ZA200404066B - 3,4-disubstituted, 3,5-disubstituted and 3,4,5-substituted piperidines and piperazines - Google Patents
3,4-disubstituted, 3,5-disubstituted and 3,4,5-substituted piperidines and piperazines Download PDFInfo
- Publication number
- ZA200404066B ZA200404066B ZA200404066A ZA200404066A ZA200404066B ZA 200404066 B ZA200404066 B ZA 200404066B ZA 200404066 A ZA200404066 A ZA 200404066A ZA 200404066 A ZA200404066 A ZA 200404066A ZA 200404066 B ZA200404066 B ZA 200404066B
- Authority
- ZA
- South Africa
- Prior art keywords
- alkyl
- alkoxy
- optionally substituted
- group
- chz
- Prior art date
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- 150000004885 piperazines Chemical class 0.000 title description 4
- 150000003053 piperidines Chemical class 0.000 title description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 643
- 150000001875 compounds Chemical class 0.000 claims description 182
- -1 1l-naphthyl Chemical group 0.000 claims description 131
- 125000003545 alkoxy group Chemical group 0.000 claims description 125
- 125000001424 substituent group Chemical group 0.000 claims description 119
- 229910052799 carbon Inorganic materials 0.000 claims description 102
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 96
- 208000024827 Alzheimer disease Diseases 0.000 claims description 62
- 125000003342 alkenyl group Chemical group 0.000 claims description 55
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 52
- 125000000304 alkynyl group Chemical group 0.000 claims description 51
- 201000010099 disease Diseases 0.000 claims description 50
- 238000000034 method Methods 0.000 claims description 49
- 206010012289 Dementia Diseases 0.000 claims description 38
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 35
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 29
- 229910052739 hydrogen Inorganic materials 0.000 claims description 27
- 150000003839 salts Chemical class 0.000 claims description 27
- 238000011282 treatment Methods 0.000 claims description 26
- 150000002148 esters Chemical class 0.000 claims description 25
- 208000010877 cognitive disease Diseases 0.000 claims description 23
- 125000001072 heteroaryl group Chemical group 0.000 claims description 23
- 208000027061 mild cognitive impairment Diseases 0.000 claims description 23
- 125000003118 aryl group Chemical group 0.000 claims description 21
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 20
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 16
- 230000003412 degenerative effect Effects 0.000 claims description 16
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 14
- 125000004568 thiomorpholinyl group Chemical group 0.000 claims description 14
- 201000010374 Down Syndrome Diseases 0.000 claims description 12
- 206010044688 Trisomy 21 Diseases 0.000 claims description 12
- RCCPEORTSYDPMB-UHFFFAOYSA-N hydroxy benzenecarboximidothioate Chemical compound OSC(=N)C1=CC=CC=C1 RCCPEORTSYDPMB-UHFFFAOYSA-N 0.000 claims description 12
- 125000004193 piperazinyl group Chemical group 0.000 claims description 12
- 125000003386 piperidinyl group Chemical group 0.000 claims description 12
- 125000004076 pyridyl group Chemical group 0.000 claims description 12
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 12
- 125000001422 pyrrolinyl group Chemical group 0.000 claims description 12
- 208000005145 Cerebral amyloid angiopathy Diseases 0.000 claims description 11
- 229910052731 fluorine Inorganic materials 0.000 claims description 11
- 125000000623 heterocyclic group Chemical group 0.000 claims description 11
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 11
- 125000002757 morpholinyl group Chemical group 0.000 claims description 11
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 claims description 10
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 10
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims description 10
- 239000001257 hydrogen Substances 0.000 claims description 10
- 125000004857 imidazopyridinyl group Chemical group N1C(=NC2=C1C=CC=N2)* 0.000 claims description 10
- 210000004558 lewy body Anatomy 0.000 claims description 9
- 229910052757 nitrogen Inorganic materials 0.000 claims description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 8
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 8
- 229910052801 chlorine Inorganic materials 0.000 claims description 8
- 125000002883 imidazolyl group Chemical group 0.000 claims description 8
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 claims description 8
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 claims description 8
- 125000002971 oxazolyl group Chemical group 0.000 claims description 8
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 claims description 8
- 125000005329 tetralinyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 claims description 8
- 125000001113 thiadiazolyl group Chemical group 0.000 claims description 8
- 230000002792 vascular Effects 0.000 claims description 8
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims description 7
- 208000032843 Hemorrhage Diseases 0.000 claims description 7
- 208000018737 Parkinson disease Diseases 0.000 claims description 7
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 7
- 230000001054 cortical effect Effects 0.000 claims description 7
- 230000007850 degeneration Effects 0.000 claims description 7
- 201000002212 progressive supranuclear palsy Diseases 0.000 claims description 7
- 230000000306 recurrent effect Effects 0.000 claims description 7
- 125000004429 atom Chemical group 0.000 claims description 6
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims description 6
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims description 6
- 125000004600 benzothiopyranyl group Chemical group S1C(C=CC2=C1C=CC=C2)* 0.000 claims description 6
- 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 6
- 125000005046 dihydronaphthyl group Chemical group 0.000 claims description 6
- 125000002541 furyl group Chemical group 0.000 claims description 6
- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 claims description 6
- 125000003406 indolizinyl group Chemical group C=1(C=CN2C=CC=CC12)* 0.000 claims description 6
- 125000001041 indolyl group Chemical group 0.000 claims description 6
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 claims description 6
- 125000005956 isoquinolyl group Chemical group 0.000 claims description 6
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 6
- 125000001715 oxadiazolyl group Chemical group 0.000 claims description 6
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 6
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 6
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 6
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 6
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 claims description 6
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 6
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 claims description 6
- 125000003107 substituted aryl group Chemical group 0.000 claims description 6
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 6
- 125000000335 thiazolyl group Chemical group 0.000 claims description 6
- 125000001544 thienyl group Chemical group 0.000 claims description 6
- 125000001425 triazolyl group Chemical group 0.000 claims description 6
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 5
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 5
- 229910052794 bromium Inorganic materials 0.000 claims description 5
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 5
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Chemical group C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 claims description 4
- 208000018282 ACys amyloidosis Diseases 0.000 claims description 4
- 208000007487 Familial Cerebral Amyloid Angiopathy Diseases 0.000 claims description 4
- 208000032849 Hereditary cerebral hemorrhage with amyloidosis Diseases 0.000 claims description 4
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 claims description 4
- 125000002047 benzodioxolyl group Chemical group O1OC(C2=C1C=CC=C2)* 0.000 claims description 4
- 125000004619 benzopyranyl group Chemical group O1C(C=CC2=C1C=CC=C2)* 0.000 claims description 4
- 125000004622 benzoxazinyl group Chemical group O1NC(=CC2=C1C=CC=C2)* 0.000 claims description 4
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 claims description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- 125000000609 carbazolyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3NC12)* 0.000 claims description 4
- 125000003016 chromanyl group Chemical group O1C(CCC2=CC=CC=C12)* 0.000 claims description 4
- 125000000259 cinnolinyl group Chemical group N1=NC(=CC2=CC=CC=C12)* 0.000 claims description 4
- 125000000332 coumarinyl group Chemical group O1C(=O)C(=CC2=CC=CC=C12)* 0.000 claims description 4
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 4
- 125000005992 dihydrobenzisothiazinyl group Chemical group 0.000 claims description 4
- 125000005993 dihydrobenzisoxazinyl group Chemical group 0.000 claims description 4
- 125000005843 halogen group Chemical group 0.000 claims description 4
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 claims description 4
- 125000005994 isobenzotetrahydrofuranyl group Chemical group 0.000 claims description 4
- 125000005995 isobenzotetrahydrothienyl group Chemical group 0.000 claims description 4
- 125000005990 isobenzothienyl group Chemical group 0.000 claims description 4
- 125000003384 isochromanyl group Chemical group C1(OCCC2=CC=CC=C12)* 0.000 claims description 4
- 125000001786 isothiazolyl group Chemical group 0.000 claims description 4
- 125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 0.000 claims description 4
- 125000001484 phenothiazinyl group Chemical group C1(=CC=CC=2SC3=CC=CC=C3NC12)* 0.000 claims description 4
- 125000001644 phenoxazinyl group Chemical group C1(=CC=CC=2OC3=CC=CC=C3NC12)* 0.000 claims description 4
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 claims description 4
- 125000006413 ring segment Chemical group 0.000 claims description 4
- 229910052717 sulfur Inorganic materials 0.000 claims description 4
- 125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 claims description 4
- 125000005958 tetrahydrothienyl group Chemical group 0.000 claims description 4
- 229930192474 thiophene Natural products 0.000 claims description 4
- 125000004306 triazinyl group Chemical group 0.000 claims description 4
- 125000004933 β-carbolinyl group Chemical group C1(=NC=CC=2C3=CC=CC=C3NC12)* 0.000 claims description 4
- 125000004070 6 membered heterocyclic group Chemical group 0.000 claims description 3
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 claims description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- 125000004594 isoindolinyl group Chemical group C1(NCC2=CC=CC=C12)* 0.000 claims description 3
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 claims description 3
- 229910052760 oxygen Inorganic materials 0.000 claims description 3
- 125000001042 pteridinyl group Chemical group N1=C(N=CC2=NC=CN=C12)* 0.000 claims description 3
- 125000006288 3,5-difluorobenzyl group Chemical group [H]C1=C(F)C([H])=C(C([H])=C1F)C([H])([H])* 0.000 claims description 2
- 125000003143 4-hydroxybenzyl group Chemical group [H]C([*])([H])C1=C([H])C([H])=C(O[H])C([H])=C1[H] 0.000 claims description 2
- 125000001318 4-trifluoromethylbenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])*)C(F)(F)F 0.000 claims description 2
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 claims description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 2
- 150000005215 alkyl ethers Chemical class 0.000 claims description 2
- 125000005037 alkyl phenyl group Chemical group 0.000 claims description 2
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 2
- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
- 150000001721 carbon Chemical group 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 125000004617 chromonyl group Chemical group O1C(=CC(C2=CC=CC=C12)=O)* 0.000 claims description 2
- 125000004852 dihydrofuranyl group Chemical group O1C(CC=C1)* 0.000 claims description 2
- 125000005043 dihydropyranyl group Chemical group O1C(CCC=C1)* 0.000 claims description 2
- 125000005052 dihydropyrazolyl group Chemical group N1(NCC=C1)* 0.000 claims description 2
- 125000005044 dihydroquinolinyl group Chemical group N1(CC=CC2=CC=CC=C12)* 0.000 claims description 2
- 125000005842 heteroatom Chemical group 0.000 claims description 2
- 125000001183 hydrocarbyl group Chemical group 0.000 claims description 2
- 229910052740 iodine Inorganic materials 0.000 claims description 2
- 125000003151 isocoumarinyl group Chemical group C1(=O)OC(=CC2=CC=CC=C12)* 0.000 claims description 2
- 239000001301 oxygen Substances 0.000 claims description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 2
- 125000004620 quinolinyl-N-oxide group Chemical group 0.000 claims description 2
- 239000011593 sulfur Substances 0.000 claims description 2
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 2
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 2
- 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 claims description 2
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims 18
- NNJMFJSKMRYHSR-UHFFFAOYSA-N 4-phenylbenzoic acid Chemical compound C1=CC(C(=O)O)=CC=C1C1=CC=CC=C1 NNJMFJSKMRYHSR-UHFFFAOYSA-N 0.000 claims 3
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 claims 3
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 claims 3
- 125000004464 hydroxyphenyl group Chemical group 0.000 claims 3
- 125000004483 piperidin-3-yl group Chemical group N1CC(CCC1)* 0.000 claims 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims 3
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 claims 2
- BGTWFLFIGDHQLW-UHFFFAOYSA-N naphthalene-1-carboxylic acid;hydrochloride Chemical compound Cl.C1=CC=C2C(C(=O)O)=CC=CC2=C1 BGTWFLFIGDHQLW-UHFFFAOYSA-N 0.000 claims 2
- XLBBQFVOBCYVAO-UHFFFAOYSA-N piperidin-3-yl benzoate Chemical compound C=1C=CC=CC=1C(=O)OC1CCCNC1 XLBBQFVOBCYVAO-UHFFFAOYSA-N 0.000 claims 2
- QQYNGKGFOZQMHD-UHFFFAOYSA-N (3-methoxyphenyl) acetate Chemical compound COC1=CC=CC(OC(C)=O)=C1 QQYNGKGFOZQMHD-UHFFFAOYSA-N 0.000 claims 1
- 125000004400 (C1-C12) alkyl group Chemical group 0.000 claims 1
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims 1
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 1
- GIVGMBPKVYSOKZ-UHFFFAOYSA-N 2-ethylhexanoic acid;hydrochloride Chemical compound Cl.CCCCC(CC)C(O)=O GIVGMBPKVYSOKZ-UHFFFAOYSA-N 0.000 claims 1
- RWFXDZIZBGXSNL-UHFFFAOYSA-N 2-methoxybenzoic acid;hydrochloride Chemical compound Cl.COC1=CC=CC=C1C(O)=O RWFXDZIZBGXSNL-UHFFFAOYSA-N 0.000 claims 1
- JCGGLXLQYKVCJQ-UHFFFAOYSA-N 2-methylbenzoic acid;hydrochloride Chemical compound Cl.CC1=CC=CC=C1C(O)=O JCGGLXLQYKVCJQ-UHFFFAOYSA-N 0.000 claims 1
- DVPLHEDOLZCKHJ-UHFFFAOYSA-N 2-phenoxyacetic acid;hydrochloride Chemical compound Cl.OC(=O)COC1=CC=CC=C1 DVPLHEDOLZCKHJ-UHFFFAOYSA-N 0.000 claims 1
- RHOPUUFLVKWWFP-UHFFFAOYSA-N 2-phenylacetic acid;hydrochloride Chemical compound Cl.OC(=O)CC1=CC=CC=C1 RHOPUUFLVKWWFP-UHFFFAOYSA-N 0.000 claims 1
- ATDBEHGVBAPKRE-UHFFFAOYSA-N 3-(2-cyclohexylethoxy)-4-(furan-3-yl)piperidine Chemical compound C1NCCC(C2=COC=C2)C1OCCC1CCCCC1 ATDBEHGVBAPKRE-UHFFFAOYSA-N 0.000 claims 1
- FIUFLISGGHNPSM-UHFFFAOYSA-M 3-(4-methoxyphenyl)propanoate Chemical compound COC1=CC=C(CCC([O-])=O)C=C1 FIUFLISGGHNPSM-UHFFFAOYSA-M 0.000 claims 1
- FQXQBFUUVCDIRK-UHFFFAOYSA-M 3-(trifluoromethyl)benzoate Chemical compound [O-]C(=O)C1=CC=CC(C(F)(F)F)=C1 FQXQBFUUVCDIRK-UHFFFAOYSA-M 0.000 claims 1
- GURJTLNIHIJDTD-UHFFFAOYSA-N 3-benzyl-5-[(3,5-difluorophenyl)methoxy]piperidine;hydrochloride Chemical compound Cl.FC1=CC(F)=CC(COC2CC(CC=3C=CC=CC=3)CNC2)=C1 GURJTLNIHIJDTD-UHFFFAOYSA-N 0.000 claims 1
- OJTPAAHKZRTSMR-UHFFFAOYSA-N 3-benzyl-5-[(3-methylphenyl)methoxy]piperidine;hydrochloride Chemical compound Cl.CC1=CC=CC(COC2CC(CC=3C=CC=CC=3)CNC2)=C1 OJTPAAHKZRTSMR-UHFFFAOYSA-N 0.000 claims 1
- QCYSDQPAJYSSNZ-UHFFFAOYSA-N 3-benzyl-5-[[4-(trifluoromethyl)phenyl]methoxy]piperidine;hydrochloride Chemical compound Cl.C1=CC(C(F)(F)F)=CC=C1COC1CC(CC=2C=CC=CC=2)CNC1 QCYSDQPAJYSSNZ-UHFFFAOYSA-N 0.000 claims 1
- 125000006497 3-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C(OC([H])([H])[H])=C1[H])C([H])([H])* 0.000 claims 1
- LXWNTLBMNCXRQN-UHFFFAOYSA-N 4'-fluoro-1,1'-biphenyl-4-carboxylic acid Chemical compound C1=CC(C(=O)O)=CC=C1C1=CC=C(F)C=C1 LXWNTLBMNCXRQN-UHFFFAOYSA-N 0.000 claims 1
- QUVFHVHLCFFINS-UHFFFAOYSA-N 4-(3-aminophenyl)benzoic acid Chemical compound NC1=CC=CC(C=2C=CC(=CC=2)C(O)=O)=C1 QUVFHVHLCFFINS-UHFFFAOYSA-N 0.000 claims 1
- SJIVTXJWSYIMDG-UHFFFAOYSA-N 4-(3-chlorophenyl)benzoic acid Chemical compound C1=CC(C(=O)O)=CC=C1C1=CC=CC(Cl)=C1 SJIVTXJWSYIMDG-UHFFFAOYSA-N 0.000 claims 1
- RMDRPJICNOYAKA-UHFFFAOYSA-N 4-(furan-3-yl)-3-phenylmethoxypiperidine Chemical compound C=1C=CC=CC=1COC1CNCCC1C=1C=COC=1 RMDRPJICNOYAKA-UHFFFAOYSA-N 0.000 claims 1
- JJSAEPYHAATHJA-UHFFFAOYSA-N 4-iodobenzoic acid;hydrochloride Chemical compound Cl.OC(=O)C1=CC=C(I)C=C1 JJSAEPYHAATHJA-UHFFFAOYSA-N 0.000 claims 1
- ZJARCXJVUWYDPB-UHFFFAOYSA-N 4-phenoxybenzoic acid;hydrochloride Chemical compound Cl.C1=CC(C(=O)O)=CC=C1OC1=CC=CC=C1 ZJARCXJVUWYDPB-UHFFFAOYSA-N 0.000 claims 1
- SRAWGZGWKCCCKW-UHFFFAOYSA-N 4-phenylbenzoic acid;hydrochloride Chemical compound Cl.C1=CC(C(=O)O)=CC=C1C1=CC=CC=C1 SRAWGZGWKCCCKW-UHFFFAOYSA-N 0.000 claims 1
- DZLGZIGLHCRIMF-UHFFFAOYSA-M 4-pyridin-4-ylbenzoate Chemical compound C1=CC(C(=O)[O-])=CC=C1C1=CC=NC=C1 DZLGZIGLHCRIMF-UHFFFAOYSA-M 0.000 claims 1
- PNLXQFOXOPGOGI-UHFFFAOYSA-N 4-tert-butylbenzoic acid;hydrochloride Chemical compound Cl.CC(C)(C)C1=CC=C(C(O)=O)C=C1 PNLXQFOXOPGOGI-UHFFFAOYSA-N 0.000 claims 1
- PTNWHEHDBNNKEO-UHFFFAOYSA-N 5-thiophen-2-ylthiophene-2-carboxylic acid Chemical compound S1C(C(=O)O)=CC=C1C1=CC=CS1 PTNWHEHDBNNKEO-UHFFFAOYSA-N 0.000 claims 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims 1
- RCBQTIDFCCOFBL-UHFFFAOYSA-N Cl.OC(=O)c1cccc(c1)-c1ccccc1 Chemical compound Cl.OC(=O)c1cccc(c1)-c1ccccc1 RCBQTIDFCCOFBL-UHFFFAOYSA-N 0.000 claims 1
- RENWPPCDYSOUFP-UHFFFAOYSA-N Cl.S1C(=CC=C1)C1=CC=C(C(=O)O)C=C1 Chemical compound Cl.S1C(=CC=C1)C1=CC=C(C(=O)O)C=C1 RENWPPCDYSOUFP-UHFFFAOYSA-N 0.000 claims 1
- 101100149256 Mus musculus Sema6b gene Proteins 0.000 claims 1
- 150000001204 N-oxides Chemical class 0.000 claims 1
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 claims 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims 1
- 235000010582 Pisum sativum Nutrition 0.000 claims 1
- 240000004713 Pisum sativum Species 0.000 claims 1
- RRPFCEOETNGQTJ-PKTZIBPZSA-N [(3r,4r)-4-phenylpiperidin-3-yl] 4-phenylbenzoate Chemical compound C1([C@H]2CCNC[C@@H]2OC(=O)C=2C=CC(=CC=2)C=2C=CC=CC=2)=CC=CC=C1 RRPFCEOETNGQTJ-PKTZIBPZSA-N 0.000 claims 1
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Description
3,4-DISUBSTITUTED, 3,5 _DISUBSTITUTED AND 3,4,5-SUBSTITUTED ® PIPERIDINES AND PIPERAZINES
The invention relates to substituted piperidine and piperazine compounds useful in the treatment of Alzheimer’s disease and more specifically to compounds that are capable of inhibiting beta-secretase, an enzyme that cleaves amyloid precursor protein to produce amyloid beta peptide (A-beta), a . major component of the amyloid plaques found in the brains of
Alzheimer’s sufferers.
Alzheimer’s disease (AD) is a progressive degenerative disease of the brain primarily associated with aging. Clinical presentation of AD is characterized by loss of memory, cognition, reasoning, judgment, and orientation. As the disease progresses, motor, sensory, and linguistic abilities are also affected until there is global impairment of multiple cognitive functions. These cognitive losses occur gradually, but typically lead to severe impairment and eventual death in the range of four to twelve years.
Alzheimer’s disease is characterized by two major pathologic observations in the brain: neurofibrillary tangles and beta amyloid (or neuritic) plaques, comprised predominantly of an aggregate of a peptide fragment know as A-beta. Individuals with AD exhibit characteristic beta-amyloid deposits in the brain (beta amyloid plaques) and in cerebral blood vessels (beta amyloid angiopathy) as well as neurofibrillary tangles.
Neurofibrillary tangles occur not only in Alzheimer’s disease but also in other dementia-inducing disorders. On autopsy, large numbers of these lesions are generally found in areas of the human brain important for memory and cognition. @ Smaller numbers of these lesions in a more restricted anatomical distribution are found in the brains of most aged humans who do not have clinical AD. Amyloidogenic plaques and vascular amyloid angiopathy also characterize the brains of individuals with Trisomy 21 (Down's Syndrome), Hereditary
Cerebral Hemorrhage with Amyloidosis of the Dutch-Type (HCHWA-
D), and other neurodegenerative disorders. Beta-amyloid is a defining feature of AD, now believed to be a causative precursor or factor in the development of disease. Deposition of A-beta in areas of the brain responsible for cognitive activities is a major factor in the development of AD. Beta-amyloid plaques are predominantly composed of amyloid beta peptide (A-beta, also sometimes designated betaa4). A-beta peptide is derived by proteolysis of the amyloid precursor protein (APP) and is comprised of 39-42 amino acids. Several proteases called secretases are involved in the processing of APP.
Clcavage of APP at the N-terminus of the A-beta peptide by
Dbeta-secretase and at the C-terminus by the gamma -secretase complex constitutes the beta-amyloidogenic pathway, i.e. the pathway by which A-beta ig formed. Cleavage of APP by alpha- secretase produces alpha-sAPP, a secreted form of APP that does not result in beta-amyloid plaque formation. This alternate pathway precludes the formation of A-beta peptide. A description of the proteolytic processing fragments of APP ig found, for example, in U.S. Patent Nos. 5,441,870; 5,721,130; and 5,942,400.
An aspartyl protease has been identified as the enzyme responsible for processing of APP at the beta-secretase cleavage : site. The beta-secretase enzyme has been disclosed using varied nomenclature, including BACE, Asp, and Memapsin. See, for example, Sindha et al., 1999, Nature 402:537-554 (p501) and published PCT application WO00/17369.
Several lines of evidence indicate that progressive @ cerebral deposition of beta-amyloid peptide (A-beta) plays a seminal role in the pathogenesis of AD and can precede cognitive symptoms by years or decades. See, for example, Selkoe, 1991,
Neuron 6:487. Release of A-beta from neuronal cells grown in culture and the presence of A-beta in cerebrospinal fluid (CSF) of both normal individuals and AD patients has been demonstrated. see, for example, Seubert et al., 1992, Nature 359:325-327.
It has been proposed that A-beta peptide accumulates as a result of APP processing by beta-secretase, thus inhibition of this enzyme's activity is desirable for the treatment of AD. In vivo processing of APP at the beta-secretase cleavage site is thought to be a rate-limiting step in A-beta production, and is thus a therapeutic target for the treatment of AD. See for example, Sabbagh, M., et al., 1997, Alz. Dis. Rev. 3, 1-19.
BACE1l knockout mice fail to produce A-beta, and present a normal phenotype. When crossed with transgenic mice that over express APP, the progeny show reduced amounts of A-beta in brain extracts as compared with control animals (Luo et al., 2001
Nature Neuroscience 4:231-232). This evidence further supports the proposal that inhibition of beta-secretase activity and reduction of A-beta in the brain provides a therapeutic method for the treatment of AD and other beta amyloid disorders.
At present there are no effective treatments for halting, preventing, or reversing the progression of Alzheimer's disease.
Therefore, there is an urgent need for pharmaceutical agents capable of slowing the progression of Alzheimer's disease and/or preventing it in the first place.
Compounds that are effective inhibitors of beta-secretase, that inhibit beta-secretase-mediated cleavage of APP, that are
S effective inhibitors of A-beta production, and/or are effective to reduce amyloid beta deposits or plaques, are needed for the treatment and prevention of disease characterized by amyloid @ beta deposits or plaques, such as AD.
The invention encompasses the substituted piperidine and ® Piperazine compounds of the formulas shown below, pharmaceutical compositions containing the compounds and methods employing such compounds or compositions in the treatment of Alzheimer’s disease and more specifically compounds that are capable of inhibiting beta-secretase, an enzyme that cleaves amyloid precursor protein to produce A-beta peptide, a major component of the amyloid plaques found in the brains of Alzheimer’s sufferers.
