ZA200501991B - Acetyl 2-hydroxy-1,3 diaminoalkanes. - Google Patents
Acetyl 2-hydroxy-1,3 diaminoalkanes. Download PDFInfo
- Publication number
- ZA200501991B ZA200501991B ZA200501991A ZA200501991A ZA200501991B ZA 200501991 B ZA200501991 B ZA 200501991B ZA 200501991 A ZA200501991 A ZA 200501991A ZA 200501991 A ZA200501991 A ZA 200501991A ZA 200501991 B ZA200501991 B ZA 200501991B
- Authority
- ZA
- South Africa
- Prior art keywords
- alkyl
- acetamide
- difluorobenzyl
- amino
- groups
- Prior art date
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- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 title 1
- 125000000217 alkyl group Chemical group 0.000 claims description 237
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 100
- 229910052736 halogen Inorganic materials 0.000 claims description 69
- 125000003545 alkoxy group Chemical group 0.000 claims description 62
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 61
- 150000002367 halogens Chemical class 0.000 claims description 60
- 150000001875 compounds Chemical class 0.000 claims description 58
- 125000003118 aryl group Chemical group 0.000 claims description 56
- -1 l-naphthyl Chemical group 0.000 claims description 55
- 125000003342 alkenyl group Chemical group 0.000 claims description 54
- 229910052799 carbon Inorganic materials 0.000 claims description 54
- 125000000304 alkynyl group Chemical group 0.000 claims description 49
- 208000024827 Alzheimer disease Diseases 0.000 claims description 40
- 125000001072 heteroaryl group Chemical group 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 31
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 28
- 125000006288 3,5-difluorobenzyl group Chemical group [H]C1=C(F)C([H])=C(C([H])=C1F)C([H])([H])* 0.000 claims description 26
- 229910052739 hydrogen Inorganic materials 0.000 claims description 20
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 16
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 12
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 11
- 150000003839 salts Chemical class 0.000 claims description 11
- 125000004432 carbon atom Chemical group C* 0.000 claims description 10
- 125000004438 haloalkoxy group Chemical group 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 9
- 125000001424 substituent group Chemical group 0.000 claims description 9
- 125000000000 cycloalkoxy group Chemical group 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 8
- 125000004076 pyridyl group Chemical group 0.000 claims description 8
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 7
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 7
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 6
- 240000002791 Brassica napus Species 0.000 claims description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 6
- 206010002022 amyloidosis Diseases 0.000 claims description 6
- 125000002619 bicyclic group Chemical group 0.000 claims description 6
- 125000001589 carboacyl group Chemical group 0.000 claims description 6
- 230000002490 cerebral effect Effects 0.000 claims description 6
- 125000002883 imidazolyl group Chemical group 0.000 claims description 6
- 125000002950 monocyclic group Chemical group 0.000 claims description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims description 6
- 125000002971 oxazolyl 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
- 125000004193 piperazinyl group Chemical group 0.000 claims description 5
- 125000003386 piperidinyl group Chemical group 0.000 claims description 5
- 125000006582 (C5-C6) heterocycloalkyl group Chemical group 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 4
- 125000002541 furyl group Chemical group 0.000 claims description 4
- 125000001475 halogen functional group Chemical group 0.000 claims description 4
- 150000002431 hydrogen Chemical class 0.000 claims description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 4
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 4
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 4
- 125000006284 3-fluorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C(F)=C1[H])C([H])([H])* 0.000 claims description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
- 230000006735 deficit Effects 0.000 claims description 3
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 3
- 125000002632 imidazolidinyl group Chemical group 0.000 claims description 3
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 3
- XOFYZVNMUHMLCC-ZPOLXVRWSA-N prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 claims description 3
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 3
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 3
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Natural products C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 claims description 2
- 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 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 125000005046 dihydronaphthyl group Chemical group 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 125000001188 haloalkyl group Chemical group 0.000 claims description 2
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 2
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 claims description 2
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 claims description 2
- 125000001041 indolyl group Chemical group 0.000 claims description 2
- 125000005956 isoquinolyl group Chemical group 0.000 claims description 2
- 125000001715 oxadiazolyl group Chemical group 0.000 claims description 2
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 claims description 2
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 2
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 claims description 2
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 claims description 2
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 2
- 125000005329 tetralinyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 claims description 2
- 125000001113 thiadiazolyl group Chemical group 0.000 claims description 2
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims 128
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims 9
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Chemical compound CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims 4
- 125000006645 (C3-C4) cycloalkyl group Chemical group 0.000 claims 3
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 claims 3
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims 3
- 125000006275 3-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C([H])C(*)=C1[H] 0.000 claims 2
- AXJDEHNQPMZKOS-UHFFFAOYSA-N acetylazanium;chloride Chemical compound [Cl-].CC([NH3+])=O AXJDEHNQPMZKOS-UHFFFAOYSA-N 0.000 claims 2
- 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 2
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims 2
- AXGWWGKUHKMPRX-ATTQYFOMSA-N methyl 3-[[(2r,3s)-3-acetamido-4-(3,5-difluorophenyl)-2-hydroxybutyl]amino]-3-(3-ethylphenyl)propanoate Chemical compound CCC1=CC=CC(C(CC(=O)OC)NC[C@@H](O)[C@H](CC=2C=C(F)C=C(F)C=2)NC(C)=O)=C1 AXGWWGKUHKMPRX-ATTQYFOMSA-N 0.000 claims 2
- RAXXELZNTBOGNW-UHFFFAOYSA-N 1H-imidazole Chemical compound C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims 1
- 125000006279 3-bromobenzyl group Chemical group [H]C1=C([H])C(=C([H])C(Br)=C1[H])C([H])([H])* 0.000 claims 1
- 125000006482 3-iodobenzyl group Chemical group [H]C1=C([H])C(=C([H])C(I)=C1[H])C([H])([H])* 0.000 claims 1
- 241000430584 Andrion Species 0.000 claims 1
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 claims 1
- 125000006287 difluorobenzyl group Chemical group 0.000 claims 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims 1
- NAJFDERKMRIWHT-KMDXXIMOSA-N n-[(2s,3r)-1-(3,5-difluorophenyl)-3-hydroxy-4-[[(4s)-6-(2-methylpropyl)-3,4-dihydro-2h-chromen-4-yl]amino]butan-2-yl]acetamide Chemical compound C([C@@H]([C@H](O)CN[C@H]1CCOC2=CC=C(C=C21)CC(C)C)NC(C)=O)C1=CC(F)=CC(F)=C1 NAJFDERKMRIWHT-KMDXXIMOSA-N 0.000 claims 1
- HLCWFSFOWQTZPY-VQTJNVASSA-N n-[(2s,3r)-1-(3,5-difluorophenyl)-3-hydroxy-4-[[1-[3-(2-methylpropyl)-1,2-oxazol-5-yl]cyclopropyl]amino]butan-2-yl]acetamide Chemical compound O1N=C(CC(C)C)C=C1C1(NC[C@@H](O)[C@H](CC=2C=C(F)C=C(F)C=2)NC(C)=O)CC1 HLCWFSFOWQTZPY-VQTJNVASSA-N 0.000 claims 1
- BKHRTNBMBFAPOJ-GJGLBJJNSA-N n-[(2s,3r)-1-(3,5-difluorophenyl)-3-hydroxy-4-[[3-hydroxy-1-(3-iodophenyl)propyl]amino]butan-2-yl]acetamide Chemical compound C([C@H](NC(=O)C)[C@H](O)CNC(CCO)C=1C=C(I)C=CC=1)C1=CC(F)=CC(F)=C1 BKHRTNBMBFAPOJ-GJGLBJJNSA-N 0.000 claims 1
- FFCLAKQJARATFW-MDEZFMAYSA-N n-[(2s,3r)-1-(3,5-difluorophenyl)-4-[(2-ethyl-9-methylfluoren-9-yl)amino]-3-hydroxybutan-2-yl]acetamide Chemical compound C([C@@H]([C@H](O)CNC1(C2=CC=CC=C2C2=CC=C(C=C21)CC)C)NC(C)=O)C1=CC(F)=CC(F)=C1 FFCLAKQJARATFW-MDEZFMAYSA-N 0.000 claims 1
- AWLCLBGTISFMBL-ZBKSJXDOSA-N n-[(2s,3r)-1-(3,5-difluorophenyl)-4-[(6-ethyl-1-methyl-3,4-dihydro-2h-quinolin-4-yl)amino]-3-hydroxybutan-2-yl]acetamide Chemical compound C([C@@H]([C@H](O)CNC1CCN(C)C2=CC=C(C=C21)CC)NC(C)=O)C1=CC(F)=CC(F)=C1 AWLCLBGTISFMBL-ZBKSJXDOSA-N 0.000 claims 1
- KPVZUTGEJKNNJI-HNBJWRTHSA-N n-[(2s,3r)-1-(3,5-difluorophenyl)-4-[(6-ethyl-2-hydroxy-2,3-dihydro-1h-inden-1-yl)amino]-3-hydroxybutan-2-yl]acetamide Chemical compound C([C@@H]([C@H](O)CNC1C(O)CC2=CC=C(C=C21)CC)NC(C)=O)C1=CC(F)=CC(F)=C1 KPVZUTGEJKNNJI-HNBJWRTHSA-N 0.000 claims 1
- RKYOBSRCJPDOQS-YDUIRMPASA-N n-[(2s,3r)-1-(3,5-difluorophenyl)-4-[(7-ethyl-1,2,3,4-tetrahydronaphthalen-1-yl)amino]-3-hydroxybutan-2-yl]acetamide Chemical compound C([C@@H]([C@H](O)CNC1CCCC2=CC=C(C=C21)CC)NC(C)=O)C1=CC(F)=CC(F)=C1 RKYOBSRCJPDOQS-YDUIRMPASA-N 0.000 claims 1
- RSZSSBCSMRWEFY-XZOQPEGZSA-N n-[(2s,3r)-1-(3,5-difluorophenyl)-4-[2-[3-(2,2-dimethylpropyl)phenyl]propan-2-ylamino]-3-hydroxybutan-2-yl]-2-fluoroacetamide Chemical compound CC(C)(C)CC1=CC=CC(C(C)(C)NC[C@@H](O)[C@H](CC=2C=C(F)C=C(F)C=2)NC(=O)CF)=C1 RSZSSBCSMRWEFY-XZOQPEGZSA-N 0.000 claims 1
- QJBDADQASJTUQI-LOSJGSFVSA-N n-[(2s,3r)-1-(3,5-difluorophenyl)-4-[[1-(3-ethylphenyl)cyclohexyl]amino]-3-hydroxybutan-2-yl]acetamide Chemical compound CCC1=CC=CC(C2(CCCCC2)NC[C@@H](O)[C@H](CC=2C=C(F)C=C(F)C=2)NC(C)=O)=C1 QJBDADQASJTUQI-LOSJGSFVSA-N 0.000 claims 1
- OQLAHBUAMAXNIT-BJKOFHAPSA-N n-[(2s,3r)-1-(3,5-difluorophenyl)-4-[[1-(3-ethylphenyl)cyclopentyl]amino]-3-hydroxybutan-2-yl]acetamide Chemical compound CCC1=CC=CC(C2(CCCC2)NC[C@@H](O)[C@H](CC=2C=C(F)C=C(F)C=2)NC(C)=O)=C1 OQLAHBUAMAXNIT-BJKOFHAPSA-N 0.000 claims 1
- RBRNTFGOGWWEIQ-FCHUYYIVSA-N n-[(2s,3r)-1-(3,5-difluorophenyl)-4-[[1-(3-ethynylphenyl)cyclopropyl]amino]-3-hydroxybutan-2-yl]acetamide Chemical compound C([C@H](NC(=O)C)[C@H](O)CNC1(CC1)C=1C=C(C=CC=1)C#C)C1=CC(F)=CC(F)=C1 RBRNTFGOGWWEIQ-FCHUYYIVSA-N 0.000 claims 1
- XOPSWJBECBNGIX-BJKOFHAPSA-N n-[(2s,3r)-1-(3,5-difluorophenyl)-4-[[1-[3-(5-formylthiophen-2-yl)phenyl]cyclopropyl]amino]-3-hydroxybutan-2-yl]acetamide Chemical compound C([C@H](NC(=O)C)[C@H](O)CNC1(CC1)C=1C=C(C=CC=1)C=1SC(C=O)=CC=1)C1=CC(F)=CC(F)=C1 XOPSWJBECBNGIX-BJKOFHAPSA-N 0.000 claims 1
- LZXCSPLKTUWYRD-POZJPKTBSA-N n-[(2s,3r)-1-(3,5-difluorophenyl)-4-[[2-(2,2-dimethylpropyl)-9h-fluoren-9-yl]amino]-3-hydroxybutan-2-yl]acetamide Chemical compound C([C@H](NC(=O)C)[C@H](O)CNC1C2=CC(CC(C)(C)C)=CC=C2C2=CC=CC=C21)C1=CC(F)=CC(F)=C1 LZXCSPLKTUWYRD-POZJPKTBSA-N 0.000 claims 1
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- WXNOFTUEXRKZCB-LHJLODMPSA-N n-[(2s,3r)-4-[(2-bromo-9-methylfluoren-9-yl)amino]-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl]acetamide Chemical compound C([C@H](NC(=O)C)[C@H](O)CNC1(C)C2=CC(Br)=CC=C2C2=CC=CC=C21)C1=CC(F)=CC(F)=C1 WXNOFTUEXRKZCB-LHJLODMPSA-N 0.000 claims 1
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- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
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Description
ACETYL 2-HYDROXY-1l, 3-DIAMINOALKANES
Field of the Invention ' The invention relates to acetyl 2-hydroxy-1,3- diaminoalkanes and to such compounds that are useful in the treatment of Alzheimer’s disease and related diseases. More specifically, it relates to such 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 (ox 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- 3 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 plagues are predominantly composed of amyloid beta peptide (A beta, also sometimes designated betana). 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.
