US20180201622A1 - Fused Bicyclic Heteroaromatic Derivatives as Kinase Inhibitors - Google Patents
Fused Bicyclic Heteroaromatic Derivatives as Kinase Inhibitors Download PDFInfo
- Publication number
- US20180201622A1 US20180201622A1 US15/924,020 US201815924020A US2018201622A1 US 20180201622 A1 US20180201622 A1 US 20180201622A1 US 201815924020 A US201815924020 A US 201815924020A US 2018201622 A1 US2018201622 A1 US 2018201622A1
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- US
- United States
- Prior art keywords
- alkyl
- methyl
- optionally substituted
- compound
- formula
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 229940043355 kinase inhibitor Drugs 0.000 title 1
- 239000003757 phosphotransferase inhibitor Substances 0.000 title 1
- 238000011282 treatment Methods 0.000 claims abstract description 39
- 210000000056 organ Anatomy 0.000 claims abstract description 17
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 14
- 230000001363 autoimmune Effects 0.000 claims abstract description 10
- 206010052779 Transplant rejections Diseases 0.000 claims abstract description 9
- 208000035475 disorder Diseases 0.000 claims abstract description 7
- 201000010099 disease Diseases 0.000 claims abstract description 6
- 230000002757 inflammatory effect Effects 0.000 claims abstract description 6
- 230000000771 oncological effect Effects 0.000 claims abstract description 6
- 230000003612 virological effect Effects 0.000 claims abstract description 6
- 201000004792 malaria Diseases 0.000 claims abstract description 5
- 230000002265 prevention Effects 0.000 claims abstract description 4
- -1 —ORa Chemical group 0.000 claims description 420
- 150000001875 compounds Chemical class 0.000 claims description 235
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 211
- 125000001424 substituent group Chemical group 0.000 claims description 116
- 229910052739 hydrogen Inorganic materials 0.000 claims description 113
- 239000001257 hydrogen Substances 0.000 claims description 113
- 238000000034 method Methods 0.000 claims description 101
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 73
- 125000001072 heteroaryl group Chemical group 0.000 claims description 67
- 125000003118 aryl group Chemical group 0.000 claims description 65
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 65
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 52
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 50
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 39
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 35
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 28
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 25
- 150000003839 salts Chemical class 0.000 claims description 20
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 16
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 15
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 14
- 229910052736 halogen Inorganic materials 0.000 claims description 14
- 239000012453 solvate Substances 0.000 claims description 13
- 150000002367 halogens Chemical class 0.000 claims description 12
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 12
- 125000001153 fluoro group Chemical group F* 0.000 claims description 11
- 125000005647 linker group Chemical group 0.000 claims description 11
- 125000004366 heterocycloalkenyl group Chemical group 0.000 claims description 10
- 229910052757 nitrogen Inorganic materials 0.000 claims description 8
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 5
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 4
- 150000001204 N-oxides Chemical class 0.000 claims description 4
- 125000004566 azetidin-1-yl group Chemical group N1(CCC1)* 0.000 claims description 4
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims description 4
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 3
- 125000004571 thiomorpholin-4-yl group Chemical group N1(CCSCC1)* 0.000 claims description 3
- 150000002431 hydrogen Chemical class 0.000 claims 6
- 230000000694 effects Effects 0.000 abstract description 8
- 229940124639 Selective inhibitor Drugs 0.000 abstract description 3
- 230000009286 beneficial effect Effects 0.000 abstract description 3
- 102000001556 1-Phosphatidylinositol 4-Kinase Human genes 0.000 abstract description 2
- 108010029190 1-Phosphatidylinositol 4-Kinase Proteins 0.000 abstract description 2
- 239000000543 intermediate Substances 0.000 description 123
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 108
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 90
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 70
- 239000007787 solid Substances 0.000 description 60
- 239000011541 reaction mixture Substances 0.000 description 57
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 54
- 239000002904 solvent Substances 0.000 description 54
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 51
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 47
- 239000000243 solution Substances 0.000 description 46
- 239000000203 mixture Substances 0.000 description 40
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 40
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 34
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 33
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 33
- 238000006243 chemical reaction Methods 0.000 description 32
- 229910002092 carbon dioxide Inorganic materials 0.000 description 28
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 27
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 26
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 24
- 239000002585 base Substances 0.000 description 24
- 235000019439 ethyl acetate Nutrition 0.000 description 23
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 21
- 210000004027 cell Anatomy 0.000 description 19
- 230000008569 process Effects 0.000 description 19
- 238000010898 silica gel chromatography Methods 0.000 description 19
- 0 [1*]C1=NC2=C([3*])[U][3H]=C2C(C)=C1.[1*]C1=NC2=C([U][3H]=C2[3*])C(C)=C1 Chemical compound [1*]C1=NC2=C([3*])[U][3H]=C2C(C)=C1.[1*]C1=NC2=C([U][3H]=C2[3*])C(C)=C1 0.000 description 18
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 17
- 125000004076 pyridyl group Chemical group 0.000 description 17
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 17
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 16
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 16
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 16
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 16
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 16
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 15
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 15
- AFABGHUZZDYHJO-UHFFFAOYSA-N 2-Methylpentane Chemical compound CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 description 14
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 14
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 14
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
- 150000007530 organic bases Chemical class 0.000 description 14
- 125000003107 substituted aryl group Chemical group 0.000 description 14
- 239000000725 suspension Substances 0.000 description 14
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 13
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 13
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 13
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 12
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 12
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 12
- 239000003153 chemical reaction reagent Substances 0.000 description 12
- 238000007799 mixed lymphocyte reaction assay Methods 0.000 description 12
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical group ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 12
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 11
- 239000012267 brine Substances 0.000 description 11
- 239000013058 crude material Substances 0.000 description 11
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 11
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 10
- 108091000080 Phosphotransferase Proteins 0.000 description 10
- 239000002253 acid Substances 0.000 description 10
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 10
- 125000004457 alkyl amino carbonyl group Chemical group 0.000 description 10
- 235000011114 ammonium hydroxide Nutrition 0.000 description 10
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 10
- 125000001309 chloro group Chemical group Cl* 0.000 description 10
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 10
- 239000000463 material Substances 0.000 description 10
- 239000012044 organic layer Substances 0.000 description 10
- 102000020233 phosphotransferase Human genes 0.000 description 10
- 238000012360 testing method Methods 0.000 description 10
- 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 9
- 125000004043 oxo group Chemical group O=* 0.000 description 9
- 238000002360 preparation method Methods 0.000 description 9
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 9
- 125000004466 alkoxycarbonylamino group Chemical group 0.000 description 8
- 125000003806 alkyl carbonyl amino group Chemical group 0.000 description 8
- 239000012071 phase Substances 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- 239000002244 precipitate Substances 0.000 description 8
- 125000000335 thiazolyl group Chemical group 0.000 description 8
- 125000001544 thienyl group Chemical group 0.000 description 8
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 description 7
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 7
- 208000023275 Autoimmune disease Diseases 0.000 description 7
- 125000004448 alkyl carbonyl group Chemical group 0.000 description 7
- 238000003556 assay Methods 0.000 description 7
- 208000032839 leukemia Diseases 0.000 description 7
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 7
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 7
- 125000001715 oxadiazolyl group Chemical group 0.000 description 7
- 125000005968 oxazolinyl group Chemical group 0.000 description 7
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 7
- 125000004750 (C1-C6) alkylaminosulfonyl group Chemical group 0.000 description 6
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 6
- 239000007832 Na2SO4 Substances 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 6
- 150000001412 amines Chemical class 0.000 description 6
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 description 6
- CBHOOMGKXCMKIR-UHFFFAOYSA-N azane;methanol Chemical compound N.OC CBHOOMGKXCMKIR-UHFFFAOYSA-N 0.000 description 6
- 125000002619 bicyclic group Chemical group 0.000 description 6
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 6
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 6
- 125000005843 halogen group Chemical group 0.000 description 6
- 125000002883 imidazolyl group Chemical group 0.000 description 6
- 239000010410 layer Substances 0.000 description 6
- 150000002632 lipids Chemical class 0.000 description 6
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 6
- 125000003373 pyrazinyl group Chemical group 0.000 description 6
- 125000003226 pyrazolyl group Chemical group 0.000 description 6
- 125000006513 pyridinyl methyl group Chemical group 0.000 description 6
- 239000000377 silicon dioxide Substances 0.000 description 6
- 229910052938 sodium sulfate Inorganic materials 0.000 description 6
- 239000000758 substrate Substances 0.000 description 6
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 5
- GAWIXWVDTYZWAW-UHFFFAOYSA-N C[CH]O Chemical group C[CH]O GAWIXWVDTYZWAW-UHFFFAOYSA-N 0.000 description 5
- 241000700605 Viruses Species 0.000 description 5
- CLZISMQKJZCZDN-UHFFFAOYSA-N [benzotriazol-1-yloxy(dimethylamino)methylidene]-dimethylazanium Chemical compound C1=CC=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 CLZISMQKJZCZDN-UHFFFAOYSA-N 0.000 description 5
- 229910052783 alkali metal Inorganic materials 0.000 description 5
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 5
- 239000000010 aprotic solvent Substances 0.000 description 5
- 125000002393 azetidinyl group Chemical group 0.000 description 5
- RROBIDXNTUAHFW-UHFFFAOYSA-N benzotriazol-1-yloxy-tris(dimethylamino)phosphanium Chemical compound C1=CC=C2N(O[P+](N(C)C)(N(C)C)N(C)C)N=NC2=C1 RROBIDXNTUAHFW-UHFFFAOYSA-N 0.000 description 5
- 239000007822 coupling agent Substances 0.000 description 5
- 125000001207 fluorophenyl group Chemical group 0.000 description 5
- 239000003112 inhibitor Substances 0.000 description 5
- 125000004458 methylaminocarbonyl group Chemical group [H]N(C(*)=O)C([H])([H])[H] 0.000 description 5
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 5
- 125000000714 pyrimidinyl group Chemical group 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- FMLPQHJYUZTHQS-QMMMGPOBSA-N tert-butyl (3s)-3-methylpiperazine-1-carboxylate Chemical compound C[C@H]1CN(C(=O)OC(C)(C)C)CCN1 FMLPQHJYUZTHQS-QMMMGPOBSA-N 0.000 description 5
- 238000004809 thin layer chromatography Methods 0.000 description 5
- 125000003944 tolyl group Chemical group 0.000 description 5
- XGRQPTXFVDRJMY-UHFFFAOYSA-N 1-isocyanato-4-methoxy-2-methylbenzene Chemical compound COC1=CC=C(N=C=O)C(C)=C1 XGRQPTXFVDRJMY-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 206010025323 Lymphomas Diseases 0.000 description 4
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 4
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 4
- 206010028980 Neoplasm Diseases 0.000 description 4
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 4
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 4
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 4
- 230000001154 acute effect Effects 0.000 description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 4
- 125000000068 chlorophenyl group Chemical group 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 125000004786 difluoromethoxy group Chemical group [H]C(F)(F)O* 0.000 description 4
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 4
- 125000002541 furyl group Chemical group 0.000 description 4
- 125000000623 heterocyclic group Chemical group 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 150000007529 inorganic bases Chemical class 0.000 description 4
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 4
- 125000000842 isoxazolyl group Chemical group 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 125000002757 morpholinyl group Chemical group 0.000 description 4
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 4
- 150000002825 nitriles Chemical class 0.000 description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 4
- 239000003921 oil Substances 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 239000003960 organic solvent Substances 0.000 description 4
- 239000001301 oxygen Substances 0.000 description 4
- 229910052760 oxygen Inorganic materials 0.000 description 4
- 125000000286 phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 4
- 125000003386 piperidinyl group Chemical group 0.000 description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 125000006239 protecting group Chemical group 0.000 description 4
- 125000002098 pyridazinyl group Chemical group 0.000 description 4
- HHVIBTZHLRERCL-UHFFFAOYSA-N sulfonyldimethane Chemical compound CS(C)(=O)=O HHVIBTZHLRERCL-UHFFFAOYSA-N 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- 125000001984 thiazolidinyl group Chemical group 0.000 description 4
- CSRZQMIRAZTJOY-UHFFFAOYSA-N trimethylsilyl iodide Chemical compound C[Si](C)(C)I CSRZQMIRAZTJOY-UHFFFAOYSA-N 0.000 description 4
