ZA200709236B - Compounds which inhibit beta-secretase activity and methods of use thereof - Google Patents
Compounds which inhibit beta-secretase activity and methods of use thereof Download PDFInfo
- Publication number
- ZA200709236B ZA200709236B ZA200709236A ZA200709236A ZA200709236B ZA 200709236 B ZA200709236 B ZA 200709236B ZA 200709236 A ZA200709236 A ZA 200709236A ZA 200709236 A ZA200709236 A ZA 200709236A ZA 200709236 B ZA200709236 B ZA 200709236B
- Authority
- ZA
- South Africa
- Prior art keywords
- unsubstituted
- substituted
- compound
- alkyl
- aryl
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 title claims description 72
- 238000000034 method Methods 0.000 title claims description 17
- 102000002659 Amyloid Precursor Protein Secretases Human genes 0.000 title claims description 7
- 108010043324 Amyloid Precursor Protein Secretases Proteins 0.000 title claims description 7
- 230000000694 effects Effects 0.000 title description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 71
- 125000003118 aryl group Chemical group 0.000 claims description 64
- 125000004404 heteroalkyl group Chemical group 0.000 claims description 58
- 125000001072 heteroaryl group Chemical group 0.000 claims description 56
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 51
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 51
- 229910052739 hydrogen Inorganic materials 0.000 claims description 46
- 239000001257 hydrogen Substances 0.000 claims description 46
- 125000002947 alkylene group Chemical group 0.000 claims description 23
- 229910052736 halogen Inorganic materials 0.000 claims description 22
- 150000002367 halogens Chemical class 0.000 claims description 20
- 125000004474 heteroalkylene group Chemical group 0.000 claims description 19
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 18
- 102100021257 Beta-secretase 1 Human genes 0.000 claims description 15
- 101710150192 Beta-secretase 1 Proteins 0.000 claims description 15
- 230000003197 catalytic effect Effects 0.000 claims description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 9
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 8
- 208000024827 Alzheimer disease Diseases 0.000 claims description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 2
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 2
- 125000005344 pyridylmethyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims 20
- 102000003908 Cathepsin D Human genes 0.000 claims 4
- 108090000258 Cathepsin D Proteins 0.000 claims 4
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims 3
- 229920000728 polyester Polymers 0.000 claims 3
- 125000004076 pyridyl group Chemical group 0.000 claims 3
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims 3
- 102100021277 Beta-secretase 2 Human genes 0.000 claims 2
- 101710150190 Beta-secretase 2 Proteins 0.000 claims 2
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims 2
- 125000001041 indolyl group Chemical group 0.000 claims 2
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims 2
- YIROYDNZEPTFOL-UHFFFAOYSA-N 5,5-Dimethylhydantoin Chemical class CC1(C)NC(=O)NC1=O YIROYDNZEPTFOL-UHFFFAOYSA-N 0.000 claims 1
- 101000713575 Homo sapiens Tubulin beta-3 chain Proteins 0.000 claims 1
- 102100036790 Tubulin beta-3 chain Human genes 0.000 claims 1
- 125000000641 acridinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3C=C12)* 0.000 claims 1
- 125000002785 azepinyl group Chemical group 0.000 claims 1
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims 1
- 125000005872 benzooxazolyl group Chemical group 0.000 claims 1
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims 1
- 125000003354 benzotriazolyl group Chemical group N1N=NC2=C1C=CC=C2* 0.000 claims 1
- 125000000609 carbazolyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3NC12)* 0.000 claims 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims 1
- 125000002576 diazepinyl group Chemical group N1N=C(C=CC=C1)* 0.000 claims 1
- 125000004212 difluorophenyl group Chemical group 0.000 claims 1
- 125000002541 furyl group Chemical group 0.000 claims 1
- 125000002883 imidazolyl group Chemical group 0.000 claims 1
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 claims 1
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 claims 1
- 125000000842 isoxazolyl group Chemical group 0.000 claims 1
- 125000002757 morpholinyl group Chemical group 0.000 claims 1
- 125000001715 oxadiazolyl group Chemical group 0.000 claims 1
- 125000002971 oxazolyl group Chemical group 0.000 claims 1
- 125000003585 oxepinyl group Chemical group 0.000 claims 1
- 125000003386 piperidinyl group Chemical group 0.000 claims 1
- 125000003226 pyrazolyl group Chemical group 0.000 claims 1
- 125000002098 pyridazinyl group Chemical group 0.000 claims 1
- 125000000714 pyrimidinyl group Chemical group 0.000 claims 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims 1
- 125000001422 pyrrolinyl group Chemical group 0.000 claims 1
- 125000000168 pyrrolyl group Chemical group 0.000 claims 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims 1
- 125000005306 thianaphthenyl group Chemical group 0.000 claims 1
- 125000000335 thiazolyl group Chemical group 0.000 claims 1
- 125000001544 thienyl group Chemical group 0.000 claims 1
- 125000003777 thiepinyl group Chemical group 0.000 claims 1
- 125000001425 triazolyl group Chemical group 0.000 claims 1
- -1 n- propyl Chemical group 0.000 description 45
- 125000001424 substituent group Chemical group 0.000 description 13
- 125000005842 heteroatom Chemical group 0.000 description 8
- 150000003254 radicals Chemical class 0.000 description 8
- 125000004432 carbon atom Chemical group C* 0.000 description 7
- 229910052757 nitrogen Inorganic materials 0.000 description 7
- 229940121773 Secretase inhibitor Drugs 0.000 description 6
- 238000009825 accumulation Methods 0.000 description 5
- 229910052760 oxygen Inorganic materials 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 201000010099 disease Diseases 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 101710137189 Amyloid-beta A4 protein Proteins 0.000 description 3
- 101710151993 Amyloid-beta precursor protein Proteins 0.000 description 3
- 102100022704 Amyloid-beta precursor protein Human genes 0.000 description 3
- DZHSAHHDTRWUTF-SIQRNXPUSA-N amyloid-beta polypeptide 42 Chemical compound C([C@@H](C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)NCC(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(O)=O)[C@@H](C)CC)C(C)C)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC(O)=O)C(C)C)C(C)C)C1=CC=CC=C1 DZHSAHHDTRWUTF-SIQRNXPUSA-N 0.000 description 3