In one aspect, the invention provides compounds of the formula I:
R2
H
(1) or a pharmaceutically acceptable salt or ester thereof, wherein Z is CH or N; wherein R; and R; are independently: (I) Ci1-Cio alkyl, optionally substituted with one, two or three substituents independently selected from the group consisting of C;-C; alkyl, -F, -C1, -Br, -I, -OH, -SH, -C=N, -
CFs, GCi-C; alkoxy, -O-phenyl, -NR;-aR;-p, where R;., and Rip are independently -H or C;-Cg alkyl, -0C=0 NR3-aRi-b, -S(=0)¢-2 Ria, -
NR;-aC=0 NRj.aRi-p, -C=0 NR;.-aR;.p,, and -S(=0)2 NR;j-aRi.p, -(CH3)g.5- (Cs3-~
Cg) cycloalkyl where cycloalkyl can be optionally substituted with one, two or three substituents selected from the group
=f of C;-C; alkyl, -r, -ci, -Br, -I, -OH, -SH, -C=N, -
CF;, C,- BE alkoxy, -O-phenyl, -CO-OH, -CO-0-(C,-C, alkyl), -NRi. o Rin; Col alkoxy- (Riam), C1-Cy alkoxy- (Ri peceroary)
CJ (II) -(CH2)m- (Ri-ary1) where n;, is zero or one and where
Ri.ary1 is phenyl, 1-naphthyl, 2-naphthyl and indanyl, indenyl, dihydronaphthyl, tetralinyl optionally substituted with one, two, three or four of the following independently selected substituents on the aryl ring: (1) C1-C¢ alkyl optionally substituted with one, two or three substituents independently selected from the group consisting of C;-C; alkyl, -F, -Cl, -Br, -I, -OH, -SH, -S(Cig alkyl), -S(aryl-C;s alkyl), -S(heteroaryl-Ci.¢ alkyl), -S=0(Ci-¢ alkyl), -8=0O(aryl-C;.¢ alkyl), -S=0O(heterocaryl-C;.¢ alkyl), -
S02 (Cy-¢ alkyl), -SO0;(aryl-C;.¢ alkyl), -SO;(heterocaryl-C,.¢ alkyl), ~-NR3-aR1-p, -C=N, -CF3, C;-C; alkoxy, Ci;-C; alkoxy- (Ri.ary1) , C1-C3 alkoxy- (Ri-heterocaryl) « (2) C;-C¢ alkenyl with one or two double bonds, optionally substituted with one, two or three substituents independently selected from the group consisting of -F, -C1, -Br, -I, -OH, -SH, -S(Ci¢ alkyl), -S(aryl-Ci.¢ alkyl), -
S(heterocaryl-Ci¢ alkyl), -8=0(Ci¢ alkyl), -S=0O(aryl-C;.¢ alkyl), -8=0(heterocaryl-C,.¢ alkyl), -S0;(C;-¢ alkyl), -S0;(aryl-Ci.¢ alkyl), -SOz(heterocaryl-C;.¢ alkyl), -C=N, -CFi;, C;-C; alkoxy, -
NRi-aRi-p, Ci1-C3 alkoxy- (Ri-aryi) , C1-Ci alkoxy- (Ri-neteroaryi) : (3) C;-C¢ alkynyl with one or two triple bonds, optionally substituted with one, two or three substituents independently selected from the group consisting of -F, -Cl, -Br, -I, -OH, -SH, -8(Ci¢ alkyl), -S(aryl-Ci.¢ alkyl), - )
S (heteroaryl-Ci.¢ alkyl), -S=0(C;.¢ alkyl), -S=0(aryl-C;.¢ alkyl), -8=0 (heteroaryl-C;_¢ alkyl), -805(Cy-¢ alkyl), -S02 (aryl-C;.¢ alkyl), -SO;(heteroaryl-Ci alkyl), -C=N, -CF;, C;-C; alkoxy, -
NR1-aRi-b, C1-C3 alkoxy- (Ri-ary1) , C1-C3 alkoxy- (Ri-neercaryl)
(4) -F, C1, -Br and -I, (5) -Ci1-Ce¢ alkoxy optionally substituted with one, two or three -F, { (6) -NRy-2Ry.3 where Ry., and Ry.; are as defined below, (7) -OH, (8) -C=N, (9) C3~C; cycloalkyl, optionally substituted with one, two or three substituents selected from the group consisting of -F, -Cl1, -Br, -I, -OH, -SH, -S(C;.¢ alkyl), -
S(aryl-C;.¢ alkyl), -S(heteroaryl-C,.¢ alkyl), -S=0(C;.¢ alkyl), -
S=0(aryl-Ci.¢ alkyl), -8=0 (heteroaryl -Ci_¢ alkyl), -805(Cq-¢ . alkyl), -S0:(aryl-C;.s¢ alkyl), -SO;(heteroaryl-C;.¢ alkyl), -C=N, -CF3, C;-C3 alkoxy, -NRiaRi-p, Ci-Ca alkoxy- (Ry.ami), Ci1-Ci; alkoxy- (Ri-netercary1) « (10) -CO- (C1-C, alkyl), (11) -S02-NR;-aRj.p, (12) -CO-NRy-aRi-pb, (13) -S0,-(C;-C4 alkyl), (ITI) -(CHz)ni- (Ri-netercaryr) Where n; is as defined above and where Ri.hetercaryi 19 selected from the group consisting of: pyridinyl, pyrimidinyl, quinolinyl, benzothienyl, indolyl, indolinyl, pryidazinyl, pyrazinyl, isoindolyl, isoquinolyl, quinazolinyl, quinoxalinyl, phthalazinyl, imidazolyl, isoxazolyl, pyrazolyl, oxazolyl, thiazolyl, indolizinyl, indazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl, furanyl, thienyl, pyrrolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, oxazolopyridinyl, imidazopyridinyl, isothiazolyl, naphthyridinyl, cinnolinyl, carbazolyl, beta- carbolinyl, isochromanyl, chromanyl, tetrahydroisoquinolinyl, - isoindolinyl, isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl, isobenzothienyl, benzoxazolyl, pyridopyridinyl,
benzotetrahydrofuranyl, benzotetrahydrothienyl, purinyl, benzodioxolyl, triazinyl, phenoxazinyl, phenothiazinyl, pteridinyl, benzothiazolyl, imidazopyridinyl, ® imidazothiazolyl, dihydrobenzisoxazinyl, benzisoxazinyl, benzoxazinyl, dihydrobenzisothiazinyl, benzopyranyl, benzothiopyranyl, coumarinyl, isocoumarinyl, chromonyl, chromanonyl, pyridinyl-N-oxide, tetrahydroquinolinyl, dihydroquinolinyl, dihydroquinolinonyl, dihydroisoquinolinonyl, dihydrocoumarinyl, dihydroisocoumarinyl, isoindolinonyl, benzodioxanyl, benzoxazolinonyl, pyrrolyl N-oxide, pyrimidinyl N-oxide, pyridazinyl N-oxide, pyrazinyl N-oxide, quinolinyl N-oxide, indolyl N-oxide, indolinyl N-oxide, isoquinolyl N-oxide, quinazolinyl N-oxide, quinoxalinyl N-oxide, phthalazinyl N- oxide, imidazolyl N-oxide, isoxazolyl N-oxide, oxazolyl N- oxide, thiazolyl N-oxide, indolizinyl N-oxide, indazolyl N- oxide, benzothiazolyl N-oxide, benzimidazolyl N-oxide, pyrrolyl N-oxide, oxadiazolyl N-oxide, thiadiazolyl N- oxide, triazolyl N-oxide, tetrazolyl N-oxide, benzothiopyranyl S-oxide, benzothiopyranyl S,S-dioxide, where the Ri-netercary1 group is bonded to - (CHz)p- by any ring atom of the parent’ Ri-hetercaryr group substituted by hydrogen such that the new bond to the Ri_netercaryi group replaces the hydrogen atom and its bond, where heteroaryl is optionally substituted with one, two, three or four of: (1) Ci1-Cs alkyl optionally substituted with one, two or three substituents independently selected from the group consisting of C;-C; alkyl, -F, -Cl, -Br, -I, -OH, -SH, -8S(C; alkyl), -S(aryl-Ci.¢ alkyl), -S(heteroaryl-C,.s alkyl), -S=0(Cy.¢ alkyl), -S=O(aryl-C,.¢ alkyl), -S=0(heterocaryl-C,.¢ alkyl), -
S0;(Ci-s-alkyl), -S0;(aryl-Ci alkyl), -SO,(heteroaryl-C, alkyl), ) -NR;-aRi-p, -C=N, -CF3, C;-C3 alkoxy, C;-C; alkoxy- (Ri—ary1) , C3-C3 alkoxy- (Ri-netercaryl) ,
(2) Ca-Cs alkenyl with one or two double bonds, optionally substituted with one, two or three substituents independently selected from the group consisting of -F, -Cl, ® -Br, -I, -OH, -SH, -S(C;.s alkyl), -S{aryl-C,.¢ alkyl), -
S (heterocaryl-C,.¢ alkyl), -S=0(C;.¢ alkyl), -S=0O(aryl-Ci.¢ alkyl), -S=0(heterocaryl-C;.¢ alkyl), -S0,(Ci¢ alkyl), -50; (aryl-Ci-e alkyl), -S0,(heterocaryl-C;.¢ alkyl), -C=N, -CF;, C,-C3 alkoxy, -
NR;-aRi-p, C1-C3 alkoxy- (Ri-ary1) , Ci1-C3 alkoxXy- (Ri-netercaryl) « (3) C2-Cg alkynyl with one or two triple bonds, optionally substituted with one, two or three substituents independently selected from the group consisting of -F, -Cl, -Br, -I, -OH, -SH, -S8(C;.¢ alkyl), -S(aryl-C;.¢ alkyl), -
S (heteroaryl-Cy.¢ alkyl), -S=0(C,.¢ alkyl), -S=O(aryl-Ci.¢ alkyl), -S=0 (heteroaryl-C;¢ alkyl), -80,(Cy.6 alkyl), -S0; (aryl-Ci.¢ alkyl), -SO;(heterocaryl-C,.¢ alkyl), -C=N, -CF3;, C;-C; alkoxy, -
NRj.aRi-b, Ci1-Ci alkoxXy- (Ri-ary1) ; C1-C3 alkoxy- (Ri-neteroaryi) . (4) -F, -C1l, -Br and -I, (5) -C1-C¢ alkoxy optionally substituted with one, two, or three -F, (6) -NRy-2Rn-3, (7) -oOH, (8) -c=N, (3) Ci3-C; cycloalkyl, optionally substituted with one, two or three substituents independently selected from the group consisting of -F, -Cl, -Br, -I, -OH, -SH, -S(Cy-¢ alkyl), -
S(aryl-C;.¢ alkyl), -S(heterocaryl-C;.¢ alkyl), -S=0(C;-¢ alkyl), -
S=0(aryl-C;.¢ alkyl), -8=0 (heterocaryl-Ci.¢ alkyl), -802(C;¢ alkyl), -S0;(aryl-Ci-¢ alkyl), -SO,(heterocaryl-C,-¢ alkyl), -C=N, -CF3, Ci1-C3; alkoxy, -NRj-aRi-p, Ci1-Ci alkoxy-(Ri-ary1), Ci1-Cs alkoxy- (Ry-netercary1) « _ (10) -CO-(C1-Cq alkyl), (11) -S02-NRj-aRi.p,
(12) -CO-NR;-aRi-p, (13) -50,- {(C,-C, alkyl), with the proviso that when n; is zero, Ri.heteroaryy 1S not bonded to the carbon chain by ® nitrogen, - (IV) = (CHz2) m - (R1-neterocycie) Where n; is as defined above and Ri-heterocycie 1s selected from the group consisting of: : morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl §,S-dioxide, piperazinyl, homopiperazinyl, pyrrolidinyl, pyrrolinyl, tetrahydropyranyl, piperidinyl, tetrahydrofuranyl, tetrahydrothienyl, homopiperidinyl, homomorpholinyl, homothiomorpholinyl, homothiomorpholinyl
S,S-dioxide, oxazolidinonyl, dihydropyrazolyl, dihydropyrrolyl dihydropyrazinyl dihydropyridinyl dihydropyrimidinyl, dihydrofuryl, dihydropyranyl ‘ tetrahydrothienyl S-oxide, tetrahydrothienyl §,S-dioxide, homothiomorpholinyl S-oxide, where the Rj-heterocyclte group is bonded by any atom of the parent Ri-neterocycie group substituted by hydrogen such that the new bond to the Rj_peterocycle group replaces the hydrogen atom and its bond, where heterocycle is optionally substituted with one, two, three or four: (1) C;-C¢ alkyl optionally substituted with one, two or three substituents independently selected from the group consisting of C,-C; alkyl, -F, -C1, -Br, -I, -OH, -SH, -
S(Ci.s alkyl), -S(aryl-Ci¢ alkyl), -S(heteroaryl-Ci¢ alkyl), - 8=0(Ci alkyl), -S=0(aryl-C;_¢ alkyl), -5=0 (heteroaryl-C,_¢ alkyl), -S02(Ci.¢ alkyl), -S0;(aryl-Ci_¢ alkyl), -S0;(heterocaryl-
Ci-s alkyl), -NRiRi.p, -C=N, =CF3;, C;-C; alkoxy, C.-C, alkoxy- (R;. aryl) » C1-C3 alkoxXy- (Ri-neteroaryl) , (2) C;-Cs alkenyl with one or two double bonds, optionally substituted with one, two or three substituents independently selected from the group consisting of -F, -Cl, -Br, -I, -OH, -SH, -S(Ci alkyl), -S(aryl-Ci-e alkyl), -
S(heteroaryl-C;¢ alkyl), -S=0(C;.¢ alkyl), -5=0(aryl-Cie alkyl), -8=0 (heteroaryl-C;¢ alkyl), -S05(Cy¢ alkyl) , -S0;(aryl-Cie alkyl), -SO;(heterocaryl-C;.¢ alkyl), -C=N, -CF3;, C,-C; alkoxy, - ® NR;.aRi.p, C1-C3 alkoxy- (Riarya) , Ci1-Ci alkoXy- (Ri-neterocaryl) (3) C2-C¢ alkynyl with one or two triple bonds, optionally substituted with one, two or three substituents independently selected from the group consisting of -F, -Cl, -Br, -I, -OH-SH, -S(Cis alkyl), -S(aryl-Ci.¢ alkyl), -
S (heteroaryl-Ci.¢ alkyl), -S=0(Cy.¢ alkyl), -S=0(aryl-C,.¢ alkyl), -8=0(heteroaryl-C;¢ alkyl), -502(Cy-¢ alkyl), -80;{(aryl-Cis alkyl), -SO;(heterocaryl-C,.¢ alkyl), -C=N, -CF;, C;-C; alkoxy, -
NR;-aRi-b, C1-C3 alkoxy- (Ri-arya) , Ci-C3 alkoxy- (Ri-neteroaryi) s (4) -F, -Cl, -Br and -1I, (5) -C1-C¢ alkoxy optionally substituted with one, two, or three -F, (6) -NRy-2Ry-3, (7) -OH, (8) -C=N, (9) Ci3-Cq cycloalkyl, optionally substituted with one, two or three substituents selected from the group consisting of -F, -Cl, -Br, -I, -OH, -SH, -S(Cis alkyl), -S(aryl-Ci.¢ alkyl), -S(heteroaryl-C;.¢ alkyl), -S=0(Ci-¢ alkyl), -S=O(aryl-C;.¢ alkyl), -S=O(heteroaryl-Ci.¢ alkyl), - 802(Ci-¢ alkyl), -SOz(aryl-Ci¢ alkyl), -S0;(heteroaryl-C;.¢ alkyl), -C=N, -CF;, C;-C3 alkoxy, -NRi.aRi-p, C3-Ci alkoxy- (Ricamyi), Ci1-Ci alkoxy- (Ri-netercaryl) (10) -CO-(C;-Cq alkyl), (11) -S50;-NRi-aRi-b, (12) -CO-NR;-aRi-b, (13) -80;-(Cy-C4 alkyl), (14) =0, with the proviso that when n, is zexO Ri-peterocycle 18 not bonded to the carbon chain by nitrogen ;
(V)-H; .. . (VI) Ry.1-Xy- where Xy is selected from the group consisting of: ® (ap) -CO-, (B) -S0;-
where Ry.1 is selected from the group consisting of:
(A) Ry-arpp Where Ry.amyi is phenyl, 1-naphthyl, 2- naphthyl, tetralinyl, indanyl, dihydronaphthyl or 6,7,8,9- tetrahydro-5H-benzo [a] cycloheptenyl, optionally substituted with one, two or three of the following substituents which can be the same or different and are:
(1) Ci-Cs alkyl, optionally substituted with one, two or three substituents selected from the group consisting of C,-C; alkyl, -F, -Cl, -Bxr, -I, -OH, -SH, -S(Cy1-¢ alkyl), -S(aryl-Ci¢ alkyl), -S(heteroaryl-Ci-s alkyl), -S=0(Ci-s alkyl), -S=0(aryl-C;.¢ alkyl), -S=O(heterocaryl-Ci.¢ alkyl), - 50,(Ci-¢ alkyl), -S0;(aryl-Ci¢ alkyl), -80, (heterocaryl-C;.¢ alkyl), -C=N, -CF3, Ci-C; alkoxy, -NRj.aRip, Ci-Cs alkoxy-(Ri-aryi), C1-Cs alkoxy - (Ri-neteroaryl)
(2) -OCH,
(3) -NO,
(4) -F, -Cl, -Br, -I,
(5) -CO-OH,
(6) -C=N,
(7) -{(CHz)o0-4-CO-NRy.2Ry-3 where Ry. and Ry-3 are the same or different and are selected from the group consisting of: (a) -H, (b) -C1-Cg¢ alkyl optionally substituted with one substitutent selected from the group consisting of: -
(i) -OH, (ii) -NH,
(c) -C1-C¢ alkyl optionally substituted with one to three groups independently selected from -F, -Cl1, -Br, and -I, ® (d) -C3-C,; cycloalkyl, (e) -(C;-C; alkyl) - (C3-C; cycloalkyl), (£) -(C1-Cg¢ alkyl) -0-(C;-C;3 alkyl), (g) -C;-C¢ alkenyl with one or two double bonds, (h) -C,-C¢ alkynyl with one or two ] triple bonds, (i) -Ci1-C¢ hydrocarbyl chain with one double bond and one triple bond, ] (3) -Ri-aryis (k) -Ri-netercaryl: + (8) -(CHz)-4-CO-(C1-Cy2 alkyl), (9) -(CHz)g-4-CO-(C,-C;2 alkenyl with one, two or three double bonds), (10) -(CHz)0-4-CO-(C2-C12 alkynyl with one, two or three triple bonds), (11) = ({CH2)0-4-CO-({C3-Cy cycloalkyl), (12) -(CHz) 0-4-CO-Ri-ary1, (13) =~ (CHg2) 0-4~CO=-Rj-hetercaryl, ) (14) - (CH) 9-4—CO-Ri_peterocycle: (15) -(CHz)-4-CO-Ry.4 where Ry.4 is selected from the group consisting of wmorpholinyl, thiomorpholinyl, piperazinyl, piperidinyl, homomorpholinyl, homothiomorpholinyl, homothiomorpholinyl S-oxide, homothiomorpholinyl §S,S-dioxide, pyrrolinyl and pyrrolidinyl where each group is optionally substituted with one, two, three, or four of C;-Cs alkyl, (16) -(CHz)0-4-CO-O-Ry.s where Rys is selected from the group consisting of: (a) C;-Cs alkyl, (b) -(CHz2) 0-2- (Ri-ary1) +
(c) C;-Cs alkenyl containing one or two double bonds, . (d) C,-Ce¢ alkynyl containing one or two @® triple bonds, (e) C3.C; cycloalkyl, (£) -(CHz2) 0-2 (Ri-neteroary1) s (17) -(CHz)o0-4-SO02-NRy-2Rx-3, (18) =~ (CHz)0-4-SO-(C,-Cs alkyl), (19) - (CH) 0-4-S02-(C1-Cy2 alkyl), (20) - (CH) 0-4-802-(C3-C; cycloalkyl), (21) - (CH) 0-4-N(H or Ry.s )-CO-O-Ry.s where Ry. s can be the same or different, (22) -(CH;)-4~N(H or Ry.s )-CO-N{(Ry-s)2, where each Ry.s is independently defined herein, (23) -(CH,) 0-4-N-CS-N (Ry-5)2, where each Ry.s is independently defined herein, (24) - (CH) ¢-4-N(-H or Ry.s) -CO-Ry-2, (25) - (CH2) 0-4~NRy-2RN-3, (26) -.(CH2) 0-4-Ru-4, (27) -(CH2)0-4~0-C0=~{C1-Cs alkyl), (28) -(CHz)0-4-0-P(O) - (ORy-1)2 where Ry.i is -H or C,-C4 alkyl, ’ (29) - (CHa) 0-4-O-CO-N(Ry-s) 2, (30) - (CH) 0-4-O-CS-N(Ry-s) 2, (31) -(CHz) 0-4-0O- (Ry-s) 2, (32) -(CH2)0-4-O-( Ry-s)2-COOH, (33) -(CHz)0-¢-S-( Rn-s)2, (34) - (CH) ¢-4-0- (C1-C¢ alkyl optionally substituted with one, two, three, four, or five of -F), (35) C3-C,; cycloalkyl, 35 . (36) C,-Cg alkenyl having one or two double : bonds and which is optionally substituted with C;-C; alkyl, -F, -cl, -Br, -I, -OH, -SH, -S(Ci.¢ alkyl), -S(aryl-Cis alkyl), -
S(heteroaryl-Ci alkyl), -S=0(Ci¢ alkyl), -S=O(aryl-Cis alkyl), -S=0(heterocaryl-C;-¢ alkyl), -805 (C16 alkyl), -80,(aryl-Ci-s alkyl), -8S0O,(heteroaryl-C;.¢ alkyl), -C=N, -CF;3;, C1-C; alkoxy, - : ® NRj.aRi-p, C1-Ci alkoxy- (Ri-ary1) , Ci-Ci alkoxy- (Ri-netercaryl) , (37) C3-C¢ alkynyl with one or two triple bonds optionally substituted with C;-C; alkyl, -F, -Cl, -Br, -1, -OH, -SH, -S(C;-¢ alkyl), -S(aryl-C,.¢ alkyl), -S(heteroaryl-Ci alkyl), -S=0(C,.¢ alkyl), -S=0O(aryl-Ci.¢ alkyl), -S=0(heterocaryl-
Cie alkyl), -50,(Ci-¢ alkyl), -S0; (aryl-Ci_¢ alkyl), -
SO, (heterocaryl-C;.s alkyl), -C=N, -CF3;, C1-C; alkoxy, -NRj-aRi-b,
C1-C3 alkoxy- (Ri-ary1), Ci1-C3 alkoxy- (Ri-neteroary1) : (38) -(CHz)0-4-N(-H Or Ry-s)-SOz-Ry.2, Or (39) -(CHz)¢-4- C3-C; cycloalkyl, (B) -Ru-hetercaryl Where Ry. netercaryi Carries the same definition as Rj-netercaryl, Where the Ry.heteroaryi group is bonded by any atom of the parent Ry-hetercaryy group substituted by hydrogen such that the new bond to the Ry-netercaryi group replaces the hydrogen atom and its bond, where heteroaryl is optionally substituted with one, two, three, or four groups independently selected from: (1) C,-C¢ alkyl, optionally substituted with one, two or three substituents selected from the group consisting of C;-C; alkyl, -F, -Cl, -Br, -I, -OH, -SH, -S(Ci alkyl), -S(aryl-C,.¢ alkyl), -S(heteroaryl-C;.¢ alkyl), -S=0(Ci_¢ alkyl), -S=0O(aryl-C;-¢ alkyl), -S=O(heterocaryl-C,.s alkyl), -
S02(Ci-¢ alkyl), -S0:{(aryl-C;.¢ alkyl), -SO;(heterocaryl-C,.¢ alkyl), -C=N, -CFi;, C;-C; alkoxy, and -NRj.aRi.p, C1-C; alkoxy- (Ri-aryi), Ci-
Cs alkoxy- (Ri-hetercaryl) / (2) -OH, (3) -NO2, (4) -F, -C1, -Br, -I, (5) -co-OH,
(6) -C=N, (7) -(CHz) 0-4-CO-NRy_2Ry-3, (C) Ruy-aryi-W-Ry-ary1:, ® (D) Ry-ary1-W-Rn-hetercaryl: (E) Run-aryl-W-Ry heterocycle: Where Ry peterocycie 18 the same as Rji-neterocycle (F) Ru-netercaryl-W-Ru-aryi1, (G) Ry-heteroaryl~W-Rx-hetercaryi, (H) Ru-netercaryl~W-Ruy-neterocycie: (I) Ruy-heterocycle~W-Rn-ary1, (J) Rn-neterocycle~W-Ry-heteroaryl. (K) Ru-neterocycie~W-Ry-neterocycle, and where W is ] (1) -(CH2)o0-4~, (2) -0-, (3) -5(0)o-2-, (4) -N{(Rn-s)-, Or (5) =-CO-; (VII) -(CRc-xRe-y) 0-4-Re-aryl where Re-x and Rey are -H,
C,-C4 alkyl optionally substituted with one or two -OH,
C,-Cs alkoxy optionally substituted with one, two, or three of -F, - (CH) -4-C3-Cy cycloalkyl,
C.-C alkenyl containing one or two double bonds,
C,-Ce¢ alkynyl containing one or two triple bonds, phenyl, and where Rc.x and Rey are taken together with the carbon to which they are attached to form a carbocycle of three, four, five, six and seven carbon atoms, optionally where one carbon atom is replaced by a heteroatom selected from the group consisting of -0-, -S-, -SO03;-, -NRy-2- and Rc.ary:p is the same as
Ry-arya 7 (VIII) -(CRc-xRe-y)o-a-Re-ary1-Re-ary1 + @® (IX) - (CRc-xRc-y) 0-a-Re-ary1~Re-heteroaryl: (X) - (CRc-xRc-y) 0-4a-Re-netercaryl=Re-aryl (XI) -(CRc-xRc-y)o0-4-Rc-heteroaryl~Rc-betercaryl: (XII) - (CRc-xRe-y)0-4—Re-aryl-Re-beterocycle and Re-neterocycle is the same as Ry-neterocycle, (XIII) - (CRc-xRc-y) 0-4-Rc-neteroaryl~Re-heterocycie: (XIV) - (CRe-xRe-y) 0-a-Re-neterocycle=Re-aryl, (XV) - (CRc-xRc-y) 0-4=Re-neterocycle~Rc-hetexoaryl s (XVI) - (CRc-xRe-y) 0-4-Re-neterocycle~Re-neterocycles (XVII) -[C(Rc-1) (Re-2)11-3-CO-N-(Rc-3)2 where Rc.:; and Rez are the same or different and are selected from the group consisting of: (A) -H, (8) -C;-C¢ alkyl, optionally substituted with one, two or three substituents selected from the group consisting of ¢C,-C; alkyl, -F, -Cl, -Br, -I, -OH, -SH, -S(Ci-¢ alkyl), -S(aryl-Cy.s alkyl), -5(heteroaryi-Ci¢ alkyl), -8=0{(Ci-¢ alkyl), -S=0(aryl-Ci-s alkyl), -S8=0(heteroaryl-Ci;.¢ alkyl), -
S0,(Cy¢ alkyl), -S0;(aryl-Ci-¢ alkyl), -SO; (heteroaryl-C;.¢ alkyl), -C=N, -CFi;, C;-C¢ alkoxy, -O-phenyl, -NRiaRip, Ci1-C3 alkoxy-(Ri- aryl) + C1-Ci alkoxy- (Ri-neteroaryi) (C) C,-C¢ alkenyl with one or two double bonds, optionally substituted with one, two or three substituents selected from the group consisting of C;-C; alkyl, -F, -Cl, -Br, -I, -OH, -SH, -8(Cy-¢ alkyl), -S(aryl-Ci-¢ alkyl), -S (heteroaryl-
Cis alkyl), -S=0{(C1-¢ alkyl), -S=0(aryl-C;_¢ alkyl), - 8=0 (heteroaryl-C;.¢ alkyl), -50,(Cy-6 alkyl), -S0; (aryl-Cs.¢ alkyl), -SO;(heteroaryl-Ci.¢ alkyl), -C=N, -CFs;, Ci-C¢ alkoxy, -O- phenyl, -NRj.aRip, C1-C3 alkoxy- (Ri-arya), C1-C; alkoxy- (Ri-netercaryl)
(D) - (CHa) 0-4-C3-C7 cycloalkyl, optionally substituted with one, two or three substituents selected from the group consisting of C;-C; alkyl, -F, -Cl, -Br, -1, -OH, -SH, ® -S(Cy.¢ alkyl), -S(aryl-C;s¢ alkyl), -S(heterocaryl-Ci.e alkyl), -
S=0(C,.¢ alkyl), -8=0(aryl-C;.¢ alkyl), -S8=0 (heteroaryl-Ci-¢ alkyl), -80;(C;.¢ alkyl), -SO0;(axryl-Cis alkyl), -50, (heteroaryl-
Cig alkyl), -C=N, -CFi;, C;-C¢ alkoxy, -O-phenyl, -NRi.aRi-pn, C1-Cs alkoxy- (Ri-ary1) , C1-C3 alkoxy- (Ri-neteroaryl) « (E) -(C1-C, alkyl) -Rci-ary1 Where Rci-aryl is as defined for Ri.ary, (F) -(C1-C4 alkyl) -Re-neteroaryls (G) -(Cy-C4 alkyl) -Rc-neterocycles (H) -Rec-neteroaryls (I) -Rc-peterocycle, and (J) -Rc’-aryis and where Rc.; is the same or different and is: (A) -H, (B) -C,-C¢ alkyl optionally substituted with one, two or three substituents selected from the group consisting of
Cc,-C; alkyl, -F, -Cl1l, -Br, -I, -OH, -SH, -8(Cy.¢ alkyl), -S(aryl-
Cy.¢ alkyl), -S (heteroaryl-C;.¢ alkyl), -8=0(Ci_¢ alkyl), -
S=0(aryl-Ci.¢ alkyl), -S=0(heteroaryl-Ci-¢ alkyl), -80, (C16 alkyl), -SO0z(aryl-Ci.¢ alkyl), -SO2(heterocaryl-Ci.¢ alkyl), -C=N, -CF;, C1-Cs¢ alkoxy, -O-phenyl, and -NRi-aRi-p, Ci1-C; alkoxy- (R1- ary)» C1-C3 alkoxy- (Ri-neteroary1) s (C) - (CH) 0-4-C3-C7 cycloalkyl, (D) -(C:-Ca alkyl) -Rei-amis (E) -(C1-C4 alkyl) -Rc-heteroaryls OX (F) ~(C1-Cs alkyl) -Re-heterocyle (XVIII) - (CHz) o-Q- (CH;)p-B, where o and p are independently integers of 1-4, Q is O, S, SO, SOz, NR;, and B is
C,.¢ alkyl, aryl, heteroaryl, or heterocycle; (XIX) -0-Rg, =-S-Ry, -NH-Rg, or N(Rg)z;
(XX) —0C (=0) -Ryg (XXI1) -C(=0)0-Ry . (XXII) —-N (Rg) C(=0) -Ro o (XXIII) ~C(=O)N (Rs) -Rs (XXIV) ~SO,N (Rg) C(=0) -Rg (XXV) -C(=0)}N (Rg) SO2-Ry (XXXVI) -SO3-Ry; wherein Rs is defined as H or C,-C¢ alkyl optionally substituted with one to three groups independently selected from -OH, -NHz, ~-F, -Cl, -Br, and -I; wherein Ry is defined as (I)- (XVIII) above and wherein R; is is Ci to C¢ alkyl , cyclohexyl, cyclopentyl, pyridinyl, phenyl, isoxazole, pyrazole, furan, thiophene, and ] other five and six membered heterocycles containing carbon, nitrogen, oxygen and sulfur, said C; to Cg alkyl, cyclohexyl, cyclopentyl, pyridinyl, phenyl, furan, thiophene may be optionally substituted with one, two or three radicals selected from CF;, OCF;, hydroxyl, halo, C;_;-alkyl, Ci-2-haloalkyl, cyano, carboxyl, Ci-2-alkoxycarbonyl, C1-2-hydroxyalkyl, thiocalkyl, aminosulfonyl, Ci.,-alkylaminosulfonyl, methyl Ci-z-haloalkoxy, amino, Ci.z;-alkylamino, phenylamino, nitro, Ci.z-alkoxy-Ci-;-alkyl,
Ci-2-alkylsulfinyl, C;.;-alkoxy and Ci.z-alkylthio. )
In another aspect of the invention, at least one of R;, R: or R; is H; in a further embodiment, at least two of R;, R; or R; is H.
