CA3050156A1 - Compounds - Google Patents
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- Publication number
- CA3050156A1 CA3050156A1 CA3050156A CA3050156A CA3050156A1 CA 3050156 A1 CA3050156 A1 CA 3050156A1 CA 3050156 A CA3050156 A CA 3050156A CA 3050156 A CA3050156 A CA 3050156A CA 3050156 A1 CA3050156 A1 CA 3050156A1
- Authority
- CA
- Canada
- Prior art keywords
- mmol
- group
- disease
- compound
- optionally substituted
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 285
- 238000011282 treatment Methods 0.000 claims abstract description 95
- 208000018737 Parkinson disease Diseases 0.000 claims abstract description 73
- 238000000034 method Methods 0.000 claims abstract description 72
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 claims abstract description 32
- 208000024827 Alzheimer disease Diseases 0.000 claims abstract description 27
- 108010020246 Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 Proteins 0.000 claims abstract description 10
- 125000001424 substituent group Chemical group 0.000 claims description 114
- 150000003839 salts Chemical class 0.000 claims description 113
- -1 C4-6heterocyclyl Chemical group 0.000 claims description 108
- 125000000623 heterocyclic group Chemical group 0.000 claims description 98
- 229910052757 nitrogen Inorganic materials 0.000 claims description 97
- 125000005843 halogen group Chemical group 0.000 claims description 88
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 85
- 102100032693 Leucine-rich repeat serine/threonine-protein kinase 2 Human genes 0.000 claims description 64
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 53
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 50
- 230000035772 mutation Effects 0.000 claims description 34
- 125000000217 alkyl group Chemical group 0.000 claims description 32
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 31
- 229910052760 oxygen Inorganic materials 0.000 claims description 29
- 229910052739 hydrogen Inorganic materials 0.000 claims description 28
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 27
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 25
- 239000003814 drug Substances 0.000 claims description 25
- 239000008194 pharmaceutical composition Substances 0.000 claims description 23
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 22
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 22
- CBOIHMRHGLHBPB-UHFFFAOYSA-N hydroxymethyl Chemical compound O[CH2] CBOIHMRHGLHBPB-UHFFFAOYSA-N 0.000 claims description 20
- 125000003545 alkoxy group Chemical group 0.000 claims description 18
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 15
- 238000004519 manufacturing process Methods 0.000 claims description 15
- 125000005842 heteroatom Chemical group 0.000 claims description 8
- 125000004122 cyclic group Chemical group 0.000 claims description 7
- 208000015122 neurodegenerative disease Diseases 0.000 claims description 7
- 230000004770 neurodegeneration Effects 0.000 claims description 6
- 125000006583 (C1-C3) haloalkyl group Chemical group 0.000 claims description 3
- 125000001153 fluoro group Chemical group F* 0.000 claims description 3
- 238000002560 therapeutic procedure Methods 0.000 claims description 3
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 2
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims 5
- 239000000203 mixture Substances 0.000 abstract description 266
- 230000000694 effects Effects 0.000 abstract description 16
- 102000009784 Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 Human genes 0.000 abstract description 9
- 238000002360 preparation method Methods 0.000 abstract description 7
- 230000008569 process Effects 0.000 abstract description 7
- 230000006806 disease prevention Effects 0.000 abstract 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 303
