ZA200307095B - Pyrazole derivatives for treating HIV. - Google Patents
Pyrazole derivatives for treating HIV. Download PDFInfo
- Publication number
- ZA200307095B ZA200307095B ZA200307095A ZA200307095A ZA200307095B ZA 200307095 B ZA200307095 B ZA 200307095B ZA 200307095 A ZA200307095 A ZA 200307095A ZA 200307095 A ZA200307095 A ZA 200307095A ZA 200307095 B ZA200307095 B ZA 200307095B
- Authority
- ZA
- South Africa
- Prior art keywords
- pyrazol
- methyl
- diethyl
- dichlorophenoxy
- alkyl
- Prior art date
Links
- 150000003217 pyrazoles Chemical class 0.000 title description 3
- -1 -OR' Chemical group 0.000 claims description 131
- 125000000217 alkyl group Chemical group 0.000 claims description 124
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 66
- 150000001875 compounds Chemical class 0.000 claims description 63
- 125000005843 halogen group Chemical group 0.000 claims description 52
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 48
- 125000002947 alkylene group Chemical group 0.000 claims description 43
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 33
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 30
- 229910052757 nitrogen Inorganic materials 0.000 claims description 24
- 150000003839 salts Chemical class 0.000 claims description 24
- 229910052799 carbon Inorganic materials 0.000 claims description 23
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 17
- 125000004432 carbon atom Chemical group C* 0.000 claims description 15
- 239000012453 solvate Substances 0.000 claims description 14
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 13
- 125000003545 alkoxy group Chemical group 0.000 claims description 12
- 125000003386 piperidinyl group Chemical group 0.000 claims description 12
- 125000004193 piperazinyl group Chemical group 0.000 claims description 11
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 11
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 11
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 10
- 125000002393 azetidinyl group Chemical group 0.000 claims description 10
- 125000001188 haloalkyl group Chemical group 0.000 claims description 10
- 125000000623 heterocyclic group Chemical group 0.000 claims description 10
- 125000002757 morpholinyl group Chemical group 0.000 claims description 10
- 239000001301 oxygen Substances 0.000 claims description 10
- 229910052760 oxygen Inorganic materials 0.000 claims description 10
- 125000004076 pyridyl group Chemical group 0.000 claims description 10
- 125000005842 heteroatom Chemical group 0.000 claims description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 8
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 8
- 125000003342 alkenyl group Chemical group 0.000 claims description 8
- 125000001153 fluoro group Chemical group F* 0.000 claims description 8
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 8
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 8
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 8
- 125000001781 1,3,4-oxadiazolyl group Chemical group 0.000 claims description 7
- 208000030507 AIDS Diseases 0.000 claims description 7
- 125000002883 imidazolyl group Chemical group 0.000 claims description 7
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 7
- 125000004504 1,2,4-oxadiazolyl group Chemical group 0.000 claims description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 6
- 239000003814 drug Substances 0.000 claims description 5
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 claims description 5
- 102100034343 Integrase Human genes 0.000 claims description 4
- 108010092799 RNA-directed DNA polymerase Proteins 0.000 claims description 4
- 239000005864 Sulphur Chemical group 0.000 claims description 4
- 125000000304 alkynyl group Chemical group 0.000 claims description 4
- 125000001624 naphthyl group Chemical group 0.000 claims description 4
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 4
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 claims description 4
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 claims description 4
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 4
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 claims description 4
- 125000001376 1,2,4-triazolyl group Chemical group N1N=C(N=C1)* 0.000 claims description 3
- 208000015181 infectious disease Diseases 0.000 claims description 3
- 238000000034 method Methods 0.000 claims description 3
- 208000011580 syndromic disease Diseases 0.000 claims description 3
- 125000001399 1,2,3-triazolyl group Chemical group N1N=NC(=C1)* 0.000 claims description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 2
- 229910019142 PO4 Inorganic materials 0.000 claims description 2
- 125000006615 aromatic heterocyclic group Chemical group 0.000 claims description 2
- 125000002785 azepinyl group Chemical group 0.000 claims description 2
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 2
- 125000002576 diazepinyl group Chemical group N1N=C(C=CC=C1)* 0.000 claims description 2
- 230000000694 effects Effects 0.000 claims description 2
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims description 2
- 125000002541 furyl group Chemical group 0.000 claims description 2
- 125000001786 isothiazolyl group Chemical group 0.000 claims description 2
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 2
- 125000002971 oxazolyl group Chemical group 0.000 claims description 2
- 125000003585 oxepinyl group Chemical group 0.000 claims description 2
- 125000003566 oxetanyl group Chemical group 0.000 claims description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 2
- 239000010452 phosphate Substances 0.000 claims description 2
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 claims description 2
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 2
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 2
- 239000003419 rna directed dna polymerase inhibitor Substances 0.000 claims description 2
- 229920006395 saturated elastomer Polymers 0.000 claims description 2
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 2
- 125000003554 tetrahydropyrrolyl group Chemical group 0.000 claims description 2
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 2
- 125000000335 thiazolyl group Chemical group 0.000 claims description 2
- 125000001544 thienyl group Chemical group 0.000 claims description 2
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzenecarbonitrile Natural products N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 claims 84
- KXDAEFPNCMNJSK-UHFFFAOYSA-N benzene carboxamide Natural products NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims 13
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims 13
- 239000008194 pharmaceutical composition Substances 0.000 claims 8
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims 4
- 238000004519 manufacturing process Methods 0.000 claims 3
- NWPNXBQSRGKSJB-UHFFFAOYSA-N o-methylbenzonitrile Natural products CC1=CC=CC=C1C#N NWPNXBQSRGKSJB-UHFFFAOYSA-N 0.000 claims 3
- 125000006505 p-cyanobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C#N)C([H])([H])* 0.000 claims 3
- NMFHKIRUHWFKKA-UHFFFAOYSA-N 3-[(3,5-diethyl-1h-pyrazol-4-yl)oxy]-5-methylbenzonitrile Chemical compound CCC1=NNC(CC)=C1OC1=CC(C)=CC(C#N)=C1 NMFHKIRUHWFKKA-UHFFFAOYSA-N 0.000 claims 2
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 claims 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N EtOH Substances CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Natural products C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims 2
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 claims 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims 2
- 230000001177 retroviral effect Effects 0.000 claims 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims 2
- NYBBRMVVCBSWRG-UHFFFAOYSA-N 1-(azetidin-3-yl)-4-(3,5-dichlorophenoxy)-3,5-diethylpyrazole Chemical compound CCC1=C(OC=2C=C(Cl)C=C(Cl)C=2)C(CC)=NN1C1CNC1 NYBBRMVVCBSWRG-UHFFFAOYSA-N 0.000 claims 1
- 125000006516 2-(benzyloxy)ethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims 1
- OHCVDGKXHXRCTA-UHFFFAOYSA-N 2-[3,5-diethyl-4-(3-fluoro-5-pyrazol-1-ylphenoxy)pyrazol-1-yl]ethanol Chemical compound CCC1=NN(CCO)C(CC)=C1OC1=CC(F)=CC(N2N=CC=C2)=C1 OHCVDGKXHXRCTA-UHFFFAOYSA-N 0.000 claims 1
- LGZJKMCHDMGPGW-UHFFFAOYSA-N 2-[4-(3,5-dichlorophenoxy)-3,5-diethylpyrazol-1-yl]-n'-hydroxyethanimidamide Chemical compound CCC1=NN(CC(=N)NO)C(CC)=C1OC1=CC(Cl)=CC(Cl)=C1 LGZJKMCHDMGPGW-UHFFFAOYSA-N 0.000 claims 1
- GSPTZLFEWGNANN-UHFFFAOYSA-N 2-[4-(3,5-dichlorophenoxy)-3,5-diethylpyrazol-1-yl]-n-(2-methoxyethyl)ethanamine Chemical compound CCC1=NN(CCNCCOC)C(CC)=C1OC1=CC(Cl)=CC(Cl)=C1 GSPTZLFEWGNANN-UHFFFAOYSA-N 0.000 claims 1
- KIBSTMKUZHGIHG-UHFFFAOYSA-N 2-[4-(3,5-dichlorophenoxy)-3,5-diethylpyrazol-1-yl]-n-(pyridin-2-ylmethyl)acetamide Chemical compound CCC1=C(OC=2C=C(Cl)C=C(Cl)C=2)C(CC)=NN1CC(=O)NCC1=CC=CC=N1 KIBSTMKUZHGIHG-UHFFFAOYSA-N 0.000 claims 1
- CXSYHEDXHVMPSC-CYBMUJFWSA-N 2-[4-(3,5-dichlorophenoxy)-5-methyl-1h-pyrazol-3-yl]-1-[(3r)-3-hydroxypiperidin-1-yl]ethanone Chemical compound C=1C(Cl)=CC(Cl)=CC=1OC=1C(C)=NNC=1CC(=O)N1CCC[C@@H](O)C1 CXSYHEDXHVMPSC-CYBMUJFWSA-N 0.000 claims 1
- MMZNOMXGKKPTNS-UHFFFAOYSA-N 2-[4-(3,5-dichlorophenoxy)-5-methyl-1h-pyrazol-3-yl]-n-(6-methylpyridin-2-yl)acetamide Chemical compound C=1C(Cl)=CC(Cl)=CC=1OC=1C(C)=NNC=1CC(=O)NC1=CC=CC(C)=N1 MMZNOMXGKKPTNS-UHFFFAOYSA-N 0.000 claims 1
- QCRVYUJLUFARAP-UHFFFAOYSA-N 2-[4-(3,5-dichlorophenoxy)-5-methyl-1h-pyrazol-3-yl]-n-[(4-fluorophenyl)methyl]acetamide Chemical compound C=1C(Cl)=CC(Cl)=CC=1OC=1C(C)=NNC=1CC(=O)NCC1=CC=C(F)C=C1 QCRVYUJLUFARAP-UHFFFAOYSA-N 0.000 claims 1
- IRLBQQZAIORVQL-UHFFFAOYSA-N 2-[4-(3,5-dichlorophenoxy)-5-methyl-1h-pyrazol-3-yl]-n-[[4-(trifluoromethyl)phenyl]methyl]acetamide Chemical compound C=1C(Cl)=CC(Cl)=CC=1OC=1C(C)=NNC=1CC(=O)NCC1=CC=C(C(F)(F)F)C=C1 IRLBQQZAIORVQL-UHFFFAOYSA-N 0.000 claims 1
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- MDUVBKHILSDHGL-UHFFFAOYSA-N 4-(3,5-dichlorophenoxy)-3,5-dimethyl-1h-pyrazole Chemical compound CC1=NNC(C)=C1OC1=CC(Cl)=CC(Cl)=C1 MDUVBKHILSDHGL-UHFFFAOYSA-N 0.000 claims 1
- LCWRBAUNEXTNHT-UHFFFAOYSA-N 4-(3,5-dichlorophenoxy)-3-(methoxymethyl)-5-methyl-1h-pyrazole Chemical compound N1N=C(C)C(OC=2C=C(Cl)C=C(Cl)C=2)=C1COC LCWRBAUNEXTNHT-UHFFFAOYSA-N 0.000 claims 1
- SYHBFTAWNXLCKW-UHFFFAOYSA-N 4-(3,5-dichlorophenoxy)-3-ethyl-5-methyl-1h-pyrazole Chemical compound CCC1=NNC(C)=C1OC1=CC(Cl)=CC(Cl)=C1 SYHBFTAWNXLCKW-UHFFFAOYSA-N 0.000 claims 1
- RXPZJHXNCSNNRT-UHFFFAOYSA-N 4-(3,5-dichlorophenoxy)-5-ethyl-1h-pyrazole Chemical compound CCC1=NNC=C1OC1=CC(Cl)=CC(Cl)=C1 RXPZJHXNCSNNRT-UHFFFAOYSA-N 0.000 claims 1
- OHDNIPQTXNSNNB-UHFFFAOYSA-N 4-(3,5-dichlorophenoxy)-5-methyl-3-[(2-methylimidazol-1-yl)methyl]-1h-pyrazole Chemical compound C=1C(Cl)=CC(Cl)=CC=1OC=1C(C)=NNC=1CN1C=CN=C1C OHDNIPQTXNSNNB-UHFFFAOYSA-N 0.000 claims 1
- NXVRWLMDZHLEJY-UHFFFAOYSA-N 5-[3,5-diethyl-1-(2-hydroxyethyl)pyrazol-4-yl]oxybenzene-1,3-dicarbonitrile;methanesulfonic acid Chemical compound CS(O)(=O)=O.CCC1=NN(CCO)C(CC)=C1OC1=CC(C#N)=CC(C#N)=C1 NXVRWLMDZHLEJY-UHFFFAOYSA-N 0.000 claims 1
- RAMUDKQWKLXCIL-UHFFFAOYSA-N 5-[5-ethyl-1-(2-hydroxyethyl)-3-propan-2-ylpyrazol-4-yl]oxybenzene-1,3-dicarbonitrile Chemical compound CC(C)C1=NN(CCO)C(CC)=C1OC1=CC(C#N)=CC(C#N)=C1 RAMUDKQWKLXCIL-UHFFFAOYSA-N 0.000 claims 1
- ZQGQHLSYVILOIR-UHFFFAOYSA-N 5-[[3-ethyl-5-(2-phenylmethoxyethyl)-1h-pyrazol-4-yl]oxy]benzene-1,3-dicarbonitrile Chemical compound C=1C(C#N)=CC(C#N)=CC=1OC=1C(CC)=NNC=1CCOCC1=CC=CC=C1 ZQGQHLSYVILOIR-UHFFFAOYSA-N 0.000 claims 1
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 claims 1
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 claims 1
- UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 claims 1
- JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 claims 1
- 150000001412 amines Chemical class 0.000 claims 1
- 125000004429 atom Chemical group 0.000 claims 1
- 125000000440 benzylamino group Chemical group [H]N(*)C([H])([H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims 1
- 229910002091 carbon monoxide Inorganic materials 0.000 claims 1
- 239000000969 carrier Substances 0.000 claims 1
- 239000003054 catalyst Substances 0.000 claims 1
- 239000003795 chemical substances by application Substances 0.000 claims 1
- 150000001860 citric acid derivatives Chemical class 0.000 claims 1
- 238000009833 condensation Methods 0.000 claims 1
- 230000005494 condensation Effects 0.000 claims 1
- GLUUGHFHXGJENI-UHFFFAOYSA-N diethylenediamine Natural products C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-M dihydrogenphosphate Chemical compound OP(O)([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-M 0.000 claims 1
- 239000003085 diluting agent Substances 0.000 claims 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims 1
- 230000002140 halogenating effect Effects 0.000 claims 1