The invention also includes a method of treating a patient who has, or in preventing a patient from getting, a disease or condition selected from the group consisting of Alzheimer's disease, for helping prevent or delay the onset of Alzheimer's disease, for treating patients with mild cognitive impairment (MCI) and preventing or delaying the onset of Alzheimer's disease in those who would progress from MCI to AD, for treating
Down's syndrome, for treating humans who have Hereditary
Cerebral Hemorrhage with Amyloidosis of the Dutch-Type, for treating cerebral amyloid angiopathy and preventing its potential consequences, i.e. single and recurrent lobar hemorrhages, for treating other degenerative dementias, including dementias of mixed vascular and degenerative origin, dementia associated with Parkinson's disease, dementia associated with progressive supranuclear palsy, dementia associated with cortical basal degeneration, or diffuse Lewy body type of Alzheimer's disease and who is in need of such treatment which includes administration of a therapeutically effective amount of a compound of formula I.
In an embodiment, this method of treatment can be used where the disease is Alzheimer's disease.
In an embodiment, this method of treatment can help prevent or delay the onset of Alzheimer's disease.
In an embodiment, this method of treatment can be used where the disease is mild cognitive impairment.
In an embodiment, this method of treatment can be used where the disease is Down’s syndrome.
In an embodiment, this method of treatment can be used where the disease is Hereditary Cerebral Hemorrhage with
Amyloidosis of the Dutch-Type. -
In an embodiment, this method of treatment can be used where the disease is cerebral amyloid angiopathy.
In an embodiment, this method of treatment can be used where the disease is degenerative dementias.
In an embodiment, this method of treatment can be used where the disease is diffuse Lewy body type of Alzheimer's disease.
In an embodiment, this method of treatment can treat an existing disease, such as those listed above.
In an embodiment, this method of treatment can prevent a disease, such as those listed above, from developing.
In an embodiment, this method of treatment can employ therapeutically effective amounts: for oral administration from about 0.1 mg/day to about 3,000, preferably about 1,000 mg/day; @ for parenteral, sublingual, intranasal, intrathecal administration from about 0.5 to about 500 mg/day, preferably about 100 mg/day; for depo administration and implants from about 0.5 mg/day to about 50 mg/day; for topical administration from about 0.5 mg/day to about 200 mg/day; for rectal administration from about 0.5 mg to about 500 mg.
In an embodiment, this method of treatment can employ therapeutically effective amounts: for oral administration from about 1 mg/day to about 100 mg/day; and for parenteral administration from about 5 to about 50 mg daily.
In an embodiment, this method of treatment can employ therapeutically effective amounts for oral administration from about 5 mg/day to about 50 mg/day.
The invention also includes a pharmaceutical composition which includes a compound of formula I or a pharmaceutically acceptable salt or ester thereof; and an inert diluent or edible carrier.
The invention also includes the use of a compound of formula I or a pharmaceutically acceptable salt or ester thereof for the manufacture of a medicament for use in treating a patient who has, or in preventing a patient from getting, a disease or condition selected from the group consisting of
Alzheimer's disease, for helping prevent or delay the onset of
Alzheimer's disease, for treating patients with mild cognitive : impairment (MCI) and preventing or delaying the onset of
Alzheimer's disease in those who would progress from MCI to AD, for treating Down’s syndrome, for treating humans who have
Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch- " Type, for treating cerebral amyloid angiopathy and preventing its potential consequences, i.e. single and recurrent lobar hemorrhages, for treating other degenerative dementias, including dementias of mixed vascular and degenerative origin, dementia associated with Parkinson's disease, dementia 9 | associated with progressive supranuclear palsy, dementia associated with cortical basal degeneration, diffuse Lewy body type of Alzheimer's disease and who is in need of such treatment.
In an embodiment, this use of a compound of formula (I) can be employed where the disease is Alzheimer's disease.
In an embodiment, this use of a compound of formula (I) can help prevent or delay the onset of Alzheimer's disease.
In an embodiment, this use of a compound of formula (I) can be employed where the disease is mild cognitive impairment.
In an embodiment, this use of a compound of formula (I) can be employed where the disease is Down’s syndrome.
In an embodiment, this use of a compound of formula (I) can be employed where the disease is Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-Type.
In an embodiment, this use of a compound of formula (I) can be employed where the disease is cerebral amyloid angiopathy.
In an embodiment, this use of a compound of formula (I) can be employed where the disease is degenerative dementias.
In an embodiment, this use of a compound of formula (I) can be employed where the disease is diffuse Lewy body type of
Alzheimer's disease.
In an embodiment, this use of a compound of formula (I) employs a pharmaceutically acceptable salt selected from the group consisting of salts of the following acids hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, citric, methanesulfonic, CH;- (CH.;)n~-COOH where n is 0 thru 4, HOOC- (CH;)n-COOH where n is as defined above, HOOC-CH=CH-COOH, and phenyl-COOH. :
The invention also includes methods for inhibiting beta- secretase activity, for inhibiting cleavage of amyloid precursor protein (APP), in a reaction mixture, at a site between Met 596
Q and Asp597, numbered for the APP-695 amino acid isotype, or at a corresponding site of an isotype or mutant thereof; for inhibiting production of amyloid beta peptide (A beta) in a cell; for inhibiting the production of beta-amyloid plaque in an animal; and for treating or preventing a disease characterized by beta-amyloid deposits in the brain. These methods each include administration of a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt or ester thereof.
The invention also includes a method for inhibiting beta- secretase activity, including exposing said beta-secretase to an ] effective inhibitory amount of a compound of formula I or a pharmaceutically acceptable salt or ester thereof.
In an embodiment, this method includes exposing said beta- secretase to said compound in vitro.
In an embodiment, this method includes exposing said beta- secretase to said compound in a cell.
In an embodiment, this method includes exposing said beta- secretase to said compound in a cell in an animal.
In an embodiment, this method includes exposing said beta- secretase to said compound in a human.
The invention also includes a method for inhibiting cleavage of amyloid precursor protein (APP), in a reaction ’ mixture, at a site between Met596 and Asp597, numbered for the
APP-695 amino acid isotype; or at a corresponding site of an isotype or mutant thereof, including exposing said reaction mixture to an effective inhibitory amount of a compound of formula I or a pharmaceutically acceptable salt or ester thereof. :
In an embodiment, this method employs a cleavage site: . between Met652 and Aspé653, numbered for the APP-751 isotype; between Met 671 and Asp 672, numbered for the APP-770 isotype;
Q between Leu596 and Asp597 of the APP-695 Swedish Mutation; between Leu652 and Asp653 of the APP-751 Swedish Mutation; or between Leu671 and Asp672 of the APP-770 Swedish Mutation.
In an embodiment, this method exposes said reaction mixture in vitro.
In an embodiment, this method exposes said reaction mixture in a cell.
In an embodiment, this method exposes said reaction mixture in an animal cell.
In an embodiment, this method exposes said reaction mixture in a human cell.
The invention also includes a method for inhibiting production of amyloid beta peptide (A beta) in a cell, including administering to said cell an effective inhibitory amount of a compound of formula I or a pharmaceutically acceptable salt or ester thereof.
In an embodiment, this method includes administering to an animal.
In an embodiment, this method includes administering to a human.
The invention also includes a method for inhibiting the production of beta-amyloid plaque in an animal, including administering to said animal an effective inhibitory amount of a compound of formula I or a pharmaceutically acceptable salt or ester thereof. :
In an embodiment, this method includes administering to a human.
The invention also includes a method for treating .or preventing a disease characterized by beta-amyloid deposits in ; the brain including administering to a patient an effective therapeutic amount of a compound of formula I or a pharmaceutically acceptable salt or ester thereof.
In an embodiment, this method employs a compound at a
Q therapeutic amount in the range of from about 0.1 to about 1000 mg/day. : . 10 In an embodiment, this method employs a compound at a therapeutic amount in the range of from about 15 to about 1500 mg/day.
In an embodiment, this method employs a compound at a therapeutic amount in the range of from about 1 to about 100 mg/day.
In an embodiment, this method employs a compound at a therapeutic amount in the range of from about 5 to about 50 mg/day.
In an embodiment, this method can be used where said disease is Alzheimer's disease.
In an embodiment, this method can be used where said disease is Mild Cognitive Impairment, Down's Syndrome, or
Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch
Type.
The invention also includes a composition including beta- secretase complexed with a compound of formula I or a pharmaceutically acceptable salt or ester thereof. .
The invention also includes a method for producing a beta- secretase complex including exposing beta-secretase to a compound of formula I or a pharmaceutically acceptable salt or ester thereof, in a reaction mixture under conditions suitable for the production of said complex.
In an embodiment, this method employs exposing in vitro.
In an embodiment, this method employs a reaction mixture that is a cell.
The invention also includes a component kit including component parts capable of being assembled, in which at least one component part includes a compound of formula (I) enclosed in a container. .
In an embodiment, this component kit includes lyophilized
Q compound, and at least one further component part includes a diluent.
The invention also includes a container kit including a plurality of containers, each container including one or more unit dose of a compound of formula I or a pharmaceutically acceptable salt or ester thereof.
In an embodiment, this container kit includes each container adapted for oral delivery and includes a tablet, gel, or capsule. ~ In an embodiment, this container kit includes each container adapted for parenteral delivery and includes a depot product, syringe, ampoule, or vial.
In an embodiment, this container kit includes each container adapted for topical delivery and includes a patch, medipad, ointment, or cream.
The invention also includes an agent kit including a compound of formula I or a pharmaceutically acceptable salt or ester thereof; and one or more therapeutic agents selected from the group consisting of an antioxidant, an anti-inflammatory, a gamma secretase inhibitor, a neurotrophic agent, an acetyl cholinesterase inhibitor, a statin, an A beta peptide, and an anti-A beta antibody.
The invention also includes a composition including: a compound of formula I or a pharmaceutically acceptable salt or ester thereof; and an inert diluent or edible carrier.
In an embodiment, this composition includes a carrier that is an oil.
The invention also includes a composition including: a compound of formula I or a pharmaceutically acceptable salt or ester thereof; and a binder, excipient, disintegrating agent, lubricant, or gildant. -
The invention also includes a composition including: a : « compound of formula I or a pharmaceutically acceptable salt ester thereof; disposed in a cream, ointment, or patch.
The invention provides compounds, compositions, kits, and methods for inhibiting beta-secretase-mediated cleavage of amyloid precursor protein (APP). More particularly, the compounds, compositions, and methods of the invention are effective to inhibit the production of A beta peptide and to treat or prevent any human or veterinary disease or condition associated with a pathological form of A beta peptide.
The compounds, compositions, and methods of the invention are useful for treating humans who have Alzheimer's Disease (AD), for helping prevent or delay the onset of AD, for treating patients with mild cognitive impairment (MCI), and preventing or delaying the onset of AD in those patients who would otherwise be expected to progress from MCI to AD, for treating Down's syndrome, for treating Hereditary Cerebral Hemorrhage with
Amyloidosis of the Dutch Type, for treating cerebral beta- amyloid angiopathy and preventing its potential consequences such as single and recurrent lobar hemorrhages, for treating other degenerative dementias, including dementias of mixed vascular and degenerative origin, for treating dementia associated with Parkinson's disease, dementia associated with progressive supranuclear palsy, dementia associated with cortical basal degeneration, and diffuse Lewy body type AD. . The compounds of the invention possess beta-secretase inhibitory activity. The inhibitory activities of the compounds of the invention are readily demonstrated, for example, using one or more of the assays described herein or known in the art.
The invention includes a method for treating a patient who has, or in preventing a patient from getting, a disease or condition selected from the group consisting of Alzheimer's disease, for helping prevent or delay the onset of Alzheimer's disease, for treating patients with mild cognitive impairment 3 (MCI) and preventing or delaying the onset of Alzheimer's : disease in those who would progress from MCI to AD, for treating
Down's syndrome, for treating humans who have Hereditary
Cerebral Hemorrhage with Amyloidosis of the Dutch-Type, for treating cerebral amyloid angiopathy and preventing its potential consequences, i.e. single and recurrent lobar hemorrhages, for treating other degenerative dementias, including dementias of mixed vascular and degenerative origin, dementia associated with Parkinson's disease, dementia associated with progressive supranuclear palsy, dementia associated with cortical basal degeneration, or diffuse Lewy body type of Alzheimer's disease and who is in need of such treatment, comprising administering to such patient a - therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or ester thereof, wherein
Z, Ry, Rp, and R; are as defined above and below.
The invention further encompasses a method for making a compound of formula (I), or a pharmaceutically acceptable salt or ester thereof, wherein Z, R;, Rz and Rj; are as defined as above or below.
The invention relates to compounds of formula I, or a pharmaceutically acceptable salt or ester thereof. The invention encompasses all steroisomers of formula I and of the other compounds disclosed herein.
Further in accordance with the embodiment of the invention described above, compounds of Formula I include those where R, 35- and R; are independently: (I) -(CHz2)m- (Ri-ary1), where n; is zero or one and where
Ri-aryi 1s phenyl, 1l-naphthyl, 2-naphthyl, indanyl, indenyl,
dihydronaphthalyl, or tetralinyl optionally substituted with one, two, three, or four of the following substituents on the aryl ring:
Q® (A) Ci1-Ce¢ alkyl optionally substituted with one, two or three substituents selected from the group consisting of ¢,-C; alkyl, -F, -Cci, -Br, -I, -OH, -SH, -C=N, -CFj, C1-G5 alkoxy, and -NR;.aRi.p, Ci-Cs alkoxy- (Ri.am1), Ci1-Cs; alkoxy- (Ri- heteroaryl) (B) C,-Cs alkenyl with one or two double bonds, optionally substituted with one, two or three substituents selected from the group consisting of -F, -Cl, -Br, -I, -OH, -
SH, -C=N, -CFs, C;-C; alkoxy, and -NR;-aRi-p, C1-Ci alkoxy- (Rj-amy1) .
C1-Ci alkoxy- (Ri-hetercaryl) . (C) C,-Cg¢ alkynyl with one or two triple bonds, optionally substituted with one, two or three substituents selected from the group consisting of -F, -Cl, -Br, -I, -OH, -
SH, -C=N, -CFi, C:-C; alkoxy, and -NR;.aRi.p, C1-Ci alkoxy- (Ri-ary1) /
C1-C3 alkoxy- (Ri-heterocaryl) « (D) -F, Cl, -Br, or -I, (E) -C1-C¢ alkoxy optionally substituted with one, two, or three -F, } (F) -NRy-2Ryn.3, where Ry.; and Ry; are independently selected from the group consisting of: (1) -H, (2) -C1-C¢ alkyl optionally substituted with one substituent selected from the group consisting of: (a) -OH, and (b) -NH, (3) -C1-C¢ alkyl optionally substituted with one to three -F, -Cl, -Br, or -I, (2) -C3-C; cycloalkyl, (5) -(C:-C; alkyl) - (C3-C; cycloalkyl), (6) -(Ci-Cs alkyl) -O-(C1-C; alkyl),
(7) -C;-Cs alkenyl with one or two double bonds, (8) -C2-C¢ alkynyl with one or two triple [ Q bonds, (9) -C1-C¢ alkyl chain with one double bond and one triple bond, (10) -Ri-ary1, where Ri-aryy is as defined above, and (11) -Ri-netercaryl: (G) -OH, (H) -C=N, (I) C3-C; cycloalkyl, optionally substituted with one, two or three substituents selected from the group consisting of -F, -Cl, -Br, -I, -OH, -SH, -C=N, -CF;, -NR;-aRi-b,
C1-C3 alkoxy, Ci1-C; alkoxy- (Ri-ary1), Ci-Cz: alkoxy- (R1-heteroaryl) » (K) —CO-(Cy-C4 alkyl), (L) -SO02-NR:-aRj-p, (M) -CO-NR;-aRi1.p, OFX (N) -SO0.-(C;-C4 alkyl), or (XI) -(CHz}npi- (Ri-peterocaryl) , Where n; is zero or one and where Ri-netercaryl 18 selected from the group consisting of: pyridinyl, pyrimidinyl, quinolinyl, benzothienyl, indolyl, indolinyl, pryidazinyl, pyrazinyl : isoindolyl, isoquinolyl, quinazolinyl, quinoxalinyl, phthalazinyl, imidazolyl, isoxazolyl, pyrazolyl, oxazolyl, thiazolyl, indolizinyl, indazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl, furanyl, thienyl, pyrrolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, oxazolopyridinyl, imidazopyridinyl, where the Ri-netercaryr group is bonded to — (CH) - by any ring atom of the parent Ri-petercary1 group substituted by hydrogen such that the new bond to the Ri-netercaryr group replaces the hydrogen atom and its bond, where heteroaryl is optionally : substituted with one, two, three, or four of:
(1) C1-C¢ alkyl optionally substituted with one, two or three substituents selected from the group consisting of
C;-C; alkyl, -¥, -cCl, -Br, -I, -OH, -SH, -C=N, -CF;, C1-G3 @ alkoxy, and -NRj.aRi-p, C1-C3 alkoxy, C;-C; alkoxy-(Ri-ary1), Ci1-Cs alkoxy - (Ri-neteroaryl) ’ (2) C,-C¢ alkenyl with one or two double bonds, optionally substituted with one, two or three substituents selected from the group consisting of -F, -Cl, -Br, -I, -OH, -
SH, -C=N, -CF;, C,-C; alkoxy, and -NR;.,R:-», where R;., and R;.p are -H or CC;-C¢ alkyl, C;-C3 alkoxy, Ci-Cs3 alkoxy-(Ri-ary1), Ci1-GCi alkoxy- (Ri-neteroaryl) « (3) C;-Cs alkynyl with one or two triple bonds, optionally substituted with one, two or three substituents selected from the group consisting of -F, -Cl, -Br, -I, -OH, -
SH, -C=N, -CF;, C;-Ci; alkoxy, and -NR;.aRi.n, where R;_, and R; are -H or (;-Cs¢ alkyl, C-C3 alkoxy, Ci-C; alkoxy-(Rj.aryi), Ci1-C; alkoxy =~ (Ri-neteroaryl) (4) -F, C¢1, -Bx, or -1I, (5) -C1-Cs alkoxy optionally substituted with one, two, or three -F, (6) —NRy_2Ry-3, (7) -OH, (8) -C=N, (9) C3-C; cycloalkyl, optionally substituted with one, two or three substituents selected from the group consisting of -F, -Cl, -Br, -I, -OH, -SH, -C=N, -CF3;, (C;-C; alkoxy, and -NR;-aR;-», where R;; and Ry, are -H or C;-Cg¢ alkyl,
C1-C3 alkoxy, C3-Ci3 alkoxy-(Ri-ary1), C1-C; alkoxy- (Rj-netercaryl) (10) —CO-(Cy-C, alkyl), : (11) -SO02-NRj_ Ri.p, . (12) -CO-NRi.3Ry1-p, OF
(13) -S0,-(C,-C4 alkyl), with the proviso that when n; is zero Ri.petercary1 1S not bonded to the carbon chain by ) nitrogen.
QQ In another embodiment, R; and R3 are independently: phenyl, 1l-naphthyl, 2-naphthyl, tetralinyl, indanyl, dihydronaphthyl or 6,7,8,9-tetrahydro-5SH- benzo [a] cycloheptenyl, each of which is optionally substituted with one, two or three of the following substituents which can be the same or different and are: (1) C,-C¢ alkyl, optionally substituted with one, two or three substituents selected from the group consisting of C,-C; alkyl, -F, -Cl, -Br, -I, -OH, -SH, -C=N, - i CF3, C:-C; alkoxy, and =-NR;..R;.p, Ci1-C3 alkoxy- (Ri-ary1) , C1-C3 alkoxy- (Ri-netercary1) / (2) -OH, (3) -NO., (4) -F, -Cl, -Br, or -I, (5) -CO-OH, oo (6) -C=N, (7) -(CHz)0-4-CO-NRy-2Rx-3, (8) -(CHz)0-4-CO-(C31-Cy2 alkyl), (9) - (CH) (-4-CO- (C,-C;; alkenyl with one, two or three double bonds}, (10) -(CHz)0-4-CO~ (C2-C;2 alkynyl with one, two or three triple bonds), (11) - (CH3)-4-CO- (C3-C,; cycloalkyl), (12) - (CHz)0-4-CO~Ri-amy1, (13) - (CH2) 0-4-CO-Ri-neteroaryls (14) -(CH:) 0-4-CO=-Ri heterocycles (15) -(CH3)0-4-CO-Ry., Where Ry, is selected from the group consisting of morpholinyl, thiomorpholinyl, : piperazinyl, piperidinyl, homomorpholinyl, homothiomorpholinyl, homothiomorpholinyl S-oxide, homothiomorpholinyl S,S-dioxide,
pyrrolinyl and pyrrolidinyl where each group is optionally substituted with one, two, three, or four of: .C;-Cs alkyl, (16) -(CHj)0-4-CO-0O-Ry.s where Ry.s is selected { from the group consisting of: (a) C;-Cg¢ alkyl, (b) - (CHa) 0-2- (Ri-ary1) , (c) C;-Cg¢ alkenyl containing one or two - double bonds, (d) C;-C¢ alkynyl containing one or two "triple bonds, (e} Ca.Cq cycloalkyl, and : (£) - (CHa) 0-2- (Ri-hetercary1) . ] (17) -(CH2) 0-4-S02-NRy-2Ry-3, (18) -(CH2)0-4-80-(Cy3-Cg alkyl), (19) -(CH2)0-4-802-(C1-C;; alkyl), (20) -(CH2)0-4-502-(C3-Cy7 cycloalkyl), - (21) -(CH3)0-4-N(H or Ry.s )~CO-0-Ry.5 where Ry. s can be the same or different, (22) -(CH2)-4-N(H or Ry.s )-CO-N(Ry.s)z2, where Ry.s Can be the same or different, (23) -(CH2)0-4-N-CS-N(Ry.5) 2, where Ry.s can be : the same or different, (24) -(CH32)0-4-N(-H Or Ry.s) -CO-Ry.» where Ry.s and Ry.» can be the same or different, (25) -(CH2)o-4-NRy-2Ry-3 where Ry.2 and Ry.3 can be the same or different, } (26) -(CHz)o-4-Rn-4, (27) -(CH2)0-4-0-CO-(C1-C¢ alkyl), (28) -(CHz2)0-4-O-P(O) - (ORy-ary1-1) 2 Where Ry.aryi.; is -H or C,-C; alkyl, (29) - (CHz) 0-4-0-CO-N (Ry-5) 2, (30) -(CH2)-4-O-CS-N(Ry-s) 2, (31) -(CHz)0-4-O- (Ry-s) 2,
(32) -(CHz)0-4-O-( Ry-s)2-COOH, (33) -(CHz)0-4-S-( Ru.s)2, : (34) - (CH) 0-4-0- (C3-C¢ alkyl optionally @® substituted with one, two, three, four, or five -F), (35) C3-C; cycloalkyl, (36) C,-C¢ alkenyl with one or two double bonds optionally substituted with C;-C; alkyl, -F, -Cl, -Br, -I, -OH, -SH, -C=N, -CF;, C;-C3; alkoxy, or -NR;.aRi.p, Ci1-C3 alkoxy- (Ra- aryl) » C1-C3 alkoxXy- (Ri-neteroaryl) , (37) C2;-Cs¢ alkynyl with one or two triple bonds optionally substituted with ¢,-C; alkyl, -F, -Cl, -Br, -I, -OH, -SH, -C=N, -CF3;, C;-C3; alkoxy, or -NRj..Ri.p, C1-Ci alkoxy- (Ri- aryl) , C1-C3; alkoxy- (Ri-neteroarya) (38) -(CHz)0-4-N(-H OT Ry.s) -SO;-Ry. where Ru.s and Ry., can be the same or different, or (39) -(CHz)o-4- C3-C; cycloalkyl.