- 239000000243 solution Substances 0.000 description 232
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 201
- 239000007787 solid Substances 0.000 description 198
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 156
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 151
- 239000012071 phase Substances 0.000 description 150
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 146
- 239000011541 reaction mixture Substances 0.000 description 144
- 238000006243 chemical reaction Methods 0.000 description 121
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 120
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 116
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 114
- 229910052938 sodium sulfate Inorganic materials 0.000 description 114
- 235000011152 sodium sulphate Nutrition 0.000 description 114
- 239000007832 Na2SO4 Substances 0.000 description 113
- 239000000047 product Substances 0.000 description 111
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 107
- 238000005160 1H NMR spectroscopy Methods 0.000 description 98
- 239000012267 brine Substances 0.000 description 98
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 98
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 88
- DNUTZBZXLPWRJG-UHFFFAOYSA-M piperidine-1-carboxylate Chemical compound [O-]C(=O)N1CCCCC1 DNUTZBZXLPWRJG-UHFFFAOYSA-M 0.000 description 74
- 239000012044 organic layer Substances 0.000 description 67
- 101000941879 Homo sapiens Leucine-rich repeat serine/threonine-protein kinase 2 Proteins 0.000 description 63
- 238000010898 silica gel chromatography Methods 0.000 description 62
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 60
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 59
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 58
- 239000003208 petroleum Substances 0.000 description 58
- 201000010099 disease Diseases 0.000 description 53
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 53
- 229910000404 tripotassium phosphate Inorganic materials 0.000 description 52
- 235000019798 tripotassium phosphate Nutrition 0.000 description 52
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 47
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 47
- 238000004440 column chromatography Methods 0.000 description 44
- 239000003921 oil Substances 0.000 description 43
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 42
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 42
- 239000000706 filtrate Substances 0.000 description 38
- 239000000741 silica gel Substances 0.000 description 34
- 229910002027 silica gel Inorganic materials 0.000 description 34
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 33
- 239000002904 solvent Substances 0.000 description 31
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 30
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 29
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 29
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 description 29
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 28
- 239000001301 oxygen Chemical group 0.000 description 28
- 239000000725 suspension Substances 0.000 description 28
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 27
- 235000017557 sodium bicarbonate Nutrition 0.000 description 26
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 26
- 238000004809 thin layer chromatography Methods 0.000 description 24
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 23
- BAPJBEWLBFYGME-UHFFFAOYSA-N Methyl acrylate Chemical compound COC(=O)C=C BAPJBEWLBFYGME-UHFFFAOYSA-N 0.000 description 22
- 239000012074 organic phase Substances 0.000 description 22
- 125000003566 oxetanyl group Chemical group 0.000 description 22
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 21
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 21