- 125000004738 (C1-C6) alkyl sulfinyl group Chemical group 0.000 description 3
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- VIWYXHGHUSEILI-UHFFFAOYSA-N methyl 2-amino-4-[4-[(4-methoxyphenyl)carbamoyl]piperazin-1-yl]thieno[3,4-d]pyrimidine-5-carboxylate Chemical compound NC=1N=C(C=2C(N=1)=CSC=2C(=O)OC)N1CCN(CC1)C(NC1=CC=C(C=C1)OC)=O VIWYXHGHUSEILI-UHFFFAOYSA-N 0.000 description 1
- CBRXVPCEXKVYAU-UHFFFAOYSA-N methyl 2-amino-4-[4-[[4-(dimethylamino)phenyl]carbamoyl]piperazin-1-yl]thieno[3,4-d]pyrimidine-5-carboxylate Chemical compound NC=1N=C(C=2C(N=1)=CSC=2C(=O)OC)N1CCN(CC1)C(NC1=CC=C(C=C1)N(C)C)=O CBRXVPCEXKVYAU-UHFFFAOYSA-N 0.000 description 1
- PBWMFBWAHYXMNZ-UHFFFAOYSA-N methyl 2-amino-4-piperazin-1-ylthieno[3,4-d]pyrimidine-5-carboxylate Chemical compound NC=1N=C(C=2C(N=1)=CSC=2C(=O)OC)N1CCNCC1 PBWMFBWAHYXMNZ-UHFFFAOYSA-N 0.000 description 1
- PUTMXTILUKFDHK-UHFFFAOYSA-N methyl 4-amino-2,5-dimethylpyrazole-3-carboxylate Chemical compound COC(=O)C1=C(N)C(C)=NN1C PUTMXTILUKFDHK-UHFFFAOYSA-N 0.000 description 1
- WMYQZQLKVASMIV-UHFFFAOYSA-N methyl 4-amino-2-methylpyrazole-3-carboxylate Chemical compound COC(=O)C1=C(N)C=NN1C WMYQZQLKVASMIV-UHFFFAOYSA-N 0.000 description 1
- BUFZZXCVOFBHLS-UHFFFAOYSA-N methyl 4-aminothiophene-3-carboxylate Chemical compound COC(=O)C1=CSC=C1N BUFZZXCVOFBHLS-UHFFFAOYSA-N 0.000 description 1
- 125000006178 methyl benzyl group Chemical group 0.000 description 1
- OIRDBPQYVWXNSJ-UHFFFAOYSA-N methyl trifluoromethansulfonate Chemical compound COS(=O)(=O)C(F)(F)F OIRDBPQYVWXNSJ-UHFFFAOYSA-N 0.000 description 1
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 1
- 125000004372 methylthioethyl group Chemical group [H]C([H])([H])SC([H])([H])C([H])([H])* 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940042472 mineral oil Drugs 0.000 description 1
- 229960004857 mitomycin Drugs 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- 206010028417 myasthenia gravis Diseases 0.000 description 1
- WWECJGLXBSQKRF-UHFFFAOYSA-N n,n-dimethylformamide;methanol Chemical compound OC.CN(C)C=O WWECJGLXBSQKRF-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000004923 naphthylmethyl group Chemical group C1(=CC=CC2=CC=CC=C12)C* 0.000 description 1
- 125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000003448 neutrophilic effect Effects 0.000 description 1
- 125000006501 nitrophenyl group Chemical group 0.000 description 1
- 231100000344 non-irritating Toxicity 0.000 description 1
- 239000002687 nonaqueous vehicle Substances 0.000 description 1
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 description 1
- 229940006093 opthalmologic coloring agent diagnostic Drugs 0.000 description 1
- 239000013110 organic ligand Substances 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 125000003566 oxetanyl group Chemical group 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 229940083251 peripheral vasodilators purine derivative Drugs 0.000 description 1
- 235000019271 petrolatum Nutrition 0.000 description 1
- 229940066842 petrolatum Drugs 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 239000002831 pharmacologic agent Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- XDJBSUYZKBVQDB-UHFFFAOYSA-N phenyl N-(2,6-dimethoxypyridin-3-yl)carbamate Chemical compound COC1=NC(=CC=C1NC(OC1=CC=CC=C1)=O)OC XDJBSUYZKBVQDB-UHFFFAOYSA-N 0.000 description 1
- NMWUBVTUFUALID-UHFFFAOYSA-N phenyl N-(6-ethoxy-2-methylpyridin-3-yl)carbamate Chemical compound CCOC1=CC=C(NC(=O)OC2=CC=CC=C2)C(C)=N1 NMWUBVTUFUALID-UHFFFAOYSA-N 0.000 description 1
- GCBVZXUSHJCTAP-UHFFFAOYSA-N phenyl n-(2-methyl-4-propan-2-yloxyphenyl)carbamate Chemical compound CC1=CC(OC(C)C)=CC=C1NC(=O)OC1=CC=CC=C1 GCBVZXUSHJCTAP-UHFFFAOYSA-N 0.000 description 1
- CEEUJGNETJPUNE-UHFFFAOYSA-N phenyl n-(4-methoxy-2-methylphenyl)carbamate Chemical compound CC1=CC(OC)=CC=C1NC(=O)OC1=CC=CC=C1 CEEUJGNETJPUNE-UHFFFAOYSA-N 0.000 description 1
- GOGYYTYYGRUMTI-UHFFFAOYSA-N phenyl n-(4-methoxy-3-methylphenyl)carbamate Chemical compound C1=C(C)C(OC)=CC=C1NC(=O)OC1=CC=CC=C1 GOGYYTYYGRUMTI-UHFFFAOYSA-N 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- PDTFCHSETJBPTR-UHFFFAOYSA-N phenylmercuric nitrate Chemical compound [O-][N+](=O)O[Hg]C1=CC=CC=C1 PDTFCHSETJBPTR-UHFFFAOYSA-N 0.000 description 1
- 125000004344 phenylpropyl group Chemical group 0.000 description 1
- 235000011007 phosphoric acid Nutrition 0.000 description 1
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 208000005987 polymyositis Diseases 0.000 description 1
- 239000001818 polyoxyethylene sorbitan monostearate Substances 0.000 description 1
- 235000010989 polyoxyethylene sorbitan monostearate Nutrition 0.000 description 1
- 229920001451 polypropylene glycol Polymers 0.000 description 1
- 229940113124 polysorbate 60 Drugs 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 238000002953 preparative HPLC Methods 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- MCSINKKTEDDPNK-UHFFFAOYSA-N propyl propionate Chemical compound CCCOC(=O)CC MCSINKKTEDDPNK-UHFFFAOYSA-N 0.000 description 1
- 201000001514 prostate carcinoma Diseases 0.000 description 1
- 125000001042 pteridinyl group Chemical group N1=C(N=CC2=NC=CN=C12)* 0.000 description 1
- 229940083082 pyrimidine derivative acting on arteriolar smooth muscle Drugs 0.000 description 1
- 150000003230 pyrimidines Chemical class 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 239000002287 radioligand Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 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
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- VILMUCRZVVVJCA-UHFFFAOYSA-M sodium glycolate Chemical compound [Na+].OCC([O-])=O VILMUCRZVVVJCA-UHFFFAOYSA-M 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 1
- YEENEYXBHNNNGV-XEHWZWQGSA-M sodium;3-acetamido-5-[acetyl(methyl)amino]-2,4,6-triiodobenzoate;(2r,3r,4s,5s,6r)-2-[(2r,3s,4s,5r)-3,4-dihydroxy-2,5-bis(hydroxymethyl)oxolan-2-yl]oxy-6-(hydroxymethyl)oxane-3,4,5-triol Chemical compound [Na+].CC(=O)N(C)C1=C(I)C(NC(C)=O)=C(I)C(C([O-])=O)=C1I.O[C@H]1[C@H](O)[C@@H](CO)O[C@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 YEENEYXBHNNNGV-XEHWZWQGSA-M 0.000 description 1
- 239000001587 sorbitan monostearate Substances 0.000 description 1
- 235000011076 sorbitan monostearate Nutrition 0.000 description 1
- 229940035048 sorbitan monostearate Drugs 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 230000003019 stabilising effect Effects 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 201000000498 stomach carcinoma Diseases 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 125000006633 tert-butoxycarbonylamino group Chemical group 0.000 description 1
- DXJOJUNLMJMJSN-VIFPVBQESA-N tert-butyl (3s)-3-ethylpiperazine-1-carboxylate Chemical compound CC[C@H]1CN(C(=O)OC(C)(C)C)CCN1 DXJOJUNLMJMJSN-VIFPVBQESA-N 0.000 description 1
- MHXBHWLGRWOABW-UHFFFAOYSA-N tetradecyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCCCCCCCCCCCCCC MHXBHWLGRWOABW-UHFFFAOYSA-N 0.000 description 1
- 125000005958 tetrahydrothienyl group Chemical group 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- DDWBRNXDKNIQDY-UHFFFAOYSA-N thieno[2,3-d]pyrimidine Chemical compound N1=CN=C2SC=CC2=C1 DDWBRNXDKNIQDY-UHFFFAOYSA-N 0.000 description 1
- 206010043778 thyroiditis Diseases 0.000 description 1
- GZNAASVAJNXPPW-UHFFFAOYSA-M tin(4+) chloride dihydrate Chemical compound O.O.[Cl-].[Sn+4] GZNAASVAJNXPPW-UHFFFAOYSA-M 0.000 description 1
- FWPIDFUJEMBDLS-UHFFFAOYSA-L tin(II) chloride dihydrate Substances O.O.Cl[Sn]Cl FWPIDFUJEMBDLS-UHFFFAOYSA-L 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 230000019432 tissue death Effects 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 238000009901 transfer hydrogenation reaction Methods 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 description 1
- 125000001680 trimethoxyphenyl group Chemical group 0.000 description 1
- FTVLMFQEYACZNP-UHFFFAOYSA-N trimethylsilyl trifluoromethanesulfonate Chemical compound C[Si](C)(C)OS(=O)(=O)C(F)(F)F FTVLMFQEYACZNP-UHFFFAOYSA-N 0.000 description 1
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- GPRLSGONYQIRFK-MNYXATJNSA-N triton Chemical compound [3H+] GPRLSGONYQIRFK-MNYXATJNSA-N 0.000 description 1
- 208000035408 type 1 diabetes mellitus 1 Diseases 0.000 description 1
- 210000003932 urinary bladder Anatomy 0.000 description 1
- 210000004291 uterus Anatomy 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 230000035899 viability Effects 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 229940051021 yellow-fever virus Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
- A61P33/06—Antimalarials
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Definitions
- the present invention relates to a family of fused bicyclic heteroaromatic derivatives, and to their use in therapy.
- the compounds provided by the present invention are selective inhibitors of phosphatidylinositol-4-kinase III ⁇ (PI4KIII ⁇ ) activity, and are accordingly of benefit as pharmaceutical agents, especially in the treatment of adverse inflammatory, autoimmune and oncological disorders, in the treatment of viral diseases and malaria, and in the management of organ and cell transplant rejection.
- PI4KIII ⁇ phosphatidylinositol-4-kinase III ⁇
- the compounds in accordance with the present invention may be beneficial as pharmacological standards for use in the development of new biological tests and in the search for new pharmacological agents.
- the compounds of this invention may be useful as radioligands in assays for detecting pharmacologically active compounds.
- WO 2013/034738 discloses that inhibitors of PI4KIII ⁇ activity are useful as medicaments for the treatment of autoimmune and inflammatory disorders, and organ and cell transplant rejection.
- WO 2010/103130 describes a family of oxazolo[5,4-d]pyrimidine, thiazolo[5,4-d]-pyrimidine, thieno[2,3-d]pyrimidine and purine derivatives that are active in a range of assays, including the Mixed Lymphocyte Reaction (MLR) test, and are stated to be effective for the treatment of immune and autoimmune disorders, and organ and cell transplant rejection.
- MLR Mixed Lymphocyte Reaction
- WO 2011/147753 discloses the same family of compounds as having significant antiviral activity.
- WO 2012/035423 discloses the same family of compounds as having significant anticancer activity.
- WO 2013/024291, WO 2013/068458, WO 2014/053581, and copending international patent application PCT/EP2013/077846 (published on 26 Jun. 2014 as WO 2014/096423) describe various series of fused pyrimidine derivatives that are stated to be of benefit as pharmaceutical agents, especially in the treatment of adverse inflammatory, autoimmune and oncological disorders, in the treatment of viral diseases, and in the management of organ and cell transplant rejection.
- Inhibitors of PI4KIII ⁇ have been identified as molecules with an ideal activity profile for the prevention, treatment and elimination of malaria (cf. C. W. McNamara et al., Nature, 2013, 504, 248-253).
- the compounds of the present invention are potent and selective inhibitors of PI4KIII ⁇ activity, inhibiting the kinase affinity of human PI4KIII ⁇ (IC 50 ) at concentrations of 50 ⁇ M or less, generally of 20 ⁇ M or less, usually of 5 ⁇ M or less, typically of 1 ⁇ M or less, suitably of 500 nM or less, ideally of 100 nM or less, and preferably of 20 nM or less (the skilled person will appreciate that a lower IC 50 figure denotes a more active compound).
- the compounds of the invention may possess at least a 10-fold selective affinity, typically at least a 20-fold selective affinity, suitably at least a 50-fold selective affinity, and ideally at least a 100-fold selective affinity, for human PI4KIII ⁇ relative to other human kinases.
- Certain compounds in accordance with the present invention are active as inhibitors when subjected to the Mixed Lymphocyte Reaction (MLR) test.
- MLR Mixed Lymphocyte Reaction
- the MLR test is predictive of immunosuppression or immunomodulation.
- certain compounds of the present invention display an IC 50 value of 10 ⁇ M or less, generally of 5 ⁇ M or less, usually of 2 ⁇ M or less, typically of 1 ⁇ M or less, suitably of 500 nM or less, ideally of 100 nM or less, and preferably of 20 nM or less (again, the skilled person will appreciate that a lower IC 50 figure denotes a more active compound).
- the compounds of the invention possess notable advantages in terms of their high potency, demonstrable efficacy at lower doses, and valuable pharmacokinetic and pharmacodynamic properties (including clearance and bioavailability).
- the present invention provides a compound of formula (IA) or (IB) or an N-oxide thereof, or a pharmaceutically acceptable salt or solvate thereof:
- Z represents hydrogen; or Z represents C 1-6 alkyl, C 2-6 alkenyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl(C 16 )alkyl, C 3-7 heterocycloalkyl, C 3-7 heterocycloalkyl(C 1-6 )alkyl, aryl, aryl(C 1-6 )alkyl, heteroaryl or heteroaryl(C 1-6 )alkyl, any of which groups may be optionally substituted by one or more substituents;
- a 1 represents hydrogen, cyano or trifluoromethyl; or A 1 represents C 1-6 alkyl, optionally substituted by one or more substituents independently selected from fluoro, —OR a , trifluoromethoxy, —NR b R c , —CO 2 R d and —CONR b R c ; or A 1 represents C 3-7 cycloalkyl;
- a 2 represents hydrogen or C 1-6 alkyl
- R 1 and R 2 independently represent hydrogen, halogen, cyano, nitro, hydroxy, trifluoromethyl, trifluoromethoxy, —OR a , —SR a , —SOR a , —SO 2 R a , —NR b R c , —CH 2 NR b R c , —NR c COR d , —CH 2 NR c COR d , —NR c CO 2 R d , —NHCONR b R c , —NR c SO 2 R c , —N(SO 2 R c ) 2 , —NHSO 2 NR b R c , —COR d , —CO 2 R d , —CONR b R c , —CON(OR a )R b or —SO 2 NR b R c ; or C 1-6 alkyl, C 3-7 cycloalkyl, C 3-7
- R 3 represents hydrogen, halogen or C 1-6 alkyl
- R 4 represents hydrogen; or R 4 represents C 1-6 alkyl, aryl, aryl(C 1-6 )alkyl, heteroaryl or heteroaryl(C 1-6 )alkyl, any of which groups may be optionally substituted by one or more substituents;
- R 5 represents hydrogen; or R 5 represents C 1-6 alkyl, optionally substituted by one or more substituents independently selected from —OR a and —NR b R c ;
- R a represents hydrogen; or R a represents C 1-6 alkyl, aryl, aryl(C 1-6 )alkyl, heteroaryl or heteroaryl(C 1-6 )alkyl, any of which groups may be optionally substituted by one or more substituents;
- R b and R c independently represent hydrogen or trifluoromethyl; or C 1-6 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl(C 1-6 )alkyl, aryl, aryl(C 1-6 )alkyl, C 3-7 heterocycloalkyl, C 3-7 heterocycloalkyl(C 1-6 )alkyl, heteroaryl or heteroaryl(C 1-6 )alkyl, any of which groups may be optionally substituted by one or more substituents; or
- R b and R c when taken together with the nitrogen atom to which they are both attached, represent azetidin-1-yl, pyrrolidin-1-yl, oxazolidin-3-yl, isoxazolidin-2-yl, thiazolidin-3-yl, isothiazolidin-2-yl, piperidin-1-yl, morpholin-4-yl, thiomorpholin-4-yl, piperazin-1-yl, homopiperidin-1-yl, homomorpholin-4-yl or homopiperazin-1-yl, any of which groups may be optionally substituted by one or more substituents;
- R d represents hydrogen; or C 1-6 alkyl, C 3-7 cycloalkyl, aryl, C 3-7 heterocycloalkyl or heteroaryl, any of which groups may be optionally substituted by one or more substituents;
- R e represents C 1-6 alkyl, aryl or heteroaryl, any of which groups may be optionally substituted by one or more substituents.