- 230000002401 inhibitory effect Effects 0.000 claims 1
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 claims 1
- 229960003966 nicotinamide Drugs 0.000 claims 1
- 235000005152 nicotinamide Nutrition 0.000 claims 1
- 239000011570 nicotinamide Substances 0.000 claims 1
- 125000001715 oxadiazolyl group Chemical group 0.000 claims 1
- 229910052763 palladium Inorganic materials 0.000 claims 1
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
- IBBMAWULFFBRKK-UHFFFAOYSA-N picolinamide Chemical compound NC(=O)C1=CC=CC=N1 IBBMAWULFFBRKK-UHFFFAOYSA-N 0.000 claims 1
- 229960005206 pyrazinamide Drugs 0.000 claims 1
- 125000006513 pyridinyl methyl group Chemical group 0.000 claims 1
- 101150028481 rol-3 gene Proteins 0.000 claims 1
- 150000003892 tartrate salts Chemical class 0.000 claims 1
- NQRYJNQNLNOLGT-UHFFFAOYSA-N tetrahydropyridine hydrochloride Natural products C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims 1
- 229940124597 therapeutic agent Drugs 0.000 claims 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 6
- 239000002253 acid Substances 0.000 description 4
- 125000004801 4-cyanophenyl group Chemical group [H]C1=C([H])C(C#N)=C([H])C([H])=C1* 0.000 description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 2
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 2
- 241000700605 Viruses Species 0.000 description 2
- 125000004567 azetidin-3-yl group Chemical group N1CC(C1)* 0.000 description 2
- 125000001246 bromo group Chemical group Br* 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 238000001640 fractional crystallisation Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 125000003626 1,2,4-triazol-1-yl group Chemical group [*]N1N=C([H])N=C1[H] 0.000 description 1
- WITMXBRCQWOZPX-UHFFFAOYSA-N 1-phenylpyrazole Chemical class C1=CC=NN1C1=CC=CC=C1 WITMXBRCQWOZPX-UHFFFAOYSA-N 0.000 description 1
- 125000004201 2,4-dichlorophenyl group Chemical group [H]C1=C([H])C(*)=C(Cl)C([H])=C1Cl 0.000 description 1
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 description 1
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 description 1
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 125000004189 3,4-dichlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(Cl)C([H])=C1* 0.000 description 1
- 125000004211 3,5-difluorophenyl group Chemical group [H]C1=C(F)C([H])=C(*)C([H])=C1F 0.000 description 1
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 description 1
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=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
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- DSLZVSRJTYRBFB-LLEIAEIESA-N D-glucaric acid Chemical compound OC(=O)[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O DSLZVSRJTYRBFB-LLEIAEIESA-N 0.000 description 1
- RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- 108010078851 HIV Reverse Transcriptase Proteins 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-M Methanesulfonate Chemical compound CS([O-])(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-L Phosphate ion(2-) Chemical compound OP([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-L 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical class C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 1
- 101150088095 RTM2 gene Proteins 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 150000001241 acetals Chemical class 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 239000004411 aluminium Substances 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M bisulphate group Chemical group S([O-])(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- 125000006367 bivalent amino carbonyl group Chemical group [H]N([*:1])C([*:2])=O 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 150000004657 carbamic acid derivatives Chemical class 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 125000004802 cyanophenyl group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 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
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 125000004212 difluorophenyl group Chemical group 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 125000004005 formimidoyl group Chemical group [H]\N=C(/[H])* 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 229940050410 gluconate Drugs 0.000 description 1
- 229930182470 glycoside Natural products 0.000 description 1
- 150000002338 glycosides Chemical class 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 150000002460 imidazoles Chemical class 0.000 description 1
- 230000002458 infectious effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 125000002346 iodo group Chemical group I* 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
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 125000004572 morpholin-3-yl group Chemical group N1C(COCC1)* 0.000 description 1
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 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
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 1
- 150000003014 phosphoric acid esters Chemical class 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 125000004307 pyrazin-2-yl group Chemical group [H]C1=C([H])N=C(*)C([H])=N1 0.000 description 1
- 125000004353 pyrazol-1-yl group Chemical group [H]C1=NN(*)C([H])=C1[H] 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
- 238000000926 separation method Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 229910021653 sulphate ion Inorganic materials 0.000 description 1
- 229940095064 tartrate Drugs 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
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 1
- 241001430294 unidentified retrovirus Species 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
PYRAZOLE DERIVATIVES FOR TREATING HIV
This invention relates to pyrazole derivatives and to processes for the preparation thereof, intermediates used in their preparation of, compositions containing them and the uses of such derivatives.
The compounds of the present invention bind to the enzyme reverse transcriptase and are modulators, especially inhibitors thereof. Reverse transcriptase is implicated in the infectious lifecycle of HIV, and compounds which interfere with the function of this enzyme have shown utility in the treatment of conditions including AIDS. There is a constant need to provide new and better modulators, especially inhibitors, of HIV reverse transcriptase since the virus is able to mutate, becoming resistant to the effects of known modulators.
The compounds of the present invention are useful in the treatment of a variety of disorders including those in which the inhibition of reverse transcriptase is implicated. Disorders of interest include those caused by Human
Immunodificiency Virus (HIV) and genetically related retroviruses, such as
Acquired Immune Deficiency Syndrome (AIDS).
European patent application EP 0 786 455 A1 discloses a class of imidazole compounds which inhibit the growth of HIV. A class of N-phenylpyrazoles which act as reverse transcriptase inhibitors are disclosed in J. Med. Chem., 2000, 43, 1034. Antiviral activity is ascribed to a class of N-(hydroxyethyi)pyrazole derivatives in US patent number 3,303,200.
According to the present invention there is provided a compound of the formula
R* R \ : _/ . N
Rr? or a pharmaceutically acceptable salt, solvate or derivative thereof, wherein: either R' is H, C4-Cs alkyl, Cs-C; cycloalkyl, phenyl, benzyl, halo, -CN, -OR’, {
-CO:R™, -CONR®R"’, R® or R’, said C4-Cs alkyl, Cs-C, cycloalkyl, phenyl and benzyl being optionally substituted by halo, -CN, -OR™, S(O),R°, -CO,R", -CONR’R", -OCONR®R', -NR°CO:R'", -NR'R"", -NR°COR'®, -SO,NR°R"°, -NR°CONR®R®, -NR°SO,R' or R'; and
R? is H, Ci-Cs alkyl, Cs-Cs alkenyl, Cs-Cs alkynyl, Cs-C, cycloalkyl, Ca-Cr cycloalkenyl, phenyl, benzyl, R? or R®, said C4-Cg alkyl, C3-C7 cycloalkyl, phenyl and benzyl being optionally substituted by halo, -OR®, -OR'?, -CN, -CO.R’, -OCONR’R’, -CONR®R®, -C(=NR®)NR°OR®, -CONR’NR°R®, -NR°R?, -NR°R™2, -NR°COR’, -NR°COR?, -NR°COR", -NR°CO,R’, -NR°CONR®R?®, -SO,NR°R®, -NR°SO:R®, -NR*SO,NR°R®, R® or R®; or, R' and R? when taken together, represent unbranched Cs-C, alkylene, optionally substituted by oxo, optionally wherein one methylene group of said Cs-
C4 alkylene is replaced by an oxygen atom or a nitrogen atom, said nitrogen atom being optionally substituted by R'°;
R%is H, C1-Cs alkyl, Ca-C; cycloalkyl, phenyl, benzyl, halo, -CN, -OR’, -CO,R°, -CONR’R®, R® or R®, said C4-Cs alkyl, Cs-C; cycloalkyl, phenyl and benzyl being optionally substituted by halo, -CN, -OR?®, -CO.R®, -CONR®R®, -OCONRR®, -NR°CO2R®, -NR°R®, -NR°COR®, -SO.NR°R®, -NR°CONR®R®, -NR°SO,R®, R® or
RY
R* is phenyl, naphthyl or pyridyl, each being optionally substituted by R®, halo, -
CN, C4Cs alkyl, Ci-Cg haloalkyl, C3-C; cycloalkyl, C-Cs alkoxy, -CONR°R®,
OR", So,R®, O-(C1-GCs alkylene)-CONR®R®, O-(C+-Cs alkylene)-NR°R®, or O-(Cs-
Cs alkylene)-OR; each R’ is independently either H, C4-Cs alkyl or Cs-C; cycloalkyl or, when two R® groups are attached to the same nitrogen atom, those two groups taken together with the nitrogen atom to which they are attached represent azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, piperazinyl, homopiperazinyl or morpholinyl, said azetidinyi, pyrrolidinyl, piperidinyl, homopiperidinyl, piperazinyl, homopiperazinyl and morpholinyl being optionally substituted by C,-Cs alkyl or ’ 35 C3-Cy cycloalkyl; each R’ is independently either H, C-Cg alkyl or C3-C7 cycloalkyl;
R” is C4-Cs alkyl or C4-C; cycloalkyl:
Fi
R? is a five or six-membered, aromatic heterocyclic group containing (i) from 1 to ] 4 nitrogen heteroatom(s) or (ii) 1 or 2 nitrogen heteroatom(s) and 1 oxygen or 1 sulphur heteroatom or (ii) 1 or 2 oxygen or sulphur heteroatom(s), said . 5 heterocyclic group being optionally substituted by halo, oxo, -CN, -COR®, -CONR’R®, -SO:NR°R®, -NR’SO,R®, -OR®, -NR°R®, -(C+-Cs alkylene)-NR°R®, C;-
Cs alkyl, fluoro(C4-Cg)alkyl or C5-C7 cycloalkyl;
R® is a four to seven-membered, saturated or partially unsaturated heterocyclic group containing (i) 1 or 2 nitrogen heteroatom(s) or (ii) 1 nitrogen heteroatom and 1 oxygen or 1 sulphur heteroatom or (iii) 1 oxygen or sulphur heteroatom, said heterocyclic group being optionally substituted by oxo, C-Cg alkyl, Cs-C; cycloalkyl, -SO;R®, -CONR’R®, -COOR?®, -CO-(C;-Cs alkylene)-OR® or -COR® and optionally substituted on a carbon atom which is not adjacent to a heteroatom by halo, -OR®, -NR°R®, -NR°COR?®, -NR*COOR?®, -NR*CONR’R?®, -NR°SO,R°® or -CN;
R' is H, R®, R®, R"®, C-Cs alkyl, Cs-C; cycloalkyl or ~(C1-Cs alkyl)-(Cs-C7 cycloalkyl), said C4-Cs alkyl and C3-C7 cycloalkyl being optionally substituted by -ORS, -OR", R®, R®, R"® or -COR'®;
R'" is H, C4-Cs alkyl or C3-C; cycloalkyl, said C-Cs alkyl and Cs-C; cycloalkyl being optionally substituted by -OR®, -NR°R®, -NR°COR®, -CONR®R®, R® or R®:
R'? is C1-Cs alkyl substituted by R®, R%, -OR®, -CONR®R®, -NR*COR® or -NR°R®;
R' is phenyl optionally substituted by halo, CN, -COR®, -CONR®R®, -SO,NR°R?, -NR°SO.R®, -OR®, -NR°R®, -(C+-Cs alkylene)-NR°R®, C4-C alkyl, halo(C+-Ce)alkyl or C3-C7 cycloalkyl; and xis0,1o0r2; with the proviso that (a) when R' and R® are both phenyl, R? is not methyl; and (b) when R' is ethoxy and R® is ethoxycarbonyl, R? is not phenyl.
In the above definitions, halo means fluoro, chloro, bromo or iodo. Unless otherwise stated, alkyl, alkenyl, alkynyl, alkylene and alkoxy groups containing the requisite number of carbon atoms can be unbranched or branched chain.
Examples of alkyl include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec- butyl and t-butyl. Examples of alkenyl include ethenyl, propen-1-yl, propen-2-yl, i propen-3-yl, 1-buten-1-yl, 1-buten-2-yl, 1-buten-3-yl, 1-buten-4-yl, 2-buten-1-yl, 2- buten-2-yl, 2-methylpropen-1-yl or 2-methylpropen-3-yl. Examples of alkynyl include ethynyl, propyn-1-yl, propyn-3-yl, 1-butyn-1-yl, 1-butyn-3-yl, 1-butyn-4-yl, 2-butyn-1-yl. Examples of alkylene include methylene, 1,1-ethylene, 1,2- ethylene, 1,1-propylene, 1,2-propylene, 2,2-propylene and 1,3-propylene. ' Examples of alkoxy include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i- butoxy, sec-butoxy and t-butoxy. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Where R' and R? are taken together, they form, along with the nitrogen atom and the carbon atom of the pyrazole ring to which they are attached, a 5- or 6-membered ring. Where a heterocyclic group R® or R® is attached to an oxygen, sulphur or nitrogen heteroatom the heterocyclic group R® or R® must be linked through a ring carbon atom. Further, where a heterocyclic group R® is attached to an oxygen, sulphur or nitrogen heteroatom the heterocyclic group R® must be linked through a ring carbon atom that is not adjacent to a ring heteratom.
The pharmaceutically acceptable salts of the compounds of the formula (I) include the acid addition and the base salts thereof.