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 21
- 238000000746 purification Methods 0.000 description 21
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 20
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 20
- KVKFRMCSXWQSNT-UHFFFAOYSA-N n,n'-dimethylethane-1,2-diamine Chemical compound CNCCNC KVKFRMCSXWQSNT-UHFFFAOYSA-N 0.000 description 19
- 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 18
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 18
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 18
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 description 18
- 239000012043 crude product Substances 0.000 description 17
- PQJJJMRNHATNKG-UHFFFAOYSA-N ethyl bromoacetate Chemical compound CCOC(=O)CBr PQJJJMRNHATNKG-UHFFFAOYSA-N 0.000 description 17
- 102200092160 rs34637584 Human genes 0.000 description 17
- 241000896938 Dikwa Species 0.000 description 16
- 125000004432 carbon atom Chemical group C* 0.000 description 16
- JRHPOFJADXHYBR-UHFFFAOYSA-N 1-n,2-n-dimethylcyclohexane-1,2-diamine Chemical compound CNC1CCCCC1NC JRHPOFJADXHYBR-UHFFFAOYSA-N 0.000 description 15
- 239000012230 colorless oil Substances 0.000 description 15
- 230000002265 prevention Effects 0.000 description 15
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 14
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 14
- 101150041968 CDC13 gene Proteins 0.000 description 13
- 125000004429 atom Chemical group 0.000 description 13
- 239000003153 chemical reaction reagent Substances 0.000 description 13
- 239000003112 inhibitor Substances 0.000 description 13
- 125000003386 piperidinyl group Chemical group 0.000 description 13
- PLRCTNAFIAHOAW-UHFFFAOYSA-N 4,6-diiodo-2-methylpyrimidine Chemical compound CC1=NC(I)=CC(I)=N1 PLRCTNAFIAHOAW-UHFFFAOYSA-N 0.000 description 12
- 229940124786 LRRK2 inhibitor Drugs 0.000 description 12
- 239000002585 base Substances 0.000 description 12
- 239000000460 chlorine Substances 0.000 description 12
- FPTGEALUVACZQM-UHFFFAOYSA-N 4,6-diiodo-2-methoxypyrimidine Chemical compound COC1=NC(I)=CC(I)=N1 FPTGEALUVACZQM-UHFFFAOYSA-N 0.000 description 11
- 239000002253 acid Substances 0.000 description 11
- 238000003818 flash chromatography Methods 0.000 description 11
- 239000000543 intermediate Substances 0.000 description 11
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 11
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 11
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Chemical compound CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 10
- 235000019439 ethyl acetate Nutrition 0.000 description 10
- 239000000377 silicon dioxide Substances 0.000 description 10
- 235000017550 sodium carbonate Nutrition 0.000 description 10
- 229910000029 sodium carbonate Inorganic materials 0.000 description 10
- TVTOCLWXRZCKIL-UHFFFAOYSA-N tert-butyl 4-(5-methyl-1H-indazol-6-yl)piperidine-1-carboxylate Chemical compound CC1=CC2=C(NN=C2)C=C1C1CCN(CC1)C(=O)OC(C)(C)C TVTOCLWXRZCKIL-UHFFFAOYSA-N 0.000 description 10
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 10
- ROADCYAOHVSOLQ-UHFFFAOYSA-N 3-oxetanone Chemical compound O=C1COC1 ROADCYAOHVSOLQ-UHFFFAOYSA-N 0.000 description 9
- 201000011240 Frontotemporal dementia Diseases 0.000 description 9
- 229910000024 caesium carbonate Inorganic materials 0.000 description 9
- 210000004027 cell Anatomy 0.000 description 9
- 239000003480 eluent Substances 0.000 description 9
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 9
- 125000006239 protecting group Chemical group 0.000 description 9
- 238000003786 synthesis reaction Methods 0.000 description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 8
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 8
- VQFAIAKCILWQPZ-UHFFFAOYSA-N bromoacetone Chemical compound CC(=O)CBr VQFAIAKCILWQPZ-UHFFFAOYSA-N 0.000 description 8