Cleavage of APP at the N-terminus of the A beta peptide by beta-secretase and at the C-terminus by one or more gamma ~ secretases constitutes the beta-amyloidogenic pathway, i.e. the pathway by which A beta is 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 is 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, Sinha 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.
BACEl 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 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 compounds of formula (I) 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 a broad aspect, the invention provides compounds of formula I
Ho OH Ris
Zo MA Mog
R; Ra Rs (I) and pharmaceutically acceptable salts thereof, wherein
Z is hydrogen, or
Z is (C3-C; cycloalkyl),-1(C1-Cs alkyl) -, (C3-C, cycloalkyl). (Cy-
Cs alkenyl) -, (C3-C; cycloalkyl). (Ca-C¢ alkynyl)- or (Ci;-C, cycloalkyl) -, wherein each of said groups is optionally substituted with 1, 2, or 3 R; groups, wherein 1 or 2 methylene groups within said (C3-C; cycloalkyl) -1(Ci-Ce alkyl) -, (C3-Cq7 cycloalkyl),.1(C2-C¢ alkenyl) -, (C3-Cy cycloalkyl) -1(C2-Cs alkynyl) -. or (C;-C,; cycloalkyl) - groups are optionally replaced with - (C=0)-;
Rz at each occurrence is independently halogen (in one aspect, F or Cl), -OH, -SH, -CN, -CF;, -OCF,, C:-Ce alkoxy, C3-C; cycloalkyl, C3-C; cycloalkoxy or -
NRiooR1017 . Ripo and R;91 at each occurrence are independently H,
Ci-Ce¢ alkyl, phenyl, CO(C;-C¢ alkyl) or S0,C;-Cg : alkyl;
X is -(C=0)- or -(SO;z)-;
Ri is C,-Cyo alkyl optionally substituted with 1, 2, or 3 groups independently selected from halogen, -OH, =0, -SH, -CN, -CF3, -OCF3, -C3.; cycloalkyl, -C;-Cs alkoxy, amino, mono- . or dialkylamino, aryl, heteroaryl, and heterocycloalkyl, wherein each aryl group is optionally substituted with 1, ! 2 or 3 Rso groups; each heteroaryl is optionally substituted with 1 or 2 Rsy groups; and each heterocycloalkyl group is optionally substituted with 1 or 2 groups that are independently Rso or =0;
Rso is selected from halogen, OH, SH, CN, -CO-(C,-C4 alkyl), -NRsRg, -$(0)¢-2- (C1-Cs alkyl), Ci-Cs alkyl, C,-
Cs alkenyl, C;-Cs¢ alkynyl, Ci;-C¢ alkoxy and C;3-Cg cycloalkyl; wherein the alkyl, alkenyl, alkynyl, alkoxy and cycloalkyl groups are optionally substituted with 1 or 2 substituents independently selected from C;-C4 alkyl, halogen, OH, -NRsRg¢, CN, C;-C, haloalkoxy,
NRsRg, and C,-C; alkoxy; wherein
Rs and Rs are independently H or C;-C¢ alkyl; or
Rs and Re and the nitrogen to which they are attached form a 5 or 6 membered heterocycloalkyl ring;
R; and Rg are independently selected from H; -C;-C, alkyl optionally substituted with 1, 2, or 3 groups independently selected from -OH, -NH,, and halogen; -C3-C¢ cycloalkyl; -(C,-C, alkyl)-O- (C.-C alkyl); -Cy-C4 alkenyl; and -C,-C,4 alkynyl;
R; and R3 are independently selected from H; F; -C;-Cs alkyl optionally substituted with -F, -OH, -C=N, -CF;, C;-Cs; ' alkoxy, or -NRsRe; -(CHz)o-2-Ri7; - (CHa)o-2-Ris; -C2-Cs alkenyl or Cz-C¢ alkynyl, wherein the alkenyl and alkynyl groups ) are optionally substituted with 1 or 2 groups that are independently -F, -OH, -C=N, -CF; or Ci-Cs; alkoxy; -(CH,),. 2-C3-C; cycloalkyl, which is optionally substituted with 1 or 2 groups that are independently -F, -OH, -C=N, -CFs,
C.-C; alkoxy and -NRsRg;
Ry» at each occurrence is an aryl group (preferably ’ selected from phenyl, 1l-naphthyl, 2-naphthyl , indanyl, indenyl, dihydronaphthyl and tetralinyl,) wherein said aryl group is optionally substituted with one or two groups that are independently -C;-Cj alkyl; -C,-C, alkoxy; CFi3; -C3-C¢ alkenyl or -C3-Cg alkynyl each of which is optionally substituted with one substituent selected from F, OH, C,-Cs alkoxy; halogen; OH; -C=N; -C3-C; cycloalkyl; -CO- (C.-C, alkyl); or -S0,-(C;-C4 alkyl);
Ria 1s a heteroaryl group (preferably selected from pyridinyl, pyrimidinyl, guinolinyl, indolyl, pryidazinyl, pyrazinyl, isoquinolyl, quinazolinyl, quinoxalinyl, phthalazinyl, imidazolyl, isoxazolyl, oxazolyl, thiazolyl, furanyl, thienyl, pyrrolyl, oxadiazolyl or thiadiazolyl,) wherein said heteroaryl groups are optionally substituted with one or two groups that are independently -C;-Cs alkyl optionally substituted with one substituent selected from OH, C=N, CF;, C;-C3; alkoxy, and -NRsRg;
Rs is selected from hydrogen, C;-C¢ alkyl, C;-C¢ alkoxy, Ci1-Cg alkoxy C;-Cs alkyl, hydroxy C;-C¢ alkyl, halo C;-C¢ alkyl, each of which is unsubstituted or substituted with 1, 2, 3, or 4 groups independently selected from halogen, C;-Cg alkyl, hydroxy, Ci-Cs alkoxy, and NH, and -Rys-Ry;; wherein
Rog 1s selected from a bond, -C(O)-, -S0,-, -COy-, -C(O)NRs-, and -NRsC(O) -,
Ry; is selected from C;-C¢ alkyl, C;-Cs alkoxy, aryl C;-Cg alkyl, heterocycloalkyl, and heteroaryl, wherein . each of the above is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently
C1-Cy alkyl, C.-C, alkoxy, halogen, haloalkyl, hydroxyalkyl, -NRsRe¢, or -C(O)NRgRs; or
R,, Ry; and the carbon to which they are attached form a C3-Cy carbocycle, wherein 1, 2, or 3 carbon atoms are optionally replaced by groups that are independently ’ selected from -O-, -8-, -S02-, -C(O)-, or -NR,-;
Re is selected from - (CHz),-3-(C3-Cs) cycloalkyl wherein the cycloalkyl is optionally substituted with 1, 2, or 3 groups independently selected from -Razos; and -CO0,- (C1-C4 alkyl) ; - (CR245R250) 0-a-aryl; - (CRa4s5R250) 0-4-heteroaryl; - (CR245R250) 0-4-heterocycloalkyl; - (CR245Rz250) 0-4-aXYl- heteroaryl; - (CR245R250) 0-4-aryl-heterocycloalkyl ; ~ {(CR245R250) 0-a~-aryl-aryl; - (CRa45R250) g-s-heterocaryl-aryl; - (CR,4sR250) 0-a-heteroaryl-heterocycloalkyl; - (CR245R250) 0-4- heteroaryl-heteroaryl; -CHR,45-CHRa50-axyl; - (CR245R250) 0-4— heterocycloalkyl-heteroaryl; - (CR245R250) 0-4~ heterccycloalkyl-heterocycloalkyl; - {CR245R250) 0-4- heterocycloalkyl-aryl; a monocyclic or bicyclic ring of 5, 6, 7 8, 9, or 10 carbons fused to 1 or 2 aryl (preferably phenyl), heteroaryl (preferably pyridyl, imidazolyl, thienyl, thiazolyl, or pyrimidyl), or heterocycloalkyl (preferably piperidinyl or piperazinyl) groups; wherein 1, 2 or 3 carbons of the monocyclic or bicyclic ring are optionally replaced with -NH-, -N(CO)o-1Ra1s- , -N(CO)g-1Ra20-, =-0O-, or =-S(=0)¢-2-, and wherein the monocyclic or bicyclic ring is optionally substituted with 1, 2 or 3 groups that are independently -Raos, -Rasas, -Raso Or =0; and -C,-Cg¢ alkenyl optionally substituted with 1, 2, or 3
Roos groups; wherein each aryl or heteroaryl group attached directly or indirectly to the - (CR245R 250) 0-4 group is optionally substituted with 1, 2, 3 or 4 R200 groups; wherein each Theterocycloalkyl attached directly ox indirectly to the -(CRassRzs0)0-4 group is optionally substituted with 1, 2, 3, or 4 Rao;
Raoo at each occurrence is independently selected from -
Ci-Cs alkyl optionally substituted with 1, 2, or 3
Rayos groups; -OH; -NOz; -halogen; -C=N; - (CH;) ¢.4-CO- ’ NR220R225; - (CHz) 9-4-CO- (C1-C4 alkyl); -(CH,)-4-CO- (C,-Cs alkenyl); -(CHz).4-CO-(Cy-Cs alkynyl); - (CH;) ¢.4-CO- ! (C3-Cy cycloalkyl); - (CH) 0-4- (CO) g-1-aryl (preferably phenyl) ; - (CHz) o-4- (CO) g-1-heteroaryl (preferably pyridyl, pyrimidyl, furanyl, imidazolyl, thienyl, oxazolyl, thiazolyl, or pyrazinyl); -(CH)g.4- (CO)o.1- heterocycloalkyl (preferably imidazolidinyl, piperazinyl, pyrrolidinyl, piperidinyl, or tetrahydropyranyl) ; - (CH2) 9-4-CO2R215; - (CHz) 6-4-5803 -
NR220R225; - (CHz) 0-4-5 (0) 0.2- (C:-Cs alkyl); - (CHz) o-4-
S(O) ¢-2- (C3-C7 cycloalkyl) ; - (CH) 0-4~N(H or Rs) -
COz2R215; -(CHz) 0-4-N(H Or Ra;5) -SO02-Raag; - (CH) 9-4-N(H or
R215) -CO-N(Rp15) 2; - (CHz) 0-4-N(-H or R215) ~CO-Raz0; - (CH) 0-4 "NR20R225; = (CH) 9.4-0-CO- (C;-Cq alkyl); =-(CH,),- 4=0~ (R215); -(CHz2) 0-4-S- (Ra1s) ; - (CHa) .4-O- (C1-Cq alkyl optionally substituted with 1, 2, 3, or 5 -F); -C3-Ce alkenyl optionally substituted with 1 or 2 Raos groups; -C;-C¢ alkynyl optionally substituted with 1 or 2 Rzos groups; adamantly, and - (CH)g.4- C3-Cy cycloalkyl; each aryl and heteroaryl group included within R200 is optionally substituted with 1, 2, or 3 groups that are independently -R,ps, -Rsi0 OF -Cy-
Ce alkyl substituted with 1, 2, or 3 groups that are independently Ryps Or Rag; : each heterocycloalkyl group included within Rz00 is optionally substituted with 1, 2, or 23 groups that are independently Ryo;
Raps at each occurrence is independently selected : from -Ci-Ce alkyl, -C2-C¢ alkenyl, -C,-C alkynyl, -C,-Ce haloalkoxy, - (CHz) 0-3 (C3-C4 : cycloalkyl), -halogen, - (CH) 4-¢-OH, -O-phenyl,
OH, SH, -(CHz)o-6-C=N, =~ (CH)0.¢-C(=0)NRz35R240, -
CF3;, = -C3-C¢ alkoxy, C;-C¢ alkoxycarbonyl, and ~NR235R240;
R;10 at each occurrence is independently selected from -C1-Cs alkyl optionally substituted with 1, 2, or 3 Res groups; -C,-C¢ alkenyl optionally substituted with 1, 2, or 3 Ry groups; Ci-Cs alkanoyl; -80,- (C1-Cs alkyl); -C,-C¢ alkynyl optionally substituted with 1, 2, or 3 Rags groups; -halogen; -C1-Cs alkoxy; -C1-Cs haloalkoxy; ~-NR220R325; -OH; -C=N; -C3-Co cycloalkyl optionally substituted with 1, 2, or 3 Rayos groups; -CO-(C;-C4 alkyl); _S0;.NRz3sRzs0; -
CO-NR235R240; -S02- (C1-C4 alkyl); and =0;
Rais at each occurrence is independently selected from -C;-Cs alkyl, - (CHz) ¢-2- (aryl), -Cy-Cs alkenyl, -C;-C¢ alkynyl, -C;.C; cycloalkyl, - (CH;) 9-2- (heteroaryl), and -{CH3) gp-2- (heterocycloalkyl) ; wherein the aryl group included within Rj;5 is optionally substituted with 1, 2, or 3 groups that are independently -
Rzos5 Or -Rs,9; wherein the heterocycloalkyl and heteroaryl groups included within Rj; are optionally substituted with 1, 2, or 3 Rao;
R220 and Ras at each occurrence are independently H, -C;-Cs¢ alkyl, -CHO, hydroxy Ci-C¢ alkyl, C;-C¢ alkoxycarbonyl, -amino C;-C¢ alkyl, -S0,-C,-Cs alkyl, C;-C¢ alkanoyl optionally substituted with up to three halogens, -C(O)NH,, -C(O)NH(C;-
