WO2010036632A1 - Azaindazole compounds as ccr1 receptor antagonists - Google Patents
Azaindazole compounds as ccr1 receptor antagonists Download PDFInfo
- Publication number
- WO2010036632A1 WO2010036632A1 PCT/US2009/057778 US2009057778W WO2010036632A1 WO 2010036632 A1 WO2010036632 A1 WO 2010036632A1 US 2009057778 W US2009057778 W US 2009057778W WO 2010036632 A1 WO2010036632 A1 WO 2010036632A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- alkyl
- pyridine
- mmol
- pyrazolo
- fluorophenyl
- Prior art date
Links
- QRUDEWIWKLJBPS-UHFFFAOYSA-N benzotriazole Chemical class C1=CC=C2N[N][N]C2=C1 QRUDEWIWKLJBPS-UHFFFAOYSA-N 0.000 title description 3
- 239000002464 receptor antagonist Substances 0.000 title description 2
- 229940044551 receptor antagonist Drugs 0.000 title description 2
- 102000004500 CCR1 Receptors Human genes 0.000 title 1
- 108010017319 CCR1 Receptors Proteins 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 220
- 238000000034 method Methods 0.000 claims abstract description 108
- 201000006417 multiple sclerosis Diseases 0.000 claims abstract description 36
- 206010039073 rheumatoid arthritis Diseases 0.000 claims abstract description 14
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 280
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 124
- 238000006243 chemical reaction Methods 0.000 claims description 104
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 95
- 125000000217 alkyl group Chemical group 0.000 claims description 92
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 87
- -1 -C(O)NH2 Chemical group 0.000 claims description 80
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 62
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 59
- 229910052739 hydrogen Inorganic materials 0.000 claims description 57
- 239000001257 hydrogen Substances 0.000 claims description 57
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 53
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 51
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 41
- 150000002431 hydrogen Chemical class 0.000 claims description 39
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 38
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 36
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 36
- SECXISVLQFMRJM-UHFFFAOYSA-N NMP Substances CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 33
- 125000000623 heterocyclic group Chemical group 0.000 claims description 33
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 33
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 32
- 125000003545 alkoxy group Chemical group 0.000 claims description 29
- 229910052757 nitrogen Inorganic materials 0.000 claims description 29
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 25
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 24
- 239000002585 base Substances 0.000 claims description 23
- 125000003118 aryl group Chemical group 0.000 claims description 22
- 125000002252 acyl group Chemical group 0.000 claims description 21
- 150000003839 salts Chemical class 0.000 claims description 21
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 20
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 20
- 229910052736 halogen Inorganic materials 0.000 claims description 19
- 150000002367 halogens Chemical class 0.000 claims description 19
- 125000004043 oxo group Chemical group O=* 0.000 claims description 19
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 18
- 125000001072 heteroaryl group Chemical group 0.000 claims description 18
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 16
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 16
- 125000003386 piperidinyl group Chemical group 0.000 claims description 16
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 15
- 229910052799 carbon Inorganic materials 0.000 claims description 15
- 125000002757 morpholinyl group Chemical group 0.000 claims description 15
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 14
- 125000003282 alkyl amino group Chemical group 0.000 claims description 14
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 14
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 13
- 125000003342 alkenyl group Chemical group 0.000 claims description 13
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 12
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 12
- 230000008569 process Effects 0.000 claims description 12
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 claims description 11
- 150000001412 amines Chemical class 0.000 claims description 11
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 claims description 11
- 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 claims description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 10
- 239000002253 acid Substances 0.000 claims description 10
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 10
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 10
- VNDYJBBGRKZCSX-UHFFFAOYSA-L zinc bromide Chemical compound Br[Zn]Br VNDYJBBGRKZCSX-UHFFFAOYSA-L 0.000 claims description 10
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 9
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 9
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 9
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 9
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 8
- MHABMANUFPZXEB-UHFFFAOYSA-N O-demethyl-aloesaponarin I Natural products O=C1C2=CC=CC(O)=C2C(=O)C2=C1C=C(O)C(C(O)=O)=C2C MHABMANUFPZXEB-UHFFFAOYSA-N 0.000 claims description 8
- 229910006069 SO3H Inorganic materials 0.000 claims description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 8
- 125000004442 acylamino group Chemical group 0.000 claims description 8
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 8
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 8
- 229910052702 rhenium Inorganic materials 0.000 claims description 8
- 239000003880 polar aprotic solvent Substances 0.000 claims description 7
- 125000004076 pyridyl group Chemical group 0.000 claims description 7
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 6
- 229910052794 bromium Inorganic materials 0.000 claims description 6
- HUCVOHYBFXVBRW-UHFFFAOYSA-M caesium hydroxide Chemical compound [OH-].[Cs+] HUCVOHYBFXVBRW-UHFFFAOYSA-M 0.000 claims description 6
- 208000037976 chronic inflammation Diseases 0.000 claims description 6
- 230000006020 chronic inflammation Effects 0.000 claims description 6
- GUVUOGQBMYCBQP-UHFFFAOYSA-N dmpu Chemical compound CN1CCCN(C)C1=O GUVUOGQBMYCBQP-UHFFFAOYSA-N 0.000 claims description 6
- 239000002798 polar solvent Substances 0.000 claims description 6
- 125000006239 protecting group Chemical group 0.000 claims description 6
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 claims description 6
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 5
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 5
- 239000003153 chemical reaction reagent Substances 0.000 claims description 5
- 125000005879 dioxolanyl group Chemical group 0.000 claims description 5
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 5
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 5
- 239000012279 sodium borohydride Substances 0.000 claims description 5
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 5
- 125000000335 thiazolyl group Chemical group 0.000 claims description 5
- 125000001544 thienyl group Chemical group 0.000 claims description 5
- 229940102001 zinc bromide Drugs 0.000 claims description 5
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 4
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 4
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 4
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 claims description 4
- 125000004473 dialkylaminocarbonyl group Chemical group 0.000 claims description 4
- 239000012458 free base Substances 0.000 claims description 4
- 229910052740 iodine Inorganic materials 0.000 claims description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 4
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 4
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 4
- 125000006376 (C3-C10) cycloalkyl group Chemical group 0.000 claims description 3
- 239000007818 Grignard reagent Substances 0.000 claims description 3
- 150000004703 alkoxides Chemical class 0.000 claims description 3
- 125000002047 benzodioxolyl group Chemical group O1OC(C2=C1C=CC=C2)* 0.000 claims description 3
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 3
- 125000004619 benzopyranyl group Chemical group O1C(C=CC2=C1C=CC=C2)* 0.000 claims description 3
- 125000000532 dioxanyl group Chemical group 0.000 claims description 3
- 150000004795 grignard reagents Chemical class 0.000 claims description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 claims description 3
- 125000002883 imidazolyl group Chemical group 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- 125000004193 piperazinyl group Chemical group 0.000 claims description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 3
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 3
- 125000004568 thiomorpholinyl group Chemical group 0.000 claims description 3
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 2
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims description 2
- 230000003213 activating effect Effects 0.000 claims description 2
- 125000004457 alkyl amino carbonyl group Chemical group 0.000 claims description 2
- 125000004414 alkyl thio group Chemical group 0.000 claims description 2
- 125000005466 alkylenyl group Chemical group 0.000 claims description 2
- 239000000969 carrier Substances 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 125000006310 cycloalkyl amino group Chemical group 0.000 claims description 2
- 239000004210 ether based solvent Substances 0.000 claims description 2
- 150000003840 hydrochlorides Chemical class 0.000 claims description 2
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 2
- 230000001590 oxidative effect Effects 0.000 claims description 2
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 150000003457 sulfones Chemical class 0.000 claims description 2
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 claims description 2
- 208000024827 Alzheimer disease Diseases 0.000 claims 1
- 206010064539 Autoimmune myocarditis Diseases 0.000 claims 1
- 206010009900 Colitis ulcerative Diseases 0.000 claims 1
- 208000011231 Crohn disease Diseases 0.000 claims 1
- 206010012442 Dermatitis contact Diseases 0.000 claims 1
- 208000009329 Graft vs Host Disease Diseases 0.000 claims 1
- 208000035895 Guillain-Barré syndrome Diseases 0.000 claims 1
- 206010020751 Hypersensitivity Diseases 0.000 claims 1
- 208000022559 Inflammatory bowel disease Diseases 0.000 claims 1
- 206010049567 Miller Fisher syndrome Diseases 0.000 claims 1
- 201000004681 Psoriasis Diseases 0.000 claims 1
- 206010040047 Sepsis Diseases 0.000 claims 1
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 claims 1
- 201000006704 Ulcerative Colitis Diseases 0.000 claims 1
- 239000002671 adjuvant Substances 0.000 claims 1
- 230000007815 allergy Effects 0.000 claims 1
- 208000006673 asthma Diseases 0.000 claims 1
- 208000020832 chronic kidney disease Diseases 0.000 claims 1
- 208000010247 contact dermatitis Diseases 0.000 claims 1
- 208000024908 graft versus host disease Diseases 0.000 claims 1
- 201000000596 systemic lupus erythematosus Diseases 0.000 claims 1
- 208000037765 diseases and disorders Diseases 0.000 abstract description 5
- 230000000694 effects Effects 0.000 abstract description 5
- 208000023275 Autoimmune disease Diseases 0.000 abstract description 4
- 230000001404 mediated effect Effects 0.000 abstract description 3
- 230000002459 sustained effect Effects 0.000 abstract description 3
- 102100031172 C-C chemokine receptor type 1 Human genes 0.000 abstract 1
- 101710149814 C-C chemokine receptor type 1 Proteins 0.000 abstract 1
- TWBYWOBDOCUKOW-UHFFFAOYSA-N isonicotinic acid Chemical compound OC(=O)C1=CC=NC=C1 TWBYWOBDOCUKOW-UHFFFAOYSA-N 0.000 description 746
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 563
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 351
- 239000000243 solution Substances 0.000 description 280
- 239000000203 mixture Substances 0.000 description 262
- 235000019439 ethyl acetate Nutrition 0.000 description 230
- 229920006395 saturated elastomer Polymers 0.000 description 133
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 121
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 120
- 239000012044 organic layer Substances 0.000 description 120
- 239000012267 brine Substances 0.000 description 114
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 114
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 113
- 239000007787 solid Substances 0.000 description 113
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 108
- 238000010898 silica gel chromatography Methods 0.000 description 104
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 90
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 89
- 229910052938 sodium sulfate Inorganic materials 0.000 description 89
- 230000015572 biosynthetic process Effects 0.000 description 84
- 238000003786 synthesis reaction Methods 0.000 description 83
- 235000011152 sodium sulphate Nutrition 0.000 description 82
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Substances CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 79
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 64
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 60
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 55
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 53
- 235000019270 ammonium chloride Nutrition 0.000 description 50
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 43
- 235000017557 sodium bicarbonate Nutrition 0.000 description 43
- 239000010410 layer Substances 0.000 description 42
- 239000013058 crude material Substances 0.000 description 38
- 239000002904 solvent Substances 0.000 description 38
- 235000019341 magnesium sulphate Nutrition 0.000 description 31
- DUWLIIPTRMQEAP-UHFFFAOYSA-N 2-methylpropane-2-sulfinic acid Chemical compound CC(C)(C)S(O)=O DUWLIIPTRMQEAP-UHFFFAOYSA-N 0.000 description 30
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 29
- 238000000746 purification Methods 0.000 description 29
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 27
- YKNZTUQUXUXTLE-UHFFFAOYSA-N [3-(trifluoromethyl)phenyl]methanamine Chemical compound NCC1=CC=CC(C(F)(F)F)=C1 YKNZTUQUXUXTLE-UHFFFAOYSA-N 0.000 description 27
- 239000000463 material Substances 0.000 description 27
- 238000004809 thin layer chromatography Methods 0.000 description 26
- 239000005909 Kieselgur Substances 0.000 description 25
- 239000000543 intermediate Substances 0.000 description 25
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 24
- 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 20
- 238000001914 filtration Methods 0.000 description 20
- 239000011541 reaction mixture Substances 0.000 description 20
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 18
- 238000010992 reflux Methods 0.000 description 18
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 16
- 239000000741 silica gel Substances 0.000 description 16
- 229910002027 silica gel Inorganic materials 0.000 description 16
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 15
- 239000002002 slurry Substances 0.000 description 14
- 238000003756 stirring Methods 0.000 description 14
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 12
- 239000003921 oil Substances 0.000 description 12
- 239000012071 phase Substances 0.000 description 12
- 229910000027 potassium carbonate Inorganic materials 0.000 description 12
- 239000000047 product Substances 0.000 description 12
- VXUYXOFXAQZZMF-UHFFFAOYSA-N titanium(IV) isopropoxide Chemical compound CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C VXUYXOFXAQZZMF-UHFFFAOYSA-N 0.000 description 12
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 11
- 150000001408 amides Chemical class 0.000 description 11
- 239000012074 organic phase Substances 0.000 description 11
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 10
- 239000003054 catalyst Substances 0.000 description 10
- RGSFGYAAUTVSQA-UHFFFAOYSA-N pentamethylene Natural products C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 10
- 239000007858 starting material Substances 0.000 description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- 125000004432 carbon atom Chemical group C* 0.000 description 9
- 229960004132 diethyl ether Drugs 0.000 description 9
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical class CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 9
- 239000000706 filtrate Substances 0.000 description 9
- YCCXQARVHOPWFJ-UHFFFAOYSA-M magnesium;ethane;chloride Chemical compound [Mg+2].[Cl-].[CH2-]C YCCXQARVHOPWFJ-UHFFFAOYSA-M 0.000 description 9
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 description 9
- 239000000725 suspension Substances 0.000 description 9
- NKOMETMTMXTMLP-UHFFFAOYSA-N (2-methylsulfonylphenyl)methanamine Chemical compound CS(=O)(=O)C1=CC=CC=C1CN NKOMETMTMXTMLP-UHFFFAOYSA-N 0.000 description 8
- CESUXLKAADQNTB-SSDOTTSWSA-N 2-methylpropane-2-sulfinamide Chemical compound CC(C)(C)[S@](N)=O CESUXLKAADQNTB-SSDOTTSWSA-N 0.000 description 8
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 8
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 8
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- 239000000460 chlorine Substances 0.000 description 8
- 238000010168 coupling process Methods 0.000 description 8
- 239000012043 crude product Substances 0.000 description 8
- 238000000589 high-performance liquid chromatography-mass spectrometry Methods 0.000 description 8
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 description 8
- 238000002360 preparation method Methods 0.000 description 8
- 230000009467 reduction Effects 0.000 description 8
- 238000006722 reduction reaction Methods 0.000 description 8
- 238000005406 washing Methods 0.000 description 8
- 108010012236 Chemokines Proteins 0.000 description 7
- 102000019034 Chemokines Human genes 0.000 description 7
- 239000007832 Na2SO4 Substances 0.000 description 7
- 239000005557 antagonist Substances 0.000 description 7