- 125000003710 aryl alkyl group Chemical group 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 230000007062 hydrolysis Effects 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- 125000005647 linker group Chemical group 0.000 description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 229910052717 sulfur Inorganic materials 0.000 description 3
- 102000009091 Amyloidogenic Proteins Human genes 0.000 description 2
- 108010048112 Amyloidogenic Proteins Proteins 0.000 description 2
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 2
- 210000004556 brain Anatomy 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 150000001721 carbon Chemical group 0.000 description 2
- 125000001153 fluoro group Chemical group F* 0.000 description 2
- 125000001188 haloalkyl group Chemical group 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 229910052698 phosphorus Inorganic materials 0.000 description 2
- 229910052710 silicon Inorganic materials 0.000 description 2
- 125000004434 sulfur atom Chemical group 0.000 description 2
- 125000004417 unsaturated alkyl group Chemical group 0.000 description 2
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 description 1
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000001462 1-pyrrolyl group Chemical group [*]N1C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 125000004174 2-benzimidazolyl group Chemical group [H]N1C(*)=NC2=C([H])C([H])=C([H])C([H])=C12 0.000 description 1
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 description 1
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000000389 2-pyrrolyl group Chemical group [H]N1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 125000000474 3-butynyl group Chemical group [H]C#CC([H])([H])C([H])([H])* 0.000 description 1
- 125000003682 3-furyl group Chemical group O1C([H])=C([*])C([H])=C1[H] 0.000 description 1
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 125000001397 3-pyrrolyl group Chemical group [H]N1C([H])=C([*])C([H])=C1[H] 0.000 description 1
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 description 1
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 1
- KDDQRKBRJSGMQE-UHFFFAOYSA-N 4-thiazolyl Chemical group [C]1=CSC=N1 KDDQRKBRJSGMQE-UHFFFAOYSA-N 0.000 description 1
- CWDWFSXUQODZGW-UHFFFAOYSA-N 5-thiazolyl Chemical group [C]1=CN=CS1 CWDWFSXUQODZGW-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 208000000044 Amnesia Diseases 0.000 description 1
- 208000037259 Amyloid Plaque Diseases 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 1
- 206010010301 Confusion and disorientation Diseases 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 208000027382 Mental deterioration Diseases 0.000 description 1
- 206010027374 Mental impairment Diseases 0.000 description 1
- 229910003849 O-Si Inorganic materials 0.000 description 1
- 229910003872 O—Si Inorganic materials 0.000 description 1
- 206010039966 Senile dementia Diseases 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 125000005237 alkyleneamino group Chemical group 0.000 description 1
- 125000005238 alkylenediamino group Chemical group 0.000 description 1
- 125000005530 alkylenedioxy group Chemical group 0.000 description 1
- 125000005529 alkyleneoxy group Chemical group 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- 125000005165 aryl thioxy group Chemical group 0.000 description 1
- 125000004104 aryloxy group Chemical group 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 125000000319 biphenyl-4-yl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 208000010877 cognitive disease Diseases 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 125000000392 cycloalkenyl group Chemical group 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 125000004366 heterocycloalkenyl group Chemical group 0.000 description 1
- 125000001183 hydrocarbyl group Chemical group 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 231100000863 loss of memory Toxicity 0.000 description 1
- HRDXJKGNWSUIBT-UHFFFAOYSA-N methoxybenzene Chemical group [CH2]OC1=CC=CC=C1 HRDXJKGNWSUIBT-UHFFFAOYSA-N 0.000 description 1
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 1
- 125000006682 monohaloalkyl group Chemical group 0.000 description 1
- 125000004572 morpholin-3-yl group Chemical group N1C(COCC1)* 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 210000001682 neurofibril Anatomy 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000004483 piperidin-3-yl group Chemical group N1CC(CCC1)* 0.000 description 1
- 125000006684 polyhaloalkyl group Polymers 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 230000002797 proteolythic effect Effects 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000004192 tetrahydrofuran-2-yl group Chemical group [H]C1([H])OC([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000005309 thioalkoxy group Chemical group 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
—._. DE ——
COMPOUNDS WHICH INHIBIT BETA-SECRETASE ACTIVITY AND
METHODS OF USE THEREOF
[0001] This application claims the benefit of U.S. Patent Application 60/669,541, filed
April 8, 2005, and U.S. Patent Application 60/717,541, filed September 14, 2005, each of which is incorporated herein by reference in their entirety for all purposes.
FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
+ [0002] The invention was made with government support under grants AG-18933 and Al- l0 38189 awarded by the National Institutes of Health. The Government has certain rights in the invention.
[0003] Alzheimer's disease is a progressive mental deterioration in a human resulting, inter alia, in loss of memory, confusion and disorientation. Alzheimer's disease accounts for the {S majority of senile dementias and is a leading cause of death in adults (Anderson, R. N., Natl
Vital Stat. Rep. 49:1-87 (2001), the teachings of which are incorporated herein in their entirety). Histologically, the brain of persons afflicted with Alzheimer's diseaseis ~~ = characterized by a distortion of the intracellular neurofibrils and the presence of senile plaques composed of granular or filamentous argentophilic masses with an amyloid protein '0 core, largely due to the accumulation of B-amyloid protein (Ap) in the brain. AB accumulation plays a role in the pathogenesis and progression of the disease (Selkoe, D.J.,
Nature 399: 23-31 (1999)) and is a proteolytic fragment of amyloid precursor protein (APP).
APP is cleaved initially by B—secretase (also referred to as memapsin 2) followed by y- secretase to generate AB (Lin, X,, ef al, Proc. Natl. Acad. Sci. USA 97:1456-1460 (2000); De 5 Stropper, B., et al., Nature 391:387-390 (1998)). :
[0004] There is a need to develop effective compounds and methods for the treatment of
Alzheimer's disease. The present invention fulfills these and other needs.