Ce alkyl), -C(O)N(C1-Cs alkyl) (C;-C¢ alkyl), -halo C;-Cs¢ alkyl, -(CH:),.2-(Cs-C; cycloalkyl), -(C1-Cs alkyl) -0-(C;-C3 alkyl), -C,-C¢ alkenyl, -
C2-Cs alkynyl, -aryl (preferably phenyl), -heteroaryl, or -heterocycloalkyl; wherein the aryl, heteroaryl and heterocycloalkyl groups included within R,,, and Ry2s is optionally substituted with 1, 2, or 3 Ruy groups,
R270 at each occurrence is independently -Raos, -
C1-C¢ alkyl optionally substituted with 1,
S 2, or 3 Raps groups; -Cy-Ce¢ alkenyl ‘ optionally substituted with 1, 2, or 3 Rags groups; -Cy-Cg alkynyl optionally substituted with 1, 2, or 3 Ros groups; - phenyl; -halogen; -C;-C¢ alkoxy; -Ci1-Cs haloalkoxy; -NRz3sRzs0; -OH; -C=N; -C3-C-, cycloalkyl optionally substituted with 1, 2, or 3 Rzs groups; -CO-(C;-C, alkyl) ; -502-NR235R240; -CO-NR235R240; | -80,-(Cy1-Cy alkyl); and =0;
Rais and Rago at each occurrence are independently -H, -C1-Cg alkyl, C2-Cs alkanoyl, -S0,-(C;-Cs alkyl), or -phenyl ;
Rz4s and Ryso at each occurrence are independently selected from H, - (CHz) ¢.4C0,C;,-Cy alkyl, - (CH2) ¢-4C (=0) C1-C4 alkyl, -C1-Cy alkyl, -C1-C4 hydroxyalkyl, -C1-C4 alkoxy, -C,-C, haloalkoxy, -(CHj)g.4-C3-Cy cycloalkyl, -C2-Cs alkenyl, -C,-C¢ alkynyl, .(CH,)o.4 aryl, -(CH,)q.4 heteroaryl, and - (CH:).4 heterocycloalkyl, or
Rass and Rpso are taken together with the carbon to which they are attached to form a monocycle or bicycle of 3, 4, 5, 6, 7 or 8 carbon atoms, where 1, 2, or 3 carbon atoms are optionally replaced by 1, 2, or 3 gropus that are independently -0-, -8S-, -802-, -C(0O) - r —NRzzg-, or -NRs30Rs20- wherein both R220 groups are alkyl; and wherein the ring is optionally substituted with 1, 2, 3, 4, 5, or 6 groups that are independently C;-C, alkyl, C.-C, alkoxy, hydroxyl, " NHz, NH(C;-Ce¢ alkyl), N(C;-C¢ alkyl) (C1-Cg alkyl), -NH-
C(0)C1~-Cs alkyl, -NH-SO0,- (Cy-Cs alkyl), or halogen;
wherein the aryl, heteroaryl or heterocycloalkyl groups included within Rags and Ras are optionally substituted with 1, 2, or 3 groups : that are independenly halogen, C;.¢ alkyl, CN or
OH.
The invention also provides methods for the treatment or prevention of Alzheimer's disease, mild cognitive impairment
Down's syndrome, Hereditary Cerebral Hemorrhage with
Amyloidosis of the Dutch-Type, cerebral amyloid angiopathy, other degenerative dementias, 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 comprising administration of a therapeutically effective amount of a compound or salt of formula I, to a patient in need thereof.
Preferably, the patient is a human.
More preferably, the disease is Alzheimer’s disease.
More preferably, the disease is dementia.
The invention also provides pharmaceutical compositions comprising a compound or salt of formula I and at least one pharmaceutically acceptable carrier, solvent, adjuvant or diluent.
The invention also provides the use of a compound or salt according to formula I for the manufacture of a medicament.
The invention also provides the use of a compound or salt of formula I for the treatment or prevention of Alzheimer's disease, mild cognitive impairment Down's syndrome, Hereditary
Cerebral Hemorrhage with Amyloidosis of the Dutch-Type, : cerebral amyloid angiopathy, other degenerative dementias, 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.
The invention also provides compounds, pharmaceutical 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, and for treating frontotemporal dementias with parkinsonism (FTDP).
The compounds of the invention possess beta-secretase inhibitory activity. The inhibitory activities of the compounds of the invention is readily demonstrated, for example, using one or more of the assays described herein or known in the art.
Unless the substituents for a particular formula are expressly defined for that formula, they are understood to ’ carry the definitions set forth in connection with the preceding formula to which the particular formula makes reference.
The invention also provides methods of preparing the compounds of the invention and the intermediates used in those methods. ‘ The invention also provides the use of compounds and pharmaceutically acceptable salts of formula I for the manufacture of a medicament for use in: treating a subject who has, or in preventing a subject from developing Alzheimer's disease (AD); preventing or delaying the onset of Alzheimer's disease; treating subjects with mild cognitive impairment (MCI); preventing or delaying the onset of Alzheimer's disease in subjects who would progress from MCI to AD; treating Down's syndrome; treating subjects who have Hereditary Cerebral
Hemorrhage with Amyloidosis of the Dutch-Type; treating cerebral amyloid angiopathy and preventing its potential consequences; treating other degenerative dementias; treating dementia associated with Parkinson's disease, progressive supranuclear palsy, or cortical basal degeneration; treating diffuse Lewy body type AD; and treating frontotemporal dementias with parkinsonism (FTDP).
As noted above, the invention provides compounds of formula I. In accordance with compounds of formula I and other applicable formulas below, when Z is (C3-C, cycloalkyl). ,(C;-Ce¢ alkyl)-, (C3-C; cycloalkyl),.1(C.-Cs alkenyl)-, (C3-C, cycloalkyl)o-1(C2-Cs alkynyl)- or (C3-C; cycloalkyl)-, 1 ox 2 methylene groups within said (C3-C; cycloalkyl),-1(Cy-Ce alkyl) -, (C3-C, cycloalkyl)e-1(C2-Cs alkenyl) -, (C3-C; cycloalkyl)g-1(Cz-Cs alkynyl) - or (C3-C, cycloalkyl)- groups are optionally replaced with -(C=0)-. This optionally substitution may be alpha to X, e.g., a,B-diketo compounds are contemplated by the invention
Further such carbonyl substitution contemplates compounds, for ) example, in which a methylene group is replaced in the cyclic portion the cycloalkyl group (to form a cyclic ketone moiety) and/or in which a methylene group is replaced in the alkyl, alkenyl or alkynyl portion of such groups.
Preferred compounds of formula I include those wherein Z is (C3-C; cycloalkyl)o-1(Ci-Ce alkyl) -, (C3-C; cycloalkyl),.;(Cz-Cs alkenyl) -, (C3-Cy cycloalkyl) .1(Cy-Cs alkynyl)- or (C3-Cy ’ cycloalkyl) -, wherein each of said groups is optionally substituted with 1, 2, or 3 R; groups;
Rz at each occurrence is independently halogen, -OH, -CN,
C.1-C¢ alkoxy, Ci3-C; cycloalkyl, C3;-C; cycloalkoxy, or -NRiooR1o01/
Rigo and R;0; are independently H, C;-Cg¢ alkyl, phenyl,
CO(C1-C¢ alkyl) or S0,C;-C¢ alkyl.
In another preferred embodiment, the invention encompasses compounds of formula I wherein Z is as defined above and X is -(C=0)-. In an alternative embodiment, X is - (C=0)-, and Z is H. In another preferred embodiment, X is - (C=0)-, and Z is C;-C4 alkyl, more preferably C;-C; alkyl, even more preferably methyl.
Preferred compounds of formula I further include those wherein R; 1s C;-Cip alkyl optionally substituted with 1 or 2 groups independently selected from halogen, -0OH, =0, -CF;, -
OCF;, -Ci3.; cycloalkyl, -C;-C, alkoxy, amino and aryl, wherein the aryl (preferably phenyl) group is optionally substituted with 1 or 2 Rss groups; :
Rso is selected from halogen, OH, -CO-(C;-C, alkyl), -NRsRg, Ci-Cs alkyl, C,-C¢ alkoxy and C3-Cg cycloalkyl; wherein the alkyl, alkoxy and cycloalkyl groups are optionally substituted with 1 or 2 substituents independently selected from C;-C;, alkyl, halogen, OH, -NRsRg¢, NR;Rg, and C,;-C; alkoxy;
Rs and R¢ at are independently H or C;-Cg¢ alkyl; or
Rs and R¢ and the nitrogen to which they are attached : form a 5 or 6 membered heterocycloalkyl ring; . and ]
R; and Rg are independently selected from -H; -C;-C, alkyl optionally substituted with 1, 2, or 3 groups independently selected from -OH, -NH,,
and halogen; -C3-C¢ cycloalkyl; and -(C1-C4 alkyl) -0-(Cy-Cq4 alkyl).
Preferred compounds of formula I also include those wherein
Ri is -CHp-phenyl where the phenyl ring is optionally ’ substituted with 1 or 2 groups independently selected from halogen, C;-C, alkyl, C;-C, alkoxy and hydroxy. More preferably, Ry is benzyl, 3-fluorobenzyl or 3,5- difluorobenzyl.
Preferred compounds of formula I include those wherein R, and R; are independently -H or -C;-Cg alkyl.
Equally preferred compounds of formula I include those wherein R;5 is H. : In another aspect, the invention provides compounds of the formula II: ion
Zo NANA
Ry (I1) and pharmaceutically acceptable salts thereof, wherein
Z is hydrogen, -Ci;-Cg¢ alkyl, -C,-C¢ alkenyl, -C,-Cs alkynyl or -
C3-Cy; cycloalkyl, where each of said groups is optionally substituted with 1 or 2 Ry; groups, wherein 1 or 2 methylene groups within said -C,-C¢ alkyl, -C,-C¢ alkenyl, -C2-Cs alkynyl or -C3;-C; cycloalkyl groups are optionally replaced with - (C=0)-;
Rz at each occurrence is independently halogen, -OH, -CN, -CF3, C1-C¢ alkoxy, C3-C; cycloalkyl, C;-C; cycloalkoxy or -NRjgoRi017
Rioo and Rip; are independently H, C;-C¢ alkyl, phenyl, CO(C;-Cs alkyl) or S0,C;-Cs alkyl; © 30 X is -C(=0)-;
Ry; is C;-Cio alkyl optionally substituted with 1 or 2 groups independently selected from halogen, -OH, =0, -CN, -CF,, -OCF3, -C3-C,; cycloalkyl, -C,-C;y alkoxy, amino, mono- dialkylamino, aryl, heteroaryl or heterocycloalkyl,
wherein the aryl group is optionally substituted with 1
Or 2 Rgso groups;
Rso is halogen, OH, CN, -CO-(C;-C4 alkyl), -NR4Rg, Cy -Ce . alkyl, C,-Ce¢ alkenyl, C,-Cs¢ alkynyl, C;-Cs alkoxy, and
C3-Cg cycloalkyl;
R; and Rg are selected from H; -C;-C4 alkyl optionally substituted with 1, 2, or 3 groups selected from -OH, -NH, and halogen; -C3-Cg cycloalkyl; -(C;-Cq alkyl)-0-(Cy-Cs alkyl); -Cz-
Cs alkenyl; and -C,-C, alkynyl;
Re is selected from - (CRz4sR2s0)0-a-aryl; - (CRassRas0)0-s-heterocaryl; - (CR245R250) 9-4-heterocycloalkyl; where the aryl and heteroaryl groups attached to the - (CRz4sRzs0)0-4- group are optionally substituted with 1, 2, 3 or 4 Ry groups; where the heterocycloalkyl group attached to the: - (CR245R250) 0-4- group is optionally substituted with 1, 2, 3, or 4 Rzi1p groups; and
Rass Rasg, Rago, and Raio are as defined above.