- 239000008346 aqueous phase Substances 0.000 description 7
- 239000007864 aqueous solution Substances 0.000 description 7
- 125000004429 atom Chemical group 0.000 description 7
- 230000008878 coupling Effects 0.000 description 7
- 238000005859 coupling reaction Methods 0.000 description 7
- 229910052760 oxygen Inorganic materials 0.000 description 7
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 7
- 239000002244 precipitate Substances 0.000 description 7
- 229910000029 sodium carbonate Inorganic materials 0.000 description 7
- LYPGDCWPTHTUDO-UHFFFAOYSA-M sodium;methanesulfinate Chemical compound [Na+].CS([O-])=O LYPGDCWPTHTUDO-UHFFFAOYSA-M 0.000 description 7
- 229910052717 sulfur Inorganic materials 0.000 description 7
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 6
- JGVINVAAUOPFDU-UHFFFAOYSA-N 1-piperidin-3-ylpropan-1-amine Chemical compound CCC(N)C1CCCNC1 JGVINVAAUOPFDU-UHFFFAOYSA-N 0.000 description 6
- RLDRYZYRJQNINL-UHFFFAOYSA-N 2-[4-(aminomethyl)pyridin-2-yl]sulfonylacetamide Chemical compound NCC1=CC=NC(S(=O)(=O)CC(N)=O)=C1 RLDRYZYRJQNINL-UHFFFAOYSA-N 0.000 description 6
- CMRXYDXPWRQUET-FVGYRXGTSA-N Cl.CS(=O)(=O)N1CC=C(C=C1OC)[C@H](CC)N Chemical compound Cl.CS(=O)(=O)N1CC=C(C=C1OC)[C@H](CC)N CMRXYDXPWRQUET-FVGYRXGTSA-N 0.000 description 6
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 6
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 6
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 6
- 239000013543 active substance Substances 0.000 description 6
- 239000012298 atmosphere Substances 0.000 description 6
- 210000004027 cell Anatomy 0.000 description 6
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 6
- 239000006260 foam Substances 0.000 description 6
- 210000002540 macrophage Anatomy 0.000 description 6
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 6
- 238000004007 reversed phase HPLC Methods 0.000 description 6
- 229910000104 sodium hydride Inorganic materials 0.000 description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
- FOFSBPLAZXHMPI-JEDNCBNOSA-N (1s)-1-(2-methylsulfonyl-1,3-thiazol-5-yl)propan-1-amine;hydrochloride Chemical compound Cl.CC[C@H](N)C1=CN=C(S(C)(=O)=O)S1 FOFSBPLAZXHMPI-JEDNCBNOSA-N 0.000 description 5
- GGZVEDKJWCLFKD-RGMNGODLSA-N (1s)-1-(5-methylsulfonylfuran-2-yl)propan-1-amine;hydrochloride Chemical compound Cl.CC[C@H](N)C1=CC=C(S(C)(=O)=O)O1 GGZVEDKJWCLFKD-RGMNGODLSA-N 0.000 description 5
- JZLXHPPZGZESTM-UHFFFAOYSA-N (2-bromo-1,3-thiazol-5-yl)methanamine Chemical compound NCC1=CN=C(Br)S1 JZLXHPPZGZESTM-UHFFFAOYSA-N 0.000 description 5
- DMVKZJOQLIFNMA-UHFFFAOYSA-N (6-ethylsulfonylpyridin-3-yl)methanamine Chemical compound CCS(=O)(=O)C1=CC=C(CN)C=N1 DMVKZJOQLIFNMA-UHFFFAOYSA-N 0.000 description 5
- RBFQJKDFLGAFME-VIFPVBQESA-N 4-[(1S)-1-aminopropyl]pyridine-2-carbonitrile Chemical compound CC[C@H](N)C1=CC=NC(C#N)=C1 RBFQJKDFLGAFME-VIFPVBQESA-N 0.000 description 5
- MLBUKBRLBUVETP-UHFFFAOYSA-N 4-bromo-1-(4-fluorophenyl)pyrazolo[3,4-c]pyridine Chemical compound C1=CC(F)=CC=C1N1C2=CN=CC(Br)=C2C=N1 MLBUKBRLBUVETP-UHFFFAOYSA-N 0.000 description 5
- DQXUDNZRXXBMNW-UHFFFAOYSA-N 5-(aminomethyl)-N-(2-methoxyethyl)pyridine-2-sulfonamide Chemical compound COCCNS(=O)(=O)C1=CC=C(CN)C=N1 DQXUDNZRXXBMNW-UHFFFAOYSA-N 0.000 description 5
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 5
- 101000577064 Lymnaea stagnalis Molluscan insulin-related peptide 1 Proteins 0.000 description 5
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 5
- 101000737895 Mytilus edulis Contraction-inhibiting peptide 1 Proteins 0.000 description 5
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Substances CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 5
- 229960000583 acetic acid Drugs 0.000 description 5
- 229910052786 argon Inorganic materials 0.000 description 5
- SRCZQMGIVIYBBJ-UHFFFAOYSA-N ethoxyethane;ethyl acetate Chemical compound CCOCC.CCOC(C)=O SRCZQMGIVIYBBJ-UHFFFAOYSA-N 0.000 description 5
- 239000012065 filter cake Substances 0.000 description 5
- 125000005842 heteroatom Chemical group 0.000 description 5
- 238000005984 hydrogenation reaction Methods 0.000 description 5
- 210000000265 leukocyte Anatomy 0.000 description 5
- 239000003446 ligand Substances 0.000 description 5
- FRIJBUGBVQZNTB-UHFFFAOYSA-M magnesium;ethane;bromide Chemical compound [Mg+2].[Br-].[CH2-]C FRIJBUGBVQZNTB-UHFFFAOYSA-M 0.000 description 5
- 239000002480 mineral oil Substances 0.000 description 5
- 235000010446 mineral oil Nutrition 0.000 description 5
- BSNXQQDVXGEJLQ-UHFFFAOYSA-N n-[5-(aminomethyl)pyrimidin-2-yl]-n-methylacetamide Chemical compound CC(=O)N(C)C1=NC=C(CN)C=N1 BSNXQQDVXGEJLQ-UHFFFAOYSA-N 0.000 description 5
- 239000000651 prodrug Substances 0.000 description 5
- 229940002612 prodrug Drugs 0.000 description 5
- 239000001632 sodium acetate Substances 0.000 description 5
- 235000017281 sodium acetate Nutrition 0.000 description 5
- HHVIBTZHLRERCL-UHFFFAOYSA-N sulfonyldimethane Chemical class CS(C)(=O)=O HHVIBTZHLRERCL-UHFFFAOYSA-N 0.000 description 5
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Substances C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 5
- NOBQXALVAMEVCC-YFKPBYRVSA-N (1S)-1-(1H-pyrazol-5-yl)propan-1-amine Chemical compound CC[C@H](N)C1=CC=NN1 NOBQXALVAMEVCC-YFKPBYRVSA-N 0.000 description 4
- ODMDCJRLFVPKGL-OADYLZGLSA-N (1S)-1-(2-methylsulfinylpyridin-4-yl)propan-1-amine Chemical compound CC[C@H](N)C1=CC=NC(S(C)=O)=C1 ODMDCJRLFVPKGL-OADYLZGLSA-N 0.000 description 4
- IGWKEWMLYSVJNC-ZETCQYMHSA-N (1s)-1-(2-bromopyridin-4-yl)propan-1-amine Chemical compound CC[C@H](N)C1=CC=NC(Br)=C1 IGWKEWMLYSVJNC-ZETCQYMHSA-N 0.000 description 4
- SXQRTSYTHHDLLS-QMMMGPOBSA-N (1s)-1-(2-methylsulfonylpyridin-4-yl)propan-1-amine Chemical compound CC[C@H](N)C1=CC=NC(S(C)(=O)=O)=C1 SXQRTSYTHHDLLS-QMMMGPOBSA-N 0.000 description 4
- NEUQGOWESXXVOM-QRPNPIFTSA-N (1s)-1-(2-methylsulfonylpyridin-4-yl)propan-1-amine;hydrochloride Chemical compound Cl.CC[C@H](N)C1=CC=NC(S(C)(=O)=O)=C1 NEUQGOWESXXVOM-QRPNPIFTSA-N 0.000 description 4
- FICNPXSWEDIGAX-UHFFFAOYSA-N (2-methylsulfonylpyridin-4-yl)methanamine;hydrochloride Chemical compound Cl.CS(=O)(=O)C1=CC(CN)=CC=N1 FICNPXSWEDIGAX-UHFFFAOYSA-N 0.000 description 4
- DCXKBZUYPJJKCB-UHFFFAOYSA-N (2-morpholin-4-ylpyrimidin-4-yl)methanamine Chemical compound NCC1=CC=NC(N2CCOCC2)=N1 DCXKBZUYPJJKCB-UHFFFAOYSA-N 0.000 description 4
- AMCICDDTKARWJB-UHFFFAOYSA-N (6-bromopyridin-3-yl)methanamine Chemical compound NCC1=CC=C(Br)N=C1 AMCICDDTKARWJB-UHFFFAOYSA-N 0.000 description 4
- KMONYXIECSWHNO-UHFFFAOYSA-N (6-methylsulfonylpyridin-3-yl)methanamine Chemical compound CS(=O)(=O)C1=CC=C(CN)C=N1 KMONYXIECSWHNO-UHFFFAOYSA-N 0.000 description 4
- 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 4
- SYPALRBQWMOMQF-UHFFFAOYSA-N 1-[4-(aminomethyl)phenyl]sulfonylpiperidin-4-ol Chemical compound C1=CC(CN)=CC=C1S(=O)(=O)N1CCC(O)CC1 SYPALRBQWMOMQF-UHFFFAOYSA-N 0.000 description 4
- PGTBHSYUXFFPOM-UHFFFAOYSA-N 3-[4-(aminomethyl)pyridin-2-yl]sulfonylpropan-1-ol Chemical compound NCC1=CC=NC(S(=O)(=O)CCCO)=C1 PGTBHSYUXFFPOM-UHFFFAOYSA-N 0.000 description 4
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 4
- RNPLGNJZSCWHEO-UHFFFAOYSA-N 4-(aminomethyl)pyridine-2-sulfonamide Chemical compound NCC1=CC=NC(S(N)(=O)=O)=C1 RNPLGNJZSCWHEO-UHFFFAOYSA-N 0.000 description 4
- WDYCTNREUCFIMN-QMMMGPOBSA-N 4-[(1S)-1-aminopropyl]-N-methylpyridin-2-amine Chemical compound CC[C@H](N)C1=CC=NC(NC)=C1 WDYCTNREUCFIMN-QMMMGPOBSA-N 0.000 description 4
- BKXOSAHIRXLDIK-WTIBDHCWSA-N 4-[(1S)-1-aminopropyl]piperidine-2-carboxamide Chemical compound CC[C@H](N)C1CCNC(C(N)=O)C1 BKXOSAHIRXLDIK-WTIBDHCWSA-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
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 description 4
- 208000009386 Experimental Arthritis Diseases 0.000 description 4
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 4
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 4
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 4
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 4
- 238000011161 development Methods 0.000 description 4
- WBKFWQBXFREOFH-UHFFFAOYSA-N dichloromethane;ethyl acetate Chemical compound ClCCl.CCOC(C)=O WBKFWQBXFREOFH-UHFFFAOYSA-N 0.000 description 4
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 4
- 239000008241 heterogeneous mixture Substances 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 150000002576 ketones Chemical class 0.000 description 4
- 238000012986 modification Methods 0.000 description 4
- 230000004048 modification Effects 0.000 description 4
- 239000001301 oxygen Substances 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- 229940086542 triethylamine Drugs 0.000 description 4
- ONDSBJMLAHVLMI-UHFFFAOYSA-N trimethylsilyldiazomethane Chemical compound C[Si](C)(C)[CH-][N+]#N ONDSBJMLAHVLMI-UHFFFAOYSA-N 0.000 description 4
- CFDYVHXWOBOSRE-LURJTMIESA-N (1S)-1-(1-methylsulfonylpyrazol-3-yl)propan-1-amine Chemical compound CC[C@H](N)C=1C=CN(S(C)(=O)=O)N=1 CFDYVHXWOBOSRE-LURJTMIESA-N 0.000 description 3
- QKDIDSBUEUVCHW-JTQLQIEISA-N (1S)-1-(2-ethylsulfonylpyridin-4-yl)butan-1-amine Chemical compound CCC[C@H](N)C1=CC=NC(S(=O)(=O)CC)=C1 QKDIDSBUEUVCHW-JTQLQIEISA-N 0.000 description 3
- AUPBPNANCOLJNK-YFKPBYRVSA-N (1S)-1-(2-methylsulfonyl-1,3-oxazol-5-yl)propan-1-amine Chemical compound CC[C@H](N)C1=CN=C(S(C)(=O)=O)O1 AUPBPNANCOLJNK-YFKPBYRVSA-N 0.000 description 3
- KCZCHUWSKGQMBN-ZETCQYMHSA-N (1S)-1-[2-(2H-tetrazol-5-yl)pyridin-4-yl]propan-1-amine Chemical compound CC[C@H](N)C1=CC=NC(C2=NNN=N2)=C1 KCZCHUWSKGQMBN-ZETCQYMHSA-N 0.000 description 3
- YKGZPHYTHVAUGN-YFKPBYRVSA-N (1s)-1-(1,3-thiazol-2-yl)propan-1-amine Chemical compound CC[C@H](N)C1=NC=CS1 YKGZPHYTHVAUGN-YFKPBYRVSA-N 0.000 description 3
- LNGVROOPSOPLSG-LURJTMIESA-N (1s)-1-(1h-pyrazol-4-yl)propan-1-amine Chemical compound CC[C@H](N)C=1C=NNC=1 LNGVROOPSOPLSG-LURJTMIESA-N 0.000 description 3
- ALZVWDSQYIZYRH-ZETCQYMHSA-N (1s)-1-(2-chloro-6-methylsulfonylpyridin-4-yl)propan-1-amine Chemical compound CC[C@H](N)C1=CC(Cl)=NC(S(C)(=O)=O)=C1 ALZVWDSQYIZYRH-ZETCQYMHSA-N 0.000 description 3
- SCNDLQRJVYYSGD-JEDNCBNOSA-N (1s)-1-(2-methylsulfonyl-1,3-oxazol-5-yl)propan-1-amine;hydrochloride Chemical compound Cl.CC[C@H](N)C1=CN=C(S(C)(=O)=O)O1 SCNDLQRJVYYSGD-JEDNCBNOSA-N 0.000 description 3
- LWQSZEJKKNHTNA-LURJTMIESA-N (1s)-1-(2-methylsulfonylpyridin-4-yl)ethanamine Chemical compound C[C@H](N)C1=CC=NC(S(C)(=O)=O)=C1 LWQSZEJKKNHTNA-LURJTMIESA-N 0.000 description 3
- AURJXOUBZDAZKR-RGMNGODLSA-N (1s)-1-(2-methylsulfonylpyridin-4-yl)ethanamine;hydrochloride Chemical compound Cl.C[C@H](N)C1=CC=NC(S(C)(=O)=O)=C1 AURJXOUBZDAZKR-RGMNGODLSA-N 0.000 description 3
- QALMRYJAYMTZHK-WCCKRBBISA-N (1s)-1-(3-bromo-1,2-oxazol-5-yl)propan-1-amine;hydrochloride Chemical compound Cl.CC[C@H](N)C1=CC(Br)=NO1 QALMRYJAYMTZHK-WCCKRBBISA-N 0.000 description 3
- CBLACADWERZJNF-FJXQXJEOSA-N (1s)-1-(4-bromopyridin-2-yl)propan-1-amine;hydrochloride Chemical compound Cl.CC[C@H](N)C1=CC(Br)=CC=N1 CBLACADWERZJNF-FJXQXJEOSA-N 0.000 description 3
- BYBBINFCDKWYGU-KLXURFKVSA-N (1s)-1-(6-bromopyridin-3-yl)propan-1-amine;dihydrochloride Chemical compound Cl.Cl.CC[C@H](N)C1=CC=C(Br)N=C1 BYBBINFCDKWYGU-KLXURFKVSA-N 0.000 description 3
- JWUZBESCMDKWCP-UHFFFAOYSA-N (2-methoxy-1,3-thiazol-5-yl)methanamine Chemical compound COC1=NC=C(CN)S1 JWUZBESCMDKWCP-UHFFFAOYSA-N 0.000 description 3
- JDXXHVSRKHJAQD-UHFFFAOYSA-N (2-methylsulfonylpyridin-4-yl)methanamine Chemical compound CS(=O)(=O)C1=CC(CN)=CC=N1 JDXXHVSRKHJAQD-UHFFFAOYSA-N 0.000 description 3
- NMHAVROYYDYQHN-UHFFFAOYSA-N (2-morpholin-4-yl-1,3-thiazol-5-yl)methanamine Chemical compound S1C(CN)=CN=C1N1CCOCC1 NMHAVROYYDYQHN-UHFFFAOYSA-N 0.000 description 3
- FEKUXLUOKFSMRO-UHFFFAOYSA-N (4-fluorophenyl)hydrazine;hydron;chloride Chemical compound Cl.NNC1=CC=C(F)C=C1 FEKUXLUOKFSMRO-UHFFFAOYSA-N 0.000 description 3
- XEHNFWVIZMCCBK-UHFFFAOYSA-N (5-methylsulfonylpyridin-2-yl)methanamine Chemical compound CS(=O)(=O)C1=CC=C(CN)N=C1 XEHNFWVIZMCCBK-UHFFFAOYSA-N 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 3
- RTWLIQFKXMWEJY-UHFFFAOYSA-N 2-bromopyridine-4-carbaldehyde Chemical compound BrC1=CC(C=O)=CC=N1 RTWLIQFKXMWEJY-UHFFFAOYSA-N 0.000 description 3
- YTIUYASFFCEBLV-UHFFFAOYSA-N 2-ethoxy-6-methylsulfonylpyridine-4-carboxylic acid Chemical compound CCOC1=CC(C(O)=O)=CC(S(C)(=O)=O)=N1 YTIUYASFFCEBLV-UHFFFAOYSA-N 0.000 description 3
- YKZYEUAXINVCEK-UHFFFAOYSA-N 2-methylsulfanyl-1,3-oxazole-5-carboxylic acid Chemical compound CSC1=NC=C(C(O)=O)O1 YKZYEUAXINVCEK-UHFFFAOYSA-N 0.000 description 3
- WPBYVMDYYFWYAY-UHFFFAOYSA-N 3,5-dibromopyridine-4-carbaldehyde Chemical compound BrC1=CN=CC(Br)=C1C=O WPBYVMDYYFWYAY-UHFFFAOYSA-N 0.000 description 3
- DXALCZRZTHZBIB-UHFFFAOYSA-N 4-(aminomethyl)-n-methylbenzenesulfonamide Chemical compound CNS(=O)(=O)C1=CC=C(CN)C=C1 DXALCZRZTHZBIB-UHFFFAOYSA-N 0.000 description 3
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 3
- WXZDLJAXXKSDHS-UHFFFAOYSA-N 5-(aminomethyl)-2-(dimethylsulfamoylamino)pyridine;dihydrochloride Chemical compound Cl.Cl.CN(C)S(=O)(=O)NC1=CC=C(CN)C=N1 WXZDLJAXXKSDHS-UHFFFAOYSA-N 0.000 description 3
- JMSPZARJFRBNRU-UHFFFAOYSA-N 5-(aminomethyl)-n-methyl-1,3-thiazol-2-amine Chemical compound CNC1=NC=C(CN)S1 JMSPZARJFRBNRU-UHFFFAOYSA-N 0.000 description 3
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 3
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
- 239000012448 Lithium borohydride Substances 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- AHJMPPSXRPYIIX-JTQLQIEISA-N N-[4-[(1S)-1-aminopropyl]pyridin-2-yl]-N-methylacetamide Chemical compound CC[C@H](N)C1=CC=NC(N(C)C(C)=O)=C1 AHJMPPSXRPYIIX-JTQLQIEISA-N 0.000 description 3
- SLAGXVLJOFBDRY-UHFFFAOYSA-N N-[5-(aminomethyl)-1,3-thiazol-2-yl]-N-methylacetamide Chemical compound CC(=O)N(C)C1=NC=C(CN)S1 SLAGXVLJOFBDRY-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 3
- 210000001744 T-lymphocyte Anatomy 0.000 description 3
- OUEZCWWPLCSVTK-VIFPVBQESA-N [4-[(1S)-1-aminopropyl]pyridin-2-yl]methanol Chemical compound CC[C@H](N)C1=CC=NC(CO)=C1 OUEZCWWPLCSVTK-VIFPVBQESA-N 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 3
- 125000001246 bromo group Chemical group Br* 0.000 description 3
- 229910002091 carbon monoxide Inorganic materials 0.000 description 3
- 125000001309 chloro group Chemical group Cl* 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 150000001879 copper Chemical class 0.000 description 3
- 150000004985 diamines Chemical class 0.000 description 3
- ZFTFAPZRGNKQPU-UHFFFAOYSA-N dicarbonic acid Chemical compound OC(=O)OC(O)=O ZFTFAPZRGNKQPU-UHFFFAOYSA-N 0.000 description 3
- 230000008034 disappearance Effects 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 239000000284 extract Substances 0.000 description 3
- 239000011737 fluorine Substances 0.000 description 3
- 229910052731 fluorine Inorganic materials 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- 230000007062 hydrolysis Effects 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 3
- NXPHGHWWQRMDIA-UHFFFAOYSA-M magnesium;carbanide;bromide Chemical compound [CH3-].[Mg+2].[Br-] NXPHGHWWQRMDIA-UHFFFAOYSA-M 0.000 description 3
- 229940098779 methanesulfonic acid Drugs 0.000 description 3
- KVKFRMCSXWQSNT-UHFFFAOYSA-N n,n'-dimethylethane-1,2-diamine Chemical compound CNCCNC KVKFRMCSXWQSNT-UHFFFAOYSA-N 0.000 description 3
- WJIBFJGHHNLCRV-UHFFFAOYSA-N n-[4-(aminomethyl)pyridin-2-yl]methanesulfonamide Chemical compound CS(=O)(=O)NC1=CC(CN)=CC=N1 WJIBFJGHHNLCRV-UHFFFAOYSA-N 0.000 description 3
- JPZKJABGOSPYDD-UHFFFAOYSA-N n-benzylmethanesulfonamide Chemical compound CS(=O)(=O)NCC1=CC=CC=C1 JPZKJABGOSPYDD-UHFFFAOYSA-N 0.000 description 3
- 230000003647 oxidation Effects 0.000 description 3
- 238000007254 oxidation reaction Methods 0.000 description 3
- RMBAVIFYHOYIFM-UHFFFAOYSA-M sodium methanethiolate Chemical compound [Na+].[S-]C RMBAVIFYHOYIFM-UHFFFAOYSA-M 0.000 description 3
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 3
- 239000011593 sulfur Substances 0.000 description 3
- 230000032258 transport Effects 0.000 description 3
- LEIMLDGFXIOXMT-UHFFFAOYSA-N trimethylsilyl cyanide Chemical compound C[Si](C)(C)C#N LEIMLDGFXIOXMT-UHFFFAOYSA-N 0.000 description 3
- 239000011701 zinc Substances 0.000 description 3
- CWZWKFRHZFPUHE-SNVBAGLBSA-N (1R)-1-(1-methylsulfonyl-2H-pyridin-4-yl)but-3-en-1-amine Chemical compound CS(=O)(=O)N1CC=C([C@H](N)CC=C)C=C1 CWZWKFRHZFPUHE-SNVBAGLBSA-N 0.000 description 2
- ARPSGZGRLARDJP-NSHDSACASA-N (1S)-1-(1-ethylsulfonyl-2H-pyridin-4-yl)but-3-en-1-amine Chemical compound CCS(=O)(=O)N1CC=C([C@@H](N)CC=C)C=C1 ARPSGZGRLARDJP-NSHDSACASA-N 0.000 description 2
- RMZLGGWRKJDTJL-VIFPVBQESA-N (1S)-1-(1-methylsulfonyl-2H-pyridin-4-yl)propan-1-amine Chemical compound CC[C@H](N)C1=CCN(S(C)(=O)=O)C=C1 RMZLGGWRKJDTJL-VIFPVBQESA-N 0.000 description 2
- TWEDJCMLSOBEHA-QMMMGPOBSA-N (1S)-3-azido-1-(2-methylsulfonylpyridin-4-yl)propan-1-amine Chemical compound CS(C1=NC=CC([C@H](CCN=[N+]=[N-])N)=C1)(=O)=O TWEDJCMLSOBEHA-QMMMGPOBSA-N 0.000 description 2
- HFGYPNPJZVMKSN-LURJTMIESA-N (1s)-1-(3-methylimidazol-4-yl)propan-1-amine Chemical compound CC[C@H](N)C1=CN=CN1C HFGYPNPJZVMKSN-LURJTMIESA-N 0.000 description 2
- PSBQUGWKNNAMFQ-ZETCQYMHSA-N (1s)-1-(4-bromopyridin-2-yl)propan-1-amine Chemical compound CC[C@H](N)C1=CC(Br)=CC=N1 PSBQUGWKNNAMFQ-ZETCQYMHSA-N 0.000 description 2
- WZUKLOGEMLKUOT-ZDUSSCGKSA-N (1s)-1-[4-bromo-1-(4-methylphenyl)sulfonylpyrrol-2-yl]propan-1-amine Chemical compound CC[C@H](N)C1=CC(Br)=CN1S(=O)(=O)C1=CC=C(C)C=C1 WZUKLOGEMLKUOT-ZDUSSCGKSA-N 0.000 description 2
- BDYCNXLYRGFBFC-UHFFFAOYSA-N (2-bromo-6-methylpyridin-4-yl)methanol Chemical compound CC1=CC(CO)=CC(Br)=N1 BDYCNXLYRGFBFC-UHFFFAOYSA-N 0.000 description 2
- VIEDTXGWMQTPOE-UHFFFAOYSA-N (2-bromo-6-methylpyridin-4-yl)methyl methanesulfonate Chemical compound CC1=CC(COS(C)(=O)=O)=CC(Br)=N1 VIEDTXGWMQTPOE-UHFFFAOYSA-N 0.000 description 2
- HQCSPTNCPFGJTF-UHFFFAOYSA-N (2-methoxy-6-methylsulfonylpyridin-4-yl)methanamine Chemical compound COC1=CC(CN)=CC(S(C)(=O)=O)=N1 HQCSPTNCPFGJTF-UHFFFAOYSA-N 0.000 description 2
- KZMXZTGEQNMAPD-VIFPVBQESA-N (3S)-3-amino-3-(1-methylsulfonyl-2H-pyridin-4-yl)propanal Chemical compound CS(=O)(=O)N1CC=C([C@@H](N)CC=O)C=C1 KZMXZTGEQNMAPD-VIFPVBQESA-N 0.000 description 2
- QPVVPWCIQWPUFP-QMMMGPOBSA-N (3S)-3-amino-3-(2-methylsulfonylpyridin-4-yl)propanal Chemical compound CS(=O)(=O)C1=CC([C@@H](N)CC=O)=CC=N1 QPVVPWCIQWPUFP-QMMMGPOBSA-N 0.000 description 2