[0005] The present invention provides novel B-secretase inhibitors and methods for their 0 use, including methods of treating Alzheimer's disease.
[0006] In one aspect, the present invention provides a B-secretase inhibitor compound having the formula:
R3 R? 6 OH 7 (hh 1A aN HA o rR 0
RS O.
[0007] In Formula (I), R! is halogen, -OH, -CFs, -NO,, -NR*R’, -OR'?, -S(O).R"), -C(O)R'?, hydrogen, substituted or unsubstituted C3-Ca alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or
Ly.
[0008] R?® is halogen, -OH, -CFs, -NO,, -NR®R®, -OR"?, -5(0).R!!, -C(O)R"?, hydrogen, : substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
[0009] R? and R® are independently halogen, -CFs, -NO,, -NR®R’, -OR'?, -S(O).R"", -C(O)R™, hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or :
LAY.
[0010] R*is halogen, -OH, -CF, -NO;, -NR*R’, -OR", -S(O),R", -C(O)R'2, hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or LAY.
[0011] R®and R’ are independently -S(O);R"", -C(O)R"?, -NR®R®, hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or -L*-Y.
[0012] The symbol n represents integers from 0 to 2.
: [0013] R® is independently -C(O)R', -S(O);R", hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. :
[0014] R’isindependently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
[0015] R'is independently -C(O)RP, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
[0016] R!!is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
If nis 2, then R!! is optionally -NR"R!S. Ifnis 1 or 2, then R! is not hydrogen.
[0017] R'is independently -NRYRY, -ORY, hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
[0018] R'is independently -ORY, .NR'®R', hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
[0019] Ris independently -NR'®R', hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
[0020] R'® and R" are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
[0021] R' and R'® are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
[0022] L'and Lr’ are independently a bond, NR", -S(O)q-~, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene. L? is substituted or unsubstituted alkylene, -NR'’-, -S(0)q-, or substituted or unsubstituted heteroalkylene.
[0023] R'is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
[0024] The symbol q represents an integer from 0 to 2.
[0025] A! and A? are independently substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. Y is a carrier moiety.
[0026] L*is a bond, -OP(OH),0-, -C(O)OR%-, -C(O)NHR?'-, -S(0);NHR?-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, or a peptidyl linker.
[0027] R*,R?, and R** are independently substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
[0028] In another aspect of the present invention, the 3-secretase inhibitor compounds of the invention can be employed in methods to decrease memapsin 2 catalytic activity, decrease hydrolysis of a B-secretase site of a memapsin 2 substrate, and/or decrease the accumulation of B-amyloid protein relative to the amount of memapsin 2 catalytic activity, hydrolysis of a
B-secretase site, and accumulation of B-amyloid protein, respectively, in the absence of the B- secretase inhibitor.
[0029] In another aspect, the present invention provides pharmaceutical compositions comprising a memapsin 2 B-secretase inhibitor compound of the invention or a memapsin 2 B-secretase inhibitor compound in combination with a pharmaceutically acceptable carrier.
[0030] In another aspect of the present invention, the B-secretase inhibitor compounds of } the invention can be employed in the treatment of diseases or conditions associated with B-
secretase activity, hydrolysis ofa B-secretase site of a B-amyloid precursor protein, and/or B- amyloid protein accumulation. Typically, a mammal is treated for the disease or condition.
In an exemplary embodiment, the disease is Alzheimer's disease. . DETAILED DESCRIPTION OF THE INVENTION
Abbreviations and Definitions
[0031] The abbreviations used herein have their conventional meaning within the chemical and biological arts. The chemical structures and formulae set forth herein are constructed according to the standard rules of chemical valency known in the chemical arts.
[0032] Where substituent groups are specified by their conventional chemical formulae, written from left to right, they equally encompass the chemically identical substituents that would result from writing the structure from right to left, e.g., -CH,O- is equivalent to -OCHz-.
[0033] The term "alkyl," by itself or as part of another substituent, means, unless otherwise stated, a straight (i.e. unbranched) or branched chain, or combination thereof, which may be fully saturated, mono- or polyunsaturated and can include di- and multivalent radicals, having the number of carbon atoms designated (i.e. C1-C;o means one to ten carbons). Examples of saturated hydrocarbon radicals include, but are not limited to, groups such as methyl, ethyl, n- propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, (cyclohexyl)methyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. An unsaturated alkyl group is one having one or more double bonds or triple bonds. Examples of unsaturated alkyl groups include, but are not limited to, vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2- (butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and the higher homologs and isomers. An alkoxy is an alkyl attached to the remainder of the molecule via an oxygen linker (-O-).
[0034] The term "alkylene" by itself or as part of another substituent means a divalent radical derived from an alkyl, as exemplified, but not limited, by -CH,CH,CH,CH>-, and further includes those groups described below as "heteroalkylene." Typically, an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with those groups having 10 or fewer carbon atoms being preferred in the present invention. A "lower alkyl" or "lower alkylene" is ashorter chain alkyl or alkylene group, generally having eight or fewer carbon atoms.
[0035] The term "heteroalkyl," by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain, or cyclic hydrocarbon radical, or combinations thereof, consisting of at least one carbon atoms and at least one heteroatom selected from the group consisting of O, N, P, Si and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. The heteroatom(s) O, N, P and S and Si may be placed at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule. Examples include, but are not limited to, -CH,-CH,-O-CHj, L -CH,-CH,-NH-CHj, -CH,-CH,-N(CH3)-CHjs, -CH,-S-CH,-CHa, -CH;-CHa,-S(0)-CHs, -
CH,-CH,-S(0),-CHj;, -CH=CH-0O-CHj, -Si(CH3)s, -CH,-CH=N-OCH3;, -CH=CH-N(CH3)-
CH, O-CHj, -O-CH,-CH;, and —~CN. Up to two heteroatoms may be consecutive, such as, for example, -CH,-NH-OCHj3 and —CH,-O-Si(CHs)s. Similarly, the term "heteroalkylene" by | : itself or as part of another substituent means a divalent radical derived from heteroalkyl, as exemplified, but not limited by, -CH,-CH,-S-CH,-CH;- and —CH,-S-CH;-CH;-NH-CH,-.
