CA2957544C - Cyclopropyl fused thiazin-2-amine compounds as beta-secretase inhibitors and methods of use - Google Patents

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Publication number

CA2957544C

CA2957544C CA2957544A CA2957544A CA2957544C CA 2957544 C CA2957544 C CA 2957544C CA 2957544 A CA2957544 A CA 2957544A CA 2957544 A CA2957544 A CA 2957544A CA 2957544 C CA2957544 C CA 2957544C

Authority

CA

Canada

Prior art keywords

amino

hept

azabicyclo

thia

methyl

Prior art date

2014-08-08

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.)

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• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 title claims description 33
• 238000000034 method Methods 0.000 title claims description 20
• 239000002439 beta secretase inhibitor Substances 0.000 title 1
• WADGHWKXQZVKFK-UHFFFAOYSA-N thiazin-2-amine Chemical class NN1SC=CC=C1 WADGHWKXQZVKFK-UHFFFAOYSA-N 0.000 title 1
• -1 cyclopropylmethoxy, 2-propynyloxy, 2-butynyloxy, 3-butynyloxy Chemical group 0.000 claims description 596
• 150000001875 compounds Chemical class 0.000 claims description 419
• 229960005206 pyrazinamide Drugs 0.000 claims description 263
• 229910052731 fluorine Inorganic materials 0.000 claims description 260
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 255
• 150000003839 salts Chemical class 0.000 claims description 221
• 229910052739 hydrogen Inorganic materials 0.000 claims description 193
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 145
• 229910052801 chlorine Inorganic materials 0.000 claims description 138
• VUWZPRWSIVNGKG-UHFFFAOYSA-N fluoromethane Chemical compound F[CH2] VUWZPRWSIVNGKG-UHFFFAOYSA-N 0.000 claims description 135
• YVOLUPPVPQLTHT-UHFFFAOYSA-N pyrido[3,4-b]pyrazin-5-amine Chemical compound C1=CN=C2C(N)=NC=CC2=N1 YVOLUPPVPQLTHT-UHFFFAOYSA-N 0.000 claims description 134
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 131
• 108010081348 HRT1 protein Hairy Proteins 0.000 claims description 118
• 102100021881 Hairy/enhancer-of-split related with YRPW motif protein 1 Human genes 0.000 claims description 118
• JNCMHMUGTWEVOZ-UHFFFAOYSA-N F[CH]F Chemical compound F[CH]F JNCMHMUGTWEVOZ-UHFFFAOYSA-N 0.000 claims description 108
• 125000001424 substituent group Chemical group 0.000 claims description 100
• 125000000842 isoxazolyl group Chemical group 0.000 claims description 85
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 78
• 125000005842 heteroatom Chemical group 0.000 claims description 72
• 125000004043 oxo group Chemical group O=* 0.000 claims description 71
• 125000000335 thiazolyl group Chemical group 0.000 claims description 61
• 125000003226 pyrazolyl group Chemical group 0.000 claims description 58
• 229910052757 nitrogen Inorganic materials 0.000 claims description 54
• 229920006395 saturated elastomer Polymers 0.000 claims description 52
• 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 50
• 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 50
• 125000002757 morpholinyl group Chemical group 0.000 claims description 49
• 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 47
• 125000000168 pyrrolyl group Chemical group 0.000 claims description 47
• 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 46
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 45