- JXSAAGNZRIDNRF-UHFFFAOYSA-N 1-piperidin-4-ylpropan-1-amine Chemical compound CCC(N)C1CCNCC1 JXSAAGNZRIDNRF-UHFFFAOYSA-N 0.000 description 2
- XQIRYUNKLVPVRR-UHFFFAOYSA-N 2-(9h-fluoren-9-ylmethoxycarbonylamino)butanoic acid Chemical compound C1=CC=C2C(COC(=O)NC(CC)C(O)=O)C3=CC=CC=C3C2=C1 XQIRYUNKLVPVRR-UHFFFAOYSA-N 0.000 description 2
- HAZOZRAPGZDOEM-UHFFFAOYSA-N 2-aminoacetohydrazide Chemical compound NCC(=O)NN HAZOZRAPGZDOEM-UHFFFAOYSA-N 0.000 description 2
- YBTKGKVQEXAYEM-UHFFFAOYSA-N 2-bromopyridine-4-carboxylic acid Chemical compound OC(=O)C1=CC=NC(Br)=C1 YBTKGKVQEXAYEM-UHFFFAOYSA-N 0.000 description 2
- HXVQPZSXXYOZMP-UHFFFAOYSA-N 2-chloropyrimidine-4-carbonitrile Chemical compound ClC1=NC=CC(C#N)=N1 HXVQPZSXXYOZMP-UHFFFAOYSA-N 0.000 description 2
- YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 description 2
- BKOOMYPCSUNDGP-UHFFFAOYSA-N 2-methylbut-2-ene Chemical compound CC=C(C)C BKOOMYPCSUNDGP-UHFFFAOYSA-N 0.000 description 2
- BTIDLVRPONKKEW-UHFFFAOYSA-N 2-methylsulfanyl-1,3-oxazole-4-carboxylic acid Chemical compound CSC1=NC(C(O)=O)=CO1 BTIDLVRPONKKEW-UHFFFAOYSA-N 0.000 description 2
- BQLGCIUPZRALSH-UHFFFAOYSA-N 2-methylsulfonylpyridine-4-carbonitrile Chemical compound CS(=O)(=O)C1=CC(C#N)=CC=N1 BQLGCIUPZRALSH-UHFFFAOYSA-N 0.000 description 2
- BPCMRIKSZVZVFS-UHFFFAOYSA-N 2-morpholin-4-ylpyrimidine-4-carbonitrile Chemical compound N#CC1=CC=NC(N2CCOCC2)=N1 BPCMRIKSZVZVFS-UHFFFAOYSA-N 0.000 description 2
- HTEARWPJCCLJNC-UHFFFAOYSA-N 3-bromo-n-methoxy-n-methyl-1,2-oxazole-5-carboxamide Chemical compound CON(C)C(=O)C1=CC(Br)=NO1 HTEARWPJCCLJNC-UHFFFAOYSA-N 0.000 description 2
- MCSXGCZMEPXKIW-UHFFFAOYSA-N 3-hydroxy-4-[(4-methyl-2-nitrophenyl)diazenyl]-N-(3-nitrophenyl)naphthalene-2-carboxamide Chemical compound Cc1ccc(N=Nc2c(O)c(cc3ccccc23)C(=O)Nc2cccc(c2)[N+]([O-])=O)c(c1)[N+]([O-])=O MCSXGCZMEPXKIW-UHFFFAOYSA-N 0.000 description 2
- GBQZTLBKTHNSOA-UHFFFAOYSA-N 4-(azidomethyl)-2-bromo-6-methylpyridine Chemical compound CC1=CC(CN=[N+]=[N-])=CC(Br)=N1 GBQZTLBKTHNSOA-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
- NYMFHDKWQKHHGM-VIFPVBQESA-N 4-[(1S)-1-aminopropyl]pyridine-2-carbaldehyde Chemical compound CC[C@H](N)C1=CC=NC(C=O)=C1 NYMFHDKWQKHHGM-VIFPVBQESA-N 0.000 description 2
- KEFLQEPOGSJUGQ-IHBJSSOOSA-N 4-[(1s)-1-(tert-butylsulfinylamino)propyl]pyridine-2-carboxamide Chemical compound CC(C)(C)S(=O)N[C@@H](CC)C1=CC=NC(C(N)=O)=C1 KEFLQEPOGSJUGQ-IHBJSSOOSA-N 0.000 description 2
- APADMXVOFQRBNQ-ZETCQYMHSA-N 4-[(1s)-1-aminopropyl]pyridine-2-carboxamide Chemical compound CC[C@H](N)C1=CC=NC(C(N)=O)=C1 APADMXVOFQRBNQ-ZETCQYMHSA-N 0.000 description 2
- WKYVGBPCXOPWEA-UHFFFAOYSA-N 4-bromopyridine-3-carbaldehyde Chemical compound BrC1=CC=NC=C1C=O WKYVGBPCXOPWEA-UHFFFAOYSA-N 0.000 description 2
- AQGSHGIMRJORQX-UHFFFAOYSA-N 5-cyano-2-(dimethylsulfamoylamino)pyridine Chemical compound CN(C)S(=O)(=O)NC1=CC=C(C#N)C=N1 AQGSHGIMRJORQX-UHFFFAOYSA-N 0.000 description 2
- ZREDSSGHFVMCQP-UHFFFAOYSA-N 5-methylsulfonylfuran-2-carboxylic acid Chemical compound CS(=O)(=O)C1=CC=C(C(O)=O)O1 ZREDSSGHFVMCQP-UHFFFAOYSA-N 0.000 description 2
- WGTUUPXIIZIOLR-UHFFFAOYSA-N 5-methylsulfonylpyridine-2-carbonitrile Chemical compound CS(=O)(=O)C1=CC=C(C#N)N=C1 WGTUUPXIIZIOLR-UHFFFAOYSA-N 0.000 description 2
- PVUKGNBRJFTFNJ-UHFFFAOYSA-N 6-bromopyridine-3-carbaldehyde Chemical compound BrC1=CC=C(C=O)C=N1 PVUKGNBRJFTFNJ-UHFFFAOYSA-N 0.000 description 2
- 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 2
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- 102100032366 C-C motif chemokine 7 Human genes 0.000 description 2
- UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- 101000797758 Homo sapiens C-C motif chemokine 7 Proteins 0.000 description 2
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 2
- LGDSHSYDSCRFAB-UHFFFAOYSA-N Methyl isothiocyanate Chemical compound CN=C=S LGDSHSYDSCRFAB-UHFFFAOYSA-N 0.000 description 2
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-Chlorosuccinimide Substances ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 2
- 239000004677 Nylon Substances 0.000 description 2
- NBBJYMSMWIIQGU-UHFFFAOYSA-N Propionic aldehyde Chemical compound CCC=O NBBJYMSMWIIQGU-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 229910006124 SOCl2 Inorganic materials 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- DLUWESHYBOWGLE-QMMMGPOBSA-N [(1s)-1-(2-methylsulfonylpyridin-4-yl)propyl]carbamic acid Chemical compound OC(=O)N[C@@H](CC)C1=CC=NC(S(C)(=O)=O)=C1 DLUWESHYBOWGLE-QMMMGPOBSA-N 0.000 description 2
- IURCGXIROVPWGE-UHFFFAOYSA-N [4-(4-methylpiperazin-1-yl)sulfonylphenyl]methanamine Chemical compound C1CN(C)CCN1S(=O)(=O)C1=CC=C(CN)C=C1 IURCGXIROVPWGE-UHFFFAOYSA-N 0.000 description 2
- PYUOTLVQJLNVSW-UHFFFAOYSA-N [4-[(4-methylpiperazin-1-yl)sulfonylmethyl]phenyl]methanamine Chemical compound C1CN(C)CCN1S(=O)(=O)CC1=CC=C(CN)C=C1 PYUOTLVQJLNVSW-UHFFFAOYSA-N 0.000 description 2
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 150000001263 acyl chlorides Chemical class 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- LEAUNMLXEXRAJI-SLTAFYQDSA-N benzyl 4-[(1s)-1-aminopropyl]-2-carbamoylpiperidine-1-carboxylate Chemical compound NC(=O)C1CC([C@@H](N)CC)CCN1C(=O)OCC1=CC=CC=C1 LEAUNMLXEXRAJI-SLTAFYQDSA-N 0.000 description 2
- 125000002619 bicyclic group Chemical group 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- XNNQFQFUQLJSQT-UHFFFAOYSA-N bromo(trichloro)methane Chemical compound ClC(Cl)(Cl)Br XNNQFQFUQLJSQT-UHFFFAOYSA-N 0.000 description 2
- YSHOWEKUVWPFNR-UHFFFAOYSA-N burgess reagent Chemical compound CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC YSHOWEKUVWPFNR-UHFFFAOYSA-N 0.000 description 2
- KXZJHVJKXJLBKO-UHFFFAOYSA-N chembl1408157 Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=CC=1C1=CC=C(O)C=C1 KXZJHVJKXJLBKO-UHFFFAOYSA-N 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 239000012230 colorless oil Substances 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- SBTSVTLGWRLWOD-UHFFFAOYSA-L copper(ii) triflate Chemical compound [Cu+2].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F SBTSVTLGWRLWOD-UHFFFAOYSA-L 0.000 description 2
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 238000006073 displacement reaction Methods 0.000 description 2
- AQBJFVCKUVWMLP-UHFFFAOYSA-N ethyl 2-ethylsulfanyl-1,3-oxazole-5-carboxylate Chemical compound CCOC(=O)C1=CN=C(SCC)O1 AQBJFVCKUVWMLP-UHFFFAOYSA-N 0.000 description 2
- UREBWPXBXRYXRJ-UHFFFAOYSA-N ethyl acetate;methanol Chemical compound OC.CCOC(C)=O UREBWPXBXRYXRJ-UHFFFAOYSA-N 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 238000007429 general method Methods 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- 150000007857 hydrazones Chemical class 0.000 description 2
- SHFJWMWCIHQNCP-UHFFFAOYSA-M hydron;tetrabutylazanium;sulfate Chemical compound OS([O-])(=O)=O.CCCC[N+](CCCC)(CCCC)CCCC SHFJWMWCIHQNCP-UHFFFAOYSA-M 0.000 description 2
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 2
- 229910052744 lithium Inorganic materials 0.000 description 2
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 2
- 239000002207 metabolite Substances 0.000 description 2
- LCNJTEDEMZMQQD-DHUJRADRSA-N methyl (2r)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-3-tritylsulfanylpropanoate Chemical compound C([C@@H](C(=O)OC)NC(=O)OCC1C2=CC=CC=C2C2=CC=CC=C21)SC(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 LCNJTEDEMZMQQD-DHUJRADRSA-N 0.000 description 2
- DXUZZMIANHJYIU-NRFANRHFSA-N methyl (2r)-2-amino-3-tritylsulfanylpropanoate Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(SC[C@H](N)C(=O)OC)C1=CC=CC=C1 DXUZZMIANHJYIU-NRFANRHFSA-N 0.000 description 2
- DAPAXVAUEVRBGS-UHFFFAOYSA-N methyl 2-chloro-6-methoxypyridine-4-carboxylate Chemical compound COC(=O)C1=CC(Cl)=NC(OC)=C1 DAPAXVAUEVRBGS-UHFFFAOYSA-N 0.000 description 2
- CBIVNBJOYPWHPA-UHFFFAOYSA-N methyl 2-methoxy-6-methylsulfanylpyridine-4-carboxylate Chemical compound COC(=O)C1=CC(OC)=NC(SC)=C1 CBIVNBJOYPWHPA-UHFFFAOYSA-N 0.000 description 2
- FRCOQTNNXQOFFL-UHFFFAOYSA-N methyl 2-methoxy-6-methylsulfonylpyridine-4-carboxylate Chemical compound COC(=O)C1=CC(OC)=NC(S(C)(=O)=O)=C1 FRCOQTNNXQOFFL-UHFFFAOYSA-N 0.000 description 2
- QCYIHBHVYVAVIH-UHFFFAOYSA-N methyl 5-methylsulfonylfuran-2-carboxylate Chemical compound COC(=O)C1=CC=C(S(C)(=O)=O)O1 QCYIHBHVYVAVIH-UHFFFAOYSA-N 0.000 description 2
- 125000002950 monocyclic group Chemical group 0.000 description 2
- 210000001616 monocyte Anatomy 0.000 description 2
- JWIHKSSWKUAEAA-YOZOHBORSA-N n-[(1s)-1-(4-bromopyridin-2-yl)propyl]-2-methylpropane-2-sulfinamide Chemical compound CC(C)(C)S(=O)N[C@@H](CC)C1=CC(Br)=CC=N1 JWIHKSSWKUAEAA-YOZOHBORSA-N 0.000 description 2
- GZEADERJKNQLKP-UHFFFAOYSA-N n-[(3-bromo-1,2-oxazol-5-yl)methyl]-2-methylpropane-2-sulfinamide Chemical compound CC(C)(C)S(=O)NCC1=CC(Br)=NO1 GZEADERJKNQLKP-UHFFFAOYSA-N 0.000 description 2
- UROMJOYNMAGHJZ-UHFFFAOYSA-N n-[4-(aminomethyl)pyrimidin-2-yl]-n-methylmethanesulfonamide Chemical compound CS(=O)(=O)N(C)C1=NC=CC(CN)=N1 UROMJOYNMAGHJZ-UHFFFAOYSA-N 0.000 description 2
- SROXZVVAOOFECR-UHFFFAOYSA-N n-methoxy-n-methyl-5-methylsulfonylfuran-2-carboxamide Chemical compound CON(C)C(=O)C1=CC=C(S(C)(=O)=O)O1 SROXZVVAOOFECR-UHFFFAOYSA-N 0.000 description 2
- 125000001624 naphthyl group Chemical group 0.000 description 2
- 125000006574 non-aromatic ring group Chemical group 0.000 description 2
- 229920001778 nylon Polymers 0.000 description 2
- 239000008188 pellet Substances 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- GPHQHTOMRSGBNZ-UHFFFAOYSA-N pyridine-4-carbonitrile Chemical compound N#CC1=CC=NC=C1 GPHQHTOMRSGBNZ-UHFFFAOYSA-N 0.000 description 2
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- 238000004366 reverse phase liquid chromatography Methods 0.000 description 2
- YBCAZPLXEGKKFM-UHFFFAOYSA-K ruthenium(iii) chloride Chemical compound [Cl-].[Cl-].[Cl-].[Ru+3] YBCAZPLXEGKKFM-UHFFFAOYSA-K 0.000 description 2
- 150000003384 small molecules Chemical class 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- HCQHANLFBAKUFB-UHFFFAOYSA-N tert-butyl n-(1h-pyrrolo[2,3-b]pyridin-4-ylmethyl)carbamate Chemical compound CC(C)(C)OC(=O)NCC1=CC=NC2=C1C=CN2 HCQHANLFBAKUFB-UHFFFAOYSA-N 0.000 description 2
- OPPPHASXHULEJN-UHFFFAOYSA-N tert-butyl n-[(1-methylsulfonylpyrrolo[2,3-b]pyridin-4-yl)methyl]carbamate Chemical compound CC(C)(C)OC(=O)NCC1=CC=NC2=C1C=CN2S(C)(=O)=O OPPPHASXHULEJN-UHFFFAOYSA-N 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 2
- AQLJVWUFPCUVLO-UHFFFAOYSA-N urea hydrogen peroxide Chemical compound OO.NC(N)=O AQLJVWUFPCUVLO-UHFFFAOYSA-N 0.000 description 2
- 238000010200 validation analysis Methods 0.000 description 2
- GTLDTDOJJJZVBW-UHFFFAOYSA-N zinc cyanide Chemical compound [Zn+2].N#[C-].N#[C-] GTLDTDOJJJZVBW-UHFFFAOYSA-N 0.000 description 2
- SSXDUSOCSNXBPO-UHFFFAOYSA-N (1-methylpyrazol-3-yl)methanamine Chemical compound CN1C=CC(CN)=N1 SSXDUSOCSNXBPO-UHFFFAOYSA-N 0.000 description 1
- KFTRXTSNTQSGNE-UHFFFAOYSA-N (1-methylpyrazol-4-yl)methanamine Chemical compound CN1C=C(CN)C=N1 KFTRXTSNTQSGNE-UHFFFAOYSA-N 0.000 description 1
- DVAZZKFSPKQNJE-UHFFFAOYSA-N (1-methylsulfonylpyrrolo[2,3-b]pyridin-4-yl)methanamine Chemical compound C1=CN=C2N(S(=O)(=O)C)C=CC2=C1CN DVAZZKFSPKQNJE-UHFFFAOYSA-N 0.000 description 1
- LNGVROOPSOPLSG-ZCFIWIBFSA-N (1R)-1-(1H-pyrazol-4-yl)propan-1-amine Chemical compound CC[C@@H](N)C=1C=NNC=1 LNGVROOPSOPLSG-ZCFIWIBFSA-N 0.000 description 1
- VFMIHVVOGMTJTK-MRVPVSSYSA-N (1R)-1-(2-bromopyridin-4-yl)but-3-en-1-amine Chemical compound C=CC[C@@H](N)C1=CC=NC(Br)=C1 VFMIHVVOGMTJTK-MRVPVSSYSA-N 0.000 description 1
- VAZRQGHMFAFFJF-SNVBAGLBSA-N (1R)-1-(4-methoxy-3-methylsulfonylphenyl)butan-1-amine Chemical compound CCC[C@@H](N)C1=CC=C(OC)C(S(C)(=O)=O)=C1 VAZRQGHMFAFFJF-SNVBAGLBSA-N 0.000 description 1
- PHIHSDQPTUANBG-SECBINFHSA-N (1R)-1-(4-methoxy-3-methylsulfonylphenyl)propan-1-amine Chemical compound CC[C@@H](N)C1=CC=C(OC)C(S(C)(=O)=O)=C1 PHIHSDQPTUANBG-SECBINFHSA-N 0.000 description 1
- WZUKLOGEMLKUOT-CYBMUJFWSA-N (1R)-1-[4-bromo-1-(4-methylphenyl)sulfonylpyrrol-2-yl]propan-1-amine Chemical compound CC[C@@H](N)C1=CC(Br)=CN1S(=O)(=O)C1=CC=C(C)C=C1 WZUKLOGEMLKUOT-CYBMUJFWSA-N 0.000 description 1
- QHQYVUVPFXNYIG-VIFPVBQESA-N (1R)-2-methoxy-1-(1-methylsulfonyl-2H-pyridin-4-yl)ethanamine Chemical compound COC[C@H](N)C1=CCN(S(C)(=O)=O)C=C1 QHQYVUVPFXNYIG-VIFPVBQESA-N 0.000 description 1
- LSCSZFGSLKTXMM-VIFPVBQESA-N (1S)-1-(1-bromo-2H-pyridin-4-yl)but-3-en-1-amine Chemical compound C=CC[C@H](N)C1=CCN(Br)C=C1 LSCSZFGSLKTXMM-VIFPVBQESA-N 0.000 description 1
- MEEXGFZPVMWZPS-QMMMGPOBSA-N (1S)-1-(1-bromo-2H-pyridin-4-yl)propan-1-amine Chemical compound CC[C@H](N)C1=CCN(Br)C=C1 MEEXGFZPVMWZPS-QMMMGPOBSA-N 0.000 description 1
- JKOOTZOXEWUPCU-JTQLQIEISA-N (1S)-1-(1-ethenyl-2H-pyridin-4-yl)propan-1-amine Chemical compound CC[C@H](N)C1=CCN(C=C)C=C1 JKOOTZOXEWUPCU-JTQLQIEISA-N 0.000 description 1
- BGSKLAZFPTXSNH-JTQLQIEISA-N (1S)-1-(1-ethylsulfonyl-2H-pyridin-4-yl)propan-1-amine Chemical compound CC[C@H](N)C1=CCN(S(=O)(=O)CC)C=C1 BGSKLAZFPTXSNH-JTQLQIEISA-N 0.000 description 1
- VVWSKQUHMPDXEV-ZETCQYMHSA-N (1S)-1-(1-methylpyrazol-4-yl)propan-1-amine Chemical compound CC[C@H](N)C=1C=NN(C)C=1 VVWSKQUHMPDXEV-ZETCQYMHSA-N 0.000 description 1
- RGTAANAOZSCEHS-VIFPVBQESA-N (1S)-1-(1-methylsulfanyl-2H-pyridin-4-yl)propan-1-amine Chemical compound CC[C@H](N)C1=CCN(SC)C=C1 RGTAANAOZSCEHS-VIFPVBQESA-N 0.000 description 1
- CWZWKFRHZFPUHE-JTQLQIEISA-N (1S)-1-(1-methylsulfonyl-2H-pyridin-4-yl)but-3-en-1-amine Chemical compound CS(=O)(=O)N1CC=C([C@@H](N)CC=C)C=C1 CWZWKFRHZFPUHE-JTQLQIEISA-N 0.000 description 1
- ZXACMSKZJDEFBN-ZETCQYMHSA-N (1S)-1-(1-methylsulfonyl-2H-pyridin-4-yl)ethanamine Chemical compound C[C@H](N)C1=CCN(S(C)(=O)=O)C=C1 ZXACMSKZJDEFBN-ZETCQYMHSA-N 0.000 description 1
- VFMIHVVOGMTJTK-QMMMGPOBSA-N (1S)-1-(2-bromopyridin-4-yl)but-3-en-1-amine Chemical compound C=CC[C@H](N)C1=CC=NC(Br)=C1 VFMIHVVOGMTJTK-QMMMGPOBSA-N 0.000 description 1
- PTAVZIWHCHMOFY-YFKPBYRVSA-N (1S)-1-(2-bromopyridin-4-yl)ethanamine Chemical compound C[C@H](N)C1=CC=NC(Br)=C1 PTAVZIWHCHMOFY-YFKPBYRVSA-N 0.000 description 1
- PFEGULKVAODWFH-JTQLQIEISA-N (1S)-1-(2-ethylsulfonylpyridin-4-yl)but-3-en-1-amine Chemical compound CCS(=O)(=O)C1=CC([C@@H](N)CC=C)=CC=N1 PFEGULKVAODWFH-JTQLQIEISA-N 0.000 description 1
- HNEIQWOMZCBFPL-ZETCQYMHSA-N (1S)-1-(2-ethylsulfonylpyridin-4-yl)ethanamine Chemical compound CCS(=O)(=O)C1=CC([C@H](C)N)=CC=N1 HNEIQWOMZCBFPL-ZETCQYMHSA-N 0.000 description 1
- JJWHFKIEOUYXLE-QMMMGPOBSA-N (1S)-1-(2-methylsulfanylpyridin-4-yl)propan-1-amine Chemical compound CC[C@H](N)C1=CC=NC(SC)=C1 JJWHFKIEOUYXLE-QMMMGPOBSA-N 0.000 description 1
- XLNUQKMEBFOZDQ-VIFPVBQESA-N (1S)-1-(2-methylsulfonylpyridin-4-yl)but-3-en-1-amine Chemical compound CS(=O)(=O)C1=CC([C@@H](N)CC=C)=CC=N1 XLNUQKMEBFOZDQ-VIFPVBQESA-N 0.000 description 1
- WZTNZJCIYWNKGT-VIFPVBQESA-N (1S)-1-(3-methoxy-4-methylsulfonylphenyl)propan-1-amine Chemical compound CC[C@H](N)C1=CC=C(S(C)(=O)=O)C(OC)=C1 WZTNZJCIYWNKGT-VIFPVBQESA-N 0.000 description 1
- VAZRQGHMFAFFJF-JTQLQIEISA-N (1S)-1-(4-methoxy-3-methylsulfonylphenyl)butan-1-amine Chemical compound CCC[C@H](N)C1=CC=C(OC)C(S(C)(=O)=O)=C1 VAZRQGHMFAFFJF-JTQLQIEISA-N 0.000 description 1
- PHIHSDQPTUANBG-VIFPVBQESA-N (1S)-1-(4-methoxy-3-methylsulfonylphenyl)propan-1-amine Chemical compound CC[C@H](N)C1=CC=C(OC)C(S(C)(=O)=O)=C1 PHIHSDQPTUANBG-VIFPVBQESA-N 0.000 description 1
- FDVOXWQQAQODEZ-ZETCQYMHSA-N (1S)-1-(4-methylsulfonyl-1H-pyrrol-2-yl)propan-1-amine Chemical compound CC[C@H](N)C1=CC(S(C)(=O)=O)=CN1 FDVOXWQQAQODEZ-ZETCQYMHSA-N 0.000 description 1
- VMGNLDMLBAXPGS-ZETCQYMHSA-N (1S)-1-(4-methylsulfonylfuran-2-yl)propan-1-amine Chemical compound CC[C@H](N)C1=CC(S(C)(=O)=O)=CO1 VMGNLDMLBAXPGS-ZETCQYMHSA-N 0.000 description 1
- IBXRRWOPSXFWDG-QMMMGPOBSA-N (1S)-1-(4-methylsulfonylpyridin-2-yl)propan-1-amine Chemical compound CC[C@H](N)C1=CC(S(C)(=O)=O)=CC=N1 IBXRRWOPSXFWDG-QMMMGPOBSA-N 0.000 description 1
- SOAGQPYPHLKQLC-ZETCQYMHSA-N (1S)-1-(4-methylsulfonylthiophen-2-yl)propan-1-amine Chemical compound CC[C@H](N)C1=CC(S(C)(=O)=O)=CS1 SOAGQPYPHLKQLC-ZETCQYMHSA-N 0.000 description 1
- OXDQAFVTFGBGII-ZETCQYMHSA-N (1S)-1-(6-ethylsulfonylpyridin-2-yl)ethanamine Chemical compound CCS(=O)(=O)C1=CC=CC([C@H](C)N)=N1 OXDQAFVTFGBGII-ZETCQYMHSA-N 0.000 description 1
- DSRCWULAOQMPOG-VIFPVBQESA-N (1S)-1-(6-ethylsulfonylpyridin-3-yl)propan-1-amine Chemical compound CC[C@H](N)C1=CC=C(S(=O)(=O)CC)N=C1 DSRCWULAOQMPOG-VIFPVBQESA-N 0.000 description 1
- ULMHWSOOULOERL-ZETCQYMHSA-N (1S)-1-(6-methoxy-1-methylsulfonyl-2H-pyridin-4-yl)ethanamine Chemical compound COC1=CC([C@H](C)N)=CCN1S(C)(=O)=O ULMHWSOOULOERL-ZETCQYMHSA-N 0.000 description 1
- DPFQEPYKTBVKII-VIFPVBQESA-N (1S)-1-(6-methoxy-1-methylsulfonyl-2H-pyridin-4-yl)propan-1-amine Chemical compound CC[C@H](N)C1=CCN(S(C)(=O)=O)C(OC)=C1 DPFQEPYKTBVKII-VIFPVBQESA-N 0.000 description 1
- SWFJPVNYKIVBCO-LURJTMIESA-N (1S)-1-(6-methylsulfonylpyridin-2-yl)ethanamine Chemical compound C[C@H](N)C1=CC=CC(S(C)(=O)=O)=N1 SWFJPVNYKIVBCO-LURJTMIESA-N 0.000 description 1
- ZONZFSMXMQNIDP-VIFPVBQESA-N (1S)-1-(6-methylsulfonylpyridin-3-yl)butan-1-amine Chemical compound CCC[C@H](N)C1=CC=C(S(C)(=O)=O)N=C1 ZONZFSMXMQNIDP-VIFPVBQESA-N 0.000 description 1
- WLJCHCWMEPUKGK-LBPRGKRZSA-N (1S)-N'-(2-methoxyethyl)-N'-methyl-1-(2-methylsulfonylpyridin-4-yl)propane-1,3-diamine Chemical compound COCCN(C)CC[C@H](N)C1=CC=NC(S(C)(=O)=O)=C1 WLJCHCWMEPUKGK-LBPRGKRZSA-N 0.000 description 1
- HBDBRIDJTAPFLQ-QMMMGPOBSA-N (1r)-1-(1-bromo-2h-pyridin-4-yl)-2-methoxyethanamine Chemical compound COC[C@H](N)C1=CCN(Br)C=C1 HBDBRIDJTAPFLQ-QMMMGPOBSA-N 0.000 description 1
- HEVZRFSPIQPAQN-JTQLQIEISA-N (1s)-1-(2-ethenylpyridin-4-yl)propan-1-amine Chemical compound CC[C@H](N)C1=CC=NC(C=C)=C1 HEVZRFSPIQPAQN-JTQLQIEISA-N 0.000 description 1
- AAWHYUXSSLEQFF-RGMNGODLSA-N (1s)-1-(2-methoxy-6-methylsulfonylpyridin-4-yl)ethanamine;hydrochloride Chemical compound Cl.COC1=CC([C@H](C)N)=CC(S(C)(=O)=O)=N1 AAWHYUXSSLEQFF-RGMNGODLSA-N 0.000 description 1
- ICIHWNOJRNUJJE-QRPNPIFTSA-N (1s)-1-(2-methoxy-6-methylsulfonylpyridin-4-yl)propan-1-amine;hydrochloride Chemical compound Cl.CC[C@H](N)C1=CC(OC)=NC(S(C)(=O)=O)=C1 ICIHWNOJRNUJJE-QRPNPIFTSA-N 0.000 description 1