- 238000004587 chromatography analysis Methods 0.000 description 8
- RWTNPBWLLIMQHL-UHFFFAOYSA-N fexofenadine Chemical group C1=CC(C(C)(C(O)=O)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 RWTNPBWLLIMQHL-UHFFFAOYSA-N 0.000 description 8
- 230000006870 function Effects 0.000 description 8
- 239000002808 molecular sieve Substances 0.000 description 8
- 229910000069 nitrogen hydride Inorganic materials 0.000 description 8
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 8
- 238000002953 preparative HPLC Methods 0.000 description 8
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 8
- 239000012258 stirred mixture Substances 0.000 description 8
- 208000031261 Acute myeloid leukaemia Diseases 0.000 description 7
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 7
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 7
- 206010012289 Dementia Diseases 0.000 description 7
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 description 7
- 238000005481 NMR spectroscopy Methods 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 7
- 238000004296 chiral HPLC Methods 0.000 description 7
- 238000004128 high performance liquid chromatography Methods 0.000 description 7
- BIWOSRSKDCZIFM-UHFFFAOYSA-N piperidin-3-ol Chemical compound OC1CCCNC1 BIWOSRSKDCZIFM-UHFFFAOYSA-N 0.000 description 7
- 239000012453 solvate Substances 0.000 description 7
- 238000002636 symptomatic treatment Methods 0.000 description 7
- 125000005983 2,5-diazabicyclo[2.2.1]heptan-2-yl group Chemical group 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 206010021245 Idiopathic thrombocytopenic purpura Diseases 0.000 description 6
- 108091000080 Phosphotransferase Proteins 0.000 description 6
- 208000031981 Thrombocytopenic Idiopathic Purpura Diseases 0.000 description 6
- 201000003710 autoimmune thrombocytopenic purpura Diseases 0.000 description 6
- 208000035475 disorder Diseases 0.000 description 6
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 6
- 230000001717 pathogenic effect Effects 0.000 description 6
- 102000020233 phosphotransferase Human genes 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 6
- 229920006395 saturated elastomer Polymers 0.000 description 6
- 238000006467 substitution reaction Methods 0.000 description 6
- 229910052717 sulfur Inorganic materials 0.000 description 6
- 229940124597 therapeutic agent Drugs 0.000 description 6
- DIOHEXPTUTVCNX-UHFFFAOYSA-N 1,1,1-trifluoro-n-phenyl-n-(trifluoromethylsulfonyl)methanesulfonamide Chemical compound FC(F)(F)S(=O)(=O)N(S(=O)(=O)C(F)(F)F)C1=CC=CC=C1 DIOHEXPTUTVCNX-UHFFFAOYSA-N 0.000 description 5
- 208000011231 Crohn disease Diseases 0.000 description 5
- 229910004373 HOAc Inorganic materials 0.000 description 5
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 5
- 206010028980 Neoplasm Diseases 0.000 description 5
- 208000027089 Parkinsonian disease Diseases 0.000 description 5
- 206010034010 Parkinsonism Diseases 0.000 description 5
- 230000001594 aberrant effect Effects 0.000 description 5
- 235000011114 ammonium hydroxide Nutrition 0.000 description 5
- 239000012298 atmosphere Substances 0.000 description 5
- 229910052799 carbon Inorganic materials 0.000 description 5
- 239000003054 catalyst Substances 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- 125000001309 chloro group Chemical group Cl* 0.000 description 5
- 238000007796 conventional method Methods 0.000 description 5
- 238000005859 coupling reaction Methods 0.000 description 5
- 230000007547 defect Effects 0.000 description 5
- 239000002552 dosage form Substances 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 5
- 239000005457 ice water Substances 0.000 description 5
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 5
- 201000006417 multiple sclerosis Diseases 0.000 description 5
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 5
