CA2629402C - Modulateurs de beta-secretase et procedes d'utilisation associes - Google Patents

Modulateurs de beta-secretase et procedes d'utilisation associes Download PDF

Info

Publication number: CA2629402C
Authority: CA; Canada
Prior art keywords: amino; acetamide; methyl; dihydrospiro; pyridin
Prior art date: 2005-11-21
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.): Expired - Fee Related

Application number

CA2629402A

Other languages

English (en)

Other versions

CA2629402A1 (fr

Inventor

Wenge Zhong

Stephen Hitchcock

Brian K Albrecht

Michael Bartberger

James Brown

Ryan Brown (Deceased)

Stuart C. Chaffee

Yuan Cheng

Michael Croghan

Russell Graceffa

Scott Harried

Dean Hickman

Daniel Horne

Randall Hungate

Ted Judd

Matthew Kaller

Charles Kreiman

Daniel La

Patricia Lopez

Craig E. Masse

Holger Monenschein

Thomas Nguyen

Thomas Nixey

Vinod F. Patel

Lewis Pennington

Matthew Weiss

Qiufen Xue

Bryant Yang

Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)

Amgen Inc

Original Assignee

Amgen Inc

Priority date (The priority date 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 date listed.)

2005-11-21

Filing date

2006-11-13

Publication date

2011-07-26

Family has litigation

First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=39708735&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=CA2629402(C) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.