- VXHLJEYPWMVMQK-YFKPBYRVSA-N (1s)-1-(2-methylsulfanyl-1,3-oxazol-5-yl)propan-1-amine Chemical compound CC[C@H](N)C1=CN=C(SC)O1 VXHLJEYPWMVMQK-YFKPBYRVSA-N 0.000 description 1
- SZZQEBUNGSSVDP-BYPYZUCNSA-N (1s)-1-(2-methylsulfonyl-1,3-thiazol-4-yl)ethanamine Chemical compound C[C@H](N)C1=CSC(S(C)(=O)=O)=N1 SZZQEBUNGSSVDP-BYPYZUCNSA-N 0.000 description 1
- GGPIMZXUUDMNKC-YFKPBYRVSA-N (1s)-1-(2-methylsulfonyl-1,3-thiazol-4-yl)propan-1-amine Chemical compound CC[C@H](N)C1=CSC(S(C)(=O)=O)=N1 GGPIMZXUUDMNKC-YFKPBYRVSA-N 0.000 description 1
- YDSOKJMNVMTTQL-BYPYZUCNSA-N (1s)-1-(2-methylsulfonyl-1,3-thiazol-5-yl)ethanamine Chemical compound C[C@H](N)C1=CN=C(S(C)(=O)=O)S1 YDSOKJMNVMTTQL-BYPYZUCNSA-N 0.000 description 1
- MDAOMTRNTRIGOV-VIFPVBQESA-N (1s)-1-(3-bromophenyl)propan-1-amine Chemical compound CC[C@H](N)C1=CC=CC(Br)=C1 MDAOMTRNTRIGOV-VIFPVBQESA-N 0.000 description 1
- HXTWUUNTLJYXFX-VKHMYHEASA-N (1s)-1-(4-bromo-1,3-thiazol-2-yl)ethanamine Chemical compound C[C@H](N)C1=NC(Br)=CS1 HXTWUUNTLJYXFX-VKHMYHEASA-N 0.000 description 1
- GTNQDNYDHHVAKC-BYPYZUCNSA-N (1s)-1-(4-bromo-1,3-thiazol-2-yl)propan-1-amine Chemical compound CC[C@H](N)C1=NC(Br)=CS1 GTNQDNYDHHVAKC-BYPYZUCNSA-N 0.000 description 1
- IWAYBHNJMMNZLT-LURJTMIESA-N (1s)-1-(4-bromo-2-methylpyrazol-3-yl)propan-1-amine Chemical compound CC[C@H](N)C1=C(Br)C=NN1C IWAYBHNJMMNZLT-LURJTMIESA-N 0.000 description 1
- FTJMYEXXZRZMGM-ZETCQYMHSA-N (1s)-1-(5-methylsulfonylthiophen-3-yl)propan-1-amine Chemical compound CC[C@H](N)C1=CSC(S(C)(=O)=O)=C1 FTJMYEXXZRZMGM-ZETCQYMHSA-N 0.000 description 1
- AMRLOHQGLKJXPZ-LURJTMIESA-N (1s)-1-(6-methylsulfonylpyridin-3-yl)ethanamine Chemical compound C[C@H](N)C1=CC=C(S(C)(=O)=O)N=C1 AMRLOHQGLKJXPZ-LURJTMIESA-N 0.000 description 1
- HFTAJPKEDFAMQP-QMMMGPOBSA-N (1s)-1-(6-methylsulfonylpyridin-3-yl)propan-1-amine Chemical compound CC[C@H](N)C1=CC=C(S(C)(=O)=O)N=C1 HFTAJPKEDFAMQP-QMMMGPOBSA-N 0.000 description 1
- NTBUIWKIABECLM-LBPRGKRZSA-N (1s)-1-[1-(4-methylphenyl)sulfonylimidazol-4-yl]propan-1-amine Chemical compound C1=NC([C@@H](N)CC)=CN1S(=O)(=O)C1=CC=C(C)C=C1 NTBUIWKIABECLM-LBPRGKRZSA-N 0.000 description 1
- CFLZGQCWZFJGDN-UHFFFAOYSA-N (2-bromo-1,3-thiazol-4-yl)methanamine Chemical compound NCC1=CSC(Br)=N1 CFLZGQCWZFJGDN-UHFFFAOYSA-N 0.000 description 1
- WANUZJQMEJLSBM-UHFFFAOYSA-N (2-bromo-6-methylpyridin-4-yl)methanamine Chemical compound CC1=CC(CN)=CC(Br)=N1 WANUZJQMEJLSBM-UHFFFAOYSA-N 0.000 description 1
- OEOAEMBKKWPLSZ-UHFFFAOYSA-N (2-bromopyridin-4-yl)methanamine Chemical compound NCC1=CC=NC(Br)=C1 OEOAEMBKKWPLSZ-UHFFFAOYSA-N 0.000 description 1
- ZSFVJBWMJXOZQB-UHFFFAOYSA-N (2-cyclopropylsulfonylpyridin-4-yl)methanamine Chemical compound NCC1=CC=NC(S(=O)(=O)C2CC2)=C1 ZSFVJBWMJXOZQB-UHFFFAOYSA-N 0.000 description 1
- BBPIOKYUBJZCLR-UHFFFAOYSA-N (2-ethylsulfonylpyridin-4-yl)methanamine Chemical compound CCS(=O)(=O)C1=CC(CN)=CC=N1 BBPIOKYUBJZCLR-UHFFFAOYSA-N 0.000 description 1
- MFZPZXRHPDVFLB-UHFFFAOYSA-N (2-methyl-6-methylsulfonylpyridin-4-yl)methanamine Chemical compound CC1=CC(CN)=CC(S(C)(=O)=O)=N1 MFZPZXRHPDVFLB-UHFFFAOYSA-N 0.000 description 1
- VMVDYMHYKBHOSX-UHFFFAOYSA-N (2-methylsulfonyl-1,3-thiazol-4-yl)methanamine Chemical compound CS(=O)(=O)C1=NC(CN)=CS1 VMVDYMHYKBHOSX-UHFFFAOYSA-N 0.000 description 1
- JRNOELYMVLPOGQ-UHFFFAOYSA-N (2-methylsulfonyl-1,3-thiazol-5-yl)methanamine Chemical compound CS(=O)(=O)C1=NC=C(CN)S1 JRNOELYMVLPOGQ-UHFFFAOYSA-N 0.000 description 1
- ITWDFVUNCISBDX-UHFFFAOYSA-N (2-methylsulfonylphenyl)methanamine;hydrochloride Chemical compound Cl.CS(=O)(=O)C1=CC=CC=C1CN ITWDFVUNCISBDX-UHFFFAOYSA-N 0.000 description 1
- ZRVZFCDHVHWOIY-UHFFFAOYSA-N (2-morpholin-4-ylpyrimidin-5-yl)methanamine Chemical compound N1=CC(CN)=CN=C1N1CCOCC1 ZRVZFCDHVHWOIY-UHFFFAOYSA-N 0.000 description 1
- ZHFJUAGCADSGMQ-IUCAKERBSA-N (2S,4S)-4-amino-4-(2-methylsulfonylpyridin-4-yl)butane-1,2-diol Chemical compound CS(=O)(=O)C1=CC([C@@H](N)C[C@H](O)CO)=CC=N1 ZHFJUAGCADSGMQ-IUCAKERBSA-N 0.000 description 1
- KLBPUVPNPAJWHZ-UMSFTDKQSA-N (2r)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-3-tritylsulfanylpropanoic acid Chemical compound C([C@@H](C(=O)O)NC(=O)OCC1C2=CC=CC=C2C2=CC=CC=C21)SC(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 KLBPUVPNPAJWHZ-UMSFTDKQSA-N 0.000 description 1
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 1
- JARBLLDDSTVWSM-IJAHGLKVSA-N (2s,3r)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-3-trityloxybutanoic acid Chemical compound O([C@H](C)[C@H](NC(=O)OCC1C2=CC=CC=C2C2=CC=CC=C21)C(O)=O)C(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 JARBLLDDSTVWSM-IJAHGLKVSA-N 0.000 description 1
- ICIJWOWQUHHETJ-UHFFFAOYSA-N (3,5-dichlorophenyl)methanamine Chemical compound NCC1=CC(Cl)=CC(Cl)=C1 ICIJWOWQUHHETJ-UHFFFAOYSA-N 0.000 description 1
- DZBHNPJZCQWUCG-UHFFFAOYSA-N (3,5-dimethylphenyl)methanamine Chemical compound CC1=CC(C)=CC(CN)=C1 DZBHNPJZCQWUCG-UHFFFAOYSA-N 0.000 description 1
- LCFSQWLCIUITOH-UHFFFAOYSA-N (3-bromo-1,2-oxazol-5-yl)methanamine Chemical compound NCC1=CC(Br)=NO1 LCFSQWLCIUITOH-UHFFFAOYSA-N 0.000 description 1
- DLEMWTVPLLIRRI-UHFFFAOYSA-N (3-bromo-1,2-oxazol-5-yl)methanamine;hydrochloride Chemical compound Cl.NCC1=CC(Br)=NO1 DLEMWTVPLLIRRI-UHFFFAOYSA-N 0.000 description 1
- PYAQTQXFMQWCHQ-UHFFFAOYSA-N (3-methylimidazol-4-yl)methanamine Chemical compound CN1C=NC=C1CN PYAQTQXFMQWCHQ-UHFFFAOYSA-N 0.000 description 1
- DQFOSYRXEOWKOY-UHFFFAOYSA-N (3-methylsulfonylphenyl)methanamine Chemical compound CS(=O)(=O)C1=CC=CC(CN)=C1 DQFOSYRXEOWKOY-UHFFFAOYSA-N 0.000 description 1
- BCYMQLXRJFRALD-QMMMGPOBSA-N (3S)-3-amino-3-(1-bromo-2H-pyridin-4-yl)propanenitrile Chemical compound N#CC[C@H](N)C1=CCN(Br)C=C1 BCYMQLXRJFRALD-QMMMGPOBSA-N 0.000 description 1
- XQRUUHBPUXOVPD-UHFFFAOYSA-N (4-bromothiophen-2-yl)methanamine Chemical compound NCC1=CC(Br)=CS1 XQRUUHBPUXOVPD-UHFFFAOYSA-N 0.000 description 1
- VMNXLLDFGVEBLE-UHFFFAOYSA-N (4-methylsulfonylphenyl)methanamine Chemical compound CS(=O)(=O)C1=CC=C(CN)C=C1 VMNXLLDFGVEBLE-UHFFFAOYSA-N 0.000 description 1
- QUBGXTCYMBTLIC-UHFFFAOYSA-N (4-methylsulfonylthiophen-2-yl)methanamine Chemical compound CS(=O)(=O)C1=CSC(CN)=C1 QUBGXTCYMBTLIC-UHFFFAOYSA-N 0.000 description 1
- XLDWJOJGHKMPOR-UHFFFAOYSA-N (4-morpholin-4-ylsulfonylphenyl)methanamine Chemical compound C1=CC(CN)=CC=C1S(=O)(=O)N1CCOCC1 XLDWJOJGHKMPOR-UHFFFAOYSA-N 0.000 description 1
- ZHFJUAGCADSGMQ-GKAPJAKFSA-N (4S)-4-amino-4-(2-methylsulfonylpyridin-4-yl)butane-1,2-diol Chemical compound CS(=O)(=O)C1=CC([C@@H](N)CC(O)CO)=CC=N1 ZHFJUAGCADSGMQ-GKAPJAKFSA-N 0.000 description 1
- OQUHYNMITHDQLD-UHFFFAOYSA-N (5-bromopyridin-3-yl)methanamine Chemical compound NCC1=CN=CC(Br)=C1 OQUHYNMITHDQLD-UHFFFAOYSA-N 0.000 description 1
- RAVKMGSIHFLQJU-UHFFFAOYSA-N (5-bromothiophen-2-yl)methanamine Chemical compound NCC1=CC=C(Br)S1 RAVKMGSIHFLQJU-UHFFFAOYSA-N 0.000 description 1
- PMUZYXXGWQBOET-UHFFFAOYSA-N (5-ethylsulfonylpyridin-3-yl)methanamine Chemical compound CCS(=O)(=O)C1=CN=CC(CN)=C1 PMUZYXXGWQBOET-UHFFFAOYSA-N 0.000 description 1
- QUDOEZIBCHMZFT-UHFFFAOYSA-N (5-methylsulfonylpyridin-3-yl)methanamine Chemical compound CS(=O)(=O)C1=CN=CC(CN)=C1 QUDOEZIBCHMZFT-UHFFFAOYSA-N 0.000 description 1
- HBWPQQXFWIVESS-UHFFFAOYSA-N (5-methylsulfonylthiophen-2-yl)methanamine Chemical compound CS(=O)(=O)C1=CC=C(CN)S1 HBWPQQXFWIVESS-UHFFFAOYSA-N 0.000 description 1
- BIFOUXRPQRJZGK-UHFFFAOYSA-N (6-cyclopropylsulfonylpyridin-3-yl)methanamine Chemical compound N1=CC(CN)=CC=C1S(=O)(=O)C1CC1 BIFOUXRPQRJZGK-UHFFFAOYSA-N 0.000 description 1
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 description 1
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 1
- CCZRURZITNMPIF-UHFFFAOYSA-N 1-(1-methylsulfonylpiperidin-4-yl)propan-1-amine Chemical compound CCC(N)C1CCN(S(C)(=O)=O)CC1 CCZRURZITNMPIF-UHFFFAOYSA-N 0.000 description 1
- OCOXYYMZTJBJJN-UHFFFAOYSA-N 1-(2-bromopyridin-4-yl)ethanone Chemical compound CC(=O)C1=CC=NC(Br)=C1 OCOXYYMZTJBJJN-UHFFFAOYSA-N 0.000 description 1
- NIYVAFTVMSJYCB-UHFFFAOYSA-N 1-(4-fluorophenyl)-n-[1-(1-methylpiperidin-3-yl)propyl]pyrazolo[3,4-c]pyridine-4-carboxamide Chemical compound C1CCN(C)CC1C(CC)NC(=O)C(C=1C=N2)=CN=CC=1N2C1=CC=C(F)C=C1 NIYVAFTVMSJYCB-UHFFFAOYSA-N 0.000 description 1
- YPQKAYVHXUHYMP-UHFFFAOYSA-N 1-(4-fluorophenyl)pyrazolo[4,3-c]pyridine Chemical compound C1=CC(F)=CC=C1N1C2=CC=NC=C2C=N1 YPQKAYVHXUHYMP-UHFFFAOYSA-N 0.000 description 1
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 1
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 1
- GMGFEPBGBPJSNR-UHFFFAOYSA-N 1-[4-(aminomethyl)phenyl]-N-(1-methylpiperidin-4-yl)methanesulfonamide Chemical compound C1CN(C)CCC1NS(=O)(=O)CC1=CC=C(CN)C=C1 GMGFEPBGBPJSNR-UHFFFAOYSA-N 0.000 description 1
- IOQCXBSDHLJQQO-UHFFFAOYSA-N 1-[4-(aminomethyl)phenyl]-N-(cyclohexylmethyl)methanesulfonamide Chemical compound C1=CC(CN)=CC=C1CS(=O)(=O)NCC1CCCCC1 IOQCXBSDHLJQQO-UHFFFAOYSA-N 0.000 description 1
- OMYFZPPRRXOESQ-UHFFFAOYSA-N 1-[4-(aminomethyl)phenyl]-N-(oxolan-2-ylmethyl)methanesulfonamide Chemical compound C1=CC(CN)=CC=C1CS(=O)(=O)NCC1OCCC1 OMYFZPPRRXOESQ-UHFFFAOYSA-N 0.000 description 1
- MXRUPLHPQAXXNJ-UHFFFAOYSA-N 1-[4-(aminomethyl)phenyl]-N-cyclohexylmethanesulfonamide Chemical compound C1=CC(CN)=CC=C1CS(=O)(=O)NC1CCCCC1 MXRUPLHPQAXXNJ-UHFFFAOYSA-N 0.000 description 1
- HZGGUPHMMGXUML-UHFFFAOYSA-N 1-[4-(aminomethyl)phenyl]-N-methyl-N-(1-methylpiperidin-4-yl)methanesulfonamide Chemical compound C=1C=C(CN)C=CC=1CS(=O)(=O)N(C)C1CCN(C)CC1 HZGGUPHMMGXUML-UHFFFAOYSA-N 0.000 description 1
- KXLAVAYUPDHDPM-UHFFFAOYSA-N 1-[4-(aminomethyl)phenyl]-n-methylmethanesulfonamide Chemical compound CNS(=O)(=O)CC1=CC=C(CN)C=C1 KXLAVAYUPDHDPM-UHFFFAOYSA-N 0.000 description 1
- MFSMJCXBRIYZJH-UHFFFAOYSA-N 1-[4-(aminomethyl)phenyl]-n-propan-2-ylmethanesulfonamide Chemical compound CC(C)NS(=O)(=O)CC1=CC=C(CN)C=C1 MFSMJCXBRIYZJH-UHFFFAOYSA-N 0.000 description 1
- LXQMHOKEXZETKB-UHFFFAOYSA-N 1-amino-2-methylpropan-2-ol Chemical compound CC(C)(O)CN LXQMHOKEXZETKB-UHFFFAOYSA-N 0.000 description 1
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Natural products C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 description 1
- WCOKFZDSARTDTH-UHFFFAOYSA-N 1h-pyrazolo[4,3-c]pyridin-4-ylmethanol Chemical compound OCC1=NC=CC2=C1C=NN2 WCOKFZDSARTDTH-UHFFFAOYSA-N 0.000 description 1
- WCXFPLXZZSWROM-UHFFFAOYSA-N 1h-pyrazolo[4,3-c]pyridine Chemical compound C1=NC=C2C=NNC2=C1 WCXFPLXZZSWROM-UHFFFAOYSA-N 0.000 description 1
- XNLFTVUEDUPLIP-UHFFFAOYSA-N 2,2,2-trifluoro-1-(6-methylsulfonylpyridin-3-yl)ethanamine Chemical compound CS(=O)(=O)C1=CC=C(C(N)C(F)(F)F)C=N1 XNLFTVUEDUPLIP-UHFFFAOYSA-N 0.000 description 1
- SYBAWUSIVYUZIZ-UHFFFAOYSA-N 2,2,2-trifluoro-1-pyridin-2-ylethanamine Chemical compound FC(F)(F)C(N)C1=CC=CC=N1 SYBAWUSIVYUZIZ-UHFFFAOYSA-N 0.000 description 1
- MKEJZKKVVUZXIS-UHFFFAOYSA-N 2,4-dibromo-1,3-thiazole Chemical compound BrC1=CSC(Br)=N1 MKEJZKKVVUZXIS-UHFFFAOYSA-N 0.000 description 1
- WOXFMYVTSLAQMO-UHFFFAOYSA-N 2-Pyridinemethanamine Chemical class NCC1=CC=CC=N1 WOXFMYVTSLAQMO-UHFFFAOYSA-N 0.000 description 1
- OZMWMNJFSYAZSA-UHFFFAOYSA-N 2-[[4-(aminomethyl)-6-methylsulfonylpyridin-2-yl]-methylamino]acetamide Chemical compound NC(=O)CN(C)C1=CC(CN)=CC(S(C)(=O)=O)=N1 OZMWMNJFSYAZSA-UHFFFAOYSA-N 0.000 description 1
- HCPAXSUAWASLFD-UHFFFAOYSA-N 2-[[4-(aminomethyl)-6-methylsulfonylpyridin-2-yl]amino]acetamide Chemical compound CS(=O)(=O)C1=CC(CN)=CC(NCC(N)=O)=N1 HCPAXSUAWASLFD-UHFFFAOYSA-N 0.000 description 1
- RXNZFHIEDZEUQM-UHFFFAOYSA-N 2-bromo-1,3-thiazole Chemical compound BrC1=NC=CS1 RXNZFHIEDZEUQM-UHFFFAOYSA-N 0.000 description 1
- DJUWIZUEHXRECB-UHFFFAOYSA-N 2-bromo-1,3-thiazole-5-carbaldehyde Chemical compound BrC1=NC=C(C=O)S1 DJUWIZUEHXRECB-UHFFFAOYSA-N 0.000 description 1
- QRXBTPFMCTXCRD-UHFFFAOYSA-N 2-chloropyridine-4-carbonitrile Chemical compound ClC1=CC(C#N)=CC=N1 QRXBTPFMCTXCRD-UHFFFAOYSA-N 0.000 description 1
- FNRMMDCDHWCQTH-UHFFFAOYSA-N 2-chloropyridine;3-chloropyridine;4-chloropyridine Chemical compound ClC1=CC=NC=C1.ClC1=CC=CN=C1.ClC1=CC=CC=N1 FNRMMDCDHWCQTH-UHFFFAOYSA-N 0.000 description 1
- ASUDFOJKTJLAIK-UHFFFAOYSA-N 2-methoxyethanamine Chemical compound COCCN ASUDFOJKTJLAIK-UHFFFAOYSA-N 0.000 description 1
- XWKFPIODWVPXLX-UHFFFAOYSA-N 2-methyl-5-methylpyridine Natural products CC1=CC=C(C)N=C1 XWKFPIODWVPXLX-UHFFFAOYSA-N 0.000 description 1
- GTCXYHZNFJRNTE-RFXRWSEHSA-N 2-methyl-n-[(1s)-1-(2-methylsulfonyl-1,3-thiazol-5-yl)propyl]propane-2-sulfinamide Chemical compound CC(C)(C)S(=O)N[C@@H](CC)C1=CN=C(S(C)(=O)=O)S1 GTCXYHZNFJRNTE-RFXRWSEHSA-N 0.000 description 1
- MUZJMBLOEPPOCH-JUGYALQGSA-N 2-methyl-n-[(1s)-1-(2-methylsulfonylpyridin-4-yl)ethyl]propane-2-sulfinamide Chemical compound CC(C)(C)S(=O)N[C@@H](C)C1=CC=NC(S(C)(=O)=O)=C1 MUZJMBLOEPPOCH-JUGYALQGSA-N 0.000 description 1
- GSEQAFOXTAPIEZ-FZADBTJQSA-N 2-methyl-n-[(1s)-1-[1-(4-methylphenyl)sulfonylpyrazol-3-yl]propyl]propane-2-sulfinamide Chemical compound N1=C([C@@H](NS(=O)C(C)(C)C)CC)C=CN1S(=O)(=O)C1=CC=C(C)C=C1 GSEQAFOXTAPIEZ-FZADBTJQSA-N 0.000 description 1
- FAQRJJNCVJYQES-UHFFFAOYSA-N 2h-benzotriazole-4-carbonitrile Chemical compound N#CC1=CC=CC2=C1N=NN2 FAQRJJNCVJYQES-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- RXGNLDFDLLMAJZ-UHFFFAOYSA-N 3-bromo-1,2-oxazole-5-carbaldehyde Chemical compound BrC=1C=C(C=O)ON=1 RXGNLDFDLLMAJZ-UHFFFAOYSA-N 0.000 description 1
- BNYKZFOZWZMEJD-UHFFFAOYSA-N 3-methylimidazole-4-carbaldehyde Chemical compound CN1C=NC=C1C=O BNYKZFOZWZMEJD-UHFFFAOYSA-N 0.000 description 1
- VLWNCJPMUMKUMF-UHFFFAOYSA-N 4-(1-hydroxypropyl)benzene-1,2-diol Chemical compound CCC(O)C1=CC=C(O)C(O)=C1 VLWNCJPMUMKUMF-UHFFFAOYSA-N 0.000 description 1
- AVLAJWPBZJNJDQ-UHFFFAOYSA-N 4-(4-bromopyrimidin-2-yl)morpholine Chemical compound BrC1=CC=NC(N2CCOCC2)=N1 AVLAJWPBZJNJDQ-UHFFFAOYSA-N 0.000 description 1
- ZVEKOCJDXSMHOY-UHFFFAOYSA-N 4-(aminomethyl)-2-methoxy-N-methylbenzenesulfonamide Chemical compound CNS(=O)(=O)c1ccc(CN)cc1OC ZVEKOCJDXSMHOY-UHFFFAOYSA-N 0.000 description 1
- WFHVUCYIFKDBQY-UHFFFAOYSA-N 4-(aminomethyl)-3-chloro-N-methylbenzenesulfonamide Chemical compound ClC1=C(CN)C=CC(S(=O)(=O)NC)=C1 WFHVUCYIFKDBQY-UHFFFAOYSA-N 0.000 description 1
- YAPFNBWASNDHCR-UHFFFAOYSA-N 4-(aminomethyl)-N-(1-hydroxypropan-2-yl)benzenesulfonamide Chemical compound CC(CO)NS(=O)(=O)C1=CC=C(C=C1)CN YAPFNBWASNDHCR-UHFFFAOYSA-N 0.000 description 1
- YKKGTZFDERRVOX-UHFFFAOYSA-N 4-(aminomethyl)-N-(2-hydroxy-2-methylpropyl)benzenesulfonamide Chemical compound CC(C)(O)CNS(=O)(=O)C1=CC=C(CN)C=C1 YKKGTZFDERRVOX-UHFFFAOYSA-N 0.000 description 1
- MWWPMBNEHDAOPD-UHFFFAOYSA-N 4-(aminomethyl)-N-(2-hydroxyethyl)benzenesulfonamide Chemical compound NCc1ccc(cc1)S(=O)(=O)NCCO MWWPMBNEHDAOPD-UHFFFAOYSA-N 0.000 description 1
- CNWHOWMWNVAEAI-UHFFFAOYSA-N 4-(aminomethyl)-n-(oxan-4-yl)benzenesulfonamide Chemical compound C1=CC(CN)=CC=C1S(=O)(=O)NC1CCOCC1 CNWHOWMWNVAEAI-UHFFFAOYSA-N 0.000 description 1
- UKAAZDOZZXTPHL-UHFFFAOYSA-N 4-(aminomethyl)-n-[2-(dimethylamino)ethyl]benzenesulfonamide Chemical compound CN(C)CCNS(=O)(=O)C1=CC=C(CN)C=C1 UKAAZDOZZXTPHL-UHFFFAOYSA-N 0.000 description 1
- HFYPOILBMUOECE-UHFFFAOYSA-N 4-(aminomethyl)-n-methyl-n-(1-methylpiperidin-4-yl)benzenesulfonamide Chemical compound C=1C=C(CN)C=CC=1S(=O)(=O)N(C)C1CCN(C)CC1 HFYPOILBMUOECE-UHFFFAOYSA-N 0.000 description 1
- PXHWVDOUOGBXHW-UHFFFAOYSA-N 4-(aminomethyl)pyridine-2-carbonitrile Chemical compound NCC1=CC=NC(C#N)=C1 PXHWVDOUOGBXHW-UHFFFAOYSA-N 0.000 description 1
- JLYXTOSSUANVPV-QMMMGPOBSA-N 4-[(1S)-1-aminoethyl]-N,N-dimethyl-6-methylsulfonyl-2H-pyridin-1-amine Chemical compound C[C@H](N)C1=CCN(N(C)C)C(S(C)(=O)=O)=C1 JLYXTOSSUANVPV-QMMMGPOBSA-N 0.000 description 1
- BQUUBDJNGPLICN-ZETCQYMHSA-N 4-[(1S)-1-aminoethyl]-N-methyl-1-methylsulfonyl-2H-pyridin-6-amine Chemical compound CNC1=CC([C@H](C)N)=CCN1S(C)(=O)=O BQUUBDJNGPLICN-ZETCQYMHSA-N 0.000 description 1
- MTQOQGRVWXZSIH-NSHDSACASA-N 4-[(1S)-1-aminopropyl]-6-methylsulfonyl-N-propan-2-yl-2H-pyridin-1-amine Chemical compound CC[C@H](N)C1=CCN(NC(C)C)C(S(C)(=O)=O)=C1 MTQOQGRVWXZSIH-NSHDSACASA-N 0.000 description 1
- UUDSAVNMSUQTCP-JTQLQIEISA-N 4-[(1S)-1-aminopropyl]-N,N-dimethyl-6-methylsulfonyl-2H-pyridin-1-amine Chemical compound CC[C@H](N)C1=CCN(N(C)C)C(S(C)(=O)=O)=C1 UUDSAVNMSUQTCP-JTQLQIEISA-N 0.000 description 1
- CXEUFWMRGAVXIU-UHFFFAOYSA-N 4-[4-(aminomethyl)phenyl]sulfonylpiperazin-2-one Chemical compound C1=CC(CN)=CC=C1S(=O)(=O)N1CC(=O)NCC1 CXEUFWMRGAVXIU-UHFFFAOYSA-N 0.000 description 1
- VDTIGYKLTROQAH-UHFFFAOYSA-N 4-bromo-1,3-thiazole Chemical class BrC1=CSC=N1 VDTIGYKLTROQAH-UHFFFAOYSA-N 0.000 description 1
- JDUXMFGFGCJNGO-UHFFFAOYSA-N 4-bromo-1,3-thiazole-2-carbaldehyde Chemical compound BrC1=CSC(C=O)=N1 JDUXMFGFGCJNGO-UHFFFAOYSA-N 0.000 description 1
- ACENKBWTBMVUKM-UHFFFAOYSA-N 4-bromo-1-(4,4-difluorocyclohexyl)pyrazolo[3,4-c]pyridine Chemical compound C1CC(F)(F)CCC1N1C2=CN=CC(Br)=C2C=N1 ACENKBWTBMVUKM-UHFFFAOYSA-N 0.000 description 1
- NSKTZQHBXJOARU-UHFFFAOYSA-N 4-bromo-1-(4-chlorophenyl)pyrazolo[3,4-c]pyridine Chemical compound C1=CC(Cl)=CC=C1N1C2=CN=CC(Br)=C2C=N1 NSKTZQHBXJOARU-UHFFFAOYSA-N 0.000 description 1
- NNUXRTPUHRKPFT-UHFFFAOYSA-N 4-bromo-1-(oxan-4-yl)pyrazolo[3,4-c]pyridine Chemical compound N1=CC=2C(Br)=CN=CC=2N1C1CCOCC1 NNUXRTPUHRKPFT-UHFFFAOYSA-N 0.000 description 1
- GXAHYXQWHWDEDY-UHFFFAOYSA-N 4-bromo-2-methylpyrazole-3-carbaldehyde Chemical compound CN1N=CC(Br)=C1C=O GXAHYXQWHWDEDY-UHFFFAOYSA-N 0.000 description 1
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- IEKCTKIJEFYPMS-UHFFFAOYSA-N 5-(aminomethyl)-2-(dimethylsulfamoylamino)pyridine Chemical compound CN(C)S(=O)(=O)NC1=CC=C(CN)C=N1 IEKCTKIJEFYPMS-UHFFFAOYSA-N 0.000 description 1
- NDAFBPAQUDUOIN-UHFFFAOYSA-N 5-(aminomethyl)-N,N-dimethylpyridine-2-sulfonamide Chemical compound CN(C)S(=O)(=O)C1=CC=C(CN)C=N1 NDAFBPAQUDUOIN-UHFFFAOYSA-N 0.000 description 1
- ZTBGRJAOENQZGE-UHFFFAOYSA-N 5-(aminomethyl)-N-(2-hydroxyethyl)pyridine-2-sulfonamide Chemical compound NCC1=CC=C(S(=O)(=O)NCCO)N=C1 ZTBGRJAOENQZGE-UHFFFAOYSA-N 0.000 description 1
- MVWKPHGNGMSDHB-UHFFFAOYSA-N 5-(aminomethyl)-N-(oxan-4-yl)pyridine-2-sulfonamide Chemical compound N1=CC(CN)=CC=C1S(=O)(=O)NC1CCOCC1 MVWKPHGNGMSDHB-UHFFFAOYSA-N 0.000 description 1
- YJIDKQVYACIBPR-UHFFFAOYSA-N 5-(aminomethyl)-n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=C(CN)C=N1 YJIDKQVYACIBPR-UHFFFAOYSA-N 0.000 description 1