• 125000005043 dihydropyranyl group Chemical group O1C(CCC=C1)* 0.000 claims description 45
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 44
• 125000002971 oxazolyl group Chemical group 0.000 claims description 42
• 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 41
• 125000005843 halogen group Chemical group 0.000 claims description 41
• 125000002950 monocyclic group Chemical group 0.000 claims description 41
• 125000002619 bicyclic group Chemical group 0.000 claims description 38
• 125000004432 carbon atom Chemical group C* 0.000 claims description 37
• DGXAOSOMFMODCF-UHFFFAOYSA-N pyrido[3,2-d]pyrimidin-4-amine Chemical compound C1=CN=C2C(N)=NC=NC2=C1 DGXAOSOMFMODCF-UHFFFAOYSA-N 0.000 claims description 37
• 208000024827 Alzheimer disease Diseases 0.000 claims description 36
• 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 36
• 125000001188 haloalkyl group Chemical group 0.000 claims description 35
• 229910052794 bromium Inorganic materials 0.000 claims description 34
• 125000001544 thienyl group Chemical group 0.000 claims description 34
• KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 claims description 33
• 125000006519 CCH3 Chemical group 0.000 claims description 32
• 125000001786 isothiazolyl group Chemical group 0.000 claims description 32
• 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 28
• 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 28
• 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 28
• QMYGFTJCQFEDST-UHFFFAOYSA-N 3-methoxybutyl acetate Chemical group COC(C)CCOC(C)=O QMYGFTJCQFEDST-UHFFFAOYSA-N 0.000 claims description 27
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 27
• 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 27
• 125000001072 heteroaryl group Chemical group 0.000 claims description 27
• 125000002541 furyl group Chemical group 0.000 claims description 26
• 125000004193 piperazinyl group Chemical group 0.000 claims description 26
• 125000001113 thiadiazolyl group Chemical group 0.000 claims description 26
• 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims description 25
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 25
• 125000006299 oxetan-3-yl group Chemical group [H]C1([H])OC([H])([H])C1([H])* 0.000 claims description 25
• 101100054666 Streptomyces halstedii sch3 gene Proteins 0.000 claims description 24
• 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 24
• 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 24
• 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 24
• 125000000623 heterocyclic group Chemical group 0.000 claims description 24
• 125000004307 pyrazin-2-yl group Chemical group [H]C1=C([H])N=C(*)C([H])=N1 0.000 claims description 24
• SQXPNCGBFIIPNW-UHFFFAOYSA-N pyrido[3,2-d]pyrimidine-7-carbonitrile Chemical compound C1=NC=NC2=CC(C#N)=CN=C21 SQXPNCGBFIIPNW-UHFFFAOYSA-N 0.000 claims description 24
• 229910052701 rubidium Inorganic materials 0.000 claims description 24
• 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 24
• 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 23
• CBOIHMRHGLHBPB-UHFFFAOYSA-N hydroxymethyl Chemical compound O[CH2] CBOIHMRHGLHBPB-UHFFFAOYSA-N 0.000 claims description 22
• 125000004857 imidazopyridinyl group Chemical group N1C(=NC2=C1C=CC=N2)* 0.000 claims description 22
• 239000012453 solvate Substances 0.000 claims description 19