In yet another embodiment, R; and R; are independently Ry- 1€(0) -; and
Ry-1 1S Rn hetercaryl Where Ry.-hetercaryr 18 selected from the group consisting of: pyridinyl, pyrimidinyl, quinolinyl, benzothienyl, indolyl, indolinyl, pryidazinyl, pyrazinyl, isoindolyl, isoquinolyl, quinazolinyl, quinoxalinyl, phthalazinyl, imidazolyl, isoxazolyl, pyrazolyl, oxazolyl, thiazolyl, indolizinyl, indazolyl, benzothiazolyl, benzimidazolyl,
Dbenzofuranyl, furanyl, thienyl, pyrrolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, oxazolopyridinyl, ) imidazopyridinyl, isothiazolyl, naphthyridinyl, cinnolinyl, carbazolyl, beta-carbolinyl, isochromanyl, chromanyl, tetrahydroisoquinolinyl, isoindolinyl, isobenzotetrahydrofuranyl, isobenzotetrahydrothi enyl, isobenzothienyl, benzoxazolyl,
pyridopyridinyl, benzotetrahydrofuranyl, benzotetrahydrothienyl, purinyl, benzodioxolyl, triazinyl, phenoxazinyl, phenothiazinyl, @ bteridinyl, benzothiazolyl, imidazopyridinyl, imidazothiazolyl, dihydrobenzisoxazinyl, benzisoxazinyl, benzoxazinyl, dihydrobenzisothiazinyl, benzopyranyl, benzothiopyranyl, coumarinyl, where the Ru-netercaryr group is bonded by any atom of the parent Ry-netercarys group substituted by hydrogen such that the new bond to the RN-heteroaryl group replaces the hydrogen atom and its bond, where heteroaryl is optionally substituted with one, two, three, or four of: (1) C1-C¢ alkyl, optionally substituted with one, two or three substituents selected from the group consisting of C,-C; alkyl, -F, -Cl, -Br, -I, -OH, -SH, -C=N, -
CFs, C;-C; alkoxy, and -NR;..R;.b, Ci1-C3; alkoxy- (Ri-ary1) , C1-C3 alkoxy - (Ri-neteroaryl) : (2) -OH, (3) -NOg, (4) -F, -Cl, -Br, or -I (5) -CO-OH, (6) -c=N, (7) = (CHa) o-4~CO-NRy-2Ry.3, (8) ~-(CHz)0-4-CO- (C1-Cy2 alkyl), (9) - (CH) -4-CO- (C,-Cy, alkenyl with one, two or three double bonds), (10) - (CH;)0-4-CO- (C2-Cy2 alkynyl with one, two or three triple bonds), (11) - (CHa) ¢-4-CO- (C3-Cy cycloalkyl), (12) -(CH2)0-4-CO-Ry-ary1, (13) - (CH) 0-4~CO-R1-neteroary1s (14) - (CH) 0-4=CO-Ri-heterocycie (15) - (CH2) 0-4-CO-Ry-4,
(16) - (CHz)0-4-CO-O-Ry-s, (17) - (CH) 0-4a-SO2~-NRy-2Rn-3, (18) - (CH;) 0-4-SO- (C;-Cs alkyl), ® (19) - (CHj) 0-a-S02-(C1-Ci2 alkyl), (20) - (CH;) v.4-S0a- (C3-C,; cycloalkyl), (21) - (CH) o-4-N(H or Ry.s ) -CO-O-Ry.s where Ru- s can be the same or different, (22) -(CH;) 0-a-N(H or Ry.s ) -CO-N(Ry-s)2, where
Ry-s can be the same or different, (23) - (CHz) 0-4-N-CS-N(Ry-s)2, where Ry.s can be the same or different, (24) - (CH) -4-N(-H or Ry.s) -CO-Ry-2 where Ry-s and Ry.» can be the same or different, (25) - (CH3) 0-a-NRy-2Ry-3 where Ry.2 and Ry.z can be the same or different, (26) -(CHz)o0-4-Ry-a, (27) = (CH3) 0-4a-0-CO- (C1-C¢ alkyl), (28) -(CH;)0-4-0-P (0) - (ORN-ary1-1) 2 Where Ry.aryl-a is -H or C;-C; alkyl, (29) -{CH3)0-4-0-CO-N(Rn-s) 2, (30) - (CHz)0-4-0-CS-N(Ry-5) 2, (31) -(CHz)0-4-0- (Ry-s) 2, (32) - (CH) 0-4-O-( Ry.s)2-COOH, (33) -(CH2)0-4-S-( Ru-s)2, (34) - (CH;)0-4-0- (C;-Cs alkyl optionally substituted with one, two, three, four, or five -F), (35) C3-C,; cycloalkyl, (36) C,-C¢ alkenyl with one or two double bonds optionally substituted with C,-C; alkyl, -F, -Cl, -Br, -I, -OH, -SH, -C=N, -CF3;, C,-C; alkoxy, or -NRi-aRi-n, Ci1-C; alkoxy-(R;- ami), Ci-Cs alkoxy- (Ri-netercaryl) s (37) C,-C¢ alkynyl with one or two triple bonds optionally substituted with C;~C; alkyl, -F, -Cl, -Br, -I,
-OH, -SH, -C=N, -CF;, C,-C; alkoxy, or -NR;.aRi.p, Ci-C; alkoxy- (Ri- © arm), Ci1-C; alkoxy- (R3-netercaryl) » pg (38) -(CH2)0-4-N(-H or Ry.s)-SO-Ry.2 where Rx-s { and Ry.» can be the same or different, or ’ (39) -(CHz)0-4- C3-C; cycloalkyl.
In a further embodiment, R; and R; are independently Rx- 1C(0)-; and Ry.1 is phenyl, 1l-naphthyl, or 2-naphthyl, each of which is optionally substituted with one, two or three of the following substituents which can be the same or different and are: (1) C1-Cs alkyl, optionally substituted with one, two or three substituents selected from the group consisting of C;-C; alkyl, -F, -Cl, -Br, -I, -OH, -SH, -C=N, -
CF3, C;-C; alkoxy, and -NR;.aRy-p, Ci-C3 alkoxy- (Ri-ary1), ©C1-GCs alkoxy- (Ri-netercaryl) , (2) -OH, (3) -NO2, (4) -F, -Cl1, -Br, or -I, (5) -CO-OH, (6) -C=N, (7) -(CHz2)0-4-CO-NRy-2Ry-3, (8) -(CHz2)0-4-CO- (C1-Cy2 alkyl), (9) -(CHz)0-4-CO- (C2-C12 alkenyl with one, two or three double bonds), (10) -(CHz)0-4-CO- (C2-Cy2 alkynyl with one, two or three triple bonds), (11) -(CH2)0-4-CO-(C3-C; cycloalkyl), (12) - (CH;) 0-4-CO-Ry-azya, (13) - (CH) 0-4~CO-R1-neteroary1: (14) -(CHz)0-4-CO-Ri-heterocycles (15) - (CH;) 9-¢~CO-Ry-4 where Ry.; is selected from the group consisting of morpholinyl, thiomorpholinyl, piperazinyl, piperidinyl, homomorpholinyl, homothiomorpholinyl,
homothiomorpholinyl S-oxide, homothiomorpholinyl S,S-dioxide, pyrrolinyl and pyrrolidinyl where each group is optionally substituted with one, two, three, or four of: C,-C¢ alkyl, ® (16) - (CHj)0.4-CO-O-Ry.s where Ry.s is selected from the group consisting of: (a) C1-C¢ alkyl, (b) -(CHz)0-2- (Ri-ary1) + (c) C2-C¢ alkenyl containing one or two double bonds, (d) C,-C¢ alkynyl containing one or two triple bonds, (e) C;3.C; cycloalkyl, and (£) -(CH2) 0-2- (Ri-heteroaryl) « (17) - (CHz) 0-4-SO2-NRy-2Rx-3, (18) - (CHz)¢-4-S0-(C1-Cg alkyl), (19) -(CHz)-4-S02.(C1-Ci2 alkyl), (20) -(CHz)0-4-S02- (C3-C7 cycloalkyl), (21) - (CH) 0-¢-N(H or Ry-s )-CO-O-Ry.s where Ry. s can be the same or different, {22) -(CH3)0-4-N(H or Ry.s )-CO-N(Rn-s)2, where
Ry.s can be the same or different, : (23) -(CH;)-4-N-CS-N(Ry-s)2, where Ry-s can be ) the same or different, (24) -(CHz) 0-4-N{(~-H Or Ry.s) -CO-Ry-2 where Ry.s and Ry.2 can be the same or different, (25) - (CHz) 0-«-NRn-2Rn-3 Where Ry.2 and Ry.3 can be the same or different, (26) -(CH2)o-4-Rn-4, (27) -(CHg3) 0-4-0-CO- (C;-Cs alkyl), (28) - (CH) 0-4-O-P (0) - (ORy-ary1-1) 2 where Ry-aryiy is -H or Ci-C, alkyl, ) (29) -(CH2) ¢-4-0-CO-N(Ry-s) 2, (30) . - (CHz) ¢-4-0-CS-N(Ry-5) 2, as
2) (31) -(CHz)0-4-O- (Ry-s) 2, (32) -(CHz)¢-4-O-( Ry-s) 2-COOH, (33) -(CH:2)0-4-S-( Rx-s)a, ® (34) -(CHz)0-4-0-(C,-C¢ alkyl optionally substituted with one, two, three, four, or five -F), (35) C3-C; cycloalkyl, (36) C;-C¢ alkenyl with one or two double bonds optionally substituted with C;-C; alkyl, -F, -Cl1, -Br, -I, -OH, -SH, -C=N, -CFs;, C;-C; alkoxy, or -NR;-zR;.5, C:-C3 alkoxy- (Ra- aryl) , C1-C3 alkoxy- (Ri-netercaryl) (37) C,-C¢ alkynyl with one or two triple bonds optionally substituted with C;-C; alkyl, -F, -Cl1, -Br, -I, -OH, -SH, -C=N, -CFi, C;-C; alkoxy, or -NRi.aRi.», Ci-Cs alkoxy- (Ri. aryl) , C1-C3 alkoxy- (Ri-neteroaryl) (38) -(CH:)4-4-N(-H or Ry.5) -SO>-Ry., where Ry-s and Ry.; can be the same or different, or (39) -(CH;)¢-4- C3-C; cycloalkyl.
In still another embodiment, R; and R; are independently Ry. 1C (0) -; and
Ry-1 is phenyl optionally substituted with one, two or three of the following substituents which can be the same or different and are: (1) Ci~C¢ alkyl, optionally substituted with one, two or three substituents selected from the group consisting of C;-C; alkyl, -F, -Cl, -Br, -I, -OH, -SH, -C=N, -
CF;, G-C3 alkoxy, and -NR; Rip, C1-C3 alkoxy- (Ry.am), Ci1-Cs alkoxy- (Ri-netercaryl) « (2) -OH, (3) -NOg, (4) -F, -C1, -Br, or -I, (5) -CO-OH, : (6) -C=N,
(7) -(CH;) 0-4-CO-NRy-2Rxy-3, (8) =-(CHz)0-4-CO-(C1-Cy2 alkyl), . (9) -(CH,)4-4-CO- (C3-C;32, alkenyl with one, two ® or three double bonds), (10) -(CHz)0-4-CO-{C3-Ci2 alkynyl with one, two or three triple bonds), (11) - (CHz) 0-4-CO- (C3-Cy; cycloalkyl), (12) -(CHz)0-4-CO-Ri-ary1: (13) -(CH2) 0-4-CO-Ri-hetercaryl, (14) - (CH) 0-4-CO-Ri-neterocycle (15) -(CH,)0-4-CO-Ry.4 Where Ry, is selected from the group consisting of morpholinyl, thiomorpholinyl, piperazinyl, piperidinyl, homomorpholinyl, homothiomorpholinyl, homothiomorpholinyl S-oxide, homothiomorpholinyl S,S-dioxide, pyrrolinyl and pyrrolidinyl where each group is optionally substituted with one, two, three, or four of: C;-Cg¢ alkyl, (16) - (CH) 0-4-CO-0-Ry.5 where Ry.; is selected from the group consisting of: (a) C1-Cg¢ alkyl, {b} -{CILz)0-2- (Ru-aryr} / (c) C,-Cs alkenyl containing one or two double bonds, (d) C;-C¢ alkynyl containing one or two triple bonds, (e) C3-C7 cycloalkyl, and (£) -(CH2)o0-2- (Ri-hetexoaryl) , (17) -(CH3) 0-4-SO2-NRy-2Ry-3, : (18) -(CH;)0-4-S0-(C1-Cg alkyl), (19) -(CH;) 0-4-S02-(C1-Cy2 alkyl), (20) -(CH;)-4-S02- (C3-C7 cycloalkyl), (21) -(CH,)0-4-N(H or Rys ) -CO-O-Ry.s where Ry. s can be thie same or different,
(22) - (CH) 0-4-N(H or Ry-s ) -CO-N(Ry.5)., where
Ry.s can be the same or different, (23) = (CHz) 9-4-N-CS-N(Ry-5) 2, where Ry.5 can be o the same or different, (24) -(CH2)0-4-N(-H or Ry.s) -CO-Ry.» where Ry-s and Ry-2 can be the same or different, (25) -(CHz) 0-4-NRy-2Rx-3 where Ry.» and Ry.; can be the same or different, (26) -(CHz2)o-4-Ry-4, (27) - (CH) 0-4-0-CO- (C,-Cs alkyl), (28) -(CHz)0-4-0-P (0) - (ORy-ary1-1) 2 Where Ry.aryi-1 is -H or C;-C, alkyl, (29) -(CHz)0-4-0-CO-N(Ry-s) 2, ] (30) -(CHz2)0-4-O-CS-N(Ry-s)2, (31) -(CHz) 0-4-0O- (Ry-s) 2, (32) -(CH2)0-4-0~ ( Ry-s)2-COOCH, (33) =-(CH2)0-4-S-( Ry-s)a2, (34) -(CHz)0.4-0- (C;-Cs alkyl optionally substituted with one, two, three, four, or five -F), (35) C;3-Cy cycioalkyl, (36) Cp-C¢ alkenyl with one or two double bonds optionally substituted with C;-Cs alkyl, -F, -Cl, -Br, -I, ~OH, -SH, -C=N, -CF3, C;-C; alkoxy, or -NR;..R;.p, C;-Cs alkoxy- (R;- aryl) , C1-Ci3 alkoxy- (Ri-neteroary1) (37) C2-C¢ alkynyl with one or two triple bonds optionally substituted with C,-C; alkyl, -f, -Cl, -Br, -I, -OH, -SH, -C=N, -CF3, C1-C; alkoxy, or -NR;.aRi.p, C1-Cs alkoxy- (Ry. ary1) , Ci-C3; alkoxy- (R1-netercary1) ' (38) -(CH2)0-4~N(-H or Ry.5) -SO,-Ry., where Ry.s and Ry.» can be the same or different, or (39) ~(CHz2)o0-4- C3-C,; cycloalkyl.
In another embodiment, R, and R3 are independently Ry-1C(O)- ; and
Ry.i is phenyl of which is optionally substituted with one, two or three of the following substituents which can be the same or different and are: ® (1) C;-C¢ alkyl, optionally substituted with one, two or three substituents selected from the group consisting of C;-C3 alkyl, -F, -Cl1l, -Br, -I, -OH, -SH, -C=N, -
CF;, C;-C; alkoxy, and -NRj-aR;.p, Ci1-C; alkoxy-(Ri.aryi), Ci1-GC; alkoxy- (Ri-hetercaryl) (2) -OH, (3) -NOg, (4) -F, -Cl, -Br, or -I, (5) -CO-OH, (6) -c=N, (7) -(CHz) 0-4-CO-NRy-2Ry-3, i (8) - (CHa) 0-4-CO-(C1-C1z alkyl), (9) -(CHz)0-4-CO-(C2-C;2 alkenyl with one, two or three double bonds), (10) - (CH) ¢-4-CO-(C,-Cy12 alkynyl with one, two or three triple bonds), (11) - (CHz) ¢-4-CO-(C3-C7 cycloalkyl), (12) -(CHz)0-4-CO-Ri-ary1, (13) -(CHz2)0-4-CO-Ri-heteroaryl, (14) - (CH) 0-4~CO-Ri heterocycles (15) -(CH:)(-4-CO-Ry-4 where Ry.4 is selected from the group consisting of morpholinyl, thiomorpholinyl, piperazinyl, piperidinyl, homomorpholinyl, homothiomorpholinyl, homothiomorpholinyl S-oxide, homothiomorpholinyl S,S-dioxide, pyrrolinyl and pyrrolidinyl where each group is optionally substituted with one, two, three, or four of: C;-C¢ alkyl, (16) -(CH;)-4-CO-O-Ry.s Where Ry.s is selected from the group consisting of: (a) Ci-Cs alkyl, (b) -(CH2)o-2- (Ri-ary1) ,
(c) C;-C¢ alkenyl containing one or two . double bonds, (d) C2-Cs alkynyl containing one or two ® triple bonds, and (e) Ci3.C; cycloalkyl, (17) -(CHz)o-4-N{(H or Ry.s )-CO-O-Ry.s where Rx- s can be the same or different, (18) -(CH3)¢-4-N(H or Ry.s )-CO-N(Ry-s)2, where
Ry-s can be the same or different, (19) -(CH3) g-4-N-CS-N(Ry-s) 2, where Ry.s can be the same or different, (20) -(CHz)¢-4-N(-H or Ry.s) -CO-Ry-2 where Rx-s and Ry.» can be the same or different, (21) -(CH3)o-4-NRy-2Ry-3 where Ry.» and Ry.3 can be the same or different, (22) -(CHz2)o-4-Ry-4, (23) - (CHa) 0-4-0-CO-(C1-C¢ alkyl), (24) -(CHz)0-4-0-CO-N(Ry-s) 2, (25) - (CHa) 0-4-O-CS-N(Ry-s) 2, (26) -(CHz)0-4-0O- (Rn-5) 2, (27) -(CHz)0-4-0O-( Ry-s)2-COOH, (28) -(CH3z)-4-0- (C1-C¢ alkyl optionally substituted with one, two, three, four, or five -F), . (29) - (CHa) 0-4-N (-H Or Ry.s) -S02-Ry., where Ry.s and Ry. can be the same or different, or (30) -(CHz)¢-4- C3-C; cycloalkyl.
In another embodiment, R; and R; are independently Ry.:C(O)- ; and )
R, represents - (CH;)ni-phenyl where n;, is zero or one and where phenyl is optionally substituted with one, two, or three of the following substituents which are the same or different: (A) C1-Cs¢ alkyl optionally substituted with one, two or three substituents selected from the group consisting of
C;-C; alkyl, -F, -C1, -Br, -I, -OH, -SH, -C=N, -CF3;, GCi-GCs3 alkoxy, and --NRj.aRip, Ci-C3 alkoxy-(Ri-ary1): C1-Cs alkoxy- (Ri- ® heteroaryl) (B) C,-C¢ alkenyl with one or two double bonds, optionally substituted with one, two or three substituents selected from the group consisting of -F, -Cl, -Br, -I, -OH, -
SH, -C=N, -CF3;, C;-C: alkoxy, and -NRj.aRi-b, Ci1-C3 alkoxy- (Ricary1) +
C;-C3 alkoxy- (Ri-heteroaryl) / (C) Ca2-C¢ alkynyl with one or two triple bonds, optionally substituted with one, two or three substituents selected from the group consisting of -F, -Cl, -Br, -I, -OH, -
SH, -C=N, -CF;, C;-C; alkoxy, and -NRi.aRi.p, C3-C; alkoxy- (Ri-ary1) +
C.-C; alkoxy- (Ri-neteroaryl) « (p) -F, Cl, -Br, or -I, (E) -C;-C¢ alkoxy optionally substituted with one, two, or three -F, (F) -NRy.oRn.3, where Ry.; and Ry.3 are independently selected from the group consisting of: : (1) -H, (2) -C1-Cs alkyl optionally substituted with one substituent selected from the group consisting of: (a) -OH, and (b) -NHz, (3) -C1-C¢ alkyl optionally substituted with one to three -F, -Cl, -Br, or -I, (4) -C3-C; cycloalkyl, (5) -(Ci-Cz alkyl) -(Cs-C; cycloalkyl), (6) -(C1-Ce¢ alkyl) -0O-(Cy-C3 alkyl), (7) -Ca-C¢ alkenyl with one or two double . bonds, ’ (8) -C;-Cs alkynyl with one or two triple bonds,
(9) -C;-Cs alkyl chain with one double bond and one triple bond, ; (10) -Ri-ary1, , and ® (11) -Ri-hetercaryl:
(G) -OH,
(H) -C=N,
(I) C3-Cy cycloalkyl, optionally substituted with one, two or three substituents selected from the group consisting of -F, -Cl, -Br, -I, -OH, -SH, -C=N, -CF;, C-Cs alkoxy, and -NRy.aR;.p, Ci-Cs alkoxy- (Ria), Ci-Cs alkoxy- (Ri-
hetercaryl) ;
(J) -CO-(C1-C4 alkyl),
(K) -S02-NRj-aRi-b,
) (Ll) -CO-NR;.aRi-bs, OT
(M) -S0,-(C1-Ce¢ alkyl).
in a further embodiment, R; and R; are independently phenyl (C;-C¢) alkyl groups where the phenyl is optionally substituted with one or two groups independently selected from
(A) C3-C¢ alkyl optionally substituted with one, two or three substituents selected from the group consisting of
¢,-C; alkyl, -F, -C1, -Br, -I, -OH, -SH, -C=N, -CF;, GC,-C; alkoxy, and -NRi1-aRi.p, Ci1-C3 alkoxy- (Ri-ama), Ci-Ci alkoxy- (Ra. heteroaryl) . =
(B) -F, Cl, -Br, or -I,
(C) -C.-C¢ alkoxy optionally substituted with one, two, or three -F,
(D) -NRy-2Ry-3, where Ry, and Ry; are independently selected from the group consisting of:
(1) -H, (2) -C1-C¢ alkyl optionally substituted with one substituent selected from the group consisting of:
(a) -OH, and : (b) -NH,
(3) -C;-C¢ alkyl optionally substituted with one to three -F, -Cl, -Br, or -I, ] (4) -C3-C; cycloalkyl, @® (5) -(C1-C; alkyl) - (C3-C; cycloalkyl), (6) -(C1-Cs alkyl)-0-(C1-C; alkyl), (9) -C;-C¢ alkyl chain with one double bond and one triple bond, (E) -OH, (F) -C=N, (BG) C3-C; cycloalkyl, optionally substituted with one, two or three substituents selected from the group consisting of -F, -Cl, -Br, -I, -OH, -SH, -C=N, -CF;, Ci-GC;5 alkoxy, and -NR;.aRi.p, C1-C3 alkoxy- (Ri-ary1), Ci1-Cs alkoxy- (Ra. heteroaryl) ’ i} (H) -CO-(C;-C; alkyl), (I) —-S03-NRi;.aR;.n, where R;., and R;., are as defined above, or (J) -CO-NR;.zR:.p, where R;., and R;.p are as defined above,
Representative R; and R; groups also independently include benzyl, 4-hydroxybenzyl, 2-fluoro-4-propylbenzyl, 3-amino-4- bromobenzyl; 3-chloro-5-methylphenethyl, 3,5-difluorobenzyl, 2- . methylphenylpropyl, 4-trifluoromethylbenzyl, 4- trifluoromethylphenethyl, 2,3-dichlorobenzyl, and 2-chloro-4- cyanobenzyl.
The invention encompasses compounds of formula I, which includes those compounds shown below wherein R,, R, and Rj; are as defined above:
—=N N—o x / / \ /
Pa AN NA° LZ . ® Ry Ra Ry Ry
N N y N i H H H
H
H [} [J N
N
(o] [o] —=—=N / OEY! 7 7 / \ Ry Ry Fo
Z R;
N Re N Ry N Ry Re
J OO \/
Shes
N Ry Ry cov ox UOT
H N
A N
. h [o] 7
AN N AN N he
NORGE
J
} h )
The invention encompasses compounds of formula I, which further includes compounds shown below, wherein R;; is - (CH) pi- (Ri-ary1) » Or -(CH2)n1-O-(Ry.ary1), wherein nl and Ry.ary1 are as defined above:
AN
[| wracon - FF 0. 0)
Ry he.
N .
H
The invention encompasses compounds contemplated by Formula
I, and more particularly those compounds shown below: 3-Alkyloxy-4-Furano-Piperidines oO 0] 0} 0] Oo / A / 4
Z 2 FH Z F
Loi Xp Sa oI OE 8)
C be
N N
H H - 3-Alkyloxy-4-isoxazolo-Piperidines 0 0] 0] Oo [N (N & { [_N v y £5 oO Lar Xoo Lode Xo
N
N H N N N
0 —Q =N =N 4 _N I! _N } a Fe) IS H 0 ~K o hes
N N N
=N —N =N
Nn b nN b Ns b RN b Xx b : oY oJ OY 0D ENS 2 N-Q - N-Q N-Q N-O
F F SZ Va U4
N N N .
H H H H H
The invention encompasses compounds contemplated by Formula ® I, and more particularly those compounds shown below: 3,5-Alkyloxy-Piperidines
Ql, a of 2p
N N H
3-Alkyloxy- and 3-Alkyl-4-Furano-Piperazines
Q Q Q gC ___ 9,8 4 (0 IT 0
N N p 3-Alkyloxy- and 3-Alkyl-4-Isoxazolo-Piperazines
Q ) ) pw, gg
ANG Ao ANY AYO
A (J (J
N H H
=! =N =N ¢ Pe ¢ saneleasicagiege
N N H H
3-Alkyloxy- and 3-Alkyl-4-Oxazolo-Piperazines o o— [o} 0
Oh SF 3 Ky 5 ~ sagcloatioatio nthe al
N N N H
The invention encompasses compounds contemplated by Formula
I, and more specifically those compounds shown below: ] oe Ho o oT SE Co
SPhenaxypipaidind-al - A no : ’ So C{$-Phancxymuthyl-plpsriain-3-yl)-maity lamina - aes C a _. No ’
FR 9 : - : - . . - “oH CL Oran dana own ants
HS-Propasyplpeidnd-yimathaxy}-pyridine Dap
CR ) - . ] - N oR ’ . . BE * - +Odn32{3-e dinJdetathoxy} pipaddind-7 elisndt . . - ] . ) - . R © . $48 Phmnosymetop pipado-d yormeityheridae . - . : . ’ - : . $ .
S-Phanaxy-plpaddia--ol . SE(\5Oifuarod-uthoxy-beazyionmeliyf-piperidin3- ying . : . sthybpyidine | .
SG oo CHEE Senringy” ’ Ethaxy-8-phaciauy-pipediclng F
The invention encompasses compounds contemplated by Formula
I, and more specifically those compounds shown below: ( | a CL © ~ . . i . Lo i - (6-Phenaxymathyl-plparazin24ilmataanal * } a (Smid cnt pipers 2 yh nasanct oo . N oN : 2 Plaecdn-t simathyl-S-apicin-yimehaxymetny)-plparazine . or . op i . . “N fen = :
Pyridi 3. yH{8-2-pyekin-2-yhatharymelryf)-poecio 2 mets amios
ER «UN ¢ ~~
H
2-{4-Bromo~phencxymethyi}-8-{4-chiara-phanaxymaethyl)-pipecating ) © 202 Pyldndyh ate ydnylogmeny) downs. } Cw 2-{4-Broma-baraylxymelhyll-8-{¢-brame-phiencxymeibyl}--natyl plpacazine oo | WY . : 2+(3,5-Difuaro-bsnzytaxymathyl)-6-2-pyridin-4-yi-sthii)-pierazine
The invention encompasses compounds contemplated by Formula
I, and more specifically those compounds shown below:
NL : : ’ ‘ ol - ]
HO. 0. } CL 0
OE > 0 Co 4-{3H-Imidazo-d-yi}-S-phanoxy-pigeddindal EY S-phencxyathybi
J /~=N CL CL Cg : o, cd . 5 | | | | T 3
Sy my stray to Sr DE Semen 2. : : r=N . . a— . . CL ge ’
I. y FithinzohSA-pipendind-d .
Te 1 ${4Broma-phenoxymethy(-5-{d-chioro-phencymetiyl)- . . ) : . _ ’ : CFy 3 To. 4341.2, 3 Trianok-4-yi)-3-{¢-trifluoromal
H5Bazyiorydimidizah lt ppaddnd porymethyl) pide /=N : . . B >
ISU CURE e 0.0 0 § 8 ¢ i oo - N . th oo a 2: . -
S-{b-Azalidin-1-yhS phancoyplasttin'd plonymetnlihizzole- carboxylic . E }
. The invention encompasses compounds contemplated by Formula ® I, and more specifically those compounds shown below: . HO co. - - . - . as } 3 . yw , N° to. 4{50.5-Oituora phenyl plpasio-S ireincyemalnyl pido tOuzokSyS phen BADIowRI i ° . . Kip . . R }
DCL Lo . Lo Sy ST a {1 Htmikdazzob 24/)-S~pyricin-3-ylaxymathyl) 1, 2.345.8-he xaltydo-E. FRlpyridnd . | . 3Cydohugi-caz-HS phanasymaty-pipeddine . NL : £2 (542.3 Cure tary naz gpa pina pine ylsarybtins
The invention encompasses compounds contemplated by Formula
II, and more specifically those compounds represented by: ® .