2006-11-13 Application filed by Amgen Inc filed Critical Amgen Inc

2007-05-31 Publication of CA2629402A1 publication Critical patent/CA2629402A1/fr

2011-07-26 Application granted granted Critical

2011-07-26 Publication of CA2629402C publication Critical patent/CA2629402C/fr

Status Expired - Fee Related legal-status Critical Current

2026-11-13 Anticipated expiration legal-status Critical

Links

238000000034 method Methods 0.000 title claims abstract description 63
108010043324 Amyloid Precursor Protein Secretases Proteins 0.000 title abstract description 21
102000002659 Amyloid Precursor Protein Secretases Human genes 0.000 title abstract description 21
150000001875 compounds Chemical class 0.000 claims abstract description 252
208000024827 Alzheimer disease Diseases 0.000 claims abstract description 34
238000011282 treatment Methods 0.000 claims abstract description 14
238000002360 preparation method Methods 0.000 claims abstract description 8
239000008194 pharmaceutical composition Substances 0.000 claims abstract description 7
DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 1116
JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 348
-1 isoquinazolinyl Chemical group 0.000 claims description 320
125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 225
125000005842 heteroatom Chemical group 0.000 claims description 122
125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 92
125000004122 cyclic group Chemical group 0.000 claims description 75
125000001188 haloalkyl group Chemical group 0.000 claims description 74
125000004432 carbon atom Chemical group C* 0.000 claims description 64
125000002950 monocyclic group Chemical group 0.000 claims description 62
125000001424 substituent group Chemical group 0.000 claims description 61
125000002619 bicyclic group Chemical group 0.000 claims description 58
229910052757 nitrogen Inorganic materials 0.000 claims description 56
229920006395 saturated elastomer Polymers 0.000 claims description 56
125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 56
125000005843 halogen group Chemical group 0.000 claims description 49
JCXJVPUVTGWSNB-UHFFFAOYSA-N Nitrogen dioxide Chemical compound O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 claims description 47
MDFFNEOEWAXZRQ-UHFFFAOYSA-N aminyl Chemical compound [NH2] MDFFNEOEWAXZRQ-UHFFFAOYSA-N 0.000 claims description 46
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 46
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 40
125000004043 oxo group Chemical group O=* 0.000 claims description 39
125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 37
125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 36
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 33
125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 31
125000006374 C2-C10 alkenyl group Chemical group 0.000 claims description 31
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 31
150000003839 salts Chemical class 0.000 claims description 31
125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 29
125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 28
125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 28
GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 claims description 26
125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 25
125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 25
125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 24
KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 claims description 23
125000000008 (C1-C10) alkyl group Chemical group 0.000 claims description 22
QMYGFTJCQFEDST-UHFFFAOYSA-N 3-methoxybutyl acetate Chemical group COC(C)CCOC(C)=O QMYGFTJCQFEDST-UHFFFAOYSA-N 0.000 claims description 22
125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 22
125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 22
229910052717 sulfur Inorganic materials 0.000 claims description 20
125000006376 (C3-C10) cycloalkyl group Chemical group 0.000 claims description 19
125000001147 pentyl group Chemical group C(CCCC)* 0.000 claims description 19
QLNJFJADRCOGBJ-UHFFFAOYSA-N propionamide Chemical compound CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 claims description 19
RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 18
HRPVXLWXLXDGHG-UHFFFAOYSA-N Acrylamide Chemical compound NC(=O)C=C HRPVXLWXLXDGHG-UHFFFAOYSA-N 0.000 claims description 17
125000000842 isoxazolyl group Chemical group 0.000 claims description 15
125000000217 alkyl group Chemical group 0.000 claims description 14
125000000304 alkynyl group Chemical group 0.000 claims description 12
125000002883 imidazolyl group Chemical group 0.000 claims description 12
125000001786 isothiazolyl group Chemical group 0.000 claims description 12
125000002971 oxazolyl group Chemical group 0.000 claims description 12
229910052760 oxygen Inorganic materials 0.000 claims description 12
125000003226 pyrazolyl group Chemical group 0.000 claims description 12
125000000714 pyrimidinyl group Chemical group 0.000 claims description 12
125000000168 pyrrolyl group Chemical group 0.000 claims description 12
125000000335 thiazolyl group Chemical group 0.000 claims description 12
125000001425 triazolyl group Chemical group 0.000 claims description 12
125000003342 alkenyl group Chemical group 0.000 claims description 11
125000003545 alkoxy group Chemical group 0.000 claims description 11
125000002757 morpholinyl group Chemical group 0.000 claims description 11
125000004193 piperazinyl group Chemical group 0.000 claims description 11
125000003386 piperidinyl group Chemical group 0.000 claims description 11
125000004076 pyridyl group Chemical group 0.000 claims description 11
125000000719 pyrrolidinyl group Chemical group 0.000 claims description 11
125000001544 thienyl group Chemical group 0.000 claims description 11
125000004306 triazinyl group Chemical group 0.000 claims description 11
125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 10
206010012289 Dementia Diseases 0.000 claims description 10
125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims description 10
125000002541 furyl group Chemical group 0.000 claims description 10
125000001715 oxadiazolyl group Chemical group 0.000 claims description 10
125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 claims description 10
125000001113 thiadiazolyl group Chemical group 0.000 claims description 10
125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 9
125000001041 indolyl group Chemical group 0.000 claims description 9
125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 claims description 9
125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 claims description 9
125000003971 isoxazolinyl group Chemical group 0.000 claims description 9
125000005968 oxazolinyl group Chemical group 0.000 claims description 9
125000002755 pyrazolinyl group Chemical group 0.000 claims description 9
125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 claims description 9
125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 9
125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 9