In another aspect, the invention provides compounds wherein
Rc is -(CRassR2s0)0-4-heterocycloalkyl (preferably piperidinyl, piperazinyl, pyrrolidinyl, 2-oxo-tetrahydroquinolinyl, 2- oxo-dihydro-1H-indolyl, or imidazolidinyl); where the heterocycloalkyl group attached to the -(CRz4s5Ras0)0-4- group is optionally substituted with 1, 2, 3, or 4 Ra, groups.
In a further preferred embodiment for compounds of formula II, Z is -C;-Cg¢ alkyl;
Ry is C;-Cio alkyl optionally substituted with 1 or 2 aryl groups, which are optionally substituted with 1 or 2 Rs, : groups, each Rgo is independently halogen, OH, CN, -NR;Rz or C,-Cg ’ alkyl,
R+ and Rg are independently -H; -C1-C4 alkyl optionally substituted with 1 or 2 groups independently selected from -OH, -NH,, and halogen; or -C3;-C¢ cycloalkyl; and
Re is - (CRy4sRus50) 0-4a-aryl or - (CR24sR2s0) 0-a-heterocaryl (preferably . the heteroaryl is pyridyl, pyrimidyl, quinolinyl, isoquinolinyl, more preferably pyridyl), where the aryl and heteroaryl groups are optionally substituted with 1
Or 2 Rago groups, where Ryo is as defined above.
Still more preferred compounds of formula II, include those wherein
Ry; is C3-Cp alkyl substituted with one aryl group, where the aryl (preferably phenyl or naphthyl, still more preferably phenyl) group is optionally substituted with 1 or 2 Rsg groups;
Re 1s - (CRp4sR250) 1-4-aryl or - (CRa4sRas0) 1-4-heteroaryl,
Raqs and R;so are independently selected from H, -(CH,),. 4C0C1-C4 alkyl, =~ (CHj).4COH, =-Ci-C,4 alkyl, -(C;,-C4 alkyl) OH, or
Rass, Rasp and the carbon to which they are attached form a monocycle or bicycle of 3, 4, 5, 6, 7 or 8 carbon atoms, where 1 or 2 carbon atoms are optionally replaced by -0-, -S-, -S0;-, or -NRjj0-, where Rj, is as defined above; and wherein the aryl and heteroaryl groups attached to the - (CR24s5R250) 1-4- groups are optionally substituted with 1 or 2 Rapp groups.
In another preferred embodiment of compounds of formula
IT,
Ry is C3-Cio alkyl substituted with one aryl group (preferably phenyl or naphthyl), which is optionally substituted with 1 or 2 Rsp groups, . Rso is independently halogen, OH, or C;-Cs alkyl;
Rc is -(CRaasRzso) aryl or - (CRassRzso) -heteroaryl, wherein the : aryl and heteroaryl groups attached to the ~- (CR245R250) 1-4- groups are optionally substituted with 1 or 2 substitutents selected from -Cl, -Br, -I, -C;-C alkyl, - (C:-C3 alkyl)OH, -CN, -C=CH, -C=C-CH,-OH, -CF,, -thienyl optionally substituted with a -C(=O)H group, -phenyl optionally substituted with 1 or 2 C;-Cs; alkyl groups, - (C1-C3 alkyl)OH group or -CO(C,-C; alkyl) group, - . isoxazolyl optionally substituted with a C;-C, alkyl group, or -(C;-C; alkyl)oxazolyl where the oxazole ring is optionally substituted with -C;-C; alkyl group;
Rz4s and Rasp at each occurance are independently -H, -C1-Cs alkyl, -(Ci-C; alkyl)CO,H, -( C;-C; alkyl)CO,(C;-C; alkyl), or -(C;-Cz; alkyl)OH, or
Rass and Rpsp are taken together with the carbon to which they are attached to form a monocycle or bicycle of 3, 4, 5, 6, 7 or 8 carbon atoms, where 1 or 2 carbon atoms is optionally replaced by -0~-, -8-, -S50,-, or -
NR320-, and
Ryo is as defined above.
In another aspect, the invention provides compounds of the formula III:
H OH Ris
AN x
R;R3 X3
Ry Xo (III) and pharmaceutically acceptable salts thereof; where
Z, X, Ri, Ry, R; and R;s are as definded above;
Xi is CH;, CHRz00, C(Rz00)2, Or -(C=0)-;
Xz, and X3 are independently CH, CHRzp0, C(Rap0)2, O, C=0, 8S,
SO,;, NH, or NRj7;
X, is a bond, CHa, CHRago, C(Rz00)2 O, C=0, S, SO,, NH, or NR; provided that when X; is -(C=0)-, X, is CHz, CHRa2qq, C(Rz00)2, 0, ) NH or NR; and the X3 group attached to X; is CH,, CHR,qq,
C (R200) 2, or SO; when X, is NH or NR; and X, is CH, CHR,go, . or C(Ragp)2 Or a bond; or -X2-X3- is -(C=0)0-, -0(C=0)-, -(C=0)NH-, -NH(C=0)- , = (C=0)NR;-, Or -NR;(C=0)-, with the proviso that X; is not
-(C=0) - and with the proviso that X; is CH;, CHRzg0, OY
C(Ra00)2 Or a bond; or -X3-X4- is -(C=0)0-, -0(C=0)-, -(C=0)NH-, -NH(C=0)-, -(C=0)NR,- : , or -NR,;(C=0)-, with the proviso that X; is CH;, CHRq0, or C(Rao0)2; OX ’ -X2-%3-%4- 1s - (C=0)NH-80,- or -S0,-NH(C=0)-, -(C=0)NR,-SO,- or -80,-NR;(C=0) -, with the proviso that X; is not -(C=0)-; and
Xs, Xe, X7 and Xz are CH or CRjo¢, Where 1 or 2 of X;, X44, X,; and
Xg 1s optionally replaced with N, and where Rys and R; are as defined above.
In a preferred embodiment of compounds of formula III, the invention further provides compounds of the formula IV:
H OH H z A Xi ~~ 2
X3
Ry Xo he (IV) wherein
Z is hydrogen, -C;-Cs¢ alkyl, -C,;-C¢ alkenyl, -C,-Cs alkynyl or -
C3-C; cycloalkyl, where each is optionally substituted with 1 or 2 Rz groups, and wherein 1 or 2 methylene groups within said -C;-C¢ alkyl, -C3-Cs alkenyl, -C,-C¢ alkynyl or -C3-C; cycloalkyl groups are optionally replaced with - (C=0) -;
Ry; at each occurrence is independently halogen, -OH, -CN, -CF;, C1-Cg¢ alkoxy, C;3;-C; cycloalkyl, C3-C; cycloalkoxy or -NRjioeoR101:
Rico and Ryo; are independently H, C;-Cg alkyl, phenyl, . CO (C;1-C¢ alkyl) or S0,C;-C¢ alkyl;
X is -C(=0)-; : Ry is C;-Cio alkyl optionally substituted with 1 or 2 groups independently selected from halogen, -OH, =0, -CN, -CF,, -OCF,;, -C3-C; cycloalkyl, -C1-C4 alkoxy, amino, mono-
dialkylamino, aryl optionally substituted with 1 or 2 Rs groups, heteroaryl or heterocycloalkyl;
Rso is halogen, OH, CN, -CO-(Ci-Cq alkyl), -NR,Rg, C;-Cs . alkyl, C;-C¢ alkenyl, C»-Cs¢ alkynyl, C,-Cs alkoxy or
C3-Cg cycloalkyl; and : R- and Rg are selected from H; -C;-C4 alkyl optionally substituted with 1, 2, or 3 groups selected from -OH, -NH, and halogen; -C3-Cg cycloalkyl; -(C;-Cs alkyl)-0-(C;-C4 alkyl); -C,-
Cs alkenyl; and -C;-C4 alkynyl.
In other preferred compounds of formula IV,
Z is -C;-C¢ alkyl;
Ry is C-Cyo alkyl optionally substituted with 1 or 2 aryl (preferably phenyl or naphthyl) groups, which are optionally substituted with 1 or 2 Rs, groups,
Rs 1s independently halogen, OH, CN, -NR;Rg or C;-Cg alkyl, R; and Rg are independently H; -C;-C4y alkyl optionally substituted with 1 or 2 groups independently selected from -OH, -NH,, and halogen; or -C3-Cg cycloalkyl; and
X1, X; or X;3 are CH; or CHR;p¢, where one of X; or X; is optionally replaced with 0, C=0, SO,, NH, NR,,
X, is a bond; and
Xs, Xe, X; and Xs are CH or CRyp, where one of Xs, Xs, Xs or Xg 1s optionally replaced with N, and :
Rago is as defined above.
In yet another preferred aspect of the invention for compounds of formula VI, R; is C;-Ci¢ alkyl substituted with one aryl group, where the aryl group is optionally substituted with 1 or 2 Rs groups; . X;, Xz and X3 are CH;, CHRa90, OY C(Ra00)2, where one of X; or X; is optionally replaced with O, NH or NR,, and where X, is a : bond; and
Xs, Xe, X; and Xs are CH or CRao, where one of Xs, Xs, X; or Xs is optionally replaced with N, where Rsy, Ra0o and R, are as defined above.
In a futher preferred embodiment of compound of formula
IV,
Ry; is C;-Cip alkyl substituted with one aryl group (preferably ’ phenyl or naphthyl, more preferably phenyl), where the aryl group is optionally substituted with 1 or 2 Rso groups, : Rso is independently halogen, OH, or C;-C¢ alkyl;
Xi, X, and X3 are CH, or CHR,o, where one of X; or Xj; is optionally replaced with O, NH or NR,;
XX, is a bond;
Xs, Xe, X; and Xg are CH or CRaoo, where one of Xs, Xe, X; and Xs is optionally replaced with N; and
Razoo 18 -Ci.4 alkyl, -halogen; -0-C;.; alkyl; -pyrrolyl or - (CH) 1-35-N (R47) 2, where R,; is as defined above.
In another aspect, the invention provides compounds of V:
LT
A 5;
Ry x, : Pe (V) and a pharmaceutically acceptable salt thereof, wherein
Z is hydrogen, -C;-Ce¢ alkyl, -C;-C¢ alkenyl, -Cz-Cs alkynyl or -
C3;-C; cycloalkyl, where each of said groups is optionally substituted with 1 or 2 Rz; groups, wherein 1 or 2 methylene groups within said -C,-C¢ alkyl, -Cz-C¢ alkenyl, -C,-C¢ alkynyl or -Ci3-C; cycloalkyl groups are optionally replaced with -(C=0)-;
Rz at each occurrence is independently halogen, -OH, -CN, -CF3, C1-C¢ alkoxy, Ci-C,; cycloalkyl, C3-C; cycloalkoxy . or -NRiooRio1;
Rio0 and Rio: are independently H, C:-C¢ alkyl, phenyl, : CO (C;-Cs alkyl) or S0,C;-Ce¢ alkyl;
X is -C(=0)-;
R, is C3-Cio alkyl optionally substituted with 1 or 2 groups independently selected from halogen, -OH, =O, -CN, -CFj,
-OCF,, -C3-C; cycloalkyl, -C;-C4 alkoxy, amino, mono- dialkylamino, aryl optionally substituted with 1 or 2 Rso groups, heteroaryl or heterocycloalkyl; ’ Rso is halogen, OH, CN, -CO-(C;-C, alkyl), -NRsRg, C;1-Cs alkyl, C,-Cg¢ alkenyl, C,-C¢ alkynyl, C;-Cg alkoxy and
C3-Cg cycloalkyl;
R» and Rg are selected from H; -C.-C¢ alkyl optionally substituted with 1, 2, or 3 groups selected from -OH, -NH: and halogen; -C3;-C¢ cycloalkyl; -(C;-Cs alkyl) -0-(C;-Cs alkyl); -C,-C; alkenyl; and -Cp-C4 alkynyl;
X;-Xg are indepdendently CH or CR;oo, where 1, 2, 3 or 4 of X; -
Xs are optionally replaced with N (more preferably, 1, 2, or 3 are replaced with N); where Ryo 1s as definded above.
In another preferred embodiment for compounds of forumula
Vv,
Z is -C1-Cs alkyl;
R; is C;-Cip alkyl optionally substituted with 1 or 2 aryl groups, where each aryl group is optionally substituted with 1 or 2 Rso groups,
Rs is independently halogen, OH, CN, -NR;sRg or C;-Cg alkyl,
R; and Rg are independently H; -C:-C; alkyl optionally substituted with 1 or 2 groups independently selected from -OH, -NH,, and halogen; or -C;-Cg cycloalkyl; and
X, - Xg are CH or CRjp, where one or two of X; - Xs is optionally replaced with N, and Rso and Rao are as defined above.