For heteroalkylene groups, heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like). Still further, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied by the direction in which the formula of the linking group is written. For example, the formula —C(O),R'- represents both —C(0),R'- and —R'C(0),-. As described above, heteroalkyl groups, as used herein, include those groups that are attached to the remainder of the molecule through a heteroatom, such as -C(O)R', -C(O)NR', -NR'R, -OR', -SR, and/or -
SO,R'. Where "heteroalkyl" is recited, followed by recitations of specific heteroalkyl groups, such as -NR'R or the like, it will be understood that the terms heteroalkyl and -NR'R" are not redundant or mutually exclusive. Rather, the specific heteroalkyl groups are recited to add clarity. Thus, the term "heteroalkyl" should not be interpreted herein as excluding specific "heteroalkyl groups, such as -NR'R" or the like.
[0036] The terms "cycloalkyl" and "heterocycloalkyl", by themselves or in combination with other terms, represent, unless otherwise stated, cyclic versions of "alkyl" and "heteroalkyl", respectively. Additionally, for heterocycloalkyl, a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule. Examples of cycloalkyl include, but are not limited to, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3- cyclohexenyl, cycloheptyl, and the like. Examples of heterocycloalkyl include, but are not limited to, 1 —(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4- morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1 —piperazinyl, 2-piperazinyl, and the like.
[0037] The terms "halo" or "halogen," by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as "haloalkyl," are meant to include monohaloalkyl and polyhaloalkyl. For : example, the term "halo(C,-C4)alkyl" is mean to include, but not be limited to, trifluoromethyl, 2,2,2-triflucroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.
[0038] The term "aryl" means, unless otherwise stated, a polyunsaturated, aromatic, hydrocarbon substituent which can be a single ring or multiple rings (preferably from 1 to 3 rings) which are fused together or linked covalently. The term "heteroaryl" refers to aryl _ groups (or rings) that contain from one to four heteroatoms selected from N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized. A heteroaryl group can be attached to the remainder of the molecule through a carbon or heteroatom. Non-limiting examples of aryl and heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3- pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4- oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5- thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4- pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5- isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, and 6-quinolyl. Substituents for each of the above noted aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below. }
[0039] For brevity, the term "aryl" when used in combination with other terms (e.g., : aryloxy, arylthioxy, arylalkyl) includes both aryl and heteroaryl rings as defined above.
Thus, the term "arylalkyl" is meant to include those radicals in which an aryl group is attached to an alkyl group (e.g., benzyl, phenethyl, pyridylmethyl and the like) including those alkyl groups in which a carbon atom (e.g., a methylene group) has been replaced by, for example, an oxygen atom (e.g., phenoxymethyl, 2-pyridyloxymethyl, 3-(1- naphthyloxy)propyl, and the like).
[0040] The term "oxo" as used herein means an oxygen that is double bonded to a carbon atom.
[0041] The term "alkylsulfonyl" as used herein means a moiety having the formula -S(O,)-
R', where R'is an alkyl group as defined above. R' may have a specified number of carbons (e.g. "C:1-C4 alkylsulfonyl").
[0042] Each of the above terms (e.g., "alkyl," "heteroalkyl," "aryl" and "heteroaryl") are , meant to include both substituted and unsubstituted forms of the indicated radical. Preferred substituents for each type of radical are provided below.
[0043] Substituents for the alkyl and heteroalkyl radicals (including those groups often - referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, ; : heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl) can be one or more of a variety of groups selected from, but not limited to: -OR', =0, =NR', =N-OR', -NRR", -SR', -halogen, - - SiRR"R™, -OC(O)R', -C(O)R', -COzR', -CONR'R", -OC(O)NRR", -NR"C(O)R’, -NR'-C(O)NR"R", -NR"C(O).R', -NR-C(NRR"R"")=NR"", -NR-C(NR'R")=NR", -S(O)R', - S(O)R!, -S(0);NR'R", -NRSO,R', -CN and -NO, in a number ranging from zero to (2m'+1), where m' is the total number of carbon atoms in such radical. R' R" R" and R"™ each preferably independently refer to hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl (e.g., aryl substituted with 1-3 halogens), substituted or unsubstituted alkyl, alkoxy or thioalkoxy groups, or arylalkyl groups. When a compound of the invention includes more than one R group, for example, each of the R groups is independently selected as are each R', R", R" and R"" groups when more than one of these groups is present. When R' and R" are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 4-, 5-, 6-, or 7-membered ring. For example, -NRR" is meant to include, but not be limited to, 1-pyrrolidinyl and 4-morpholinyl. From the above discussion of substituents, one of skill in the art will understand that the term "alkyl" is meant to include groups including carbon atoms bound to groups other than hydrogen groups, such as haloalkyl (e.g., -CF3 and —CH,CF3;) and acyl (e.g., -C(O)CHj, -C(O)CF3, -C(O)CH,0OCHj3, and the like).