125000002769 thiazolinyl group Chemical group 0.000 claims description 9
125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims description 8
125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 8
125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims description 8
125000003354 benzotriazolyl group Chemical group N1N=NC2=C1C=CC=C2* 0.000 claims description 8
125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 claims description 8
125000001624 naphthyl group Chemical group 0.000 claims description 8
125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 7
YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 7
125000002098 pyridazinyl group Chemical group 0.000 claims description 7
239000012453 solvate Substances 0.000 claims description 7
KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 claims description 6
KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 6
YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 6
239000003814 drug Substances 0.000 claims description 6
125000003373 pyrazinyl group Chemical group 0.000 claims description 6
UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 6
125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 5
125000004603 benzisoxazolyl group Chemical group O1N=C(C2=C1C=CC=C2)* 0.000 claims description 5
125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 claims description 5
101100495912 Arabidopsis thaliana CHR12 gene Proteins 0.000 claims description 4
125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 4
ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 claims description 4
FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims description 4
125000002393 azetidinyl group Chemical group 0.000 claims description 4
229910052739 hydrogen Inorganic materials 0.000 claims description 4
PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 claims description 4
125000003831 tetrazolyl group Chemical group 0.000 claims description 4
125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 3
JYEUMXHLPRZUAT-UHFFFAOYSA-N 1,2,3-triazine Chemical compound C1=CN=NN=C1 JYEUMXHLPRZUAT-UHFFFAOYSA-N 0.000 claims description 3
206010008111 Cerebral haemorrhage Diseases 0.000 claims description 3
201000010374 Down Syndrome Diseases 0.000 claims description 3
PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 claims description 3
WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 claims description 3
CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 3
206010044688 Trisomy 21 Diseases 0.000 claims description 3
206010002022 amyloidosis Diseases 0.000 claims description 3
208000010877 cognitive disease Diseases 0.000 claims description 3
ZLTPDFXIESTBQG-UHFFFAOYSA-N isothiazole Chemical compound C=1C=NSC=1 ZLTPDFXIESTBQG-UHFFFAOYSA-N 0.000 claims description 3
238000004519 manufacturing process Methods 0.000 claims description 3
WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical compound C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 claims description 3
VLLMWSRANPNYQX-UHFFFAOYSA-N thiadiazole Chemical compound C1=CSN=N1.C1=CSN=N1 VLLMWSRANPNYQX-UHFFFAOYSA-N 0.000 claims description 3
229930192474 thiophene Natural products 0.000 claims description 3
150000003852 triazoles Chemical class 0.000 claims description 3
125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 2
VQGHMDXJFVFTGK-XZLNYOFQSA-N (e)-3-(4-bromofuran-2-yl)-n-[(2s,3r)-4-[[(4s)-6-ethylspiro[3,4-dihydrochromene-2,1'-cyclobutane]-4-yl]amino]-3-hydroxy-1-phenylbutan-2-yl]prop-2-enamide Chemical compound C1([C@@H](NC[C@@H](O)[C@H](CC=2C=CC=CC=2)NC(=O)\C=C\C=2OC=C(Br)C=2)C2)=CC(CC)=CC=C1OC12CCC1 VQGHMDXJFVFTGK-XZLNYOFQSA-N 0.000 claims description 2
125000004399 C1-C4 alkenyl group Chemical group 0.000 claims description 2
239000003937 drug carrier Substances 0.000 claims description 2
FOQIMCMQAHVRSZ-CCIHKAHMSA-N n-[(2s,3r)-1-(1-acetylpiperidin-3-yl)-4-[[(4s)-6-ethylspiro[3,4-dihydrochromene-2,1'-cyclobutane]-4-yl]amino]-3-hydroxybutan-2-yl]acetamide Chemical compound C1([C@@H](NC[C@@H](O)[C@H](CC2CN(CCC2)C(C)=O)NC(C)=O)C2)=CC(CC)=CC=C1OC12CCC1 FOQIMCMQAHVRSZ-CCIHKAHMSA-N 0.000 claims description 2
BDUKFURARPTELL-CCDWMCETSA-N n-[(2s,3r)-1-(3-cyanophenyl)-4-[[(4s)-6-ethylspiro[3,4-dihydrochromene-2,1'-cyclobutane]-4-yl]amino]-3-hydroxybutan-2-yl]-2-methoxyacetamide Chemical compound C1([C@@H](NC[C@@H](O)[C@H](CC=2C=C(C=CC=2)C#N)NC(=O)COC)C2)=CC(CC)=CC=C1OC12CCC1 BDUKFURARPTELL-CCDWMCETSA-N 0.000 claims description 2
DRNVFBXXOGITRL-OIFRRMEBSA-N n-[(2s,3r)-1-(3-cyanophenyl)-4-[[(4s)-6-ethylspiro[3,4-dihydrochromene-2,1'-cyclobutane]-4-yl]amino]-3-hydroxybutan-2-yl]-2-phenoxyacetamide Chemical compound C1([C@@H](NC[C@@H](O)[C@H](CC=2C=C(C=CC=2)C#N)NC(=O)COC=2C=CC=CC=2)C2)=CC(CC)=CC=C1OC12CCC1 DRNVFBXXOGITRL-OIFRRMEBSA-N 0.000 claims description 2
CZOPXKQMSNLYKH-CCDWMCETSA-N n-[(2s,3r)-1-(3-cyanophenyl)-4-[[(4s)-6-ethylspiro[3,4-dihydrochromene-2,1'-cyclobutane]-4-yl]amino]-3-hydroxybutan-2-yl]propanamide Chemical compound C([C@H](NC(=O)CC)[C@H](O)CN[C@@H]1C2=CC(CC)=CC=C2OC2(CCC2)C1)C1=CC=CC(C#N)=C1 CZOPXKQMSNLYKH-CCDWMCETSA-N 0.000 claims description 2
WFLXNGWTEYYRAX-KKUQBAQOSA-N n-[(2s,3r)-1-(4-chlorophenyl)-4-[[(4s)-6-(2,2-dimethylbut-3-ynyl)spiro[3,4-dihydropyrano[2,3-b]pyridine-2,1'-cyclobutane]-4-yl]amino]-3-hydroxybutan-2-yl]acetamide Chemical compound C([C@H](NC(=O)C)[C@H](O)CN[C@@H]1C2=CC(CC(C)(C)C#C)=CN=C2OC2(CCC2)C1)C1=CC=C(Cl)C=C1 WFLXNGWTEYYRAX-KKUQBAQOSA-N 0.000 claims description 2
UTERZPGUGZHCAR-PCCBWWKXSA-N n-[(2s,3r)-3-hydroxy-1-phenyl-4-[[(4s)-2,6,6-trimethyl-5,7-dihydro-4h-1-benzofuran-4-yl]amino]butan-2-yl]acetamide Chemical compound C([C@H](NC(=O)C)[C@H](O)CN[C@@H]1C=2C=C(C)OC=2CC(C)(C)C1)C1=CC=CC=C1 UTERZPGUGZHCAR-PCCBWWKXSA-N 0.000 claims description 2
OAPVYUJRXSHJFV-RGYUWNBKSA-N n-[(2s,3r)-4-[[(2s,4s)-6-(2,2-dimethylpropyl)spiro[3,4-dihydropyrano[2,3-b]pyridine-2,3'-oxolane]-4-yl]amino]-3-hydroxy-1-phenylbutan-2-yl]-2-methoxyacetamide Chemical compound C([C@H](NC(=O)COC)[C@H](O)CN[C@@H]1C2=CC(CC(C)(C)C)=CN=C2O[C@@]2(COCC2)C1)C1=CC=CC=C1 OAPVYUJRXSHJFV-RGYUWNBKSA-N 0.000 claims description 2
OUCWEAFTVAXJCV-KMDXXIMOSA-N n-[(2s,3r)-4-[[(4s)-2-ethyl-6,6-dimethyl-5,7-dihydro-4h-1-benzothiophen-4-yl]amino]-3-hydroxy-1-phenylbutan-2-yl]-2-(2-oxopyrrolidin-1-yl)acetamide Chemical compound C([C@@H]([C@H](O)CN[C@@H]1C=2C=C(SC=2CC(C)(C)C1)CC)NC(=O)CN1C(CCC1)=O)C1=CC=CC=C1 OUCWEAFTVAXJCV-KMDXXIMOSA-N 0.000 claims description 2
HPDATYCGMJPNRR-CCDWMCETSA-N n-[(2s,3r)-4-[[(4s)-6-(2,2-dimethylpropyl)-8-methoxyspiro[3,4-dihydropyrano[2,3-c]pyridine-2,1'-cyclobutane]-4-yl]amino]-1-(3-fluorophenyl)-3-hydroxybutan-2-yl]acetamide Chemical compound C([C@@H](C=1C=C(CC(C)(C)C)N=C(C=1O1)OC)NC[C@@H](O)[C@H](CC=2C=C(F)C=CC=2)NC(C)=O)C21CCC2 HPDATYCGMJPNRR-CCDWMCETSA-N 0.000 claims description 2
CJFICTWFZUPKMS-RWSKJCERSA-N n-[(2s,3r)-4-[[(4s)-6-(2,2-dimethylpropyl)spiro[3,4-dihydropyrano[2,3-b]pyridine-2,1'-cyclobutane]-4-yl]amino]-3-hydroxy-1-phenylbutan-2-yl]-2-(3-oxo-1h-isoindol-2-yl)acetamide Chemical compound C1([C@@H](NC[C@@H](O)[C@H](CC=2C=CC=CC=2)NC(=O)CN2C(C3=CC=CC=C3C2)=O)C2)=CC(CC(C)(C)C)=CN=C1OC12CCC1 CJFICTWFZUPKMS-RWSKJCERSA-N 0.000 claims description 2