In another preferred embodiment for compounds of forumula : v,
R, is C;-Cio alkyl substituted with one aryl group, where the aryl group (preferably phenyl) is optionally substituted with 1 or 2 Rgp groups,
Rep is independently selected from halogen, OH, or C;-Cq alkyl;
Claims (16)
1. A compound of the formula I: Ho OH Ris A R; R2 Rs (I) or pharmaceutically acceptable salts thereof, wherein Z is hydrogen, or 7 is (C3-C; cycloalkyl)o.1(Ci1-Cs alkyl)-, (C3-Cy cycloalkyl) p-1(Ca- Ce alkenyl) -, (C3-Cq cycloalkyl) o-1(Cy-Cs alkynyl) - or (C3-Cy cycloalkyl) -, wherein each of said groups is optionally substituted with 21, 2, or 3 Rz groups, wherein 1 or 2 methylene groups within said (C3-Cy cycloalkyl) -1(Ci-Cs alkyl) -, (C3-Cq cycloalkyl) o-1(C2-Cs alkenyl) -, (C3-C4 cycloalkyl) o-1(C2-Cs alkynyl) - or (C;3-Cy cycloalkyl) - groups are optionally replaced with -(C=0)-; R, at each occurrence is independently halogen (in one aspect, F or Cl), -OH, -SH, -CN, -CFj3, -0OCF;, C1-Cg alkoxy, Ci3-C; cycloalkyl, C;3-Cy cycloalkoxy or - NRjooR1017 Rioo and Rip; at each occurrence are independently H, C,-Cs alkyl, phenyl, CO(C;-C¢ alkyl) or S50,Ci-Cs alkyl; X is -(C=0)- or -(80z)-; R, is C,-Ci¢ alkyl optionally substituted with 1, 2, or 3 groups independently selected from halogen, -OH, =0, -SH, -CN, -CF;, -OCFi3, -C;.o cycloalkyl, -Ci-C4 alkoxy, amino, mono- or dialkylamino, aryl, heteroaryl, and heterocycloalkyl, wherein each aryl group is optionally substituted with 1, 2 or 3 Rs, groups; each heteroaryl is optionally substituted with 1 or 2 Rs groups; and each heterocycloalkyl group is optionally substituted with 1 or 2 groups that are independently Rso Or =O;
Rs 1s selected from halogen, OH, SH, CN, -CO-(Ci-C4 alkyl), -NRsRg, -S(O)g-2-(Ci-Cq alkyl), Ci1-Ce alkyl, Cao- Ce alkenyl, C,-Cs¢ alkynyl, Ci1-C¢ alkoxy and GC;-Cg cycloalkyl; wherein the alkyl, alkenyl, alkynyl, alkoxy and cycloalkyl groups are optionally substituted with 1 or 2 substituents independently selected from C;-C4 alkyl, halogen, OH, -NRsRg, CN, C;-C4 haloalkoxy, NR,Rg, and C;-C, alkoxy; wherein Rs and R¢ are independently H or C;-C¢ alkyl; or Re and R¢ and the nitrogen to which they are attached form a 5 or 6 membered heterocycloalkyl ring; R, and Rs are independently selected from H; -C;-C4 alkyl optionally substituted with 1, 2, or 3 groups independently selected from -OH, -NH;, and halogen; -C3-Cg¢ cycloalkyl; -(C;-Cq alkyl) -O- (C;-Cq alkyl); -Co-Cy alkenyl; and -C,-Cy alkynyl; R, and R; are independently selected from H; F; -C1-Cs¢ alkyl optionally substituted with -F, -OH, -C=N, -CF3, C3-Cj alkoxy, or -NRsRg; - (CHz)o-2-Ri7; -(CH2)o-2-Ris; -C2-Cs alkenyl or C,-C¢ alkynyl, wherein the alkenyl and alkynyl groups are optionally substituted with 1 or 2 groups that are independently -F, -OH, -C=N, -CF; or C;-C3; alkoxy; - (CHy) o- ,-C3-C; cycloalkyl, which is optionally substituted with 1 or 2 groups that are independently -F, -OH, -C=N, -CFj, C,-C3 alkoxy and -NRgRg; R;; at each occurrence is an aryl group (preferably selected from phenyl, l-naphthyl, 2-naphthyl , indanyl, indenyl, dihydronaphthyl and tetralinyl,) wherein said aryl group is optionally substituted with one .or two groups that are independently -C;-C, alkyl; -C;-C4 alkoxy; CF3; -C;-C¢ alkenyl or -C;-Cq alkynyl each of which is optionally substituted with one substituent selected from F, OH, C.-C; alkoxy; halogen; OH; -C=N; -C3-C; cycloalkyl; -CO- (C1-Cy alkyl); or -80,-(C1-C4 alkyl); Rig 1s a heteroaryl group (preferably selected from pyridinyl, pyrimidinyl, guinolinyl, indolyl, pryidazinyl, pyrazinyl, isoquinolyl, quinazolinyl, quinoxalinyl, phthalazinyl, imidazolyl, isoxazolyl, oxazolyl, thiazolyl, furanyl, thienyl, pyrrolyl, oxadiazolyl or thiadiazolyl,) wherein said heteroaryl groups are optionally substituted with one or two groups that are independently -C;-Cs alkyl optionally substituted with one substituent selected from OH, C=N, CF;, C1-C; alkoxy, and -NRgRg; Ris 1s selected from hydrogen, C;-C¢ alkyl, C;-C¢ alkoxy, Ci1-Cg alkoxy C1-Cs alkyl, hydroxy C;-C¢ alkyl, halo C;-C¢ alkyl, each of which is unsubstituted or substituted with 1, 2, 3, or 4 groups independently selected from halogen, C;-Cg alkyl, hydroxy, Ci:-Cs alkoxy, and NH,, and -Rzs-R;;; wherein Rg 1s selected from a bond, -C(0) -, -505-, -CO5-, -C(O)NRs-, and -NRsC(O) -, Ry7 is selected from C;-Cs¢ alkyl, C;-C¢ alkoxy, aryl C;-Cs alkyl, Theterocycloalkyl, and heteroaryl, wherein each of the above is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently Cy~-Cy alkyl, Cy1-C4 alkoxy, halogen, haloalkyl, hydroxyalkyl, -NRsR¢, or -C(O)NRgRs; Or
R., Riz; and the carbon to which they are attached form a Ci;-C, carbocycle, wherein 1, 2, or 3 carbon atoms are optionally replaced by groups that are independently selected from -0-, -S-, -50,-, -C(0O)-, or -NRy;-; Re 1s selected from -(CHz),-3-(C3-Cg) cycloalkyl wherein the cycloalkyl 1s optionally substituted with 1, 2, or 3 groups independently selected from -Rzps; and -CO,-(Cy-C, alkyl); - (CR245R250) 0-4a-aryl; - (CR245R250) g-4~heteroaryl ; - (CR245R250) 0-a-heterocycloalkyl; - (CRa45R250) 0-4-axryl-
heteroaryl; - (CR24s5R250) 0-s-aryl-heterocycloalkyl; - (CR245R250) 9-a-axryl-aryl; - (CR245R250) 0-a-heteroaryl-aryl; - (CR245R250) 0-4-heteroaryl-heterocycloalkyl; ~ (CR245R250) 0-4- heteroaryl-heteroaryl; -CHR45-CHRas0-aryl; - (CR24sRzs0) 0-4" heterocycloalkyl-heterocaryl; - (CRza5R250) 0-4 heterocycloalkyl-heterocycloalkyl; - (CR245R250) 0-4- heterocycloalkyl-aryl; a monocyclic ox bicyclic ring of s, 6, 7 8, 9, or 10 carbons fused to 1 or 2 aryl (preferably phenyl), heteroaryl (preferably pyridyl, imidazolyl, thienyl, thiazolyl, or pyrimidyl), or heterocycloalkyl (preferably piperidinyl or piperazinyl) groups; wherein 1, 2 or 3 carbons of the monocyclic or bicyclic ring are optionally replaced with -NH-, -N(CO)(.1Ra1s- , -N(CO)g-1Rz20-, -0-, or -S(=0)y.2-, and wherein the monocyclic or bicyclic ring is optionally substituted with 1, 2 or 3 groups that are independently -Raos, -Raas, -Raso or =0; and -C;-C¢ alkenyl optionally substituted with 1, 2, or 3 Rags groups; wherein each aryl or heteroaryl group attached directly or indirectly to the - (CR245R250) 0-4 group is optionally substituted with 1, 2, 3 or 4 Rapo groups; wherein each heterocycloalkyl attached directly or indirectly to the - (CRassRzs0)0-4 group is optionally substituted with 1, 2, 3, ox 4 Raip;
R.o0o at each occurrence is independently selected from - C,-C¢ alkyl optionally substituted with 1, 2, or 3 Ras groups; -OH; -NO,; -halogen; -C=N; -(CHz),-4-CO- NR220R225; - (CHz)0-.4-CO- (C1-Cs alkyl); -(CHz)0-4-CO-(C2-Cq ) alkenyl); - (CH) .4-CO-(C2-Cg alkynyl); -(CHz),-4-CO- (C3-C, cycloalkyl); -(CHz)o-4-(CO)o-1-aryl (preferably phenyl) ; - (CHz) 0-4- (CO) g-1-heterocaryl (preferably pyridyl, pyrimidyl, furanyl, imidazolyl, thienyl, oxazolyl, thiazolyl, or pyrazinyl); -(CHz)o-a- (CO)o-1~ heterocycloalkyl (preferably imidazolidinyl, piperazinyl, pyrrolidinyl, piperidinyl, or tetrahydropyranyl); - (CHz)o-4-COaRa1s; - (CHa) 0-4-SO2-
NR220R225; - (CH3) 0-4-8 (0) ¢-2- (C1-Cs alkyl) ; - (CHz2) 0-4- S (0) g-2- (C3-C4 cycloalkyl) ; - (CH,) 0-4a-N(H or Rais) - CO2Rz15; = (CHa) 0-4-N(H Or Rais) -S02-Raz0; = (CHa)o-4-N(H or R215) ~CO-N (R215) 2; - (CH) 0-4-N(-H or R15) -CO-Raz20; - (CHz) 0-4-NRz20Rz225;, - (CH) -4-0-CO-(C1-C¢ alkyl); -(CHz)o- 4-0- (Rais) ; =~ (CHa2) 0-4-S- (Rais); -(CHz2)0-4-0-(C1-Cs¢ alkyl optionally substituted with 1, 2, 3, or 5 -F); -C2-Cg alkenyl optionally substituted with 1 or 2 Rags groups; -C,;-Ce¢ alkynyl optionally substituted with 1 or 2 Rags groups; adamantly, and -(CHz)o-.a- C3-Cy cycloalkyl;
each aryl and heteroaryl group included within Rjgo is optionally substituted with 1, 2, or 3 groups that are independently -Raps, -Raip Or -Ci- C¢ alkyl substituted with 1, 2, or 3 groups that are independently Raps Or Raip;
each ‘heterocycloalkyl group included within Rj is optionally substituted with 1, 2, or 3 groups that are independently Rig;
Rayos at each occurrence is independently selected from -C1-C¢ alkyl, -C3;-C¢ alkenyl, -C,-Cq alkynyl, ~-C1-Cg haloalkoxy, - (CH) 9-3 (C3-C4 cycloalkyl), -halogen, -(CH;)s-s-OH, -O-phenyl, OH, SH, - (CHz) 9-¢-C=N, - (CHz)0-¢-C(=0)NRz35R250, - CFy, -C;-Cg alkoxy, C1-Cs alkoxycarbonyl, and -NR235R240;
R210 at each occurrence is independently selected : from . -C;-Cs alkyl optionally substituted with 1, 2, or 3 Raps groups; -C,-C¢ alkenyl optionally substituted with 1, 2, or 3 Rjes groups; C;-Cg alkanoyl; -80,- (C1-C¢ alkyl); -C2-Cs alkynyl optionally substituted with 1, 2, or 3 Rag groups; -halogen; -C1-Cg alkoxy; -C,-Cs haloalkoxy; -NR230R595; -OH; -C=N; -C3-C4 cycloalkyl optionally substituted with 1, 2, or
3 Raps groups; -CO-(Ci-C, alkyl); _S0;.NRz3sRz40; - CO-NR335R240; -803-(C1-C4 alkyl); and =0;
Rois at each occurrence 1s independently selected from -C1-C¢ alkyl, - (CHz) 9-2- (aryl), -Cy-Cg alkenyl, -C;-C¢ alkynyl, -Ci;.C; cycloalkyl, - (CHj) 9-2- (heteroaryl), and - (CH2) ¢-2-
(heterocycloalkyl) ; wherein the aryl group included within Ras is optionally substituted with 1, 2, or 3 groups that are independently - Raps Or -Rjz10; wherein the heterocycloalkyl and heteroaryl groups included within Rj5 are optionally substituted with 1, 2, or 3 Rag;
Raz0 and Rass at each occurrence are independently H, -C;~-C¢ alkyl, -CHO, hydroxy C;-Cs alkyl, C1-Cg alkoxycarbonyl, -amino C;-C¢ alkyl, -S0,-C;-Cg alkyl, C;-C¢ alkanoyl optionally substituted with up to three halogens, -C(O)NH;, -C(O)NH(C;i- Ce alkyl), -C(O)N(C1-C¢ alkyl) (C;-C¢ alkyl), -halo C;-C¢ alkyl, -(CH)o-2-(C3-C; cycloalkyl), -(C1-C¢ alkyl) -0-(Cy-C; alkyl), -C,-C¢ alkenyl, - C,-Cs alkynyl, -aryl (preferably phenyl), -heteroaryl, or -heterocycloalkyl; wherein the aryl, heteroaryl and heterocycloalkyl groups included within Ra; and Ras 1s optionally substituted with 1, 2, or 3 Rj; groups, R270 at each occurrence is independently -Raps, - C1-Cs alkyl optionally substituted with 1, ’ 2, or 3 Roos groups; -Cy-Cg alkenyl optionally substituted with 1, 2, or 3 Ry groups; -Cy~-Ce alkynyl optionally substituted with 1, 2, or 3 Rie groups; - phenyl; -halogen; -C;-C¢ alkoxy; -C;-Cg haloalkoxy; -NRz3sRa40; -OH; -C=N; -C3-Cy cycloalkyl optionally substituted with 1, 2, or 3 Rays groups; -CO-(C;-Cq alkyl); -S5S02-NR235R240; -CO-NR235R2407 -S03- (C1-C4 alkyl); and =0; Ra3s and Rago at each occurrence are independently -H, -C;-Cg alkyl, C,-Cg alkanoyl, -S0;- (C1-C¢ alkyl), or -phenyl; Rass and Rpso at each occurrence are independently selected from H, - (CH) 0.4C0O2C1-C4 alkyl, - (CH3) 0-4C (=0) C1-C4 alkyl, -C1-C4 alkyl, -C1-C4 hydroxyalkyl, -C1-C4 alkoxy, -Ci1-C; halocalkoxy, -(CHz)g-4-C3-C; cycloalkyl, -C,-Cg alkenyl, -C3;-Cs alkynyl, -(CHz)¢-4 aryl, -(CHz)o-4 heteroaryl, and -(CH,)o.1 heterocycloalkyl, or Rass and Ryso are taken together with the carbon to which they are attached to form a monocycle or bicycle of 3, 4, 5, 6, 7 or 8 carbon atoms, where 1, 2, or 3 carbon atoms are optionally replaced by 1, 2, or 3 gropus that are independently -0O-, -S-, -S0;-, -C(O)- , -NR320-, Or -NR;3;0Rs;0- wherein both Ri; groups are alkyl; and wherein the ring is optionally substituted with 1, 2, 3, 4, 5, or 6 groups that are independently C;-C, alkyl, ¢C;-Csy alkoxy, hydroxyl, NH,, NH(C;-C¢ alkyl), N(C,-Cs alkyl) (C:-C¢ alkyl), -NH- C(0)C1-Cs alkyl, -NH-S0,-(C,-Cs alkyl), or halogen; wherein the aryl, heteroaryl or heterocycloalkyl groups included within Ras and Rpsg are optionally substituted with 1, 2, or 3 groups that are independenly halogen, C;-¢ alkyl, CN or OH.