- any of the groups in the compounds of formula (IA) or (IB) above is stated to be optionally substituted, this group may be unsubstituted, or substituted by one or more substituents. Typically, such groups will be unsubstituted, or substituted by one or two substituents.
- the salts of the compounds of formula (IA) or (IB) will be pharmaceutically acceptable salts.
- Other salts may, however, be useful in the preparation of the compounds of the invention or of their pharmaceutically acceptable salts.
- Suitable pharmaceutically acceptable salts of the compounds of this invention include acid addition salts which may, for example, be formed by mixing a solution of the compound of the invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulphuric acid, methanesulphonic acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid or phosphoric acid.
- a pharmaceutically acceptable acid such as hydrochloric acid, sulphuric acid, methanesulphonic acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid or phosphoric acid.
- the compounds of the invention carry an acidic moiety, e.g.
- suitable pharmaceutically acceptable salts thereof may include alkali metal salts, e.g. sodium or potassium salts; alkaline earth metal salts, e.g. calcium or magnesium salts; and salts formed with suitable organic ligands, e.g. quaternary ammonium salts.
- alkali metal salts e.g. sodium or potassium salts
- alkaline earth metal salts e.g. calcium or magnesium salts
- suitable organic ligands e.g. quaternary ammonium salts.
- the present invention includes within its scope solvates of the compounds of formula (IA) or (IB) above.
- Such solvates may be formed with common organic solvents, e.g. hydrocarbon solvents such as benzene or toluene; chlorinated solvents such as chloroform or dichloromethane; alcoholic solvents such as methanol, ethanol or isopropanol; ethereal solvents such as diethyl ether or tetrahydrofuran; or ester solvents such as ethyl acetate.
- the solvates of the compounds of formula (IA) or (IB) may be formed with water, in which case they will be hydrates.
- Suitable alkyl groups which may be present on the compounds of the invention include straight-chained and branched C 1-6 alkyl groups, for example C 1-4 alkyl groups. Typical examples include methyl and ethyl groups, and straight-chained or branched propyl, butyl, pentyl and hexyl groups. Particular alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, 2,2-dimethylpropyl and 3-methylbutyl. Derived expressions such as “C 1-6 alkoxy”, “C 1-6 alkylthio”, “C 1-6 alkylsulphonyl” and “C 1-6 alkylamino” are to be construed accordingly.
- Suitable C 2-6 alkenyl groups include vinyl, allyl and prop-1-en-2-yl.
- Suitable C 3-7 cycloalkyl groups which may comprise benzo-fused analogues thereof, include cyclopropyl, cyclobutyl, cyclopentyl, indanyl, cyclohexyl and cycloheptyl.
- Suitable aryl groups include phenyl and naphthyl, preferably phenyl.
- Suitable aryl(C 1-6 )alkyl groups include benzyl, phenylethyl, phenylpropyl and naphthylmethyl.
- Suitable heterocycloalkyl groups which may comprise benzo-fused analogues thereof, include oxetanyl, azetidinyl, tetrahydrofuranyl, dihydrobenzofuranyl, pyrrolidinyl, indolinyl, thiazolidinyl, imidazolidinyl, tetrahydropyranyl, chromanyl, piperidinyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, piperazinyl, 1,2,3,4-tetrahydro-quinoxalinyl, homopiperazinyl, morpholinyl, benzoxazinyl and thiomorpholinyl.
- heterocycloalkenyl groups examples include oxazolinyl.
- Suitable heteroaryl groups include furyl, benzofuryl, dibenzofuryl, thienyl, benzothienyl, dibenzothienyl, pyrrolyl, indolyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[3,2-c]pyridinyl, pyrazolyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[3,4-d]pyrimidinyl, indazolyl, oxazolyl, benzoxazolyl, isoxazolyl, thiazolyl, benzothiazolyl, isothiazolyl, imidazolyl, imidazo[2,1-b]thiazolyl, benzimidazolyl, imidazo[1,2-a]pyridinyl, imidazo[4,5-b]pyridinyl, purinyl, imidazo[1,2-a]pyrimidinyl, imidazo[1,2-
- halogen as used herein is intended to include fluorine, chlorine, bromine and iodine atoms, typically fluorine, chlorine or bromine.
- compounds of formula (IA) or (IB) may exist as tautomers, for example keto (CH 2 C ⁇ O) ⁇ enol (CH ⁇ CHOH) tautomers or amide (NHC ⁇ O) ⁇ hydroxyimine (N ⁇ COH) tautomers.
- Formula (IA) or (IB) and the formulae depicted hereinafter are intended to represent all individual tautomers and all possible mixtures thereof, unless stated or shown otherwise.
- each individual atom present in formula (IA) or (IB), or in the formulae depicted hereinafter may in fact be present in the form of any of its naturally occurring isotopes, with the most abundant isotope(s) being preferred.
- each individual hydrogen atom present in formula (IA) or (IB), or in the formulae depicted hereinafter may be present as a 1 H, 2 H (deuterium) or 3 H (tritium) atom, preferably 1 H.
- each individual carbon atom present in formula (IA) or (IB), or in the formulae depicted hereinafter may be present as a 12 C, 13 C or 14 C atom, preferably 12 C.
- X represents N. In another embodiment, X represents CH.
- T represents N. In another embodiment, T represents C—R 2 .
- U represents oxygen. In a second embodiment, U represents sulfur. In a third embodiment, U represents N—R 4 . In a first embodiment, T represents N and U represents oxygen or N—R 4 . In a first aspect of that embodiment, T represents N and U represents oxygen. In a second aspect of that embodiment, T represents N and U represents N—R 4 .
- T represents C—R 2 and U represents sulfur or N—R 4 .
- T represents C—R 2 and U represents sulfur.
- T represents C—R 2 and U represents N—R 4 .
- Selected sub-classes of compounds in accordance with the present invention include the compounds of formula (IA-1), (IA-2), (IB-1), (IB-2) and (IB-3):
- Particular sub-classes of compounds in accordance with the present invention include the compounds of formula (IA-1), (IA-2), (IB-1) and (IB-2) as defined above.
- the invention provides a compound of formula (IA-1) as defined above.
- the invention provides a compound of formula (IA-2) as defined above.
- the invention provides a compound of formula (IB-1) as defined above.
- the invention provides a compound of formula (IB-2) as defined above.
- the invention provides a compound of formula (IB-3) as defined above.
- Q represents a group of formula (Qa) as defined above.
- Q represents a group of formula (Qb) as defined above.
- Q represents a group of formula (Qc) as defined above.
- Q represents a group of formula (Qd) as defined above.
- Q represents a group of formula (Qe) as defined above.
- Q represents a group of formula (Qa) as defined above, this may be a group of formula (Qa-1), (Qa-2), (Qa-3), (Qa-4), (Qa-5) or (Qa-6):
- Y, Z, A 1 and A 2 are as defined above.
- Q represents a group of formula (Qa-1) as defined above.
- Q represents a group of formula (Qa-2) as defined above.
- Q represents a group of formula (Qa-3) as defined above.
- Q represents a group of formula (Qa-4) as defined above.
- Q represents a group of formula (Qa-5) as defined above.
- Q represents a group of formula (Qa-6) as defined above.
- V represents —CH 2 — or —C(CH 3 ) 2 —. In a first aspect of that embodiment, V represents —CH 2 —. In a second aspect of that embodiment, V represents —C(CH 3 ) 2 —.
- Q represents a group of formula (Qb) and V represents —CH 2 — or —C(CH 3 ) 2 —
- the bicyclic moiety containing the integer V is a 2,5-diazabicyclo[2.2.1]-heptane ring system.
- V represents —CH 2 CH 2 —.
- Q represents a group of formula (Qb) and V represents —CH 2 CH 2 —
- the bicyclic moiety containing the integer V is a 2,5-diazabicyclo[2.2.2]octane ring system.
- Q represents a group of formula (Qc) or (Qd) and V represents —CH 2 CH 2 —
- the bicyclic moiety containing the integer V is a 3,8-diazabicyclo[3.2.1]octane ring system.
- V represents —CH 2 CH 2 CH 2 —.
- Q represents a group of formula (Qb) and V represents —CH 2 CH 2 CH 2 —
- the bicyclic moiety containing the integer V is a 6,8-diazabicyclo[3.2.2]nonane ring system.
- Q represents a group of formula (Qc) or (Qd) and V represents —CH 2 CH 2 CH 2 —
- the bicyclic moiety containing the integer V is a 7,9-diazabicyclo[3.3.1]nonane ring system.
- the C 3-7 cycloalkyl group of which W is the residue is spiro-fused to the adjacent six-membered ring containing two nitrogen atoms.
- the cyclic group of which W is the residue is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
- the cyclic group of which W is the residue is a C 4-6 cycloalkyl group.
- the cyclic group of which W is the residue is cyclobutyl.
- Y represents a covalent bond, or a linker group selected from —C(O)—, —S(O)—, —S(O) 2 —, —C(O)O—, —C(O)N(R 5 )— and —S(O) 2 N(R 5 )—, or a linker group of formula (Ya) as defined above.
- Y represents a covalent bond, or a linker group selected from —C(O)—, —C(O)O— and —C(O)N(R 5 )—, or a linker group of formula (Ya) as defined above.
- Y represents a covalent bond, or a linker group selected from —C(O)— and —C(O)N(R 5 )—.
- Y represents a covalent bond, or a linker group selected from —C(O)—, —S(O)—, —S(O) 2 —, —C(O)O—, —C(O)N(R 5 )— and —S(O) 2 N(R 5 )—.
- Suitable values of Y include —C(O)—, —S(O)—, —S(O) 2 —, —C(O)O—, —C(O)N(R 5 )— and —S(O) 2 N(R 5 )—.
- Typical values of Y include —C(O)—, —C(O)N(R 5 )— and —C(O)C(O)—.
- Selected values of Y include —C(O)— and —C(O)N(R 5 )—.
- Y represents a covalent bond.
- Y represents —C(O)—.
- Y represents —S(O)—.
- Y represents —S(O) 2 —.
- Y represents —C(O)O—.
- Y represents —C(O)N(R 5 )—.
- Y represents —C(O)C(O)—.
- Y represents —S(O) 2 N(R 5 )—.
- Y represents a group of formula (Ya) as defined above.
- Z represents hydrogen; or Z represents C 1-6 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl(C 1-6 )alkyl, C 3-7 heterocycloalkyl, C 3-7 heterocycloalkyl(C 1-6 )alkyl, aryl, aryl(C 1-6 )alkyl, heteroaryl or heteroaryl(C 1-6 )alkyl, any of which groups may be optionally substituted by one or more substituents.
- Z represents C 1 - 6 alkyl, C 2-6 alkenyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl(C 1-6 )alkyl, C 3-7 heterocycloalkyl, C 3-7 heterocycloalkyl(C 1-6 )alkyl, aryl, aryl(C 1-6 )alkyl, heteroaryl or heteroaryl(C 1-6 )alkyl, any of which groups may be optionally substituted by one or more substituents.
- Z represents C 1-6 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl(C 1-6 )alkyl, C 3-7 heterocycloalkyl, C 3-7 heterocycloalkyl(C 1-6 )alkyl, aryl, aryl(C 1-6 )alkyl, heteroaryl or heteroaryl(C 1-6 )alkyl, any of which groups may be optionally substituted by one or more substituents.
- Z represents C 3-7 cycloalkyl, C 3-7 heterocycloalkyl, aryl or heteroaryl, any of which groups may be optionally substituted by one or more substituents.
- Z represents aryl or heteroaryl, either of which groups may be optionally substituted by one or more substituents.
- Z represents hydrogen.
- Z represents optionally substituted C 1-6 alkyl.
- Z represents optionally substituted C 2-6 alkenyl.
- Z represents optionally substituted C 3-7 cycloalkyl.
- Z represents optionally substituted C 3-7 cycloalkyl(C 1-6 )alkyl.
- Z represents optionally substituted C 3-7 heterocycloalkyl.
- Z represents optionally substituted C 3-7 heterocycloalkyl(C 1-6 )alkyl.
- Z represents optionally substituted aryl.
- Z represents optionally substituted aryl(C 1-6 )alkyl. In a tenth embodiment, Z represents optionally substituted heteroaryl. In an eleventh embodiment, Z represents optionally substituted heteroaryl(C 1-6 )alkyl.
- Z is other than hydrogen.
- Typical values of Z include methyl, ethyl, isopropenyl, cyclopropyl, indanyl, cyclopropylmethyl, cyclopentylethyl, dihydrobenzofuranyl, pyrrolidinyl, indolinyl, dihydrobenzofuranylmethyl, morpholinylmethyl, morpholinylethyl, phenyl, benzyl, phenylethyl, furyl, benzofuryl, thienyl, indolyl, pyrazolyl, indazolyl, isoxazolyl, thiazolyl, benzothiazolyl, imidazolyl, benzimidazolyl, imidazo[1,2-c]pyridinyl, benzothiadiazolyl, pyridinyl, quinolinyl, isoquinolinyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinox
- Z examples include phenyl, pyridinyl and pyrazinyl, any of which groups may be optionally substituted by one or more substituents.
- Suitable values of Z include phenyl and pyridinyl, either of which groups may be optionally substituted by one or more substituents.
- Z is unsubstituted. In another embodiment, Z is substituted by one or more substituents, typically by one, two or three substituents, suitably by one or two substituents. In one aspect of that embodiment, Z is monosubstituted. In another aspect of that embodiment, Z is disubstituted. In a further aspect of that embodiment, Z is trisubstituted.
- Typical examples of optional substituents on Z include one or more substituents independently selected from halogen, cyano, nitro, C 1-6 alkyl, trifluoromethyl, cyano-(C 1-6 )alkyl, (C 3-7 )heterocycloalkyl, halo(C 3-7 )heterocycloalkyl, (C 1-6 )alkyl(C 3-7 )hetero-cycloalkyl, (C 2-6 )alkoxycarbonyl(C 3-7 )heterocycloalkyl, dihalo(C 3-7 )heterocycloalkyl, (C 3-7 )heterocycloalkyl(C 1-6 )alkyl, (C 1-6 )alkyl(C 3-7 )heterocycloalkyl(C 1-6 )alkyl, heteroaryl, hydroxy, oxo, C 1-6 alkoxy, difluoromethoxy, trifluoromethoxy, trifluor
- Selected examples of optional substituents on Z include one or more substituents independently selected from C 1-6 alkyl, trifluoromethyl, (C 3-7 )heterocycloalkyl, dihalo(C 3-7 )heterocycloalkyl, C 1-6 alkoxy, trifluoromethoxy and di(C 1-6 )alkylamino.