FKUSUFVBJLHBPS-HZFUHODCSA-N n-[(2s,3r)-4-[[(4s)-6-(2,2-dimethylpropyl)spiro[3,4-dihydropyrano[2,3-b]pyridine-2,1'-cyclobutane]-4-yl]amino]-3-hydroxy-1-phenylbutan-2-yl]-2-(5-methylpyrazol-1-yl)acetamide Chemical compound CC1=CC=NN1CC(=O)N[C@H]([C@H](O)CN[C@@H]1C2=CC(CC(C)(C)C)=CN=C2OC2(CCC2)C1)CC1=CC=CC=C1 FKUSUFVBJLHBPS-HZFUHODCSA-N 0.000 claims description 2
FZRDGNVMKBNQIT-CCDWMCETSA-N n-[(2s,3r)-4-[[(4s)-6-ethylspiro[3,4-dihydrochromene-2,1'-cyclobutane]-4-yl]amino]-3-hydroxy-1-phenylbutan-2-yl]-2-(2-oxo-1,3-oxazolidin-3-yl)acetamide Chemical compound C1([C@@H](NC[C@@H](O)[C@H](CC=2C=CC=CC=2)NC(=O)CN2C(OCC2)=O)C2)=CC(CC)=CC=C1OC12CCC1 FZRDGNVMKBNQIT-CCDWMCETSA-N 0.000 claims description 2
YHACHHURHPYYGI-OIFRRMEBSA-N n-[(2s,3r)-4-[[(4s)-6-ethylspiro[3,4-dihydrochromene-2,1'-cyclobutane]-4-yl]amino]-3-hydroxy-1-phenylbutan-2-yl]-2-phthalazin-1-ylsulfanylacetamide Chemical compound C1([C@@H](NC[C@@H](O)[C@H](CC=2C=CC=CC=2)NC(=O)CSC=2C3=CC=CC=C3C=NN=2)C2)=CC(CC)=CC=C1OC12CCC1 YHACHHURHPYYGI-OIFRRMEBSA-N 0.000 claims description 2
FCTGWYSVAGSHCI-KMDXXIMOSA-N n-[(2s,3r)-4-[[(4s)-8-chloro-6-(2,2-dimethylpropyl)spiro[3,4-dihydropyrano[2,3-c]pyridine-2,1'-cyclobutane]-4-yl]amino]-1-(3-fluorophenyl)-3-hydroxybutan-2-yl]acetamide Chemical compound C([C@H](NC(=O)C)[C@H](O)CN[C@@H]1C2=CC(CC(C)(C)C)=NC(Cl)=C2OC2(CCC2)C1)C1=CC=CC(F)=C1 FCTGWYSVAGSHCI-KMDXXIMOSA-N 0.000 claims description 2
KNEPBZMJMJUNQX-UHFFFAOYSA-N pent-4-ynamide Chemical compound NC(=O)CCC#C KNEPBZMJMJUNQX-UHFFFAOYSA-N 0.000 claims description 2
229940080818 propionamide Drugs 0.000 claims description 2
KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims 2
208000005145 Cerebral amyloid angiopathy Diseases 0.000 claims 2
208000018737 Parkinson disease Diseases 0.000 claims 2
206010048327 Supranuclear palsy Diseases 0.000 claims 2
230000001054 cortical effect Effects 0.000 claims 2
230000007850 degeneration Effects 0.000 claims 2
230000003412 degenerative effect Effects 0.000 claims 2
210000004558 lewy body Anatomy 0.000 claims 2
208000027061 mild cognitive impairment Diseases 0.000 claims 2
ZUTJTMUOWJGQBF-HZFUHODCSA-N 2-(1,3-benzothiazol-2-yloxy)-n-[(2s,3r)-4-[[(4s)-6-ethylspiro[3,4-dihydrochromene-2,1'-cyclobutane]-4-yl]amino]-3-hydroxy-1-phenylbutan-2-yl]acetamide Chemical compound C1([C@@H](NC[C@@H](O)[C@H](CC=2C=CC=CC=2)NC(=O)COC=2SC3=CC=CC=C3N=2)C2)=CC(CC)=CC=C1OC12CCC1 ZUTJTMUOWJGQBF-HZFUHODCSA-N 0.000 claims 1
JRDCYXKZYKGTNK-YTCPBCGMSA-N 2-(3,5-dimethyl-1,2-oxazol-4-yl)-n-[(2s,3r)-4-[[(4s)-6-(2,2-dimethylpropyl)spiro[3,4-dihydropyrano[2,3-b]pyridine-2,1'-cyclobutane]-4-yl]amino]-3-hydroxy-1-phenylbutan-2-yl]acetamide Chemical compound CC1=NOC(C)=C1CC(=O)N[C@H]([C@H](O)CN[C@@H]1C2=CC(CC(C)(C)C)=CN=C2OC2(CCC2)C1)CC1=CC=CC=C1 JRDCYXKZYKGTNK-YTCPBCGMSA-N 0.000 claims 1
YGYAGJFOMUUTBI-YTCPBCGMSA-N 2-(3-chloro-2-methylphenyl)sulfanyl-n-[(2s,3r)-4-[[(4s)-6-ethylspiro[3,4-dihydrochromene-2,1'-cyclobutane]-4-yl]amino]-3-hydroxy-1-phenylbutan-2-yl]acetamide Chemical compound C1([C@@H](NC[C@@H](O)[C@H](CC=2C=CC=CC=2)NC(=O)CSC=2C(=C(Cl)C=CC=2)C)C2)=CC(CC)=CC=C1OC12CCC1 YGYAGJFOMUUTBI-YTCPBCGMSA-N 0.000 claims 1
XDASZKNLEKIPAS-XQTSOSNCSA-N 3-(benzimidazol-1-yl)-n-[(2s,3r)-4-[[(4s)-6-ethylspiro[3,4-dihydrochromene-2,1'-cyclobutane]-4-yl]amino]-3-hydroxy-1-phenylbutan-2-yl]-2-methylpropanamide Chemical compound C1([C@@H](NC[C@@H](O)[C@H](CC=2C=CC=CC=2)NC(=O)C(C)CN2C3=CC=CC=C3N=C2)C2)=CC(CC)=CC=C1OC12CCC1 XDASZKNLEKIPAS-XQTSOSNCSA-N 0.000 claims 1
125000004938 5-pyridyl group Chemical group N1=CC=CC(=C1)* 0.000 claims 1
PCBZRNYXXCIELG-WYFCWLEVSA-N COC1=CC=C(C[C@H](NC(=O)OC2CCCC3(C2)OOC2(O3)C3CC4CC(C3)CC2C4)C(=O)N[C@@H]2[C@@H](CO)O[C@H]([C@@H]2O)N2C=NC3=C2N=CN=C3N(C)C)C=C1 Chemical compound COC1=CC=C(C[C@H](NC(=O)OC2CCCC3(C2)OOC2(O3)C3CC4CC(C3)CC2C4)C(=O)N[C@@H]2[C@@H](CO)O[C@H]([C@@H]2O)N2C=NC3=C2N=CN=C3N(C)C)C=C1 PCBZRNYXXCIELG-WYFCWLEVSA-N 0.000 claims 1
229940125810 compound 20 Drugs 0.000 claims 1
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 1
RZVBZFXUKAEOIB-JIMJEQGWSA-N n-[(2s,3r)-1-(3,5-difluorophenyl)-4-[[(1r)-7-(2,2-dimethylpropyl)-3,3-dimethyl-4-oxo-1,2-dihydronaphthalen-1-yl]amino]-3-hydroxybutan-2-yl]acetamide Chemical compound C([C@H](NC(=O)C)[C@H](O)CN[C@H]1C2=CC(CC(C)(C)C)=CC=C2C(=O)C(C)(C)C1)C1=CC(F)=CC(F)=C1 RZVBZFXUKAEOIB-JIMJEQGWSA-N 0.000 claims 1
DMSRCGAVUVUKMW-FQJHJXCSSA-N n-[(2s,3r)-1-(3,5-difluorophenyl)-4-[[(2r,4r)-6-(2,2-dimethylpropyl)spiro[3,4-dihydropyrano[2,3-b]pyridine-2,3'-oxolane]-4-yl]amino]-3-hydroxybutan-2-yl]acetamide Chemical compound C([C@H](NC(=O)C)[C@H](O)CN[C@H]1C2=CC(CC(C)(C)C)=CN=C2O[C@]2(COCC2)C1)C1=CC(F)=CC(F)=C1 DMSRCGAVUVUKMW-FQJHJXCSSA-N 0.000 claims 1
DMSRCGAVUVUKMW-CDILPITASA-N n-[(2s,3r)-1-(3,5-difluorophenyl)-4-[[(2r,4s)-6-(2,2-dimethylpropyl)spiro[3,4-dihydropyrano[2,3-b]pyridine-2,3'-oxolane]-4-yl]amino]-3-hydroxybutan-2-yl]acetamide Chemical compound C([C@H](NC(=O)C)[C@H](O)CN[C@@H]1C2=CC(CC(C)(C)C)=CN=C2O[C@]2(COCC2)C1)C1=CC(F)=CC(F)=C1 DMSRCGAVUVUKMW-CDILPITASA-N 0.000 claims 1
UDTZUCALHYIIIT-HPUZDQILSA-N n-[(2s,3r)-1-(3,5-difluorophenyl)-4-[[(2s,4s)-6-ethylspiro[3,4-dihydrochromene-2,3'-oxolane]-4-yl]amino]-3-hydroxybutan-2-yl]acetamide Chemical compound C1([C@@H](NC[C@@H](O)[C@H](CC=2C=C(F)C=C(F)C=2)NC(C)=O)C2)=CC(CC)=CC=C1O[C@@]12CCOC1 UDTZUCALHYIIIT-HPUZDQILSA-N 0.000 claims 1
OMAIZYGPTREULJ-GMQQYTKMSA-N n-[(2s,3r)-1-(3,5-difluorophenyl)-4-[[(4s)-6-(2,2-dimethylpropyl)-8-propan-2-yloxyspiro[3,4-dihydropyrano[2,3-c]pyridine-2,1'-cyclobutane]-4-yl]amino]-3-hydroxybutan-2-yl]acetamide Chemical compound C([C@@H](C=1C=C(CC(C)(C)C)N=C(C=1O1)OC(C)C)NC[C@@H](O)[C@H](CC=2C=C(F)C=C(F)C=2)NC(C)=O)C21CCC2 OMAIZYGPTREULJ-GMQQYTKMSA-N 0.000 claims 1
BQLRKQYKBHSHRU-CCDWMCETSA-N n-[(2s,3r)-1-(3-bromo-4-fluorophenyl)-4-[[(4s)-6-(2,2-dimethylpropyl)spiro[3,4-dihydropyrano[2,3-b]pyridine-2,1'-cyclobutane]-4-yl]amino]-3-hydroxybutan-2-yl]acetamide Chemical compound C([C@H](NC(=O)C)[C@H](O)CN[C@@H]1C2=CC(CC(C)(C)C)=CN=C2OC2(CCC2)C1)C1=CC=C(F)C(Br)=C1 BQLRKQYKBHSHRU-CCDWMCETSA-N 0.000 claims 1
ZNHPLLVKRFJFLT-RBZQAINGSA-N n-[(2s,3r)-1-(3-cyanophenyl)-3-hydroxy-4-[[(1r)-7-methoxy-3,3-dimethyl-4-oxo-1,2-dihydronaphthalen-1-yl]amino]butan-2-yl]-2-methoxyacetamide Chemical compound C([C@H](NC(=O)COC)[C@H](O)CN[C@H]1C2=CC(OC)=CC=C2C(=O)C(C)(C)C1)C1=CC=CC(C#N)=C1 ZNHPLLVKRFJFLT-RBZQAINGSA-N 0.000 claims 1
NMJUOWGWEULNHY-RBZQAINGSA-N n-[(2s,3r)-1-(3-cyanophenyl)-3-hydroxy-4-[[(1r)-7-methoxy-3,3-dimethyl-4-oxo-1,2-dihydronaphthalen-1-yl]amino]butan-2-yl]acetamide Chemical compound C([C@@H]([C@H](O)CN[C@@H]1CC(C)(C)C(=O)C2=CC=C(C=C21)OC)NC(C)=O)C1=CC=CC(C#N)=C1 NMJUOWGWEULNHY-RBZQAINGSA-N 0.000 claims 1
NMJUOWGWEULNHY-KMDXXIMOSA-N n-[(2s,3r)-1-(3-cyanophenyl)-3-hydroxy-4-[[(1s)-7-methoxy-3,3-dimethyl-4-oxo-1,2-dihydronaphthalen-1-yl]amino]butan-2-yl]acetamide Chemical compound C([C@@H]([C@H](O)CN[C@H]1CC(C)(C)C(=O)C2=CC=C(C=C21)OC)NC(C)=O)C1=CC=CC(C#N)=C1 NMJUOWGWEULNHY-KMDXXIMOSA-N 0.000 claims 1