LL
Rf” "2" "Ry
Ro aw
Ry = Ry = Ry =
H
' +40 gs 0 4-CHy , 7-0 Fo . +5 0-3- \ ’ HI 0 “ 8 > ° 4-0 (
BY wi, 3", = x
Ry of of- —_ /™N “OL ho oo \~ O- + - nu xr ; = es
Rg |§ o—& []
Rg =H, OH, NH, .
Se
Rs = H, OH, NH, NHCH; < '
Rs = H, OCHs, CH,CH,0H other alkyl, or alkyl ethers (wherein Zis CH or N) 1s
The invention encompasses compounds contemplated by Formula ® I, and more specifically those compounds shown below:
H H
SDS DON sPoue
H
Lo
SUV
LJ
N
H
The invention encompasses compounds contemplated by Formula
I, and more specifically those preferred compounds shown below, . where R in each compound may independently be R; or R;, and ® wherein R,, R,, R; Z are as defined above.
Ry R; R Ry wo | l Lo hg Die I a” he J ) y )
H H pM) ) i i) ra 4 4
TUTTO TO
!
N N N
) )
H H H
I i i
Ro re _R TU ~ ~ RO _R n ( o),, " R . ) F) t
H H h \ i i
R 4 o RR 2 s AR aN 2 _R hy, | R y y y
La : H H \
R < R Ry z R
I
)
H H
The invention encompasses compounds contemplated by Formula ® I, and more specifically those preferred R; groups as shown below. In another more preferred embodiement, Rz is not a halogenated phenyl, benzyl, aryl or heteroaryl.
Co Moraprefarred: 7
A substiiuted 5-memberad heterocycle .' : . (Cabonpointolaliachemant) ©: : = Ny EN IN )
Gg GQ QQ GQ a a
Isoxazole Furan ~~ Oxazole Thlazole Imidazols Pyrazole Tdazde
A substituted 6-mambersd heterncycla . . . {Caan point of altactiament) . - .. ) : ~N xy N co RE . Lo ’ N ’ . . . - . ' A ’ a Pyridine Pyrimidine Pymazine “Triazine : . * wore CL : SE . . A hydroxy substituted phenyl - . Co {Carbost point of nitachement) Co
AH
Co Where the aryliheteroury! substitution Is “smal . ’ Swhas: © . .
So Co One ortwo, sama ordifferants. - © EN © : : Halogen (F, CL, Br) oT
Subslitled C~Ca Alkyl (mathyl, ethyl, tiflucramethyl ,..} Lo : " CCaAllylamino (RHN-) LS
In yet another embodiment, the invention encompasses ® compounds contemplated by Formula I, and more specifically those preferred compounds as shown below. Possible substitutions off of the imidazole ring include aryl and alkyl groups.
H
H N
N go! 0) o
F3C
H H
N N
= NC
Ny 7 5
H
H
J@! KIVY wf ©
F
H
N "9
GW C
(0) “Cy ®
F
In yet another embodiment, the invention encompasses . compounds contemplated by Formula I, and more specifically those ) preferred compounds as shown below.
R
0) g <) hi J 0 ) 0 0 AJ (0) Oo
Nn © N N +R JR R 1 eS | 7 &) Pe R
Z ) x = = lo] 0 or A 0) Oo
N N No © ~ R
Rx Al » P
Het Het H ie 0 AT 0 Or oO
N © N N
R
R
AD AR » =z ~ | Z PP Het or? 0-7 ox” 0) 0] 0)
N N N
R
ZR
Z JEN I 2 £2
N
S of of oof
No © © o)
N N
In another aspect, the invention provides compounds of the formula: . .
N
Js
Oo Ryo =
SLA~
Rap or a pharmaceutically acceptable salt or ester thereof, wherein 2’ is CH or N; wherein Rj; is absent, -OH, or halo; wherein Ryo is C;-g alkyl, Cis alkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycl, substituted heterocycl, phenyl, substituted phenyl, C;.s alkyl-phenyl, or Ci.s alkyl-substittued phenyl.
More preferably, R;, is absent, -OH, or Cl, Br, I or F; further Ry, is selected from the group consisting essentially of -CH;, -CH3;CH,-Ph-O-CH3, -Ph-Ph-CO;H, -Ph-Ph-OCH;, -Ph-Ph-C(CHs)j, -Ph-Ph-0OCF;, -Ph-Ph-F, -Ph-C(=0)-Ph, -Ph-Ph-CN, -Ph-Ph-NH;, -Ph-
C{CH;)3, -CH(CH,CHs) (CH,CHCH.CH3), -CH,CH;Ph, -Ph-0O-Ph, naphthalene, -Ph-Ph-Cl, -Ph-(OCH;3);, -CH;-Ph-OCH;, -CH;-Ph, -Ph-
Ph-S (=0) ;CH;, -Ph-Ph, pyridyl, Ph, Ph-I, -Ph-Ph-S-CH,, -Ph- pyridyl, -Ph-NH,, -Ph-NO;, -Ph-CF;, -Ph-CH;, -Ph-Ph-CF;, -Ph-Ph- (OCH;),, -Ph-OCH;, -Ph-CN, -CH,-O-Ph, -Ph-OCF3;, -CH,-PhF,,
[1 y. — ———Ph—N
ZF :
NW CFs I \ / . .
Ss Ss 4 > ; Re s
In a more preferred embodiement Z is CH. In accordance with this embodiment, a single substituent attached to a Ph-ring is in the ortho position; alternatively, a single substituent attached to a Ph-ring is in the meta position; also alternatively, a single substituent attached to a Ph-ring is in the para position. Further, di-substituents attached to a Ph- ring are in di-meta positions; alternatively, di-substituents attached to a Ph-ring are in a meta and para position.
In another aspect, the invention includes compounds of the formula 0
CT ~~
N
H wherein Rsp is aryl or substituted aryl. More preferably, Rso is selected form the group consisting of -Ph, -PhBr, -Ph-C(CH3);, -
PhF, -PhCl, -PhCN, napthyl, -Ph(CH;):, -Ph-Ph, -PhI, -Ph-OCH;, -
PhCl., -Ph-PhCN, and -Ph-(OCH;).. In accordance with this embodiment, a single substituent attached to a Ph-ring is in the ortho position; alternatively, a single substituent attached to a Ph-ring is in the meta position; also alternatively, a single substituent attached to a Ph-ring is in the para position. ) ® Further, di-substituents attached to a Ph-ring are in di-meta positions; alternatively, di-substituents attached to a Ph-ring are in a meta and para position. :
In yet another embodiment, the invention includes compounds of the formula
Ro ! 0” reo
ZZ
\_/ wherein Reo is aryl, substituted aryl, Ci.¢ alkyl, C;-¢ alkenyl,
C;-¢ cycloalkyl, C,-¢ alkyl-C,.¢ cycloalkyl; and wherein R;; is t-butoxycarbonyl or H. More preferably, Reo is selected from the group consisting of -Ph, -Ph-Ph, napthyl, -Ph-
O0-Ph, -PhC(CH;3)i, anthracinyl, -PhCH;, -Ph(OCH;)., -PhBr, -
PhS (=0) 2CH3;, C(=CH;)CH;, cyclohexyl, -CH;-cyclohexyl, -CH(CH,):, and -CH(CH,CH;),. In accordance with this embodiment, a single substituent attached to a Ph-ring is in the ortho position; alternatively, a single substituent attached to a Ph-ring is in the meta position; also altermatively, a single substituent } attached to a Ph-ring is in the para position. Further, di- substituents attached to a Ph-ring are in di-meta positions; alternatively, di-substituents attached to a Ph-ring are in a meta and para position. :
The compounds of the present invention, and pharmaceutically acceptable salts or esters thereof, are useful for treating humans who have Alzheimer's disease, for helping prevent or delay the onset of Alzheimer's disease, for treating patients with mild cognitive impairment (MCI) and preventing Or @® delaying the onset of Alzheimer's disease in those who would progress from MCI to AD, for treating Down's syndrome, for treating humans who have Hereditary Cerebral Hemorrhage with
Amyloidosis of the Dutch-Type, for treating cerebral amyloid angiopathy and preventing its potential consequences, i.e. single and recurrent lobar hemorrhages, for treating other degenerative dementias, including dementias of mixed vascular and degenerative origin, dementia associated with Parkinson's disease, dementia associated with progressive supranuclear palsy, dementia associated with cortical basal degeneration, diffuse Lewy body type of Alzheimer's disease. It is preferred that the disease is Alzheimer's disease.
The compounds of the present invention are also useful to inhibit beta-secretase and reduce or inhibit the formation of placque.
When treating these diseases, compounds of the present invention can either be used individually or together as is best for the patient.
With regard to these diseases the term "treating" means that compounds of the present invention can be used in humans with existing disease. The compounds of the present invention will not necessarily cure the patient who has the disease but will delay or slow the progression of the disease thereby giving the individual a more useful life span.
The term "preventing" means that that if the compounds of the present invention are administered to those who do not now have the disease but who would normally get the disease or be at increased risk for the disease, they will not get the disease.
In addition, "preventing" also includes delaying the development of the disease in an individual who will ultimately get the disease or would be at risk for the disease. By delaying the onset of the disease, compounds of the present invention have ) prevented the individual from getting the disease during the period in which the individual would normally have gotten the disease or reduce the rate of development of the disease or some of its effects but for the administration of compounds of the present invention up to the time the individual ultimately gets the disease.
In treating or preventing the above diseases the compounds of the present invention are administered in a therapeutically effective amount. The therapeutically effective amount will vary depending on the particular compound used and the route of administration as is known to those skilled in the art. ]
In treating a patient with any of the diagnosed above conditions a physician should begin administration of one or more of the compounds of the present invention immediately and continue indefinitely.
In treating patients who do not at the present have
Alzheimer's disease, but who are believed to be at substantial risk for getting Alzheimer's disease in the future, the physician should start treatment when the patient first experiences early pre-Alzheimer's symptoms such as, memory or cognitive problems associated with aging. In addition, there are some patients who are at high risk because of having the genetic marker APOE4 which is predictive for Alzheimer's disease. In these situations, even though the patient does not have the disease, the administration of the compounds of the present invention should be started before disease symptoms appear and treatment continued indefinitely to prevent or delay them from possibly getting the disease.
The compounds of the present invention can be administered orally, parenterally (IV, IM, depo-IM, SQ and depo-SQ), sublingually, intranasally (inhalation), intrathecally,
topically and rectally. The invention here is the compounds of . the present invention. There is nothing new about the routes of administration nor the dosage forms. Dosage forms known to those ® skilled in the art are suitable for delivery of the compounds of the present invention.
When administered orally, the compounds of the present invention can be administered in usual dosage forms for oral administration as is well known to those skilled in the art.
These dosage forms include the usual solid unit dosage forms of tablets and capsules as well as liquid dosage forms such as solutions, suspensions and elixirs. When the solid dosage forms are used, it is preferred that they be of the sustained release type so that the compounds of the present invention need to be administered only once or twice daily.
The oral dosage forms are administered to the patient one "20 thru four times daily. It is preferred that the compounds of the present invention be administered either three or fewer time, more preferably once or twice daily. Hence, it is preferred that the compounds of the present invention be administered in solid dosage form and further it is preferred that the solid dosage form be a sustained release form which permits once or twice daily dosing. It is preferred that whatever dosage form is used, that it be designed so as to protect the compounds of the present invention from the acidic environment of the stomach.
Enteric coated tablets are well known to those skilled in the art. In addition, capsules filled with small spheres each coated to protect from the acidic stomach, are also well known to those skilled in the art. When administered orally the therapeutically effective amount is from about 0.1 mg/day to about 3,000 mg/day, preferably about 1,000 mg/day. It is more preferred that the : 35 oral dosage is from about 1 mg/day to about 100 mg/day. It is more preferred that the oral dosage is from about 5 mg/day to : about 50 mg/day. It is understood that while a patient may be started on one dose, that dose may have to be varied over time as the patient's condition changes. ® In addition, the compounds of the present invention can be administered parenterally. When administered parenterally they can be administered IV, IM, depo-IM, SQ or depo-SQ. When administered parenterally, the compounds of the present invention should deliver a therapeutically effective amount about 0.5 to about 100 mg/day, preferably from about 5 to about 50 mg daily. When a depo formulation is used for injection once a month or once every two weeks, the dose should be about 0.5 mg/day to about 50 mg/day or on a monthly amount the dose for one month should be from about 15 mg to about 1,500 mg. Because of the forgetfulness of the patients with Alzheimer's disease, it is preferred that the parenteral dosage form be a depo-IM injection.
The compounds of the present invention can be given sublingually. When given sublingually, the compounds of the present invention should be given one thru four times daily in the same amount as for IM administration.
The compounds of the present invention can be given intranasally. When given by this route of administration, the appropriate dosage forms are a nasal spray or dry powder as is known to those skilled in the art. The dosage of the compounds of the present invention for intranasal administration is the same as for IM administration.
The compounds of the present invention can be given intrathecally. When given by this route of administration the appropriate dosage form can be a parenteral dosage form as is known to those skilled in the art. The dosage of the compounds of the present invention for intrathecal administration is the same "as for IM administration.
The compounds of the present invention can be given : topically. When given by this route of administration, the appropriate dosage form is a cream, ointment or patch. Because : of the amount of the compounds of the present invention needed ® to administered the patch is preferred. Further, two or more patches may be needed. When administered topically, the dosage is from about 0.5 mg/day to about 200 mg/day. However, the amount that can be delivered by a patch is limited. Therefore, two or more patches may be required. The number and size of the patch is not important, what is important is that a therapeutically effective amount of the compounds of the present invention be delivered as is known to those skilled in the art. The compounds of the present invention can be administered rectally by suppository as is known to those skilled in the art. When administered by suppository, the therapeutically effective amount is from about 0.5 mg to about 500 mg.
The compounds of the present invention can be administered by implants as is known to those skilled in the art. When administering a compound of the present invention by implant, the therapeutically effective amount is the same as for depot administration.
Again, the invention here is the compounds of the present invention of the present invention. There is nothing novel about the route of administration nor the dosage forms for administering the compounds of the present invention. Given a particular compounds of the present invention, and a desired dosage form, one skilled in the art would know how to prepare the appropriate dosage form for the compounds of the present invention.
The compounds of the present invention are used in the same manner by the same routes of administration using the same pharmaceutical dosage forms and at the same dosing schedule for treating patients with MCI (mild cognitive impairment) and preventing or delaying the onset of Alzheimer's disease in those who would progress from MCI to AD, for treating Down's syndrome, for treating humans who have Hereditary Cerebral Hemorrhage with
Amyloidosis of the Dutch-Type, for treating cerebral amyloid ® angiopathy and preventing its potential consequences, i.e. single and recurrent lobar hemorrhages, for treating other degenerative dementias, including dementias of mixed vascular and degenerative origin, dementia associated with Parkinson's disease, dementia associated with progressive supranuclear palsy, dementia associated with cortical basal degeneration, diffuse
Lewy body type of Alzheimer's disease.
The compounds of the present invention can be used with each other or with other agents used to treat or prevent the conditions listed above. Such agents include gamma-secretase inhibitors, anti-amyloid vaccines and pharmaceutical agents such as donepezil hydrochloride (ARICEPT Tablets), tacrine hydrochloride (COGNEX Capsules) or other acetylcholine esterase inhibitors and with direct or indirect neurotropic agents of the future.
In addition, the compounds of the present invention can also be used with inhibitors of P-glycoproten (P-gp). The use of
P-gp inhibitors is known to those skilled in the art. See for’ ’ example, Cancer Research, 53, 4595-4602 (1993), Clin. Cancer
Res., 2, 7-12 (1996), Cancer Research, 56, 4171-4179 (1996),
International Publications W099/64001 and WO01/10387. The important thing is that the blood level of the P-gp inhibitor be such that it exerts its effect in inhibiting P-gp from : decreasing brain blood levels of the compounds of the present invention. To that end the P-gp inhibitor and the compounds of the present invention can be administered at the same time, by the same or different route of administration, or at different ° times. The important thing is not the time of administration but having an effective blood level of the P-gp inhibitor.
Claims (8)
- WHAT IS CLAIMED IS: N °® 1. A compound of the formula I: Ra Ry : Rs J H (1) or a pharmaceutically acceptable salt or ester thereof, wherein 2 is CH or N; wherein R; and R; are independently: (I) C,-Cio alkyl, optionally substituted with one, two or three substituents independently selected from the group consisting of C;-C; alkyl, -¥, -Cl, -Br, -I, -OH, -SH, -C=N, - CF;, C;-C3 alkoxy, -O-phenyl, -NR;_,R;.;, where Ri.a and R;.p are independently -H or C;-Cg¢ alkyl, -0C=0 NRi-aRi.n, -S(=0)a-2 Ri.a, -NR;..C=0 NR;.aRi.p, -C=0O NR; zRi.p, and -S(=0)2 NRi.aRi.b, - (CHz)o-3-(C3~ Cg) cycloalkyl where cycloalkyl can be optionally substituted with one, two or three substituents selected from the group consisting of C;-C; alkyl, -F, -Cl1, -Br, -I, -OH, -SH, -C=N, - CF, C1-C¢ alkoxy, -O-phenyl, -CO-OH, -CO-0-(C;-C; alkyl), -NR;.aRi.p; Ci1-Ca alkoxy- (Ri-ary1) » Ci1-Cs alkoxy- (Ri-neterocaryl) , (II) -(CH2)pmi- (Ri-ary1) where my is zero or one and where Ri-aryi is phenyl, 1l-naphthyl, 2-naphthyl and indanyl, indenyl, dihydronaphthyl, tetralinyl optionally substituted with one, two, three or four of the following independently selected substituents on the aryl ring: (1) C;-Cs alkyl optionally substituted with one, two or three substituents independently selected from the group consisting of C;-Cy alkyl, -F, -Cl, -Br, -I, -OH, -SH, -S(Cis alkyl), -S(aryl-Ci.¢ alkyl), -S(heteroaryl-C;.¢ alkyl), -S=0(Ci-s alkyl), -S=0O(aryl-Ci.¢ alkyl), -S=O(hetercaryl-C;¢ alkyl). - [ S02{C1¢ alkyl), -SOz(aryl-C;.¢ alkyl), -SO;(heterocaryl-C;.¢ alkyl), -NR;.aR;.p, -C=N, -CF3;, C;-C3 alkoxy, C;-C; alkoxy- (Ri-ary1), C1-Cs alkoxy- (Ri-netercaryl) s (2) C;-Cs alkenyl with one or two double bonds, optionally substituted with one, two or three substituents independently selected from the group consisting of -F, -Cl, -Br, -I, -OH, -SH, -S{(Ci.s alkyl), -S(aryl-Cis alkyl), - S(heterocaryl-C;.¢ alkyl), -S=0(C;-¢ alkyl), -S=0O(aryl-C;.¢ alkyl), -S=0(heteroaryl-C;¢ alkyl), -805(Cy-¢ alkyl), ~-S0;(aryl-Ci-¢ A alkyl), -8S0;(heterocaryl-C;.¢ alkyl), -C=N, -CFi;, C;-C; alkoxy, - NR;-aRi-p, C1-C; alkoxy-(Ri-ary1) , C1-C3 alkoxy- (Ri-neteroary1) , (3) C;-Cs alkynyl with one or two triple bonds, optionally substituted with one, two or three substituents independently selected from the group consisting of -F, -Cl, -Br, -I, -OH, -SH, -S(C.¢ alkyl), -S(aryl-Ci.¢ alkyl), - S (heterocaryl-C,.¢ alkyl), -S=0(C;-¢ alkyl), -S=0O(aryl-C,.¢ alkyl), -S=0 (heterocaryl-Ci-¢ alkyl), -802(C1.¢ alkyl), -80;(axryl-Ci¢ alkyl), -SO,(heteroaryl-C;.¢ alkyl), -C=N, -CF3;, C.-C; alkoxy, - NRi-aRi-p, C1-Ci alkoxy- (Ri-ary1), Ci1-Cz alkoxy- (Ri-neteroaryl) s (4) -F, C1, -Br and -I, (5) -C;-C¢ alkoxy optionally substituted with one, two or three -F, (6) -NRy.2Rn-3 where Ry. and Ry; are as defined below, (7) -CH, (8) -C=N, : (9) C3-C; cycloalkyl, optionally substituted with one, two or three substituents selected from the group consisting of -F, -Cl, -Br, -I, -OH, -SH, -S(C.¢ alkyl), -S({aryl-Ci.¢ alkyl), -S(heteroaryl-Ci.¢ alkyl), -S=0(Ci.¢ alkyl), - S=0(aryl-Ci.s alkyl), -8=0 (heteroaryl-Ci-¢ alkyl), -S02(Ci alkyl), -S0,(aryl-Ci.s¢ alkyl), -SO(heterocaryl-Ci.s alkyl), -C=N, ® -CF;, C3-C; alkoxy, -NRi.aRi.p, Ci1-C; alkoxy- (Ri-amy), Ci1-C3 alkoXy- (Ri-netercaryl) s (10) -CO- (C:-C4 alkyl), (11) -S0;-NR;-aRi-b, (12) -CO-NR;-aR1-b, (13) -S0,-(C;-Cs4 alkyl), (III) -(CHz)ni- (Ri-neteroaryr) Where n, is as defined above and where Rj netercaryr 1s selected from the group consisting of: pyridinyl, pyrimidinyl, quinolinyl, benzothienyl, indolyl, indolinyl, pryidazinyl, pyrazinyl, isoindolyl, isoquinolyl, quinazolinyl, quinoxalinyl, phthalazinyl, imidazolyl, isoxazolyl, pyrazolyl, oxazolyl, thiazolyl, indolizinyl, indazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl, furanyl, thienyl, pyrrolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, oxazolopyridinyl, imidazopyridinyl, isothiazolyl, naphthyridinyl, cinnolinyl, carbazolyl, beta- carbolinyl, isochromanyl, chromanyl, tetrahydroisoquinolinyl, isoindolinyl, isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl, isobenzothienyl, benzoxazolyl, pyridopyridinyl, benzotetrahydrofuranyl, benzotetrahydrothienyl, purinyl, benzodioxolyl, triazinyl, phenoxazinyl, phenothiazinyl, pteridinyl, benzothiazolyl, imidazopyridinyl, imidazothiazolyl, dihydrobenzisoxazinyl, benzisoxazinyl, benzoxazinyl, dihydrobenzisothiazinyl, benzopyranyl, benzothiopyranyl, coumarinyl, isocoumarinyl, chromonyl, chromanonyl, pyridinyl-N-oxide, tetrahydroquinolinyl, dihydroquinolinyl, dihydroquinolinonyl, ) dihydroisoquinolinonyl, dihydrocoumarinyl, dihydroisocoumarinyl, isoindolinonyl, benzodioxanyl,benzoxazolinonyl, pyrrolyl N-oxide, pyrimidinyl N-oxide, pyridazinyl N-oxide, pyrazinyl N-oxide, quinolinyl N-oxide, indolyl N-oxide, indolinyl N-oxide, isoquinolyl N-oxide, ® quinazolinyl N-oxide, quinoxalinyl N-oxide, phthalazinyl N- oxide, imidazolyl N-oxide, isoxazolyl N-oxide, oxazolyl N- oxide, thiazolyl N-oxide, indolizinyl N-oxide, indazolyl N- oxide, Dbenzothiazolyl N-oxide, benzimidazolyl N-oxide, pyrrolyl N-oxide, oxadiazolyl N-oxide, thiadiazolyl N- oxide, triazolyl N-oxide, tetrazolyl N-oxide, benzothiopyranyl S-oxide, benzothiopyranyl S,S-dioxide,where the Ri-neteroaryr group is bonded to -(CHz)mi- by any ring atom of the parent Rj-hetercaryr group substituted by hydrogen such that the new bond to the Ri-netercaryr group replaces the hydrogen atom and its bond, where ‘heteroaryl is optionally substituted with one, two, three or four of:(1) C,-C¢ alkyl optionally substituted with one, two or three substituents independently selected from the group consisting of ¢,-C; alkyl, -F, -Cl, -Br, -I, -OH, -SH, -S(Ci-s alkyl), -S(aryl-C;.