Suitable acid addition salts are formed from acids which form non-toxic salts and examples are the hydrochloride, hydrobromide, hydroiodide, sulphate, bisulphate, nitrate, phosphate, hydrogen phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate, succinate, saccharate, benzoate, methanesulphonate, ethanesulphonate, benzenesulphonate, para- toluenesulphonate and pamoate salts.
Suitable base salts are formed from bases which form non-toxic salts and examples are the sodium, potassium, aluminium, calcium, magnesium, zinc and diethanolamine sals.
For a review on suitable salts see Berge et al, J. Pharm. Sci., 66, 1-19, 1977. ) The pharmaceutically acceptable solvates of the compounds of the formula (1) include the hydrates thereof. ) 35
Also included within the present scope of the compounds of the formula (I) are polymorphs thereof.
The compounds of formula (I) may be modified to provide pharmaceutically acceptable derivatives thereof at any of the functional groups in the compounds.
Examples of such derivatives are described in: Drugs of Today, Volume 19,
Number 9, 1983, pp 499 — 538; Topics in Chemistry, Chapter 31, pp 306 — 316; . 5 and in “Design of Prodrugs” by H. Bundgaard, Elsevier, 1985, Chapter 1 (the disclosures in which documents are incorporated herein by reference) and include: esters, carbonate esters, hemi-esters, phosphate esters, nitro esters, sulfate esters, sulfoxides, amides, sulphonamides, carbamates, azo-compounds, : phosphamides, glycosides, ethers, acetals and ketals.
A compound of the formula (I) may contain one or more asymmetric carbon atoms and therefore exist in two or more stereoisomeric forms. The present invention includes the individual stereoisomers of the compounds of the formula (1) together with, where appropriate, the individual tautomers thereof, and mixtures thereof.
Separation of diastereoisomers may be achieved by conventional techniques, e.g. by fractional crystallisation, chromatography or high performance liquid chromatography (HPLC) of a stereoisomeric mixture of a compound of the formula (I) or a suitable salt or derivative thereof. An individual enantiomer of a compound of the formula (1) may also be prepared from a corresponding optically pure intermediate or by resolution, such as by HPLC of the corresponding racemate using a suitable chiral support or by fractional crystallisation of the diastereoisomeric salts formed by reaction of the corresponding racemate with a suitable optically active acid or base, as appropriate.
Preferably, R, when taken separately, is H, C;-Cs alkyl, C3-C7 cycloalkyl or OR’, said C4-Cs alkyl and C5-C; cycloalkyl being optionally substituted by halo, -CN, -OR™, S(0)R™, -CO.R', -CONR®R'’, -OCONR’R'’, -NR°CO,R", -NR'°R"", -NRP°COR'™, -SO.NR°R', -NR’CONR’R', -NR°SO.R" or R™.
Preferably, R', when taken separately, is H, C1-Cs alkyl, Cs-C7 cycloalkyl or -OR?, said C4-Cs alkyl being optionally substituted by halo, -OR™, -NR'R!', -NR°COR'® or R'.
Preferably, R', when taken separately, is H, C4-C4 alkyl, cyclopropyl, or -OCH,, said Cy-C, alkyl being optionally substituted by bromo, -OH, -O(C;-C; alkyl), -NR'°R"", -NHCOR" or R™,
Preferably, R', when taken separately, is H, -CHs, -CH2CHa, ~CH(CHa)s, ~C(CHs)s, cyclopropyl, -OCHs, -CH.OH, -CH2OCH3, -CH2OCH,CHa, -CH.Br, ~CHzNH,, -CH2NHCH3, -CHaN(CH),, -CHNHCHx(cyclopropyt),
-CH>NHCH,CH>0CHs3, -CHoNHCH>CHoNHCOCHS, -CH:NHCO(4-cyanophenyl), -CH2NHCO(3-cyanophenyl), -CH,NHCH;(4-cyanophenyl), ~CH,NHCH,(4- fluorophenyl), -CH,NHCH3(4-methoxyphenyl), -CH2NHCH2(4- aminosulphonylphenyl), -CH,NHCH,(4-aminocarbonylphenyl), -CH,NHCH.(pyrid- . 5 3-yb, -CH2N(CHj3)(4-cyanophenylmethyl), ~-CH2N(CH>CH,OH})(4- cyanophenylmethyl), 4-methoxypiperidin-1-yimethyl, 4-aminocarbonylpiperidin-1- ylmethyl, 4-methylcarbonylaminopiperidin-1-ylmethyl, piperazin-1-yimethyl, 4- methylpiperazin-1-yimethyl, 4-methylcarbonyipiperazin-1-yimethyl, 4- methoxymethylcarbonylpiperazin-1-ylmethyl, 4-methoxycarbonylpiperazin-1- yimethyl, 4-methylsulphonylpiperazin-1-ylmethyl, morpholin-4-yimethyl, 2- methylimidazol-1-yimethyl, pyrazol-1-ylmethyl or 1,2,4-triazol-1-yimethyi.
Preferably, R', when taken separately, is, -CHas, -CH2CHa, cyclopropyi, -CH,NHCH,(4-cyanophenyl), -CHaNHCH(4-fluorophenyl), -CHoNHCHx(4- methoxyphenyl), -CH:NHCHz(4-aminosulphonylphenyl) or -CH,NHCH,(4- aminocarbonylphenyl).
Preferably, R?, when taken separately, is H, C4-Cs alkyl, C3-Cs alkenyl or R°, said
C1-Cs alkyl being optionally substituted by halo, -OR®, -OR'2, -CN, -CO,R’, -OCONR’R®, -CONR’R®, -C(=NR®*)NR°OR®, -CONR°NR°R®, -NR°R®, -NR°R "2, -NR°COR’, -NR°COR’, -NR°COR'", -NR*CO,R®, -NR°*CONR’R®, -SO.NR°R®, -NR°SO,R®, R® or R®,
Preferably, R?, when taken separately, is H, C;-Cs alkyl, Cs-Cs alkenyl or R®, said
C4-Cs alkyl being optionally substituted by -OR®, -OR'?, -CN, -CO.R’, -CONR°R®, -C(=NR®)NR°OR®, -CONR®NRR’, -NR°R®, -NR°R'?, -NR°COR?®, -NR°COR'?, -NR°CO2R°, R®or R®.
Preferably, R?, when taken separately, is H, C-Cs alkyl, propenyl or R®, said C4-
C3 alkyl being optionally substituted by -OH, -OCHjs, -OCH,CH,NH,, -CN, -CO2CHs, -CO,CH,CHjs, -CONH,, -C(=NH)NHOH, -CONHNH,, -NH,, -NHCHj, -N(CH3)2, -NHCHCH,NHCOCH;, -NHCH,CH,OCH3, -NHCH,R®, -NHCORS®, -NHCOCH,OCH;z, -NHCO,C(CHs)s, R® or R®.
Preferably, R?, when taken separately, is H, methyl, -CH,CH=CH,, -CH-CN, -CH20CH3, -CH2CONH,, -CH,CONHNH;, -CH>CO,CHg, -CH.CO>CH-CHs, -CH2C(=NH)NHOH, -CH,CH,0OH, -CH2CH>0OCHS3;, -CH>CH,NHo, -CH2CH2NHCOCH,0CHs, -CH2CH2NHCO,C(CHj)s, 2-(pyrid-2- ) 35 ylcarbonylamino)eth-1-yl, 2-(pyrazin-2-ylcarbonylamino)eth-1-yl, -CH2CH20OCH,;CH,NH,, -CH,CH2NHCHs, -CH2CH2N(CHg),, -CH,CHNHCH,CH2NHCOCHS;, -CHCH,NHCH,CH,OCHa, -CH,CH(OH)CHj;, (3-hydroxypyrazol-5-yl)methyl, 2-hydroxy-1,3,4-oxadiazol-5- yimethyl, 2-amino-1,3,4-oxadiazol-6-yl, 5-hydroxy-1,2,4-oxadiazol-3-yimethyl, 6- i hydroxy-2-methylpyrimidin-4-yimethyl, 6-hydroxy-2-aminopyrimidin-4-ylmethyl, 2- (morpholin-4-yl)eth-1-yl, 2-(4-methylcarbonylpiperazin-1-yl)eth-1-yl, morpholin-3- ylmethyl, (2-(tetrahydrofuran-2-ylmethylamino)eth-1-yl, 1-methylazetidin-3-yl or azetidin-3-yl.
Preferably, R?, when taken separately, is H, -CH,CH,OH or -CH;CH,NH,
Preferably, R' and R? when taken together, represent unbranched C;-C, alkylene, optionally substituted by oxo, wherein one methylene group of said Ca-
C, alkylene is replaced by an oxygen atom or a nitrogen atom, said nitrogen atom being optionally substituted by R'°.
Preferably, R' and R? when taken together, represent unbranched propylene wherein one methylene group is replaced by an oxygen atom or unbranched butylene wherein one methylene group is replaced by a nitrogen atom, said propylene and butylene being optionally substituted by oxo and said nitrogen atom being optionally substituted by R'°.
Preferably, R' and R?, when taken together, represent >-OCH-CH,-", “CONHCH.CH,-¥, “CHoNHCH.CH,-Y, *CH2N(CH3)CH,CH,-, “CH,N(4- cyanophenylmethyl)CH.CHz-Y or *CH,N(4-methoxyphenylmethyl)CH.CH,-Y wherein xX’ represents the point of attachment to the carbon atom of the pyrazole ring and 'y’ represents the point of attachment to the nitrogen atom of the pyrazole ring.
Preferably, R® is H or C4-Cs alkyl, said C-Cg alkyl being optionally substituted by halo, -CN, -OR®, -CO,R®, -CONR’R®, -OCONR°R®, -NR°*CO.R®, -NR°R, -NR°COR®, -SO.NR’R®, -NR’*CONR’R®, -NR®SO,R®, R® or R°.
Preferably, R® is H or C4-Cs alkyl.
Preferably, R% is H or C1-C, alkyl.
Preferably, R® is H, -CHa, -CH2CHa, -CH(CHa)2 or -C(CHa)s.
Preferably, R® is CHa, -CHa2CHj, -CH(CHa), or cyclopropyl.
Preferably, R* is phenyl optionally substituted by R®, halo, -CN, C;-Cs alkyl, C1-Cs haloalkyl, Cs-C7 cycloalkyl or C4-Cs alkoxy.
Preferably, R* is phenyl substituted by R®, halo, -CN, C4-Cs alkyl, C4-Cg haloalkyl,
Cs-C; cycloalkyl or C4-Cg alkoxy. ) 35 Preferably, R* is phenyl substituted by halo, -CN or C4-Cg alkyl.
Preferably, R* is phenyl substituted by fluoro, chloro, -CN or methyl.
Preferably, R*is 3-cyanophenyl, 4-chlorophenyl, 3-chlorophenyl, 2-chlorophenyl, 3-fluorophenyl, 2-fluorophenyl, 3,5-dichlorophenyl, 2,6-dichlorophenyl, 2,3- dichlorophenyl, 2,4-dichlorophenyl, 3,4-dichlorophenyl, 2,5-dichlorophenyl, 2,6-
difluorophenyl, 2,3-diflucrophenyl, 3,5-difluorophenyl, 2,5-difluorophenyl, 3,5- dicyanophenyl, 3,5-dimethylphenyl, 4-fluoro-3-methylphenyl, 3-cyano-4- fluorophenyl, 3-cyano-5-fluorophenyl, 2-chloro-4-cyanophenyl, 3-chloro-5- ] cyanophenyl, 3-cyano-5-methylphenyl or 4-cyano-2,6-dimethylphenyl.
Preferably, R* is 3,5-dicyanophenyl, 3-cyano-5-fluorophenyl, 3-chloro-5- cyanophenyl or 3-cyano-5-methylphenyl.
In an alternative set of preferences:
Preferably, R* is phenyl optionally substituted by R®, halo, -CN, C+-Cs alkyl, C4-Cs haloalkyl, C5-C; cycloalkyl, C4-Cs alkoxy, -CONR’R®, OR", So.R®, O-(Ci-Cs alkylene)-CONR°R®, O-(C;-C; alkylene)-NR°R®, or O-(C:-Cs alkylene)-OR®: or naphthyl.
Preferably, R* is phenyl substituted by R®, halo, -CN, C;-Cs alkyl, C1-Cs haloalkyl,
Cs-C; cycloalkyl, C1-Cs alkoxy, -CONR’R®, OR, So,R®, O-(C:-Cs alkylene)-
CONR°R®, O-(C4-Cs alkylene)-NR°R®, or O-(C;-Cs alkylene)-ORE.
Preferably, R® is pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,4-oxadiazolyl, 1,3,4- oxadiazolyl, furanyl, thienyl, pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl, each being optionally substituted by halo, -CN, -COR?®, -CONR®R®, -SO,NR°R?, -NR°SO,R’, -OR’, -NR°R®, -(C4-Cs alkylene)-NR°R®, C-Cs alkyl, fluoro(Cs-
Ce)alkyl or C3-C; cycloalkyl.
Preferably, R? is imidazolyl, pyrazolyl, 1,24-triazolyl, 1,2,4-oxadiazoly!, 1,3,4- oxadiazolyl, pyridinyl, pyrazinyl or pyrimidinyl, each being optionally substituted by halo, -CN, -COR®, -CONR’R®, -SO.NR°R?, -NR°SO,R?, -OR®, -NR°R’, -(C1-Cs alkylene)-NR°R®, C4-Cs alkyl, fluoro(C+-Cg)alkyl or Cs-C; cycloalkyi.
Preferably, R® is imidazolyl, pyrazolyl, 1,24-triazolyl, 1,2,4-oxadiazolyl, 1,3,4- oxadiazolyl, pyridinyl, pyrazinyl or pyrimidinyl, each being optionally substituted by -OR®, -NR°R® or C;-Cs alkyl.
Preferably, R® is imidazolyl, pyrazolyl, 1,24-triazolyl, 1,2,4-oxadiazolyl, 1,3,4- oxadiazolyl, pyridinyl, pyrazinyl or pyrimidinyl, each being optionally substituted by -OH, -NH. or methyl.