WUSBKIIPHRACDX-KKUQBAQOSA-N n-[(2s,3r)-1-(3-cyanophenyl)-4-[[(4s)-6-(2,2-dimethylpropyl)spiro[3,4-dihydropyrano[2,3-b]pyridine-2,1'-cyclobutane]-4-yl]amino]-3-hydroxybutan-2-yl]acetamide Chemical compound C([C@H](NC(=O)C)[C@H](O)CN[C@@H]1C2=CC(CC(C)(C)C)=CN=C2OC2(CCC2)C1)C1=CC=CC(C#N)=C1 WUSBKIIPHRACDX-KKUQBAQOSA-N 0.000 claims 1
GSSLCFLHVNRVIG-KKUQBAQOSA-N n-[(2s,3r)-1-(3-cyanophenyl)-4-[[(4s)-6-ethylspiro[3,4-dihydrochromene-2,1'-cyclobutane]-4-yl]amino]-3-hydroxybutan-2-yl]-2-(2-oxo-1,3-oxazolidin-3-yl)acetamide Chemical compound C1([C@@H](NC[C@@H](O)[C@H](CC=2C=C(C=CC=2)C#N)NC(=O)CN2C(OCC2)=O)C2)=CC(CC)=CC=C1OC12CCC1 GSSLCFLHVNRVIG-KKUQBAQOSA-N 0.000 claims 1
XYLJFRJPLIJCKC-CCDWMCETSA-N n-[(2s,3r)-1-(3-cyanophenyl)-4-[[(4s)-6-ethylspiro[3,4-dihydrochromene-2,1'-cyclobutane]-4-yl]amino]-3-hydroxybutan-2-yl]acetamide Chemical compound C1([C@@H](NC[C@@H](O)[C@H](CC=2C=C(C=CC=2)C#N)NC(C)=O)C2)=CC(CC)=CC=C1OC12CCC1 XYLJFRJPLIJCKC-CCDWMCETSA-N 0.000 claims 1
IAPFLLDNGSEQJC-KMDXXIMOSA-N n-[(2s,3r)-1-(3-cyanophenyl)-4-[[(4s)-6-ethylspiro[3,4-dihydropyrano[2,3-b]pyridine-2,1'-cyclobutane]-4-yl]amino]-3-hydroxybutan-2-yl]-2-methoxyacetamide Chemical compound C1([C@@H](NC[C@@H](O)[C@H](CC=2C=C(C=CC=2)C#N)NC(=O)COC)C2)=CC(CC)=CN=C1OC12CCC1 IAPFLLDNGSEQJC-KMDXXIMOSA-N 0.000 claims 1
OAXMWLBSWJPLPK-GGFLZPDSSA-N n-[(2s,3r)-1-(3-fluorophenyl)-3-hydroxy-4-[[(4s)-6-[(2s)-3,3,3-trifluoro-2-methylpropyl]spiro[3,4-dihydropyrano[2,3-b]pyridine-2,1'-cyclobutane]-4-yl]amino]butan-2-yl]acetamide Chemical compound C1([C@@H](NC[C@@H](O)[C@H](CC=2C=C(F)C=CC=2)NC(C)=O)C2)=CC(C[C@H](C)C(F)(F)F)=CN=C1OC12CCC1 OAXMWLBSWJPLPK-GGFLZPDSSA-N 0.000 claims 1
QWEFESYGNDNUMN-CCDWMCETSA-N n-[(2s,3r)-1-(4-chloro-3-fluorophenyl)-4-[[(4s)-6-(2,2-dimethylpropyl)spiro[3,4-dihydropyrano[2,3-b]pyridine-2,1'-cyclobutane]-4-yl]amino]-3-hydroxybutan-2-yl]acetamide Chemical compound C([C@H](NC(=O)C)[C@H](O)CN[C@@H]1C2=CC(CC(C)(C)C)=CN=C2OC2(CCC2)C1)C1=CC=C(Cl)C(F)=C1 QWEFESYGNDNUMN-CCDWMCETSA-N 0.000 claims 1
ZPZXFRAHZVMTJS-FQJHJXCSSA-N n-[(2s,3r)-1-(4-chlorophenyl)-4-[[(2r,4r)-6-(2,2-dimethylpropyl)spiro[3,4-dihydropyrano[2,3-b]pyridine-2,3'-oxolane]-4-yl]amino]-3-hydroxybutan-2-yl]acetamide Chemical compound C([C@H](NC(=O)C)[C@H](O)CN[C@H]1C2=CC(CC(C)(C)C)=CN=C2O[C@]2(COCC2)C1)C1=CC=C(Cl)C=C1 ZPZXFRAHZVMTJS-FQJHJXCSSA-N 0.000 claims 1
DYVCXXGYOURUSA-KKUQBAQOSA-N n-[(2s,3r)-1-(4-chlorophenyl)-4-[[(4s)-6-(2,2-dimethylbutyl)spiro[3,4-dihydropyrano[2,3-b]pyridine-2,1'-cyclobutane]-4-yl]amino]-3-hydroxybutan-2-yl]acetamide Chemical compound C1([C@@H](NC[C@@H](O)[C@H](CC=2C=CC(Cl)=CC=2)NC(C)=O)C2)=CC(CC(C)(C)CC)=CN=C1OC12CCC1 DYVCXXGYOURUSA-KKUQBAQOSA-N 0.000 claims 1
ODDWWSJGPLLKFI-CXSMSNRLSA-N n-[(2s,3r)-1-(4-chlorophenyl)-4-[[(4s)-6-[(1s)-1-fluoro-2,2-dimethylpropyl]spiro[3,4-dihydropyrano[2,3-b]pyridine-2,1'-cyclobutane]-4-yl]amino]-3-hydroxybutan-2-yl]acetamide Chemical compound C([C@H](NC(=O)C)[C@H](O)CN[C@@H]1C2=CC(=CN=C2OC2(CCC2)C1)[C@@H](F)C(C)(C)C)C1=CC=C(Cl)C=C1 ODDWWSJGPLLKFI-CXSMSNRLSA-N 0.000 claims 1
ZOLBYEQOYZQBEW-CCDWMCETSA-N n-[(2s,3r)-1-[4-chloro-3-(trifluoromethyl)phenyl]-4-[[(4s)-6-(2,2-dimethylpropyl)spiro[3,4-dihydropyrano[2,3-b]pyridine-2,1'-cyclobutane]-4-yl]amino]-3-hydroxybutan-2-yl]acetamide Chemical compound C([C@H](NC(=O)C)[C@H](O)CN[C@@H]1C2=CC(CC(C)(C)C)=CN=C2OC2(CCC2)C1)C1=CC=C(Cl)C(C(F)(F)F)=C1 ZOLBYEQOYZQBEW-CCDWMCETSA-N 0.000 claims 1
DWYZIQWQHNIECY-ISJGIBHGSA-N n-[(2s,3r)-3-hydroxy-4-[[(1r)-7-(2-methoxyethylamino)-3,3-dimethyl-4-oxo-1,2-dihydronaphthalen-1-yl]amino]-1-phenylbutan-2-yl]acetamide Chemical compound C([C@@H]([C@H](O)CN[C@@H]1CC(C)(C)C(=O)C2=CC=C(C=C21)NCCOC)NC(C)=O)C1=CC=CC=C1 DWYZIQWQHNIECY-ISJGIBHGSA-N 0.000 claims 1
GMHCBOGSXGMCIF-KKUQBAQOSA-N n-[(2s,3r)-3-hydroxy-4-[[(4s)-6-(3-methylbutyl)spiro[3,4-dihydropyrano[2,3-b]pyridine-2,1'-cyclobutane]-4-yl]amino]-1-phenylbutan-2-yl]-2-methoxyacetamide Chemical compound C([C@H](NC(=O)COC)[C@H](O)CN[C@@H]1C2=CC(CCC(C)C)=CN=C2OC2(CCC2)C1)C1=CC=CC=C1 GMHCBOGSXGMCIF-KKUQBAQOSA-N 0.000 claims 1
UUQAXOVTDUHVNH-WDTRASESSA-N n-[(2s,3r)-3-hydroxy-4-[[(4s)-6-[[(2r)-2-methyloxolan-2-yl]methyl]spiro[3,4-dihydropyrano[2,3-b]pyridine-2,1'-cyclobutane]-4-yl]amino]-1-phenylbutan-2-yl]acetamide Chemical compound C([C@H](NC(=O)C)[C@H](O)CN[C@@H]1C2=CC(C[C@]3(C)OCCC3)=CN=C2OC2(CCC2)C1)C1=CC=CC=C1 UUQAXOVTDUHVNH-WDTRASESSA-N 0.000 claims 1
YNHWCLFEEDJTNJ-GYUKIKGESA-N n-[(2s,3r)-3-hydroxy-4-[[(4s)-6-[[(2r)-oxolan-2-yl]methyl]spiro[3,4-dihydrochromene-2,1'-cyclobutane]-4-yl]amino]-1-phenylbutan-2-yl]acetamide Chemical compound C([C@H](NC(=O)C)[C@H](O)CN[C@@H]1C2=CC(C[C@@H]3OCCC3)=CC=C2OC2(CCC2)C1)C1=CC=CC=C1 YNHWCLFEEDJTNJ-GYUKIKGESA-N 0.000 claims 1
AFNUOMRXRGRYLK-HMNRDNJPSA-N n-[(2s,3r)-3-hydroxy-4-[[(4s)-6-[[(2r)-oxolan-2-yl]methyl]spiro[3,4-dihydropyrano[2,3-b]pyridine-2,1'-cyclobutane]-4-yl]amino]-1-phenylbutan-2-yl]acetamide Chemical compound C([C@H](NC(=O)C)[C@H](O)CN[C@@H]1C2=CC(C[C@@H]3OCCC3)=CN=C2OC2(CCC2)C1)C1=CC=CC=C1 AFNUOMRXRGRYLK-HMNRDNJPSA-N 0.000 claims 1
KGBBCOHRANKVDH-ZCLKUGBOSA-N n-[(2s,3r)-3-hydroxy-4-[[(4s)-6-[[(2s)-oxolan-2-yl]methyl]spiro[3,4-dihydropyrano[2,3-b]pyridine-2,1'-cyclobutane]-4-yl]amino]-1-phenylbutan-2-yl]-2-methoxyacetamide Chemical compound C([C@H](NC(=O)COC)[C@H](O)CN[C@@H]1C2=CC(C[C@H]3OCCC3)=CN=C2OC2(CCC2)C1)C1=CC=CC=C1 KGBBCOHRANKVDH-ZCLKUGBOSA-N 0.000 claims 1
ZDOVUIOQKZPCLW-GMQQYTKMSA-N n-[(2s,3r)-4-[[(1s)-7-(cyclopentylamino)-3,3-dimethyl-4-oxo-1,2-dihydronaphthalen-1-yl]amino]-3-hydroxy-1-phenylbutan-2-yl]acetamide Chemical compound C([C@H](NC(=O)C)[C@H](O)CN[C@@H]1C2=CC(NC3CCCC3)=CC=C2C(=O)C(C)(C)C1)C1=CC=CC=C1 ZDOVUIOQKZPCLW-GMQQYTKMSA-N 0.000 claims 1
ATMWAUGXRCWLBS-CDILPITASA-N n-[(2s,3r)-4-[[(2r,4s)-6-(2,2-dimethylpropyl)spiro[3,4-dihydropyrano[2,3-b]pyridine-2,3'-oxolane]-4-yl]amino]-1-(3-fluorophenyl)-3-hydroxybutan-2-yl]acetamide Chemical compound C([C@H](NC(=O)C)[C@H](O)CN[C@@H]1C2=CC(CC(C)(C)C)=CN=C2O[C@]2(COCC2)C1)C1=CC=CC(F)=C1 ATMWAUGXRCWLBS-CDILPITASA-N 0.000 claims 1
YXXSUWYLMCDEAZ-XWZVPRMZSA-N n-[(2s,3r)-4-[[(2r,4s)-6-chloro-8-morpholin-4-ylspiro[3,4-dihydrochromene-2,3'-oxolane]-4-yl]amino]-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl]acetamide Chemical compound C([C@H](NC(=O)C)[C@H](O)CN[C@@H]1C2=C(C(=CC(Cl)=C2)N2CCOCC2)O[C@]2(COCC2)C1)C1=CC(F)=CC(F)=C1 YXXSUWYLMCDEAZ-XWZVPRMZSA-N 0.000 claims 1
BIHRVTGDRMCRBV-QXUYBEEESA-N n-[(2s,3r)-4-[[(2r,4s)-6-chlorospiro[3,4-dihydropyrano[2,3-b]pyridine-2,3'-oxolane]-4-yl]amino]-3-hydroxy-1-phenylbutan-2-yl]acetamide Chemical compound C([C@H](NC(=O)C)[C@H](O)CN[C@@H]1C2=CC(Cl)=CN=C2O[C@]2(COCC2)C1)C1=CC=CC=C1 BIHRVTGDRMCRBV-QXUYBEEESA-N 0.000 claims 1
LTKKNMVAMBUECM-NAVOWQOKSA-N n-[(2s,3r)-4-[[(2s,4s)-1'-acetyl-6-ethylspiro[3,4-dihydrochromene-2,3'-pyrrolidine]-4-yl]amino]-3-hydroxy-1-phenylbutan-2-yl]acetamide Chemical compound C1([C@@H](NC[C@@H](O)[C@H](CC=2C=CC=CC=2)NC(C)=O)C2)=CC(CC)=CC=C1O[C@]12CCN(C(C)=O)C1 LTKKNMVAMBUECM-NAVOWQOKSA-N 0.000 claims 1
RPLRVPIJGAVSFX-KEZQHZCBSA-N n-[(2s,3r)-4-[[(2s,4s)-6-bromo-2-methyl-2-(trifluoromethyl)-3,4-dihydrochromen-4-yl]amino]-3-hydroxy-1-phenylbutan-2-yl]acetamide Chemical compound C([C@H](NC(=O)C)[C@H](O)CN[C@@H]1C2=CC(Br)=CC=C2O[C@@](C)(C1)C(F)(F)F)C1=CC=CC=C1 RPLRVPIJGAVSFX-KEZQHZCBSA-N 0.000 claims 1