- XPGIBDJXEVAVTO-UHFFFAOYSA-N 5-bromo-2-chloropyrimidine Chemical compound ClC1=NC=C(Br)C=N1 XPGIBDJXEVAVTO-UHFFFAOYSA-N 0.000 description 1
- DMSHUVBQFSNBBL-UHFFFAOYSA-N 5-bromopyridine-2-carbonitrile Chemical compound BrC1=CC=C(C#N)N=C1 DMSHUVBQFSNBBL-UHFFFAOYSA-N 0.000 description 1
- YCNXGPMGMAKDPM-UHFFFAOYSA-N 5-bromothiophene-3-carboxylic acid Chemical compound OC(=O)C1=CSC(Br)=C1 YCNXGPMGMAKDPM-UHFFFAOYSA-N 0.000 description 1
- KDVBYUUGYXUXNL-UHFFFAOYSA-N 6-aminopyridine-3-carbonitrile Chemical compound NC1=CC=C(C#N)C=N1 KDVBYUUGYXUXNL-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 description 1
- 229910000013 Ammonium bicarbonate Inorganic materials 0.000 description 1
- 208000032116 Autoimmune Experimental Encephalomyelitis Diseases 0.000 description 1
- 208000030767 Autoimmune encephalitis Diseases 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- 102100031092 C-C motif chemokine 3 Human genes 0.000 description 1
- 101710155856 C-C motif chemokine 3 Proteins 0.000 description 1
- 102100032367 C-C motif chemokine 5 Human genes 0.000 description 1
- SOHPTLCPABGBCD-UHFFFAOYSA-N CC(C)NS(=O)(=O)CNCC1=CC=CC=C1 Chemical compound CC(C)NS(=O)(=O)CNCC1=CC=CC=C1 SOHPTLCPABGBCD-UHFFFAOYSA-N 0.000 description 1
- QZBSIIKZCSLQHY-RLWMBFFFSA-N CC[C@@H](C(N=C1)=C[S+]1S(C)(=O)=O)[NH-] Chemical compound CC[C@@H](C(N=C1)=C[S+]1S(C)(=O)=O)[NH-] QZBSIIKZCSLQHY-RLWMBFFFSA-N 0.000 description 1
- JRIZKMYHAIFPDD-RLWMBFFFSA-N CC[C@@H](C1=CN=C[S+]1S(C)(=O)=O)[NH-] Chemical compound CC[C@@H](C1=CN=C[S+]1S(C)(=O)=O)[NH-] JRIZKMYHAIFPDD-RLWMBFFFSA-N 0.000 description 1
- STGYVHCSYODNIK-UHFFFAOYSA-N CNS(=O)(=O)CNCC1=CC=CC=C1 Chemical compound CNS(=O)(=O)CNCC1=CC=CC=C1 STGYVHCSYODNIK-UHFFFAOYSA-N 0.000 description 1
- XODXWGUYQQFGTE-UHFFFAOYSA-N CS(=O)(=O)C1=CC(CNC(O)=O)=CC=N1 Chemical compound CS(=O)(=O)C1=CC(CNC(O)=O)=CC=N1 XODXWGUYQQFGTE-UHFFFAOYSA-N 0.000 description 1
- FBXJBMRXNZQCHM-UHFFFAOYSA-N CS(=O)(=O)c1ccc(CN)c(O)c1 Chemical compound CS(=O)(=O)c1ccc(CN)c(O)c1 FBXJBMRXNZQCHM-UHFFFAOYSA-N 0.000 description 1
- ZJLDLHLWDNZRJP-UHFFFAOYSA-N CS(=O)(=O)c1ccc(CN)cc1O Chemical compound CS(=O)(=O)c1ccc(CN)cc1O ZJLDLHLWDNZRJP-UHFFFAOYSA-N 0.000 description 1
- XLAXLBOCONONFN-ITZCMCNPSA-N C[C@@H](C(N=C1)=C[S+]1S(C)(=O)=O)[NH-] Chemical compound C[C@@H](C(N=C1)=C[S+]1S(C)(=O)=O)[NH-] XLAXLBOCONONFN-ITZCMCNPSA-N 0.000 description 1
- IQPPOBAUQKZSLZ-ITZCMCNPSA-N C[C@@H](C1=CN=C[S+]1S(C)(=O)=O)[NH-] Chemical compound C[C@@H](C1=CN=C[S+]1S(C)(=O)=O)[NH-] IQPPOBAUQKZSLZ-ITZCMCNPSA-N 0.000 description 1
- QDHHCQZDFGDHMP-UHFFFAOYSA-N Chloramine Chemical group ClN QDHHCQZDFGDHMP-UHFFFAOYSA-N 0.000 description 1
- RXWHULKLNWGAAT-FJXQXJEOSA-N Cl.CS(=O)(=O)N1CC=C(C=C1)[C@H](C)N Chemical compound Cl.CS(=O)(=O)N1CC=C(C=C1)[C@H](C)N RXWHULKLNWGAAT-FJXQXJEOSA-N 0.000 description 1
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 1
- 239000007821 HATU Substances 0.000 description 1
- 101000797762 Homo sapiens C-C motif chemokine 5 Proteins 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 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
- 206010023203 Joint destruction Diseases 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 241001529936 Murinae Species 0.000 description 1
- CAOKJPJFQSJHHA-UHFFFAOYSA-N N-[4-(aminomethyl)-2-(methanesulfonamido)-1H-pyridin-2-yl]methanesulfonamide Chemical compound CS(=O)(=O)NC1(NS(C)(=O)=O)NC=CC(CN)=C1 CAOKJPJFQSJHHA-UHFFFAOYSA-N 0.000 description 1
- VZJGRJYPOIGWIO-UHFFFAOYSA-N N-[5-(aminomethyl)pyridin-2-yl]-N-(2-methoxyethyl)methanesulfonamide Chemical compound COCCN(S(C)(=O)=O)C1=CC=C(CN)C=N1 VZJGRJYPOIGWIO-UHFFFAOYSA-N 0.000 description 1
- VPOHNDGUDUOAPN-UHFFFAOYSA-N N-[5-(aminomethyl)pyridin-2-yl]-N-[2-(dimethylamino)ethyl]methanesulfonamide Chemical compound CN(C)CCN(S(C)(=O)=O)C1=CC=C(CN)C=N1 VPOHNDGUDUOAPN-UHFFFAOYSA-N 0.000 description 1
- RUZWCAWXQMOZSL-UHFFFAOYSA-N N-[5-(aminomethyl)pyridin-2-yl]-N-methylmethanesulfonamide Chemical compound CS(=O)(=O)N(C)C1=CC=C(CN)C=N1 RUZWCAWXQMOZSL-UHFFFAOYSA-N 0.000 description 1
- LIKOCFSYXCHMLN-UHFFFAOYSA-N N-[5-(aminomethyl)pyridin-2-yl]cyclopropanesulfonamide Chemical compound N1=CC(CN)=CC=C1NS(=O)(=O)C1CC1 LIKOCFSYXCHMLN-UHFFFAOYSA-N 0.000 description 1
- WILKDPZSBWPYEW-UHFFFAOYSA-N OCCN(C)S(=O)(=O)C1=CC=C(CN)C=C1 Chemical compound OCCN(C)S(=O)(=O)C1=CC=C(CN)C=C1 WILKDPZSBWPYEW-UHFFFAOYSA-N 0.000 description 1
- 101150062967 PHOX2A gene Proteins 0.000 description 1
- SIOXPEMLGUPBBT-UHFFFAOYSA-N Picolinic acid Natural products OC(=O)C1=CC=CC=N1 SIOXPEMLGUPBBT-UHFFFAOYSA-N 0.000 description 1
- 241000219061 Rheum Species 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 239000012317 TBTU Substances 0.000 description 1
- 229910003074 TiCl4 Inorganic materials 0.000 description 1
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 1
- DHVHORCFFOSRBP-UHFFFAOYSA-N [3,5-bis(trifluoromethyl)phenyl]methanamine Chemical compound NCC1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1 DHVHORCFFOSRBP-UHFFFAOYSA-N 0.000 description 1
- IGZNDNGPEIYQPX-UHFFFAOYSA-N [3-(methylsulfonylmethyl)phenyl]methanamine Chemical compound CS(=O)(=O)CC1=CC=CC(CN)=C1 IGZNDNGPEIYQPX-UHFFFAOYSA-N 0.000 description 1
- MUIXPGZYRCQACO-UHFFFAOYSA-N [3-methylsulfonyl-5-(trifluoromethyl)phenyl]methanamine Chemical compound CS(=O)(=O)c1cc(CN)cc(c1)C(F)(F)F MUIXPGZYRCQACO-UHFFFAOYSA-N 0.000 description 1
- HBVSXVODAPCXAC-UHFFFAOYSA-N [4-(4-methoxypiperidin-1-yl)sulfonylphenyl]methanamine Chemical compound C1CC(OC)CCN1S(=O)(=O)C1=CC=C(CN)C=C1 HBVSXVODAPCXAC-UHFFFAOYSA-N 0.000 description 1
- YNOSHLVJNFWEDO-UHFFFAOYSA-N [4-(morpholin-4-ylsulfonylmethyl)phenyl]methanamine Chemical compound C1=CC(CN)=CC=C1CS(=O)(=O)N1CCOCC1 YNOSHLVJNFWEDO-UHFFFAOYSA-N 0.000 description 1
- OYXKNMUWTZQUCG-UHFFFAOYSA-N [4-(piperidin-1-ylsulfonylmethyl)phenyl]methanamine Chemical compound C1=CC(CN)=CC=C1CS(=O)(=O)N1CCCCC1 OYXKNMUWTZQUCG-UHFFFAOYSA-N 0.000 description 1
- DBGUUPDUZXSAJF-UHFFFAOYSA-N [Cu+].[I+] Chemical compound [Cu+].[I+] DBGUUPDUZXSAJF-UHFFFAOYSA-N 0.000 description 1
- CLZISMQKJZCZDN-UHFFFAOYSA-N [benzotriazol-1-yloxy(dimethylamino)methylidene]-dimethylazanium Chemical compound C1=CC=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 CLZISMQKJZCZDN-UHFFFAOYSA-N 0.000 description 1
- PBCJIPOGFJYBJE-UHFFFAOYSA-N acetonitrile;hydrate Chemical compound O.CC#N PBCJIPOGFJYBJE-UHFFFAOYSA-N 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- 238000010976 amide bond formation reaction Methods 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 235000012538 ammonium bicarbonate Nutrition 0.000 description 1
- 239000001099 ammonium carbonate Substances 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 229940040526 anhydrous sodium acetate Drugs 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- YCOXTKKNXUZSKD-UHFFFAOYSA-N as-o-xylenol Natural products CC1=CC=C(O)C=C1C YCOXTKKNXUZSKD-UHFFFAOYSA-N 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 150000008107 benzenesulfonic acids Chemical class 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=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
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000004541 benzoxazolyl group Chemical group O1C(=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
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 description 1
- 150000003939 benzylamines Chemical class 0.000 description 1
- ZTQSAGDEMFDKMZ-UHFFFAOYSA-N butyric aldehyde Natural products CCCC=O ZTQSAGDEMFDKMZ-UHFFFAOYSA-N 0.000 description 1
- JHRWWRDRBPCWTF-OLQVQODUSA-N captafol Chemical compound C1C=CC[C@H]2C(=O)N(SC(Cl)(Cl)C(Cl)Cl)C(=O)[C@H]21 JHRWWRDRBPCWTF-OLQVQODUSA-N 0.000 description 1
- 125000001589 carboacyl group Chemical group 0.000 description 1
- 125000004452 carbocyclyl group Chemical group 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 238000010531 catalytic reduction reaction Methods 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 239000002975 chemoattractant Substances 0.000 description 1
- 230000035605 chemotaxis Effects 0.000 description 1
- VDQQXEISLMTGAB-UHFFFAOYSA-N chloramine T Chemical compound [Na+].CC1=CC=C(S(=O)(=O)[N-]Cl)C=C1 VDQQXEISLMTGAB-UHFFFAOYSA-N 0.000 description 1
- 125000000068 chlorophenyl group Chemical group 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- GBRBMTNGQBKBQE-UHFFFAOYSA-L copper;diiodide Chemical compound I[Cu]I GBRBMTNGQBKBQE-UHFFFAOYSA-L 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 125000001162 cycloheptenyl group Chemical group C1(=CCCCCC1)* 0.000 description 1
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 1
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 125000004856 decahydroquinolinyl group Chemical group N1(CCCC2CCCCC12)* 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 238000012217 deletion Methods 0.000 description 1
- 230000037430 deletion Effects 0.000 description 1
- NPOMSUOUAZCMBL-UHFFFAOYSA-N dichloromethane;ethoxyethane Chemical compound ClCCl.CCOCC NPOMSUOUAZCMBL-UHFFFAOYSA-N 0.000 description 1
- SPWVRYZQLGQKGK-UHFFFAOYSA-N dichloromethane;hexane Chemical class ClCCl.CCCCCC SPWVRYZQLGQKGK-UHFFFAOYSA-N 0.000 description 1
- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 1
- 125000005046 dihydronaphthyl group Chemical group 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- ZFLDTEIDAGWEEI-UHFFFAOYSA-N ethyl 2-chloro-1,3-oxazole-5-carboxylate Chemical compound CCOC(=O)C1=CN=C(Cl)O1 ZFLDTEIDAGWEEI-UHFFFAOYSA-N 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- MFFXVVHUKRKXCI-UHFFFAOYSA-N ethyl iodoacetate Chemical compound CCOC(=O)CI MFFXVVHUKRKXCI-UHFFFAOYSA-N 0.000 description 1
- 230000028023 exocytosis Effects 0.000 description 1
- 208000012997 experimental autoimmune encephalomyelitis Diseases 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000005755 formation reaction Methods 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
- BHEPBYXIRTUNPN-UHFFFAOYSA-N hydridophosphorus(.) (triplet) Chemical compound [PH] BHEPBYXIRTUNPN-UHFFFAOYSA-N 0.000 description 1
- 150000002430 hydrocarbons Chemical group 0.000 description 1
- COQRGFWWJBEXRC-UHFFFAOYSA-N hydron;methyl 2-aminoacetate;chloride Chemical compound Cl.COC(=O)CN COQRGFWWJBEXRC-UHFFFAOYSA-N 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 1
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- SNHMUERNLJLMHN-UHFFFAOYSA-N iodobenzene Chemical compound IC1=CC=CC=C1 SNHMUERNLJLMHN-UHFFFAOYSA-N 0.000 description 1
- NIZHERJWXFHGGU-UHFFFAOYSA-N isocyanato(trimethyl)silane Chemical compound C[Si](C)(C)N=C=O NIZHERJWXFHGGU-UHFFFAOYSA-N 0.000 description 1
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 description 1
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- BLQJIBCZHWBKSL-UHFFFAOYSA-L magnesium iodide Chemical compound [Mg+2].[I-].[I-] BLQJIBCZHWBKSL-UHFFFAOYSA-L 0.000 description 1
- 229910001641 magnesium iodide Inorganic materials 0.000 description 1
- CCERQOYLJJULMD-UHFFFAOYSA-M magnesium;carbanide;chloride Chemical compound [CH3-].[Mg+2].[Cl-] CCERQOYLJJULMD-UHFFFAOYSA-M 0.000 description 1
- GJPQPKKESVWENL-UHFFFAOYSA-L magnesium;ethanesulfinate;bromide Chemical compound [Mg+2].[Br-].CCS([O-])=O GJPQPKKESVWENL-UHFFFAOYSA-L 0.000 description 1
- RYEXTBOQKFUPOE-UHFFFAOYSA-M magnesium;propane;chloride Chemical compound [Mg+2].[Cl-].CC[CH2-] RYEXTBOQKFUPOE-UHFFFAOYSA-M 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 1
- XSKGHSUHOYEBTK-UHFFFAOYSA-N methyl 2,6-dichloropyridine-4-carboxylate Chemical compound COC(=O)C1=CC(Cl)=NC(Cl)=C1 XSKGHSUHOYEBTK-UHFFFAOYSA-N 0.000 description 1
- HTGDXQVCBISJRX-UHFFFAOYSA-N methyl 2-bromo-6-methylpyridine-4-carboxylate Chemical compound COC(=O)C1=CC(C)=NC(Br)=C1 HTGDXQVCBISJRX-UHFFFAOYSA-N 0.000 description 1
- RVMQMYULLXRSDU-QHCPKHFHSA-N methyl 3-[5-[(1s)-1-[[1-(4-fluorophenyl)pyrazolo[3,4-c]pyridine-4-carbonyl]amino]butyl]pyridin-3-yl]sulfonylpropanoate Chemical compound N([C@@H](CCC)C=1C=C(C=NC=1)S(=O)(=O)CCC(=O)OC)C(=O)C(C=1C=N2)=CN=CC=1N2C1=CC=C(F)C=C1 RVMQMYULLXRSDU-QHCPKHFHSA-N 0.000 description 1
- FBPIDMAELBIRLE-UHFFFAOYSA-N methyl 5-bromofuran-2-carboxylate Chemical compound COC(=O)C1=CC=C(Br)O1 FBPIDMAELBIRLE-UHFFFAOYSA-N 0.000 description 1
- NQMRYBIKMRVZLB-UHFFFAOYSA-N methylamine hydrochloride Chemical compound [Cl-].[NH3+]C NQMRYBIKMRVZLB-UHFFFAOYSA-N 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 230000002297 mitogenic effect Effects 0.000 description 1
- IFMIJMHTCMJEKV-UHFFFAOYSA-N n-(4-cyanopyrimidin-2-yl)-n-methylmethanesulfonamide Chemical compound CS(=O)(=O)N(C)C1=NC=CC(C#N)=N1 IFMIJMHTCMJEKV-UHFFFAOYSA-N 0.000 description 1
- HHXBORNQIJORQO-UHFFFAOYSA-N n-(5-bromopyrimidin-2-yl)-n-methylacetamide Chemical compound CC(=O)N(C)C1=NC=C(Br)C=N1 HHXBORNQIJORQO-UHFFFAOYSA-N 0.000 description 1
- ZHRNLYMDLCXYFO-UHFFFAOYSA-N n-(5-cyanopyrimidin-2-yl)-n-methylacetamide Chemical compound CC(=O)N(C)C1=NC=C(C#N)C=N1 ZHRNLYMDLCXYFO-UHFFFAOYSA-N 0.000 description 1
- KEKCBMWGXJQRTR-UHFFFAOYSA-N n-(methylsulfamoyl)-1-phenylmethanamine Chemical compound CNS(=O)(=O)NCC1=CC=CC=C1 KEKCBMWGXJQRTR-UHFFFAOYSA-N 0.000 description 1
- NQRLWYOGUKWPEG-YQDUUYOCSA-N n-[(1r)-1-(2-bromopyridin-4-yl)propyl]-2-methylpropane-2-sulfinamide Chemical compound CC(C)(C)S(=O)N[C@H](CC)C1=CC=NC(Br)=C1 NQRLWYOGUKWPEG-YQDUUYOCSA-N 0.000 description 1
- FVBURCMLMKIPNZ-MSSWUJIJSA-N n-[(1r)-1-(3-bromo-1,2-oxazol-5-yl)propyl]-2-methylpropane-2-sulfinamide Chemical compound CC(C)(C)S(=O)N[C@H](CC)C1=CC(Br)=NO1 FVBURCMLMKIPNZ-MSSWUJIJSA-N 0.000 description 1
- VMFKMRULGSJQSW-RSXQAXDFSA-N n-[(1s)-1-(1-cyano-2h-pyridin-4-yl)propyl]-2-methylpropane-2-sulfinamide Chemical compound CC(C)(C)S(=O)N[C@@H](CC)C1=CCN(C#N)C=C1 VMFKMRULGSJQSW-RSXQAXDFSA-N 0.000 description 1
- PXPOIESCMRNWJW-UOCSPZAXSA-N n-[(1s)-1-(2-bromopyridin-4-yl)ethyl]-2-methylpropane-2-sulfinamide Chemical compound CC(C)(C)S(=O)N[C@@H](C)C1=CC=NC(Br)=C1 PXPOIESCMRNWJW-UOCSPZAXSA-N 0.000 description 1
- FVBURCMLMKIPNZ-RWNHWRGESA-N n-[(1s)-1-(3-bromo-1,2-oxazol-5-yl)propyl]-2-methylpropane-2-sulfinamide Chemical compound CC(C)(C)S(=O)N[C@@H](CC)C1=CC(Br)=NO1 FVBURCMLMKIPNZ-RWNHWRGESA-N 0.000 description 1
- MPNSTAHEGQFZOM-FAQQKDIKSA-N n-[(1s)-1-(6-bromopyridin-3-yl)butyl]-2-methylpropane-2-sulfinamide Chemical compound CC(C)(C)S(=O)N[C@@H](CCC)C1=CC=C(Br)N=C1 MPNSTAHEGQFZOM-FAQQKDIKSA-N 0.000 description 1
- UCEUEIAMBYYPNY-UHFFFAOYSA-N n-[(2-methoxyphenyl)methyl]methanesulfonamide Chemical compound COC1=CC=CC=C1CNS(C)(=O)=O UCEUEIAMBYYPNY-UHFFFAOYSA-N 0.000 description 1
- NXXLTLWAYHAIIM-UHFFFAOYSA-N n-[(3-methoxyphenyl)methyl]methanesulfonamide Chemical compound COC1=CC=CC(CNS(C)(=O)=O)=C1 NXXLTLWAYHAIIM-UHFFFAOYSA-N 0.000 description 1
- WSMTWDAXFRDUSV-UHFFFAOYSA-N n-[5-(aminomethyl)pyrimidin-2-yl]-n-methylmethanesulfonamide Chemical compound CS(=O)(=O)N(C)C1=NC=C(CN)C=N1 WSMTWDAXFRDUSV-UHFFFAOYSA-N 0.000 description 1
- NWJUMMHVDMNYMJ-UHFFFAOYSA-N n-benzyl-1,1,1-trifluoromethanamine Chemical compound FC(F)(F)NCC1=CC=CC=C1 NWJUMMHVDMNYMJ-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
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000012285 osmium tetroxide Substances 0.000 description 1
- 229910000489 osmium tetroxide Inorganic materials 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- LXNAVEXFUKBNMK-UHFFFAOYSA-N palladium(II) acetate Substances [Pd].CC(O)=O.CC(O)=O LXNAVEXFUKBNMK-UHFFFAOYSA-N 0.000 description 1
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 238000010647 peptide synthesis reaction Methods 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 1
- 239000012286 potassium permanganate Substances 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 239000013014 purified material Substances 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- YLHJACXHRQQNQR-UHFFFAOYSA-N pyridine;2,4,6-tris(ethenyl)-1,3,5,2,4,6-trioxatriborinane Chemical compound C1=CC=NC=C1.C=CB1OB(C=C)OB(C=C)O1 YLHJACXHRQQNQR-UHFFFAOYSA-N 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 description 1
- UKLNMMHNWFDKNT-UHFFFAOYSA-M sodium chlorite Chemical compound [Na+].[O-]Cl=O UKLNMMHNWFDKNT-UHFFFAOYSA-M 0.000 description 1
- 229960002218 sodium chlorite Drugs 0.000 description 1
- BBMHARZCALWXSL-UHFFFAOYSA-M sodium dihydrogenphosphate monohydrate Chemical compound O.[Na+].OP(O)([O-])=O BBMHARZCALWXSL-UHFFFAOYSA-M 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- YICFALDKKMHFLT-UHFFFAOYSA-M sodium;3-methoxy-3-oxopropane-1-sulfinate Chemical compound [Na+].COC(=O)CCS([O-])=O YICFALDKKMHFLT-UHFFFAOYSA-M 0.000 description 1
- XZPVPNZTYPUODG-UHFFFAOYSA-M sodium;chloride;dihydrate Chemical compound O.O.[Na+].[Cl-] XZPVPNZTYPUODG-UHFFFAOYSA-M 0.000 description 1
- KKVTYAVXTDIPAP-UHFFFAOYSA-M sodium;methanesulfonate Chemical compound [Na+].CS([O-])(=O)=O KKVTYAVXTDIPAP-UHFFFAOYSA-M 0.000 description 1
- 239000011343 solid material Substances 0.000 description 1
- 239000012258 stirred mixture Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- QAHVHSLSRLSVGS-UHFFFAOYSA-N sulfamoyl chloride Chemical compound NS(Cl)(=O)=O QAHVHSLSRLSVGS-UHFFFAOYSA-N 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000008409 synovial inflammation Effects 0.000 description 1
- 210000005222 synovial tissue Anatomy 0.000 description 1
- NCWCLCDTDRJSEH-YVNMAJEFSA-N tert-butyl n-[(1s)-1-(2-carbamoylpiperidin-4-yl)propyl]carbamate Chemical compound CC(C)(C)OC(=O)N[C@@H](CC)C1CCNC(C(N)=O)C1 NCWCLCDTDRJSEH-YVNMAJEFSA-N 0.000 description 1
- BSEGISZQCANNOB-UHFFFAOYSA-N tert-butyl n-[(2-methylsulfonylpyridin-4-yl)methyl]carbamate Chemical compound CC(C)(C)OC(=O)NCC1=CC=NC(S(C)(=O)=O)=C1 BSEGISZQCANNOB-UHFFFAOYSA-N 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000000464 thioxo group Chemical group S=* 0.000 description 1
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- 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
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- 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
-
- 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
-
- 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
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
Definitions
- This invention relates to azaindazoles that are useful as antagonists of CCRl activity and are thus useful for treating a variety of diseases and disorders that are mediated or sustained through the activity of CCRl including autoimmune diseases, such as rheumatoid arthritis and multiple sclerosis.