Preferably, R® is pyrazol-1-yl, 2-methylimidazol-1-yl, 1,2,4-triazol-1-yl, 3- hydroxypyrazol-5-yl, 2-hydroxy-1,3,4-oxadiazol-5-yl, 2-amino-1,3,4-oxadiazol-5-yl, : 35 5-hydroxy-1,2,4-oxadiazol-3-yl, 2-methyl-4-hydroxypyrimidin-6-yl, 2-amino-4- hydroxypyrimidin-6-yl, pyridin-3-yl, pyridin-2-yl or pyrazin-2-yl.
Preferably, R® is azetidinyl, tetrahydropyrrolyl, piperidinyl, azepinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, oxepinyl, morpholinyl, piperazinyl or diazepinyl, each being optionally substituted by oxo, C4-Cg alkyl, C3-C cycloalkyl, -SO,R®, -CONR°R?®, -COOR?®, -CO-(C1-Cs alkylene)-OR® or -COR?® and optionally substituted on a carbon atom which is not adjacent to a heteroatom by halo, -OR®, -NR°R®, -NR°COR’, -NR°COOR?, -NR°CONRR®, -NR*SO.R’ or -CN.
Preferably, R° is azetidinyl, piperidinyl, tetrahydrofuranyl, piperazinyl or morpholinyl, each being optionally substituted by oxo, C1-Cs alkyl, Cz-C; cycloalkyl, -SO;R°®, -<CONR’R®, -COOR?®, -CO-(C+-C; alkylene)-OR® or -COR® and optionally substituted on a carbon atom which is not adjacent to a heteroatom by halo, -OR®, -NR°R®, -NR°COR?®, -NR’COOR?®, -NR°CONR®R®, -NR*SO,R® or -CN.
Preferably, R® is azetidinyl, piperidinyl, tetrahydrofuranyl, piperazinyl or morpholinyl, each being optionally substituted by C;-Cs alkyl, -SO,R®, -CONR®R®, -COOR®, -CO-(C+-Cs alkylene)-OR® or -COR’ and optionally substituted on a’ carbon atom which is not adjacent to a heteroatom by -OR® or -NR°COR®.
Preferably, R® is azetidinyl, piperidinyi, tetrahydrofuranyl, piperazinyl or morphoninyl, each being optionally substituted by -CHj3, -SO>CH3;, -CONH,, -COOCHs3, -COCH,OCH; or -COCH3; and optionally substituted on a carbon atom which is not adjacent to a heteroatom by -OCH3; or -NHCOCHs.
Preferably, R® is 4-methoxypiperidin-1-yl, 4-aminocarbonylpiperidin-1-yl, 4- methylcarbonylaminopiperidin-1-yl, piperazin-1-yi, 4-methylpiperazin-i-yl, 4- methylcarbonylpiperazin-1-yl, 4-methoxymethylcarbonyipiperazin-1-yl, 4- methoxycarbonylpiperazin-1-yl, 4-methylsulphonyipiperazin-1-yl, morpholin-4-yl, tetrahydrofuran-2-yl, morpholin-3-yl, azetidin-3-yl or 1-methylazetidin-3-yl.
Preferably, R'is H, R®, R®, R'®, C-Cs alkyl or -(C+-Cs alkyl)-(Cs-C7 cycloalkyl), said C4-Cs alkyl being optionally substituted by -OR®, -OR", R®, R®, R™ or -COR™,
Preferably, R'® is H, R®, R®, R"®, C4-Cs alkyl or -(C4-Cs alkyl)-(Cs-C; cycloalkyl), said C4-Cs alkyl being optionally substituted by -OR® or R*2,
Preferably, R" is H, R®, R®, R"®, -CHs, -CHyCH; or -CHa(cyclopropyl), said -CHs; and -CH.CHjs being optionally substituted by -OCH; or R'.
Preferably, R'is H, R®, R®, R"®, -CHg, -CHyCHs, -CH.CH,OCH3 -CHy(cyclopropyl), 4-cyanophenylmethyl, 4-fluorophenylmethyl, 4- methoxyphenyimethyl, 4-aminosulphonylphenyimethyl or 4- aminocarbonylphenylmethyl. } 35
Preferably, R'is H or C4-Cs alkyl, said C4-Cs alkyl being optionally substituted by -OR®, -NR°R®, -NR°COR®, -CONR°R®, R® or R’.
Preferably, R"" is H or C-Cg alkyl, said C4-Cs alkyl being optionally substituted by -OR® or -NR°COR’.
Claims (43)
- 279 B CLAIMS: 1. A compound of the formula (I) . Rr R' \ 2 i A Cm re or a pharmaceutically acceptable salt, solvate or derivative thereof, wherein: either R' is H, C;-C; alkyl, C3-C; cycloalkyl, phenyl, benzyl, halo, -CN, -OR’, -CO:R'", -CONR’R™, R® or R®, said C,-Cs alkyl, C5-C; cycloalkyl, phenyl and benzyl being optionally substituted by halo, -CN, -OR', S(O),R'°, -CO,R'", -CONR°R', -OCONR’RY, -NR°CO:R'", -NR'R', -NR’COR'", -SO,NR°R™, -NR°CONR°R'’, -NR°SO:R'® or R™; and R? is H, Ci-Cs alkyl, Cs-Cs alkenyl, Cs-Cs alkynyl, Cs-C; cycloalkyl, Cs-C; cycloalkenyl, phenyl, benzyl, R® or R®, said C;-Cs alkyl, Cs-C; cycloalkyl, phenyl and benzyl being optionally substituted by halo, -OR®, -OR'?, -CN, -CO,R’, -OCONR®R®, -CONR’R®, -C(=NR°)NR°OR®, -CONR®NR®R®, -NR°R®, -NR°R'2, -NR°COR®, -NR°COR®, -NR°COR', -NR°CO,R®, -NR*CONR®R®, -SO,NR°R’, -NR°SO.R®, -NR°SONR°R’, R® or R®; or, R' and R? when taken together, represent unbranched Cs-C, alkylene, optionally substituted by oxo, optionally wherein one methylene group of said : Cs-C4 alkylene is replaced by an oxygen atom or a nitrogen atom, said nitrogen : atom being optionally substituted by R'®; ; : R% is H, C4-Cs alkyl, C3-C; cycloalkyl, phenyl, benzyl, halo, -CN, -OR’, -CO.R®, -CONR®R®, R® or R®, said C4-Cs alkyl, Cs-C7 cycloalkyl, phenyl and benzyl being optionally substituted by halo, -CN, -OR®, -CO.R®, -CONR®R®, -OCONR®R®, -NR°CO,R®, -NR°R®, -NR®COR®, -SO.NR°R®, -NR°CONR’R®, -NR°SO.R®, R® or RY R* is phenyl, naphthyl or pyridyl, each being optionally substituted by R®, halo, ! -CN, C1-Cs alkyl, C4-Cg haloalkyl, C3-C7 cycloalkyl, C;-C¢ alkoxy, -CONR®R®, iOR™, SoR®, O-(C1-Cs alkylene)-CONR®R®, O-(Ci-Cs alkylene)-NR°R®, or 0-(C+-Cs alkylene)-OR®; - each R® is independently either H, C4-Cs alkyl or C5-C; cycloalkyl or, when two R® groups are attached to the same nitrogen atom, those two groups taken together : with the nitrogen atom to which they are attached represent azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, piperazinyl, homopiperazinyl or morpholinyl, said azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, piperazinyi, homopiperazinyl and morpholinyl being optionally substituted by C+-Cs alkyl or Cs-C; cycloalkyl; each R® is independently either H, C1-Cg alky! or C5-C7 cycloalkyl; R’ is C-Cs alkyl or C3-C7 cycloalkyl;R® is a five or six-membered, aromatic heterocyclic group containing (i) from 1 to 4 nitrogen heteroatom(s) or (ii) 1 or 2 nitrogen heteroatom(s) and 1 oxygen or 1 sulphur heteroatom or (iii) 1 or 2 oxygen or sulphur heteroatom(s), said heterocyclic group being optionally substituted by halo, oxo, -CN, -COR® -CONR’R®, -SO,NR°R°, -NR’SO.R’, -OR®, -NR°R®, -(Ci-Cs alkylene)-NR°R®, C4-Ce alkyl, fluoro(C+-Ce)alkyl or Cs-Cy cycloalkyl; R® is a four to seven-membered, saturated or partially unsaturated heterocyclic group containing (i) 1 or 2 nitrogen heteroatom(s) or (ii) 1 nitrogen heteroatom and 1 oxygen or 1 sulphur heteroatom or (ji) 1 oxygen or sulphur heteroatom, said heterocyclic group being optionally substituted by oxo, C;-Cs alkyl, C5-C; cycloalkyl, -SO2R®, -CONR®R®, -COOR®, -CO-(C+-Cs alkylene)-OR® or -COR® and optionally substituted on a carbon atom which is not adjacent to a heteroatom by halo, -OR®, -NR°R®, -NR®*COR®, -NR°COOR?®, -NR°CONR®R®, -NR°SO,R°® or -CN;R" is H, R® R% R', C;-Cs alkyl, Cs-C7 cycloalkyl or -(C-Cs alkyl)-(Cs-Cy cycloalkyl), said C¢-Cs alkyl and C3-C; cycloalkyl being optionally substituted by -OR?®, -OR", R®, R%, R"® or -COR"™; : 35 R'" is H, C+-Cs alkyl or C5-C; cycloalkyl, said C1-Cs alkyl and Cs-C; cycloalkyl being optionally substituted by -OR®, -NR°R®, -NR*COR®, -CONR®R®, R® or R®; R'? is C4-Cs alkyl substituted by R®, R®, -OR®, -CONR®R®, -NR°COR® or -NR°R®;R' is phenyl optionally substituted by halo, -CN, -COR®, -CONR®R?®, -SO.NR°R?, -NR°SO,R’, -OR®, -NR°R®, -(C4-Cs alkylene)-NR°R®, C;-C; alkyi, halo(C1-Ce)alkyl or C3-C7 cycloalkyl; and xis0,1o0r2; with the proviso that (a) when R' and R® are both phenyl, R? is not methyl; and (b) when R' is ethoxy and R? is ethoxycarbonyl, R? is not phenyl.
- 2. A compound according to claim 1 wherein R', when taken separately, is H, C+-Cs alkyl, Cs-C; cycloalkyl or -OR’, said C4-Cs alkyl and C3-C; cycloalkyl being optionally substituted by halo, -CN, -OR", S(O)R", -CO.R', -CONR’R', -OCONR®R"™, -NR°CO-R', -NR'R"", -NR’*COR", -SO.NR°R®, -NR*CONR’R", -NR°SO.R™ or R™.
- 3. A compound according to claim 1 or 2 wherein R', when taken separately, is H, C-Cs alkyl, C5-C; cycloalkyl or -OR’, said C-Cs alkyl being optionally substituted by halo, -OR™, -NR'"R"!, -NR* COR" or R'°.
- 4. A compound according to any preceding claim wherein RZ, when taken. separately, is H, C4-Cg alkyl, Cs-Cs alkenyl or R®, said C4-Cs alkyl being optionally substituted by halo, -OR°, -OR", -CN, -CO.R’, -OCONR°R®, -CONR°R’, -C(=NR°)NR°OR®, -CONR’NR°R®, -NR°R®, -NR°R'?, -NR°COR®, -NR°COR®, -NR°COR", -NR’CO:R®, -NR°CONR’R®, -SO,NR°R’, -NR°SO,R®, R® or R®.
- 5. A compound according to any preceding claim wherein R?, when taken separately, is H, C1-Cs alkyl, C3-Cs alkenyl or R®, said C;-Cg alkyl being optionally substituted by -OR’, -OR', -CN, -CO;R’, -CONR°R’, -C(=NR°)NR°OR’ -CONR®NR®R®, -NR°R®, -NR°R'?, -NR°COR®, -NR°COR'2, -NR°CO.R®, R® or R®.
- 6. A compound according to claim 1 wherein R' and R?, when taken together, represent unbranched Cs-C4 alkylene, optionally substituted by oxo, wherein one methylene group of said Cs-C4 alkylene is replaced by an oxygen atom or a nitrogen atom, said nitrogen atom being optionally substituted by R*°, - 35
- 7. A compound according to claims 1 or 6 wherein R' and R?, when taken together, represent unbranched propylene wherein one methylene group is replaced by an oxygen atom or unbranched butylene wherein one methylene group is replaced by a nitrogen atom, said propylene and butylene being optionally substituted by oxo and said nitrogen atom being optionally substituted by R'.
- : 8. A compound according to any preceding claim wherein Ris H or C1-Ce alkyl, said C4-Cg alkyl being optionally substituted by halo, -CN, -OR®, -CO,R5, : -CONR®R®, -OCONR°R®°, -NR’CO.R’, -NRR®, -NRP°COR®, -SO.NR°R’, -NR°CONR’R®, -NR°SO:R’, R® or R®.
- 9. A compound according to any preceding claim wherein R® is H or Ci-Cs alkyl.
- 10. A compound according to any preceding claim wherein R* is phenyl optionally substituted by R®, halo, -CN, C-Cs alkyl, C:-Cg haloalkyl, Cs-C; cycloalkyl, C4-Cs alkoxy, -CONR®R®, OR", So,R°®, O-(C4-Cs alkylene)-CONR®R®, O-(C4-Cs alkylene)-NR°R®, or O-(C4-Cs alkylene)-OR®; or naphthyl.
- 11. A compound according to any preceding claim wherein R* is phenyl substituted by R®, halo, -CN, C,-Cs alkyl, C4-Cg haloalkyl, C3-C; cycloalkyl, C1-Cs alkoxy, -CONR°R®, OR", SoR® 0-(Ci-Cs alkylene)-CONR’R®, O-(C-Cs alkylene)-NR®R®, or O-(C4-Ce alkylene)-OR®.
- 12. A compound according to any preceding claim wherein R* is phenyl substituted by RE, halo, -CN, C¢-Cs alkyl, C1-Cs haloalkyl, C3-C; cycloalkyl! or C1 -Cs alkoxy.