WEFKDLDYYSHQRC-JBRSBNLGSA-N n-[(2s,3r)-4-[[(4r)-8-(dimethylamino)-6-ethyl-2,2-dimethyl-3,4-dihydrochromen-4-yl]amino]-3-hydroxy-1-phenylbutan-2-yl]acetamide Chemical compound C([C@@H]([C@H](O)CN[C@H]1C=2C=C(C=C(C=2OC(C)(C)C1)N(C)C)CC)NC(C)=O)C1=CC=CC=C1 WEFKDLDYYSHQRC-JBRSBNLGSA-N 0.000 claims 1
RJEWKGNHSJODHQ-WPFOTENUSA-N n-[(2s,3r)-4-[[(4s)-1-acetyl-6-bromo-2,2-dimethyl-3,4-dihydroquinolin-4-yl]amino]-3-hydroxy-1-phenylbutan-2-yl]acetamide Chemical compound C([C@H](NC(=O)C)[C@H](O)CN[C@@H]1C2=CC(Br)=CC=C2N(C(C)=O)C(C)(C)C1)C1=CC=CC=C1 RJEWKGNHSJODHQ-WPFOTENUSA-N 0.000 claims 1
NOKVDNHDDCOIBW-KKUQBAQOSA-N n-[(2s,3r)-4-[[(4s)-6-(2,2-dimethylpropyl)-2,2-dimethyl-3,4-dihydro-1h-quinolin-4-yl]amino]-1-(4-fluorophenyl)-3-hydroxybutan-2-yl]acetamide Chemical compound C([C@H](NC(=O)C)[C@H](O)CN[C@@H]1C2=CC(CC(C)(C)C)=CC=C2NC(C)(C)C1)C1=CC=C(F)C=C1 NOKVDNHDDCOIBW-KKUQBAQOSA-N 0.000 claims 1
ZQWWGBZQRZMGBQ-KKUQBAQOSA-N n-[(2s,3r)-4-[[(4s)-6-(2,2-dimethylpropyl)-2,2-dimethyl-3,4-dihydro-1h-quinolin-4-yl]amino]-3-hydroxy-1-phenylbutan-2-yl]acetamide Chemical compound C([C@H](NC(=O)C)[C@H](O)CN[C@@H]1C2=CC(CC(C)(C)C)=CC=C2NC(C)(C)C1)C1=CC=CC=C1 ZQWWGBZQRZMGBQ-KKUQBAQOSA-N 0.000 claims 1
ZTDPMDMKRAIUPD-GMQQYTKMSA-N n-[(2s,3r)-4-[[(4s)-6-(2,2-dimethylpropyl)-8-propan-2-yloxyspiro[3,4-dihydropyrano[2,3-c]pyridine-2,1'-cyclobutane]-4-yl]amino]-1-(3-fluorophenyl)-3-hydroxybutan-2-yl]acetamide Chemical compound C([C@@H](C=1C=C(CC(C)(C)C)N=C(C=1O1)OC(C)C)NC[C@@H](O)[C@H](CC=2C=C(F)C=CC=2)NC(C)=O)C21CCC2 ZTDPMDMKRAIUPD-GMQQYTKMSA-N 0.000 claims 1
CLMFBRCNMBGVJX-GMQQYTKMSA-N n-[(2s,3r)-4-[[(4s)-6-(2,2-dimethylpropyl)-8-propan-2-yloxyspiro[3,4-dihydropyrano[2,3-c]pyridine-2,1'-cyclobutane]-4-yl]amino]-1-(4-fluorophenyl)-3-hydroxybutan-2-yl]acetamide Chemical compound C([C@@H](C=1C=C(CC(C)(C)C)N=C(C=1O1)OC(C)C)NC[C@@H](O)[C@H](CC=2C=CC(F)=CC=2)NC(C)=O)C21CCC2 CLMFBRCNMBGVJX-GMQQYTKMSA-N 0.000 claims 1
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WJVNQJPUPQIALJ-CSPCWVBQSA-N n-[(2s,3r)-4-[[(4s)-6-(2,2-dimethylpropyl)spiro[3,4-dihydropyrano[2,3-b]pyridine-2,1'-cyclobutane]-4-yl]amino]-3-hydroxy-1-(2-methylcyclopropyl)butan-2-yl]acetamide Chemical compound CC1CC1C[C@H](NC(C)=O)[C@H](O)CN[C@@H]1C2=CC(CC(C)(C)C)=CN=C2OC2(CCC2)C1 WJVNQJPUPQIALJ-CSPCWVBQSA-N 0.000 claims 1
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AUEKLZQTRXTDNY-HZFUHODCSA-N n-[(2s,3r)-4-[[(4s)-6-(2,2-dimethylpropyl)spiro[3,4-dihydropyrano[2,3-b]pyridine-2,1'-cyclobutane]-4-yl]amino]-3-hydroxy-1-phenylbutan-2-yl]-2-(2-methyl-1,3-thiazol-4-yl)acetamide Chemical compound S1C(C)=NC(CC(=O)N[C@@H](CC=2C=CC=CC=2)[C@H](O)CN[C@@H]2C3=CC(CC(C)(C)C)=CN=C3OC3(CCC3)C2)=C1 AUEKLZQTRXTDNY-HZFUHODCSA-N 0.000 claims 1
CSKPRONIDMGAKP-HZFUHODCSA-N n-[(2s,3r)-4-[[(4s)-6-(2,2-dimethylpropyl)spiro[3,4-dihydropyrano[2,3-b]pyridine-2,1'-cyclobutane]-4-yl]amino]-3-hydroxy-1-phenylbutan-2-yl]-2-(3-methyl-1,2-oxazol-5-yl)acetamide Chemical compound O1N=C(C)C=C1CC(=O)N[C@H]([C@H](O)CN[C@@H]1C2=CC(CC(C)(C)C)=CN=C2OC2(CCC2)C1)CC1=CC=CC=C1 CSKPRONIDMGAKP-HZFUHODCSA-N 0.000 claims 1
JWZDYRNVJUQSFE-KKUQBAQOSA-N n-[(2s,3r)-4-[[(4s)-6-(2,2-dimethylpropyl)spiro[3,4-dihydropyrano[2,3-b]pyridine-2,1'-cyclobutane]-4-yl]amino]-3-hydroxy-1-phenylbutan-2-yl]-2-(triazol-2-yl)acetamide Chemical compound C1([C@@H](NC[C@@H](O)[C@H](CC=2C=CC=CC=2)NC(=O)CN2N=CC=N2)C2)=CC(CC(C)(C)C)=CN=C1OC12CCC1 JWZDYRNVJUQSFE-KKUQBAQOSA-N 0.000 claims 1
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NSFNRHDXSOQIKI-CXSMSNRLSA-N n-[(2s,3r)-4-[[(4s)-6-[(1s)-1-fluoro-2,2-dimethylpropyl]spiro[3,4-dihydropyrano[2,3-b]pyridine-2,1'-cyclobutane]-4-yl]amino]-1-(4-fluorophenyl)-3-hydroxybutan-2-yl]acetamide Chemical compound C([C@H](NC(=O)C)[C@H](O)CN[C@@H]1C2=CC(=CN=C2OC2(CCC2)C1)[C@@H](F)C(C)(C)C)C1=CC=C(F)C=C1 NSFNRHDXSOQIKI-CXSMSNRLSA-N 0.000 claims 1
HCSAUHXMCQXWJH-XLRUWRGTSA-N n-[(2s,3r)-4-[[(4s)-6-[(2r)-3-fluoro-2-methylpropyl]spiro[3,4-dihydropyrano[2,3-b]pyridine-2,1'-cyclobutane]-4-yl]amino]-1-(4-fluorophenyl)-3-hydroxybutan-2-yl]acetamide Chemical compound C1([C@@H](NC[C@@H](O)[C@H](CC=2C=CC(F)=CC=2)NC(C)=O)C2)=CC(C[C@H](CF)C)=CN=C1OC12CCC1 HCSAUHXMCQXWJH-XLRUWRGTSA-N 0.000 claims 1
BNKKNNRDNAMWKW-FDFHNCONSA-N n-[(2s,3r)-4-[[(4s)-6-bromo-2,2-dimethyl-3,4-dihydro-1h-quinolin-4-yl]amino]-3-hydroxy-1-phenylbutan-2-yl]acetamide Chemical compound C([C@H](NC(=O)C)[C@H](O)CN[C@@H]1C2=CC(Br)=CC=C2NC(C)(C)C1)C1=CC=CC=C1 BNKKNNRDNAMWKW-FDFHNCONSA-N 0.000 claims 1
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PUWMOTSQDRSSHT-OHSXHVKISA-N n-[(2s,3r)-4-[[(4s)-6-chloro-8-morpholin-4-ylspiro[3,4-dihydrochromene-2,1'-cyclobutane]-4-yl]amino]-1-(3-cyanophenyl)-3-hydroxybutan-2-yl]acetamide Chemical compound C([C@H](NC(=O)C)[C@H](O)CN[C@@H]1C2=C(C(=CC(Cl)=C2)N2CCOCC2)OC2(CCC2)C1)C1=CC=CC(C#N)=C1 PUWMOTSQDRSSHT-OHSXHVKISA-N 0.000 claims 1
XCDLZZNRQMUGRN-OHSXHVKISA-N n-[(2s,3r)-4-[[(4s)-6-ethyl-2,2-dimethyl-8-pyrrolidin-1-yl-3,4-dihydrochromen-4-yl]amino]-3-hydroxy-1-phenylbutan-2-yl]acetamide Chemical compound C([C@@H](C=1C=C(C=2)CC)NC[C@@H](O)[C@H](CC=3C=CC=CC=3)NC(C)=O)C(C)(C)OC=1C=2N1CCCC1 XCDLZZNRQMUGRN-OHSXHVKISA-N 0.000 claims 1
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WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 1
150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
239000002798 polar solvent Substances 0.000 description 1
229920001155 polypropylene Polymers 0.000 description 1
NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical class [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 description 1
239000012286 potassium permanganate Substances 0.000 description 1
LJCNRYVRMXRIQR-OLXYHTOASA-L potassium sodium L-tartrate Chemical compound [Na+].[K+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O LJCNRYVRMXRIQR-OLXYHTOASA-L 0.000 description 1
238000009117 preventive therapy Methods 0.000 description 1
150000003138 primary alcohols Chemical class 0.000 description 1
108090000765 processed proteins & peptides Proteins 0.000 description 1
230000007425 progressive decline Effects 0.000 description 1
230000000750 progressive effect Effects 0.000 description 1
RLJWTAURUFQFJP-UHFFFAOYSA-N propan-2-ol;titanium Chemical compound [Ti].CC(C)O.CC(C)O.CC(C)O.CC(C)O RLJWTAURUFQFJP-UHFFFAOYSA-N 0.000 description 1
WEHMFTWWOGBHCR-UHFFFAOYSA-N propyl 4-methoxybenzoate Chemical compound CCCOC(=O)C1=CC=C(OC)C=C1 WEHMFTWWOGBHCR-UHFFFAOYSA-N 0.000 description 1
125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
230000002797 proteolythic effect Effects 0.000 description 1
230000006337 proteolytic cleavage Effects 0.000 description 1
238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
239000012264 purified product Substances 0.000 description 1
125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
125000003072 pyrazolidinyl group Chemical group 0.000 description 1
GRJJQCWNZGRKAU-UHFFFAOYSA-N pyridin-1-ium;fluoride Chemical compound F.C1=CC=NC=C1 GRJJQCWNZGRKAU-UHFFFAOYSA-N 0.000 description 1