- Suitable examples of optional substituents on Z include one or more substituents independently selected from C 1-6 alkyl, dihalo(C 3-7 )heterocycloalkyl, C 1-6 alkoxy, trifluoromethoxy and di(C 1-6 )alkylamino.
- Typical examples of specific substituents on Z include fluoro, chloro, bromo, cyano, nitro, methyl, ethyl, isopropyl, tert-butyl, trifluoromethyl, cyanomethyl, azetidinyl, pyrrolidinyl, piperazinyl, morpholinyl, fluoroazetidinyl, fluoropyrrolidinyl, methyl-piperazinyl, tert-butoxycarbonylpiperazinyl, difluoroazetidinyl, difluoropyrrolidinyl, difluoropiperidinyl, pyrrolidinylmethyl, pip eridinylmethyl, morpholinylmethyl, methyl-piperazinylmethyl, pyrazolyl, imidazolyl, hydroxy, oxo, methoxy, ethoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, tri
- Selected examples of specific substituents on Z include methyl, trifluoromethyl, azetidinyl, difluoroazetidinyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy and dimethylamino.
- Suitable examples of specific substituents on Z include methyl, difluoroazetidinyl, methoxy, ethoxy, trifluoromethoxy and dimethylamino.
- Selected values of Z include phenoxymethyl, chlorophenoxymethyl, methoxyphenoxymethyl, tert-butoxycarbonylmethyl, benzyloxycarbonylmethyl, phenoxyethyl, isopropenyl, cyclopropyl, indanyl, cyclopropylmethyl, cyclopentylethyl, (methyl)(oxo)pyrrolidinyl, dihydrobenzofuranyl, methylindolinyl, dihydrobenzofuranyl-methyl, morpholinylmethyl, morpholinylethyl, phenyl, nitrophenyl, methylphenyl, ethylphenyl, cyanomethylphenyl, morpholinylphenyl, pyrazolylphenyl, imidazolylphenyl, methoxyphenyl, difluoromethoxyphenyl, trifluoromethoxyphenyl, morpholinylethoxy-phenyl, ethylenedioxy
- Representative values of Z include methoxyphenyl, dimethylaminophenyl, (methoxy)(methyl)phenyl, (isopropoxy)(methyl)phenyl, (methyl)(trifluoromethoxy)-phenyl, (azetidinyl)(methyl)pyridinyl, (difluoroazetidinyl)(methyl)pyridinyl, (methoxy)-(trifluoromethyl)pyridinyl, dimethoxypyridinyl, (ethoxy)(methyl)pyridinyl, (dimethylamino)(methyl)pyridinyl and (dimethylamino)(methyl)pyrazinyl.
- Typical values of Z include methoxyphenyl, dimethylaminophenyl, (methoxy)(methyl)phenyl, (methyl)(trifluoromethoxy)phenyl, (difluoroazetidinyl)-(methyl)pyridinyl, dimethoxypyridinyl and (ethoxy)(methyl)pyridinyl.
- Z represents methoxyphenyl, especially 4-methoxyphenyl.
- Z represents dimethylaminophenyl, especially 4-(dimethylamino)phenyl.
- Z represents (methoxy)(methyl)phenyl. In a first aspect of that embodiment, Z represents 4-methoxy-2-methylphenyl. In a second aspect of that embodiment, Z represents 4-methoxy-3-methylphenyl.
- Z represents (difluoromethoxy)(methyl)phenyl, especially 4-(difluoromethoxy)-2-methylphenyl.
- Z represents (methyl)(trifluoromethoxy)phenyl, especially 2-methyl-4-(trifluoromethoxy)phenyl.
- Z represents imidazo[1,2-a]pyridinyl, especially imidazo-[1,2-a]pyridin-8-yl.
- Z represents (difluoroazetidinyl)(methyl)pyridinyl, especially 6-(3,3-difluoroazetidin-1-yl)-2-methylpyridin-3-yl.
- Z represents (methoxy)(methyl)pyridinyl. In a first aspect of that embodiment, Z represents 6-methoxy-2-methylpyridin-3-yl. In a second aspect of that embodiment, Z represents 6-methoxy-5-methylpyridin-3-yl.
- Z represents dimethoxypyridinyl, especially 2,6-dimethoxypyridin-3-yl.
- Z represents (ethoxy)(methyl)pyridinyl, especially 6-ethoxy-2-methylpyridin-3-yl.
- Z represents (isopropoxy)(methyl)pyridinyl, especially 6-isopropoxy-2-methylpyridin-3-yl.
- Z represents (difluoromethoxy)(methyl)pyridinyl, especially 6-(difluoromethoxy)-2-methylpyridin-3-yl.
- Z represents (isopropoxy)(methyl)phenyl, especially 4-isopropoxy-2-methylphenyl.
- Z represents (azetidinyl)(methyl)pyridinyl, especially 6-(azetidin-1-yl)-2-methylpyridin-3-yl.
- Z represents (methoxy)(trifluoromethyl)pyridinyl, especially 5-methoxy-6-(trifluoromethyl)pyridin-2-yl.
- Z represents (dimethylamino)(methyl)pyridinyl, especially 6-(dimethylamino)-2-methylpyridin-3-yl.
- Z represents (dimethylamino)(methyl)pyrazinyl, especially 5-(dimethylamino)-3-methylpyrazin-2-yl.
- a 1 represents hydrogen, cyano or trifluoromethyl; or A 1 represents C 1-6 alkyl, optionally substituted by one or more substituents independently selected from —OR a , —NR b R c , —CO 2 R d and —CONR b R c ; or A 1 represents C 3-7 cycloalkyl.
- a 1 represents hydrogen or cyano; or A 1 represents C 1-6 alkyl, optionally substituted by one or more substituents independently selected from —OR a , —CO 2 R d and —CONR b R c ; or A 1 represents C 3-7 cycloalkyl.
- a 1 represents hydrogen; or A 1 represents C 1-6 alkyl, optionally substituted by —OR a .
- a 1 represents hydrogen or C 1-6 alkyl.
- a 1 represents hydrogen. In a second embodiment, A 1 represents cyano. In a third embodiment, A 1 represents trifluoromethyl. In a fourth embodiment, A 1 represents C 1-6 alkyl, optionally substituted by one or more substituents independently selected from fluoro, —OR a , trifluoromethoxy, —NR b R c , —CO 2 R d and —CONR b R c . In a first aspect of that embodiment, A 1 represents C 1-6 alkyl, optionally substituted by one or more substituents independently selected from —OR a , —NR b R c , —CO 2 R d and —CONR b R c .
- a 1 represents C 1-6 alkyl, optionally substituted by one or more substituents independently selected from —OR a , —CO 2 R d and —CONR b R c .
- a 1 represents C 1-6 alkyl, optionally substituted by one or more substituents independently selected from —OR a and —NR b R c .
- a 1 represents unsubstituted C 1-6 alkyl, typically methyl, ethyl, isopropyl or isobutyl, especially methyl or ethyl.
- a 1 represents C 1-6 alkyl monosubstituted by —OR a , —CO 2 R d or —CONR b R c .
- a 1 represents C 1-6 alkyl monosubstituted by —OR a or —NR b R c .
- a 1 represents C 1-6 alkyl monosubstituted by —OR a , especially hydroxyethyl.
- a 1 represents C 1-6 alkyl disubstituted by two substituents independently selected from —OR a and —NR b R c .
- a 1 represents C 3-7 cycloalkyl, especially cyclopropyl.
- Selected values of A 1 include hydrogen, cyano, methyl, ethyl, isopropyl, isobutyl, —CH 2 OR a , —CH 2 CH 2 OR a , —CH 2 CO 2 R d , —CH 2 CONR b R c and cyclopropyl.
- Illustrative values of A 1 include hydrogen, methyl, ethyl and —CH 2 CH 2 OR a .
- Particular values of A 1 include hydrogen, methyl, ethyl and hydroxyethyl.
- Apposite values of A 1 include hydrogen, methyl and ethyl.
- a first particular value of A 1 is hydrogen.
- a second particular value of A 1 is methyl.
- a third particular value of A 1 is ethyl.
- a fourth particular value of A 1 is hydroxyethyl, especially 2-hydroxyethyl.
- a 2 represents hydrogen. In another embodiment, A 2 represents C 1-6 alkyl, especially methyl.
- Selected values of A 2 include hydrogen and methyl.
- R 1 represents hydrogen, halogen, cyano, nitro, hydroxy, trifluoromethyl, trifluoromethoxy, —OR a , —SO 2 R a , —NR b R c , —CH 2 NR b R c , —NR c COR d , —CH 2 NR c COR d , —NR c CO 2 R d , —NHCONR b R c , —NR c SO 2 R e , —NHSO 2 NR b R c , —COR d , —CO 2 R d , —CONR b R c , —CON(OR a )R b or —SO 2 NR b R c ; or R 1 represents C 1-6 alkyl, aryl or heteroaryl, any of which groups may be optionally substituted by one or more substituents.
- R 1 represents hydrogen, —NR b R c or —NR c COR d ; or R 1 represents C 1-6 alkyl, which group may be optionally substituted by one or more substituents.
- Suitable values of R 1 include hydrogen and —NR b R c .
- R 1 represents hydrogen. In a second embodiment, R 1 represents cyano. In a third embodiment, R 1 represents —OR a . In a fourth embodiment, R 1 represents —SR a . In a fifth embodiment, R 1 represents —SO 2 R a . In a sixth embodiment, R 1 represents —NR b R c . In a seventh embodiment, R 1 represents —NR c COR d . In an eighth embodiment, R 1 represents optionally substituted C 1-6 alkyl. In one aspect of that embodiment, R 1 represents optionally substituted methyl.
- R 1 examples include one or more substituents independently selected from halogen, cyano, nitro, C 1-6 alkyl, trifluoromethyl, aryl(C 1-6 )alkyl, hydroxy, C 1-6 alkoxy, difluoromethoxy, trifluoromethoxy, aryloxy, C 1-4 alkylenedioxy, C 1-6 alkoxy(C 1-6 )alkyl, C 1-6 alkylthio, C 1-6 alkylsulphonyl, oxo, amino, C 1-6 alkylamino, di(C 1-6 )alkylamino, C 2-6 alkylcarbonylamino, C 2-6 alkoxycarbonylamino, aryl(C 1-6 )alkoxycarbonylamino, C 1-6 alkylaminocarbonylamino, arylaminocarbonylamino, C 1-6 alkylsulphonylamino, formyl, C 2-6 alkylcarbonyl
- substituents on R 1 include one or more substituents independently selected from fluoro, chloro, bromo, cyano, nitro, methyl, ethyl, tert-butyl, trifluoromethyl, benzyl, hydroxy, methoxy, difluoromethoxy, trifluoromethoxy, phenoxy, methylenedioxy, ethylenedioxy, methoxymethyl, methylthio, methylsulphonyl, oxo, amino, methylamino, dimethylamino, acetylamino, methoxycarbonylamino, ethoxycarbonylamino, benzyloxycarbonylamino, ethylaminocarbonylamino, butylaminocarbonylamino, phenylaminocarbonylamino, methylsulphonylamino, formyl, acetyl, carboxy, methoxycarbonyl, aminocarbonyl, methylaminocarbon
- R 2 represents hydrogen, cyano, hydroxy, trifluoromethyl, —NR c CO 2 R d , —COR d , —CO 2 R d , —CONR b R c or —CON(OR a )R b ; or R 2 represents C 1-6 alkyl, C 3-7 cycloalkyl, aryl, C 3-7 heterocycloalkyl, C 3-7 heterocycloalkenyl or heteroaryl, any of which groups may be optionally substituted by one or more substituents.
- R 2 represents hydrogen, —CO 2 R d , —CONR b R c or —CON(OR a )R b ; or R 2 represents C 3-7 heterocycloalkenyl, which group may be optionally substituted by one or more substituents.
- R 2 represents hydrogen. In a second embodiment, R 2 represents cyano. In a third embodiment, R 2 represents hydroxy. In a fourth embodiment, R 2 represents trifluoromethyl. In a fifth embodiment, R 2 represents —NR c CO 2 R d . In a sixth embodiment, R 2 represents —COR d . In a seventh embodiment, R 2 represents —CO 2 R d . In an eighth embodiment, R 2 represents —CONR b R c . In a ninth embodiment, R 2 represents —CON(OR a )R b . In a tenth embodiment, R 2 represents optionally substituted C 1-6 alkyl.
- R 2 represents unsubstituted C 1-6 alkyl. In a second aspect of that embodiment, R 2 represents monosubstituted C 1-6 alkyl. In a third aspect of that embodiment, R 2 represents disubstituted C 1-6 alkyl. In an eleventh embodiment, R 2 represents optionally substituted C 3-7 cycloalkyl. In a first aspect of that embodiment, R 2 represents unsubstituted C 3-7 cycloalkyl. In a second aspect of that embodiment, R 2 represents monosubstituted C 3-7 cycloalkyl. In a third aspect of that embodiment, R 2 represents disubstituted C 3-7 cycloalkyl.
- R 2 represents optionally substituted aryl. In a first aspect of that embodiment, R 2 represents unsubstituted aryl. In a second aspect of that embodiment, R 2 represents monosubstituted aryl. In a third aspect of that embodiment, R 2 represents disubstituted aryl. In a thirteenth embodiment, R 2 represents optionally substituted C 3-7 heterocycloalkyl. In a first aspect of that embodiment, R 2 represents unsubstituted C 3-7 heterocycloalkyl. In a second aspect of that embodiment, R 2 represents monosubstituted C 3-7 heterocycloalkyl.
- R 2 represents disubstituted C 3-7 heterocycloalkyl.
- R 2 represents optionally substituted C 3-7 heterocycloalkenyl.
- R 2 represents unsubstituted C 3-7 heterocycloalkenyl.
- R 2 represents monosubstituted C 3-7 heterocycloalkenyl.
- R 2 represents disubstituted C 3-7 heterocycloalkenyl.
- R 2 represents optionally substituted heteroaryl.
- R 2 represents unsubstituted heteroaryl.
- R 2 represents monosubstituted heteroaryl.
- R 2 represents disubstituted heteroaryl.
- R 2 represents optionally substituted C 1-6 alkyl
- suitable values include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl, any of which groups may be optionally substituted by one or more substituents.
- Selected values include methyl, hydroxymethyl, chloropropyl and isobutyl.
- Particular values include methyl and isobutyl, especially methyl.
- R 2 represents optionally substituted C 3-7 cycloalkyl
- a suitable value is cyclohexyl, optionally substituted by one or more substituents.
- R 2 represents optionally substituted aryl
- a suitable value is phenyl, optionally substituted by one or more substituents.
- Selected values include phenyl, fluorophenyl, chlorophenyl and methoxyphenyl.
- R 2 represents optionally substituted C 3-7 heterocycloalkyl
- typical values include azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl, any of which groups may be optionally substituted by one or more substituents.