¢ alkyl), -S(heteroaryl-C;.¢ alkyl), =-S=0(Ci-¢ alkyl), -8=0O(aryl-C;.¢ alkyl), -S=O(heterocaryl-C;.¢ alkyl), -S0,(C:.¢ alkyl), -S0,(aryl-C;-¢ alkyl), -SO,(heteroaryl-Ci.¢ alkyl), -NR;-aRi.p, -C=N, -CF;, C;-C3 alkoxy, Ci-C3 alkoxy-(Ri-ary1), Ci-Cs alkoxy - (Ri-nheteroaryl) «(2) C;-C¢ alkenyl with one or two double bonds, optionally substituted with one, two or three substituents independently selected from the group consisting of -F, -Cl, -Br, -I, -OH, -SH, -S(C;.¢ alkyl), -S(aryl-C;.¢ alkyl), - S (heteroaryl-C;_¢ alkyl), -S=0(C;.¢ alkyl), -S=0(aryl-C;.s alkyl), -8=0 (heteroaryl-C;_s alkyl), ~S05(C;y-¢ alkyl), -S0; (aryl-Ci-s alkyl), -SO;(heteroaryl-C;¢ alkyl), -C=N, -CF;, C,-C; alkoxy, -NRj-aRi-b, C1-Ciz alkoxy- (Ri-ary1) , Ci1-C3 alkoxy- (Ri-netercaryi)(3) C,-C¢ alkynyl with one or two triple bonds, optionally substituted with one, two or three substituents independently selected from the group consisting of -F, -Cl, -Br, -I, -OH, -SH, -S (Cie alkyl), -S(aryl-Ci.¢ alkyl), - S (heteroaryl-C;.¢ alkyl), -S=0(Ci.¢ alkyl), -S=0O(aryl-Ci alkyl), ® -S=0(heteroaryl-C;_s alkyl), -80, (Ci-s alkyl), -80, (aryl -Ci-s alkyl), -SO,(heterocaryl-C;.¢ alkyl), -C=N, -CF3;, Ci-C3 alkoxy, - NRj_aRi.p, C3-Ci alkoxy- (Ri-ary1), Ci1-Ci alkoxy- (Ri-netercaryl)(4) -F, -Cl1, -Br and -I,(5) -C;-C¢ alkoxy optionally substituted with one, two, or three -F,(6) -NRy_2Rxn-3,(7) -OH, -(8) -C=N,(9) C;-C,; cycloalkyl, optionally substituted with one, two or three substituents independently selected from the group consisting of -F, -Cl, -Br, -I, -OH, -SH, -S(Cy-¢ alkyl), -S(aryl-Ci.¢ alkyl), -S(heteroaryl-C;.¢ alkyl), -S=0(Cis alkyl), - S=0(aryl-C;-¢ alkyl), 5-0 (heteroaryl-Ci alkyl), -805(Ci1-6 alkyl), -S0;(axryl-Ci.¢ alkyl), -850;(heteroaryl-Ci alkyl), -C=N, -CFi;, C;-C; alkoxy, =-NR;-aRi.p, Ci1-Ci alkoxy-(Ri-ary1) , Ci-Ci alkoxy- (Ra-neteroaryl) ,(10) -CO-(Cy-C4 alkyl),(11) -S02-NRi-aRi-b,(12) -CO-NRi-aRi-b,(13) -80,-(C;-Cq alkyl), with the proviso that when n; is zero, Ri-netercaryi 1S not bonded to the carbon chain by nitrogen, .(IV) - (CH) n1- (Ri-neterocycie) Where my is as defined above and Ri-peterocycle 1S selected from the group consisting of: morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S,S-dioxide, piperazinyl, homopiperazinyl,pyrrolidinyl, pyrrolinyl, tetrahydropyranyl, piperidinyl,tetrahydrofuranyl, tetrahydrothi enyl, homopiperidinyl, homomorphol inyl, homothiomorpholinyl, homothiomorpholinylS, S-dioxide, oxazolidinonyl, dihydropyrazolyl, dihydropyrrolyl dihydropyrazinyl dihydropyridinyl dihydropyrimidinyl, dihydrofuryl, dihydropyranyl, ® tetrahydrothienyl S-oxide, tetrahydrothienyl §,S-dioxide, homothiomorpholinyl S-oxide,where the Ri-neterocycie group is bonded by any atom of the parent Rji.peterocycie group substituted by hydrogen such that the new bond to the Ri heterocycie group replaces the hydrogen atom and its bond, where heterocycle is optionally substituted with one, two, three or four:(1) C1-Cs alkyl optionally substituted with one, two or three substituents independently selected from the group consisting of ¢,-C; alkyl, -F, -Cl, -Br, -I, -OH, -SH, - S(Cy-¢ alkyl), -S(aryl-C;-¢ alkyl), -S(heteroaryl-C;.¢ alkyl), - S=0(Ci.¢ alkyl), -S=0(aryl-C,.s alkyl), -S=0 (heteroaryl-Ci._¢ alkyl), -80,(Ci-¢ alkyl), -S0,(aryl-C¢ alkyl), -S0O,(heterocaryl- Ci-¢ alkyl), -NRi_zRip, -C=N, -CFi, Ci1-C3 alkoxy, C;-C; alkoxy- (R;- aryl) , C1-Ci alkoxy- (Ri-neteroaryl) :(2) C;-C¢ alkenyl with one or two double bonds, optionally substituted with one, two or three substituents independently selected from the group consisting of -F, -Cl, -Br, -I, -OH, -SH, -S(Ci.s alkyl), -S(aryl-C,s alkyl), - S(hetercaryl-C,.¢ alkyl), -8S=0(C;.¢ alkyl), -S=0O(aryl-C,.¢ alkyl), -5=0 (heteroaryl-C;.¢ alkyl), -S802(Cy.6 alkyl), -80;(aryl-Cig alkyl), -SO;(heterocaryl-C,¢ alkyl), -C=N, -CF;, C,-C; alkoxy, -NRi-aRi-p, C1-C;3 alkoxy- (Ri-aryi) , Ci-Cs alkoxy- (Ri-netercaryl) :(3) C2-C¢ alkynyl with one or two triple bonds, optionally substituted with one, two or three substituents independently selected from the group consisting of -F, -Cl, -Br, -I, -OH-SH, -S(C;.¢ alkyl), -S(aryl-C;.¢ alkyl), -S(heteroaryl-Ci.¢ alkyl), -S=0(C,.¢ alkyl), -S=O(aryl-Ci.¢ alkyl), -5=0 (heteroaryl-C,.¢ alkyl), -S02(C3-¢ alkyl), -80z (aryl-C;alkyl), -80;(heterocaryl-C;.¢ alkyl), -C=N, -CF;, C;-C; alkoxy, - . NR; .aRi-p, -C1-Cas alkoxy- (Ri-ary1) , Ci1-C3 alkoxy- (Ri-neteroaryl) « (4) -F, -Cl, -Br and -I, ® (5) -C;-C¢ alkoxy optionally substituted with one, two, or three -F, (6) -NRw-2Rn-3, (7) -OH, (8) -C=N, (9) Ca-Cq cycloalkyl, optionally substituted with one, two or three substituents selected from the group consisting of -F, -Cl, -Br, -I, -OH, -SH, -S(Ci-s alkyl), -S(aryl-C;¢ alkyl), -S(heteroaryl-C;.¢ alkyl), -S=0(Ci-¢ alkyl), -S=O(aryl-Ci.¢ alkyl), -S=O(heterocaryl-C;.s alkyl), - S0,(Ci_¢ alkyl), -S0z(aryl-C;.¢ alkyl), -S0;(heteroaryl-C,.¢ alkyl), -C=N, -CF;, C;-C; alkoxy, =-NR;.aRi.p, €Ci1-C3 alkoxy-(Ri-ary1). Ci1-Ci alkoxy- (Ri-neteroaxyl) » (10) -CO-(C3-Cy4 alkyl), (11) -S02-NR;-aRi-p, (12) -CO-NRi_aRi pb, (13) -S02-(Cy-Cs alkyl), ] (14) =0, with the proviso that when n;, is Zero Rj-peterocycie 1S not bonded to the carbon chain by nitrogen; (V) -H; (VI) Ry-1-Xy- where Xy is selected from the group consisting of: (a) -co-, (B) -S0,- where Ry.; is selected from the group consisting of: (A) Ry-aryi where Ry.aryn is phenyl, 1l-naphthyl, 2- naphthyl, tetralinyl, indanyl, dihydronaphthyl or 6,7,8,9- tetrahydro-SH-benzo[alcycloheptenyl, optionally substituted with one, two or three of the following substituents which can be the same or different and are:(1) C;-C¢ alkyl, optionally substituted with one, two or three substituents selected from the group consisting of C;-Cs; alkyl, -F, -Cl, -Br, -I, -OH, -8H, -S(Cis ® alkyl), -S(aryl-C;.s alkyl), -S(heteroaryl-C;.¢ alkyl), -S=0(Ci-s alkyl), -S=0O(aryl-Ci-¢ alkyl), -S=0(heteroaryl-C;.¢ alkyl), - S0,(C;.¢ alkyl), -SO,(aryl-Ci.¢ alkyl), -SO;(heterocaryl-C,.¢ alkyl). -C=N, -CF;, C1-C; alkoxy, -NRy.aR;.p, Ci1-C3 alkoxy-(Ri-ary1), €Ci1-Ca alkoxy- (Rj-heteroaryl) « (2) -OH, (3) -NOz, (4) -F, -C1, -Br, -I, (5) -CO-OH, . (6) -C=N, (7) -(CH2)0-4-CO-NRy-2Rn-3 Where Ry. and Rn are the same or different and are selected from the group consisting of:(a) -H,(b) -C3-Cs alkyl optionally substituted with one substitutent selected from the group consisting of:(i) -OH, (11) -NH,, (¢) -C1-Cs alkyl optionally substituted with one to three groups independently selected from -F, -Cl, -Br, and -I, (d) -C;3-C; cycloalkyl,(e) -{(Ci-C; alkyl) -(C3-Cy cycloalkyl),(£f) -(C1-Ce alkyl) -O-(Ci-C; alkyl),(g) -C2-C¢ alkenyl with one or two double bonds,(h) -C;-Cs alkynyl with one or two triple bonds,(i) -C,-C¢ hydrocarbyl chain with one double bond and one triple bond, . (3) -Ri arya, ® (kK) ~Ri-netercaryis (8) -(CH;)q-4-CO- (C1-C12 alkyl), (9) -(CHz)0-4-CO- (C2-Ci12 alkenyl with one, two or three double bonds), (10) -(CHaz)0-4-CO-(C2-C;2 alkynyl with one, two or three triple bonds), (11) -(CHz)¢-4-CO- (C3-C7 cycloalkyl), (12) -(CHz2)0-4-CO-Ry-ary1, (13) -(CHz) 9-4-CO-R1 heteroaryl, (14) -(CHz) 0-4~CO-Ri-neterocycie: . (15) -(CH2)0-4-CO-Ry.a where Ry, is selected from the group consisting of morpholinyl, thiomorpholinyl, piperazinyl, piperidinyl, homomorpholinyl, homothiomorpholinyl, homothiomorpholinyl S-oxide, homothiomorpholinyl §,S-dioxide, pyrrolinyl and pyrrolidinyl where each group is optionally substituted with one, two, three, or four of C;-Cs alkyl, (16) -(CHz)(-4-CO-0O-Ry-s where Ry.s is selected from the group consisting of: (a) C1-C¢ alkyl, (b) -(CHz)o-2- (Ri-arp) , (c) C2-C¢ alkenyl containing one or two double bonds, (d) C;-C¢ alkynyl containing one or two triple bonds, (e) C3-C; cycloalkyl, (f) - (CH) 0-2- (Ri-petercary1) , (17) -(CHz)0-4-SO2-NRy-2Ry-3, (18) -(CH,)-4-S0- (C;-Cs alkyl), : (19) -(CHz)0-4-50;-(C1-C12 alkyl), (20) -(CHz)-4-S02- (C3-C7 cycloalkyl),(21) -(CHp)-4-N(H or Ry.s )-CO-O-Ry.s where Ry. . can be the same or different, (22) -(CH2)0-4-N(H or Ry.s )-CO-N(Ry.s),, where ( each Ry-s is independently defined herein, (23) - (CH) ¢-4-N-CS-N(Ry.5) 2, where each Ry-s iS independently defined herein,(24) - (CH) 0-4~N(-H or Ry-s) ~-CO-Ry.2, (25) - (CH) o-¢~NRy_2Ry.3,(26) - (CHy) o-e-Ra-a.(27) - (CHa) ¢-4~0-CO- (C,-Cg alkyl),(28) -(CHz)0-4-0O-P (0) - (ORy.1), where Ry, is -H or C;-C, alkyl,(29) -(CHz)-4-0-CO-N (Ry-s) 2,(30) - (CHa) 0-4-0~CS-N (Ry-5) 2,(31) -(CHaz)0-4-0- (Ru-s) 2,(32) -(CHz2)¢-4-0~-( Ry.s)2-COOH, (33) -(CH2)0-4-S-( Ru-s) 2, (34) ~ (CH) 0-4-0- (C1-Cs alkyl optionally substituted with one, two, three, four, or five of -F),(35) C3-C; cycloalkyl,(36) C2-Cs alkenyl having one or two double bonds and which is optionally substituted with C1-C; alkyl, -F, -Cl, -Br, -I, -OH, -SH, -S(C;.¢ alkyl), -S(aryl-Ci. alkyl), - S (hetercaryl-Ci.¢ alkyl), -S=0(C;.¢ alkyl), -8=0(aryl-C;.¢ alkyl), -S=0(heteroaryl-C,.¢ alkyl), -S02(Ci.¢ alkyl), -S0; (axryl-C;_¢ alkyl), -SO;(heteroaryl-C;.¢ alkyl), -C=N, -CF3, C1-C; alkoxy, - NR3-aRi-b, C1-C; alkoxy- (Ri-ary1) , C1-C; alkoxy- (Ri-neteroaryl) :: (37) C2-Cs alkynyl with one or two triple bonds optionally substituted with C1-C; alkyl, -F, -C1, -Br, -I, -OH, -SH, -8(Ci.¢ alkyl), -S(aryl-C;¢ alkyl), -S (heteroaryl-c,alkyl), -S=0(Ci alkyl), -S=O(aryl-Cis alkyl), -S=0(heteroaryl-Ci-¢ alkyl), =~ -50,(Ci¢ alkyl), -80; (aryl-Ci_¢ alkyl), -5S SOz(heterocaryl-C;.¢ alkyl), -C=N, -CFi;, C;-C3 alkoxy, -NRj-aRi-b, C1-C3 alkoxy- (Ri-ary1),» C1-Ci alkoxy- (Ri-neteroaryl) (38) -(CH3)¢-4-N(-H or Ry.s)-SO,-Ry.,, OT ® (39) -(CHz)g-4- C3-Cy; cycloalkyl, (B) -Ry-neteroaryl Where Ry.netercaryy Carries the same definition as Ri-netercaryl, Where the Ry-hetercaryi group is bonded by any atom of the parent Ry-netercaryr group substituted by hydrogen such that the new bond to the Ry heteroaryl group replaces the hydrogen atom and its bond, where heteroaryl is optionally substituted with one, two, three, or four groups independently selected from:(1) C1-Cs alkyl, optionally substituted with one, two or three substituents selected from the group consisting of C,-C; alkyl, -F, -Cl, -Br, -I, -OH, -SH, -S(Ci alkyl), -S(aryl-Ci.¢ alkyl), -S(heterocaryl-C;.¢ alkyl), -S=0(Cis alkyl), -S=O(aryl-Ci¢ alkyl), -S=O(heteroaryl-C;.¢ alkyl), - S02 (C16 alkyl), -S0:(aryl-C;-¢ alkyl), -SO,(heteroaryl-C,.¢ alkyl), -C=N, -CF;, C;-C; alkoxy, and -NR;.zR;.p, C:i-C; alkoxy- (Ri-ary1) , Ci- C3 alkoxy- (Ri-netercary1) ,(2) -OH,(3) -NOg, }(4) -F, -Cl, -Br, -I,(5) -CO-OH,(6) -C=N,(7) - (CHz) 9-4-CO-NRy-zRx-3,(C) Ry-ary1-W-Rn-ary1,(D) Rn-ary1-W-Ry-netercaryl. (E) Ry-ary1-W-Ry-neterocycle. where Ry. peterocycle iS the same as Rj _neterocycle (F) Ry-heteroary) ~W-Ry-ary1, (G) Ry-heteroaryl “W-Ry-heteroaryl (H) Ru-neteroaryl ~W-Ru_neterocycles (I) Ru-neterocycle-W-Rn-aryi,(J) Ru-heterocycle” W-RN-neteroaryl (K) Rn-neterocycie~ W-Ru_neterocycie, and where W is ® (1) -(CHz2)o-s-, (2) -0O-, (3) -S(0)o-2-, (4) -N(Rn-s)-, or (5) -CO-; : (VII) -(CRec-xRec-y)o-4-Re-ary1 where Re.x and Rc., are -H, C;-Cs alkyl optionally substituted with one or two -OH, C1-C, alkoxy optionally substituted with one, two, or three of -F, - (CHz) 0-4-C3-C; cycloalkyl, C2-C¢ alkenyl containing one or two double bonds, C;-C¢ alkynyl containing one or two triple bonds, phenyl, and where Rc.x and Rey are taken together with the carbon to which they are attached to form a carbocycle of three, four, five, six and seven carbon atoms, optionally where one carbon atom is replaced by a heteroatom selected from the group consisting of -0-, -S-, -S802-, -NRy.2- and Rc.aryi is the same as Ry-ary1i (VIII) - (CRc-xRc-y) 0-4~Re-ary1-Re-aryl + (IX) -{CRc-xRc-y) 0-a~Rc-ary1~Re-hetercaryl (X) - (CRe-xRe-y) 0-4-Re-neteroaryl ~Re-ary1 - (XI) - (CRc-xRec-y) 0-4-Re-hetercaryl=Re-heteroaryl s (XII) - (CRc-xRe-y) 0-4-Re-aryl~Re-neterocycle @nd Re-neterocycle 18 the same as Ry.neterocycle, (XIII) - (CRc-xRc-y) 0-4~Re-heteroaryl=Re-heterocycles : (XIV) - (CRc-xRe-y) 0-4-Re-neterocycle-Re-aryl,(XV) - (CRc-xRe-y) 0-4~Re-heterocycle~Re-heteroaryl N (XVI) -(CRc-xRec-y) 0-4-Re-heterocycie~Re-heterocycles (XVII) -[C(Rc-1) (Rc-2)]11-3-CO-N-(Rc¢.3)2 where Re. and Rc-2 ® are the same or different and are selected from the group consisting of: (aA) -H,(B) -C1-Cs alkyl, optionally substituted with one, two or three substituents selected from the group consisting of (;-C; alkyl, -F, -Cl, -Br, -I, -OH, -SH, -S(Ci-g alkyl), -S(aryl-C,.s alkyl), -S(heteroaryl-C;.s alkyl), -S=0(Ci-s alkyl), -S8=0O(aryl-Cy.¢ alkyl), -S=O(heterocaryl-C,.¢ alkyl), - S02(Ci.¢ alkyl), -S0,(aryl-C,.¢ alkyl), -SO,(heterocaryl-C,.¢ alkyl), -C=N, -C¥F;, C.-C¢ alkoxy, -O-phenyl, -NR;_ Rip, C;-C; alkoxy- (Ri- aryl) » C1-C3 alkoxy- (Ri-neteroaryi) /(C) C2-C¢ alkenyl with one or two double bonds,optionally substituted with one, two or three substituents selected from the group consisting of C,-C; alkyl, -F, -Cl, -Br, -I, -OH, -SH, -8(Ci¢ alkyl), -S(aryl-Ci.¢ alkyl), -S(heteroaryl- Ci alkyl), -S=0(Cy_¢ alkyl), -8=0(aryl-Ci.¢ alkyl), - S=0 (heteroaryl-C; ¢ alkyl), -S0, (C16 alkyl), -80; (aryl-Ci¢ alkyl), -80; (heterocaryl-C;.¢ alkyl), -C=N, -CF;, C1-Cs¢ alkoxy, -O- phenyl, -NRi-aRi.p, C1-C3; alkoxy- (Ri-ary1) , Ci-C3 alkoxy- (Ri-netercary1) ,(D) - (CHz) 0-4-C3-Cy cycloalkyl, optionally substituted with one, two or three substituents selected from the group consisting of C;-C; alkyl, -F, -Cl, -Br, -I, -OH, -SH,-S(Ci.¢ alkyl), -S(aryl-C,.¢ alkyl), -S(heteroaryl-C;.¢ alkyl), - 8=0(Ci-¢ alkyl), -S=0(aryl-Ci-¢ alkyl), -5=0 (heteroaryl-C;_ alkyl), -S02(Ci.s alkyl), -S0;(aryl-Cis alkyl), -SO;(heteroaryl- Ci-¢ alkyl), -C=N, -CFi;, C;-C¢ alkoxy, -O-phenyl, -NR;.-.R;.p, C1-Cs alkoxy- (Ri-ary1) , C1-Cs alkoxy- (Ri-netercaryl) ,(BE) -(C-C, alkyl)-Rci-aryy where Rercaryt 18 as defined for Rj-aryi: } ’(F) -(C1-Cs alkyl) -Rc-heteroaryls(G) -(C1-Cy alkyl) ~Re-heterocyele: } (H) -Rc-netercaryl: (I) -Rec-heterocycie, and ® (3) ~Rer-am, and where Rc.3 is the same or different and is: (A) -H, (B) -C1-Cs alkyl optionally substituted with one, two or three substituents selected from the group consisting of C1-C3 alkyl, -F, -C1, -Br, -I, -OH, -SH, -S(Ci¢ alkyl), -s{aryl- Cys alkyl), -S (heteroaryl-C;.¢ alkyl), -8=0(C;.¢ alkyl), - 8S=0(aryl-C;_¢ alkyl), -8=0 (heteroaryl-C;. alkyl), ~802(Cy.6 alkyl), -S0;(aryl-Ci¢ alkyl), -SO,(heteroaryl-C,.¢ alkyl), -C=N, -CF3, C3-C¢ alkoxy, -O-phenyl, and -NRi.aRip, Ci1-C; alkoxy- (Ry. aryl); C1-C3 alkoxy- (Ri-heteroary1) (C) -(CHz2)0-4-C3-C; cycloalkyl, (D) -(Ci-C¢ alkyl) -Reiarp, (E) -(C1-C¢ alkyl) -Rc-hetercaryl, OX (F) -(Cy-Cs alkyl) -Rc-neterocycle; (XVIII) -(CH2) o-Q-(CHz) p-B, where o and p are independently integers of 1-4, Q is 0, §, SO, SOz, NR, and B isC.¢ alkyl, aryl, heteroaryl, or heterocycle; (XIX) -O-Ry, =-S-Ry, -NH-Ry;, or N(Rs),; (XXVII) -0C(=0)-Ry (XXVIII) -C(=0)O0-R, (XXIX) ~N (Rg) C (=O) -Rs (XXX) ~C(=0) N (Rg) -Ry (XXX1) ~S02N (Rg) C(=0) -Re (XXXII) -C(=0)N (Rg) SO;-Rsg (XXXITII) -SO3-Rs; wherein Rg; is defined as H or C1-C¢ alkyl optionally substituted with one to three groups independently selected from -OH, -NH,, -F, -Cl, -Br, and -I; wherein Ry is defined as (I)- (XVIII) above and wherein R; is is C, to Cs alkyl , cyclohexyl, cyclopentyl, pyridinyl, phenyl, isoxazole, pyrazole, furan, thiophene, and other five and six membered heterocycles containing carbon, ® nitrogen, oxygen and sulfur, said C, to Cg alkyl, cyclohexyl, cyclopentyl, pyridinyl, phenyl, furan, thiophene may be optionally substituted with one, two or three radicals selected from CF;, OCF;, hydroxyl, halo, C;.,-alkyl, Ci-2-haloalkyl, cyano, carboxyl, C;.;-alkoxycarbonyl, C,_;-hydroxyalkyl, thioalkyl, aminosulfonyl, C;.;-alkylaminosulfonyl, methyl C, ,-haloalkoxy, amino, Cj.p-alkylamino, phenylamino, nitro, Cj;.;-alkoxy-C;.,-alkyl,Ci.z-alkylsulfinyl, C;.;-alkoxy and C;-3-alkylthio.
- 2. A compound according to claim 1, wherein at least one of R;, Ry, or R; is H.
- 3. A compound accorind to claim 1, wherein at least two of R;, R; or R; is H.
- 4. A compound according to claim 1, wherein R; and R; are independently: (I) -(CH2)mi-~ (Ri-ary1), where n; is zero or one and where Ri-arya is phenyl, 1l-naphthyl, 2-naphthyl, indanyl, indenyl, dihydronaphthalyl, or tetralinyl optionally substituted with one, two, three, or four of the following substituents on the aryl ring: (A) Ci-Cs alkyl optionally substituted with one, two or three substituents selected from the group consisting of C-C; alkyl, -F, -Cl, -Br, -I, -OH, -SH, -C=N, -CF;, C,;-Cs alkoxy, and -NRi-aRi.p, Ci1-C; alkoxy- (Ri.aryjy), Ci-C3 alkoxy- (R;- heteroaryl) s (B) C2-Cs alkenyl with one or two double bonds, optionally substituted with one, two or three substituents selected from the group consisting of -F, -Cl, -Br, -I, ~-OH, -SH, -C=N, -CF;, C;-C; alkoxy, and -NR;-aRi-p, Ci-C3 alkoxy- (Ri-ary1) C1-C3 alkoxy - (Ri-netercaryl) , . (C) C2-Cs alkynyl with one or two triple bonds, ( optionally substituted with one, two or three substituents selected from the group consisting of -F, -Cl, -Br, -I, -OH, - SH, -C=N, -CF;, C;-Ci alkoxy, and -NR;.aRi.p, Ci-C3 alkoxy- (Ri-ary1) C1-C; alkoxy- (Ri-netercaryl) (D) -F, C1, -Br, or -I, (BE) -C3-C¢ alkoxy optionally substituted with one, two, or three -F, (F) —-NRy-zRy-3, where Ry. and Ry.; are independently selected from the group consisting of: . (1) -H, (2) -C3-C¢ alkyl optionally substituted with one substituent selected from the group consisting of: (a) -OH, and (b) -NH:, (3) -C1-C¢ alkyl optionally substituted with one to three -F, -Cl, -Br, or -I, (4) -C3-C; cycloalkyl, (5) -(C;-Cz alkyl) - (C3-Cy cycloalkyl), (6) -(C1-Cs alkyl) -0-(C1-C3 alkyl), (7) -C;-C¢ alkenyl with one or two double bonds, (8) -C,-C¢ alkynyl with one or two triple bonds, (9) -C1-C¢ alkyl chain with one double bond and one triple bond, (10) -Rj-ary1, where Rj.ary) is as defined above, and (11) -Ri-netercaryl: ’ (G) -CH, (H) -C=N,(I) C3-C; cycloalkyl, optionally substituted with one, two or three substituents selected from the group consisting of -F, -Cl, -Br, -I, -OH, -SH, -C=N, -CF;, -NR;-aRi-b: ® Ci-C3 alkoxy, Ci-C; alkoxXy- (Ri-ary1), C1-Cs alkoxy- (Ri-peteroaryl) : (K) —-CO-(C;-Cq alkyl), (L) —-S02-NRj-aRj-p, (M) —-CO-NR;i-2R:.n, or (N} -80,-(C;-C4 alkyl), or (II) -(CHz)ni- (Ri-hetercaryi) , Where n; is zero or one and where Ri.petercaryr is selected from the group consisting of: pyridinyl, pyrimidinyl, quinolinyl, benzothienyl, indolyl, indolinyl, pryidazinyl, pyrazinyl, isoindolyl, isoquinolyl, quinazolinyl, quinoxalinyl, phthalazinyl, imidazolyl, isoxazolyl, pyrazolyl, oxazolyl, thiazolyl, indolizinyl, indazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl, furanyl, thienyl, pyrrolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, oxazolopyridinyl, imidazopyridinyl, where the Ri-netercaryn group is bonded to ~ (CHj) pi- by any ring atom of the parent Ri-hetercaryr group substituted by hydrogen such that the new bond to the Ri-hetercaryr group replaces the hydrogen atom and its bond, where heteroaryl is optionally substituted with one, two, three, or four of:(1) C1-C¢ alkyl optionally substituted with one, two or three substituents selected from the group consisting of C1-C; alkyl, -F, -Cl, -Br, -I, -OH, -SH, -C=N, -CF;, GC;-C,alkoxy, and -NR;.aRi.p, Ci1-C; alkoxy, C,-C; alkoxy- (Ri-ary1) , C1-Ca alkoxy- (Ri-neteroaryl)) (2) C;-Cs¢ alkenyl with one or two double bonds, optionally substituted with one, two or three substituents selected from the group consisting of -F, -Cl, -Br, -I, -OH, -SH, -C=N, -CF3, C1-C; alkoxy, and -NR; .R;.,, where R;., and Ri.p are “H or C-C¢ alkyl, €-C; alkoxy, Ci-C; alkoxy- (Ream), Cy-C, alkoxy- (Ri-netercaryl)(3) C.-Cs alkynyl with one or two triple bonds, optionally substituted ‘with one, two or three substituents selected from the group consisting of -F, -Cl, -Br, -I, -OH, - ® SH, -C=N, -CF3, C;-Ci alkoxy, and -NRj-sR;.n, where R;., and R;.p are -H or C;-C¢ alkyl, C;-Ci alkoxy, Ci-C3 alkoxy-(Ri.amy1), Ci1-Ca alkoxy- (Ri-neteroaryl) (4) -F, Cl, -Br, or -I, (5) -C1-Cg alkoxy optionally substituted with one, two, or three -F, (6) —NRy-2Rn-3, (7) -OH, (8) -C=N, (9) C3-C; cycloalkyl, optionally substituted with one, two or three substituents selected from the group consisting of -¥, -Cl1, -Br, -I, -OH, -SH, -C=N, -CF;, C;-C3 alkoxy, and -NR;.,R;.n, where R;.. and R;.p are -H or C;-Cg¢ alkyl, C;-C3 alkoxy, C;-C; alkoxy-(Ri-aryi), Ci1-Ci alkoxy- (Ri-netercaryi) : (10) -CO-(Ci-Cs alkyl), (11) -SO0;-NRi-aRi-b, (12) -CO-NR3i-aRi.p, OFX (13) -S0,-(C1-C, alkyl) , with the proviso that when n; is zero Rj petercaryi 18 not bonded to the carbon chain by nitrogen.