125000005493 quinolyl group Chemical group 0.000 description 1
238000009790 rate-determining step (RDS) Methods 0.000 description 1
JWEQRJSCTFBRSI-PCLIKHOPSA-N rboxylate Chemical compound COC(=O)C1C(N2C3=O)C4=CC=CC=C4OC1(C)N=C2S\C3=C\C(C=1)=CC=C(OC)C=1COC1=CC=CC=C1C JWEQRJSCTFBRSI-PCLIKHOPSA-N 0.000 description 1
239000012070 reactive reagent Substances 0.000 description 1
230000008707 rearrangement Effects 0.000 description 1
238000010992 reflux Methods 0.000 description 1
230000001105 regulatory effect Effects 0.000 description 1
230000004044 response Effects 0.000 description 1
229960004889 salicylic acid Drugs 0.000 description 1
239000011986 second-generation catalyst Substances 0.000 description 1
230000001953 sensory effect Effects 0.000 description 1
125000004469 siloxy group Chemical group [SiH3]O* 0.000 description 1
BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
239000012312 sodium hydride Substances 0.000 description 1
239000001476 sodium potassium tartrate Substances 0.000 description 1
235000011006 sodium potassium tartrate Nutrition 0.000 description 1
GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 1
235000010265 sodium sulphite Nutrition 0.000 description 1
239000012321 sodium triacetoxyborohydride Substances 0.000 description 1
239000008247 solid mixture Substances 0.000 description 1
125000006850 spacer group Chemical group 0.000 description 1
230000003595 spectral effect Effects 0.000 description 1
125000003003 spiro group Chemical group 0.000 description 1
239000011550 stock solution Substances 0.000 description 1
125000000547 substituted alkyl group Chemical group 0.000 description 1
239000001384 succinic acid Substances 0.000 description 1
125000000446 sulfanediyl group Chemical group *S* 0.000 description 1
150000003456 sulfonamides Chemical class 0.000 description 1
239000001117 sulphuric acid Substances 0.000 description 1
235000011149 sulphuric acid Nutrition 0.000 description 1
230000002194 synthesizing effect Effects 0.000 description 1
238000010189 synthetic method Methods 0.000 description 1
239000011975 tartaric acid Substances 0.000 description 1
235000002906 tartaric acid Nutrition 0.000 description 1
125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
HLXWZKNGXZQJRD-NWDGAFQWSA-N tert-butyl (4s,5s)-5-(hydroxymethyl)-2,2-dimethyl-4-(1,3-thiazol-4-ylmethyl)-1,3-oxazolidine-3-carboxylate Chemical compound OC[C@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1CC1=CSC=N1 HLXWZKNGXZQJRD-NWDGAFQWSA-N 0.000 description 1
BBQPJRDXMLUQQS-UONOGXRCSA-N tert-butyl (4s,5s)-5-(hydroxymethyl)-2,2-dimethyl-4-[(1-methyl-2-oxopyridin-4-yl)methyl]-1,3-oxazolidine-3-carboxylate Chemical compound O=C1N(C)C=CC(C[C@@H]2N(C(C)(C)O[C@@H]2CO)C(=O)OC(C)(C)C)=C1 BBQPJRDXMLUQQS-UONOGXRCSA-N 0.000 description 1
IBXSYHFLHFCJIM-QWHCGFSZSA-N tert-butyl (4s,5s)-5-(hydroxymethyl)-2,2-dimethyl-4-[(2-methyl-1,3-thiazol-4-yl)methyl]-1,3-oxazolidine-3-carboxylate Chemical compound S1C(C)=NC(C[C@@H]2N(C(C)(C)O[C@@H]2CO)C(=O)OC(C)(C)C)=C1 IBXSYHFLHFCJIM-QWHCGFSZSA-N 0.000 description 1
QZADYKCRWNOHDY-UONOGXRCSA-N tert-butyl (4s,5s)-5-(hydroxymethyl)-2,2-dimethyl-4-[(2-propyl-1,3-thiazol-4-yl)methyl]-1,3-oxazolidine-3-carboxylate Chemical compound S1C(CCC)=NC(C[C@@H]2N(C(C)(C)O[C@@H]2CO)C(=O)OC(C)(C)C)=C1 QZADYKCRWNOHDY-UONOGXRCSA-N 0.000 description 1
KOSUEEHCWCBDGU-LSDHHAIUSA-N tert-butyl (4s,5s)-5-(hydroxymethyl)-2,2-dimethyl-4-[[4-(trifluoromethyl)phenyl]methyl]-1,3-oxazolidine-3-carboxylate Chemical compound OC[C@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1CC1=CC=C(C(F)(F)F)C=C1 KOSUEEHCWCBDGU-LSDHHAIUSA-N 0.000 description 1
HQYWYJNRRYDWBH-RBUKOAKNSA-N tert-butyl (4s,5s)-5-[[tert-butyl(dimethyl)silyl]oxymethyl]-2,2-dimethyl-4-(pyridin-4-ylmethyl)-1,3-oxazolidine-3-carboxylate Chemical compound CC(C)(C)[Si](C)(C)OC[C@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1CC1=CC=NC=C1 HQYWYJNRRYDWBH-RBUKOAKNSA-N 0.000 description 1
LFFHUSLDLGZRLE-VQTJNVASSA-N tert-butyl (4s,5s)-5-[[tert-butyl(dimethyl)silyl]oxymethyl]-2,2-dimethyl-4-[(2-methylpyridin-4-yl)methyl]-1,3-oxazolidine-3-carboxylate Chemical compound C1=NC(C)=CC(C[C@@H]2N(C(C)(C)O[C@@H]2CO[Si](C)(C)C(C)(C)C)C(=O)OC(C)(C)C)=C1 LFFHUSLDLGZRLE-VQTJNVASSA-N 0.000 description 1
YQOVSXOMVSFKCM-LEWJYISDSA-N tert-butyl (4s,5s)-5-[[tert-butyl(dimethyl)silyl]oxymethyl]-4-[[2-[tert-butyl(dimethyl)silyl]-1,3-thiazol-4-yl]methyl]-2,2-dimethyl-1,3-oxazolidine-3-carboxylate Chemical compound CC(C)(C)[Si](C)(C)OC[C@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1CC1=CSC([Si](C)(C)C(C)(C)C)=N1 YQOVSXOMVSFKCM-LEWJYISDSA-N 0.000 description 1
NVPOUMXZERMIJK-QWHCGFSZSA-N tert-butyl n-[(1s)-1-[(2s)-oxiran-2-yl]-2-phenylethyl]carbamate Chemical compound C([C@H](NC(=O)OC(C)(C)C)[C@@H]1OC1)C1=CC=CC=C1 NVPOUMXZERMIJK-QWHCGFSZSA-N 0.000 description 1
GJQCIUCPNVIROB-ZWKOTPCHSA-N tert-butyl n-[(2s,3s)-3-[tert-butyl(dimethyl)silyl]oxy-1-(3-fluorophenyl)-4-oxobutan-2-yl]carbamate Chemical compound CC(C)(C)OC(=O)N[C@H]([C@H](O[Si](C)(C)C(C)(C)C)C=O)CC1=CC=CC(F)=C1 GJQCIUCPNVIROB-ZWKOTPCHSA-N 0.000 description 1
150000003509 tertiary alcohols Chemical class 0.000 description 1
150000003512 tertiary amines Chemical class 0.000 description 1
125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 description 1
125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 1
CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
PHCBRBWANGJMHS-UHFFFAOYSA-J tetrasodium;disulfate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O PHCBRBWANGJMHS-UHFFFAOYSA-J 0.000 description 1
150000003536 tetrazoles Chemical class 0.000 description 1
WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
125000004495 thiazol-4-yl group Chemical group S1C=NC(=C1)* 0.000 description 1
150000003557 thiazoles Chemical class 0.000 description 1
150000003568 thioethers Chemical class 0.000 description 1
150000003573 thiols Chemical class 0.000 description 1
JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 1
238000006257 total synthesis reaction Methods 0.000 description 1
238000011830 transgenic mouse model Methods 0.000 description 1
YLGRTLMDMVAFNI-UHFFFAOYSA-N tributyl(prop-2-enyl)stannane Chemical compound CCCC[Sn](CCCC)(CCCC)CC=C YLGRTLMDMVAFNI-UHFFFAOYSA-N 0.000 description 1
WVMSIBFANXCZKT-UHFFFAOYSA-N triethyl(hydroxy)silane Chemical compound CC[Si](O)(CC)CC WVMSIBFANXCZKT-UHFFFAOYSA-N 0.000 description 1
125000005034 trifluormethylthio group Chemical group FC(S*)(F)F 0.000 description 1
FIQMHBFVRAXMOP-UHFFFAOYSA-N triphenylphosphane oxide Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)(=O)C1=CC=CC=C1 FIQMHBFVRAXMOP-UHFFFAOYSA-N 0.000 description 1
150000003672 ureas Chemical class 0.000 description 1
238000003828 vacuum filtration Methods 0.000 description 1
230000002792 vascular Effects 0.000 description 1
125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
230000001755 vocal effect Effects 0.000 description 1
238000010626 work up procedure Methods 0.000 description 1
239000011592 zinc chloride Substances 0.000 description 1
235000005074 zinc chloride Nutrition 0.000 description 1