- R 2 represents optionally substituted C 3-7 heterocycloalkenyl
- a typical value is oxazolinyl, optionally substituted by one or more substituents. Suitable values include oxazolinyl, methyloxazolinyl, isopropyloxazolinyl and dimethyloxazolinyl.
- R 2 represents optionally substituted heteroaryl
- typical values include pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, tetrazolyl and triazinyl, any of which groups may be optionally substituted by one or more substituents.
- Suitable values include oxadiazolyl and pyridinyl, either of which groups may be optionally substituted by one or more substituents.
- Selected values include methyloxadiazolyl, isopropyloxadiazolyl, tert-butyloxadiazolyl and pyridinyl.
- R 2 represents hydrogen, cyano, hydroxy, trifluoro-methyl, —NR c CO 2 R d , —COR d , —CO 2 R d , —CONR b R c or —CON(OR a )R b ; or R 2 represents C 1-6 alkyl, cyclohexyl, phenyl, oxazolinyl, oxadiazolyl or pyridinyl, any of which groups may be optionally substituted by one or more substituents.
- R 2 represents hydrogen, —CO 2 R d , —CONR b R c or —CON(OR a )R b ; or R 2 represents oxazolinyl, which group may be optionally substituted by one or more substituents.
- Typical examples of optional substituents on R 2 include one or more substituents independently selected from halogen, cyano, nitro, C 1-6 alkyl, trifluoromethyl, hydroxy, C 1-6 alkoxy, difluoromethoxy, trifluoromethoxy, C 1-6 alkylthio, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, amino, C 1-6 alkylamino, di(C 1-6 )alkylamino, C 2-6 alkylcarbonylamino, C 2-6 alkoxycarbonylamino, C 1-6 alkylsulfonylamino, formyl, C 2-6 alkylcarbonyl, carboxy, C 2-6 alkoxycarbonyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, di(C 1-6 )alkylaminocarbonyl, aminosulfonyl, C 1-6 alkylaminosulfonyl and di(C 1-6
- Typical examples of specific substituents on R 2 include one or more substituents independently selected from fluoro, chloro, bromo, cyano, nitro, methyl, ethyl, isopropyl, tert-butyl, trifluoromethyl, hydroxy, methoxy, isopropoxy, difluoromethoxy, trifluoro-methoxy, methylthio, methylsulfinyl, methylsulfonyl, amino, methylamino, dimethyl-amino, acetylamino, methoxycarbonylamino, methylsulfonylamino, formyl, acetyl, carboxy, methoxycarbonyl, aminocarbonyl, methylaminocarbonyl, dimethylamino-carbonyl, aminosulfonyl, methylaminosulfonyl and dimethylaminosulfonyl.
- R 2 examples include hydrogen, cyano, hydroxy, trifluoromethyl, —NR c CO 2 R d , —COR d , —CO 2 R d , —CONR b R c , —CON(OR a )R b , methyl, hydroxymethyl, chloro-propyl, isobutyl, cyclohexyl, phenyl, fluorophenyl, chlorophenyl, methoxyphenyl, oxazolinyl, methyloxazolinyl, isopropyloxazolinyl, dimethyloxazolinyl, methyl-oxadiazolyl, isopropyloxadiazolyl, tert-butyloxadiazolyl and pyridinyl.
- Suitable values of R 2 include hydrogen, —CO 2 R d , —CONR b R c , —CON(OR a )R b and oxazolinyl.
- R 3 represents hydrogen or C 1-6 alkyl.
- R 3 represents hydrogen. In a second embodiment, R 3 represents halogen, especially fluoro or chloro. In a first aspect of that embodiment, R 3 represents fluoro. In a second aspect of that embodiment, R 3 represents chloro. In a third embodiment, R 3 represents C 1-6 alkyl, especially methyl.
- Typical values of R 3 include hydrogen and methyl.
- R 4 represents hydrogen; or R 4 represents C 1-6 alkyl, aryl or heteroaryl, any of which groups may be optionally substituted by one or more substituents.
- R 4 represents hydrogen; or R 4 represents C 1-6 alkyl, which group may be optionally substituted by one or more substituents.
- R 4 represents hydrogen. In a second embodiment, R 4 represents optionally substituted C 1-6 alkyl. In a first aspect of that embodiment, R 4 represents unsubstituted C 1-6 alkyl. In a second aspect of that embodiment, R 4 represents monosubstituted C 1-6 alkyl. In a third aspect of that embodiment, R 4 represents disubstituted C 1-6 alkyl. In a third embodiment, R 4 represents optionally substituted aryl. In a first aspect of that embodiment, R 4 represents unsubstituted aryl. In a second aspect of that embodiment, R 4 represents monosubstituted aryl. In a third aspect of that embodiment, R 4 represents disubstituted aryl.
- R 4 represents optionally substituted aryl(C 1-6 )alkyl. In a first aspect of that embodiment, R 4 represents unsubstituted aryl(C 1-6 )alkyl. In a second aspect of that embodiment, R 4 represents monosubstituted aryl(C 1-6 )alkyl. In a third aspect of that embodiment, R 4 represents disubstituted aryl(C 1-6 )alkyl. In a fifth embodiment, R 4 represents optionally substituted heteroaryl. In a first aspect of that embodiment, R 4 represents unsubstituted heteroaryl. In a second aspect of that embodiment, R 4 represents monosubstituted heteroaryl.
- R 4 represents disubstituted heteroaryl.
- R 4 represents optionally substituted heteroaryl(C 1-6 )alkyl.
- R 4 represents unsubstituted heteroaryl(C 1-6 )alkyl.
- R 4 represents monosubstituted heteroaryl(C 1-6 )alkyl.
- R 4 represents disubstituted heteroaryl(C 1-6 )alkyl.
- R 4 represents optionally substituted C 1-6 alkyl
- suitable values include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl, any of which groups may be optionally substituted by one or more substituents.
- Selected values include methyl, ethyl, n-propyl, isopropyl and isobutyl, especially methyl.
- R 4 represents optionally substituted aryl
- a suitable value is phenyl, optionally substituted by one or more substituents.
- Selected values include phenyl, fluorophenyl, chlorophenyl and methoxyphenyl. A particular value is fluorophenyl.
- R 4 represents optionally substituted aryl(C 1-6 )alkyl
- a suitable value is benzyl, optionally substituted by one or more substituents.
- Selected values include benzyl, fluorobenzyl, chlorobenzyl and methoxybenzyl. A particular value is fluoro-benzyl.
- R 4 represents optionally substituted heteroaryl
- typical values include pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, tetrazolyl and triazinyl, any of which groups may be optionally substituted by one or more substituents.
- Suitable values include oxadiazolyl and pyridinyl, either of which groups may be optionally substituted by one or more substituents.
- Selected values include methyloxadiazolyl, isopropyloxadiazolyl, tert-butyloxadiazolyl and pyridinyl.
- R 4 represents optionally substituted heteroaryl(C 1-6 )alkyl
- a suitable value is pyridinylmethyl, optionally substituted by one or more substituents.
- R 4 represents hydrogen; or R 4 represents C 1-6 alkyl, phenyl, benzyl, oxadiazolyl, pyridinyl or pyridinylmethyl, any of which groups may be optionally substituted by one or more substituents.
- R 4 represents hydrogen; or R 4 represents C 1-6 alkyl or phenyl, either of which groups may be optionally substituted by one or more substituents.
- R 4 represents hydrogen; or R 4 represents C 1-6 alkyl, which group may be optionally substituted by one or more substituents.
- Typical examples of optional substituents on R 4 include one or more substituents independently selected from halogen, cyano, nitro, C 1-6 alkyl, trifluoromethyl, hydroxy, C 1-6 alkoxy, difluoromethoxy, trifluoromethoxy, C 1-6 alkylthio, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, amino, C 1-6 alkylamino, di(C 1-6 )alkylamino, C 2-6 alkylcarbonylamino, C 2-6 alkoxycarbonylamino, C 1-6 alkylsulfonylamino, formyl, C 2-6 alkylcarbonyl, carboxy, C 2-6 alkoxycarbonyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, di(C 1-6 )alkylaminocarbonyl, aminosulfonyl, C 1-6 alkylaminosulfonyl and di(C 1-6
- Typical examples of specific substituents on R 4 include one or more substituents independently selected from fluoro, chloro, bromo, cyano, nitro, methyl, ethyl, isopropyl, tert-butyl, trifluoromethyl, hydroxy, methoxy, isopropoxy, difluoromethoxy, trifluoro-methoxy, methylthio, methylsulfinyl, methylsulfonyl, amino, methylamino, dimethyl-amino, acetylamino, methoxycarbonylamino, methylsulfonylamino, formyl, acetyl, carboxy, methoxycarbonyl, aminocarbonyl, methylaminocarbonyl, dimethylamino-carbonyl, aminosulfonyl, methylaminosulfonyl and dimethylaminosulfonyl.
- Typical values of R 4 include hydrogen, methyl, phenyl, fluorophenyl, chloro-phenyl, methoxyphenyl, benzyl, methyloxadiazolyl, isopropyloxadiazolyl, tert-butyl-oxadiazolyl, pyridinyl and pyridinylmethyl.
- R 4 represents hydrogen or C 1-6 alkyl.
- R 4 represents hydrogen. In another embodiment, R 4 represents C 1-6 alkyl, especially methyl.
- R 4 represents methyl
- R 5 represents hydrogen or C 1-6 alkyl.
- Suitable values of R 5 include hydrogen and methyl.
- R 5 represents hydrogen. In another embodiment, R 5 represents C 1-6 alkyl, optionally substituted by one or more substituents independently selected from —OR a and —NR b R c . In one aspect of that embodiment, R 5 represents unsubstituted C 1-6 alkyl, especially methyl. In another aspect of that embodiment, R 5 represents C 1-6 alkyl monosubstituted by —OR a or —NR b R c . In a further aspect of that embodiment, R 5 represents C 1-6 alkyl disubstituted by two substituents independently selected from —OR a and —NR b R c .
- Suitable substituents on R a , R b , R c , R d or R e , or on the heterocyclic moiety —NR b R c include halogen, C 1-6 alkyl, C 1-6 alkoxy, difluoromethoxy, trifluoromethoxy, alkoxy(C 1-6 )alkyl, C 1-6 alkylthio, C 1-6 alkylsulphinyl, C 1-6 alkylsulphonyl, hydroxy, hydroxy(C 1-6 )alkyl, amino(C 1-6 )alkyl, cyano, trifluoromethyl, oxo, C 2-6 alkylcarbonyl, carboxy, C 2-6 alkoxycarbonyl, C 2-6 alkylcarbonyloxy, amino, C 1-6 alkylamino, di(C 1-6 )alkylamino, phenylamino, pyridinylamino, C 2-6 alkylcarbonylamin
- Typical examples of specific substituents on R a , R b , R c , R d or R e , or on the heterocyclic moiety —NR b R c include fluoro, chloro, bromo, methyl, ethyl, isopropyl, methoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, methoxymethyl, methylthio, ethylthio, methylsulphinyl, methylsulphonyl, hydroxy, hydroxymethyl, hydroxyethyl, aminomethyl, cyano, trifluoromethyl, oxo, acetyl, carboxy, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, acetoxy, amino, methylamino, ethylamino, dimethylamino, phenylamino, pyridinylamino, acetylamino, acety
- R a represents hydrogen; or R a represents C 1-6 alkyl, aryl(C 1-6 )alkyl or heteroaryl(C 1-6 )alkyl, any of which groups may be optionally substituted by one or more substituents.
- R a represents C 1-6 alkyl, aryl(C 1-6 )alkyl or heteroaryl(C 1-6 )alkyl, any of which groups may be optionally substituted by one or more substituents.
- Apposite values of R a include hydrogen; and methyl, ethyl, benzyl or isoindolyl-propyl, any of which groups may be optionally substituted by one or more substituents.
- R a Selected values of R a include methyl, ethyl, benzyl and isoindolylpropyl, any of which groups may be optionally substituted by one or more substituents.
- R a Selected examples of suitable substituents on R a include C 1-6 alkoxy and oxo.
- R a Selected examples of specific substituents on R a include methoxy and oxo.
- R a represents hydrogen. In another embodiment, R a represents optionally substituted C 1-6 alkyl. In one aspect of that embodiment, R a ideally represents unsubstituted C 1-6 alkyl, especially methyl. In another aspect of that embodiment, R a ideally represents substituted C 1-6 alkyl, e.g. methoxyethyl. In another embodiment, R a represents optionally substituted aryl. In one aspect of that embodiment, R a represents unsubstituted aryl, especially phenyl. In another aspect of that embodiment, R a represents monosubstituted aryl, especially methylphenyl.
- R a represents optionally substituted aryl(C 1-6 )alkyl, ideally unsubstituted aryl(C 1-6 )alkyl, especially benzyl.
- R a represents optionally substituted heteroaryl.
- R a represents optionally substituted heteroaryl(C 1-6 )alkyl, e.g. dioxoisoindolylpropyl.
- R a examples include methyl, methoxyethyl, benzyl and dioxoisoindolyl-propyl.
- R a represents hydrogen or C 1-6 alkyl.
- R a Individual values of R a include hydrogen and methyl.
- R b represents hydrogen or trifluoromethyl; or C 1-6 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl(C 1-6 )alkyl, aryl, aryl(C 1-6 )alkyl, C 3-7 heterocycloalkyl, C 3-7 heterocycloalkyl(C 1-6 )alkyl, heteroaryl or heteroaryl(C 1-6 )alkyl, any of which groups may be optionally substituted by one or more substituents.
- R b include hydrogen; or C 1-6 alkyl, aryl(C 1-6 )alkyl, C 3-7 heterocycloalkyl or C 3-7 heterocycloalkyl(C 1-6 )alkyl, any of which groups may be optionally substituted by one or more substituents.
- Typical values of R b include hydrogen and C 1-6 alkyl.
- R b represents hydrogen or trifluoromethyl; or methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-methylpropyl, tert-butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, phenyl, benzyl, phenylethyl, azetidinyl, tetrahydrofuryl, tetrahydrothienyl, pyrrolidinyl, piperidinyl, homopiperidinyl, morpholinyl, azetidinylmethyl, tetrahydrofurylmethyl, pyrrolidinylmethyl, pyrrolidinylethyl, pyrrolidinyl, piperidin
- R b include hydrogen; or methyl, ethyl, n-propyl, benzyl, pyrrolidinyl or morpholinylpropyl, any of which groups may be optionally substituted by one or more substituents.
- R b Selected examples of suitable substituents on R b include C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylsulphinyl, C 1-6 alkylsulphonyl, hydroxy, cyano, C 2-6 alkoxycarbonyl, di-(C 1-6 )alkylamino and C 2-6 alkoxycarbonylamino.
- R b Selected examples of specific substituents on R b include methoxy, methylthio, methylsulphinyl, methylsulphonyl, hydroxy, cyano, tert-butoxycarbonyl, dimethylamino and tert-butoxycarbonylamino.