2. A compound according to claim 1, wherein Z is (C3-C, cycloalkyl) -1(C1-Cs alkyl) -, (C3-Cq cycloalkyl) -1(Ca-Cg alkenyl) -, (C3-C; cycloalkyl),1(C-Cs alkynyl)- or (C3-Cy cycloalkyl) -, wherein each of said groups is optionally substituted with 1, 2, or 3 R; groups;
wherein, Rz; at each occurrence is independently halogen, - OH, -CN, C:-Cs alkoxy, C3-C, cycloalkyl, C3;-C, cycloalkoxy, -NRigoR101; : where R;o0 and Rion are independently H, C;-C¢ alkyl, phenyl, CO(C;-C¢ alkyl) or S0,C;-Cs alkyl.
3. A compound according to claim 1, wherein X is - (C=0) -.
4. A compound according to claim 3, wherein Z is H. :
5. A compound according to claim 1, wherein R; is C;-Cio alkyl optionally substituted with 1 or 2 groups independently selected from halogen, -OH, =0, -CF;, -OCF;, -Ci;.; cycloalkyl, - ¢;-C; alkoxy, amino or aryl, wherein the aryl group is optionally substituted with 1 or 2 Rs, groups; wherein Rs 1s selected from halogen, OH, -CO-(C;-C, alkyl), ~-NR-Rg, C1-Cs alkyl, C1-Cs alkoxy and C3-Cg cycloalkyl; wherein the alkyl, alkoxy and cycloalkyl groups are optionally substituted with 1 or 2 substituents independently selected from C;-C, alkyl, halogen, OH, -NRsRg, NR;Rs, and C;-C; alkoxy; wherein Rs and R¢ at are independently H or C;-C¢ alkyl; or wherein Rs and Rg and the nitrogen to which they are attached form a 5 or 6 membered heterocycloalkyl ring; and wherein R; and Rg are independently selected from -H; -C;-C, alkyl optionally substituted with 1, 2, or 3 : groups independently selected from ~-OH, -NH,, and halogen; - C3-C¢ cycloalkyl; -(C;-C4 alkyl) -0-(C;-C, alkyl).
6. A compound according to claim 5, wherein R, is -CH,- phenyl where the phenyl ring is optionally substituted with 1 or 2 groups independently selected from halogen, C;-C; alkyl,
C.-C; alkoxy and hydroxy. .
’
7. A compound according to claim 6, wherein Ry is benzyl, 3-fluorobenzyl or 3,5-difluorobenzyl.
8. A compound according to claim 1, wherein Rs is H.
9. A compound according to claim 7, wherein Rs is H.
10. A compound according to claim 1 of the formula II: Hoon Ne Ri (1m) wherein 2 is hydrogen, -C;-Cs alkyl, -C,-C¢ alkenyl, -C;-Cs alkynyl or -C3-C; cycloalkyl, where each of said groups is optionally substituted with 1 or 2 Rz groups, wherein 1 or 2 methylene groups within said -C;-Cs alkyl, -Cy-Ce¢ alkenyl, -Cs- Ce alkynyl or -C3-C; cycloalkyl groups are optionally replaced with -(C=0)-; wherein Rz; at each occurrence is independently halogen, - OH, -CN, -CF;, Ci-C¢ alkoxy, Ci-C, cycloalkyl, C3-Cy cycloalkoxy or -NRjgoRig1; where Rigo and R;0; are independently H, C1-C¢ alkyl, phenyl, CO(C;-C¢ alkyl) or S0,C;-Cs alkyl; wherein X is -C(=0)-; wherein R; is C;-Cio alkyl optionally substituted with 1 or 2 groups independently selected from halogen, -OH, =0, -CN, -CFj,
. -OCF3, -C3-Cy cycloalkyl, -C1-C4 alkoxy, amino, mono- dialkylamino, aryl, heteroaryl or heterocycloalkyl, wherein
. the aryl group is optionally substituted with 1 or 2 Rg groups;
where Rs, is halogen, OH, CN, -CO-(C;-C,4 alkyl), -NR;Rs, Ci- Ce alkyl, C,-C¢ alkenyl, C;-C¢ alkynyl, C;-Ces alkoxy and Cs- Cg cycloalkyl; ’ where R; and Rg are selected from H; -C;-C, alkyl optionally substituted with 1, 2, or 3 groups selected from -OH, -NH, and halogen; -C3-Cs cycloalkyl; -(C;-Cs alkyl)-0-(Ci-Cs alkyl); -Cao-C4 alkenyl; and -C,-C; alkynyl; wherein R¢ is selected from - (CRa¢sRase) 0-a-2ryl; - (CR245R250) 0-4a-heterocaryl; - (CRa45R250) 0-4-heterocycloalkyl; where the aryl group attached to the - (CRzgsRase)o-a- group is optionally substituted with 1, 2, 3 or 4 Ryo groups; where the heteroaryl group attached to the - (CRzssRaso) 0-4- group is optionally substituted with 1, 2, 3, or 4 Rao groups; where the heterocycloalkyl group attached to the - (CRz4sRzs0)o-a- group is optionally substituted with 1, 2, 3, or 4 Raz groups.
11. A compound according to claim 10, wherein 7Z is -C1-Cg alkyl; R, is C1-Cio alkyl substituted with 1 phenyl group, where the phenyl group attached to the alkyl is optionally substituted with 1 or 2 Rsy groups, where each Rs is independently halogen, OH, CN, or C;-Cs¢ alkyl; and Re 1S - (CRzssRazso) 0-a-aryl or - (CRassRaso)o-4-heteroaryl, where the aryl and . heteroaryl groups are optionally substituted with 1 or 2 Rage groups.
12. A compound according to claim 1 which is : N-T(1S,2R)-3-[(3-bromobenzyl)amino] -1-(3,5- difluorobenzyl) -2-hydroxypropyl]l acetamide; ’ : N- ((18,2R) -1- (3,5-difluorobenzyl) -2-hydroxy-3-{ [ (4R)-6- isopropyl-2,2-dioxido-3,4-dihydro-1H-isothiochromen-4- yl]amino}propyl)acetamide;
N- ((1S,2R) -1-(3,5-difluorobenzyl) -2-hydroxy-3-{[(4S)-6- isopropyl-2,2-dioxido-3,4~-dihydro-1H-isothiochromen-4- yllamino}propyl) acetamide; :
N-{(18,2R) -1-(3,5-diflucrobenzyl) -3-[(6-ethyl-2,2-
dioxido-3,4-dihydro-1H-isothiochromen-4-yl)aminol]-2- hydroxypropyl }acetamide;
N-{(18,2R) -1-(3,5-difluorobenzyl)-3-[(6-ethyl-2,2- dioxido-3,4-dihydro-1H-isothiochromen-4-yl)amino] -2- hydroxypropyl acetamide;
N-[(1S,2R) -3-{[1- (3-bromophenyl) cyclopropyl] amino}-1- (3,5-difluorobenzyl) -2-hydroxypropyl] acetamide hydrochloride; methyl 3-{[(2R,3S)-3-(acetylamino)-4-(3,5- difluorophenyl) -2-hydroxybutyl]amino}-3- (3- bromophenyl) propanoate; N-{(18,2R) -1-(3,5-difluorobenzyl) -3- [(3- ethylbenzyl) amino] -2-hydroxypropyl }acetamide;
methyl 3-{[(2R,3S)-3-(acetylamino)-4-(3,5- difluorcphenyl) -2-hydroxybutyl]lamino}-3- (3- ethylphenyl) propanoate;
3-{[(2R,38) -3- (acetylamino) -4-(3,5-difluorophenyl) -2- hydroxybutyljamino}-3-(3-ethylphenyl) propanoic acid;
N-((1S,2R) -1-(3,5-difluorobenzyl) -3-{ [1- (3-ethylphenyl) - 3-hydroxypropyllamino}-2-hydroxypropyl)acetamide;
N-{(1S,2R) -1-(3,5-difluorobenzyl) -2-hydroxy-3-[(1S) -
1,2,3,4-tetrahydronaphthalen-1-ylaminol propyl }acetamide;
N-{(1S,2R) -1-(3,5-difluorobenzyl) -3-{(2,2-dioxido-3,4- dihydro-1H-isothiochromen-4-yl) amino] -2- hydroxypropyl }acetamide;
N-[1- (3,5-Difluoro-benzyl) -3- (6-ethyl-2,2-dioxo-2A%-
isothiochroman-4-ylamino) -2-hydroxy-propyl]-2-methylamino- acetamide; :
N-{(18,2R) -1-(3,5-difluorobenzyl) -2-hydroxy-3-[(3- iodobenzyl) amino] propyl }acetamide;
methyl 3-{[(2R,38)-3- (acetylamino)-4-(3,5- difluorophenyl) -2-hydroxybutyl]l amino}-3- (3- iodophenyl) propanoate; : methyl 3-{[(2R,3S)-3- (acetylamino)-4-(3,5- difluorophenyl)-2-hydroxybutyl]amino}-3-[3-(3-hydroxyprop-1- ’ ynyl) phenyl] propanoate; N-((1S,2R)-1-(3,5-difluorobenzyl) -2-hydroxy-3-{[3- hydroxy-1- (3-iodophenyl) propyl] amino }propyl) acetamide; methyl 3-{[(2R,3S)-3-(acetylamino)-4-(3,5- difluorophenyl)-2-hydroxybutyl]amino}-3-[3-(3- hydroxypropyl) phenyl] propanoate; N-{(1S,2R)~-1-(3,5-difluorobenzyl) -2-hydroxy-3-[(7- methoxy-1, 2,3, 4-tetrahydronaphthalen-1- yl) amino] propyl}acetamide; 2-Amino-N-[1- (3,5-difluoro-benzyl) -3- (6-ethyl-2,2-dioxo- 2A%-isothiochroman-4-ylamino) -2-hydroxy-propyl] -acetamide; N-((18,2R)-1-(3,5-difluorobenzyl) -3-{[6-ethyl-2- (methylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-4-yllamino}-2- hydroxypropyl) acetamide; : N-((1S,2R)-1-(3,5-difluorobenzyl) -3-{ [(1S) -7-ethyl- 1,2,3,4-tetrahydronaphthalen-1-yllamino}-2- hydroxypropyl) acetamide; N- ((18,2R)-1-(3,5-diflucrobenzyl) -3-{ [(1R) -7-ethyl- 1,2,3,4-tetrahydronaphthalen-1-yllamino}-2- hydroxypropyl) acetamide; N-[(1S,2R)-3-{[1- (3-bromophenyl)cyclopropyl]lamino}-1- (3,5-difluorobenzyl) -2-hydroxypropyll acetamide; methyl 3-{[(2R,38)-3- (acetylamino)-4-(3,5- difluorophenyl) -2-hydroxybutyl]amino}-3-[3-(5-formylthien-2- vyl)phenyl]propanoate; methyl 3-{[(2R,3S)-3-(acetylamino)-4-(3,5- difluorophenyl) -2-hydroxybutyllamino}-3-(2'-acetyl-1,1"'- biphenyl-3-yl) propanoate;
N-[1-(3,5-Difluoro-benzyl) -3-(6-ethyl-2,2-dioxo-2A°- isothiochroman-4-ylamino) -2-hydroxy-propyll} -3-methyl- butyramide;
N-[(1S,2R)-1-(3,5-difluorobenzyl) -2-hydroxy-3- ({1-[3'-
(hydroxymethyl) -1,1'-biphenyl-3- ylleyclopropyl}amino) propyl] acetamide;
N-[(1S,2R) -1-(3,5-difluorobenzyl) -3- ({1-[3-(5- formylthien-2-yl) phenyl] cyclopropyl }amino) -2- hydroxypropyl] acetamide;
N-{(18,2R) -1-(3,5-diflucrobenzyl) -3- (9H-fluoren-9- ylamino) -2-hydroxypropyl] acetamide;