- This invention also relates to pharmaceutical compositions comprising these compounds, methods of using these compounds in the treatment of various diseases and disorders, processes for preparing these compounds and intermediates useful in these processes.
- Chemotactic Cytokine Receptor 1 belongs to a large family (>20) of chemotactic cytokine (chemokine) receptors that interact with specific chemokines (>50) to mediate leukocyte trafficking, granule exocytosis, gene transcription, mitogenic effects and apoptosis. Chemokines are best known for their ability to mediate basal and inflammatory leukocyte trafficking.
- chemokines MIP-I alpha/CCL3, MCP3/CCL7 and RANTES/CCL5
- RA rheumatoid arthritis
- MS multiple sclerosis
- Macrophage inflammatory protein 1 alpha (MIP-I alpha), macrophage chemoattractant protein 3 (MCP-3) and regulated on activation, normal T- cell expressed and secreted (RANTES) are all found in the CNS of MS patients, while MIP-I alpha and RANTES are found in the CNS in the experimental autoimmune encephalomyelitis (EAE) model of MS (Review: Gerard and Rollins (2001) Nature Immunology). Macrophages and ThI cells in the inflamed synovia of RA patients are also major producers of MIP-I alpha and RANTES, which continuously recruit leukocytes to the synovial tissues of RA patients to propagate chronic inflammation (Volin et al. (1998) Clin.
- mice with antibodies specific for the CCRl ligand MIP-I alpha have also been shown to be effective in preventing development of acute and relapsing EAE by reducing the numbers of T cells and macrophages recruited to the CNS (Karpus et al. (1995) /. Immunology; Karpus and Kennedy (1997) /. Leukocyte Biology).
- at least one CCRl ligand has been demonstrated to recruit leukocytes to the CNS and propagate chronic inflammation in EAE, providing further in vivo validation for the role of CCRl in EAE and MS.
- the present invention provides novel compounds which block the interaction of CCRl and its ligands and are thus useful for treating a variety of diseases and disorders that are mediated or sustained through the activity of CCRl including autoimmune diseases, such as rheumatoid arthritis and multiple sclerosis.
- This invention also relates to pharmaceutical compositions comprising these compounds, methods of using these compounds in the treatment of various diseases and disorders, processes for preparing these compounds and intermediates useful in these processes.
- W is carbon and Y is nitrogen or, W is nitrogen and Y is carbon;
- Ari is carbocycle, heteroaryl or heterocyclyl each optionally substituted by one to three
- Ar 2 is carbocycle, heteroaryl or heterocyclyl, each optionally substituted by one to three
- Ri is hydrogen, C 1-6 alkyl or C 1-6 alkoxyCi-6 alkyl
- R 2 , R 3 are each independently hydrogen, C 1-6 alkyl or C 1-6 alkenyl, wherein the Ci_ 6 alkyl or alkenyl is optionally partially or fully halogenated or substituted with one to three groups independently selected from cyano, C 1-6 alkoxy, hydroxyl, -CO 2 C 1 - 6 alkyl, - C(O)N(R 6 )(R f ), -N(R 6 )(R f ) and heterocyclyl optionally substituted by oxo;
- Ra is Ci-6 alkyl, C 3-1 O cycloalkyl, Cr 6 alkoxy, Cr 6 alkylthio, Cr 6 alkylsulfonyl, Cr 6 alkoxycarbonyl, amino, mono-or di-Ci-6 alkylamino, C3-6 cycloalkylamino, Cr 6 alkylaminocarbonyl, Cr 6 acyl, Cr 6 acylamino, Cr 6 dialkylaminocarbonyl, hydroxyl, halogen, cyano, nitro, oxo, R -J -S(O) 1n -NH-, R.j-NH-S(O) m -, aryl or carboxyl; Rb is hydroxyl, carboxyl, halogen, -(CH 2 ) n -CN, -(CH 2 )n-CO 2 C 1 -6alkyl, nitro, -SO 3 H, d- 6 alkyl, C 2 - 6 alkenyl, C 2
- each R c , Rj are independently hydrogen, Cr 6 alkyl, Cr 6 acyl, C 3 _io cycloalkyl, Cr 6 alkoxy, hydroxyCi-6 alkyl, cyano-Ci-6 alkyl, Cr 6 alkylCi-6 alkoxy, Cr 6 alkylsulfonyl, Ci-6 alkoxycarbonylCo-salkyl, -(CH 2 ) n -C(0)-NR e Rf or -(CH 2 ) n -NR e R f ;
- each R e , R f are independently hydrogen, Cr 6 alkyl, C 3 _io cycloalkyl, Cr 6 alkoxy, Cr 6 alkoxyCi_6alkyl, mono-or diCi_6alkylaminoCi_6alkyl, hydroxyCi-6 alkyl or Cr 6 acyl;
- R 4 is hydrogen, C 1-6 alkyl, C 3 _ 6 cycloalkyl, heterocyclyl (CH 2 ) O-1 , mono-or di-Q- 6 alkylamino, mono-or di-i_ 6 alkylamino(CH 2 ) 2 _ 3 N(R e )-, aryl or heteroaryl each optionally substituted with 1 to 3 Cr 6 alkyl, C 3 _ 6 cycloalkyl, Cr ⁇ alkoxy, halogen, hydroxyl, oxo, carboxyl, -C(O)NR e Rf, amino, mono-or di-Q-6 alkylamino, Cr 6 alkoxycarbonyl or Cr 6 acylamino;
- each n, x are independently 0-3;
- each m is independently 0-2;
- R 2 , R 3 are each independently hydrogen, C 1-6 alkyl or C 1-6 alkenyl, wherein the C 1-6 alkyl or alkenyl is optionally partially or fully halogenated or substituted with one to three groups independently selected from hydroxyl, -CO2C1-6 alkyl, -C(O)N(R e )(Rf), - N(Re)(Rf), and heterocyclyl;
- each R c , Ra are independently hydrogen, Cr 6 alkyl, Cr 6 acyl, C 3-1 O cycloalkyl, Cr 6 alkoxy, hydroxyCi-6 alkyl, Cr 6 alkylCi-6 alkoxy, Cr 6 alkylsulfonyl, Cr 6 alkoxycarbonylCo- 3 alkyl or -(CH 2 ) n -NR e R f .
- W is carbon and Y is nitrogen;
- Ari is phenyl, cyclohexyl or tetrahydropyranyl each optionally substituted by one to three
- Ar 2 is phenyl, pyridyl, pyrazolyl, imidazolyl, thiophenyl, thiazolyl, cyclohexyl, piperidinyl, morpholinyl or piperazinyl, each optionally substituted by one to three R b ;
- R 2 is hydrogen, C 1-6 alkyl or C 1-6 alkenyl, wherein the Ci_ 6 alkyl or alkenyl is optionally partially or fully halogenated or substituted with one to three groups independently selected from hydroxyl, -CO 2 Ci. 6 alkyl, -C(O)N(R 6 )(Rf), -N(R 6 )(Rf), morpholinyl, thiomorpholinyl and piperidinyl;
- R 3 is hydrogen
- R 3 is Ci- 3 alkyl, Cr 3 alkoxy, methylsulfonyl, mono-or di-Ci- 3 alkylamino, Cr 3 acyl, Cr 3 acylamino, Cr 3 dialkylaminocarbonyl, halogen, cyano or nitro;
- Rb is hydroxyl, carboxyl, halogen, -(CH 2 ) n -CN, -(CH 2 )n-CO 2 C 1 -6alkyl, nitro, -SO 3 H, d- 6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, C 3 - 10 cycloalkyl, C r6 alkoxy, C 1-6 alkylC(O)-, -(CH 2 ) n - NR c R d , R 4 -S(O) 1n (CH 2 )O-I-, R 4 -S(O) 1n -NR 6 -, R 4
- each R c , Ra are independently hydrogen, Cr 6 alkyl, Cr 6 acyl, C 3-1 O cycloalkyl, Cr 6 alkoxy, hydroxyCi-6 alkyl, Cr 6 alkylCi-6 alkoxy, Cr 6 alkylsulfonyl, Cr 6 alkoxycarbonylCo-salkyl or -(CH 2 ) n -NR e R f ;
- each R e , Rf are independently hydrogen, Cr 6 alkyl, C 3-1 O cycloalkyl, Cr 6 alkoxy, Cr 6 alkoxyCi_6alkyl, mono-or diCi_6alkylaminoCi_6alkyl, hydroxyCi-6 alkyl or Cr 6 acyl;
- R 4 is hydrogen, C 1-6 alkyl, C 3 _ 6 cycloalkyl, heterocyclyl (CH 2 ) O-1 , mono-or di-Cr 6 alkylamino, mono-or di-i_ 6 alkylamino(CH 2 ) 2 _ 3 N(Ci_ 6 alkyl)-, aryl or heteroaryl each optionally substituted with 1 to 2 Cr 6 alkyl, C 3-6 cycloalkyl, Cr 6 alkoxy, halogen, hydroxyl, oxo, carboxyl, -C(O)NR e R f , amino, mono-or di-Cr 6 alkylamino, Cr 6 alkoxycarbonyl or Cr 6 acylamino.
- Ari is phenyl is substituted by one to two R 3 ;
- Ar 2 is phenyl, pyridyl, pyrazolyl, thiophenyl, thiazolyl, cyclohexyl or piperidinyl, each optionally substituted by one or two R b ;
- R 3 is mono-or di-Ci- 3 alkylamino, halogen or nitro
- R b is hydroxyl, carboxyl, -F, -Cl, -Br, -CF 3 , -CN, -SO 3 H, -CH 3 , -OCH 3 , CH 3 C(O)-, - (CH 2 ) n -CO 2 Ci_ 6 alkyl, -NR c R d , R 4 -S(O) m (CH 2 ) 0 -i-, R 4 -S(O) 2 -NR 6 -, R 4 -NR 6 -S (O) 2 (CH 2 ) 0 - i-, -NR f -C(O)-R 6 , -C(O) 2 NH 2 , morpholinyl or tetrazolyl;
- each R c , Rj are independently hydrogen, Cp 3 alkyl, Cp 3 acyl or Cp 6 alkoxycarbonylCo- 3 alkyl;
- each R 6 , R f are independently hydrogen, C 1 - 3 alkyl, C 1 - 3 alkoxyCi_ 3 alkyl or mono-or diC 1 _ 3 alkyl aminoC 1 _ 3 alkyl ;
- R 4 is hydrogen, Ci. 4 alkyl, C 3 - 6 cycloalkyl, -N(CH 3 ) 2 , (CH 3 ) 2 NCH 2 CH 2 N(CH 3 )-, or heterocyclyl(CH 2 )o-i, wherein the heterocyclyl is selected from piperidinyl, morpholinyl, piperidinyl, tetrahydropyranyl, pyrrolidinyl and l,l,-dioxo-perhydro-l,2-thiazin-2-yl, each R 4 optionally substituted with -OCH 3 , hydroxyl, oxo, carboxyl, -C(O)NH 2 , amino, -
- R a is -F or -Cl
- R b is hydroxyl, -F, -Cl, -Br, -CF 3 , -CN, -SO 3 H, -OCH 3 , CH 3 C(O)-, -(CH 2 ) n -C ⁇ 2Ci. 6 alkyl, -NReRd, R 4 -S(O) 1n -, R 4 -S(O) 2 -NR 6 -, R 4 -NRe-S(O) 2 (CH 2 ) 0 -i-, -C(O) 2 NH 2 morpholinyl or tetrazolyl;
- each R c , Ra are independently hydrogen, CH 3 or CH 3 C(O)-;
- each R 6 , R f are independently hydrogen, -CH 3 , or -CH 2 CH 2 OCH 3 ;
- R 4 is hydrogen, Ci- 4 alkyl, C 3 . 6 cycloalkyl, -N(CH 3 ) 2 , (CHs) 2 NCH 2 CH 2 N(CH 3 )-, or heterocyclyl, wherein the heterocyclyl is selected from piperidinyl, morpholinyl, piperidinyl, tetrahydropyranyl, pyrrolidinyl and l,l,-dioxo-perhydro-l,2-thiazin-2-yl, each R 4 optionally substituted with -OCH 3 , hydroxyl, oxo, amino, -N(CH 3 ) 2 or Cp 2 alkoxycarbonyl.
- R 2 , R 3 are each independently hydrogen or Q_ 6 alkyl optionally partially or fully halogenated or substituted with one to three groups selected from cyano, Ci_ 6 alkoxy and heterocyclyl optionally substituted by oxo.
- R 2 , R 3 are each independently hydrogen or Ci_ 3 alkyl optionally partially or fully halogenated or substituted with one group selected from cyano, Ci_ 3 alkoxy and heterocyclyl chosen from dioxolanyl, tetrahydropyranyl, dioxanyl, tetrahydrofuranyl, benzofuranyl, benzopyranyl and benzodioxolyl each optionally substituted by oxo.
- a compound of the formula (I) as provided immediately above, and wherein
- R 2 , R 3 are each independently hydrogen or C 1-3 alkyl optionally partially or fully halogenated or substituted with one group selected from cyano, C 1-3 alkoxy and dioxolanyl optionally substituted by oxo.
- R c is hydrogen or Cp 6 alkyl and Rj is cyano-Ci-6 alkyl or -(CH 2 ) n -C(O)-NR e Rf; each R e , Rf are independently hydrogen, C 1-6 alkyl.
- Ar 2 is pyridyl
- R b is Cp 6 alkyl optionally substituted with hydroxyl.
- Another aspect of the invention provides for a process of making a compound of the formula (I):
- Ar 1 , Ar 2 , R 3 and R 2 are defined in separate embodiments as they are defined in each of the separate embodiments for formula (I) above;
- Xi and X 2 are each independently a halogen chosen from Br and I;
- reaction is performed in a suitable polar aprotic solvent such as NMP, DMF, DMAC, or DMPU, preferably NMP; with a suitable base such as an aqueous hydroxide base such as KOH, NaOH, LiOH or CsOH, or an alkoxide base such as NaOMe, NaOEt, KOt-Bu or KOt-amyl, preferably, most preferably KOH; at a temperature range of 20- 100 0 C, most preferably about 8O 0 C; to provide a compound of the formula (IV), and optionally subsequently isolating (IV).
- a suitable polar aprotic solvent such as NMP, DMF, DMAC, or DMPU, preferably NMP
- a suitable base such as an aqueous hydroxide base such as KOH, NaOH, LiOH or CsOH, or an alkoxide base such as NaOMe, NaOEt, KOt-Bu or KOt-amyl, preferably, most preferably K
- a salt preferably an HCl salt
- a salt comprising i) reacting the compound (VII) with NaS-R wherein R is chosen from Cl-IO alkyl and aryl, in the presence of a polar solvent such as THF, diethyl ether, 1,4-dioxane, methyl tert-butyl ether, NMP, DMF, DMAC, preferably THF, at 0 to 100 0 C, preferably 55 0 C, and subsequently oxidizing with NaBO 3 in AcOH to provide the sulfone of formula (VIII);
- a polar solvent such as THF, diethyl ether, 1,4-dioxane, methyl tert-butyl ether, NMP, DMF, DMAC, preferably THF, at 0 to 100 0 C, preferably 55 0 C, and subsequently oxidizing with NaBO 3 in AcOH to provide the sulfone of formula (VIII);
- an acid such as HCl or TFA, preferably HCl
- a polar solvent such as isopropanol, methanol, ethanol, n-propanol, and n- butanol, preferably isopropanol, at 20 to 8O 0 C, preferably 65 0 C, to provide the desired compound of formula Via:
- DMF dimethylformamide
- NMP iV-methylpyrrolidinone
- DMAC iV,iV-dimethylacetamide
- DMPU N,iV'-dimethylpropylene urea
- MTBE methyl tert-butyl ether
- DME 1,2-dimethoxyethane
- the invention also relates to pharmaceutical preparations, containing as active substance one or more compounds of the invention, or the pharmaceutically acceptable derivatives thereof, optionally combined with conventional excipients and/or carriers.
- Compounds of the invention also include their isotopically-labelled forms.
- An isotopically-labelled form of an active agent of a combination of the present invention is identical to said active agent but for the fact that one or more atoms of said active agent have been replaced by an atom or atoms having an atomic mass or mass number different from the atomic mass or mass number of said atom which is usually found in nature.
- isotopes which are readily available commercially and which can be incorporated into an active agent of a combination of the present invention in accordance with well established procedures, include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, e.g., 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 0, 31 P, 32 P, 35 S, 18 F, and 36 Cl, respectively.
- An active agent of a combination of the present invention, a prodrug thereof, or a pharmaceutically acceptable salt of either which contains one or more of the above-mentioned isotopes and/or other isotopes of other atoms is contemplated to be within the scope of the present invention.
- the invention includes the use of any compounds of described above containing one or more asymmetric carbon atoms may occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. Isomers shall be defined as being enantiomers and diastereomers. All such isomeric forms of these compounds are expressly included in the present invention.
- Each stereogenic carbon may be in the R or S configuration, or a combination of configurations.
- Some of the compounds of the invention can exist in more than one tautomeric form.
- the invention includes methods using all such tautomers.
- Ci_ 4 alkoxy is a C 1-4 alkyl with a terminal oxygen, such as methoxy, ethoxy, propoxy, butoxy.
- All alkyl, alkenyl and alkynyl groups shall be understood as being branched or unbranched where structurally possible and unless otherwise specified. Other more specific definitions are as follows:
- Carbocycles include hydrocarbon rings containing from three to twelve carbon atoms. These carbocycles may be either aromatic or non-aromatic ring systems. The non- aromatic ring systems may be mono- or polyunsaturated.
- Preferred carbocycles include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptanyl, cycloheptenyl, phenyl, indanyl, indenyl, benzocyclobutanyl, dihydronaphthyl, tetrahydronaphthyl, naphthyl, decahydronaphthyl, benzocycloheptanyl and benzocycloheptenyl. Certain terms for cycloalkyl such as cyclobutanyl and cyclobutyl shall be used interchangeably.
- heterocycle refers to a stable nonaromatic 4-8 membered (but preferably, 5 or 6 membered) monocyclic or nonaromatic 8-11 membered bicyclic or spirocyclic heterocycle radical which may be either saturated or unsaturated.
- Each heterocycle consists of carbon atoms and one or more, preferably from 1 to 4 heteroatoms chosen from nitrogen, oxygen and sulfur.
- the heterocycle may be attached by any atom of the cycle, which results in the creation of a stable structure.
- heteroaryl shall be understood to mean an aromatic 5-8 membered monocyclic or 8-11 membered bicyclic ring containing 1-4 heteroatoms such as N, O and S.
- heterocycles and heteroaryl include but are not limited to, for example furanyl, pyranyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, tetrahydropyranyl, dioxanyl, dioxolanyl, tetrahydrofuranyl, oxazolyl, isoxazolyl, thiazolyl, pyrazolyl, pyrrolyl, imidazolyl, thienyl, thiadiazolyl, thiomorpholinyl, 1,1- dioxo-l ⁇ 6 -thiomorpholinyl, morpholinyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyrrolidinyl, piperidinyl, piperazinyl, purinyl, quinolinyl, dihydro-2H- quinolinyl, isoquinolin
- heteroatom as used herein shall be understood to mean atoms other than carbon such as O, N, S and P.
- one or more carbon atoms can be optionally replaced by heteroatoms: O, S or N, it shall be understood that if N is not substituted then it is NH, it shall also be understood that the heteroatoms may replace either terminal carbon atoms or internal carbon atoms within a branched or unbranched carbon chain.
- Such groups can be substituted as herein above described by groups such as oxo to result in definitions such as but not limited to: alkoxycarbonyl, acyl, amido and thioxo.
- aryl as used herein shall be understood to mean aromatic carbocycle or heteroaryl as defined herein.
- Each aryl or heteroaryl unless otherwise specified includes it's partially or fully hydrogenated derivative.
- quinolinyl may include decahydroquinolinyl and tetrahydroquinolinyl
- naphthyl may include its hydrogenated derivatives such as tetrahydranaphthyl.
- Other partially or fully hydrogenated derivatives of the aryl and heteroaryl compounds described herein will be apparent to one of ordinary skill in the art.
- nitrogen and sulfur include any oxidized form of nitrogen and sulfur and the quaternized form of any basic nitrogen.
- -S-C 1-6 alkyl radical unless otherwise specified, this shall be understood to include -S(O)-Ci_ 6 alkyl and - S(O) 2 -Ci -6 alkyl.
- alkyl refers to a saturated aliphatic radical containing from one to ten carbon atoms or a mono- or polyunsaturated aliphatic hydrocarbon radical containing from two to twelve carbon atoms. A mono- or polyunsaturated aliphatic hydrocarbon radical must contain at least one double or triple bond, respectively.
- Alkyl refers to both branched and unbranched alkyl groups. It should be understood that any combination term using an "alk” or “alkyl” prefix refers to analogs according to the above definition of “alkyl”. For example, terms such as “alkoxy”, “alkythio” refer to alkyl groups linked to a second group via an oxygen or sulfur atom.
- halogen as used in the present specification shall be understood to mean bromine, chlorine, fluorine or iodine, preferably fluorine.
- alkyl a nonlimiting example would be -CH 2 CHF 2 , -CF 3 etc.
- the compounds of the invention are only those which are contemplated to be 'chemically stable' as will be appreciated by those skilled in the art. For example, a compound which would have a 'dangling valency', or a 'carbanion' are not compounds contemplated by the inventive methods disclosed herein.
- the invention includes pharmaceutically acceptable derivatives of compounds of formula (I).
- a "pharmaceutically acceptable derivative” refers to any pharmaceutically acceptable salt or ester, or any other compound which, upon administration to a patient, is capable of providing (directly or indirectly) a compound useful for the invention, or a pharmacologically active metabolite or pharmacologically active residue thereof.
- a pharmacologically active metabolite shall be understood to mean any compound of the invention capable of being metabolized enzymatically or chemically. This includes, for example, hydroxylated or oxidized derivative compounds of the invention.
- Pharmaceutically acceptable salts include those derived from pharmaceutically acceptable inorganic and organic acids and bases.
- suitable acids include hydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, glycolic, lactic, salicylic, succinic, toluene-p-sulfuric, tartaric, acetic, citric, methanesulfonic, formic, benzoic, malonic, naphthalene-2- sulfuric and benzenesulfonic acids.
- Other acids, such as oxalic acid while not themselves pharmaceutically acceptable, may be employed in the preparation of salts useful as intermediates in obtaining the compounds and their pharmaceutically acceptable acid addition salts.
- Salts derived from appropriate bases include alkali metal (e.g., sodium), alkaline earth metal
- prodrugs of compounds of the invention include those compounds that, upon simple chemical transformation, are modified to produce compounds of the invention. Simple chemical transformations include hydrolysis, oxidation and reduction. Specifically, when a prodrug is administered to a patient, the prodrug may be transformed into a compound disclosed hereinabove, thereby imparting the desired pharmacological effect.
- the compounds of formula I may be made using the general synthetic methods described below, which also constitute part of the invention.
- the invention additionally provides for methods for making compounds of formula I.
- the compounds of the invention may be prepared by the general methods and examples presented below, and methods known to those of ordinary skill in the art and reported in the chemical literature. Unless otherwise specified, solvents, temperatures, pressures, and other reaction conditions may be readily selected by one of ordinary skill in the art. Specific procedures are provided in the Synthetic Examples section. Intermediate benzyl amines are commercially available, or may be synthesized via catalytic reduction of the corresponding aryl nitriles with Pd/C (Van Rompaey, K. et al. Tetrahedron, 2003, 59 (24), 4421) or Raney Ni (Gould, F. et al. J.
- Intermediate aminomethylpyridines may also be commercially available or prepared by methods known to those skilled in the art.
- methods of preparing 1-substituted-l- (pyridyl)methylamines from aldehydes or ketones are known (see, Kuduk, S. D. et al. Tetrahedron Lett. 2004, 45, 6641 and Chelucci, G. Tetrahedron: Asymmetry 2006, 17, 3163) and methods of preparing homoallylic primary amines are known (see, Kobayashi, S. et al. J. Am. Chem. Soc. 2006, 128, 11038).
- Bodanszky The Practice of Peptide Synthesis (Springer- Verlag: 1984), which is hereby incorporated by reference in its entirety), for example, by reacting a carboxylic acid and an amine in the presence of l-(3-dimethylaminopropyl)-3- ethylcarbodiimide (EDC) and 1-hydroxybenzotriazole. Reaction progress may be monitored by conventional methods such as thin layer chromatography (TLC). Intermediates and products may be purified by methods known in the art, including column chromatography, HPLC or recrystallization.
- TLC thin layer chromatography
- a hydrazine of the formula (III) (free base or a suitable salt form such as a hydrochloride salt) bearing Ar 1 is reacted with 3,5-dibromo-4- pyridinecarboxaldehyde (Ha) in the presence of sodium acetate in a suitable solvent such as EtOH to provide the hydrazone X.
- Reaction of X with a suitable diamine catalyst such as £ra «s- ⁇ f,iV'-dimethylcyclohexane-l,2-diamine in the presence of a copper salt such as CuI and a suitable base such as K 2 CO 3 and in a suitable solvent such as iV-methyl-2- pyrrolidinone (NMP) provides the l-substituted-4-bromo-azaindazole IVa.