- 5. A compound according to claim 1, wherein R; and Rj; are independently: phenyl, 1l-naphthyl, 2-naphthyl, tetralinyl, indanyl, dihydronaphthyl or 6,7,8,9-tetrahydro-SH- benzo [a] cycloheptenyl, each of which is optionally substituted with one, two or three of the following substituents which can be the same or different and are: (1) Ci-C¢ alkyl, optionally substituted with one, two or three substituents selected from the group consisting of ¢;-C; alkyl, -F, -Cl, -Br, -I, -OH, -SH, -C=N, - CF3, C-C3 alkoxy, and -NR;..Ri.p, C:i-Cs alkoxy- (Ri-ary1) , C1-Cs alkoxy - (Ri-neteroaryl) ® (2) -OH, (3) -NOg, (4) -F, -C1, -Br, or -I, (5) -CO-OH, (6) -C=N, (7) -(CHz) 0-4-CO-NRy-2Rn-3, (8) -(CHz),-4~CO- (C1-C13 alkyl), (9) -(CH2) 4-4-CO- (C5-Cy, alkenyl with one, two or three double bonds), (10) -(CH;)¢-4-CO- (C3-C32 alkynyl with one, two or three triple bonds), (11) ~- (CH) ¢-4-CO- (C3-C5 cycloalkyl), (12) - (CH) 0-a-CO-Ri-ary1, (13) - (CH) 0-4=-CO-Rj_nheterocaryl, (14) - (CH,) 9-4-CO-Ri heterocycle; (15) -(CH3)¢.4-CO-Ry., where Ry-4 is selected from the group consisting of morpholinyl, thiomorpholinyl, piperazinyl, piperidinyl, homomorpholinyl, homothiomorpholinyl, homothiomorpholinyl S-oxide, homothiomorpholinyl S,S-dioxide, pyrrolinyl and pyrrolidinyl where each group is optionally substituted with one, two, three, or four of: C1-Cs alkyl, (16) -(CHz)-4-CO-O-Ry.s where Ry.s is selected from the group consisting of: (a) C1-Cs alkyl, (b) -(CH2) 0-2- (Ri-ary1) , (c) C2-C¢ alkenyl containing one or two double bonds, (d) C;-C¢ alkynyl containing one or two triple bonds, (e) C;.C; cycloalkyl, and(£) -(CH2)o-2- (Ri-hetercary1) / .. . (17) -(CH2) 0-4-SO2-NRy-2Rx-3, (18) -(CH;)-4-SO-(Cy-Cs alkyl), @® (19) -(CHz)0-4-S0,-(C1-C;, alkyl), (20) - (CHz)-4-S02-(C3-C; cycloalkyl), (21) -(CH2)0-4-N(H Or Ry.s )-CO-O-Ry.s where Ry- s can be the same or different, (22) -(CHz)0-4-N(H or Ry-s )-CO-N(Ry.s),, where Ry-s can be the same or different, (23) -(CH;)0-4-N-CS-N(Ry-s)2, where Ry.s can be the same or different, (24) - (CH2) g-4-N(-H or Ry.5) -CO-Ry., where Ry-s and Ry., can be the same or different, (25) -(CHz) 0-4-NRy-2Ry-3 where Ry.» and Ry.; can be the same or different, (26) -(CH:)0-4-Ru-4, (27) - (CH) -4-0-CO- (C;-C¢ alkyl), (28) -(CHz2)0-4-0-P (0) - (ORy-ary1-1) 2 Where Ry-aryi-1 is -H or C,-C4 alkyl, (29) -(CHz)0-4-O-CO-N(Ry-s5) 2, (30) -(CH;)0-4-0O-CS-N(Ry-s) 2, (31) -(CHz2)o0-4-0- (Ry-s) 2, (32) -(CH;)o0-4-0O-( Ry-s)2-COOH, (33) -(CHz)0-4-5S-( Ru-s)2, (34) -(CH;)0-4-0-(C3-C¢ alkyl optionally substituted with one, two, three, four, or five -F), (35) C3-C; cycloalkyl, (36) C3-Cs alkenyl with one or two double bonds optionally substituted with C;-C; alkyl, -F, -Cl, -Br, -I, -OH, -SH, -C=N, -CF;, C1-C; alkoxy, or -NRi-sRi.n, C;-C; alkoxy- (R,. ami), C1-C3; alkoxy- (Ri-neteroary1) « (37) Cp-Cs¢ alkynyl with one or two triple bonds optionally substituted with C;-C; alkyl, -F, -Cl, -Br, -I,-OH, -SH, -C=N, -CFs3, C;-C; alkoxy, or -NR;.aRi-p, Ci-C; alkoxy- (Ri- aryl) , C1-C; alkoxy-(Ri-netercaryl) , - (38) -(CH.)(-4-N(-H or Ry.s) -SO,-Ry.; where Ry-s ® and Ry, can be the same or different, or (39) -(CH;)¢.4- Ci-Cy cycloalkyl.
- 6. A compound according to claim 1, wherein R; and R; are independently Ry-1:C(0O) -; and Ry-1 1S Ru-heterocaryl Where Ry-hetercaryl 1S selected from the group consisting of: pyridinyl, pyrimidinyl, quinolinyl, benzothienyl, indolyl, indolinyl, pryidazinyl, pyrazinyl, isoindolyl, ] isoquinolyl, quinazolinyl, quinoxalinyl, phthalazinyl, imidazolyl, isoxazolyl, pyrazolyl, oxazolyl, thiazolyl, indolizinyl, indazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl, furanyl, thienyl, pyrrolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, oxazolopyridinyl, imidazopyridinyl, isothiazolyl, naphthyridinyl, cinnolinyl, carbazolyl, beta-carbolinyl, isochromanyl, chromanyl, tetrahydroisoquinolinyl, isoindolinyl, isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl, isobenzothienyl, benzoxazolyl, pyridopyridinyl, benzotetrahydrofuranyl, benzotetrahydrothienyl, purinyl, : benzodioxolyl, triazinyl, phenoxazinyl, phenothiazinyl, pteridinyl, benzothiazolyl, imidazopyridinyl, imidazothiazolyl, dihydrobenzisoxazinyl, benzisoxazinyl, benzoxazinyl, dihydrobenzisothiazinyl, benzopyranyl, benzothiopyranyl, coumarinyl, where the Ry-netercaryt group is bonded by any atom of the parent Ry-neteroaryl group substituted by hydrogen such that the new bond to the Ry.petercaryi group replaces the hydrogen atom and its bond, where heteroaryl is optionally substituted with one, two, three, or four of: . (1) C;-C¢ alkyl, optionally substituted with ® one, two or three substituents selected from the group consisting of C,-C; alkyl, -F, -Cl, -Br, -I, -OH, -SH, -C=N, - CFs, C;-C3 alkoxy, and -NR;.aRi.p, C1-C3; alkoxy- (Ri-ama), Ci-Ca alkoxy- (Ri-hetercaryl) « (2) -OH, (3) -NOg, (4) -F, -Cl, -Br, or -1 (5) -CO-OH, (6) -cC=N, (7) -(CHz) ¢-4-CO-NRy-2Ry-3, (8) -(CHz)0-4-CO-(C1-Ci2 alkyl), (9) -(CH;)¢-4-CO- (C2-C;1, alkenyl with one, two or three double bonds), (10) = (CHz)0-4-CO- (C3-Cy; alkynyl with one, two or three triple bonds), (11) -(CHz2)0-4-CO-(C3-C; cycloalkyl), (12) - (CHz) 0-4-CO-Ry-ary1, (13) - (CH) 0-4-CO-Ri-netercaryl: (14) -(CHz) 0-4-CO-Ri-neterocycle: (15) ~-(CH2) ¢-4-CO-Ry-4, (16) -(CHz)0-4-CO-0O-Ry.s, (17) -(CHz) 0-4-S02-NRy-2Rx-3, (18) -(CHz)0-4-SO-(C1-Cg alkyl), (19) -(CHz)0-4~802-(C1-Cy2 alkyl), (20) -(CHz) 0-4-802- (C3-C; cycloalkyl), (21) -(CHz)0-4-N(H or Ry.s ) -CO-O-Ry.s where Ry. s can be the same or different, (22) -(CHz)0-4-N(H or Ry.s ) -CO-N{Ry.s)2, where ) Ry-s can be the same or different,y (23) -(CH,) 0-¢~-N-CS-N(Ry.s)2, where Ry.s can be the same or different, (24) - (CH) g-4~N(-H or Ry.5) ~-CO-Ry-» where Ry-s @ and Ry., can be the same or different, (25) -(CH,) g-4-NRy_2Ry-3 where Ry. and Ry.; can be the same or different, (26) -(CHz2)o-a~Rn-4: (27) - (CH) 0-4-0-CO-(C;-C¢ alkyl), (28) -(CHz)-4-0-P (O) - (ORy-ary1-1) 2 where Ry-aryl-1 is -H or C,-C,; alkyl, (29) - (CH3) 6-4-0-CO-N{(Ry-s5) 2, (30) -(CH2)0-4-0-CS-N(Ry-s) 2, (31) -(CH2)0-4-O- (Rn-s) 2, (32) -(CHz)¢-4-0-( Ry.s) 2- COOH, © (33) -(CH2)0-4-S-( Rys)2, (34) -(CHz)0-4-0-(C1-C¢ alkyl optionally substituted with one, two, three, four, or five -F), (35) C5-Cq cycloalkyl, (36) C3-Cs alkenyl with one or two double bonds optionally substituted with C,-C; alkyl, -F, ~Cl, -Br, -I, -OH, -SH, -C=N, -CF;, C;-C; alkoxy, or -NR;.;Ri.p, C1-C; alkoxy- (R;- ary1) + C1-Cs alkoxy- (Ri-heteroary1) s ; (37) C;-Cs alkynyl with one or two triple bonds optionally substituted with C,-C; alkyl, -F, -Cl, -Br, -I, -OH, -SH, -C=N, -CF;3;, C;-C; alkoxy, or -NR;-aRi-p, C1-C3 alkoxy- (R;- army1), Ci-C; alkoxy- (Ri-netercaryl) , (38) -(CH3)-4-N{(-H or Ry.s) -S02-Ry., where Ry.s and Ry-z can be the same or different, or (39) -(CHz)¢-4- C3-C; cycloalkyl.
- 7. A compound according to claim 1, wherein R, and R; are independently Ry-1C (0) -; and Ry; is phenyl, l1-naphthyl, or 2- naphthyl, each of which is optionally substituted with one, two or three of the following ‘substituents which can be the same OT different and are: (1) C;-C¢ alkyl, optionally substituted with J one, two or three substituents selected from the group consisting of C.-C; alkyl, -F, -CI, -Br, -I, -OH, -SH, -Cc=N, - CF3, C;-C3; alkoxy, and -NR;.aRyp, Ci1-C3 alkoxy-(Ri-ama)., Ci1-GCs alkoxy- (Ri-hetercaryl) . (2) -OH, (3) -NOg, (4) -F, -Cl1, -Br, or -I, (5) -CO-OH, (6) -C=N, (7) - (CHz)0-4-CO-NRy.2RN-3, . (8) -(CHz)0-4-CO-{C1-Cy2 alkyl), (9) -(CH;)p.4-CO-(C,-Cy, alkenyl with one, two or three double bonds), (10) - (CH3)-4-CO-(C2-Cy2 alkynyl with one, two or three triple bonds), (11) - (CH) -4-CO-(C3-Cy cycloalkyl), (12) -(CHz)0-4-CO-Ri.ary1, (13) -(CHz) 0-4-CO-Ri-neteroaryl, (14) = (CHa) o-¢~CO-Ry-neterocycte (15) -(CHp)o-4-CO-Ry-4 where Ry-4 is selected from the group consisting of morpholinyl, thiomorpholinyl, piperazinyl, piperidinyl, homomorpholinyl, homothiomorpholinyl, homothiomorpholinyl S-oxide, homothiomorpholinyl S,8-dioxide, pyrrolinyl and pyrrolidinyl where each group is optionally gubstituted with one, two, three, or four of: C;-C¢ alkyl, (16) -(CHz)0-4-CO-0O-Ry.s where Ry-s is selected from the group consisting of: ) (a) C;-C¢ alkyl, (b) - (CHa) 0-2- (Ri-ary1) ,(c) C,-Cs alkenyl containing one or two double bonds, {(d) C,-Cs alkynyl containing one or two ® triple bonds, (e} C3-C; cycloalkyl, and (£) -(CH2)o-2- (Ri-neteroaryl) , (17) -(CHz) 0-4-SO2-NRy-2RN-3, (18) - (CH3)(-4-SO- (C1-Cg alkyl), - (19) - (CHz) 0-4-80a- (C1-Czz alkyl), (20) -(CH2)0-4-S02- (C3-C; cycloalkyl), (21) - (CH) ¢-4-N(H or Ry-s )-CO-0O-Ry.s where Ry. s can be the same or different, (22) -(CH3)9-4-N(H or Ry-s )-CO-N{Ry-s)., where Rx-s can be the same or different, (23) -(CH3)0-4-N-CS-N(Rn.s)2, where Ry.g can be the same or different, (24) -(CH2)0-4-N(-H or Ry.s)-CO-Ry., where Ry-s and Ry. can be the same or different, (25) -(CH;)0-4-NRy-2Ry-3 where Ry. and Ry.3; can be the same or different, (26) -(CHz)o0-4-Ry-4. (27) - (CH) 0.4-O-CO- (C;-Cs alkyl), (28) -(CHz2)0-4-O-P (0) ~ (ORy-ary1-1) 2 where Ry.ary1-a is -H or C,-C4 alkyl, (29) -(CH;)-4-O-CO-N(Ry-5) 2, (30) -(CH2)0-4~-O-CS-N(Ry-5) 2, (31) -(CHz)0-4-O- (Ru-s) 2, (32) -(CHz)0-4-O-( Ry-s)2-COOH, : (33) -(CHz)0-4-S-( Ru.s5)2, (34) - (CH) ¢-4-O- (C1-Cs alkyl optionally substituted with one, two, three, four, or five -F), (35) C;-C; cycloalkyl, :(36) C2-C¢ alkenyl with one or two double . bonds optionally substituted with C;-C; alkyl, -F, -Cl, -Br, -I, PS -OH, -SH, -C=N, -CF;, C,-C; alkoxy, or -NRi.aRi.p, Ci-Cs alkoxy- (Ri- aryl) , C1-C3; alkoxy - (Ri-neteroary1) s (37) C;-Cs alkynyl with one or two triple bonds optionally substituted with C;-Cs alkyl, -r, -Cl, -Br, -I, -OH, -8H, -C=N, -CF3, C;-C; alkoxy, or -NR;_,Ri., C;-Cs alkoxy- (Ri- aryl) , C1-C3 alkoxy - (Ryi-heteroaryl) « (38) ~-(CH:)0-4-N(-H Or Ry.g) -SO,-Ry.; where Ry-s and Ry. can be the same or different, or (39) - (CHz)g-4~- C3-C, cycloalkyl.8. A compound according to claim 1, wherein R; and R; are independently Ry.1C(0) -; andRy.1 is phenyl optionally substituted with one, two or three of the following substituents which can be the same or different and are: (1) Ci1-C¢ alkyl, optionally substituted with one, two or three substituents selected from the group consisting of C;-C; alkyl, -F, -Cl, -Br, .-I, -OH, -8H, -C=N, - CF3, C1-C3 alkoxy, and -NR;-aRj;.p, Ci-Cs alkoxy- (Ricary1) , C1-Cs; alkoxy- (Ri-netercaryl) r (2) -OH, (3) -NO2, (4) -F, -Cl, -Br, or -I, (5) -CO-OH, (6) -C=N, (7) -(CHz) 0-4~CO-NRy_2Ry-3, (8) -(CHz)0-4-CO-(C3-Ci2 alkyl), (9) -(CHj)0-4~CO- (C2-Cy2 alkenyl with one, two or three double bonds),(10) -(CHj3) 9-4-CO-(C3-Cy2 alkynyl with one, two or three triple bonds), } (11) - (CH) ¢-4-CO-(C3-C; cycloalkyl), ® (12) - (CH2)0-4-CO-Ri-ary1, (13) - (CH) 0-4-CO-Ri-hetercaryl, (14) - (CHz) 0-4-CO-Ra-heterocycles (15) - (CHj) 0-4a-CO-Ry.4 where Ry.4 is selected from the group consisting of morpholinyl, thiomorpholinyl, piperazinyl, piperidinyl, homomorpholinyl, homothiomorpholinyl, homothiomorpholinyl S-oxide, homothiomorpholinyl S,S-dioxide, pyrrolinyl and pyrrolidinyl where each group is optionally substituted with one, two, three, or four of: C;-Cg alkyl, (16) - (CH) 0-4-CO-0O-Ry.s where Ry.s is selected from the group consisting of: (a) C1-C¢ alkyl, (b) -(CHz)0-2- (Ri-ary1) + (c) C2-C¢ alkenyl containing one or two double bonds, (d) C2-C¢ alkynyl containing one or two triple bonds, (e) C3.-C; cycloalkyl, and (£) -(CHz)o-2- (Ri-petercaryl) s (17) -(CHz) -4-SO2-NRy-2Rn-3, (18) -(CH2)0-4-SO-(C1-Cs alkyl), (19) -(CHz)0-4-S02-(C1-Cy2 alkyl), (20) -(CH3)0-4-S02-(C3-C; cycloalkyl), (21) - (CH) 9-¢-N(H or Ry.s ) -CO-O-Ry.s where Ry. s can be the same or different, (22) -(CHz)o0-4-N(H or Ry-s ) -CO-N(Ry-s)2, whereRy.s can be the same or different, (23) -(CH;) 9-4-N-CS-N(Ry-s)2, where Ry.s can be. the same or different,(24) - (CH) 9-4-N(-H or Ry.s) -CO-Ry.2 where Ry-s and Ry., can be the same or different, . (25) -(CH3) 0-4-NRy-2Ry-3 where Ry.» and Ry.3 can ® be the same or different, (26) -(CH2) 0-4-Rn-a. (27) -(CH3)0-4-0-CO- (C1-C¢ alkyl), (28) -(CHz)9-4-O-P(O) - (ORy-ary1-1) 2 Where Ry.aryl-1 is -H or C;-C; alkyl, (29) -(CHz)-4-O-CO-N(Rx-s5) 2, (30) -(CHz)0-4-0-CS-N(Ry-s)2, (31) -(CHz)0-4-0- (Ry-s) 2, (32) -(CHz)0-4-0-( Ry-s)2-COOH, (33) -(CHz)0-4-S-( Ry-s)2z, (34) - (CHz) 9-4-0- (C1-Cs alkyl optionally substituted with one, two, three, four, or five -F), (35) C3-C; cycloalkyl, (36) C3-Cs alkenyl with one or two double bonds optionally substituted with C;-C; alkyl, -F, -Cl, -Br, -I, -OH, -SH, -C=N, -CF;, C;-C; alkoxy, or -NRi_gR;-p, Ci1-Ci alkoxy- (R;- aryl) ; C1-C3 alkoxy- (Ry-netercary1) / (37) C2-C¢ alkynyl with one or two triple bonds optionally substituted with C;-C; alkyl, -F, -Cl1, -Br, -I, -OH, -SH, -C=N, -CF;, C;-C; alkoxy, or -NR;.zR;-p, Ci1-C; alkoxy- (Rj. aryl) » Ci1-C3 alkoxy- (Ri-heteroaryl) / (38) -(CHz)0-4-N(-H or Ry.s) -SO,-Ry-2 where Ry.g and Ry.» can be the same or different, or (39) -(CH2)0-4- C3-Cy cycloalkyl.9. A compound according to claim 1, wherein R; and R; are independently Ry.,C(0)-; and Ry-1 is phenyl of which is optionally substituted with one, two or three of the following substituents which can be the same or different and are:(1) Ci1-C¢ alkyl, optionally substituted with one, two or three substituents selected from the group . consisting of C;-C; alkyl, -F, -Cl, -Br, -I, -OH, -SH, -C=N, -_ CF3, C;-Ci3 alkoxy, and -NR;.,R;.p, Ci-Cs alkoxy- (Ri-ary1), Ci1-Cs alkoxy- (Ri-netercaryl)(2) -OH,(3) -NOg, (4) -F, -Cl1l, -Br, or -I, (5) -CO-0OH, (6) -C=N, (7) -(CHz)0-4-CO-NRy_2Ry-3, (8) -(CHz)-4-CO-(C1-Cy2 alkyl), (9) -(CH;).4-CO-(C;-C;, alkenyl with one, two or three double bonds), (10) - (CHz) ¢-4~CO-(C2-Cy2 alkynyl with one,two or three triple bonds),(11) - (CHz) ¢-4-CO-(C3-C5 cycloalkyl), (12) - (CH) 0-4-CO-Ry-ary1,(13) -(CH2) 0-4-CO-Ri-netercary1:(14) - (CH2) 9-4~CO-R1 heterocycle:(15) - (CHz)-4-CO-Ry.4 Where Ry.4 is selected from the group consisting of morpholinyl, thiomorpholinyl, piperazinyl, piperidinyl, homomorpholinyl, homothiomorpholinyl, homothiomorpholinyl S-oxide, homothiomorpholinyl S,S-dioxide, pyrrolinyl and pyrrolidinyl where each group is optionally substituted with one, two, three, or four of: C1-Cs alkyl,(16) -(CHz2)0-4-CO-O-Ry.5 where Ry.s is selected from the group consisting of: (a) C1-Cs alkyl, (b) - (CH) 0-2~ (R1-ary1) . oo© (c) C2-Cs alkenyl containing one or two double bonds,(d) C2-C¢ alkynyl containing one or two triple bonds, and (e) C3.Cy cycloalkyl, ® (17) -(CHp) 0-4-N(H or Ry.s )-CO-O-Ry.s where Ru. s can be the same or different, (18) -(CHz)o0-4-N(H or Ry.s )-CO-N(Ry.s)a, where Ry-s can be the same or different, (19) -(CH;)-4-N-CS-N(Ry-5)2, where Ry.s can be the same or different, (20) =~ (CH) ¢-4-N(-H or Ry.s)-CO-Ry., where Ry.s and Ry. can be the same or different, (21) - (CHz) 0-4~NRy-2Ry-3 where Ry. and Ry.; can be the same or different, (22) - (CH2) 0-4-Rn-4/ (23) -(CH;)0-4-0-CO-(C;-C¢ alkyl), (24) - (CH) 0-4-0O-CO-N (Rx-s) 2, (25) -(CHz2) 0-4-0-CS-N(Ry-s) 2, (26) - (CH) 0-2-O- (Rx-5) 2, (27) -(CHz)0-4-O-( Ry-s)2-COOH, (28) =~ (CH;)0-4-0-(C1~C¢ alkyl optionally substituted with one, two, three, four, or five -F), (29) - (CH) 0-4-N(-H or Ry.5)-SO,-Ry., where Ry.s and Ry. can be the same or different, or (30) -(CHz)o-4a- C3-C; cycloalkyl.10. A compound according to claim 1, wherein R; and R; are independently Ry.1C(0)-; and R; represents - (CHz)ni-phenyl where n; is zero or one and where phenyl is optionally substituted with one, two, or three of the following substituents which are the same or different:35 . (A) C1-C¢ alkyl optionally substituted with one, two or three substituents selected from the group consisting of C,-C3 alkyl, -F, -Cl, -Br, -I, -OH, -SH, -C=N, -CFi, C;-C,alkoxy, and -NRi1.aRi-p, Ci-C3 alkoxy-(Ri.am1). Ci1-Cz alkoxy- (Ri- heteroaryl) » -(B) C,-Cs¢ alkenyl with one or two double bonds, ® optionally substituted with one, two or three substituents selected from the group consisting of -F, -Cl, -Br, -I, -OH, -SH, -C=N, -CF;, C;-C; alkoxy, and -NR;aRy.p, Ci-Ci alkoxy- (Ri-aryi) C1-C3 alkoxy- (Ri-neteroaryl)(C) C,-C¢ alkynyl with one or two triple bonds, optionally substituted with one, two or three substituents selected from the group consisting of -F, -Cl, -Br, -I, -OH, -SH, -C=N, -CF;, C1-C; alkoxy, and -NRj Rip, C1-C; alkoxy- (Ri-amy). C1-C3 alkoxy- (Ri-netercaryl) / )(D) -F, Cl, -Br, or -I, (BE) -C,-C¢ alkoxy optionally substituted with one, two, or three -F,(F) —-NRy_2Rn-3, where Ry. and Ry.i are independently selected from the group consisting of:(1) -H,(2) -C;-Cs alkyl optionally substituted with one substituent selected from the group consisting of:(a) -OH, and(b) -NH;, ’ (3) -C;-C¢ alkyl optionally substituted with one to three -F, -Cl, -Br, or -I,(4) -C3-C; cycloalkyl,(5) -(C1-Cy alkyl) - (C3-C; cycloalkyl),(6) -(C1-C¢ alkyl) -0O-(C1-C3 alkyl),(7) -C2-Cg alkenyl with one or two double bonds,(8) -C2-C¢ alkynyl with one or two triple bonds,(9) -C1-C¢ alkyl chain with one double bond and one triple bond, .(10) -Riamy1, , and } (11) -Ri-netercaryl: (G) -OH, ® (H) -C=N, (I) C3-C; cycloalkyl, optionally substituted with one, two or three substituents selected from the group consisting of -F, -Cl, -Br, -I, -OH, -SH, -C=N, -CF;, Ci1-C; alkoxy, and -NRj.aRi.p, Ci-C3 alkoxy-(Ri-aryi), Ci1-Ci alkoxy- (Ri- heteroaryl) (J) -CO- (C1-C4 alkyl), (K) -S02-NR;-aRi-p, (L) -CO-NRj;.aRi.p, Or (M) -S0,-(Cy-C4 alkyl).11. A copmpounds according to claim 1, wherein R; and Ri are independently phenyl (C,-C¢) alkyl groups where the phenyl is optionally substituted with one or two groups independently selected from (A) C1-C¢ alkyl optionally substituted with one, two or three substituents selected from the group consisting of C,-C; alkyl, -F, -C1l, -Br, -I, -OH, -SH, -C=N, -CFi, C;-C3 alkoxy, and -NRi1-aRi.p, C1-C3 alkoxy-(Rj-ary1), Ci1-C; alkoxy- (R;- heteroaryl) « (B) -F, Cl, -Br, or -I, (C) -C;-Cs alkoxy optionally substituted with one, two, or three -F, (D) -NRy-2Ry-3, where Ry. and Ry.; are independently selected from the group consisting of: (1) -H, . (2) -C1-Cs alkyl optionally substituted with one substituent selected from the group consisting of: (a) -OH, and (b) -NHp,(3) -C1-Cs alkyl optionally substituted with one to three -F, -Cl, -Br, or -I, (4) -C3-C,; cycloalkyl, ® (5) -(C1-C; alkyl) - (C3-C, cycloalkyl), (6) -(C1-C¢ alkyl) -0-(C;-Cs alkyl), (9) -C1-Cg¢ alkyl chain with one double bond and one triple bond, (E) -OH, (F) -C=N, (G) C3-C; cycloalkyl, optionally substituted with one, two or three substituents selected from the group consisting of -F, -Cl, -Br, -I, -OH, -SH, -C=N, -CF;, C-C; alkoxy, and -NRj.aRi-b, Ci1-Cs3 alkoxy-(Ricaryi), Ci1-C; alkoxy- (Ri-. heteroaryl) s (H) -CO- (C;-C4 alkyl), (I) -S0;-NR;.;R;-p, where R;., and Ry, are as defined above, or } (J) -CO-NR;-aR:.p, where R;., and R;.p, are as defined above.12. A compound according to claim 1, wherein R; and R; are independently benzyl, 4-hydroxybenzyl, 2-fluoro-4-propylbenzyl, 3-amino-4-bromobenzyl ; 3-chloro-5-methylphenethyl, 3,5- difluorobenzyl, 2-methylphenylpropyl, 4-trifluoromethylbenzyl, 4-trifluoromethylphenethyl, 2,3-dichlorobenzyl, and 2-chloro-4- cyanobenzyl.13. A compound of the formula:0 0 ==N N—0 / J \ \ / Vs oN NP F } PS Ry Ry Ry Ry nN N y N H f H H H H b N (o] (0) —===N / / \ 0 AZ AN N° / \ R R Ra _=N 1 3 N Re N Ry N Ry fe Pe X Ry N Re fi F y y y T T ® Re H H H N fi N H N . h fo "A Q! NA Me N Ry of yr LT wherein R;, R; and R; are as defined in claim 1.14. A compound of the formula: ‘ IAN ~——H,F, Clar OH FF “0 Ry hd . [+] HN . n . wherein Ry; is -(CH2)pi- (Ri-ary1), Or - (CHp)ny-O- (Ri-ary1) , wherein ni and Ri.ary1 are as defined in claim 1.15. A compound of the formula: ® QO Q lo] 0] 2 / YZ / Z 4 SZ () Lp Xr Kp Con ONE N N 4 2 () . ' ! { _N {N 4 hy i 4 3 N oY Sg Toc bess a N H N N "H =N Ci oh S JPN J SAA OO J oh H H N =N —N =N x b N b NN b XY b N b 2 oY oh OY 0 Ny N N N i SUN UE US + GR > PR i16. A compound of the formula: ® » or . SSI > (TO rT (0 CYTO (FY (FO Ch Gh & Sb A spaNeagiege (0 rT 0 (IY17. A compund of the formula: a Ho . | - } .- . B . . - Tr : “HN 0” J or ® JO AGH SPheacxy-pipeddind-ol a. hi to o o . : C{%-Fhenoxymethyl-piparidin-3-yi}-mathytimineRB . . RF. Ne ] 3-Ethory-S-phancay-plperidine ie -. ’ hes ’ SPhanoxymetinybpipeidndal : ~~ . . i . oC RE : h R : oy 3-EthoxymatyhS phanaxycety piowidioe : } ’ . Lo 2{2{3-2Pyridia-2-yethaxymathyl)}piparidin-3-yil-ethyll-pyrazinie . Pewmentbopypperds : ~~ 07 Co £3 0 : 3H{S-Propary ploarda-3-yimathaxy)-pyridoe I g . - oe EPI BS Lyridin Smaiony) iain Boy attend HS-Phanaxymathyl-gipaddin-3-yicxymeltty pyridine oo Co "- . Qary ¥ . SE TCL. S-Phancay-pl peddin-3-of . 3{5-(3.5-Difluoro~4-methaxy-baaxyloxymslity -plperidin-3-yloxym : 3-Ethaxy-S-phanaxy-piparicina 7 ) i I} i. R+43,5-Diuaro-pheaf-sthyfHS-(pyridied methoxyl pipasidin-3.-aive- 18. A compound of the formula: ® J NS GE. Ho Ye NS RI SE. Co HN ] . . : : } HY Yo Co (e-{aH+-imidazol-4-ylaymelyi}-piperain2yjmathanat . X } : . N O = . cpena cI 2Pipwikiin-1-yimathyl-8-{yrida-dyimethoxymetind)-plparazine ] }- . pt J ] : . . ~CY . . a Rk t a. SSP | ] } ~y SE 24{4-Bromo-phenaxymethyi)-8-{4-chioro-phanaxymatiyl}-pipecazina 3 © 22PyMnd uy) kid slcmetyl shudon oo 8 2{d-Bromo-banzyloxymalhyl)-8-{4-bramo-pancrymalivd}-+-nethyl-plpsrazingN . RI l : oC 23,5 Difucro-benzplaymayik 6-2 prided et-siperazioe19. A compound of the formula: Sp Co Co oo. ggB . | oo - ) _H | N y Hrimidazt-lSonenony-pipedandal tscuazalldn3-y S-phancxymatiyk-pipetdin 3 yimethaxymathy) pyridineB F. ~ : RN EE = No Lo or faa : n syiSsh — . (4-Fluoro-4-{ fucto-furan-3-41)-5-{pyrkdin-3-yiaxy methyi}- 2 LD 0 oo or ) No I 2 S-{Pyridia-3-ylaxymethyl}-4-hiazal-5-4-plpwridind-ol ¢ : ; , - SCydohaxytmathaxymettyt4{3-melttd imicazol-+ 41) 59 . : ar. . a PropHib-ZH mz SA Soin formants © ’ - 0 ’ . . . { - 7 3{4-Broma-phanoxymety()-5-(4-clicro-phencxym Calg emsm— 0” Lo : Co nya a ZT seman 3{5-Banzylouy-d-imicaza-1t-ppaddin-d-doxymalhf)-pyridics } =N . M ’ . . = . ~./ . & : . . : . N N . . : Cy Rx y—< . . ] (| - N 0)