Classifications

- 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
- C07D405/02—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 two hetero rings
- C07D405/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
- 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
- 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
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
- C07D311/68—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with nitrogen atoms directly attached in position 4
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
- 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
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered

Landscapes

Organic Chemistry (AREA)
Chemical & Material Sciences (AREA)
Health & Medical Sciences (AREA)
Bioinformatics & Cheminformatics (AREA)
Engineering & Computer Science (AREA)
Neurosurgery (AREA)
Neurology (AREA)
Biomedical Technology (AREA)
Veterinary Medicine (AREA)
Pharmacology & Pharmacy (AREA)
Life Sciences & Earth Sciences (AREA)
Animal Behavior & Ethology (AREA)
General Health & Medical Sciences (AREA)
Public Health (AREA)
Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
Medicinal Chemistry (AREA)
General Chemical & Material Sciences (AREA)
Chemical Kinetics & Catalysis (AREA)
Hospice & Palliative Care (AREA)
Psychology (AREA)
Psychiatry (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Nitrogen Condensed Heterocyclic Rings (AREA)
Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Pyrane Compounds (AREA)
Plural Heterocyclic Compounds (AREA)
Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Quinoline Compounds (AREA)
Thiazole And Isothizaole Compounds (AREA)
Furan Compounds (AREA)

CA2629402A 2005-11-21 2006-11-13 Modulateurs de beta-secretase et procedes d'utilisation associes Expired - Fee Related CA2629402C (fr)

Applications Claiming Priority (5)

Application Number	Priority Date	Filing Date	Title
US73910805P	2005-11-21	2005-11-21
US60/739,108		2005-11-21
US85482406P	2006-10-27	2006-10-27
US60/854,824		2006-10-27
PCT/US2006/044058 WO2007061670A1 (fr)	2005-11-21	2006-11-13	Modulateurs de beta-secretase et procedes d'utilisation associes

Publications (2)

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CA2629402A1 CA2629402A1 (fr)	2007-05-31
CA2629402C true CA2629402C (fr)	2011-07-26

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EP (1)	EP1971598A1 (fr)
JP (1)	JP5274258B2 (fr)
AR (1)	AR057985A1 (fr)
AU (1)	AU2006316620B2 (fr)
CA (1)	CA2629402C (fr)
PE (1)	PE20070645A1 (fr)
TW (1)	TW200800966A (fr)
WO (1)	WO2007061670A1 (fr)

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WO2005004802A2 (fr)	2003-06-30	2005-01-20	Merck & Co., Inc.	Inhibiteurs de la beta-secretase a base de n-alkyle phenylcarboxamide pour le traitement de la maladie d'alzheimer
AU2004255191A1 (en)	2003-07-01	2005-01-20	Merck & Co., Inc.	Phenylcarboxylate beta-secretase inhibitors for the treatment of Alzheimer's disease
GB0317491D0 (en) *	2003-07-25	2003-08-27	Novartis Ag	Organic compounds
JP2007522129A (ja) *	2004-01-21	2007-08-09	エランファーマシューティカルズ，インコーポレイテッド	アスパラギン酸プロテアーゼ阻害薬を用いるアミロイドーシスの処置方法
US20050239832A1 (en) *	2004-03-09	2005-10-27	Varghese John	Methods of treatment of amyloidosis using bi-cyclic aspartyl protease inhibitors
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2006
- 2006-11-13 EP EP06837478A patent/EP1971598A1/fr not_active Withdrawn
- 2006-11-13 CA CA2629402A patent/CA2629402C/fr not_active Expired - Fee Related
- 2006-11-13 JP JP2008541258A patent/JP5274258B2/ja not_active Expired - Fee Related
- 2006-11-13 WO PCT/US2006/044058 patent/WO2007061670A1/fr active Application Filing
- 2006-11-13 AU AU2006316620A patent/AU2006316620B2/en not_active Ceased
- 2006-11-20 PE PE2006001476A patent/PE20070645A1/es not_active Application Discontinuation
- 2006-11-21 TW TW095143035A patent/TW200800966A/zh unknown
- 2006-11-21 AR ARP060105083A patent/AR057985A1/es unknown

Also Published As

Publication number	Publication date
EP1971598A1 (fr)	2008-09-24
CA2629402A1 (fr)	2007-05-31
JP2009516684A (ja)	2009-04-23
TW200800966A (en)	2008-01-01
AR057985A1 (es)	2008-01-09
AU2006316620A1 (en)	2007-05-31
PE20070645A1 (es)	2007-08-24
AU2006316620B2 (en)	2011-03-03
JP5274258B2 (ja)	2013-08-28
WO2007061670A1 (fr)	2007-05-31

Publication	Publication Date	Title
US7973047B2 (en)	2011-07-05	Beta-Secretase modulators and methods of use
CA2629466C (fr)	2011-05-24	Modulateurs de la beta-secretase et procedes d'utilisation de ceux-ci
AU2009291602B2 (en)	2013-02-14	Spiro-tetracyclic ring compounds as betasecretase modulators and methods of use
AU2008257145B2 (en)	2011-11-10	Substituted hydroxyethyl amine compounds as Beta-secretase modulators and methods of use
AU2011207679B2 (en)	2013-10-10	Amino heteroaryl compounds as beta-secretase modulators and methods of use
CA2629402C (fr)	2011-07-26	Modulateurs de beta-secretase et procedes d'utilisation associes
CA2629462C (fr)	2011-11-01	Modulateurs de beta-secretase et procedes d'utilisation
WO2009064418A1 (fr)	2009-05-22	Composés d'hydroxyéthylamine substituée en tant que modulateurs de bêta-sécrétase et leurs procédés d'utilisation
US8552181B2 (en)	2013-10-08	Substituted hydroxyethyl amine compounds as beta-secretase modulators and methods of use
US7951838B2 (en)	2011-05-31	Substituted spirocyclic chromanamine compounds as Beta-Secretase modulators and methods of use

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2008-05-12	EEER	Examination request
2015-12-26	MKLA	Lapsed	Effective date: 20151113