ROCK | |
EP3652165B1 (en) | Five membered-aminoheterocyclic and 5,6-or 6,6-membered bicyclic aminoheterocyclic inhibitors of rock for the treatment of heart failure | |
WO2015002926A1 (en) | Tricyclic pyrido-carboxamide derivatives as rock inhibitors |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 16703378 Country of ref document: EP Kind code of ref document: A1 |
|
REEP | Request for entry into the european phase |
Ref document number: 2016703378 Country of ref document: EP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 15541725 Country of ref document: US |
|
ENP | Entry into the national phase |
Ref document number: 2017536259 Country of ref document: JP Kind code of ref document: A |
|
NENP | Non-entry into the national phase |
Ref country code: DE |