- [8] A ’ CON : oo N Co (-3Hmidazc oS own fai aol main S{-Azatdi-5hS phencay-slperidi losymetifiazsle 2 cuban - .20. A compound of the formula: . . . N . . H. A ) 445 (Pyidind poatcxymathyl-dparidin-Tyl phenol . H{S-{3.5-Cituoro phanyi-pperido-3yimathosy ath pyriding . H : N : , to RT SE oo » L fon oo : } .: . a . Oy . te . to. A(t Fini aro 2-y)-S-{pytidlnSataxymattiy)}-1.2.34.8.6-ha atv o- (IAD pyridinyd _ > . 3{3-Chiaro-beazyloxymatiryl)-S-phenyh-4-2 H-pyraal-3-vil-plosridine . : Aw Ch (512.3-O unr ghacyii4-dszob pbpiparidn-yimaty yicin--yimettybarina21. A compound according to Formula II: . H LL R™ Z "Rs R; (IT) or a pharmaceutically acceptable salt or ester thereof, wherein Z is CH or N, and R;, R; and R; are defined as follows: R= R; = Rs = - H J +40 of AV J $-CHs 7/0 Fo . +3 O-4- . To os a a > Ry. * \ “i, —-3 , or rg ( ¥ a N Rs Br 0% or Of + or 4H . HN 4 OH SE 151 fg Re =H, OH, NH, . Pq Ry =H, OH, NHp, NHCH;3 < ’ Rs = H, OCH, CH2CH,0H other alkyl, or alkyl ethers15 . :® 22. A compound of the formula: H H CLD) H Jo H Qo LJ YT BD ORRRd : N H23. A compound of the formula: ’ Rs Ra R Ry ® oN J) IA hg J hg Di _” hg TT Ry [A R; a ! . ! ~o J ~ on An z on \ ) fo * oo” ? As z 0” R A z ee od) l N 1-2 N N i] hn J) Re R; CR . | _ ! . MAO by 5” AN ‘ a (0), | I ¥ N " A 0) 1) Ry Rs . l " ~Y hid SN - Nv R Ne h H where R in each compound may independently be R; or R;, wherein Z is CH or N, and wherein R;, R; and R; are as defined in claim1.24. A compound according to claim 1, wherein R; is an optionally substituted five-membered heterocycle of the formula: yo BE > BEE e BEE «AE o So 3 Ng A Yao by ly isoxazole Fuwan °° ~ Oxazole Thlazola Imidazola "Pyrazols Trlazala )25. A compound according to claim 1, wherein R, is an optionally substituted six-membered heterocycle of the formula:SION SI RE N° 7 . N PY 5 Pyridine Pyimidine Pyrazine “Triazino26. A compound according to claim 1, wherein R; is an optionally substituted phenol.27. A compound according to claim 1, wherein R, is not a halogenated phenyl, benzyl, aryl or heteroaryl.28. A compound of the formula: . H H N N ® o oC FaC H H N N = NC Ny / I H H N N “NIN lSF . H N "eo O te, CL ° ae ® (0 F wherein the imidazole ring, when present is optionally substituted with an aryl or alkyl group.29. A compound of the formula: . R 9 A ® lo) 0 0 I lo) Nn © N N SR SR yp ~R oS § oy LG Zi J kr 0] 9 o oJ (o) o 0 N N N -R Ra PA » aS Het Het Het or AT © x o) Na N N R Zz AN ZR 2 © Jes QO x, Zz oA - 0° onl CY°3 Oo 0] N N N R 3 J <l 4 oY N iq) Ss 0] 0 0 N N N30. A compound of the formula: . ® H—a (+/-)-(3R,4R) -4-(3- i hydroxyphenyl) piperidin-3-yl 1,1"'- 9 biphenyl-4-carboxylate hydrochloride TO, OH HOOC— CF, {(+/-)-(3R,4R) -4- (4- H chlorophenyl)piperidin-3-yl 1,1'- N 0 biphenyl -4-carboxylate “e a, rifluoroacetate he a F (+/-1-(3R, 4R) -4- (4- i o hlorophenyl)piperidin-3-yl (3,5- H difluorophenyl) acetate mn (0) F AN ZZ5 . (+/-)- (3R, 4R) -4-phenylpiperidin-3-yl Ho 1-naphthoate hydrochloride TCE (+/-)-(3R,4R) -4- (4- F fluorophenyl)piperidin-3-yl 1,1'- © F biphenyl-4-carboxylate y OH trifluoroacetate ® y oO “ey “Cy F (+/-) - (3R, 4R) -4-phenylpiperidin-3-yl 4- (trifluoromethoxy) benzoate hydrochloride aH \ rg i F - x as F (+/-)- (38,48) -4-phenylpiperidin-3-yl 4-iodobenzoate hydrochloride N © . ~~ H p—a GH " |(+/-)-(3R,4R) -4-phenylpiperidin-3-yl phenoxyacetate hydrochloride : “TO aH (+/-)- (3R,4R) -4-phenylpiperidin-3-yl “'la- (trifluoromethyl) benzoate o hydrochloride ® = CF, QH (+/-)- (3R,4R)-4-phenylpiperidin-3-yl 4 -cyanobenzoate hydrochloride Sw lo) (+/-)- (3R,4R) -4-phenylpiperidin-3-yl JL 3-methylbenzoate trifluorocacetate HO™ CF, Cf Cl 3; TU (+/-) - (3R,4R) -4-phenylpiperidin-3-yl ’ -methoxybenzoate trifluoroacetate 0 oer, [e] . _0(+/-) - (3R, 4R) -4-phenylpiperidin-3-yl GH 2 -methoxybenzoate hydrochloride ® H 0 ng I CH (+/-) - (3R, 4R) -4-phenylpiperidin-3-yl benzoate hydrochloride N O os (+/-)- (38,48) -4-phenylpiperidin-3-yl g ',4'-dimethoxy~-1,1'-biphenyl-4- o $ ? arboxylate hydrochloride y 0 1 H—a (+/-)- (38,48) -4-phenylpiperidin-3-yl BB a 4- (5-chlorothien-2-yl) benzoate S hydrochloride «0 lo] N H—a (+/-)- (38,48) -4-phenylpiperidin-3-yl CF, 41 - (trifluoromethyl) -1,1'-biphenyl-4- $ carboxylate hydrochloride ve Lo} H—aH—Q (+/-)- (3R,4R) -4-phenylpiperidin-3-yl H 2 -methylbenzoate hydrochloride no O H—a (+/-) - (3R, 4R) -4-phenylpiperidin-3-yl 3- (trifluoromethyl) benzoate hydrochloride .., F “0 F F HCI (+/-)- (3R, 4R) -4-phenylpiperidin-3-yl 4-nitrobenzoate hydrochloride fo) NL NO, (+/-)- (3R,4R)-4-phenylpiperidin-3-yl an -naphthoate hydrochloride fo) NO(+/-) - (3R, 4R) -4-phenylpiperidin-3-yl 4 -aminobenzoate dihydrochlorideNn . ~y an nH, (+/-)- (38,48) -4-phenylpiperidin-3-yl 4 -pyridin-4-ylbenzoate Z W H—G dihydrochloride [x “0 0 N w—a (+/-)- (38,48) -4-phenylpiperidin-3-yl Se 4'- (methylthio)-1,1'-biphenyl-4- C carboxylate hydrochloride oo lo} N w—a (+/-)- (3S,4S)-4-phenylpiperidin-3-yl 3-iodobenzoate hydrochloride 0 J (0) Nha (+/-)- (3R,4R)-4-(3- H hydroxyphenyl)piperidin-3-yl benzoate 0 hydrochloride “0 y . HO a”i (+/-)- (3R,4R)-4-(3- fo) hydroxyphenyl) piperidin-3-yl benzoate . hydrochloride ney Xn ® ‘ NN F OH > F 0 (3R, 4R) -4-phenylpiperidin-3-yl 1,1'- biphenyl-4-carboxylate aH UO x (+/-)- (35,48) -4-phenylpiperidin-3-yl 1,1'-biphenyl-3-carboxylate hydrochloride N 0 : H H—a Pr (+/-)- (38,48) -4-phenylpiperidin-3-yl N 4-thien-2-ylbenzoate hydrochloride 4 sNO . 0] N H—Q (+/-) - (38,48) -4-phenylpiperidin-3-yl0..0 4'- (methylsulfonyl)-1,1'-biphenyl-4- “) 8S arboxylate hydrochloride oo LJ o H—a oo(+/-)- (3R,4R) ~4-phenylpiperidin-3-yl CH phenylacetate hydrochloride N “ F (+/-)- (3R,4R)-4-phenylpiperidin-3-yl 2S an (3-methoxyphenyl) acetate I trifluorocacetate i 1 2 “ng 0” F (+/-) - (3R,4R) -4-phenylpiperidin-3-yl 2 , 4-dimethoxybenzoate 0 rifluoroacetate H [o] ( 7 Il 0” aH (+/-)-(3R,4R) -4-phenylpiperidin-3-yl (1R, 28) -2- phenylcyclopropanecarboxylate Pi hydrochloride "rg ‘oy,(+/-)- (38,4S)-4-phenylpiperidin-3-yl g 3'-chloro-1,1'-biphenyl-4-carboxylate . g a hydrochloride ® n° H Hea (+/-)- (38,48) -4-phenylpiperidin-3-yl a 4'-chloro-1,1l'-biphenyl-4-carboxylate g hydrochloride ro lo) H H—a (+/-)- (3R,4R) -4-phenylpiperidin-3-yl GH 1-naphthoate hydrochloride HN . { Co H—a (+/-)- (3R,4R) -4-phenylpiperidin-3-yl ( N o 4 -phenoxybenzoate hydrochloride “NOLO } 0 (+/-)- (3R,4R) -4-phenylpiperidin-3-yl Ho A. ~-phenylpropancate trifluoroacetate 3 i :a . NY aH (+/-)-(3R, 4R) -4-phenylpiperidin-3-yl H 2-ethylhexanoate hydrochloride N lo) (+/-)-(3s,48) -4-phenylpiperidin-3-yl 4-tert-butylbenzoate hydrochloride od 0 O N H h—a (+/-)-(38,4S) -4-phenylpiperidin-3-yl 4g N 3'-amino-1, 1'-biphenyl-4-carboxylate . o 4g Ha dihydrochloride o H—a Oo H—a (+/-)- (38,48) -4-phenylpiperidin-3-yl ® 3- (5-chlorothien-2-yl) benzoate “3 hydrochloride OR AN 0 $4 N H—a a (+/-)- (38,48) -4-phenylpiperidin-3-yl g '-cyano-1,1'-biphenyl-4-carboxylate o $ CN hydrochloride (Generated by ACD/Name » software) ) H H—QCH (+/-)-(3R,4R) -4-phenylpiperidin-3-yl H 2,2'-bithiophene-5-carboxylate N o hydrochloride Oo JN (+/-)- (3R,4R) -4-phenylpiperidin-3-yl 5-phenylthiophene-2-carboxylate an hydrochloride R , s o (+/-)-(38,4R) -4- [ (1R) ~cyclohexa-2,4- dien-1-yllpiperidin-3-yl 4- o g @ benzoylbenzoate hydrochloride ) lo} fe F (+/-)-(3S,4S) -4-phenylpiperidin-3-yl g 4'-fluoro-1,1'-biphenyl-4-carboxylate 0) hydrochloride «0 SN,” © NN ba Oc, (+/-)-(35,48) -4-phenylpiperidin-3-yl g 4' - (trifluoromethoxy) -1,1'-biphenyl- 0 C] 4 ~carboxylate hydrochloride H—a aH (+/-) - (3R, 4R) -4-phenylpiperidin-3-yl H -pyridin-2-ylthiophene-2-carboxylate N o dihydrochloride , s = o OOCH .+ WO 03/043987 PCT/US02/37037 _ (+/-)-(38,48) -4-phenylpiperidin-3-yl hc, 4-[3- (trifluoromethyl) -1H-pyrazol-1- Co o STI N vll benzoate hydrochloride fo ® yo (+/-) - (35,48) -4-phenylpiperidin-3-yl 4'-tert-butyl-1,1'-biphenyl-4- arboxylate hydrochloride x. J 0 Hwa (+/-)- (38,48) -4-phenylpiperidin-3-yl o 4 '-methoxy-1,1'-biphenyl-4- g =~ carboxylate hydrochloride 0 J 0 Nha (+/-)-4'-({[(38,48) -4- cop phenylpiperidin-3-yl]oxy}carbonyl) - ® AT 1,1'-biphenyl-4-carboxylic acid “7 hydrochloride CN Sh 0 H H—a : (+/-) - (3R, 4R) -4-phenylpiperidin-3-yl aH 3- (4-methoxyphenyl) propanoate hydrochloride \ gy 0” an (+/-) - (3R, 4R) -4-phenylpiperidin-3-yl " acetate hydrochloride a(+/-)-(3R, 4R) -4-pyridin-3- aH lpiperidin-3-yl acetate ihydrochloride lo} ® ng 7 Nan. A Y N Ne CY BrN . H Br or N H Nea Sr N CY A, y or N oO = N. = NEIHeo ® S “he ge31. A compound selected from the group consisting of 3- benzyl-5-[(3,5-difluorobenzyl) oxy] piperidine hydrochloride; 3- benzyl-5-[ (3-methylbenzyl) oxy] piperidine hydrochloride; 3- benzyl-5-{[4- (trifluoromethyl) benzyl] oxy}piperidine hydro chloride; 3- ({5-benzylpiperidin-3-yl]oxy}methyl) benzonitrile; 3- Dbenzyl-5-[(3-methoxybenzyl)oxylpiperidine hydrochloride; 5- benzylpiperidin-3-yl 1,1'-biphenyl-4-carboxylate trifluorocacetate.32. A compound selected from the group consisting of 3- Benzyloxy-4-furan-3-yl-piperidine-1l-carboxylic acid tert-butyl ester;3- (Biphenyl-4-ylmethoxy) -4-furan-3-yl-piperidine-1- carboxylic acid tert-butyl ester;4-Furan-3-yl-3- (naphthalen-2- ylmethoxy) -piperidine-1-carboxylic acid tert-butyl ester;4- Furan-3-yl-3- (naphthalen-1-ylmethoxy) -piperidine-1-carboxylic acid tert-butyl ester;4-Furan-3-yl-3-(4-phenoxy-benzyloxy) - piperidine-l-carboxylic acid tert-butyl ester;3-(4-tert-Butyl- benzyloxy) -4-furan-3-yl-piperidine-1-carboxylic acid tert-butyl ester; 3- (Anthracen-9-ylmethoxy) -4-furan-3-yl-piperidine-1- carboxylic acid tert-butyl ester;4-Furan-3-yl-3- (3-methyl- Dbenzyloxy)-piperidine-l-carboxylic acid tert-butyl estex;3-(3,5- Dimethoxy-benzyloxy) -4-furan-3-yl-piperidine-1-carboxylic acid tert-butyl ester; 3- (4-Bromo-benzyloxy) -4-furan-3-yl-piperidine-5S 1l-carboxylic acid tert-butyl ester; 4-Furan-3-yl-3- (4- methanesul fonyl-benzyloxy) -piperidine-1-carboxylic acid tert- butyl ester;4-Furan-3-yl-3- (2-methyl-allyloxy) -piperidine-1- ® carboxylic acid tert-butyl ester; 3-Cyclohexylmethoxy-4-furan-3- yl-piperidine-1-carboxylic acid tert-butyl ester;3-(2- Cyclohexyl-ethoxy) -4-furan-3-yl-piperidine-1-carboxylic acid tert-butyl ester; 4-Furan-3-yl-3-isobutoxy-piperidine-1- carboxylic acid tert-butyl ester; 3-(2-Ethyl-butoxy) -4-furan-3- yvl-piperidine-1l-carboxylic acid tert-butyl ester; 3-Benzyloxy-4- furan-3-yl-piperidine;3- (Biphenyl-4-ylmethoxy) -4-furan-3-yl- piperidine;4-Furan-3-yl-3- (naphthalen-2-ylmethoxy) -piperidine;4- Furan-3-yl-3- (naphthalen-1-ylmethoxy) -piperidine;4-Furan-3-yl-3- (4 -phenoxy-benzyloxy) -piperidine;3- (4-tert-Butyl-benzyloxy) -4- furan-3-yl-piperidine;3- (Anthracen-9-ylmethoxy) -4-furan-3-yl- ) piperidine;4-Furan-3-yl-3- (3-methyl-benzyloxy) -piperidine;3- (3,5-Dimethoxy-benzyloxy) -4-furan-3-yl-piperidine;3- (4-Bromo- benzyloxy) -4-furan-3-yl-piperidine;4-Furan-3-yl-3-(2-methyl- allyloxy) -piperidine;3-Cyclohexylmethoxy-4-furan-3-yl- piperidine; 3- (2-Cyclohexyl-ethoxy) -4-furan-3-yl-piperidine;4- Furan-3-yl-3-isobutoxy-piperidine;3- (2-Ethyl-butoxy)-4-furan-3- yl-piperidine.33. A compound of the formula: > te Ny C C) Ug 7) oN wo X 7 CL J 9 ° <QBoc B pe b . z 2 NS 1 9 5 Oo le} / oO J (ONG Boc Boc Boc N N N *, 0 "0 “10 z SN Oo } lo) J 0) [0] } Boc Boc Boc Boc N N N N “oy PN : "oy ~ [ J “ug ad AAG O oO 0 OH H H N N N 7 7 z CJ (J J §J H H H N N N Y / \ J Y )/ H H H N00 C es, 0 ® eae MCh z 7 Zz lo] J ® o J le} / lo} ~ H H H N N N peas! or be OO % Br 4 Zz H H H N N N . \ J { ) Sh MG va 7 7 - / © J 0 0-4 ]34. A method for treating a patient who has, or in N preventing a patient from getting, a disease or condition LJ selected from the group consisting of Alzheimer's disease, for helping prevent or delay the onset of Alzheimer's disease, for treating patients with mild cognitive impairment (MCI) and preventing or delaying the onset of Alzheimer's disease in those who would progress from MCI to AD, for treating Down's syndrome, for treating humans who have Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-Type, for treating cerebral amyloid angiopathy and preventing its potential consequences, i.e. single and recurrent lobar hemorrhages, for treating other degenerative dementias, including dementias of mixed vascular and degenerative origin, dementia associated with Parkinson's disease, dementia associated with progressive supranuclear palsy, dementia associated with cortical basal degeneration, or diffuse Lewy body type of Alzheimer's disease and who is in need of such treatment, comprising administering to such patient a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or ester thereof, wherein 2, R;, R; and Rj; are as defined in claim 1.35. A method for making a compound of formula (I), or a pharmaceutically acceptable salt or ester thereof, wherein Z, R;, R; and Rj; are as defined in claim 1.36. A compound of the formula:H N fo) ® J = SLAZ Rao or a pharmaceutically acceptable salt or ester thereof, wherein Z' is CH or N; wherein Rj, is absent, -OH, or halo; wherein Ryo is Cis alkyl, Cis alkoxy, aryl, substituted aryl, a heteroaryl, substituted heteroaryl, heterocycl, substituted heterocycl, phenyl, substituted phenyl, Cig alkyl-phenyl, or Ci.g alkyl-substittued phenyl.37. A compound according to claim 36, wherein Rj, is absent, -OH, or Cl, Br, I or F.38. A compound according to claim 37, wherein Ry, is selected from the group consisting essentially of -CHs, -CH,CH,- Ph-0-CH;, -Ph-Ph-CO;H, -Ph-Ph-OCH;, -Ph-Ph-C(CH;) 3, -Ph-Ph-OCF;, - Ph-Ph-F, -Ph-C(=0)-Ph, -Ph-Ph-CN, -Ph-Ph-NH;, -Ph-C(CH3);, - CH (CH,CH3) (CH,CH.CH,CH;) , -CH,CH,Ph, -Ph-0-Ph, naphthalene, -Ph- Ph-Cl, -Ph-(OCH3),, -CH,-Ph-OCH;, -CH;-Ph, -Ph-Ph-S(=0),CH;, -Ph- Ph, pyridyl, Ph, Ph-I, -Ph-Ph-S-CHj, -Ph-pyridyl, -Ph-NH,, -Ph- NO, -Ph-CF;, -Ph-CH;, -Ph-Ph-CF;, -Ph-Ph- (OCH3) ,, -Ph-OCH;, -Ph- CN, -CH;-O-Ph, -Ph-OCFi3, -CH,-PhF,,QO. —r< ——Ph—NZF . NN, J NA® . Ss S J pi —— ] ~ci9 . Co39. A compound according to claim 38, wherein Z is CH.40. A compound according to claim 39, wherein a single substituent attached to a Ph-ring is in the ortho position.41. A compound according to claim 39, wherein a single substituent attached to a Ph-ring is in the meta position.42. A compound according to claim 39, wherein a single substituent attached to a Ph-ring is in the para position.43. A compound according to claim 39, wherein di- substituents attached to a Ph-ring are in di-meta positions.44. A compound according to claim 39, wherein di- substituents attached to a Ph-ring are in a meta and para position. .45. A compound of the formula ‘O Rso CY ~~ N H @ wherein Rs is aryl or substituted aryl.46. A compound according to claim 45, wherein Rs, is selected form the group consisting of -Ph, -PhBr, -Ph-C(CHa)3, - PhF, -PhCl, -PhCN, napthyl, -Ph(CH3),, -Ph-Ph, -PhI, -Ph-OCH;, - PhCl,, -Ph-PhCN, and -Ph- (OCH,),.47. A compound according to claim 46, wherein a single substituent attached to a Ph-ring is in the ortho position. ]48. A compound according to claim 46, wherein a single substituent attached to a Ph-ring is in the meta position.49. A compound according to claim 46, wherein a single substituent attached to a Ph-ring is in the para position.50. A compound according to claim 46, wherein di- substituents attached to a Ph-ring are in di-meta positions.51. A compound according to claim 46, wherein di- substituents attached to a Ph-ring are in a meta and para position.52. A compound of the formula ’ 30I" . \ Reso o” = o / wherein Reo is aryl, substituted aryl, Ci alkyl, Ci-¢ alkenyl, Cis cycloalkyl, C,.¢ alkyl-Ci.¢ cycloalkyl; and wherein R;o is t-butoxycarbonyl or H.53. A compound according to claim 52, wherein Rg is selected from the group consisting of -Ph, -Ph-Ph, napthyl, -Ph- O-Ph, -PhC (CH3) 3, anthracinyl, -PhCH,, -Ph (OCH;) 2s ~-PhBr, - PhS (=0) ,CH3;, C(=CH;)CHi;, cyclohexyl, -CHz-cyclohexyl, -CH(CH;)., and -CH (CH,CH;) 3.54. A compound according to claim 53, wherein a single substituent attached to a Ph-ring is in the ortho position.55. A compound according to claim 53, wherein a single substituent attached to a Ph-ring is in the meta position.56. A compound according to claim 53, wherein a single substituent attached to a Ph-ring is in the para position.57. A compound according to claim 53, wherein di- substituents attached to a Ph-ring are in di-meta positions.58. A compound according to claim 53, wherein di- : substituents attached to a Ph-ring are in a meta and para position.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US33270801P | 2001-11-19 | 2001-11-19 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ZA200404066B true ZA200404066B (en) | 2007-12-27 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ZA200404066A ZA200404066B (en) | 2001-11-19 | 2004-05-25 | 3,4-disubstituted, 3,5-disubstituted and 3,4,5-substituted piperidines and piperazines |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN1863530A (en) |
| ZA (1) | ZA200404066B (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20110048491A (en) * | 2008-07-28 | 2011-05-11 | 에자이 알앤드디 매니지먼트 가부시키가이샤 | Spiroaminodihydrothiazine Derivatives |
-
2002
- 2002-11-19 CN CN 02827271 patent/CN1863530A/en active Pending
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| CN1863530A (en) | 2006-11-15 |
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