- R b include hydrogen, methyl, methoxyethyl, methylthioethyl, methylsulphinylethyl, methylsulphonylethyl, hydroxyethyl, cyanoethyl, dimethylamino-ethyl, tert-butoxycarbonylaminoethyl, dihydroxypropyl, benzyl, pyrrolidinyl, tert-butoxycarbonylpyrrolidinyl and morpholinylpropyl.
- Apposite values of R b include hydrogen and methyl.
- R b represents hydrogen. In another embodiment, R b represents C 1-6 alkyl, especially methyl.
- R c include hydrogen; or C 1-6 alkyl, C 3-7 cycloalkyl or C 3-7 heterocycloalkyl, any of which groups may be optionally substituted by one or more substituents.
- R c represents hydrogen, C 1-6 alkyl or C 3-7 cycloalkyl.
- Rc include hydrogen; or methyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyranyl and piperidinyl, any of which groups may be optionally substituted by one or more substituents.
- Rc Selected examples of suitable substituents on Rc include C 2-6 alkylcarbonyl and C 2-6 alkoxycarbonyl.
- R c Selected examples of specific substituents on R c include acetyl and tert-butoxycarbonyl.
- R c include hydrogen, methyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyranyl, acetylpiperidinyl and tert-butoxycarbonylpiperidinyl,
- R c represents hydrogen or C 1-6 alkyl.
- R c is hydrogen.
- R c represents C 1-6 alkyl, especially methyl or ethyl, particularly methyl.
- R c represents C 3-7 cycloalkyl, e.g. cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
- the moiety —NR b R c may suitably represent azetidin-1-yl, pyrrolidin-1-yl, oxazolidin-3-yl, isoxazolidin-2-yl, thiazolidin-3-yl, isothiazolidin-2-yl, piperidin-1-yl, morpholin-4-yl, thiomorpholin-4-yl, piperazin-1-yl, homopiperidin-1-yl, homomorpholin-4-yl or homopiperazin-1-yl, any of which groups may be optionally substituted by one or more substituents.
- R c substituents on the heterocyclic moiety —NR b R c include C 1-6 alkyl, C 1-6 alkylsulphonyl, hydroxy, hydroxy(C 1-6 )alkyl, amino(C 1-6 )alkyl, cyano, oxo, C 2-6 alkylcarbonyl, carboxy, C 2-6 alkoxycarbonyl, amino, C 2-6 alkylcarbonyl-amino, C 2-6 alkylcarbonylamino(C 1-6 )alkyl, C 2-6 alkoxycarbonylamino, C 1-6 alkyl-sulphonylamino and aminocarbonyl.
- Selected examples of specific substituents on the heterocyclic moiety —NR b R c include methyl, methylsulphonyl, hydroxy, hydroxymethyl, aminomethyl, cyano, oxo, acetyl, carboxy, ethoxycarbonyl, amino, acetylamino, acetylaminomethyl, tert-butoxy-carbonylamino, methylsulphonylamino and aminocarbonyl.
- R b R c Specific values of the moiety —NR b R c include azetidin-1-yl, hydroxyazetidin-1-yl, hydroxymethylazetidin-1-yl, (hydroxy)(hydroxymethyl)azetidin-1-yl, aminomethyl-azetidin-1-yl, cyanoazetidin-1-yl, carboxyazetidin-1-yl, aminoazetidin-1-yl, aminocarbonylazetidin-1-yl, pyrrolidin-1-yl, aminomethylpyrrolidin-1-yl, oxopyrrolidin-1-yl, acetylaminomethylpyrrolidin-1-yl, tert-butoxycarbonylaminopyrrolidin-1-yl, oxo-oxazolidin-3-yl, hydroxyisoxazolidin-2-yl, thiazolidin-3-yl, oxothiazolidin-3
- R d represents hydrogen; or C 1-6 alkyl, aryl or heteroaryl, any of which groups may be optionally substituted by one or more substituents.
- R d examples include hydrogen, methyl, ethyl, isopropyl, 2-methylpropyl, tert-butyl, cyclopropyl, cyclobutyl, phenyl, thiazolidinyl, thienyl, imidazolyl and thiazolyl, any of which groups may be optionally substituted by one or more substituents.
- R d Selected examples of suitable substituents on R d include halogen, C 1-6 alkyl, C 1-6 alkoxy, oxo, C 2-6 alkylcarbonyloxy and di(C 1-6 )alkylamino.
- R d Selected examples of particular substituents on R d include fluoro, methyl, methoxy, oxo, acetoxy and dimethylamino.
- R d represents hydrogen. In another embodiment, R d represents optionally substituted C 1-6 alkyl. In one aspect of that embodiment, R d ideally represents unsubstituted C 1-6 alkyl, e.g. methyl, ethyl, isopropyl, 2-methylpropyl or tert-butyl, especially methyl or ethyl, particularly methyl. In another aspect of that embodiment, R d ideally represents substituted C 1-6 alkyl, e.g. substituted methyl or substituted ethyl, including acetoxymethyl, dimethylaminomethyl and trifluoroethyl. In another embodiment, R d represents optionally substituted aryl.
- R d represents unsubstituted aryl, especially phenyl. In another aspect of that embodiment, R d represents monosubstituted aryl, especially methylphenyl. In a further aspect of that embodiment, R d represents disubstituted aryl, e.g. dimethoxyphenyl. In a further embodiment, R d represents optionally substituted heteroaryl, e.g. thienyl, chlorothienyl, methylthienyl, methylimidazolyl or thiazolyl. In another embodiment, R d represents optionally substituted C 3-7 cycIoalkyl, e.g. cyclopropyl or cyclobutyl. In a further embodiment, R d represents optionally substituted C 3-7 heterocycloalkyl, e.g. thiazolidinyl or oxothiazolidinyl.
- R d selected examples include hydrogen, methyl, ethyl, acetoxymethyl, dimethylaminomethyl, ethyl, trifluoroethyl, isopropyl, 2-methylpropyl, tert-butyl, cyclopropyl, cyclobutyl, phenyl, dimethoxyphenyl, thiazolidinyl, oxothiazolidinyl, thienyl, chlorothienyl, methylthienyl, methylimidazolyl and thiazolyl.
- R d represents hydrogen or C 1-6 alkyl.
- R d Individual values of R d include hydrogen, methyl and ethyl.
- R d is ethyl
- R e represents C 1-6 alkyl or aryl, either of which groups may be optionally substituted by one or more substituents.
- R e Selected examples of suitable substituents on R e include C 1-6 alkyl, especially methyl.
- R e represents optionally substituted C 1-6 alkyl, ideally unsubstituted C 1-6 alkyl, e.g. methyl or propyl, especially methyl.
- R e represents optionally substituted aryl.
- R e represents unsubstituted aryl, especially phenyl.
- R e represents monosubstituted aryl, especially methylphenyl.
- R e represents optionally substituted heteroaryl.
- Selected values of R e include methyl, propyl and methylphenyl.
- One sub-class of compounds according to the invention is represented by the compounds of formula (IIA-1) or (IIB-1), and pharmaceutically acceptable salts and solvates thereof:
- a 11 represents hydrogen, cyano, C 1-6 alkyl, —CH 2 OR a , —CH 2 CH 2 OR a , —CH 2 CO 2 R d , —CH 2 CONR b R c or C 3-7 cycloalkyl;
- R 11 represents hydrogen or amino
- X, T, U, Z, R 3 , R a , R b , R c and R d are as defined above.
- a 11 represents hydrogen or C 1-6 alkyl.
- a 11 represents hydrogen. In a second embodiment, A 11 represents cyano. In a third embodiment, A 11 represents C 1-6 alkyl, typically methyl, ethyl, isopropyl or isobutyl, especially methyl or ethyl. In a fourth embodiment, A 11 represents —CH 2 OR a . In a fifth embodiment, A 11 represents —CH 2 CH 2 OR a . In a sixth embodiment, A 11 represents —CH 2 CO 2 R d . In a seventh embodiment, A 11 represents —CH 2 CONR b R c . In an eighth embodiment, A 11 represents C 3-7 cycloalkyl, especially cyclopropyl.
- Selected values of A 11 include hydrogen, cyano, methyl, ethyl, isopropyl, isobutyl, —CH 2 OR a , —CH 2 CH 2 OR a , —CH 2 CO 2 R d , —CH 2 CONR b R c and cyclopropyl.
- Illustrative values of A 11 include hydrogen, methyl, ethyl and —CH 2 CH 2 OR a .
- Particular values of A 11 include hydrogen, methyl, ethyl and 2-hydroxyethyl.
- Apposite values of A 11 include hydrogen, methyl and ethyl.
- a first particular value of A 11 is hydrogen.
- a second particular value of A 11 is methyl.
- a third particular value of A 11 is ethyl.
- a fourth particular value of A 11 is 2-hydroxyethyl.
- R 11 is hydrogen. In a second embodiment, R 11 is —NH 2 .
- Another sub-class of compounds according to the invention is represented by the compounds of formula (IIA-2) or (IIB-2), and pharmaceutically acceptable salts and solvates thereof:
- the compounds in accordance with the present invention are beneficial in the treatment and/or prevention of various human ailments. These include inflammatory, autoimmune and oncological disorders; viral diseases and malaria; and organ and cell transplant rejection.
- Inflammatory and autoimmune disorders include systemic autoimmune disorders, autoimmune endocrine disorders and organ-specific autoimmune disorders.
- Systemic autoimmune disorders include systemic lupus erythematosus (SLE), psoriasis, vasculitis, polymyositis, scleroderma, multiple sclerosis, ankylosing spondylitis, rheumatoid arthritis and Sjögren's syndrome.
- Autoimmune endocrine disorders include thyroiditis.
- Organ-specific autoimmune disorders include Addison's disease, haemolytic or pernicious anaemia, glomerulonephritis (including Goodpasture's syndrome), Graves' disease, idiopathic thrombocytopenic purpura, insulin-dependent diabetes mellitus, juvenile diabetes, uveitis, inflammatory bowel disease (including Crohn's disease and ulcerative colitis), pemphigus, atopic dermatitis, autoimmune hepatitis, primary biliary cirrhosis, autoimmune pneumonitis, autoimmune carditis, myasthenia gravis and spontaneous infertility.
- Oncological disorders which may be acute or chronic, include proliferative disorders, especially cancer, in animals, including mammals, especially humans.
- Particular categories of cancer include haematological malignancy (including leukaemia and lymphoma) and non-haematological malignancy (including solid tumour cancer, sarcoma, meningioma, glioblastoma multiforme, neuroblastoma, melanoma, gastric carcinoma and renal cell carcinoma).
- Chronic leukaemia may be myeloid or lymphoid.
- leukaemia include lymphoblastic T cell leukaemia, chronic myelogenous leukaemia (CML), chronic lymphocytic/lymphoid leukaemia (CLL), hairy-cell leukaemia, acute lymphoblastic leukaemia (ALL), acute myelogenous leukaemia (AML), myelodysplastic syndrome, chronic neutrophilic leukaemia, acute lymphoblastic T cell leukaemia, plasmacytoma, immunoblastic large cell leukaemia, mantle cell leukaemia, multiple myeloma, acute megakaryoblastic leukaemia, acute megakaryocytic leukaemia, promyelocytic leukaemia and erythroleukaemia.
- CML chronic myelogenous leukaemia
- CLL chronic lymphocytic/lymphoid leukaemia
- ALL acute lymphoblastic leukaemia
- AML acute myelogenous leukaemia
- lymphoma include malignant lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, lymphoblastic T cell lymphoma, Burkitt's lymphoma, follicular lymphoma, MALT1 lymphoma and marginal zone lymphoma.
- non-haematological malignancy include cancer of the prostate, lung, breast, rectum, colon, lymph node, bladder, kidney, pancreas, liver, ovary, uterus, cervix, brain, skin, bone, stomach and muscle.
- Viral diseases include infections caused by various families of virus, including the Retroviridae, Flaviviridae, Picornaviridae.
- Various genera within the Retroviridae family include Alpharetrovirus, Betaretrovirus, Gammaretrovirus, Deltaretrovirus, Epsilonretrovirus, Lentivirus and Spumavirus .
- Members of the Lentivirus genus include human immunodeficiency virus 1 (HIV-1) and human immunodeficiency virus 2 (HIV-2).
- Various genera within the Flaviviridae family include Flavivirus, Pestivirus, Hepacivirus and Hepatitis G Virus .
- Flavivirus genus include Dengue fever virus, yellow fever virus, West Nile encephalitis virus and Japanese encephalitis virus.
- Pestivirus genus include bovine viral diarrhoea virus (BVDV), classical swine fever virus and border disease virus 2 (BDV-2).
- BVDV bovine viral diarrhoea virus
- BDV-2 classical swine fever virus
- HCV hepatitis C virus
- HCV hepatitis G virus
- hepatitis G virus include hepatitis G virus.
- Picornaviridae family Various genera within the Picornaviridae family include Aphthovirus, Avihepatovirus, Cardiovirus, Enterovirus, Erbovirus, Hepatovirus, Kobuvirus, Parechovirus, Sapelovirus, Senecavirus, Teschovirus and Tremovirus .
- Enterovirus genus include poliovirus, coxsackie A virus, coxsackie B virus and rhinovirus.
- Organ transplant rejection includes the rejection of transplanted or grafted organs or cells (both allografts and xenografts), including graft-versus-host reaction disease.
- organ as used herein means all organs or parts of organs in mammals, particularly humans, including kidney, lung, bone marrow, hair, cornea, eye (vitreous), heart, heart valve, liver, pancreas, blood vessel, skin, muscle, bone, intestine and stomach.
- rejection as used herein means all reactions of the recipient body or the transplanted organ which ultimately lead to cell or tissue death in the transplanted organ, or adversely affect the functional ability and viability of the transplanted organ or the recipient. In particular, this means acute and chronic rejection reactions.
- Cell transplant rejection includes the rejection of cell transplants and xeno- transplantation.
- the major hurdle for xenotransplantation is that even before the T lymphocytes (responsible for the rejection of allografts) are activated, the innate immune system (especially T-independent B lymphocytes and macrophages) is activated. This provokes two types of severe and early acute rejection, referred to as hyperacute rejection and vascular rejection respectively.
- Conventional immunosuppressant drugs, including cyclosporine A are ineffective in xenotransplantation.
- the compounds in accordance with the present invention are not liable to this drawback.
- the ability of the compounds of this invention to suppress T-independent xeno-antibody production as well as macrophage activation may be demonstrated by their ability to prevent xenograft rejection in athymic, T-deficient mice receiving xenogenic hamster-heart grafts.
- the present invention also provides a pharmaceutical composition which comprises a compound in accordance with the invention as described above, or a pharmaceutically acceptable salt or solvate thereof, in association with one or more pharmaceutically acceptable carriers.