[0044] Similar to the substituents described for the alkyl radical, substituents for the aryl and heteroaryl groups are varied and are selected from, for example: halogen, -OR', -NR'R", -SR!, -halogen, -SiRR"R", -OC(O)R', -C(O)R’, -CO,R', -CONR'R", -OC(O)NRR", -NR"C(O)R', -NR'-C(O)NR"R"', -NR"C(O);R', -NR-C(NR'R"R"")=NR"", -NR-C(NRR")=NR"', -S(O)R', -S(0)2R’, -S(0):NRR", -NRSO;R', -CN and -NOg, -R', -N3, -CH(Ph),, fluoro(C,;-Cs)alkoxy, and fluoro(C;-Cs)alkyl, in a number ranging from zero to the total number of open valences on the aromatic ring system; and where R', R", R" and R"" are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or
Claims (2)
- ER WHATIS CLAIMED IS: 0) En —1 1. A compound having the formula: Se Co ‘Rr! - R3 R2 | . Seana ll o rR oOo 1 2 RS , 3 wherein 4 R! is halogen, -OH, -CFs, -NO,, -NR®*R’, -OR"?, -S(O).R"", -C(O)R", hydrogen, substituted or unsubstituted C3-Cy alkyl, substituted or 6 unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, 7 substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted 8 aryl, substituted or unsubstituted heteroaryl, or hy; 9 R’ is halogen, -OH, -CF;, -NO,, -NR®R?, -OR'?, -S(O):R", -C(O)R", hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted 11 heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or 12 unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or 13 substituted or unsubstituted heteroaryl; 14 R? and R? are independently halogen, -CFs, -NO,, -NR®R?, -OR'?, -S(0).R"", -C(O)R'?, hydrogen, substituted or unsubstituted alkyl, substituted or 16 unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, 17 substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted 18 aryl, substituted or unsubstituted heteroaryl, or -L*-Y; 19 R* is halogen, -OH, -CFj, -NO,, -NR®R’, -OR'%, -S(O),R"}, -C(O)R", "hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted 21 heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or 22 unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, 23 substituted or unsubstituted heteroaryl, or -L*-Y; 2 R® and R’ are independently -S(O);R'!, -C(O)R'?, -NR°R®, hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, 26 substituted or unsubstituted cycloalkyl, substituted or unsubstituted 27 heterocycloalkyl, substituted or unsubstituted aryl, substituted or 28 unsubstituted heteroaryl, or -L*-Y;THe iS . l bs i fin, ie9 n is independently 0, 1, or 2; Conky 0 RY is independently -C(O)R ">, -S(O);R", hydrogen, substituted or — 1 unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or CT Ry 2 unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, hn 3 substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;4 Ris independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,6 substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted v7 aryl, or substituted or unsubstituted heteroaryl;8 R!® is independently -C(O)R", substituted or unsubstituted alkyl, substituted9 or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,0 substituted or unsubstituted heterocycloalkyl, substituted or unsubstitutedH aryl, or substituted or unsubstituted heteroaryl;12 R! is independently hydrogen, substituted or unsubstituted alkyl, substitutedI3 or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,4 substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted' aryl, or substituted or unsubstituted heteroaryl, wherein if n is 2, then RM!16 is optionally NR RS, and wherein ifnis 1 or 2, then R! is not hydrogen;7 R" is independently -NR®RY, -ORY, hydrogen, substituted or unsubstituted : 18 alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted19 cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or50 unsubstituted aryl, or substituted or unsubstituted heteroaryl;31 R" is independently -ORY, -NR®RY, hydrogen, substituted or unsubstituted32 alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted 53 cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or54 unsubstituted aryl, or substituted or unsubstituted heteroaryl,55 R'is independently -NR'®R'®, hydrogen, substituted or unsubstituted alkyl,56 substituted or unsubstituted heteroalkyl, substituted or unsubstituted57 cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or58 unsubstituted aryl, or substituted or unsubstituted heteroaryl, wherein59 R' and R" are independently hydrogen, substituted or unsubstituted alkyl,60 substituted or unsubstituted heteroalkyl, substituted or unsubstituted61 cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or 62 unsubstituted aryl, or substituted or unsubstituted heteroaryl;33 a RS and R'6 are independently hydrogen, substituted or unsubstituted alkyl, 4 substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or ol — w 36 unsubstituted aryl, or substituted or unsubstituted heteroaryl, 37 L! and L? are independently a bond, -NR'-, -S(0)q-, substituted or 38 unsubstituted alkylene, or substituted or unsubstituted heteroalkylene; : 59 © Lis substituted or unsubstituted alkylene, -NR'"-, -S(0)q-, or substituted or 70 unsubstituted heteroalkylene; 71 R'is independently hydrogen, substituted or unsubstituted alkyl, substituted 72 or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, 73 substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted 74 aryl, or substituted or unsubstituted heteroaryl, - , 75 | qis independently 0, 1, or 2; 76 | A! and A? are independently substituted or unsubstituted cycloalkyl, 77 substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted 78 aryl, or substituted or unsubstituted heteroaryl; 79 Y is a carrier moiety; and 80 L* is a bond, -OP(OH),0-, -C(O)OR-, -C(O)NHR?'