methyl 3-{[(2R,38)-3- (acetylamino) -4-(3,5- difluorophenyl) -2-hydroxybutyl]amino}-3-[3- (trifluoromethyl) phenyl] propanoate;
methyl 3-{[(2R,38)-3-(acetylamino)-4-(3,5- difluorophenyl) -2-hydroxybutyl]amino}-3- (3- cyanophenyl) propanoate;
N- [1-(3,5-Difluoro-benzyl) -3- (6-ethyl-2,2-dioxo-2A%- isothiochroman-4-ylamino) -2-hydroxy-propyll} -3-hydroxy-2,2-
dimethyl-propionamide;
N- ((18,2R) -1- (3, 5-difluorobenzyl) -3-{[1-(3- ethylphenyl) cyclopropyl] amino}-2-hydroxypropyl) acetamide;
methyl 3-{[(2R,38)-3- (acetylamino) -4-(3,5- difluorophenyl) -2-hydroxybutyl]amino}-3- (3-
bromophenyl) propanoate;
N- ((1S,2R) -1- (3, 5-difluorobenzyl) -3-{[1-(3- ethynylphenyl) cyclopropyl] amino} -2-hydroxypropyl) acetamide;
N-[(1S,2R) -3-[(2-bromo-9H-fluoren-9-vyl)amino] -1-(3,5- difluorobenzyl) -2-hydroxypropyl] acetamide;
N-{(1S,2R)-1-(3,5-difluorobenzyl) -3-[(2-ethyl-9H-fluoren- 9-y1)amino] -2-hydroxypropyl acetamide;
N-{(1S,2R) -1-(3,5-difluorobenzyl) -3-[(2,2-dioxido-3,4- dihydro-1, 2-benzoxathiin-4-yl)amino] -2- hydroxypropyl acetamide;
N-{(1S8,2R)-1-(3,5-difluorobenzyl) -2-hydroxy-3- [(6-iodo- 3,4-dihydro-2H-chromen-4-yl)amino] propyl }acetamide;
N-((1S,2R)-1-(3,5-difluorobenzyl) -2-hydroxy-3-{[ (4S) -6-
: iodo-3,4-dihydro-2H-chromen-4-yl] amino }propyl) acetamide; N- ((1S,2R) -1-(3,5-difluorobenzyl) -2-hydroxy-3-{[ (4R) -6- iodo-3,4-dihydro-2H-chromen-4-yl]lamino}propyl) acetamide;
N-[1- (3,5-Difluoro-benzyl) -3- (6-ethyl-2,2-dioxo-2A°%- isothiochroman-4-ylamino) -2-hydroxy-propyl] -3-hydroxy- propionamide;
N-{(18,2R)-1-(3,5-difluorobenzyl) -3-[(6-ethyl-2,2- dioxido-3,4-dihydro-1,2-benzoxathiin-4-yl)amino] -2- hydroxypropyl }acetamide;
N-{(18,2R)-1-(3,5-difluorobenzyl) -3-[(6-ethyl-2,2- dioxido-3,4-dihydro-1,2-benzoxathiin-4-yl)amino] -2-
hydroxypropyl }acetamide;
N- ((18,2R)-1-(3,5-difluorobenzyl) -3-{[4-(3- ethylphenyl) tetrahydro-2H-pyran-4-yl]lamino}-2- hydroxypropyl) acetamide;
N- ((1S,2R)-1-(3,5-difluorobenzyl) -3-{[1-(3-
ethylphenyl)butyllamino}-2-hydroxypropyl)acetamide;
N- ((1S,2R)-1-(3,5-difluocrobenzyl) -3-{[(4S)-6-ethyl-3,4- dihydro-2H-chromen-4-yl] amino} -2-hydroxypropyl) acetamide;
N- ((1S,2R)-1-(3,5-difluorobenzyl) -3-{[(4R)-6-ethyl-3,4- dihydro-2H-chromen-4-yl]l amino} -2-hydroxypropyl) acetamide;
N-{(1S,2R)-1-(3,5-difluorobenzyl) -3-[(7-ethyl-1,2,3,4- tetrahydronaphthalen-1-yl) amino] -2-hydroxypropyl }acetamide;
N- [1- (3,5-Difluoro-benzyl) -3- (6-ethyl-2,2-dioxo-2A%- isothiochroman-4-ylamino) -2-hydroxy-propyl] -3-hydroxy- butyramide;
N- ((1S,2R) -1-(3,5-difluorobenzyl) -3-{ [1-(3- ethylphenyl) cyclohexyl] amino} -2-hydroxypropyl) acetamide;
N- ((1S,2R)-1-(3,5-difluorobenzyl) -3-{[1-(3- ethylphenyl) cyclopentyl] amino} -2-hydroxypropyl)acetamide;
N-{(18,2R)-1-(3,5-difluorobenzyl)-3-[(6-ethyl-3,4- dihydro-1H-isothiochromen-4-yl) amino] -2- hydroxypropyl }acetamide; ' N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(2-ethyl-5-fluoro- 9H-fluoren-9-yl) amino] -2-hydroxypropyl }acetamide;
) methyl (3S)-3-{[(2R,38)-3- (acetylamino)-4-(3,5- difluorophenyl) -2-hydroxybutyl]lamino}-3- (3- ethylphenyl)butanoate;
N-((1S,2R)-1-(3,5-difluorobenzyl) -2-hydroxy-3-{[1-(3- isobutylisoxazol-5-yl)cyclopropyl]amino}propyl)acetamide; N-[1-(3,5-Difluoro-benzyl)-3- (6-ethyl-2,2-dioxo-2A%- isothiochroman-4-ylamino) -2-hydroxy-propyl] -2-phenyl- acetamide; N-{(1S,2R) -1-(3,5-difluorobenzyl)-3-{(2-ethyl-7-fluoro- 9H-fluoren-9-yl)amino] -2-hydroxypropyl }acetamide; methyl (3R)-3-{[(2R,38)-3- (acetylamino)-4-(3,5- difluorophenyl) -2-hydroxybutyl]lamino}-3- (3- ethylphenyl)butanocate; N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(2,5- dipropylbenzyl) amino] -2-hydroxypropyl acetamide; {[1-(3,5-Difluoro-benzyl) -3- (6-ethyl-2,2-dioxo-2A°%- isothiochroman-4-ylamino) -2-hydroxy-propylcarbamoyl] -methyl } - methyl-carbamic acid tert-butyl ester; N-{(18,2R)-1-(3,5-difluorobenzyl) -2-hydroxy-3-[(2- isobutyl-9H-fluoren-9-yl)aminol propyl }acetamide; N- ((1S,2R)-1-(3,5-difluorobenzyl) -3-{ [ (18) -6-ethyl-2,3- dihydro-1H-inden-1-yl]amino}-2-hydroxypropyl) acetamide; N-[1-(3,5-Difluoro-benzyl)-3- (6-ethyl-2,2-dioxo-2A°%- isothiochroman-4-ylamino) -2-hydroxy-propyl] -2-methyl-2- methylamino-propionamide; N- ((1S,2R)-1-(3,5-difluorobenzyl) -3-{ [1-ethyl-1-(3- ethylphenyl)propyl]lamino}-2-hydroxypropyl)acetamide; N-{(1S,2R)-1-(3,5-difluorobenzyl) -3-[ (6-ethyl-2,2- dioxido-3,4-dihydro-1H-2, l1-benzothiazin-4-yl) amino] -2- hydroxypropyl acetamide;
N-{(18,2R) -1-(3,5-difluorobenzyl)-3-[(6-ethyl-2,2- dioxido-3,4-dihydro-1H-2, 1-benzothiazin-4-yl) amino] -2- hydroxypropyl acetamide;
: N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(6-ethyl-3-methyl- 2,2-dioxido-3,4-dihydro-1H-isothiochromen-4-yl)amino]-2- ) hydroxypropyl }acetamide;
N-{(1S,2R) -1-(3,5-difluorobenzyl)-3-[(6-ethyl-3-methyl- 2,2-dioxido-3,4-dihydro-1H-isothiochromen-4-yl)amino]-2- hydroxypropyl acetamide;
N-{(1S,2R)-1-(3,5-difluorobenzyl) -3-[(6-ethyl-1-methyl- 1,2,3,4-tetrahydroquinolin-4-yl) amino] -2- hydroxypropyl }acetamide;
methyl 3-{[(2R,3S)-3- (acetylamino)-4-(3,5- difluorophenyl) -2-hydroxybutyl]amino}-3-(3-
ethylphenyl)propanoate;
N-[1-(3,5-Difluoro-benzyl) -3- (6-ethyl-2,2-dioxo-2A°- isothiochroman-4-ylamino) -2-hydroxy-propyl] -2- (1H-imidazol-4- yl) -acetamide;
methyl 3-{[(2R,3S)-3- (acetylamino)-4-(3,5-
difluorophenyl) -2-hydroxybutyl]amino}-3-(3- ethylphenyl)propanoate;
N-[(1S,2R)-3-[(2-bromo-9-methyl-9H-fluoren-9-yl)amino] -1- (3,5-difluorobenzyl) -2-hydroxypropyl] acetamide;
N-((1S,2R) -1-(3,5-difluorobenzyl) -3-{[2- (1-ethylpropyl) -
9H-fluoren-9-yllamino}-2-hydroxypropyl)acetamide;
N-[(1S,2R)-3-[(2-cyclopentyl-9H-fluoren-9-yl) amino] -1-
(3,5-difluorobenzyl) -2-hydroxypropyl]lacetamide;
N-[1- (3,5-Difluoro-benzyl) -3- (6-ethyl-2,2-dioxo-2A%- isothiochroman-4-ylamino) -2-hydroxy-propyl] -propionamide;
N-{(1S,2R)-1-(3,5-difluorobenzyl) -3-[(2-ethyl-9-methyl- 9H-fluoren-9-yl) amino] -2-hydroxypropyl }acetamide;
N- [(1S,2R)-3-[(2-cyclohexyl-9H-fluoren-9-yl) amino] -1-
(3,5-difluorobenzyl) -2-hydroxypropyllacetamide;
N-((1S,2R)-1-(3,5-difluorobenzyl) -3-{[1-(4-ethylpyridin-
2-yl)cyclopropyllamino}-2-hydroxypropyl)acetamide;
rnaxn LE Tr 117 Hove CRpVL TNO’ FA LUPO CRPPPORs Elan No. 00447-PCL-NEW - N- ((18,2R) -1- (3, 5-difluorobenzyl) -2-hydroxy-3-{ [ (45) -6- (1H-pyrrol-3-yl) -3, 4-dihydro-2H-chromen-4-
. yllamino}propyl)acetamide; N-((1S,2R) -1- (3, 5-difluorobenzyl) -3-{ [(5R) -3~-ethyl-
‘ 6.7.8,9-tetrahydro-5H-benzo [7]annulen-5-yllamino}-2- hydroxypropyl) acetamide; N- [(18,2R) -3-{ [1- (3-bromophenyl) -1-methylethyl]amino}-1- (3,5-difluorobenzyl) -2-hydroxypropyllacetamide; N- ((18,2R) -1- (3,5-difluorobenzyl) -3-{ [2~ (dimethylamino) - 9H-fluoren-9-yllamino}-2-hydroxypropyl) acetamide; N- ( (1S, 2R) -1- (3, 5-difluorobenzyl) -2-hydroxy-3-{ (18) -7- propyl-1,2,3,4-tetrahydronaphthalen-1- yllamino}propyl) acetamide; N-[(1S,2R) -1- (3, 5-difluorobenzyl) -3- ({ (18) -7- [ (dimethylamino) methyll-1,2,3,4-tetrahydronaphthalen-1- y1}amino) -2-hydroxypropyllacetamide; N-T(18,2R)-3-{[(18)-7-bromo-1,2,3, 4-tetrahydronaphthalen- 1-yl]amino}-1- (3,5-difluorobenzyl) -2-hydroxypropyllacetamide; N- ((1S,2R) -1-(3,5-difluorobenzyl) -2-hydroxy-3-{{1-(3- propylphenyl) cyclopropyl] amino}propyl) acetamide; N- ((1S,2R) -1- (3,5~difluorobenzyl) ~3-{[1-(3- : ethylphenyl) cycloheptyllamino}-2-hydroxypropyl) acetamide; N-{(18,2R) -1- (3,5-difluorobenzyl) -2-hydroxy-3- [(6- isopropyl-3,4-dihydro-2H-chromen-4-yl) amino} propyl}acetamide; N-{(1S,2R) -1- (3,5-difluorobenzyl) -3- [(6-ethyl-2-hydroxy- 2,3-dihydro-1H-inden-1-yl) amino] -2-hydroxypropyl }acetamide; N-{(18,2R)-~1- (3,5-difluorobenzyl) -3- [(2-ethyl-6-flucro- 9H-fluoren-9-yl) amino] -2-hydroxypropyl}acetamide; N- ( (18, 2R) -1- (3,5-difluorobenzyl) -2-hydroxy-3-{[2- ‘methoxymethyl) -9H-fluoren-9-yl]amino}propyl) acetamide; N-((18,2R) -1- (3,5-difluorobenzyl) -3-{ [1- (3-ethylphenyl) - . 2- (5-methyl-1,3-oxazol-2-yl)ethyllamino}-2- hydroxypropyl) acetamide hydrochloride; N-[(18,2R) -1- (3,5-difluorobenzyl) -3~ (3, 4-dihydro-2H- chromen-4-ylamino) -2-hydroxypropyll acetamide;
Ele, 0h Loin ben aeons TT