- intermediate IVa may be heated with pressurized CO, in the presence of a suitable base and catalyst as described above in absolute ethanol to provide the ethyl ester XL
- the ester is then hydrolyzed for example by treatment with a suitable base such as KOH under aqueous conditions to provide carboxylic acid V.
- a suitable base such as KOH under aqueous conditions to provide carboxylic acid V.
- This may then be reacted with an amine of formula VI under coupling conditions well known in the art such as by treatment with SOCl 2 to form the intermediate acyl chloride followed by reaction with intermediate VI in the presence of a base such as Et 3 N or K 2 CO 3 to provide the desired compound of formula Ia.
- the intermediate acyl chloride may be reacted in situ or isolated first if desired.
- a hydrazine of the formula (III) (free base or a suitable salt form such as a hydrochloride salt) bearing Ar 1 is reacted with 4-bromo-3- pyridinecarboxaldehyde XII in the presence of sodium acetate in a suitable solvent such as EtOH to provide the hydrazone XIII.
- Reaction of XIII with a suitable diamine catalyst such as £raws- ⁇ f, ⁇ f'-dimethylcyclohexane-l,2-diamine in the presence of a copper salt such as CuI and a suitable base such as K 2 CO 3 and in a suitable solvent such as N- methyl-2-pyrrolidinone (NMP) provides the l-substituted-5-azaindazole XIV.
- a suitable oxidizing agent such as m-chloroperbenzoic acid or hydrogen peroxide in a suitable solvent such as dichloromethane (DCM) or EtOAc provides the iV-oxide XV.
- 5-azaindazole XVIII is reacted with AriX (XIX) where X is a halogen (Br or I) in the presence of a suitable diamine catalyst such as trans-N, N'- dimethylcyclohexane-l,2-diamine in the presence of a copper salt such as CuI and a suitable base such as K 2 CO 3 in a suitable solvent such as DMF to provide a 1-substituted- 5-azaindazole XX.
- Alcohol XX may then be treated with manganese (IV) oxide in the presence of sodium cyanide and an amine of formula VI in a suitable solvent such as THF to provide the desired compound of formula Ib.
- Compounds of formula I (which includes Ia and Ib) prepared by the above methods may be further converted to additional compounds of formula I by methods known in the art and exemplified in the Synthetic Examples section below.
- the reaction was diluted with water (300 mL) and the solid was collected by filtration washing with water.
- the filtrate was diluted with water (200 mL) and extracted with EtOAc (2 x 100 mL).
- the combined organic layers were washed with brine (2 x 100 mL).
- the still moist filter cake was dissolved in EtOAc and combined with the extracted organic layers, dried over magnesium sulfate, treated with activated carbon) and filtered through a pad of diatomaceous earth and a layer of silica gel.
- the reaction was the diluted with saturated aqueous ammonium chloride (10 mL) and extracted with EtOAc (4 x 7 mL). The combined organic layers were washed with saturated aqueous ammonium chloride (3 x 7 mL), brine (7 mL), aqueous K 2 CO 3 (7 mL), brine (7 mL), dried over magnesium sulfate, filtered and concentrated. The solid was triturated with ether to afford the title compound.
- the reaction was monitored by TLC (EtOAc) indicating a major new more polar product than starting bromide.
- the reaction was diluted with first saturated aqueous potassium carbonate (5 mL) and then saturated aqueous ammonium chloride (10 mL) and extracted with EtOAc (5 x 10 mL). The combined organic layers were washed with saturated aqueous ammonium chloride (3 x 10 mL), brine (3 x 10 mL), dried over magnesium sulfate, treated with activated carbon, filtered through diatomaceous earth and concentrated.
- the material from the column was purified a second time by using preparative silica gel TLC eluting with methanol-EtOAc (1:9).
- the material from the plate was triturated with EtOAc-ether-hexanes to afford the title compound.
- Example 13 Synthesis of l-(4-Fluorophenyl)-lH-pyrazolo[3,4-c]pyridine-4- carboxylic acid 4-(4-hydroxy-piperidine-l-sulfonyl)-benzylamide (13)
- the desired fractions were combined, neutralized with saturated aqueous sodium bicarbonate and extracted with dichloromethane (3 x 20 mL). The combined organic layers were dried over MgSO 4 , filtered and concentrated to afford the title compound as an off white solid.
- Example 17 Synthesis of l-(4-Fluorophenyl)-lH-pyrazolo[3,4-c]pyridine-4- carboxylic acid [(S)-l-(2-carbamoyl-pyridin-4-yl)-propyl]-amide (17a) and 4-((S)-I- ⁇ [l-(4-Fluorophenyl)-lH-pyrazolo[3,4-c]pyridine-4-carbonyl]-amino ⁇ -propyl)- pyridine-2-carboxylic acid (17b)
- Example 25 Synthesis of l-(4-Fluorophenyl)-lH-pyrazolo[3,4-c]pyridine-4- carboxylic acid [l-(l-methanesulfonyl-piperidin-3-yl)-propyl]-amide (25)
- Example 28 Synthesis of l-(4-Fluorophenyl)-lH-pyrazolo[3,4-c]pyridine-4- carboxylic acid [l-(l-methyl-piperidin-4-yl)-propyl]-amide (28)
- a solution of aqueous HCl was prepared from concentrated HCl (55 rnL) and water (195 rnL). About 10 mL of this HCl solution was charged to the reaction mixture to achieve pH 6-7. The batch was then heated to 55 0 C, and the remaining -240 mL of the HCl solution was charged. The batch was cooled to ambient temperature over 1 hour, and held at this temperature for 1 hour. The batch was then filtered, and the solid washed with water and /-PrOAc.
- Example 31 Synthesis of l-(4-Fluorophenyl)-lH-pyrazolo[3,4-c]pyridine-4- carboxylic acid [(15,35)-3,4-dihydroxy-l-(2-methanesulfonyl-pyridin-4-yl)-butyl]- amide (31a) and l-(4-Fluorophenyl)-lH-pyrazolo[3,4-c]pyridine-4-carboxylic acid [(15,3/f)-3,4-dihydroxy-l-(2-methanesulfonyl-pyridin-4-yl)-butyl]-amide (31b)
- Example 33 Synthesis of l-(4-Fluorophenyl)-lH-pyrazolo[3,4-c]pyridine-4- carboxylic acid [(5)-3-hydroxy-l-(2-methanesulfonyl-pyridin-4-yl)-propyl]-amide
- Desired fractions from the column was made basic with saturated aqueous sodium bicarbonate (2 mL), concentrated to half of the original volume and extracted with EtOAc (3 x 10 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated to afford the title compound as a white solid.
- TMSCN trimethylsilyl cyanide
- Example 38 Synthesis of l-(4-Fluorophenyl)-lH-pyrazolo[3,4-c]pyridine-4- carboxylic acid (6-methanesulfonyl-2-oxo-l,2-dihydropyridin-4-ylmethyl)-amide
- Example 40 Synthesis of l-(4-Fluorophenyl)-lH-pyrazolo[3,4-c]pyridine-4- carboxylic acid [(S)-l-(l-methanesulfonyl-lH-pyrazol-3-yl)-propyl]-amide (40)
- NaSMe (6.74 g, 90 wt.%, 1.2 eq) was charged to a flask followed by THF (10 niL). To the slurry was charged a solution of 2-chloro-4-cyanopyridine (10.0 g, 72.2 mmol, 1.0 eq) in THF (20 rnL). The reaction mixture was heated at 5O 0 C for 2 hours. The batch was then treated with NaBO 3 «4H 2 O (33.31 g, 3.0 eq) followed by AcOH (50 rnL). The reaction mixture was heated at 55 0 C for 16 hours.
- reaction mixture was then cooled to 0-5 0 C and treated with methanol (10 mL) followed by water (40 mL) and finally a solution of di-tert-buty ⁇ dicarbonate (15.06 g, 69.0 mmol, 1.15 eq) in THF (10 mL).
- the batch was stirred at ambient temperature for 2 hours, and then the THF and MeOH was removed by distillation under vacuum at 55 0 C.
- To the resulting slurry was added water (40 mL), toluene (20 mL) and heptane (40 mL). The slurry was stirred for 1 hour at ambient temperature and filtered.
- tert-buty ⁇ (2-(methylsulfonyl)pyridin-4- yl)methylcarbamate (20.0 g, 65.65 mmol, 94.0 wt.%) followed by /-PrOH (140 rnL).
- the slurry was stirred and treated with concentrated HCl (16.4 rnL, 196.96 mmol, 3.0 eq), and then heated to 65 0 C and held at this temperature for 3 hours.
- the batch was cooled to 20- 25 0 C, held at this temperature for at least 2 hours, and then filtered.
- the solid was washed with /-PrOH and then oven dried under vacuum to afford the title compound as a white solid, 13.45 g, >99 wt.% purity, 92% yield.
- 2-Methylsulfanyl-oxazole-5-carboxylic acid was converted to (5 r )-l-(2-methanesulfanyl- oxazol-5-yl)-propylamine hydrochloride (45) via the Weinreb amide using the same methods as described in Example 43.
- 2-Methylsulfanyl-oxazole-5-carboxylic acid was converted to (5 r )-l-(2-methanesulfanyl- oxazol-5-yl)-ethylamine hydrochloride via the Weinreb amide using the same methods as described in Example 43 except methyl magnesium bromide was substituted for ethyl magnesium chloride.
- Example 46 Synthesis of l-(4-Fluorophenyl)-lH-pyrazolo[3,4-c]pyridine-4- carboxylic acid [(S)-l-(2-methanesulfonyl-oxazol-5-yl)-propyl]-amide (46)
- the Weinreb amide of 2-methanesulfonyl-6-ethoxy-isonicotinic acid was also converted to (S)- 1 -(2-methanesulfonyl-6-methoxy-pyridin-4-yl)-ethylamine hydrochloride according to methods described in Example 43 except during the Grignard addition methyl magnesium bromide was added to the Weinreb amide instead of ethyl magnesium chloride to afford the corresponding methyl ketone.
- Example 48 Synthesis of l-(4-Fluorophenyl)-lH-pyrazolo[3,4-c]pyridine-4- carboxylic acid [(S)-l-(6-methanesulfonyl-2-oxo-l,2-dihydropyridin-4-yl)-propyl]- amide (48)
- the crude material was purified by silica gel chromatography eluting with a gradient of 0-10% methanol in dichloromethane.
- the material was further purified by preparative thin layer silica gel chromatography eluting with methanol-dichloromethane (2:98) to afford the title compound.
- the crude material was purified by silica gel chromatography eluting with a gradient of 0-10% methanol in dichloromethane. The purification was repeated eluting with a gradient of 0-7% methanol in dichloromethane. The material from the purification was diluted with dichloromethane (1 mL) followed by hexanes (5 mL). The solid was collected by filteration to afford the title compound.
- Example 54 Synthesis of l-(4-Fluorophenyl)-lH-pyrazolo[3,4-c]pyridine-4- carboxylic acid (5-methylamino-l,3,4-thiadiazol-2-ylmethyl)-amide (54)
- the compound was purified by silica gel chromatography eluting with a gradient of 0-100% ethyl acetate in hexanes provided l-(2-bromo-thiazol-5-yl)-propan-l-ol.
- the compound was purified by silica gel chromatography eluting with a gradient of 0-100% ethyl acetate in hexanes to afford l-(2-bromo-thiazol-5-yl)-propan-l-one.
- the organic layer was washed with saturated aqueous sodium bicarbonate (100 mL), dried over sodium sulfate, filtered and concentrated.
- the material was purified by silica gel chromatography eluting with a gradient of 0-10% methanol in dichloromethane. Two fractions were obtained that both match the desired by mass, indicating two diastereomers.
- the first eluting diastereomer corresponded to the i ⁇ S-diastereomer
- the second eluting distereomer corresponded to the R,R- diastereomer in a 1:3 ratio, respectively.
- Each diastereomer was carried on separately without further purification.
- Example 60 Synthesis of l-(4-Fluorophenyl)-lH-pyrazolo[3,4-c]pyridine-4- carboxylic acid [l-(4-carbamoyl-5-methyl-oxazol-2-yl)-propyl]-amide (60)
- Example 61 Synthesis of l-(4-Fluorophenyl)-lH-pyrazolo[3,4-c]pyridine-4- carboxylic acid [l-(5-methyl-4-methylcarbamoyl-oxazol-2-yl)-propyl]-amide (61)
- Example 63 Synthesis of l-(4-Fluorophenyl)-lH-pyrazolo[3,4-c]pyridine-4- carboxylic acid ⁇ l-[4-(carbamoylmethyl-carbamoyl)-5-methyl-oxazol-2-yl]-propyl ⁇ - amide (63)
- Example 70 Synthesis of l-(4-Fluorophenyl)-lH-pyrazolo[3,4-c]pyridine-4- carboxylic acid [(S)-l-(2-methanesulfonyl-pyridin-4-yl)-2-(2-oxo-l,3-dioxolan-4-yl)- ethyl]-amide (70)
- the 1 H NMR of the crude material revealed a 7:3 ratio of diastereomers, 2-methyl-propane-2- sulfinic acid [(S)- l-(3-bromo-isoxazol-5-yl)-propyl] -amide and 2-methyl-propane-2- sulfinic acid [(R)- l-(3-bromo-isoxazol-5-yl)-propyl] -amide, respectively.
- the mixture was purified by silica gel chromatography eluting with a gradient of 20-100% EtOAc in heptane. MS m/z 309.41 (M), 311.38 (M+2).
- the reaction was re- subjected to the above condition for an additional 5 hours at which time the mixture was filtered through diatomaceous earth, rinsed with MeOH, filtered and concentrated.
- the crude material was purified by reversed-phase HPLC (Sunfire PrepCl ⁇ OBD 5 uM 30 x 150 mm column, eluted with 15-85% acetonitrile in water, with 0.1% TFA). Fractions containing the desired product were concentrated in vacuo, made basic with a few drops of saturated sodium bicarbonate solution and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated to afford the title compound as a white solid.
- Example 80 Synthesis of l-(4-Fluorophenyl)-lH-pyrazolo[3,4-c]pyridine-4- carboxylic acid [(5)-l-((25,4/f)-2-carbamoyl-l-methanesulfonyl-piperidin-4-yl)- propyl]-amide (80a) and l-(4-Fluorophenyl)-lH-pyrazolo[3,4-c]pyridine-4- carboxylic acid [(S)-l-((2/f,4S)-2-carbamoyl-l-methanesulfonyl-piperidin-4-yl)- propyl]-amide (80b)
- Example 81 Synthesis of l-(4-Fluorophenyl)-lH-pyrazolo[3,4-c]pyridine-4- carboxylic acid [(S)-l-(2-hydroxymethyl-pyridin-4-yl)-propyl]-amide (81)
- the intermediate ketone, l-(2-bromo-pyridin-4-yl)-propan-l-one can be prepared via a Grignard addition to a Weinreb amide derived from commercially available 2-bromo-isonicotinic acid.
- (l-(2-bromo-pyridin-4-yl)-propan-l-one could be converted to the corresponding methyl sulfone via the above procedure to afford l-(2-methanesulfonyl- pyridin-4-yl)-propan-l-one.
- l-(2-Methanesulfonyl-pyridin-4-yl)-propan-l-one can be converted to the title compound by methods described in example 82.
- Example 83 Synthesis of l-(4-Fluorophenyl)-lH-pyrazolo[3,4-c]pyridine-4- carboxylic acid [(S)-l-(2-methanesulfonyl-pyridin-4-yl)-propyl]-amide (83)
- Example 84 Synthesis of l-(4-Fluorophenyl)-lH-pyrazolo[3,4-c]pyridine-4- carboxylic acid [(/f)-l-(2-bromo-pyridin-4-yl)-2-methoxy-ethyl]-amide (84) HCI
- Example 85 l-(4-Fluorophenyl)-lH-pyrazolo[3,4-c]pyridine-4-carboxylic acid [(S)- l-[2-(4-methyl-piperazin-l-yl)-pyridin-4-yl]-propyl ⁇ -amide (85)
- the crude material was filtered through diatomaceous earth and washed with EtOAc (200 mL). The aqueous layer was separated and extracted with EtOAc (100 mL). The combined organic layers were washed with saturated aqueous sodium carbonate (100 mL), brine (100 mL), dried over magnesium sulfate, filtered and concentrated.
- the crude material was purified by silica gel chromatography eluting with a gradient of 5-30% EtOAc in hexanes to afford 1- (2-bromo-pyridin-4-yl)-ethanone as white needles.
- the intermediate ketone (l-(2-bromo-pyridin-4-yl)-ethanone) can be accessed via a Grignard addition to a Weinreb amide derived from commercially available 2-bromo-isonicotinic acid.
- the reaction was diluted with saturated aqueous NH 4 Cl (90 mL), saturated aqueous NaHCO 3 (10 mL), and EtOAc (150 mL), and sonicated for 10 minutes to dissolve all the solids.
- the aqueous phase was separated and the organic layer was washed with a mixture of saturated aqueous NH 4 Cl (90 mL) in saturated aqueous NaHCO 3 (10 mL).
- the combined aqueous layers were extracted with EtOAc (150 mL).
- the combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated.
- (l-(2-bromo-pyridin-4-yl)-ethanone) could be converted to the corresponding methyl sulfone via the above procedure to afford l-(2-methanesulfonyl- pyridin-4-yl)-ethanone.
- l-(2-Methanesulfonyl-pyridin-4-yl)-ethanone can be converted to the title compound by methods described in example 86.
- the solid was adsorbed onto silica gel and purified by silica gel chromatography eluting with a gradient of 10-50% ethyl acetate in hexanes (compound precipitated on the column but dissolved over time at high ethyl acetate concentration) to afford 6- (dimethylaminosulfonylamino)-3-cyanopyridine as a white solid
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Immunology (AREA)
- Diabetes (AREA)
- Pulmonology (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Hematology (AREA)
- Dermatology (AREA)
- Rheumatology (AREA)
- Emergency Medicine (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Obesity (AREA)
- Hospice & Palliative Care (AREA)
- Psychiatry (AREA)
- Pain & Pain Management (AREA)
- Endocrinology (AREA)
- Transplantation (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Physical Education & Sports Medicine (AREA)
- Urology & Nephrology (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Abstract
Description
Claims
Priority Applications (15)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP09792818.8A EP2346868B1 (en) | 2008-09-26 | 2009-09-22 | Azaindazole compounds as ccr1 receptor antagonists |
CN2009801472064A CN102227425A (en) | 2008-09-26 | 2009-09-22 | Azaindazole compounds as ccr1 receptor antagonists |
JP2011529154A JP5507567B2 (en) | 2008-09-26 | 2009-09-22 | Azaindazole compounds as CCR1 receptor antagonists |
AP2011005685A AP2739A (en) | 2008-09-26 | 2009-09-22 | Azaindazole compounds as CCRI receptor antagonists |
AU2009296839A AU2009296839A1 (en) | 2008-09-26 | 2009-09-22 | Azaindazole compounds as CCR1 receptor antagonists |
MX2011002951A MX2011002951A (en) | 2008-09-26 | 2009-09-22 | Azaindazole compounds as ccr1 receptor antagonists. |
BRPI0919844A BRPI0919844A2 (en) | 2008-09-26 | 2009-09-22 | azaindazole compounds as ccr1 receptor antagonists |
EA201100524A EA201100524A1 (en) | 2008-09-26 | 2009-09-22 | AZAINDAZOLES AS ANTAGONISTS OF CCR1 RECEPTOR |
CA2737472A CA2737472A1 (en) | 2008-09-26 | 2009-09-22 | Azaindazole compounds as ccr1 receptor antagonists |
UAA201105061A UA103634C2 (en) | 2008-09-26 | 2009-09-22 | Azaindazole compounds as ccr1 receptor antagonists |
NZ591115A NZ591115A (en) | 2008-09-26 | 2009-09-22 | Azaindazole compounds as ccr1 receptor antagonists |
ZA2011/00625A ZA201100625B (en) | 2008-09-26 | 2011-01-25 | Azaindazole compounds as ccr1 receptor antagonists |
IL210857A IL210857A0 (en) | 2008-09-26 | 2011-01-25 | Azaindazole compounds as ccr1 receptor antagonists |
TN2011000144A TN2011000144A1 (en) | 2009-09-22 | 2011-03-24 | Composes azaindazole en tant qu'antagonistes des recepteurs ccri |
MA33724A MA32655B1 (en) | 2008-09-26 | 2011-03-24 | Compounds selectively modulating the cb2 receptor |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US10040108P | 2008-09-26 | 2008-09-26 | |
US61/100,401 | 2008-09-26 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2010036632A1 true WO2010036632A1 (en) | 2010-04-01 |
Family
ID=41349302
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2009/057778 WO2010036632A1 (en) | 2008-09-26 | 2009-09-22 | Azaindazole compounds as ccr1 receptor antagonists |
Country Status (24)
Country | Link |
---|---|
US (4) | US7879873B2 (en) |
EP (1) | EP2346868B1 (en) |
JP (1) | JP5507567B2 (en) |
KR (1) | KR20110060904A (en) |
CN (1) | CN102227425A (en) |
AP (1) | AP2739A (en) |
AR (1) | AR073689A1 (en) |
AU (1) | AU2009296839A1 (en) |
BR (1) | BRPI0919844A2 (en) |
CA (1) | CA2737472A1 (en) |
CL (1) | CL2011000668A1 (en) |
CO (1) | CO6351735A2 (en) |
EA (1) | EA201100524A1 (en) |
EC (1) | ECSP11010932A (en) |
IL (1) | IL210857A0 (en) |
MA (1) | MA32655B1 (en) |
MX (1) | MX2011002951A (en) |
NZ (1) | NZ591115A (en) |
PE (1) | PE20110854A1 (en) |
TW (1) | TW201018683A (en) |
UA (1) | UA103634C2 (en) |
UY (1) | UY32140A (en) |
WO (1) | WO2010036632A1 (en) |
ZA (1) | ZA201100625B (en) |
Cited By (24)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2010106333A1 (en) * | 2009-03-19 | 2010-09-23 | Medical Research Council Technology | Compounds |
US7879873B2 (en) | 2008-09-26 | 2011-02-01 | Boehringer Ingelheim International Gmbh | Azaindazole compounds as CCR1 receptor antagonists |
WO2011056440A1 (en) * | 2009-10-27 | 2011-05-12 | Boehringer Ingelheim International Gmbh | Heterocyclic compounds as ccr1 receptor antagonists |
WO2011071730A1 (en) | 2009-12-08 | 2011-06-16 | Boehringer Ingelheim International Gmbh | Process for synthesis of intermediates useful for making substituted indazole and azaindazole compounds |
US8008327B2 (en) | 2008-04-29 | 2011-08-30 | Boehringer Ingelheim International Gmbh | Indazole compounds as CCR1 receptor antagonists |
WO2011137109A1 (en) * | 2010-04-30 | 2011-11-03 | Boehringer Ingelheim International Gmbh | Azaindazole amide compounds as ccr1 receptor antagonists |
US20110288294A1 (en) * | 2010-05-21 | 2011-11-24 | Michael Nonnenmacher | Preparation process for an inhibitor of a blood clotting factor |
WO2012087782A1 (en) | 2010-12-23 | 2012-06-28 | Boehringer Ingelheim International Gmbh | Pyrazolopiperidine compounds as ccr1 receptor antagonists |
US8293917B2 (en) | 2008-05-06 | 2012-10-23 | Boehringer Ingelheim International Gmbh | Pyrazole compounds as CCR1 antagonists |
CN102775365A (en) * | 2011-05-10 | 2012-11-14 | 无锡立诺康医药科技有限公司 | Synthesis process for 5-amino-substitued-isoxazole compound or acid salt thereof |
WO2012163848A1 (en) | 2011-05-27 | 2012-12-06 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and pharmaceutical compositions for the treatment of crohn's disease |
WO2013060865A1 (en) | 2011-10-28 | 2013-05-02 | Galderma Research & Development | New leukocyte infiltrate markers for rosacea and uses thereof |
US8598167B1 (en) | 2011-02-28 | 2013-12-03 | Epizyme, Inc. | Substituted 6,5-fused bicyclic heteroaryl compounds |
EP2771011A1 (en) * | 2011-10-24 | 2014-09-03 | Glaxosmithkline Intellectual Property (No. 2) Limited | Chemical compounds |
US9056858B2 (en) | 2009-10-21 | 2015-06-16 | Boehringer Ingelheim International Gmbh | Indazole and pyrazolopyridine compounds as CCR1 receptor antagonists |
FR3016880A1 (en) * | 2014-01-29 | 2015-07-31 | Guillaume Laconde | PROCESS FOR THE PREPARATION OF N-ACYL BENZOTRIAZOLE |
WO2015140658A1 (en) | 2014-03-17 | 2015-09-24 | Pfizer Inc. | Diacylglycerol acyltransferase 2 inhibitors for use in the treatment of metabolic and related disorders |