-, -S(O),NHR*-, 81 substituted or unsubstituted alkylene, substituted or unsubstituted 82 heteroalkylene, or a peptidyl linker, wherein 83 © R®, R?, and R* are independently substituted or unsubstituted alkyl, 84 : substituted or unsubstituted heteroalkyl, substituted or unsubstituted 85 cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted 86 or unsubstituted aryl, or substituted or unsubstituted heteroaryl.1 2. The compound of claim 1, wherein R! is hydrogen, halogen, -NR*R®, 2 -ORY, or-S(O).R".1 3. The compound of claim 1, wherein R' is hydrogen, -NR’S(O).R"*, 2 -OR", or -S(O).R'%.1 4. The compound of claim 1, wherein R' is hydrogen or -NR’S(O).R".1 5. The compound of claim 1, wherein R’, R®, R, R"®, and R"" are 2 independently hydrogen, substituted or unsubstituted Ci-Cyg alkyl, substituted orSUPER... 3 unsubstituted 2 to 20 membered heteroalkyl, substituted or unsubstituted Cs-C; cyclo alkyl 4 substituted or unsubstituted 5 to 7 membered heterocycloalkyl, substituted or unsubstituted ; aryl, substituted or unsubstituted heteroaryl, or Ay.1 6. The compound of claim 1, wherein each substituted or unsubstituted 2 alkyleneisan R2-substituted or unsubstituted C;-Cy alkylene, each substituted or 3 unsubstituted heteroalkylene is an R*-substituted or unsubstituted 2 to 20 membered 4 heteroalkylene, each substituted or unsubstituted alkyl is an R*-substituted or unsubstituted 5 C1-Cyo alkyl, each substituted or unsubstituted heteroalkyl is an R®-substituted or 6 unsubstituted 2 to 20 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is 7 an R®-substituted or unsubstituted Cs-C; cycloalkyl, each substituted or unsubstituted 8 heterocycloalkyl is an R*-substituted or unsubstituted 5 to 7 membered heterocycloalkyl, 9 each substituted or unsubstituted heteroaryl is an R%-substituted or unsubstituted heteroaryl, 0 and each substituted or unsubstituted aryl is an R*-substituted or unsubstituted aryl, wherein (1 R? is independently oxo, halogen, -CN, -CFs, -OCFs, -OR”, -S(O)R”, 12 _OCH3, -C(O)R¥, -NR*R¥, -NR*®C(O)RY, -C(O)NR™R”, R”- 13 substituted or unsubstituted C;-Cy allyl, R*>-substituted or unsubstituted 2 4 to 20 membered heteroalkyl, R%®-substituted or unsubstituted Cs-Cy (5 cycloalkyl, R¥-substituted or unsubstituted 5 to 7 membered 16 heterocycloalkyl, R**-substituted or unsubstituted heteroaryl, or R*- 17 substituted or unsubstituted aryl; 18 R* is independently halogen, -CN, -CF3, -OCF3, -OCHj, OR, -S(O)R”, 19 OCH, -C(O)R?’, .-NR®R?, -NR®C(O)R?, -C(O)NR*R”, R®- substituted or unsubstituted C;-Cyp alkyl, R*-substituted or unsubstituted 2 21 to 20 membered heteroalkyl, R?-substituted or unsubstituted Cs-Cy 22 cycloalkyl, R%.substituted or unsubstituted 5 to 7 membered 23 heterocycloalkyl, R%%_substituted or unsubstituted heteroaryl, or R%. 24 substituted or unsubstituted aryl; t is independently 0, 1, or 2; 26 R%, R®, and R* are independently hydrogen, R%.substituted or unsubstituted 27 : Ci-Cyo alkyl, R®-substituted or unsubstituted 2 to 20 membered 28 heteroalkyl, R?-substituted or unsubstituted Cs-C; cycloalkyl, R- 29 substituted or unsubstituted 5 to 7 membered heterocycloalkyl, R%.SF fo substituted or unsubstituted heteroaryl, or Nw 2] aryl, wherein if t is 1 or 2, then R? is not hydrogen, and wherein R? is independently oxo, halogen, -CN, -OH, -CFs, -OCFs, -OCHs, unsubstituted C;-Ca alkyl, unsubstituted 2 to 20 membered heteroalkyl, unsubstituted Cs-Cy cycloalkyl, unsubstituted 5 to 7 membered heterocycloalkyl, unsubstituted aryl, or unsubstituted ) heteroaryl, and - R* is independently halogen, -CN, -OH, -CF3, -OCF3, -OCH;, } unsubstituted C;-Cso alkyl, unsubstituted 2 to 20 membered ) heteroalkyl, unsubstituted Cs-Cy cycloalkyl, unsubstituted 5 to 7 ) membered heterocycloalkyl, unsubstituted aryl, or unsubstituted l heteroaryl. :1. The compound of claim 6, wherein R?, R, RS, R%, R'%, R", and R' are 2? independently R™-substituted or unsubstituted C;-Cao alkyl, R%.substituted or unsubstituted 3 2 to 20 membered heteroalkyl, R®-substituted or unsubstituted Cs-C7 cycloalkyl, RE. 4 substituted or unsubstituted 5 to 7 membered heterocycloalkyl, R2*_substituted or unsubstituted heteroaryl, or R**-substituted or unsubstituted aryl.1 8. The compound of claim 7, wherein 2 RY, R®, and R* are independently hydrogen, R*-substituted or unsubstituted3 C.-C alkyl, or R¥ substituted or unsubstituted 2 to 20 membered 4 heteroalkyl; BE R? is independently oxo, halogen, -CN, -CFs, -OCFs, -OR”, SOR”, 6 _OCHj, -C(O)RY’, -NR*®R?, -NR*C(O)R”, -C(O)NR?*R”, R*- 7 substituted or unsubstituted C;-Cy alkyl, or R®-substituted or 8 unsubstituted 2 to 20 membered heteroalkyl; and 9 Ris independently halogen, -CN, -CF3, -OCF3, -OCHj, -OR?, -S(O)RY, -OCHs, -C(O)RY, -NR?*R?, -NR®C(O)R”, -C(O)NR*R”, R*- (1 substituted or unsubstituted C,-Cy alkyl, orR**-substituted or 12 unsubstituted 2 to 20 membered heteroalkyl.1 9. The compound of claim 6, wherein R%, R®, R%, R°, R'", R"!, and R*? are 2 substituted or unsubstituted C;-Cqg alkyl or substituted or unsubstituted heterocycloalkyl.ET Baa“Hep1 10. The compound of claim 6, wherein R% R®, R® R’ R® R! and R'? are a2 unsubstituted C;-Cy alkyl.E 1 11. The compound of claim 6, wherein R%, R?, R®, R%, R!