• IPEHBUMCGVEMRF-UHFFFAOYSA-N pyrazinecarboxamide Chemical compound NC(=O)C1=CN=CC=N1 IPEHBUMCGVEMRF-UHFFFAOYSA-N 0.000 claims description 18
• 229910052717 sulfur Inorganic materials 0.000 claims description 18
• DZHSAHHDTRWUTF-SIQRNXPUSA-N amyloid-beta polypeptide 42 Chemical compound C([C@@H](C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)NCC(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(O)=O)[C@@H](C)CC)C(C)C)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC(O)=O)C(C)C)C(C)C)C1=CC=CC=C1 DZHSAHHDTRWUTF-SIQRNXPUSA-N 0.000 claims description 16
• 125000001153 fluoro group Chemical group F* 0.000 claims description 15
• 238000011282 treatment Methods 0.000 claims description 15
• 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 claims description 14
• 125000004076 pyridyl group Chemical group 0.000 claims description 14
• 125000000714 pyrimidinyl group Chemical group 0.000 claims description 14
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 13
• 210000004556 brain Anatomy 0.000 claims description 13
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 13
• 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 claims description 12
• 125000003373 pyrazinyl group Chemical group 0.000 claims description 12
• 125000002098 pyridazinyl group Chemical group 0.000 claims description 12
• 239000002253 acid Substances 0.000 claims description 11
• 125000004438 haloalkoxy group Chemical group 0.000 claims description 11
• 230000009467 reduction Effects 0.000 claims description 10
• 239000003795 chemical substances by application Substances 0.000 claims description 8
• QUPDWYMUPZLYJZ-UHFFFAOYSA-N ethyl Chemical group C[CH2] QUPDWYMUPZLYJZ-UHFFFAOYSA-N 0.000 claims description 7
• 206010012289 Dementia Diseases 0.000 claims description 6
• 101001043818 Mus musculus Interleukin-31 receptor subunit alpha Proteins 0.000 claims description 6
• 239000003814 drug Substances 0.000 claims description 6
• 238000004519 manufacturing process Methods 0.000 claims description 6
• 239000008194 pharmaceutical composition Substances 0.000 claims description 6
• 125000006559 (C1-C3) alkylamino group Chemical group 0.000 claims description 5
• 210000001175 cerebrospinal fluid Anatomy 0.000 claims description 5
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
• 230000007505 plaque formation Effects 0.000 claims description 5
• HUTNOYOBQPAKIA-UHFFFAOYSA-N 1h-pyrazin-2-one Chemical compound OC1=CN=CC=N1 HUTNOYOBQPAKIA-UHFFFAOYSA-N 0.000 claims description 4
• 125000001715 oxadiazolyl group Chemical group 0.000 claims description 4
• 208000005145 Cerebral amyloid angiopathy Diseases 0.000 claims description 3
• 125000001309 chloro group Chemical group Cl* 0.000 claims description 3
• 208000010877 cognitive disease Diseases 0.000 claims description 3
• OYRRZWATULMEPF-UHFFFAOYSA-N pyrimidin-4-amine Chemical compound NC1=CC=NC=N1 OYRRZWATULMEPF-UHFFFAOYSA-N 0.000 claims description 3
• 125000001425 triazolyl group Chemical group 0.000 claims description 3
• KFZMGEQAYNKOFK-UHFFFAOYSA-N 2-propanol Substances CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 2
• 208000028698 Cognitive impairment Diseases 0.000 claims description 2
• 201000010374 Down Syndrome Diseases 0.000 claims description 2
• 208000012902 Nervous system disease Diseases 0.000 claims description 2
• 206010044688 Trisomy 21 Diseases 0.000 claims description 2
• WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 2
• 230000007850 degeneration Effects 0.000 claims description 2
• 125000004274 oxetan-2-yl group Chemical group [H]C1([H])OC([H])(*)C1([H])[H] 0.000 claims description 2
• 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims 7
• 229940125810 compound 20 Drugs 0.000 claims 2
• JAXFJECJQZDFJS-XHEPKHHKSA-N gtpl8555 Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)N[C@H](B1O[C@@]2(C)[C@H]3C[C@H](C3(C)C)C[C@H]2O1)CCC1=CC=C(F)C=C1 JAXFJECJQZDFJS-XHEPKHHKSA-N 0.000 claims 2
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 1
• 206010008111 Cerebral haemorrhage Diseases 0.000 claims 1
• QWCQNWYYXOEOCG-ARBPTSGCSA-N NC=1S[C@]2(C[C@H]2[C@@](N=1)(C)C1=C(C(=CC(=C1)NC(=O)C1=NC=C(N=C1)OCC#C)F)F)C(=O)OC Chemical compound NC=1S[C@]2(C[C@H]2[C@@](N=1)(C)C1=C(C(=CC(=C1)NC(=O)C1=NC=C(N=C1)OCC#C)F)F)C(=O)OC QWCQNWYYXOEOCG-ARBPTSGCSA-N 0.000 claims 1
• MTGMNKBRNQNEFJ-FNVCAUGXSA-N NC=1S[C@]2(C[C@H]2[C@@](N=1)(C)C=1C=C(C=C(C=1F)F)NC=1C2=C(N=CN=1)C=C(C=N2)OCC#C)C(F)F Chemical compound NC=1S[C@]2(C[C@H]2[C@@](N=1)(C)C=1C=C(C=C(C=1F)F)NC=1C2=C(N=CN=1)C=C(C=N2)OCC#C)C(F)F MTGMNKBRNQNEFJ-FNVCAUGXSA-N 0.000 claims 1
• PGWFGJYIXZOJDU-GCCWUPBUSA-N NC=1S[C@]2(C[C@H]2[C@@](N=1)(C)C=1C=C(C=C(C=1F)F)NC=1C2=C(N=CN=1)C=C(C=N2)OCC=1N=C(OC=1C)C)COC Chemical compound NC=1S[C@]2(C[C@H]2[C@@](N=1)(C)C=1C=C(C=C(C=1F)F)NC=1C2=C(N=CN=1)C=C(C=N2)OCC=1N=C(OC=1C)C)COC PGWFGJYIXZOJDU-GCCWUPBUSA-N 0.000 claims 1
• WSKZEYATKWLEJL-NTUVXCKYSA-N NC=1S[C@]2(C[C@H]2[C@@](N=1)(C)C=1C=C(C=C(C=1F)F)NC=1C2=C(N=CN=1)C=C(C=N2)OCCOC)COC Chemical compound NC=1S[C@]2(C[C@H]2[C@@](N=1)(C)C=1C=C(C=C(C=1F)F)NC=1C2=C(N=CN=1)C=C(C=N2)OCCOC)COC WSKZEYATKWLEJL-NTUVXCKYSA-N 0.000 claims 1
• AGPHPRAMUFTZTL-QTLGCAHFSA-N NC=1S[C@]2(C[C@H]2[C@@](N=1)(C)C=1C=C(C=C(C=1F)F)NC=1N=CC(=C2C=C(C=NC=12)OCC#C)F)COC Chemical compound NC=1S[C@]2(C[C@H]2[C@@](N=1)(C)C=1C=C(C=C(C=1F)F)NC=1N=CC(=C2C=C(C=NC=12)OCC#C)F)COC AGPHPRAMUFTZTL-QTLGCAHFSA-N 0.000 claims 1
• XSKWWFDMFJWRPG-AJHZIAPWSA-N NC=1S[C@]2(C[C@H]2[C@@](N=1)(C)C=1C=C(C=C(C=1F)F)NC=1N=CC(=C2C=C(C=NC=12)OCC=1OC=CN=1)F)C(F)F Chemical compound NC=1S[C@]2(C[C@H]2[C@@](N=1)(C)C=1C=C(C=C(C=1F)F)NC=1N=CC(=C2C=C(C=NC=12)OCC=1OC=CN=1)F)C(F)F XSKWWFDMFJWRPG-AJHZIAPWSA-N 0.000 claims 1
• PWTKMVLSFSKWMP-AFWDCEBSSA-N NC=1S[C@]2(C[C@H]2[C@@](N=1)(C)C=1C=C(C=C(C=1F)F)NC=1N=CC(=C2C=C(C=NC=12)OCC=1OC=CN=1)F)COC Chemical compound NC=1S[C@]2(C[C@H]2[C@@](N=1)(C)C=1C=C(C=C(C=1F)F)NC=1N=CC(=C2C=C(C=NC=12)OCC=1OC=CN=1)F)COC PWTKMVLSFSKWMP-AFWDCEBSSA-N 0.000 claims 1
• ZOTXQTIORGEDIT-BEVDRBHNSA-N NC=1S[C@]2(C[C@H]2[C@@](N=1)(CF)C=1C=C(C=CC=1F)NC(=O)C1=NC=C(C=C1)Cl)C=1N=NNC=1 Chemical compound NC=1S[C@]2(C[C@H]2[C@@](N=1)(CF)C=1C=C(C=CC=1F)NC(=O)C1=NC=C(C=C1)Cl)C=1N=NNC=1 ZOTXQTIORGEDIT-BEVDRBHNSA-N 0.000 claims 1
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• KDARIEFFIVBDRF-ZPMCFJSWSA-N NC=1S[C@]2(C[C@H]2[C@@](N=1)(CF)C=1C=C(C=CC=1F)NC(=O)C1=NC=C(N=C1)OCC#C)COCC(F)(F)F Chemical compound NC=1S[C@]2(C[C@H]2[C@@](N=1)(CF)C=1C=C(C=CC=1F)NC(=O)C1=NC=C(N=C1)OCC#C)COCC(F)(F)F KDARIEFFIVBDRF-ZPMCFJSWSA-N 0.000 claims 1
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• 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 51
• IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 50
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