- 108090000623 proteins and genes Proteins 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- 150000003384 small molecules Chemical class 0.000 description 5
- 239000007858 starting material Substances 0.000 description 5
- QEXQBLSDCBIEAI-UHFFFAOYSA-N tert-butyl 4-(5-chloro-1H-indazol-6-yl)piperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(CC1)C1=CC2=C(C=NN2)C=C1Cl QEXQBLSDCBIEAI-UHFFFAOYSA-N 0.000 description 5
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-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
- VOKRXODWYVBLIB-UHFFFAOYSA-N 4,6-diiodo-2-methylsulfanylpyrimidine Chemical compound CSC1=NC(I)=CC(I)=N1 VOKRXODWYVBLIB-UHFFFAOYSA-N 0.000 description 4
- AJGFAOMMXJDNSZ-UHFFFAOYSA-N 4-(5-methyl-1H-indazol-6-yl)cyclohexan-1-one Chemical compound CC=1C=C2C=NNC2=CC=1C1CCC(CC1)=O AJGFAOMMXJDNSZ-UHFFFAOYSA-N 0.000 description 4
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- INBHOPYATVVLEM-UHFFFAOYSA-N 5-bromo-4-chloro-2-methylaniline Chemical compound CC1=CC(Cl)=C(Br)C=C1N INBHOPYATVVLEM-UHFFFAOYSA-N 0.000 description 4
- 208000012661 Dyskinesia Diseases 0.000 description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical class CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 4
- 208000012902 Nervous system disease Diseases 0.000 description 4
- 208000025966 Neurological disease Diseases 0.000 description 4
- 101100030361 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) pph-3 gene Proteins 0.000 description 4
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 4
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 4
- 239000005864 Sulphur Chemical group 0.000 description 4
- 150000007513 acids Chemical class 0.000 description 4
- 239000000556 agonist Substances 0.000 description 4
- 230000003281 allosteric effect Effects 0.000 description 4
- 102000003802 alpha-Synuclein Human genes 0.000 description 4
- 108090000185 alpha-Synuclein Proteins 0.000 description 4
- 229910052801 chlorine Inorganic materials 0.000 description 4
- 208000010877 cognitive disease Diseases 0.000 description 4
- 229940126214 compound 3 Drugs 0.000 description 4
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 4
- CSJLBAMHHLJAAS-UHFFFAOYSA-N diethylaminosulfur trifluoride Chemical compound CCN(CC)S(F)(F)F CSJLBAMHHLJAAS-UHFFFAOYSA-N 0.000 description 4
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 4
- 239000000284 extract Substances 0.000 description 4
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- 239000005720 sucrose Substances 0.000 description 1
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- MXDZFXHHNOXHLF-KWQFWETISA-N tert-butyl (1S,4S)-1-(hydroxymethyl)-2-oxa-5-azabicyclo[2.2.1]heptane-5-carboxylate Chemical compound OC[C@@]12OC[C@@H](N(C1)C(=O)OC(C)(C)C)C2 MXDZFXHHNOXHLF-KWQFWETISA-N 0.000 description 1
- UXAWXZDXVOYLII-UHFFFAOYSA-N tert-butyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate Chemical compound C1C2N(C(=O)OC(C)(C)C)CC1NC2 UXAWXZDXVOYLII-UHFFFAOYSA-N 0.000 description 1
- CKLZFKAQVPBCPX-UHFFFAOYSA-N tert-butyl 3-hydroxy-3-methyl-4-(5-methyl-1H-indazol-6-yl)piperidine-1-carboxylate Chemical compound C1(=C(C2CCN(CC2(C)O)C(=O)OC(C)(C)C)C=C2NN=CC2=C1)C CKLZFKAQVPBCPX-UHFFFAOYSA-N 0.000 description 1
- VWSBNWIPICCWAM-UHFFFAOYSA-N tert-butyl 3-methyl-4-oxopiperidine-1-carboxylate Chemical compound CC1CN(C(=O)OC(C)(C)C)CCC1=O VWSBNWIPICCWAM-UHFFFAOYSA-N 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- 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
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/08—Bridged systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/08—Bridged systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/08—Bridged systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Psychology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Enzymes And Modification Thereof (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Plural Heterocyclic Compounds (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2017072601 | 2017-01-25 | ||