%, R'!, and R'? are 2 unsubstituted C,-Cs alkyl. ) :1 12. The compound of claim 1, wherein R? and R? are independently2 hydrogen, halogen, or unsubstituted C;-Cy alkyl.1 13. The compound of claim 6, wherein R’ is RZ-substituted or2 unsubstituted Cs-C; cycloalkyl, R*-substituted or unsubstituted 5 to 7 membered3 heterocycloalkyl, R**-substituted or unsubstituted heteroaryl, or R*_substituted or4 unsubstituted aryl.1 14. The compound of claim 6, wherein R’ is R**-substituted or2 unsubstituted heteroaryl, or R**-substituted or unsubstituted aryl.1 15. The compound of claim 6, wherein R’ is R*-substituted or2 unsubstituted aryl.1 16. The compound of claim 1, wherein R’ is selected from substituted or2 unsubstituted tetrahydrofuranyl, substituted or unsubstituted tetrahydropyranyl, and3 substituted or unsubstituted pyridylmethyl.1 17. The compound of claim 16, wherein L? is unsubstituted C;-Cs alkyl.1 18. The compound of claim 17, wherein L? is methylene.1 "19. The compound of claim 15, wherein R** is halogen, -CN, -OH, -CF3,2 unsubstituted C;-Cy alkyl, or unsubstituted alkoxy.1 20. The compound of claim 19, wherein R° is a difluorophenyl.1 21. The compound of claim 15, wherein R’ is phenyl.1 22. The compound of claim 21, wherein 1? is unsubstituted C,-Cs2 alkylene. ooSE rm bee1 23. The compound of claim 21, wherein L? is unsubstituted 2 to 5 2 membered heteroalkylene. 1 24. The compound of claim 23, wherein Lis -(CH,)e-S-, wherein the 2 symbol e represents an integer from 0 to 10. 1 25. The compound of claim 24, wherein e is 1. : 1 26. The compound of claim 1, wherein A’ and A? are independently 2 substituted or unsubstituted Cs-C7 cycloalkyl, substituted or unsubstituted 5 to 7 membered 3 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. 1 27. The compound of claim 1, wherein A? is substituted or unsubstituted 2 aryl, or substituted or unsubstituted heteroaryl. 1 28. The compound of claim 1, wherein A! and A? are independently 2 substituted or unsubstituted phenyl, substituted or unsubstituted pyrazolyl, substituted or 3 unsubstituted furanyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted 4 isoxazolyl, substituted or unsubstituted oxadiazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted pyridyl, substituted or 6 unsubstituted pyrimidyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted 7 thiazolyl, substituted or unsubstituted triazolyl, substituted or unsubstituted thienyl, 8 substituted or unsubstituted dihydrothieno-pyrazolyl, substituted or unsubstituted 9 thianaphthenyl, substituted or unsubstituted carbazolyl, substituted or unsubstituted benzimidazolyl, substituted or unsubstituted benzothienyl, substituted or unsubstituted 11 benzofuranyl, substituted or unsubstituted indolyl, substituted or unsubstituted quinolinyl, 12 substituted or unsubstituted benzotriazolyl, substituted or unsubstituted benzothiazolyl, 13 substituted or unsubstituted benzooxazolyl, substituted or unsubstituted benzimidazolyl, 14 substituted or unsubstituted isoquinolinyl, substituted or unsubstituted isoindolyl, substituted or unsubstituted acridinyl, substituted or unsubstituted benzoisazolyl, substituted or 16 unsubstituted dimethylhydantoin, substituted or unsubstituted pyrazinyl, substituted or 17 unsubstituted tetrahydrofuranyl, substituted or unsubstituted pyrrolinyl, substituted or 18 unsubstituted pyrrolidinyl, substituted or unsubstituted morpholinyl, substituted or 19 unsubstituted indolyl, substituted or unsubstituted diazepinyl, substituted or unsubstituted azepinyl, substituted or unsubstituted thiepinyl, substituted or unsubstituted piperidinyl, ot”21 substituted or unsubstituted oxepinyl. ! 1 | 29. The compound of claim 1, wherein A? is substituted or unsubstituted 2 aryl 1 30. The compound of claim 1, wherein A? is substituted or unsubstituted 2 phenyl. 1 31. The compound of claim 1, wherein A? is substituted or unsubstituted2 heteroaryl.1 32. The compound of claim 1, wherein A? is substituted or unsubstituted2 pyridyl ] 33. The compound of claim 1, wherein 13 and L! are independently a2 bond, unsubstituted alkylene, or unsubstituted heteroalkylene. 1 34. The compound of claim 1, wherein L? and L' are independently a2 bond, unsubstituted C,-Cy alkylene, or unsubstituted 2 to 20 membered heteroalkylene. 1 35. The compound of claim 1, wherein L* and L' are independently a2 bond, unsubstituted C;-Cs alkylene, or unsubstituted 2 to 5 membered heteroalkylene. 1 36. The compound of claim 1, wherein L? is C;-Cs alkylene.1 37. The compound of claim 1, wherein L! is a branched unsubstituted C;-
- 2 Cs alkylene.1 38. The compound of claim 1, wherein 1? is unsubstituted C1-Cyo alkylene, 2 or unsubstituted 2 to 20 membered heteroalkylene.1 39. The compound of claim 1, wherein L? is unsubstituted C;-Cs alkylene, ~~ . 2 or unsubstituted 2 to 5 membered heteroalkylene.1 40. The compound of claim 1, wherein L? is unsubstituted C;-Cs alkylene.1 41. The compound of claim 1, wherein L? is a branched unsubstituted C;-2 Cs alkylene.NE‘ (A rg1 42, The compound of claim 1, wherein Lis methylene. ~ A 1 43. The compound of claim 40, wherein A? is substituted or unsubstituted 2 heteroaryl or substituted or unsubstituted aryl.1 44. The compound of claim 43, wherein Al is substituted or unsubstituted 2 heteroaryl, or substituted or unsubstituted aryl.1 45. The compound of claim 44, wherein A? is substituted or unsubstituted 2 phenyl or substituted or unsubstituted pyridyl.1 46. The compound of claim 44, wherein A! is substituted or unsubstituted 2 phenyl or substituted or unsubstituted pyridyl.1 47. The compound of claim 45, wherein L%is methylene.1 48. The compound of claim 1, wherein if R'is -NR®R® and R® is2 -S(0);R", then R® is hydrogen.1 49. The compound of claim 48, wherein R’ is substituted or unsubstituted 2 alkyl1 50. The compound of claim 48, wherein R’ is unsubstituted C;-Cs alkyl.1 51. The compound of claim 48, wherein R? and R? are hydrogen.1 52. The compound of claim 1, wherein if R! is hydrogen, then R® is not2 ‘hydrogen.1 53. The compound of claim 52, wherein RS is substituted or unsubstituted 2 alkyl1 54, The compound of claim 52, wherein RS is unsubstituted C,-Cs alkyl.1 ' 55. The compound of claim 52, wherein R® is substituted or unsubstituted 2 C3-Cs cycloalkyl.1 56. The compound of claim 52, wherein RS is substituted or unsubstituted 2 cyclopropyl.a) Il Ty [my ld i [=D (ny UNENSYS WO 2006/110668 : SSBCTIUS2006/013342 Loa a, : NCTA ed 1 57. The compound of claim 54, wherein R'is hydrogen. 