- 13. A compound according to any preceding claim wherein R* is phenyl substituted by halo, -CN or C4-Cs alkyl.
- 14. A compound according to any preceding claim wherein R® is pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furanyl, thienyl, pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl, each being optionally substituted by halo, -CN, -COR®, -CONR°R®, -S0:NR°R®, -NR°SO,R®, -OR®, -NR°R®, -(C1-Cs alkylene)-NR®R®, C;-Cg alkyl, fluoro(C1-Cg)alkyl or C3-C7 cycloalkyl. :
- 15. A compound according to any preceding claim wherein R® is imidazolyl, pyrazolyl, 1,2 4-triazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, pyridinyl, pyrazinyl or pyrimidinyl, each being optionally substituted by halo, -CN, -COR®,
- -CONR°R®, -SO.NR°R’, -NR°SO.R®, -OR®, -NR°R’, -(C,-Cs alkylene)-NR°R®, C1-Cs alkyl, fluoro(C4-Ce)alkyl or Cs-C7 cycloalkyl. : 16. A compound according to any preceding claim wherein R® is imidazolyl, pyrazolyl, 1,2,4-triazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, pyridinyl, pyrazinyl : or pyrimidinyl, each being optionally substituted by -OR®, -NR°R® or C4-Cs alkyl.
- 17. A compound according to any preceding claim wherein R® is azetidinyl, tetrahydropyrrolyl, piperidinyl, azepinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, oxepinyl, morpholinyl, piperazinyl or diazepinyl, each being optionally substituted by oxo, C;-Cs alkyl, Cs-C; cycloalkyl, -SO,R®, -CONR®R®, -COOR?®, -CO-(C+-Cs alkylene)-OR® or -COR® and optionally substituted on a carbon atom which is not adjacent to a heteroatom by halo, -OR®, -NR°R®, -NR’COR?®, -NR°COOR?®, -NR°*CONR®R®, -NR®SO,R® or -CN.
- 18. A compound according to any preceding claim wherein R® is azetidinyl, piperidinyl, tetrahydrofuranyl, piperazinyl or morpholinyl, each being optionally substituted by oxo, C:-Cs alkyl, Cs-C; cycloalkyl, -SO;R®, -CONR®R?, -COOR?, -CO-(C4-Cs alkylene)-OR® or -COR® and optionally substituted on a carbon atom which is not adjacent to a heteroatom by halo, -OR®, -NR°R®, -NR°COR, -NR°COOR?, -NR*CONR®RS, -NR°SO,R° or -CN.
- 19. A compound according to any preceding claim wherein R® is azetidinyl, piperidinyl, tetrahydrofuranyl, piperazinyl or morpholinyl, each being optionally substituted by C-Cs alkyl, -SO:R®, -CONR’R®, -COOR®, -CO-(C;-Cs alkylene)- OR?® or -COR® and optionally substituted on a carbon atom which is not adjacent to a heteroatom by -OR® or -NR°*COR®.
- 20. A compound according to any preceding claim wherein R'is H, R®, R®, R"®, C4-Cs alkyl or -(C4-Cs alkyl)-(Cs-C7 cycloalkyl), said C;-Cs alkyl being optionally substituted by -OR®, -OR™, R®, R°, R" or -COR™, :
- 21. A compound according to any preceding claim wherein R'® is H, R?, R®, R'®, C1-Cs alkyl or -(C4-Cg alkyl)-(Cs-C cycloalkyl), said C;-Cs alkyl being optionally : 35 substituted by -OR® or R™.
- 22. A compound according to any preceding claim wherein R" is H or C1-Cs alkyl, said C4-Cs alkyl being optionally substituted by -OR®, -NR®RS5, -NR*COR, -CONR°RS, R® or R®.
- 23. A compound according to any preceding claim wherein R'is H or C4-Cq alkyl, said C,-Cs alkyl being optionally substituted by -OR® or -NR’COR®.
- 24. A compound according to any preceding claim wherein R% is C4-C, alkyl substituted by R®, R®, -OR®, -CONR’R®, -NR°COR?® or -NR°R°.
- 25. A compound according to any preceding claim wherein R'? is C-C, alkyl substituted by R®, -OR®, -NR*COR® or -NR°R®,
- 26. A compound according to any preceding claim wherein R™ is phenyl substituted by halo, -CN, -COR®, -CONR’R®, -SO,NR®R®, -NR°SO,R°, -OR®, -NR°R®, -(C;-Cs alkylene)-NR°R®, C4-Cs alkyl, halo(Ci-Cg)alkyl or Cs-C; cycloalkyl.
- 27. A compound according to any preceding claim wherein R' is phenyl substituted by halo, -CN, -CONR’R?, -SO,NR°R® or -OR>.
- 28. 2-[4-(3,5-Dichlorophenoxy)-3,5-dimethyl-1H-pyrazol-1-yljethanol; 2-[4-(3,5-Dichlorophenoxy)-3,5-diethyl-1H-pyrazol-1-yljethanol; 4-(3,5-Dichlorophenoxy)-3,5-diethyl-1 H-pyrazole; [4-~(3,5-Dichlorophenoxy)-3,5-diethyl-1 H-pyrazol-1-yllacetonitrile; 5-{{4-(3,5-Dichlorophenoxy)-3,5-diethyl-1 H-pyrazol-1-yijmethyl}-1 H-pyrazol-3-ol; 6-{[4-(3,5-Dichlorophenoxy)-3,5-diethyl-1 H-pyrazol-1-yljmethyl}-2-methyl-4(3H)- pyrimidinone; 2-Amino-6-{[4-(3,5-dichlorophenoxy)-3,5-diethyl-1 H-pyrazol-1-yljmethyl}-4(3H)- pyrimidinone; 2-[4-(3,5-Dichlorophenoxy)-3,5-diethyl-1 H-pyrazol-1-yl]-N- hydroxyethanimidamide; Methyl [4-(3,5-dichlorophenoxy)-3,5-diethyl-1H-pyrazol-1-yljacetate; 2-[4-(3,5-Dichlorophenoxy)-3,5-diethyl- 1 H-pyrazol-1-yljacetamide; 2-[4-(3,5-Dichlorophenoxy)-3,5-diethyl-1 H-pyrazol-1-yllacetohydrazide; Co 5-{[4-(3,5-Dichlorophenoxy)-3,5-diethyl-1 H-pyrazol-1-ylimethyl}-1,3,4-oxadiazol- 2(3H)-one; - 35 2-[4-(3,5-Dichlorophenoxy)-3,5-diethyl-1 H-pyrazol-1-yllethylamine; 3-{{4-(3,5-Dichlorophenoxy)-3,5-diethyl-1 H-pyrazol-1-yljmethyl}-1,2 4-oxadiazol- 5-0; 5-{[4-(3,5-Dichlorophenoxy)-3,5-diethyl-1 H-pyrazol-1-yljmethyl}-1,3,4-oxadiazol- 2-amine;285 | oT N-{2-[4-(3,5-Dichlorophenoxy)-3,5-diethyl-1 H-pyrazol-1-yljethyl}-2- methoxyacetamide; N-{2-[4-(3,5-dichlorophenoxy)-3,5-diethyl-1H-pyrazol-1-yl]ethyl}-2- : pyridinecarboxamide;N-{2-[4-(3,5-dichlorophenoxy)-3,5-diethyl-1H-pyrazol-1-yllethyl}-2- pyrazinecarboxamide; 3-{[3,5-Diethyl-1-(2-hydroxyethyl)-1H-pyrazol-4-ylloxy}benzonitrile; 4-{[3,5-diethyl-1-(2-hydroxyethyl)-1 H-pyrazol-4-ylJoxy}-3,5-dimethylbenzonitrile; 3-chloro-4-{[3,5-diethyl-1-(2-hydroxyethyl)-1 H-pyrazol-4-ylloxy}benzonitrile;5-{3,5-diethyl-1-(2-hydroxyethyl)-1H-pyrazol-4-ylloxy}-2-fluorobenzonitrile; 2-[4-(4-chlorophenoxy)-3,5-diethyl-1 H-pyrazol-1-yl]ethanol; 2-[4-(3-chlorophenoxy)-3,5-diethyl-1 H-pyrazol-1-yllethanol; 2-[4-(2-chlorophenoxy)-3,5-diethyl-1 H-pyrazol-1-yljethanol; 2-[4-(2,6-dichlorophenoxy)-3,5-diethyl-1 H-pyrazol-1-yllethanol;156 2-[4-(2,3-dichlorophenoxy)-3,5-diethyl-1 H-pyrazol-1-yllethanol; 2-[4-(2,4-dichlorophenoxy)-3,5-diethyl-1 H-pyrazol-1-yllethanol; 2-[3,5-diethyl-4-(2-fluorophenoxy)-1H-pyrazol-1-yllethanol; 2-[3,5-diethyl-4-(3-fluorophenoxy)-1H-pyrazol-1-yllethanol; 2-[4-(3,5-dimethylphenoxy)-3,5-diethyl-1 H-pyrazol-1-yl]ethanol;2-[3,5-diethyl-4-(4-fluoro-3-methylphenoxy)-1H-pyrazol-1-yllethanol; 2-[4-(2,5-dichlorophenoxy)-3,5-diethyl-1 H-pyrazol-1-yljethanol; 2-[4-(2,5-dichlorophenoxy)-3,5-diethyl-1H-pyrazol-1-ylJethanol; 2-[4-(3,4-dichlorophenoxy)-3,5-diethyl-1H-pyrazol-1-yilethanol; 2-[4-(2,6-difluorophenoxy)-3,5-diethyl-1H-pyrazol-1-yllethanol;2-[4-(2,5-difluorophenoxy)-3,5-diethyl-1 H-pyrazol-1-yllethanol; 2-[4-(3,5-difluorophenoxy)-3,5-diethyl-1 H-pyrazol-1-yllethanol; 4-(3,5-Dichlorophenoxy)-3,5-diethyl-1-(2-methoxyethyl)-1 H-pyrazole; 4-(3,5-dichlorophenoxy)-3,5-diethyl-1-(methoxymethyl)-1 H-pyrazole; 4-(3,5-dichlorophenoxy)-3,5-diethyl-1-methyl-1H-pyrazole;4-(3,5-Dichlorophenoxy)-3-ethyl-1H-pyrazole; 4-{2-[4-(3,5-Dichlorophenoxy)-3,5-diethyl-1H-pyrazol-1-yllethyl}morpholine; N-{2-[4-(3,5-dichlorophenoxy)-3,5-diethyl-1H-pyrazol-1-yl]ethyl}-N-(2-methoxyethyl)amine; 1-(1-{2-[4-(3,5-dichlorophenoxy)-3,5-diethyl-1 H-pyrazol-1-yl]ethyl}-4- : 35 piperidinyl)ethanone; N-{2-[4-(3,5-dichlorophenoxy)-3,5-diethyl-1 H-pyrazol-1-yljethyl}-N,N- dimethylamine; N-[2-({2-[4-(3,5-dichlorophenoxy)-3,5-diethyl-1 H-pyrazol-1- yllethyl}Jamino)ethyl]lacetamide;N-{2-[4-(3,5-dichlorophenoxy)-3,5-diethyl-1H-pyrazol-1-yllethyl}-N-methylamine; N-{2-[4-(3,5-dichlorophenoxy)-3,5-diethyl-1 H-pyrazol-1-yljethyl}- N-(tetrahydro-2- furanylmethyl)amine; 3-{[4-(3,5-Dichlorophenoxy)-3,5-diethyl-1H-pyrazol-1-ylimethyl}morpholine;1-(3-Azetidinyl)-4-(3,5-dichlorophenoxy)-3,5-diethyl-1 H-pyrazole;: 7-(3,5-Dichiorophenoxy)-6-ethyl-2,3-dihydropyrazolo[5,1-b][1,3]oxazole; 4-(3,5-Dichlorophenoxy)-3,5-dimethyl-1H-pyrazole; 1-[4-(3,5-Dichlorophenoxy)-3,5-diethyl-1 H-pyrazol-1-yl}-2-propanol; 2-{2-[4-(3,5-Dichlorophenxoy)-3,5-diethyl-1H-pyrazol-1-yl)ethoxy}ethanamine;4-{[4-(3,5-Dichlorophenoxy)-3-methyl-1H-pyrazol-5-ylimethylimorpholine; 4-(3,5-Dichlorophenoxy)-3-methyl-5-[(2-methyl-1 H-imidazol-1-yl)methyl]-1 H- pyrazole; 2-[4-(3,5-Dichlorophenoxy)-3-ethyl-5-methoxy-1H-pyrazol-1-yl}ethanol; 1-{[4-(3,5-Dichlorophenoxy)-3-methyl-1H-pyrazol-5-yljmethyl}-1H-1,2,4-triazole;3-[(3,5-Diethyl-1H-pyrazol-4-yl)oxylbenzonitrile; 3-{[1-(2-Aminoethyl)-3,5-diethyl-1 H-pyrazol-4-yljoxy}benzonitrile; 2-[4-(3-Cyanophenoxy)-3,5-diethyl-1H-pyrazol-1-yllacetamide;Ethyl [4-(3-cyanophenoxy)-3,5-diethyl-1 H-pyrazol-1-yllacetate; 1-Allyl-4-(3,5-dichlorophenoxy)-3,5-diethyl-1 H-pyrazole;N-{[4-(3,5-Dichlorophenoxy)-3-methyl-1H-pyrazol-5-yljmethyl}-N-(4- methoxybenzyl)amine; N-(cyclopropylmethyl)[4-(3,5-dichlorophenoxy)-3-methyl-1 H-pyrazol-5- yllmethanamine;[4-(3,5-dichiorophenoxy)-3-methyl- 1 