N-((18,2R)~1~(3,5-difluorobenzyl) -3-{ [2-ethyl-5- (trifluoromethyl) -9H-fluoren-9-yllamino}-2-
hydroxypropyl) acetamide;
N-((18,2R)-1-(3,5-difluorobenzyl) -2-hydroxy-3-{[2~ (3-
, methylbutyl) -9H-fluoren-9-yl] amino}propyl) acetamide;
N-{(18,2R) -1-(3,5-difluorobenzyl) -2-hydroxy-3-[(2- isopropyl-9H-fluoren-9-yl)amino] propyl acetamide;
N-{(1S,2R)-1-(3,5-difluorobenzyl) -2-hydroxy-3-[(2- neopentyl-9H-fluoren-9-yl)amino] propyl }acetamide;
N-{(18,2R)~1-(3,5-difluorobenzyl) -2-hydroxy-3-[ (2- isopropenyl-9H-fluoren-9-yl)amino] propyl }acetamide;
N-((18,2R)-1-(3,5-difluorobenzyl) -3-{[1- (3-ethylphenyl) - l1-methylethyl] amino} -2-hydroxypropyl) acetamide hydrochloride;
N-((1S,2R)-1-(3,5-difluorobenzyl) -2-hydroxy-3-{[ (4S) -6- isobutyl-3,4-dihydro-2H-chromen-4-yl]amino}propyl) acetamide;
N-[(1S8,2R) -3-{[(48) -6-cyano-3,4-dihydro~2H-chromen-4- yllamino}-1-(3,5-difluorobenzyl) -2-hydroxypropyll acetamide;
N-((18,2R) -1-(3,5-difluorobenzyl) -2-hydroxy-3-{[ (48) -6- neopentyl-3, 4-dihydro-2H-chromen-4-yl}amino}propyl) acetamide;
N-{(18,2R)-1-(3,5-difluorobenzyl) -2-hydroxy-3-[ (6- neopentyl-3, 4~dihydro-2H-chromen-4-yl) amino] propyl }acetamide;
N-((18,2R)-1-(3,5-diflucrobenzyl) -2-hydroxy-3-{ [2- (isopropylamino) -9H-fluoren-9-yll amino }propyl) acetamide;
N-((18,2R)-1-(3,5-difluorobenzyl) -2-hydroxy-3-{[1-(3- isobutylphenyl) cyclopropyl] amino }propyl) acetamide;
N- ({(18,2R)-1-(3,5-difluorobenzyl) -2-hydroxy-3-{[(4- isobutyl-1,1'-biphenyl-2-yl)methyl]amino}propyl)acetamide;
N- ((18,2R)~1-(3,5-difluorobenzyl) -3-{[7-(2,2- dimethylpropyl) ~5-ethyl-1,2,3,4-tetrahydronaphthalen-1- yllamino}-2-hydroxypropyl) acetamide;
N- ((1S,2R) -1-(3,5-difluorobenzyl) -3-{[(4R) -6-(2,2- dimethylpropyl) -3,4-dihydro-2H-chromen-4-yllamino}-2- oo hydroxypropyl) acetamide;
N- ((18,2R)~1-(3,5-difluorcobenzyl) -3-{[(18)-7-(2,2- dimethylpropyl) ~-1,2, 3, 4-tetrahydronaphthalen-1-yllamino}-2- hydroxypropyl) acetamide;
N-[(1S,2R) -3-{[1-(3-tert-butylphenyl)cyclohexyl]lamino}-1- (3,5-difluorobenzyl) -2-hydroxypropyl] acetamide;
N-[(18,2R)-3-{[4- (3-tert-butylphenyl)tetrahydro-2H-pyran-
v 4-yllamino}-1-(3,5-difluorobenzyl) -2-hydroxypropyl] acetamide; N- ((1S,2R) -1-(3,5-difluorobenzyl)-3-{[6-(2,2- ) dimethylpropyl) -1,2,3,4-tetrahydroquinolin-4-yllamino}-2- hydroxypropyl) acetamide;
N- ((1S,2R)-1-(3,5-difluorcbenzyl)-2-hydroxy-3-{[1-(3- isopropylphenyl) -4-oxocyclohexyl] amino}propyl) acetamide;
N-[(1S,2R)-3-{[(4S8)-6-(2,2-dimethylpropyl)-3,4-dihydro- 2H-chromen-4-yl]lamino}-1- (3-fluorobenzyl) -2- hydroxypropyl] acetamide;
N- ((1S,2R) -1-(3,5-difluorobenzyl)-3-{[5-(2,2-
dimethylpropyl) -2- (1H-imidazol~1i-yl)benzyl]amino}-2- hydroxypropyl) acetamide;
N- ((18,2R)-1-(3,5-difluorobenzyl)-3-{[7-(2,2- dimethylpropyl) -1-methyl-1,2,3,4-tetrahydronaphthalen-1- yllamino}-2-hydroxypropyl)acetamide;
N- ((18,2R) -1-(3,5-difluorobenzyl)-3-{[6-(2,2-
dimethylpropyl) -4-methyl-3,4-dihydro-2H-chromen-4-yl]lamino}-2- hydroxypropyl) acetamide;
N- ((18,2R) -1- (3-fluoro-4-hydroxybenzyl) -2-hydroxy-3-{ [1- (3-isopropylphenyl) cyclohexyl] amino }propyl) acetamide;
N- ((1S,2R) -1- (3,5-difluorobenzyl) -2-hydroxy-3-{[1- (3-
isopropylphenyl) cyclohexyl] amino}propyl) -2-fluoroacetamide;
N-((1S,2R) -1-[3-(allyloxy) -5-fluorobenzyl] -2-hydroxy-3- {[1- (3-isopropylphenyl) cyclohexyl] amino}propyl)acetamide; N-[(1S,2R) -1-(3,5-difluorobenzyl) -3- ({1-[3-(2,2- dimethylpropyl) phenyl] -1-methylethyl }amino) -2-hydroxypropyl] - 2-fluoroacetamide; . N- ((18,2R)-1-(3,5-difluorobenzyl) -3-{[(18)-7-(2,2- dimethylpropyl) -1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2- ) hydroxypropyl) -2-fluoroacetamide; N-[(1S8,2R) -1-(3,5-difluorobenzyl) -2-hydroxy-3- ({1- [3-(3- thienyl) phenyl] cyclohexyl }amino) propyl] acetamide;
N-[(1S,2R)-1- (3,5-difluorobenzyl) -3- ({1-[4-(2,2- dimethylpropyl)pyridin-2-yljcyclopropyl amino) -2- hydrexypropyllacetamide; N- ((1R, 2S) -1- (3,5-difluorobenzyl)-2-hydroxy-3-{[(18)-7- propyl-1,2,3,4-tetrahydronaphthalen-1- vv1lamino}propyl) acetamide; N-{ (1S, 2R) ~1- (3, 5-difluorobenzyl)~-2-hydroxy-3-{[1-(3- isobutylphenyl) cyclohexyl] amino}propyl) acetamide; N- ( (1S, 2R) -2-hydroxy-1- (4-hydroxybenzyl) -3-{ [1-(3- isopropylphenyl) cyclohexyl] amino}propyl) acetamide; N- ((1R, 28) -1-(3,5-difluorobenzyl)-3-{[(1S)-7-ethyl- 1,2,3,4-tetrahydronaphthalen-1-yl}amino}-2-hydroxypropyl) -2- ethoxyacetamide; or N-((1S,2R) -1-(3,5-difluorobenzyl)-3-{[(1R) -7-ethyl- 1,2,3,4-tetrahydronaphthalen-1-yllamino}-2-hydroxypropyl)-2,2- difluorocacetamide; or a pharmaceutically acceptable salt thereof.
13. A method for preparing a compound of the formula Ho OH Ris A Ry R2 Ry or a pharmaceutically acceptable salt thereof, wherein Zz, X, R,, Ra, Ry3, Rys and R. are as defined in claim 1.
14. A compound according to claim 1 for use in treating a subject who has, or creventing a subject from devslcoping Alzheimer's disease (AD); crevanting or delaying the onset of Alzheimer's disease; treating subjects with mild <ccgrnicive impairment (MCI; ; preventing or delaying the onset <I Alzheimer's disease in 390 subjects who would progrzss i{rcm MCI to AD; trzating Cown’s syndreme; Creating subjects who have Hereditary Cerebral levrorrhage with Amyloidosis of the Cutch-Type; treating czrabral amyloid angicpathy and oygreventing its potential 157 AMENDED SHEET
IS. A compound according to claim 1. substantially as herein described and exemplified.
16. A method according to claim 13. substantially as herein described and exemplified. 458a AMENDED SHEET
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US40945302P | 2002-09-10 | 2002-09-10 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ZA200501991B true ZA200501991B (en) | 2006-01-25 |
Family
ID=35353421
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ZA200501991A ZA200501991B (en) | 2002-09-10 | 2005-03-09 | Acetyl 2-hydroxy-1,3 diaminoalkanes. |
Country Status (5)
| Country | Link |
|---|---|
| CN (1) | CN100384824C (en) |
| AP (1) | AP2005003247A0 (en) |
| CR (1) | CR7720A (en) |
| TN (1) | TNSN05067A1 (en) |
| ZA (1) | ZA200501991B (en) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE102010030538A1 (en) * | 2010-06-25 | 2011-12-29 | Bayer Schering Pharma Aktiengesellschaft | 6,7-Dihydro-5H-benzo [7] annulene derivatives, process for their preparation, pharmaceutical preparations containing them and their use for the preparation of medicaments |
| DE102011087987A1 (en) * | 2011-12-08 | 2013-06-13 | Bayer Intellectual Property Gmbh | 6,7-Dihydro-5H-benzo [7] annulene derivatives, process for their preparation, pharmaceutical preparations containing them and their use for the preparation of medicaments |
| BR112019001407A2 (en) * | 2016-07-29 | 2019-07-09 | Pgi Drug Discovery Llc | compounds and compositions and uses thereof |
| CN109790079B (en) * | 2016-07-29 | 2022-06-03 | 香港科技大学 | C (sp) of organozinc reagents and heterocyclic (pseudo) halides3)-C(sp2) Cross-coupling reaction |
| JP7191085B2 (en) | 2017-08-02 | 2022-12-16 | サノビオン ファーマシューティカルズ インク | Isochroman compounds and uses thereof |
| CN113189089B (en) * | 2021-03-19 | 2022-05-17 | 四川轻化工大学 | Ozone detection reagent and preparation device and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US5482947A (en) * | 1990-11-19 | 1996-01-09 | Talley; John J. | Retroviral protease inhibitors |
| US6150416A (en) * | 1997-02-04 | 2000-11-21 | The Regents Of The University Of California | Nanomolar, non-peptide inhibitors of cathepsin D |
-
2003
- 2003-09-10 AP AP2005003247A patent/AP2005003247A0/en unknown
- 2003-09-10 CN CNB03824988XA patent/CN100384824C/en not_active Expired - Fee Related
-
2005
- 2005-03-08 TN TNP2005000067A patent/TNSN05067A1/en unknown
- 2005-03-09 ZA ZA200501991A patent/ZA200501991B/en unknown
- 2005-03-09 CR CR7720A patent/CR7720A/en not_active Application Discontinuation
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| Publication number | Publication date |
|---|---|
| CN1694870A (en) | 2005-11-09 |
| CN100384824C (en) | 2008-04-30 |
| CR7720A (en) | 2005-07-14 |
| TNSN05067A1 (en) | 2007-05-14 |
| AP2005003247A0 (en) | 2005-03-31 |
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