1 58. The compound of claim 57, wherein R? and R? are hydrogen.J 1 59. A method of treating Alzheimer's disease in a subject in need thereof, 2 the method comprising administering to the subject in need of such treatment an effectiver 3 amount of the compound of claim 1. 1 60. A method of reducing memapsin 2 catalytic activity, the method 2 comprising contacting a memapsin 2 protein with an effective amount of the compound of 3 claim1. E 1 61.. The method of claim 60, wherein said memapsin 2 beta-secretase is 2 contacted in a cell. 1 62. A method of selectively reducing memapsin 2 catalytic activity relative 2 tomemapsin 1 catalytic activity, the method comprising contacting a memapsin 2 protein 3 with an effective amount of the compound of claim 1 in the presence of memapsin 1 beta- 4 secretase. 1 63. A method of selectively reducing memapsin 2 catalytic activity relative 2 to cathepsin D catalytic activity, the method comprising contacting a memapsin 2 protein 3 with an effective amount of the compound of claim 1 in the presence of cathepsin D. 1 64. A method of selectively reducing memapsin 2 catalytic activity relative 2 tomemapsin 1 catalytic activity and cathepsin D catalytic activity, the method comprising 3 contacting a memapsin 2 protein with an effective amount of the compound of claim 1 in the 4 presence of memapsin 1 beta-secretase and cathepsin D.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US66954105P | 2005-04-08 | 2005-04-08 |
Publications (1)
Publication Number | Publication Date |
---|---|
ZA200709236B true ZA200709236B (en) | 2009-06-24 |
Family
ID=39548350
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
ZA200709236A ZA200709236B (en) | 2005-04-08 | 2006-04-10 | Compounds which inhibit beta-secretase activity and methods of use thereof |
Country Status (2)
Country | Link |
---|---|
CN (1) | CN101198583A (en) |
ZA (1) | ZA200709236B (en) |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101845014B (en) * | 2009-03-23 | 2012-07-11 | 北京华素制药股份有限公司 | Method for reducing heteroaromatic carboxylic acid into heteroaromatic alcohol |
CN101863962B (en) * | 2010-05-07 | 2013-02-27 | 清华大学 | Polypeptide for inhibiting enzyme digestion of beta secretase and application thereof |
US20120053200A1 (en) * | 2010-09-01 | 2012-03-01 | Harald Mauser | Bace 2 inhibitors |
CN113563250B (en) * | 2021-07-28 | 2023-07-07 | 南华大学 | Tryptamine benzoate derivative and preparation and application thereof |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
PE20020276A1 (en) * | 2000-06-30 | 2002-04-06 | Elan Pharm Inc | SUBSTITUTE AMINE COMPOUNDS AS ß-SECRETASE INHIBITORS FOR THE TREATMENT OF ALZHEIMER |
-
2006
- 2006-04-10 CN CNA2006800207195A patent/CN101198583A/en active Pending
- 2006-04-10 ZA ZA200709236A patent/ZA200709236B/en unknown
Also Published As
Publication number | Publication date |
---|---|
CN101198583A (en) | 2008-06-11 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
ES2926153T3 (en) | Compounds and Methods for Modulating Interleukin-2-Inducible T-Cell Kinase | |
WO2015085238A1 (en) | Inhibitors of lpxc | |
JP6294277B2 (en) | Modulators of HEC1 activity and methods therefor | |
JP5837936B2 (en) | Alkylsulfinyl-substituted thiazolide compounds | |
WO1999042455A1 (en) | Antiviral agents | |
JP2007525494A5 (en) | ||
WO2012106534A2 (en) | Hiv integrase inhibitors | |
CA2940954A1 (en) | Nitazoxanide and tizoxanide for the treatment of rhinovirus and rhabdovirus infections | |
CA3017567A1 (en) | Compounds and methods for modulating bruton's tyrosine kinase | |
US20210355103A1 (en) | Parg inhibitors and method of use thereof | |
TW201910329A (en) | Substituted five-membered and six-membered heterocyclic compound, preparation method thereof, pharmaceutical combination and use thereof | |
ZA200709236B (en) | Compounds which inhibit beta-secretase activity and methods of use thereof | |
CA1257875A (en) | N, n'-bis(sulfonyl) hydrazines having antineoplastic activty | |
EP2917190A1 (en) | New benzene sulfonamide thiazole compounds | |
CA2966423C (en) | Potent gamma-secretase modulators | |
AU2009280042B2 (en) | Methods for treating injury associated with exposure to an alkylating species | |
EP4061341A1 (en) | Caspase 6 inhibitors and uses thereof | |
US20200392099A1 (en) | Agents and methods for treating dysproliferative diseases | |
WO2021163192A1 (en) | Myc inhibitors and uses thereof | |
ES2651312T3 (en) | N-acylhydrazone derivatives for a selective T-cell inhibitor drug and against lymphoid neoplasia | |
WO2021143923A1 (en) | Boronic acid derivatives | |
JP2019529409A (en) | Dithio ETP derivative | |
JP2023550473A (en) | Small molecule compounds and compositions | |
WO2019178166A1 (en) | Amphiphilic thiol compounds and uses thereof | |
WO2022221519A1 (en) | Synthetic rocaglates with broad-spectrum antiviral activities and uses thereof |