EP2877458A4 (en) * | 2012-07-25 | 2016-08-10 | Sova Pharmaceuticals Inc | Cystathionine-y-gamma-lyase (cse) inhibitors |
WO2017068089A2 (en) | 2015-10-23 | 2017-04-27 | Vifor (International) Ag | Novel ferroportin inhibitors |
WO2017081312A1 (en) | 2015-11-13 | 2017-05-18 | Basf Se | Substituted oxadiazoles for combating phytopathogenic fungi |
WO2017081310A1 (en) | 2015-11-13 | 2017-05-18 | Basf Se | Substituted oxadiazoles for combating phytopathogenic fungi |
WO2017155909A1 (en) | 2016-03-07 | 2017-09-14 | The Global Alliance For Tb Drug Development, Inc. | Antibacterial compounds and uses thereof |
WO2018192973A1 (en) | 2017-04-18 | 2018-10-25 | Vifor (International) Ag | Ferroportin-inhibitor salts |
US10272072B2 (en) | 2010-09-03 | 2019-04-30 | Forma Tm, Llc | Compounds and compositions for the inhibition of NAMPT |
Families Citing this family (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2820017B1 (en) * | 2012-03-02 | 2016-12-21 | Genentech, Inc. | Pyridinyl and pyrimidinyl sulfoxide and sulfone derivatives |
EP2970306A4 (en) * | 2013-03-15 | 2016-08-03 | Epizyme Inc | Substituted 6,5-fused bicyclic heteroaryl compounds |
US9045477B2 (en) * | 2013-03-15 | 2015-06-02 | Epizyme, Inc. | Substituted 6,5-fused bicyclic heteroaryl compounds |
BR112016021962A2 (en) | 2014-04-14 | 2023-01-20 | Boehringer Ingelheim Int | COMPOUNDS, PHARMACEUTICAL COMPOSITION AND THEIR USES AS GAMMA ROR MODULATORS |
CN111393376B (en) * | 2020-05-11 | 2022-05-13 | 安徽赛迪生物科技有限公司 | Synthetic method of 2-chloropyrimidine-4-formic acid |
WO2021262878A1 (en) * | 2020-06-24 | 2021-12-30 | Oregon Health & Science University | Novel molecule for modulation of innate immune responses controlled by sting protein |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2003105853A1 (en) * | 2002-06-12 | 2003-12-24 | Chemocentryx, Inc. | 1-aryl-4-substituted piperazines derivatives for use as ccr1 antagonists for the treatment of inflammation and immune disorders |
WO2007002293A2 (en) * | 2005-06-22 | 2007-01-04 | Chemocentryx, Inc. | Azaindazole compounds and methods of use |
Family Cites Families (56)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5242931A (en) | 1988-06-09 | 1993-09-07 | Kyowa Hakko Kogyo Co., Ltd. | Tricyclic compounds as TXA2 antagonists |
US4999363A (en) | 1988-06-09 | 1991-03-12 | Kyowa Hakko Kogyo Co., Ltd. | Tricyclic compounds |
US5750542A (en) | 1993-09-28 | 1998-05-12 | Pfizer | Benzisoxazole and benzisothizole derivatives as cholinesterase inhibitors |
BR9205811A (en) | 1991-03-28 | 1994-06-28 | Pfizer | Heterocyclic derivatives of cyclic amines |
US5612360A (en) | 1992-06-03 | 1997-03-18 | Eli Lilly And Company | Angiotensin II antagonists |
RU2105005C1 (en) | 1992-07-03 | 1998-02-20 | Кумиай Кемикал Индастри Ко., Лтд. | Condensed heterocyclic derivative, method of its synthesis and herbicide agent |
WO1995000509A1 (en) | 1993-06-25 | 1995-01-05 | Kumiai Chemical Industry Co., Ltd. | Indazolesulfonylurea derivative, use thereof, and intermediate for production thereof |
CA2207201A1 (en) | 1994-12-06 | 1996-06-13 | Caroline Henry | Azetidine, pyrrolidine and piperidine derivatives as 5ht1 receptor agonists |
GB9519563D0 (en) | 1995-09-26 | 1995-11-29 | Merck Sharp & Dohme | Therapeutic agents |
GB9523583D0 (en) | 1995-11-17 | 1996-01-17 | Merck Sharp & Dohme | Therapeutic agents |
US5760028A (en) | 1995-12-22 | 1998-06-02 | The Dupont Merck Pharmaceutical Company | Integrin receptor antagonists |
WO1997023480A1 (en) | 1995-12-22 | 1997-07-03 | The Du Pont Merck Pharmaceutical Company | Novel integrin receptor antagonists |
JPH101478A (en) | 1996-06-11 | 1998-01-06 | Kumiai Chem Ind Co Ltd | Indazolesulfonylurea derivative and herbicide |
GB9615449D0 (en) | 1996-07-23 | 1996-09-04 | Merck Sharp & Dohme | Therapeutic agents |
KR20010031783A (en) | 1997-11-04 | 2001-04-16 | 데이비드 존 우드 | Therapeutically Active Compounds Based on Indazole Bioisostere Replacement of Catechol in PDE4 Inhibitors |
US6331640B1 (en) | 1998-10-13 | 2001-12-18 | Hoffmann-La Roche Inc. | Diaminopropionic acid derivatives |
WO2000076970A2 (en) | 1999-06-14 | 2000-12-21 | Eli Lilly And Company | Serine protease inhibitors |
AU5414000A (en) | 1999-06-14 | 2001-01-02 | Eli Lilly And Company | Compounds |
AU5895500A (en) | 1999-06-29 | 2001-01-31 | Cor Therapeutics, Inc. | Novel indazole peptidomimetics as thrombin receptor antagonists |
GB0030306D0 (en) | 2000-12-13 | 2001-01-24 | Lilly Co Eli | Compounds |
GB0030303D0 (en) | 2000-12-13 | 2001-01-24 | Lilly Co Eli | Compounds |
GB0030304D0 (en) | 2000-12-13 | 2001-01-24 | Lilly Co Eli | Compounds |
GB0030305D0 (en) | 2000-12-13 | 2001-01-24 | Lilly Co Eli | Compounds |
US6897231B2 (en) | 2000-07-31 | 2005-05-24 | Signal Pharmaceuticals, Inc. | Indazole derivatives as JNK inhibitors and compositions and methods related thereto |
US7211594B2 (en) | 2000-07-31 | 2007-05-01 | Signal Pharmaceuticals, Llc | Indazole compounds and compositions thereof as JNK inhibitors and for the treatment of diseases associated therewith |
US20050009876A1 (en) | 2000-07-31 | 2005-01-13 | Bhagwat Shripad S. | Indazole compounds, compositions thereof and methods of treatment therewith |
US7058826B2 (en) | 2000-09-27 | 2006-06-06 | Amphus, Inc. | System, architecture, and method for logical server and other network devices in a dynamically configurable multi-server network environment |
US20020052373A1 (en) | 2000-10-26 | 2002-05-02 | Zorn Stevin H. | Combination treatment for dementia or cognitive deficits associated with alzheimer's disease and parkinson's disease |
CA2465207C (en) | 2001-11-01 | 2011-01-04 | Icagen, Inc. | Pyrazole-amides and -sulfonamides |
WO2008011131A2 (en) | 2006-07-21 | 2008-01-24 | Takeda Pharmaceutical Company Limited | Amide compounds |
WO2003053941A2 (en) * | 2001-12-20 | 2003-07-03 | Bristol-Myers Squibb Company | Barbituric acid derivatives as inhibitors of tnf-alpha converting enzyme (tace) and/or matrix metalloproteinases |
EP1497278B1 (en) | 2002-04-11 | 2010-05-26 | Boehringer Ingelheim Pharmaceuticals Inc. | Heterocyclic amide derivatives as cytokine inhibitors |
WO2003101968A1 (en) | 2002-05-31 | 2003-12-11 | Eisai Co., Ltd. | Pyrazole compound and medicinal composition containing the same |
TW200500341A (en) | 2002-11-12 | 2005-01-01 | Astrazeneca Ab | Novel compounds |
SE0203825D0 (en) | 2002-12-20 | 2002-12-20 | Astrazeneca Ab | Novel fused heterocycles and uses thereof |
US7129264B2 (en) | 2003-04-16 | 2006-10-31 | Bristol-Myers Squibb Company | Biarylmethyl indolines and indoles as antithromboembolic agents |
US20040220170A1 (en) | 2003-05-01 | 2004-11-04 | Atkinson Robert N. | Pyrazole-amides and sulfonamides as sodium channel modulators |
JP2007502307A (en) | 2003-08-15 | 2007-02-08 | アストラゼネカ アクチボラグ | Fused heterocycles as inhibitors of glutamate racemase (MURI) |
US7960417B2 (en) | 2005-02-24 | 2011-06-14 | Merck Sharp & Dohme Corp. | Benzazole potentiators of metabotropic glutamate receptors |
GB0504828D0 (en) * | 2005-03-09 | 2005-04-13 | Merck Sharp & Dohme | Therapeutic agents |
LT2444079T (en) | 2005-05-17 | 2017-03-27 | Sarcode Bioscience Inc. | Compositions and Methods for Treatment of Eye Disorders |
WO2007028083A2 (en) | 2005-09-01 | 2007-03-08 | Eli Lilly And Company | 6-arylalkylamino- 2,3,4,5-tetrahydro-1h-benzo[d]azepines as 5-ht2c receptor agonists |
EP1940394A4 (en) | 2005-10-25 | 2009-07-08 | Smithkline Beecham Corp | Chemical compounds |
TW200829578A (en) * | 2006-11-23 | 2008-07-16 | Astrazeneca Ab | Chemical compounds 537 |
CN101743242A (en) * | 2007-06-29 | 2010-06-16 | 苏尼西斯制药有限公司 | Heterocyclic compounds useful as RAF kinase inhibitors |
CA2696725A1 (en) | 2007-08-10 | 2009-03-26 | Crystalgenomics, Inc. | Pyridine derivatives and methods of use thereof |
GB0716292D0 (en) | 2007-08-21 | 2007-09-26 | Biofocus Dpi Ltd | Imidazopyrazine compounds |
WO2009085256A1 (en) * | 2007-12-27 | 2009-07-09 | Panacos Pharmaceuticals, Inc. | Anti-hiv compounds |
US8008327B2 (en) | 2008-04-29 | 2011-08-30 | Boehringer Ingelheim International Gmbh | Indazole compounds as CCR1 receptor antagonists |
CA2722811C (en) | 2008-05-06 | 2016-07-05 | Boehringer Ingelheim International Gmbh | Pyrazole compounds as ccr1 antagonists |
CN102227425A (en) | 2008-09-26 | 2011-10-26 | 贝林格尔·英格海姆国际有限公司 | Azaindazole compounds as ccr1 receptor antagonists |
KR20120087923A (en) | 2009-10-21 | 2012-08-07 | 베링거 인겔하임 인터내셔날 게엠베하 | Indazole and pyrazolopyridine compounds as ccr1 receptor antagonists |
EP2493875B1 (en) | 2009-10-27 | 2014-08-06 | Boehringer Ingelheim International GmbH | Heterocyclic compounds as ccr1 receptor antagonists |
CN102596908A (en) | 2009-12-08 | 2012-07-18 | 贝林格尔.英格海姆国际有限公司 | Process for synthesis of intermediates useful for making substituted indazole and azaindazole compounds |
JP5793182B2 (en) | 2010-04-30 | 2015-10-14 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | Azaindazole amide compounds as CCR1 receptor antagonists |
EP2655371B1 (en) | 2010-12-23 | 2015-02-25 | Boehringer Ingelheim International GmbH | Pyrazolopiperidine compounds as ccr1 receptor antagonists |
-
2009
- 2009-09-22 CN CN2009801472064A patent/CN102227425A/en active Pending
- 2009-09-22 NZ NZ591115A patent/NZ591115A/en not_active IP Right Cessation
- 2009-09-22 MX MX2011002951A patent/MX2011002951A/en active IP Right Grant
- 2009-09-22 PE PE2011000789A patent/PE20110854A1/en not_active Application Discontinuation
- 2009-09-22 JP JP2011529154A patent/JP5507567B2/en active Active
- 2009-09-22 AU AU2009296839A patent/AU2009296839A1/en not_active Abandoned
- 2009-09-22 UA UAA201105061A patent/UA103634C2/en unknown
- 2009-09-22 KR KR1020117006720A patent/KR20110060904A/en not_active Application Discontinuation
- 2009-09-22 US US12/564,129 patent/US7879873B2/en active Active
- 2009-09-22 EA EA201100524A patent/EA201100524A1/en unknown
- 2009-09-22 CA CA2737472A patent/CA2737472A1/en not_active Abandoned
- 2009-09-22 WO PCT/US2009/057778 patent/WO2010036632A1/en active Application Filing
- 2009-09-22 BR BRPI0919844A patent/BRPI0919844A2/en not_active IP Right Cessation
- 2009-09-22 AP AP2011005685A patent/AP2739A/en active
- 2009-09-22 EP EP09792818.8A patent/EP2346868B1/en active Active
- 2009-09-24 UY UY0001032140A patent/UY32140A/en not_active Application Discontinuation
- 2009-09-25 TW TW098132530A patent/TW201018683A/en unknown
- 2009-09-25 AR ARP090103709A patent/AR073689A1/en unknown
-
2010
- 2010-12-16 US US12/969,753 patent/US8063065B2/en active Active
-
2011
- 2011-01-25 IL IL210857A patent/IL210857A0/en unknown
- 2011-01-25 ZA ZA2011/00625A patent/ZA201100625B/en unknown
- 2011-03-17 CO CO11033549A patent/CO6351735A2/en active IP Right Grant
- 2011-03-24 MA MA33724A patent/MA32655B1/en unknown
- 2011-03-25 CL CL2011000668A patent/CL2011000668A1/en unknown
- 2011-03-29 EC EC2011010932A patent/ECSP11010932A/en unknown
- 2011-10-14 US US13/273,509 patent/US8163918B2/en active Active
-
2012
- 2012-02-08 US US13/368,397 patent/US8338610B2/en active Active
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2003105853A1 (en) * | 2002-06-12 | 2003-12-24 | Chemocentryx, Inc. | 1-aryl-4-substituted piperazines derivatives for use as ccr1 antagonists for the treatment of inflammation and immune disorders |
WO2007002293A2 (en) * | 2005-06-22 | 2007-01-04 | Chemocentryx, Inc. | Azaindazole compounds and methods of use |
Cited By (47)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8008327B2 (en) | 2008-04-29 | 2011-08-30 | Boehringer Ingelheim International Gmbh | Indazole compounds as CCR1 receptor antagonists |
US8263597B2 (en) | 2008-04-29 | 2012-09-11 | Boehringer Ingelheim International Gmbh | Indazole compounds as CCR1 receptor antagonists |
US8293917B2 (en) | 2008-05-06 | 2012-10-23 | Boehringer Ingelheim International Gmbh | Pyrazole compounds as CCR1 antagonists |
US7879873B2 (en) | 2008-09-26 | 2011-02-01 | Boehringer Ingelheim International Gmbh | Azaindazole compounds as CCR1 receptor antagonists |
US8063065B2 (en) | 2008-09-26 | 2011-11-22 | Boehringer Ingelheim International Gmbh | Azaindazole compounds as CCR1 receptor antagonists |
US8163918B2 (en) | 2008-09-26 | 2012-04-24 | Boehringer Ingelheim International Gmbh | Azaindazole compounds as CCR1 receptor antagonists |
US8338610B2 (en) | 2008-09-26 | 2012-12-25 | Boehringer Ingelheim International Gmbh | Pyridinyl compounds useful as intermediates |
WO2010106333A1 (en) * | 2009-03-19 | 2010-09-23 | Medical Research Council Technology | Compounds |
US9056858B2 (en) | 2009-10-21 | 2015-06-16 | Boehringer Ingelheim International Gmbh | Indazole and pyrazolopyridine compounds as CCR1 receptor antagonists |
WO2011056440A1 (en) * | 2009-10-27 | 2011-05-12 | Boehringer Ingelheim International Gmbh | Heterocyclic compounds as ccr1 receptor antagonists |
US8927550B2 (en) | 2009-10-27 | 2015-01-06 | Boehringer Ingelheim International Gmbh | Heterocyclic compounds as CCR1 receptor antagonists |
JP2013512954A (en) * | 2009-12-08 | 2013-04-18 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | Methods for the synthesis of intermediates effective in the formation of substituted indazole and azaindazole compounds |
WO2011071730A1 (en) | 2009-12-08 | 2011-06-16 | Boehringer Ingelheim International Gmbh | Process for synthesis of intermediates useful for making substituted indazole and azaindazole compounds |
WO2011137109A1 (en) * | 2010-04-30 | 2011-11-03 | Boehringer Ingelheim International Gmbh | Azaindazole amide compounds as ccr1 receptor antagonists |
US8871786B2 (en) | 2010-04-30 | 2014-10-28 | Boehringer Ingelheim International Gmbh | Azaindazole amide compounds as CCR1 receptor antagonists |
US20110288294A1 (en) * | 2010-05-21 | 2011-11-24 | Michael Nonnenmacher | Preparation process for an inhibitor of a blood clotting factor |
US11547701B2 (en) | 2010-09-03 | 2023-01-10 | Valo Health, Inc. | Compounds and compositions for the inhibition of NAMPT |
US10772874B2 (en) | 2010-09-03 | 2020-09-15 | Forma Tm, Llc | Compounds and compositions for the inhibition of NAMPT |
US10456382B2 (en) | 2010-09-03 | 2019-10-29 | Forma Tm, Llc | Compounds and compositions for the inhibition of NAMPT |
US10272072B2 (en) | 2010-09-03 | 2019-04-30 | Forma Tm, Llc | Compounds and compositions for the inhibition of NAMPT |
WO2012087782A1 (en) | 2010-12-23 | 2012-06-28 | Boehringer Ingelheim International Gmbh | Pyrazolopiperidine compounds as ccr1 receptor antagonists |
US8546442B2 (en) | 2010-12-23 | 2013-10-01 | Boehringer Ingelheim International Gmbh | Pyrazolopiperidine compounds as CCR1 receptor antagonists |
US8962620B2 (en) | 2011-02-28 | 2015-02-24 | Epizyme, Inc. | Substituted 6,5-fused bicyclic heteroaryl compounds |
US10273223B2 (en) | 2011-02-28 | 2019-04-30 | Epizyme, Inc. | Substituted 6,5-fused bicyclic heteroaryl compounds |
US8598167B1 (en) | 2011-02-28 | 2013-12-03 | Epizyme, Inc. | Substituted 6,5-fused bicyclic heteroaryl compounds |
US9637472B2 (en) | 2011-02-28 | 2017-05-02 | Epizyme, Inc. | Substituted 6,5-fused bicyclic heteroaryl compounds |
US9206157B2 (en) | 2011-02-28 | 2015-12-08 | Epizyme, Inc. | Substituted 6,5-fused bicyclic heteroaryl compounds |
CN102775365A (en) * | 2011-05-10 | 2012-11-14 | 无锡立诺康医药科技有限公司 | Synthesis process for 5-amino-substitued-isoxazole compound or acid salt thereof |
WO2012163848A1 (en) | 2011-05-27 | 2012-12-06 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and pharmaceutical compositions for the treatment of crohn's disease |
EP2771011A1 (en) * | 2011-10-24 | 2014-09-03 | Glaxosmithkline Intellectual Property (No. 2) Limited | Chemical compounds |
US9174984B2 (en) | 2011-10-24 | 2015-11-03 | Glaxosmithkline Intellectual Property (No.2) Limited | Chemical compounds |
EP2771011A4 (en) * | 2011-10-24 | 2015-04-15 | Glaxosmithkline Ip No 2 Ltd | Chemical compounds |
WO2013060865A1 (en) | 2011-10-28 | 2013-05-02 | Galderma Research & Development | New leukocyte infiltrate markers for rosacea and uses thereof |
AU2018200635B2 (en) * | 2012-07-25 | 2019-07-04 | Sova Pharmaceuticals, Inc. | Cystathionine-y-gamma-lyase (CSE) inhibitors |
EP2877458A4 (en) * | 2012-07-25 | 2016-08-10 | Sova Pharmaceuticals Inc | Cystathionine-y-gamma-lyase (cse) inhibitors |
US9771339B2 (en) | 2012-07-25 | 2017-09-26 | Sova Pharmaceuticals, Inc. | Cystathionine-γ-lyase (CSE) inhibitors |
US10227314B2 (en) | 2012-07-25 | 2019-03-12 | Sova Pharmaceuticals, Inc. | Cystathionine-gamma-lyase (CSE) inhibitors |
FR3016880A1 (en) * | 2014-01-29 | 2015-07-31 | Guillaume Laconde | PROCESS FOR THE PREPARATION OF N-ACYL BENZOTRIAZOLE |
FR3016879A1 (en) * | 2014-01-29 | 2015-07-31 | Guillaume Laconde | PROCESS FOR THE PREPARATION OF N-ACYL BENZOTRIAZOLE |
WO2015140658A1 (en) | 2014-03-17 | 2015-09-24 | Pfizer Inc. | Diacylglycerol acyltransferase 2 inhibitors for use in the treatment of metabolic and related disorders |
WO2017068089A2 (en) | 2015-10-23 | 2017-04-27 | Vifor (International) Ag | Novel ferroportin inhibitors |
WO2017068089A3 (en) * | 2015-10-23 | 2017-07-27 | Vifor (International) Ag | Ferroportin inhibitors |
WO2017081312A1 (en) | 2015-11-13 | 2017-05-18 | Basf Se | Substituted oxadiazoles for combating phytopathogenic fungi |
WO2017081310A1 (en) | 2015-11-13 | 2017-05-18 | Basf Se | Substituted oxadiazoles for combating phytopathogenic fungi |
WO2017155909A1 (en) | 2016-03-07 | 2017-09-14 | The Global Alliance For Tb Drug Development, Inc. | Antibacterial compounds and uses thereof |
EP4148053A1 (en) | 2016-03-07 | 2023-03-15 | The Global Alliance for TB Drug Development, Inc. | Antibacterial compounds and uses thereof |
WO2018192973A1 (en) | 2017-04-18 | 2018-10-25 | Vifor (International) Ag | Ferroportin-inhibitor salts |
Also Published As
Publication number | Publication date |
---|---|
AP2739A (en) | 2013-09-30 |
ECSP11010932A (en) | 2011-04-29 |
JP5507567B2 (en) | 2014-05-28 |
US20110086846A1 (en) | 2011-04-14 |
PE20110854A1 (en) | 2011-12-23 |
US8338610B2 (en) | 2012-12-25 |
IL210857A0 (en) | 2011-04-28 |
BRPI0919844A2 (en) | 2019-09-24 |
US20120035370A1 (en) | 2012-02-09 |
JP2012503664A (en) | 2012-02-09 |
EP2346868A1 (en) | 2011-07-27 |
US7879873B2 (en) | 2011-02-01 |
CN102227425A (en) | 2011-10-26 |
AR073689A1 (en) | 2010-11-24 |
KR20110060904A (en) | 2011-06-08 |
UA103634C2 (en) | 2013-11-11 |
CL2011000668A1 (en) | 2011-10-28 |
EP2346868B1 (en) | 2016-01-27 |
MX2011002951A (en) | 2011-04-26 |
MA32655B1 (en) | 2011-09-01 |
ZA201100625B (en) | 2011-09-28 |
US8163918B2 (en) | 2012-04-24 |
UY32140A (en) | 2010-04-30 |
TW201018683A (en) | 2010-05-16 |
US8063065B2 (en) | 2011-11-22 |
US20100093724A1 (en) | 2010-04-15 |
AU2009296839A1 (en) | 2010-04-01 |
NZ591115A (en) | 2012-10-26 |
CO6351735A2 (en) | 2011-12-20 |
EA201100524A1 (en) | 2011-10-31 |
CA2737472A1 (en) | 2010-04-01 |
AP2011005685A0 (en) | 2011-04-30 |
US20120136158A1 (en) | 2012-05-31 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP2346868B1 (en) | Azaindazole compounds as ccr1 receptor antagonists | |
EP2493875B1 (en) | Heterocyclic compounds as ccr1 receptor antagonists | |
EP2297112B1 (en) | Pyrazole compounds as ccr1 antagonists | |
EP2424858B1 (en) | Cxcr3 receptor antagonists | |
EP2285783B1 (en) | Indazole compounds as ccr1 receptor antagonists | |
AU2007325780B9 (en) | Heteroaryl amide derivatives | |
EP2491028B1 (en) | Indazole and pyrazolopyridine compounds as ccr1 receptor antagonists | |
WO2007058832A2 (en) | Pyrrolo (2, 3-b) pyridine derivatives useful as tec kinase inhibitors | |
TW200900068A (en) | Novel N,N'-2,4-dianilinopyrimidine derivatives, the preparation thereof, their use as medicaments, pharmaceutical compositions and, in particular, as IKK inhibitors | |
CA2735521A1 (en) | Indolizine inhibitors of leukotriene production |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
WWE | Wipo information: entry into national phase |
Ref document number: 200980147206.4 Country of ref document: CN |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 09792818 Country of ref document: EP Kind code of ref document: A1 |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2009296839 Country of ref document: AU |
|
WWE | Wipo information: entry into national phase |
Ref document number: 591115 Country of ref document: NZ |
|
ENP | Entry into the national phase |
Ref document number: 2009296839 Country of ref document: AU Date of ref document: 20090922 Kind code of ref document: A |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2737472 Country of ref document: CA |
|
WWE | Wipo information: entry into national phase |
Ref document number: 11033549 Country of ref document: CO |
|
WWE | Wipo information: entry into national phase |
Ref document number: MX/A/2011/002951 Country of ref document: MX |
|
ENP | Entry into the national phase |
Ref document number: 20117006720 Country of ref document: KR Kind code of ref document: A |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2186/DELNP/2011 Country of ref document: IN |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2011000668 Country of ref document: CL Ref document number: 2011529154 Country of ref document: JP Ref document number: 000789-2011 Country of ref document: PE |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
WWE | Wipo information: entry into national phase |
Ref document number: 12011500641 Country of ref document: PH |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2009792818 Country of ref document: EP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 201100524 Country of ref document: EA |
|
WWE | Wipo information: entry into national phase |
Ref document number: DZP2011000287 Country of ref document: DZ |
|
ENP | Entry into the national phase |
Ref document number: PI0919844 Country of ref document: BR Kind code of ref document: A2 Effective date: 20110325 |