H-pyrazol-5-yl}-N, N-dimethylmethanamine;[4-(8,5-dichlorophenoxy)-3-methyl-1H-pyrazol-5-yl]-N-methylmethanamine; 1-{[4-(3,5-dichlorophenoxy)-3-methyl-1 H-pyrazol-5-yllmethyl}-4-methylpiperazine; 1-{[4-(3,5-dichlorophenoxy)-3-methyl-1 H-pyrazol-5-yljmethyl}-4- piperidinecarboxamide;N-{[4-(3,5-dichlorophenoxy)-3-methyl-1 H-pyrazol-5-ylimethyl}-2-methoxyethanamine; 1-acetyl-4-{[4-(3,5-dichlorophenoxy)-3-methyl-1 H-pyrazol-5-yllmethyl}piperazine; N-[2-({[4-(3,5-dichlorophenoxy)-3-methyl-1 H-pyrazol-5-yllmethyl}amino)ethyllacetamide; N-(1-{[4-(3,5-dichlorophenoxy)-3-methyi-1H-pyrazol-5-ylimethyl}-4-’ 35 piperidinyl)acetamide; 1-{[4-(3,5-dichlorophenoxy)-3-methyl-1 H-pyrazol-5-yllmethyl}-4- methoxypiperidine; 3-Chloro-5-[(3,5-dimethyl-1 H-pyrazol-4-yl)oxyjbenzonitrile; 3-{[5-(Aminomethyl)-3-methyl-1H-pyrazol-4-ylJoxy}-5-chlorobenzonitrile;3-Chloro-5-{[3-methyl-5-(1-piperazinylmethyl)-1 H-pyrazol-4-ylJoxy}benzonitrile; 3-Chloro-5-[(5-{[(4-cyanobenzyl)amino]methyl}-3-methyl- 1 H-pyrazol-4- yl)oxylbenzonitrile;: 3-Chloro-5-[(3-methyl-5-{[4-(methylsulfonyl)-1-piperazinyljmethyl}-1 H-pyrazol-4-yloxylbenzonitrile;3-Chloro-5-[(5-{[4-(methoxyacetyl)-1-piperazinyllmethyl}-3-methyl-1 H-pyrazol-4- yl)oxy]benzonitrile; Methyl 4-{[4-(3-chloro-5-cyanophenoxy)-3-methyl-1H-pyrazol-5-yljmethyl}-1- piperazinecarboxylate;4-[({[4-(3-Chloro-5-cyanophenoxy)-3-methyl-1H-pyrazol-5- yllmethyl}amino)methyllbenzenesulfonamide; 4-(3,5-Dichlorophenoxy)-5-(methoxymethyl)-3-methyl-1 H-pyrazole; 3-tert-Butyl-4-(3,5-dichlorophenoxy)-5-methyl-1 H-pyrazole; 4-(3,5-Dichlorophenoxy)-3-ethyl-5-methyl-1 H-pyrazole;4-Cyano-N-{[4-(3,5-dichlorophenoxy)-3-methyl-1 H-pyrazol-5- yllmethyl}benzamide;~3-Cyano-N-{[4-(3,5-dichlorophenoxy)-3-methyl-1 H-pyrazol-5- yljmethyl}benzamide; N-{{4-(3,5-Dichlorophenoxy)-3-methyl-1 H-pyrazol-5-yljmethyl}-N-(3-pyridinylmethyl)amine; 3-({5-[(4-Acetyl-1-piperazinyl)methyl]-3-methyl-1 H-pyrazol-4-yl}oxy)-5- chlorobenzonitrile; 3-Chloro-5-[(5-{[(4-cyanobenzyl)(methyl)amino]methyl}-3-methyi-1 H-pyrazol-4- yl)oxylbenzonitrile;3-Chloro-5-[(5-{[(4-cyanobenzyl)(2-hydroxyethyl)amino]methyl}-3-methyl-1 H- pyrazol-4-yl)oxylbenzonitrile;~ 3-Chloro-5-({3-methyl-5-[(2-methyl-1 H-imidazol-1-yl)methyl]-1 H-pyrazol-4- yl}oxy)benzonitrile; 2-(4-(3,5-Dichlorophenoxy)-3-methyl-5-{[(3-pyridinyimethyl)amino]methyl}-1 H- pyrazol-1-ylhethanol; 5-[(3-Isopropyl-5-methyl-1 H-pyrazol-4-yl)oxylisophthalonitrile; 5-{[1-(2-Hydroxyethyl)-3-isopropyl-5-methyl-1 H-pyrazol-4-ylJoxylisophthalonitrile;: 3-(3,5-Dichlorophenoxy)-2-ethyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one; 3-(3,5-Dichlorophenoxy)-2-ethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine; 3-(3,5-Dichlorophenoxy)-2-ethyl-5-methyl-4,5,6,7-tetrahydropyrazolo[1,5- alpyrazine; 4-[(3-(3,5-Dichlorophenoxy)-2-ethyl-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4 H)- yymethyllbenzonitrile; ]3-(3,5-Dichlorophenoxy)-2-ethyl-5-(4-methoxybenzyl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine; [1-(2-Aminoethyl)-4-(3,5-dichlorophenoxy)-3-ethyl-1 H-pyrazol-5-yljmethanol; : 2-[4-(3,5-Dichlorophenoxy)-5-(ethoxymethyl)-3-ethyl-1H-pyrazol-1-yllethylamine; 2-[4-(3,5-dichlorophenoxy)-3-ethyl-5-(1 H-pyrazol-1-ylmethyl)-1H-pyrazol-1-: yllethylamine;N-{[1-(2-aminoethyl)-4-(3,5-dichlorophenoxy)-3-ethyl-1 H-pyrazol-5-yljmethy}-N- (4-methoxybenzyl)amine; 4-[({[1-(2-aminoethyl)-4-(3,5-dichlorophenoxy)-3-ethyl-1 H-pyrazol-5-yljmethyl}amino)methyllbenzonitrile; 2-[5-[(4-Acetyl-1-piperazinyl)methyl]-4-(3,5-dichiorophenoxy)-3-ethyl-1 H-pyrazol- 1-yllethylamine;N-[2-({[1-(2-Aminoethyl)-4-(3,5-dichlorophenoxy)-3-ethyl-1 H-pyrazol-5- yllmethyl}amino)ethyllacetamide;[4-(3,5-Dichlorophenoxy)-3-methyl-1H-pyrazol-5-yllmethanamine hydrobromide; N-{[4-(3,5-Dichlorophenoxy)-3-methyl-1H-pyrazol-5-yllmethyl}-N-(4- fluorobenzyl)amine; } 4-[({[4~(3,5-Dichlorophenoxy)-3-methyl-1H-pyrazol-5- ylJmethyl}amino)methyl]benzonitrile;3-Chloro-5-[(1,3,5-trimethyl-1 H-pyrazol-4-yl)oxy]benzonitrile; 3-Chloro-5-[(5-{[(4-cyanobenzyl)amino]methyl}-1,3-dimethyl-1 H-pyrazol-4- yl)oxylbenzonitrile; 3-Chloro-5-{[1-(2-hydroxyethyl)-3,5-dimethyl-1 H-pyrazol-4-yljoxy}benzonitrile; 3-Chiloro-5-{[5-{[(4-cyanobenzyl)amino]methyl}-1-(2-hydroxyethyl)-3-methyi-1H-pyrazol-4-ylJoxy}benzonitrile; 4-[({[4-(3-Chloro-5-cyanophenoxy)-3-methyi-1H-pyrazol-5- ylimethyl}amino)methyljbenzamide; 3-{[3,5-diethyl-1-(2-hydroxyethyl)-1H-pyrazol-4-yl]oxy}-5-fluorobenzonitrile;- 3-{[3,5-diethyl-1-(2-hydroxyethyl)-1 H-pyrazol-4-ylJoxy}-5-methylbenzonitrile;5-{[3,5-diethyl-1-(2-hydroxyethyl)- 1 H-pyrazol-4-ylloxy}isophthalonitrile; 3-chloro-5-{[3,5-diethyl-1-(2-hydroxyethyl)-1 H-pyrazol-4-ylloxy}benzonitrile; 3-[(3,5-diethyl-1H-pyrazol-4-yl)oxy]-5-fluorobenzonitrile;5-[(3,5-diethyl-1H-pyrazol-4-yl)oxylisophthalonitrile; 3-[(3,5-diethyl-1H-pyrazol-4-yl)oxy]-5-methylbenzonitrile;: 35 3-chloro-5-[(3,5-diethyl-1H-pyrazol-4-yl)oxylbenzonitrile; 3-{[1-(2-aminoethyl)-3,5-diethyl-1 H-pyrazol-4-ylloxy}-5-methylbenzonitrile; 3-{[1-(2-aminoethyl)-3,5-diethyl-1 H-pyrazol-4-ylloxy}-5-chlorobenzonitrile; 5-{[1-(2-aminoethyl)-3,5-diethyl-1 H-pyrazol-4-yljoxy}isophthalonitrile; 3-{[1-(2-aminoethyt)-3,5-diethyl-1 H-pyrazol-4-ylJoxy}-5-fluorobenzonitrile;5-[(3-cyclopropyl-5-ethyl-1H-pyrazol-4-yl)oxyjisophthalonitrile; 5-[(3-tert-butyl-5-methyl-1 H-pyrazol-4-yl)oxylisophthalonitrile; 5-[(5-ethyl-3-isopropyl-1H-pyrazol-4-yl)oxyJisophthalonitrile; : 4-(3,5-Dichlorophenoxy)-3,5-diethyl-1-(1-methyl-3-azetidinyl)-1 H-pyrazole; 2-4-(3,5-Dichlorophenoxy)-3-ethyl-1H-pyrazol-1-yljethylamine; 2-[4-(3,5-Dichlorophenoxy)-5-ethyl-1 H-pyrazol-1-yllethylamine; tert-Butyl 2-[4-(3,5-dichlorophenoxy)-3-ethyl-5-(hydroxymethyl)-1 H-pyrazol-1- yllethylcarbamate; tert-Butyl 2-[4-(3,5-dichlorophenoxy)-5-(ethoxymethyl)-3-ethyl-1 H-pyrazol-1-yllethylcarbamate; tert-Butyl 2-[5-(bromomethyl)-4-(3,5-dichlorophenoxy)-3-ethyl-1 H-pyrazol-1- yllethyicarbamate; tert-Butyl 2-[5-(aminomethyl)-4-(3,5-dichlorophenoxy)-3-ethyl-1 H-pyrazol-1- yllethylcarbamate;tert-Butyl 2-[5-[(4-acetyl-1-piperazinyl)methyl]-4-(3,5-dichlorophenoxy)-3-ethyl-1 H-pyrazol-1-yllethylcarbamate;tert-Butyl 2-[4-(3,5-dichlorophenoxy)-3-ethyl-5-(1H-pyrazol-1-yimethyl)-1 H- pyrazol-1-yijethylcarbamate; :tert-Butyl 2-[5-({[2-(acetylamino)ethyljamino}methyl)-4-(3,5-dichlorophenoxy)-3- ’ethyl-1H-pyrazol-1-yljethylcarbamate; tert-Butyl 2-(4-(3,5-dichlorophenoxy)-3-ethyl-5-{[(4-methoxybenzyl)aminojmethyl}- 1 H-pyrazol-1-yl)ethylcarbamate; tert-Butyl 2-[5-{[(4-cyanobenzyl)amino]methyl}-4-(3,5-dichlorophenoxy)-3-ethyl-1 H-pyrazol-1-yllethylcarbamate;3-{[5-(Bromomethyl)-1,3-dimethyl-1 H-pyrazol-4-ylloxy}-5-chiorobenzonitrile; 3-[(3,5-Diethyl-1-methyl-1 H-pyrazol-4-yl)oxy]benzonitrile; 3-{[3,5-Diethyl-1-(2-methoxyethyl)-1H-pyrazol-4-yljoxy}benzonitrile; 3-({5-[2-(Benzyloxy)ethyl]-3-ethyl-1 H-pyrazol-4-yljoxy)-5-fluorobenzonitrile; 3-{[3-Ethyl-5-(2-hydroxyethyl)-1 H-pyrazol-4-yl]oxy}-5-fluorobenzonitrile;3-({5-[2-(4-Cyanophenoxy)ethyl]-3-ethyl-1 H-pyrazol-4-yl}oxy)-5-fluorobenzonitrile; 3-[(3-Ethyl-5-{2-[(2-methyl-3-pyridinyl)oxylethyl}-1 H-pyrazol-4-yl)oxy]-5- fluorobenzonitrile;: 3-({3-Ethyl-5-[2-(3-pyridinyloxy)ethyl]-1 H-pyrazol-4-yl}oxy)-5-fluorobenzonitrile; 3-[(5-{2-[(2-Amino-3-pyridinyl)oxylethyl}-3-ethyl-1 H-pyrazol-4-yl)oxy]-5-- 35 fluorobenzonitrile; 5-({5-[2-(benzyloxy)ethyl]-3-ethyl-1 H-pyrazol-4-yl}oxy)isophthalonitrile; 5-{[3-Ethyl-5-(2-hydroxyethyl)-1 H-pyrazol-4-ylJoxy}isophthalonitrile; 3-{[5-(Aminomethyl)-1-(2-hydroxyethyl)-3-methyl-1 H-pyrazol-4-yljoxy}-5- chlorobenzonitrile;5-[(1-Allyl-3-tert-butyl-5-methyl-1 H-pyrazol-4-yl)oxyJisophthalonitrile; 5-{[3-tert-Butyl-1-(2-hydroxyethyl)-5-methyl-1 H-pyrazol-4-yljoxy}isophthalonitrile; 5-{[1-(2-Aminoethyl)-3-tert-butyl-5-methyl-1H-pyrazol-4-ylJoxy}isophthalonitrile; 3-{[3,5-Diethyl-1-(2-hydroxyethyl)-1 H-pyrazol-4-ylloxy}-5-(1 H-1,2,4-triazol-1- ylbenzonitrile;: 3-{[3,5-diethyl-1-(2-hydroxyethyl)-1H-pyrazol-4-ylloxy}-5-(4-oxo-1(4 H)- pyridinyl)benzonitrile; 3-{[3,5-diethyl-1-(2-hydroxyethyl)- 1 H-pyrazoi-4-ylloxy}-5-(1H-1,2,3-triazol-1- ybenzonitrile;3-{[3,5-diethyl-1-(2-hydroxyethyl)-1H-pyrazol-4-ylJoxy}-5-(2H-1,2,3-triazol-2- yl)benzonitrile; 3-{[3,5-Diethyl-1-(2-hydroxyethyl)-1 H-pyrazol-4-yljoxy}-5-fluorobenzamide; 3-{[3,5-Diethyl-1-(2-hydroxyethyl)-1H-pyrazol-4-ylJoxy}-5-(1 H-pyrazol-1- yl)benzamide;3-{[3,5-Diethyl-1-(2-hydroxyethyl)-1 H-pyrazol-4-ylloxy}-5-(2-oxo-1(2H)- pyridinyl)benzamide; 3-{[3,5-Diethyl-1-(2-hydroxyethyl)-1 H-pyrazol-4-ylloxy}-5-(6-oxo-1(6H)- pyridazinyl)benzamide; 3-{[3,5-Diethyl-1-(2-hydroxyethyl)-1 H-pyrazol-4-ylloxy}-5-(2,3-dimethyl-5-0x0-2,5-dihydro-1H-pyrazol-1-yl)benzamide; 