| CNPCT/CN2017/072601 | 2017-01-25 | ||
| PCT/CN2018/073729 WO2018137593A1 (en) | 2017-01-25 | 2018-01-23 | Compounds |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA3050156A1 true CA3050156A1 (en) | 2018-08-02 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA3050156A Abandoned CA3050156A1 (en) | 2017-01-25 | 2018-01-23 | Compounds |
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|---|---|
| US (1) | US10858367B2 (enExample) |
| EP (1) | EP3573956A4 (enExample) |
| JP (1) | JP2020505398A (enExample) |
| CN (1) | CN110446700A (enExample) |
| BR (1) | BR112019015278A2 (enExample) |
| CA (1) | CA3050156A1 (enExample) |
| WO (1) | WO2018137593A1 (enExample) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| KR102558308B1 (ko) * | 2018-09-27 | 2023-07-24 | 주식회사 엘지화학 | 3-아자바이사이클로[3,1,1]헵탄 유도체 및 이를 포함하는 약제학적 조성물 |
| EP3980412B1 (en) | 2019-06-06 | 2025-08-13 | Merck Sharp & Dohme LLC | 1-pyrazolyl, 5-, 6- disubstituted indazole derivatives as lrrk2 inhibitors, pharmaceutical compositions, and uses thereof |
| JP2023514654A (ja) * | 2020-02-25 | 2023-04-06 | ブイアイビー ブイゼットダブリュ | ロイシンリッチリピートキナーゼ２のアロステリック調節因子 |
| WO2022155419A1 (en) * | 2021-01-15 | 2022-07-21 | ESCAPE Bio, Inc. | Indazoles and azaindazoles as lrrk2 inhibitors |
| US11780851B2 (en) | 2021-10-27 | 2023-10-10 | H. Lundbeck A/S | LRRK2 inhibitors |
| US11958865B1 (en) | 2022-09-15 | 2024-04-16 | H. Lundbeck A/S | Leucine-rich repeat kinase 2 (LRRK2) inhibitors |
| WO2025201511A1 (zh) * | 2024-03-29 | 2025-10-02 | 上海京新生物医药有限公司 | 吲唑衍生物及其制备方法与应用 |
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| JP5752691B2 (ja) * | 2009-09-29 | 2015-07-22 | グラクソ グループ リミテッドＧｌａｘｏ Ｇｒｏｕｐ Ｌｉｍｉｔｅｄ | 新規化合物 |
| EP2489663A1 (en) * | 2011-02-16 | 2012-08-22 | Almirall, S.A. | Compounds as syk kinase inhibitors |
| WO2014134772A1 (en) | 2013-03-04 | 2014-09-12 | Merck Sharp & Dohme Corp. | Compounds inhibiting leucine-rich repeat kinase enzyme activity |
| KR20160106622A (ko) | 2014-01-29 | 2016-09-12 | 글락소스미스클라인 인털렉츄얼 프로퍼티 디벨로프먼트 리미티드 | 화합물 |
| WO2016036586A1 (en) * | 2014-09-03 | 2016-03-10 | Merck Sharp & Dohme Corp. | Compounds inhibiting leucine-rich repeat kinase enzyme activity |
| JP6746679B2 (ja) | 2015-07-23 | 2020-08-26 | グラクソスミスクライン、インテレクチュアル、プロパティー、ディベロップメント、リミテッドＧｌａｘｏｓｍｉｔｈｋｌｉｎｅ Ｉｎｔｅｌｌｅｃｔｕａｌ Ｐｒｏｐｅｒｔｙ Ｄｅｖｅｌｏｐｍｅｎｔ Ｌｉｍｉｔｅｄ | 化合物 |
| CA3050021A1 (en) * | 2017-01-25 | 2018-08-02 | Glaxosmithkline Intellectual Property Development Limited | Compounds |
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2018
- 2018-01-23 CN CN201880019059.1A patent/CN110446700A/zh active Pending
- 2018-01-23 BR BR112019015278A patent/BR112019015278A2/pt not_active Application Discontinuation
- 2018-01-23 CA CA3050156A patent/CA3050156A1/en not_active Abandoned
- 2018-01-23 WO PCT/CN2018/073729 patent/WO2018137593A1/en not_active Ceased
- 2018-01-23 US US16/480,797 patent/US10858367B2/en not_active Expired - Fee Related
- 2018-01-23 JP JP2019540061A patent/JP2020505398A/ja active Pending
- 2018-01-23 EP EP18745270.1A patent/EP3573956A4/en not_active Withdrawn
Also Published As
| Publication number | Publication date |
|---|---|
| EP3573956A4 (en) | 2020-08-12 |
| BR112019015278A2 (pt) | 2020-04-14 |
| US10858367B2 (en) | 2020-12-08 |
| CN110446700A (zh) | 2019-11-12 |
| JP2020505398A (ja) | 2020-02-20 |
| US20190359623A1 (en) | 2019-11-28 |
| EP3573956A1 (en) | 2019-12-04 |
| WO2018137593A1 (en) | 2018-08-02 |
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Legal Events
| Date | Code | Title | Description |
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| FZDE | Discontinued |
Effective date: 20230725 |