- compositions according to the invention may take a form suitable for oral, buccal, parenteral, nasal, topical, ophthalmic or rectal administration, or a form suitable for administration by inhalation or insufflation.
- the pharmaceutical compositions may take the form of, for example, tablets, lozenges or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methyl cellulose); fillers (e.g. lactose, microcrystalline cellulose or calcium hydrogenphosphate); lubricants (e.g. magnesium stearate, talc or silica); disintegrants (e.g. potato starch or sodium glycollate); or wetting agents (e.g. sodium lauryl sulphate).
- binding agents e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methyl cellulose
- fillers e.g. lactose, microcrystalline cellulose or calcium hydrogenphosphate
- lubricants e.g. magnesium stearate, talc or silica
- disintegrants e.g. potato starch or sodium glycollate
- Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use.
- Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents, emulsifying agents, non-aqueous vehicles or preservatives.
- the preparations may also contain buffer salts, flavouring agents, colouring agents or sweetening agents, as appropriate.
- Preparations for oral administration may be suitably formulated to give controlled release of the active compound.
- compositions may take the form of tablets or lozenges formulated in conventional manner.
- the compounds of formula (IA) or (IB) may be formulated for parenteral administration by injection, e.g. by bolus injection or infusion.
- Formulations for injection may be presented in unit dosage form, e.g. in glass ampoules or multi-dose containers, e.g. glass vials.
- the compositions for injection may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising, preserving and/or dispersing agents.
- the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use.
- the compounds of formula (IA) or (IB) may also be formulated as a depot preparation. Such long-acting formulations may be administered by implantation or by intramuscular injection.
- the compounds according to the present invention may be conveniently delivered in the form of an aerosol spray presentation for pressurised packs or a nebuliser, with the use of a suitable propellant, e.g. dichlorodifluoromethane, fluorotrichloromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas or mixture of gases.
- a suitable propellant e.g. dichlorodifluoromethane, fluorotrichloromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas or mixture of gases.
- compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient.
- the pack or dispensing device may be accompanied by instructions for administration.
- the compounds of use in the present invention may be conveniently formulated in a suitable ointment containing the active component suspended or dissolved in one or more pharmaceutically acceptable carriers.
- Particular carriers include, for example, mineral oil, liquid petroleum, propylene glycol, polyoxyethylene, polyoxypropylene, emulsifying wax and water.
- the compounds of use in the present invention may be formulated in a suitable lotion containing the active component suspended or dissolved in one or more pharmaceutically acceptable carriers.
- Particular carriers include, for example, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, benzyl alcohol, 2-octyldodecanol and water.
- the compounds of use in the present invention may be conveniently formulated as micronized suspensions in isotonic, pH-adjusted sterile saline, either with or without a preservative such as a bactericidal or fungicidal agent, for example phenylmercuric nitrate, benzylalkonium chloride or chlorhexidine acetate.
- a preservative such as a bactericidal or fungicidal agent, for example phenylmercuric nitrate, benzylalkonium chloride or chlorhexidine acetate.
- compounds may be formulated in an ointment such as petrolatum.
- the compounds of use in the present invention may be conveniently formulated as suppositories. These can be prepared by mixing the active component with a suitable non-irritating excipient which is solid at room temperature but liquid at rectal temperature and so will melt in the rectum to release the active component.
- suitable non-irritating excipient include, for example, cocoa butter, beeswax and polyethylene glycols.
- daily dosages may range from around 10 ng/kg to 1000 mg/kg, typically from 100 ng/kg to 100 mg/kg, e.g. around 0.01 mg/kg to 40 mg/kg body weight, for oral or buccal administration, from around 10 ng/kg to 50 mg/kg body weight for parenteral administration, and from around 0.05 mg to around 1000 mg, e.g. from around 0.5 mg to around 1000 mg, for nasal administration or administration by inhalation or insufflation.
- the compounds of formula (IA) or (IB) above may be prepared by a process which comprises reacting a compound of formula Q-H with a compound of formula (IIIA) or (IIIB):
- the leaving group L 1 is typically a halogen atom, e.g. chloro.
- the reaction will generally be carried out in the presence of a base, typically an organic amine such as triethylamine or N,N-diisopropylethylamine.
- a base typically an organic amine such as triethylamine or N,N-diisopropylethylamine.
- the reaction is conveniently effected at ambient or elevated temperature in a suitable solvent, e.g. a lower alkanol such as ethanol or n-butanol, a cyclic ether solvent such as tetrahydrofuran, 2-methyltetrahydrofuran or 1,4-dioxane, or a dipolar aprotic solvent such as N,N-dimethyl-formamide.
- a suitable solvent e.g. a lower alkanol such as ethanol or n-butanol
- a cyclic ether solvent such as tetrahydrofuran, 2-methyltetrahydrofuran or 1,4-dio
- the leaving group L 1 may be hydroxy (—OH), in which case the reaction may be accomplished at a suitable temperature (ambient or elevated) in a solvent such as acetonitrile or N,N-dimethylformamide, ideally in the presence of a coupling agent such as benzotriazol-1—yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP) or (benzotriazol-1—yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP), and a base, e.g. an organic base such as 1,8—diazabicyclo[5.4.0]undec-7—ene (DBU).
- a coupling agent such as benzotriazol-1—yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP) or (benzotriazol-1—yloxy)tripyrrolidinophosphonium hexafluoro
- the compounds of formula (IA) or (IB) above wherein Y represents —C(O)—, —S(O) 2 —or —C(O)O— may be prepared by a process which comprises reacting a compound of formula L 2 —C(O)—Z, L 2 —S(O) 2 —Z or L 2 —C(O)O—Z respectively with a compound of formula (IVA-1), (IVA-2), (IVA-3), (IVA-4), (IVA-5), (IVB-1), (IVB-2), (IVB-3), (IVB-4) or (IVB-5):
- the leaving group L 2 is typically a halogen atom, e.g. chloro.
- the reaction is conveniently effected at ambient temperature in a suitable solvent, e.g. an ethereal solvent such as 1,4-dioxane, or a chlorinated solvent such as dichloro-methane, typically in the presence of a base.
- a suitable solvent e.g. an ethereal solvent such as 1,4-dioxane, or a chlorinated solvent such as dichloro-methane
- a suitable base for use in the reaction may be an organic base such as N,N-diisopropylethylamine, or an inorganic base such as potassium carbonate.
- the leaving group L 2 may be 2-methyl-3-(trifluoromethylsulfonyl)-1H-imidazol-3-ium-1-yl, in which case the reaction may conveniently be effected at ambient temperature in an organic solvent such as acetonitrile.
- the compounds of formula (IA) or (IB) above wherein Y represents —C(O)— may be prepared by a process which comprises reacting a compound of formula (IVA-1), (IVA-2), (IVA-3), (IVA-4), (IVA-5), (IVB-1), (IVB-2), (IVB-3), (IVB-4) or (IVB-5) as defined above with a compound of formula Z—CO 2 H.
- the compounds of formula (IA) or (IB) above wherein Y represents —C(O)C(O)— may be prepared by a process which comprises reacting a compound of formula (IVA-1), (IVA-2), (IVA-3), (IVA-4), (IVA-5), (IVB-1), (IVB-2), (IVB-3), (IVB-4) or (IVB-5) as defined above with a compound of formula Z—C(O)CO 2 H.
- the reaction is conveniently effected at ambient temperature in a suitable solvent, e.g. a dipolar aprotic solvent such as N,N-dimethylformamide, typically in the presence of a coupling reagent and a base.
- a suitable coupling reagent for use in the reaction may be O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU).
- a suitable base for use in the reaction may be an organic base such as N,N-diisopropyl-ethylamine.
- the compounds of formula (IA) or (IB) above wherein Y represents —C(O)NH— may be prepared by a process which comprises reacting a compound of formula (IVA-1), (IVA-2), (IVA-3), (IVA-4), (IVA-5), (IVB-1), (IVB-2), (IVB-3), (IVB-4) or (IVB-5) as defined above with an isocyanate derivative of formula Z—N ⁇ C ⁇ O, wherein Z is as defined above.
- the reaction is conveniently effected at a suitable temperature, e.g. ambient temperature or a temperature in the region of 0° C., in a suitable solvent or mixture of solvents.
- a suitable temperature e.g. ambient temperature or a temperature in the region of 0° C.
- solvent or solvents may typically be selected as appropriate from an ethereal solvent such as 1,4-dioxane or tetrahydrofuran, a chlorinated solvent such as dichloromethane, a nitrile-containing solvent such as acetonitrile, and a dipolar aprotic solvent such as N,N-dimethylformamide.
- the reaction may optionally be performed in the presence of a base, e.g. an organic base such as diisopropylamine, N,N-diisopropylethyl-amine or triethylamine.
- the compounds of formula (IA) or (IB) above wherein Y represents —C(O)NH— may be prepared by a process which comprises reacting a compound of formula (IVA-1), (IVA-2), (IVA-3), (IVA-4), (IVA-5), (IVB-1), (IVB-2), (IVB-3), (IVB-4) or (IVB-5) as defined above with a compound of formula Z—NH 2 , wherein Z is as defined above, in the presence of triphosgene or 1,1′-carbonyldiimidazole.
- reaction is conveniently effected at ambient temperature in a suitable solvent, e.g. a chlorinated solvent such as dichloromethane, or a dipolar aprotic solvent such as N,N-dimethylformamide, typically in the presence of a base, e.g. an organic base such as N,N-diisopropylethylamine.
- a suitable solvent e.g. a chlorinated solvent such as dichloromethane, or a dipolar aprotic solvent such as N,N-dimethylformamide
- a base e.g. an organic base such as N,N-diisopropylethylamine.
- the compounds of formula (IA) or (IB) above wherein Y represents —C(O)NH— may be prepared by a two-step process which comprises: (i) reacting a compound of formula Z—NH 2 , wherein Z is as defined above, with phenyl chloroformate; and (ii) reacting the material thereby obtained with a compound of formula (IVA-1), (IVA-2), (IVA-3), (IVA-4), (IVA-5), (IVB-1), (IVB-2), (IVB-3), (IVB-4) or (IVB-5) as defined above.
- Step (i) of the above process is conveniently effected at a suitable temperature, e.g. ambient temperature or a temperature in the region of 0° C., in a suitable solvent, e.g. a cyclic ether solvent such as tetrahydrofuran or a chlorinated solvent such as dichloro-methane, typically in the presence of a base, e.g. an organic base such as pyridine or triethylamine.
- Step (ii) is conveniently effected at ambient or elevated temperature in a suitable solvent, e.g.
- a sulfoxide solvent such as dimethyl sulfoxide, or a nitrile-containing solvent such as acetonitrile, or a C 1-4 alkanol such as ethanol, or a chlorinated solvent such as dichloromethane, typically in the presence of a base, e.g. an organic base such as N,N-diisopropylethylamine.
- a base e.g. an organic base such as N,N-diisopropylethylamine.
- the compounds of formula (IA) or (IB) above wherein Y represents —S(O) 2 NH— may be prepared by a two-step process which comprises: (i) reacting a compound of formula (IVA-1), (IVA-2), (IVA-3), (IVA-4), (IVA-5), (IVB-1), (IVB-2), (IVB-3), (IVB-4) or (IVB-5) as defined above with methyl trifluoromethanesulfonate; and (ii) reacting the material thereby obtained with a compound of formula Z—NH 2 , wherein Z is as defined above.
- Step (i) of the above process is conveniently effected at a temperature in the region of 0° C. in a suitable solvent, typically a chlorinated solvent such as dichloromethane.
- Step (ii) is conveniently effected at an elevated temperature in a suitable solvent, e.g. a nitrile-containing solvent such as acetonitrile.
- the leaving group L 3 is typically a halogen atom.
- the reaction is conveniently effected at ambient temperature in a suitable solvent, e.g. a dipolar aprotic solvent such as N,N-dimethylformamide, or a chlorinated solvent such as dichloromethane, typically in the presence of a base.
- a suitable solvent e.g. a dipolar aprotic solvent such as N,N-dimethylformamide, or a chlorinated solvent such as dichloromethane
- a suitable base for use in the reaction may be an organic base such as triethylamine, or an inorganic base such as caesium carbonate.
- Steps (i) and (ii) of the above process are conveniently effected at ambient temperature in a suitable solvent, e.g. a C 1-4 alkanol such as methanol.
- Step (i) is typically performed in the presence of a base, e.g. an organic base such as triethylamine.
- the reducing agent for use in step (ii) may suitably be an alkali metal borohydride such as sodium borohydride.
- the compounds of formula (IA) or (IB) above wherein Y represents a linker group of formula (Ya) as defined above may be prepared by a process which comprises reacting a compound of formula (IVA-1), (IVA-2), (IVA-3), (IVA-4), (IVA-5), (IVB-1), (IVB-2), (IVB-3), (IVB-4) or (IVB-5) as defined above with a compound of formula (V):
- the leaving group L 4 is typically a C 1-4 alkoxy group, e.g. ethoxy.
- reaction is conveniently effected at ambient temperature in a suitable solvent, e.g. a lower alkanol such as ethanol, typically in the presence of a base, e.g. an organic base such as triethylamine.
- a suitable solvent e.g. a lower alkanol such as ethanol
- a base e.g. an organic base such as triethylamine.
- the intermediates of formula (IVA-1), (IVA-2), (IVA-3), (IVA-4), (IVA-5), (IVB-1), (IVB-2), (IVB-3), (IVB-4) or (IVB-5) above may be prepared by reacting a compound of formula (IIIA) or (IIIB) as defined above with a compound of formula (VIA), (VIB), (VIC), (VID) or (VIE):
- V, W, A 1 and A 2 are as defined above, and R P represents hydrogen or an N-protecting group; followed, as necessary, by removal of the N-protecting group R P .
- the N-protecting group R P is typically tert-butoxycarbonyl (BOC).
- the N-protecting group R P is typically benzyl.
- reaction between compound (IIIA) or (IIIB) and compound (VIA), (VIB), (VIC), (VID) or (VIE) is conveniently accomplished under conditions analogous to those described above for the reaction between the compound of formula Q-H and compound (IIIA) or (IIIB).
- N-protecting group R P is BOC
- subsequent removal of the BOC group may typically be accomplished by treatment with an acid, e.g. a mineral acid such as hydrochloric acid or sulphuric acid, or an organic acid such as trifluoroacetic acid.
- the BOC group may be removed by treatment with trimethylsilyl trifluoromethanesulfonate and 2,6—lutidine, typically at ambient temperature in a suitable solvent, e.g. a chlorinated solvent such as dichloromethane.
- the BOC group may be removed by treatment with trimethylsilyl iodide, typically at ambient temperature in a suitable solvent, e.g. a chlorinated solvent such as chloroform.
- N-protecting group R P is benzyl
- subsequent removal of the benzyl group may typically be accomplished by catalytic hydrogenation.
- transfer hydrogenation conditions will be employed.