5-{[3-Cyclopropyl-5-ethyl-1-(2-hydroxyethyl)-1H-pyrazol-4-ylloxy}isophthalonitrile; 5-{[5-Cyclopropyl-3-ethyl-1-(2-hydroxyethyl)-1H-pyrazol-4-yljoxy}isophthalonitrile; 5-{[5-Ethyl-1-(2-hydroxyethyl)-3-isopropyl-1H-pyrazol-4-yl]oxy}isophthalonitrile; 5-{[3-Ethyl-1-(2-hydroxyethyl)-5-isopropyl-1H-pyrazol-4-ylloxy}isophthalonitrile;2-[4-(3,5-Dicyanophenoxy)-3,5-diethyl-1H-pyrazol-1-yllethyl carbamate; N-{2-[4-(3,5-Dicyanophenoxy)-3,5-diethyl-1H-pyrazol-1-yllethyl}sulfamide; N-{2-[4-(3,5-Dicyanophenoxy)-3,5-diethyl-1H-pyrazol-1-yljethyl}-2- methoxyacetamide; 5-{[1-(3-Azetidinyl)-3,5-diethyl-1H-pyrazol-4-yijoxy}isophthalonitrile; :5-{[3,5-Diethyl-1-(3-hydroxypropyl)-1H-pyrazol-4-ylJoxy}lisophthalonitrile; 5-[(3,5-Diethyl-1-methyl-1H-pyrazol-4-yl)oxylisophthalonitrile; 5-{[3,5-Diethyl-1-(2-methoxyethyl)-1 H-pyrazol-4-ylJoxy}isophthalonitrile;’ 5-{[1-(3-Aminopropyl)-3,5-diethyl-1 H-pyrazol-4-ylJoxy}isophthalonitrile; methyl [4-(3,5-Dicyanophenoxy)-3,5-diethyl-1H-pyrazol-1-yljacetate;2-[4-(8,5-Dicyanophenoxy)-3,5-diethyl-1H-pyrazol-1-yljacetamide; 5-{[3,5-Diethyl-1-(hydroxymethyl)-1 H-pyrazol-4-ylJoxy}isophthalonitrile; 3-[({[4-(3-cyano-5-fluorophenoxy)-3-methyl-1 H-pyrazol-5- ylimethyl}amino)methyllbenzamide;4-{({[4-(3-Cyano-5-fluorophenoxy)-3-methyi-1H-pyrazol-5- yllmethyl}amino)methyllbenzamide; 4-[({[4-(8,5-Dicyanophenoxy)-3-methyl-1 H-pyrazol-5- ylimethyl}amino)methyllbenzamide; 3-[({[4-(3-Chloro-5-cyanophenoxy)-3-methyl-1H-pyrazol-5-: ylimethyl}amino)methyl]benzamide; 4-[({[4-(3-Cyano-5-methylphenoxy)-3-methyl-1H-pyrazol-5- yllmethyl}amino)methyl]benzamide; 4-[({[4-(3-Cyanophenoxy)-3-methyl-1H-pyrazol-5-yljmethyl}amino)methyllbenzamide; 5-[(3,5-Dicyclopropyl-1H-pyrazol-4-yl)oxylisophthalonitrile; 5-{[3,5-Dicyclopropyl-1-(2-hydroxyethyl)-1 H-pyrazol-4-yljoxylisophthalonitrile; 5-{[1-(2-Aminoethyl)-3,5-dicyclopropyl-1H-pyrazol-4-yljoxylisophthalonitrile; 3-{[3-cyclopropyl-1-(2-hydroxyethyl)-5-methyl-1 H-pyrazol-4-ylloxy}-5-methylbenzonitrile; 3-{[5-cyclopropyl-1-(2-hydroxyethyl)-3-methyl-1 H-pyrazol-4-yljoxy}-5- methylbenzonitrile; 3-[3-Cyclopropyl-1-(2-amino-ethyl)-5-methyl-1H-pyrazol-4-yloxy]-5-methyl- benzonitrile;3-[(3-Cyclopropyl-5-methyl-1H-pyrazol-4-yl)oxy]-5-methylbenzonitrile; 3-{[1-(3-Aminopropyl)-3,5-diethyl-1 H-pyrazol-4-ylloxy}-5-methylbenzonitrile; 3-{[3,5-Diethyl-1-(2-hydroxyethyl)- 1 H-pyrazol-4-yiJoxy}-4-methoxybenzonitrile; 2-[3,5-Diethyl-4-(1-naphthyloxy)-1H-pyrazol-1-yllethanol; 2-[3,5-Diethyl-4-(2-naphthyloxy)-1 H-pyrazol-1-yllethanol,2-{4-[3,5-Di(1H-pyrazol-1-yl)phenoxy]-3,5-diethyl-1 H-pyrazol-1-yl}ethanol; 2-{3,5-Diethyl-4-[3-fluoro-5-(1 H-pyrazol-1-yl)phenoxy]- 1 H-pyrazol-1-yl}ethanol; 3-{[3,5-Diethyl-1-(2-hydroxyethyl)-1 H-pyrazol-4-ylloxy}-5-methoxybenzonitrile; 2-{4-(3,5-Difluorophenoxy)-3,5-diethyl-1H-pyrazol-1-yllethylamine; 3-{[1-(2-Aminoethyl)-3,5-diethyl-1 H-pyrazol-4-ylJoxy}-5-fluorobenzamide;3-[(3-Isopropyl-5-methyl-1 H-pyrazol-4-yl)oxy]-5-methylbenzonitrile; 3-{[1-(2-Aminoethyl)-3-isopropyl-5-methyl-1 H-pyrazol-4-ylJoxy}-5- methylbenzonitrile;2-{4-(3,5-Dichlorophenoxy)-3,5-diethyl-1H-pyrazol-1-yl}-N-(2- pyridinylmethyl)acetamide;) 35 [4-(3,5-Dichlorophenoxy)-3-methyl-1 H-pyrazol-5-yllacetonitrile; 1-{[4-(3,5-Dichlorophenoxy)-3-methyl-1 H-pyrazol-5-yllacetyl}piperidine; (3R)-1-{[4-(3,5-Dichlorophenoxy)-3-methyl-1 H-pyrazol-5-yl]acetyl}-3-piperidinol; N-(2,4-Dichlorobenzyl)-2-[4-(3,5-dichlorophenoxy)-3-methyl-1 H-pyrazol-5- yllacetamide;292 PTT2-[4-(3,5-Dichlorophenoxy)-3-methyl-1H-pyrazol-5-yl]-N-(6-methyl-2-pyridinyl)acetamide;2-[4-(3,5-Dichlorophenoxy)-3-methyl-1H-pyrazol-5-yl]-N-[4- (trifluoromethyl)benzyl]acetamide;N-(3-Chlorobenzyl)-2-{4-(3,5-dichlorophenoxy)-3-methyl-1H-pyrazol-5-yllacetamide;2-[4-(3,5-Dichlorophenoxy)-3-methyl-1 H-pyrazol-5-yl}-N-[2-(trifluoromethyl)benzyllacetamide;2-[4-(3,5-Dichlorophenoxy)-3-methyl-1 H-pyrazol-5-yl]-N-(4-fluorobenzyl)acetamide; N-Benzyl-2-[4-(3,5-dichlorophenoxy)-3-methyl-1 H-pyrazol-5-yl}-N- methylacetamide; 3-chloro-5-[(5-{[(2-chlorobenzyl)amino]methyl}-3-methyl-1 H-pyrazol-4- yl)oxy]benzonitrile;3-({5-[(Benzylamino)methyli}-3-methyl-1 H-pyrazol-4-yl}oxy)-5-chlorobenzonitrile; 3-[(5-{[Benzyl(methyl)amino]methyi}-3-methyl-1 H-pyrazol-4-yl)oxy]-5- chlorobenzonitrile; 3-Chloro-5-{[5-({[(5-chloro-2-pyridinyl)methyl]Jamino}methyl)-3-methyl-1 H-pyrazol- 4-ylloxy}benzonitrile;3-Chloro-5-[(3-methyl-5-{[(4-pyridinylmethyl)amino]methyl}-1 H-pyrazol-4- yl)oxylbenzonitrile; 3-Chloro-5-[(3-methyl-5-{[(4-methylbenzyl)amino]methyl}- 1 H-pyrazol-4- yl)oxylbenzonitrile; 3-Chloro-5-[(5-{[(3-methoxypropyl)amino]methyl}-3-methyl-1 H-pyrazol-4-yl)oxylbenzonitrile; 4-[2-({[4-(3-Chloro-5-cyanophenoxy)-3-methyl-1 H-pyrazol-5- ylimethyl}amino)ethyilbenzenesulfonamide; 3-Chloro-5-{[3-methyl-5-({[(1S)-1-phenylethyllamino}methyl)-1H-pyrazol-4- yljoxy}benzonitrile;3-Chloro-5-[(5-{[(4-chiorobenzyl)amino]methyl}-3-methyl-1 H-pyrazol-4- yl)oxy]benzonitrile; 3-Chloro-5-{(3-methyl-5-{[methyl(2-phenylethyl)amino]methyl}-1 H-pyrazol-4-yloxy]benzonitrile; 3-Chloro-5-({3-methyl-5-[(1 H-pyrazol-3-ylamino)methyl]-1 H-pyrazol-4- ’ 35 ylloxy)benzonitrile; N-[2-({[4-(3-Chloro-5-cyanophenoxy)-3-methyl-1 H-pyrazol-5- yllmethyl}amino)ethyljacetamide; . : 3-Chloro-5-[(5-{[(3-chlorobenzyl)amino]methyl}-3-methyl-1 H-pyrazol-4- yloxylbenzonitrile; {3-Chioro-5-{[5-({[3-fluoro-5-(trifluoromethyl)benzyllamino}methyl)-3-methyl-1 H- pyrazol-4-ylloxy}benzonitrile; 3-Chloro-5-[(3-methyl-5-{[(6-methyl-2-pyridinyl)amino]methyl}-1H-pyrazol-4- : yl)oxylbenzonitrile; 3-Chloro-5-{(5-{[(4-hydroxy-6-methyl-2-pyrimidinyl)amino]methyl}-3-methyl-1 H- : pyrazol-4-yl)oxy]benzonitrile; 3-Chloro-5-[(5-{[(4-fluorobenzyl)amino]methyl}-3-methyl-1 H-pyrazol-4- yl)oxy]benzonitrile; 3-Chloro-5-{[5-({[(1 R)-2-hydroxy-1-phenylethyllamino}methyl)-3-methyl- 1 H-pyrazol-4-yljoxy}benzonitrile; 3-({5-[(Benzylamino)methyl]-3-methyl-1H-pyrazol-4-yl}oxy)-5-chlorobenzonitrile; 3-Chloro-5-[(5-{[(3-methoxybenzyl)amino]jmethyl}-3-methyl-1 H-pyrazol-4- yhoxylbenzonitrile; 3-Chloro-5-{[3-methyl-5-({[4- (trifluoromethyl)benzyllamino}methyl)-1 H-pyrazol-4-ylloxy}benzonitrile; 3-Chloro-5-{[5-({[(1 R)-1-(hydroxymethyl)-2-methylpropyl]lamino}methyl)-3-methyl-1 H-pyrazol-4-yljoxy}benzonitrile; 3-Chloro-5-[(5-{[(2-methoxybenzyl)amino]methyl}-3-methyl-1 H-pyrazol-4- yl)oxylbenzonitrile;3-Chloro-5-{[3-methyl-5-({[2-(2-thienyl)ethyl]Jamino}methyl)-1 H-pyrazol-4- ylloxy}benzonitrile; : 3-Chloro-5-[(3-methyl-5-{[(3-pyridinylmethyl)amino]methyl}-1 H-pyrazol-4- yl)oxylbenzonitrile; 3-Chloro-5-{[3-methyl-5-({[2-(irifluoromethyl)benzyllamino}methyl)-1 H-pyrazol-4-ylloxy}benzonitrile; 3-Chloro-5-[(5-{[(2,4-dichlorobenzyl)aminolmethyl}-3-methyl-1H-pyrazol-4- yl)oxylbenzonitrile; 3-Chloro-5-[(3-methyl-5-{[(2-pyridinylmethyl)amino]methyl}-1 H-pyrazoi-4- yl)oxylbenzonitrile; 3-Chloro-5-[(5-{[(3,4-dichlorobenzyl)amino]methyl}-3-methyl-1H-pyrazol-4- yl)oxylbenzonitrile; 3-Chloro-5-[(3-methyl-5-{[(3-phenylpropyl)amino}methyl}-1 H-pyrazol-4-: yl)oxylbenzonitrile; 3-Chloro-5-[(5-{[(4-methoxybenzyl)amino]methyl}-3-methyl-1 H-pyrazol-4- - 35 yloxylbenzonitrile; 3-{[3,5-Diethyl-1-(2-hydroxyethyl)-1 H-pyrazol-4-ylJoxy}-5- (methylsulfanyl)benzonitrile; 3-{[3,5-Diethyl-1-(2-hydroxyethyl)-1H-pyrazol-4-yljoxy}-5- (methylsulfinyl)benzonitrile;3-{[3,5-Diethyl-1-(2-hydroxyethyl)-1H-pyrazol-4-yljoxy}-5- (methylsulfonyl)benzonitrile; 3-{[8,5-Diethyl-1-(2-hydroxyethyl)-1 H-pyrazol-4-ylJoxy}-5-{2- : (dimethylamino)ethoxy]benzonitrile;3-{[3,5-Diethyl-1-(2-hydroxyethyl)-1H-pyrazol-4-yljoxy}-5-[2- (methylamino)ethoxy]benzonitrile; 2-(3-Cyano-5-{[3,5-diethyl-1-(2-hydroxyethyl)-1 H-pyrazol-4- ylloxy}phenoxy)acetamide; 3-{[3,5-Diethyl-1-(2-hydroxyethyl)-1 H-pyrazol-4-ylloxy}-5-(2-methoxyethoxy)benzonitrile; 3-{[1-(2-Aminoethyl)-3,5-diethyl-1 H-pyrazol-4-ylloxy}-5-methoxybenzonitrile; 3-{[1-(2-Aminoethyl)-3,5-diethyl-1H-pyrazol-4-ylloxy}-5-(1 H-pyrazol-1- yl)benzonitrile; 3,5-Dichlorophenyl-3-methyl-5-[(3-methyl-1,2,4-oxadiazol-5-yl)methyl}-1 H-pyrazol-4-yl ether; 3-Fluoro-5-{[1-(2-hydroxyethyl)-5-methyl-3-(trifluoromethyl)-1 H-pyrazol-4- ylloxy}benzonitrile; 5-[(3,5-Diethyl-1-{2-[(2-methoxyethoxy)methoxylethyl}-1 H-pyrazol-4- yl)oxylisophthalonitrile; 3-Cyano-5-{[3,5-diethyl-1-(2-hydroxyethyl)-1 H-pyrazol-4-yljoxy}benzamide; 5-{[5-Ethyl-3-(1-hydroxyethyl)-1 H-pyrazol-4-yl]oxylisophthalonitrile; 5-{[5-Ethyl-3-(1-hydroxyethyl)-1-(2-hydroxyethyl)-1H-pyrazol-4- ylloxylisophthalonitrile; 3-{[3,5-Diethyl-1-(2-hydroxyethyl)-1H-pyrazol-4-ylloxy}-5-(5-trifluoromethyi-1,2,4-oxadiazol-3-yl)benzonitrile; 3-{[3,5-Diethyl-1-(2-hydroxyethyl)-1H-pyrazol-4-ylJoxy}-5-(5-methyl-1,2,4- oxadiazol-3-yl)benzonitrile; 3-{[3,5-Diethyl-1-(2-hydroxyethyl)-1 H-pyrazol-4-yljoxy}-5-(5-ethyl-1,2,4-oxadiazol- 3-yl)benzonitrile;3-{[3,5-Diethyl-1-(2-hydroxyethyl)-1 H-pyrazol-4-yljoxy}-5-(5-isopropyl-1,2,4- oxadiazol-3-yl)benzonitrile; 5-[({[4-(3-Chloro-5-cyanophenoxy)-3-methyl-1H-pyrazol-5- ylimethyl}lamino)methyli]nicotinamide; 2-[({[4-(3-Chloro-5-cyanophenoxy)-3-methyl-1H-pyrazol-5-yllmethyl}amino)methyljisonicotinamide; Di(tert-butyl) 2-[4-(3,5-dicyanophenoxy)-3,5-diethyl-1 H-pyrazol-1-yljethyl phosphate; 2-[4-(3,5-Dicyanophenoxy)-3,5-diethyl-1 H-pyrazol-1-yllethyl dihydrogen phosphate;5-{[3,5-Diethyl-1-(2-hydroxyethyl)-1 H-pyrazol-4-yljoxy}isophthalonitrile sulfate salt; 5-{[3,5-Diethyl-1-(2-hydroxyethyl)-1 H-pyrazol-4-ylJoxy}isophthalonitrile ; 5-{[3,5-Diethyl-1-(2-hydroxyethyl)-1H-pyrazol-4-yl]Joxy}isophthalonitrile tosylate salt; : 5-{[3,5-Diethyl-1-(2-hydroxyethyl)-1H-pyrazol-4-yl]oxy}isophthalonitrile mesylate salt; 3-{[1-(2-Aminoethyl)-3,5-diethyl-1 H-pyrazol-4-ylJoxy}-5-methylbenzonitrile bis- mesylate salt; 3-{[1-(2-Aminoethyl)-3,5-diethyl-1 H-pyrazol-4-ylJoxy}-5-methylbenzonitrile phosphate salt; 3-{[1-(2-Aminoethyl)-3,5-diethyl-1H-pyrazol-4-ylJoxy}-5-methylbenzonitrile (L) tartrate salt; 3-{[1-(2-Aminoethyl)-3,5-diethyl-1H-pyrazol-4-yl]oxy}-5-methylbenzonitrile succinate salt; 3-{[1-(2-Aminoethyl)-3,5-diethyl-1 H-pyrazol-4-ylloxy}-5-methylbenzonitrile (L) citrate salt; or a pharmaceutically acceptable salt, solvate or derivative thereof.
- 29. 3-{[8,5-diethyl-1-(2-hydroxyethyl)-1 H-pyrazol-4-yljoxy}-5-fluorobenzonitrile; 3-{[3,5-diethyl-1-(2-hydroxyethyl)-1H-pyrazol-4-yiJoxy}-5-methylbenzonitrile; 5-{[3,5-diethyl-1-(2-hydroxyethyl)-1H-pyrazol-4-ylJoxy}isophthalonitrile; 3-chloro-5-{[3,5-diethyl-1-(2-hydroxyethyl)-1 H-pyrazol-4-ylJoxy}benzonitrile; 5-[(3,5-diethyl-1 H-pyrazol-4-yl)oxylisophthalonitrile; 3-[(3,5-diethyl-1 H-pyrazol-4-yl)oxy]-5-methylbenzonitrile; 3-chloro-5-[(3,5-diethyl-1 H-pyrazol-4-yl)oxy]benzonitrile; 3-{[1-(2-aminoethyl)-3,5-diethyl-1 H-pyrazol-4-ylJoxy}-5-methylbenzonitrile; 3-{[1-(2-aminoethyl)-3,5-diethyl-1 H-pyrazol-4-yljoxy}-5-chlorobenzonitrile; 5-{[1-(2-aminoethyl)-3,5-diethyl-1H-pyrazol-4-ylJoxy}isophthalonitrile; or a pharmaceutically acceptable salt, solvate or derivative thereof
- 30. A compound of the formula (1) R* R' L , 2 pa Rr’ ora pharmaceutically acceptable salt or solvate thereof, wherein:R' is H, Cy-Cs alkyl, -OC4-Cs alkyl, -OCs-C; cycloalkyl, said C4-Cg alkyl being optionally substituted by R'; R?is H, Ci-Cs alkyl, propenyl or C-linked R'™, said C;-C; alkyl being optionally ‘ substituted by -OH, -OCHs, -OCH5CHoNH,, -CN, -CO2CHs, -CONHo, -C(=NH)NH,, -CONHNH2, -NH,, -NHCHj; -N(CHaj)2, -NHCH>CH,NHCOCHS, -NHCH,CH,OCHj, -NHCH,R'", -NHCOR'®, -NHCOCH,OCHg, or R™ R%is C4-Cs alkyl; R* is phenyl optionally substituted by halo, -CN, C4-Cg alkyl, C;-Cs haloalkyl, C;-C7 cycloalkyl or C4-Cg alkoxy; and RY is azefidinyl, tetrahydrofuranyl, morpholinyi, piperazinyl, pyrazolyl, oxadiazolyl, pyridinyl or pyrimidinyl each being optionally substituted by -OH, -NHa, oxo or C4-Cg alkyl or -CO(C1-Cs alkyl).
- 31. A pharmaceutical composition including a compound of the formula (l) or a pharmaceutically acceptable salt, solvate or derivative thereof, according to any preceding claim, together with one or more pharmaceutically acceptable excipients, diluents or carriers.
- 32. A pharmaceutical composition according to claim 31 including one or more additional therapeutic agents.
- 33. A compound of the formula (I) or a pharmaceutically acceptable salt, solvate or derivative thereof according to any of claims 1 to 30, or a pharmaceutical composition according to claim 31 or 32, for use as a medicament.
- 34. A compound of the formula (I) or a pharmaceutically acceptable salt, solvate or derivative thereof according to any of claims 1 to 30, or a pharmaceutical composition according to claim 31 or 32, for use as a reverse transcriptase inhibitor or modulator.
- 35. A compound of the formula (I) or a pharmaceutically acceptable salt, solvate or derivative thereof according to any of claims 1 to 30, or a pharmaceutical composition according to claim 31 or 32, for use in the treatment© WO0 02085860 PCT/IB02/01234 of an HIV, or genetically-related retroviral, infection or a resulting acquired immune deficiency syndrome (AIDS).
- 36. The use of a compound of the formula (I) or a pharmaceutically acceptable salt, solvate or derivative thereof according to any of claims 1 to 30, or a pharmaceutical composition according to claim 31 or 32, for the manufacture of a medicament having reverse transcriptase inhibitory or modulating activity.
- 37. The use of a compound of the formula (I) or a pharmaceutically acceptable salt, solvate or derivative thereof according to any of claims i io 30, or a pharmaceutical composition according to claim 31 or 32, for the manufacture of a medicament for the treatment of an HIV, or genetically-related retroviral, infection or a resulting acquired immune deficiency syndrome (AIDS).
- 38. A process for preparing a compound of the formula (1) or a salt, solvate or pharmaceutically acceptable derivative thereof according to any of claims 1 to 30, which comprises: AMENDED SHEET ”(A) except where either R' or R® is halo, -OR® or CN, condensation of a compound of the formula (11), (VI) or (Vii) 4 4 R Rr’ R R' rR* 1 ONG 0 1 R L o | © To ar RO ROL 3 R= 0 VD or (vi)with a compound of the formula HNNHR? (V) or a salt or hydrate thereof; (B) for the preparation of a compound of the formula (I) in which R' or R® is -OR®, reaction of, respectively, a compound of the formulae (XI) or (XIV) 4 4 A ba Q 13 0) R! Daf (XH) Da (XIV) R N\ L N\ NR? or NS R2 with an alcohol of the formula (XXI) R®OH (XX)in the presence of a suitable palladium catalyst and carbon monoxide; (C) for the preparation of a compound of the formula (f) in which R' or R® is -OR®, reaction of, respectively, a compound of the formulae (XV) or (XVI),i 4 4 A J Q oH R! Da (XV) Daf (XVI) R= _N HO™X _N_ N~ ~R? or N~ R> y© Wo 2085860 PCT/IB02/01234 with a compound of the formula (XXI) ROH (xX) under dehydrating conditions; or (D) for the preparation of a compound of the formula (I) in which R' or R® is halo, reaction of, respectively, a compound of the formulae (XV) or (XVI) —4 4 a R =" R' ={ ow ={ ov RN No HON _N. N" TR? of NN“ R? with a halogenating agent; or (E) interconversion of a compound of formula (1) into another compound of formula (1); or (F) deprotecting a protected derivative of compound of formula (1); and optionally converting a compound of formula ()) prepared by any one of processes (A) to (F) into pharmaceutically acceptable salt, solvate or derivative thereof.
- 39. A compound of the formulae (If), (VI), (VII), (tl) or Xv).
- 40. A compound according to any one of claims 1, 30, 33, 34, 35 or 39, substantially as herein described and exemplified.
- 41. A pharmaceutical composition according to any one of claims 31, 33,34 0r 35, substantially as herein described and exemplified.
- 42. Use according to claim 36 or 37, substantially as herein described and exemplified.
- 43. A process according to claim 38, substantially as herein described and Co exemplified. oo AMENDED SHEET I B
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB0108999A GB0108999D0 (en) | 2001-04-10 | 2001-04-10 | Pyrazole derivatives |
Publications (1)
Publication Number | Publication Date |
---|---|
ZA200307095B true ZA200307095B (en) | 2004-09-10 |
Family
ID=9912631
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
ZA200307095A ZA200307095B (en) | 2001-04-10 | 2003-09-10 | Pyrazole derivatives for treating HIV. |
Country Status (7)
Country | Link |
---|---|
EC (1) | ECSP034800A (en) |
GB (1) | GB0108999D0 (en) |
GT (1) | GT200200067A (en) |
HN (1) | HN2002000081A (en) |
TN (1) | TNSN03088A1 (en) |
UA (1) | UA75124C2 (en) |
ZA (1) | ZA200307095B (en) |
-
2001
- 2001-04-10 GB GB0108999A patent/GB0108999D0/en not_active Ceased
-
2002
- 2002-04-04 UA UA2003109151A patent/UA75124C2/en unknown
- 2002-04-05 GT GT200200067A patent/GT200200067A/en unknown
- 2002-04-08 HN HN2002000081A patent/HN2002000081A/en unknown
-
2003
- 2003-07-08 TN TNPCTIB/2002/001234A patent/TNSN03088A1/en unknown
- 2003-09-10 ZA ZA200307095A patent/ZA200307095B/en unknown
- 2003-10-09 EC ECSP034800 patent/ECSP034800A/en unknown
Also Published As
Publication number | Publication date |
---|---|
GB0108999D0 (en) | 2001-05-30 |
ECSP034800A (en) | 2003-12-01 |
GT200200067A (en) | 2002-12-24 |
TNSN03088A1 (en) | 2005-12-23 |
HN2002000081A (en) | 2003-11-15 |
UA75124C2 (en) | 2006-03-15 |
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