- a suitable hydrogenation catalyst of use in this procedure may be a transition metal catalyst such as palladium on carbon. The reaction will conveniently be performed at an elevated temperature in the presence of a hydrogen donor such as ammonium formate.
- a suitable chlorinating agent for use in the above procedure is phosphorus oxychloride.
- the reaction is conveniently effected by mixing the reagents at an elevated temperature, typically in the presence of a base, e.g. an organic amine such as N,N-diisopropylethylamine or N,N-dimethylaniline.
- a base e.g. an organic amine such as N,N-diisopropylethylamine or N,N-dimethylaniline.
- the intermediates of formula (IVA-1), (IVA-2), (IVA-3), (IVA-4), (IVA-5), (IVB-1), (IVB-2), (IVB-3), (IVB-4) and (IVB-5) correspond to compounds in accordance with the present invention wherein Y represents a covalent bond and Z is hydrogen.
- the intermediates of formula (VIA), (VIB), (VIC), (VID) or (VIIE) wherein R P is hydrogen correspond to intermediates of formula Q-H wherein Y represents a covalent bond and Z is hydrogen.
- the intermediates of formula (VIA), (VIB), (VIC), (VID) or (VIE) wherein R P is BOC correspond to intermediates of formula Q-H wherein Y represents —C(O)O— and Z is tert-butyl.
- the intermediates of formula (VIA), (VIB), (VIC), (VID) or (VIE) wherein R P is benzyl correspond to intermediates of formula Q-H wherein Y represents a covalent bond and Z is benzyl.
- the intermediates of formula (VIIA) and (VIIB) correspond to intermediates of formula (IIIA) or (IIIB) wherein L 1 is hydroxy.
- the starting materials of formula (V), (VIA), (VIB), (VIC), (VID), (VIE), (VIIA) and (VIIB) may be prepared by methods analogous to those described in the accompanying Examples, or by standard methods well known from the art.
- any compound of formula (IA) or (IB) initially obtained from any of the above processes may, where appropriate, subsequently be elaborated into a further compound of formula (IA) or (IB) by techniques known from the art.
- a compound comprising a N—BOC moiety may be converted into the corresponding compound comprising a N—H moiety by treatment with an acid, e.g. a mineral acid such as hydrochloric acid, or an organic acid such as trifluoroacetic acid.
- a compound wherein R 1 represents halogen, e.g. chloro may be converted into the corresponding compound wherein R 1 represents amino (—NH 2 ) in a two-step procedure which comprises: (i) treatment with benzylamine or 4-methoxybenzylamine; and (ii) removal of the benzyl or 4-methoxybenzyl moiety from the material thereby obtained by catalytic hydrogenation or by treatment with an acid, e.g. a mineral acid such as sulfuric acid, or an organic acid such as trifluoroacetic acid.
- an acid e.g. a mineral acid such as sulfuric acid, or an organic acid such as trifluoroacetic acid.
- a compound wherein R 1 represents —SR a may be converted into the corresponding compound wherein R 1 represents —SO 2 R a by treatment with an oxidising agent, typically 3-chloroperoxybenzoic acid (MCPBA).
- an oxidising agent typically 3-chloroperoxybenzoic acid (MCPBA).
- a compound wherein R 1 represents —SO 2 R a , e.g. methylsulfonyl, may be converted into the corresponding compound wherein R 1 represents —OR a by treatment with a sodium salt of formula NaOR a .
- a compound wherein R 1 represents —SO 2 R a , e.g. methylsulfonyl may be converted into the corresponding compound wherein R 1 represents cyano by treatment with a cyanide salt, e.g. an alkali metal cyanide salt such as sodium cyanide.
- a compound wherein R 1 represents —SO 2 R a e.g.
- methylsulfonyl may be converted into the corresponding compound wherein R 1 represents —NR b R c by treatment with an amine of formula H—NR b R c .
- a compound wherein R 1 represents —SO 2 R a e.g. methylsulfonyl, may be converted into the corresponding compound wherein R 1 represents —NH 2 by treatment with ammonium hydroxide.
- a compound wherein R 2 represents —CO 2 R d , in which R d is other than hydrogen, may be converted into the corresponding compound wherein R 2 represents carboxy (—CO 2 H) by treatment with a base, typically an alkali metal hydroxide such as sodium hydroxide.
- a base typically an alkali metal hydroxide such as sodium hydroxide.
- a compound wherein R 2 represents carboxy (—CO 2 H) may be converted into the corresponding compound wherein R 2 represents —CONR b R c or —CON(OR a )R b by treatment with the appropriate reagent of formula H—NR b R c or H—N(OR a )R b respectively.
- the reaction may typically be performed in the presence of a coupling agent such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) and an additive such as 1-hydroxybenzotriazole hydrate (HOBT), optionally in the presence of a base, e.g. an organic base such as N,N-diisopropylethylamine.
- a coupling agent such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) and an additive such as 1-hydroxybenzotriazole hydrate (HOBT)
- EDC 1-
- reaction may be performed in the presence of a coupling agent such as O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU) and a base, e.g. an organic base such as N,N-diisopropylethylamine.
- a coupling agent such as O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU)
- TBTU O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate
- base e.g. an organic base such as N,N-diisopropylethylamine.
- a compound wherein R 2 represents carboxy (—CO 2 H) may be converted into the corresponding compound wherein R 2 represents —CONH 2 by treatment with ammonium chloride, typically in the presence of a coupling agent such as EDC and an additive such as HOBT, suitably in the presence of a base, e.g. an organic base such as diisopropylamine or N,N-diisopropylethylamine.
- a coupling agent such as EDC and an additive such as HOBT
- a base e.g. an organic base such as diisopropylamine or N,N-diisopropylethylamine.
- R 2 represents —CONH 2 may be converted into the corresponding compound wherein R 2 represents cyano (—CN) by treatment with phosphorus oxychloride.
- a compound wherein R 2 represents —CONH 2 may be converted into the corresponding compound wherein R 2 represents cyano in a two-step procedure which comprises: (i) treatment with cyanuric chloride; and (ii) treatment of the material thereby obtained with water.
- a compound wherein R 2 represents carboxy (—CO 2 H) may be converted into the corresponding compound wherein R 2 represents hydrogen by heating in the presence of a base, e.g. an organic amine such as triethylamine.
- a base e.g. an organic amine such as triethylamine.
- a compound wherein R 2 represents carboxy (—CO 2 H) may be converted into the corresponding compound wherein R 2 represents hydroxymethyl (—CH 2 OH) in a two-step procedure which comprises: (i) treatment with ethyl chloroformate and triethylamine; and (ii) treatment of the material thereby obtained with a reducing agent, typically an alkali metal borohydride such as sodium borohydride.
- a reducing agent typically an alkali metal borohydride such as sodium borohydride.
- a compound wherein R 2 represents carboxy (—CO 2 H) may be converted into the corresponding compound wherein R 2 represents hydroxy in a two-step procedure which comprises: (i) treatment with diphenyl phosphoryl azide; and (ii) treatment of the material thereby obtained with water.
- a compound wherein R 2 represents carboxy (—CO 2 H) may be converted into the corresponding compound wherein R 2 represents —NHCO 2 R d , wherein R d is other than hydrogen, in a two-step procedure which comprises: (i) treatment with diphenyl phosphoryl azide; and (ii) treatment of the material thereby obtained with the appropriate reagent of formula R d —OH.
- a compound wherein R 2 represents carboxy (—CO 2 H) may be converted into the corresponding compound wherein R 2 represents a 3-substituted 1,2,4—oxadiazol-5—yl moiety in a two-step procedure which comprises: (i) treatment with an appropriately-substituted N′—hydroxyamidine derivative, typically in the presence of a coupling agent such as O-(7—azabenzotriazol-1—yl)-N,N,N′, N′-tetramethyluronium hexafluorophosphate (HATU), suitably in the presence of a base, e.g.
- a coupling agent such as O-(7—azabenzotriazol-1—yl)-N,N,N′, N′-tetramethyluronium hexafluorophosphate (HATU), suitably in the presence of a base, e.g.
- an organic base such as N,N-diisopropyl-ethylamine
- a strong base suitably a strong inorganic base, e.g. an alkali metal tert-butoxide such as potassium tert-butoxide.
- a compound wherein R 2 represents 4,5-dihydrooxazol-2-yl may be prepared from the corresponding compound wherein R 2 represents —CONR b R c , in which R b represents —CH 2 CH 2 OH and R c represents hydrogen, by heating with a condensing agent such as N,N′-diisopropylcarbodiimide, typically in the presence of copper(II) trifluoromethane-sulfonate.
- a condensing agent such as N,N′-diisopropylcarbodiimide
- a compound wherein R 4 represents hydrogen may be converted into the corresponding compound wherein R 4 represents C 1-6 alkyl, e.g. methyl, by treatment with a C 1-6 alkyl halide, e.g. iodomethane, usually in the presence of a base, suitably an inorganic base, e.g. potassium carbonate.
- a C 1-6 alkyl halide e.g. iodomethane
- a base suitably an inorganic base, e.g. potassium carbonate.
- the desired product can be separated therefrom at an appropriate stage by conventional methods such as preparative HPLC; or column chromatography utilising, for example, silica and/or alumina in conjunction with an appropriate solvent system.
- the diastereomers may then be separated by any convenient means, for example by crystallisation, and the desired enantiomer recovered, e.g. by treatment with an acid in the instance where the diastereomer is a salt.
- a racemate of formula (IA) or (IB) may be separated using chiral HPLC.
- a particular enantiomer may be obtained by using an appropriate chiral intermediate in one of the processes described above.
- a particular enantiomer may be obtained by performing an enantiomer-specific enzymatic biotransformation, e.g.
- any of the above synthetic sequences it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry , ed. J. F. W. McOmie, Plenum Press, 1973; and T. W. Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 3 rd edition, 1999.
- the protecting groups may be removed at any convenient subsequent stage utilising methods known from the art.
- the compounds in accordance with this invention potently inhibit the activity of human PI4KIII ⁇ .
- Compounds were assayed using a PI4Kbeta Adapta assay. Compounds were screened in 1% DMSO (final) as 3-fold serial dilutions from a starting concentration of 10 ⁇ M.
- the 2 ⁇ PI4KB (PI4K beta)/PI Lipid Kinase Substrate mixture was prepared in 50 mM HEPES pH 7.5, 0.1% CHAPS, 1 mM EGTA, 4 mM MgCl 2 .
- the final 10 ⁇ L Kinase Reaction consisted of 7.5-60 ng PI4K ⁇ , and 100 ⁇ M PI Lipid Kinase Substrate in 32.5 mM HEPES pH 7.5, 0.05% CHAPS, 0.5 mM EGTA, 2 mM MgCl 2 .
- the final ATP concentration in the assay was 10 ⁇ M.
- the detection mix consisted of EDTA (30 mM), Eu-anti-ADP antibody (6 nM) and ADP tracer. The detection mix contained the EC60 concentration of tracer for 5-150 ⁇ M ATP.
- ATP was added to compound, followed by addition of a PI4K ⁇ /PI Lipid Kinase Substrate mixture.
- the plate was shaken for 30 seconds to mix, then briefly centrifuged.
- the reaction mixture was incubated for 60 minutes at room temperature.
- the detection mix was added, then the plate was shaken and centrifuged.
- the plate was incubated for 60 minutes at room temperature and read on a fluorescence plate reader.
- the data was fitted with XLfit from IDBS using model number 205.
- Certain compounds in accordance with this invention are potent inhibitors when measured in the MLR test described below.
- PBMCs Human peripheral blood mononuclear cells
- Responder cells (0.12 ⁇ 106), Stimulator cells (0.045 ⁇ 106) and compounds (in different concentrations) were cocultured for 6 days in RPMI 1640 medium (BioWhittaker, Lonza, Belgium) supplemented with 10% fetal calf serum, 100 U/ml Geneticin (Gibco, LifeTechnologies, UK). Cells were cultured in triplicate in flat-bottomed 96-well microtiter tissue culture plates (TTP, Switzerland). After 5 days, cells were pulsed with 1 ⁇ Ci of methyl- 3 H thymidine (MP Biomedicals, USA), harvested 18 h later on glass filter paper and counted.
- Proliferation values were expressed as counts per minute (cpm), and converted to % inhibition with respect to a blank MLR test (identical but without added compound).
- the IC 50 was determined from a graph with at least four points, each derived from the mean of 2 experiments. The IC 50 value represents the lowest concentration of test compound (expressed in ⁇ M) that resulted in a 50% inhibition of the MLR.
- Tin(II) chloride dihydrate (7.42 g, 32.9 mmol) was added to a solution of Intermediate 12 (1.31 g, 6.58 mmol) in EtOH (50 mL). The reaction was heated at 50° C. with stirring for 3.5 h, then cooled to room temperature and concentrated in vacuo. The residue was diluted with DCM and treated with 2M aqueous NaOH solution. A viscous thick precipitate formed. The mixture was filtered through celite, and the two layers were separated. The aqueous layer was extracted with DCM (twice). The combined organic layers were passed through a phase separator cartridge, then evaporated.
- Example 1 To a solution of Example 1 (160 mg, 0.36 mmol) in absolute EtOH (10 mL) was added sodium hydride (60% in mineral oil, 15 mg, 0.36 mmol) under nitrogen. The reaction mixture was stirred at r.t. for 18 h under nitrogen, then partitioned between DCM and water and separated. The aqueous layer was extracted with DCM (twice). The combined organic phases were dried with anhydrous MgSO 4 , concentrated, and purified by silica gel chromatography (DCM:MeOH 10:1), to provide the title compound (85 mg, 52%) as a yellow solid.
- DCM:MeOH 10:1 silica gel chromatography
- the reaction mixture was stirred for 24 h at r.t., after which time the mixture was evaporated in vacuo, then extracted using DCM and brine.
- the crude residue was purified using silica gel chromatography (EtOAc:cyclohexane 4:1).
- the resulting isolated solids (124 mg, 0.33 mmol) were dissolved in DCM (4 mL) and MCPBA (165 mg, 0.67 mmol) was added at 0° C.
- the reaction mixture was stirred at r.t. for 2 h, whereupon 2N aqueous Na 2 SO 3 solution (3 mL) was added.
- the mixture was extracted using EtOAc and 2N aqueous NaOH solution, then brine.
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Abstract
Description
- The present invention relates to a family of fused bicyclic heteroaromatic derivatives, and to their use in therapy. The compounds provided by the present invention are selective inhibitors of phosphatidylinositol-4-kinase IIIβ (PI4KIIIβ) activity, and are accordingly of benefit as pharmaceutical agents, especially in the treatment of adverse inflammatory, autoimmune and oncological disorders, in the treatment of viral diseases and malaria, and in the management of organ and cell transplant rejection.
- In addition, the compounds in accordance with the present invention may be beneficial as pharmacological standards for use in the development of new biological tests and in the search for new pharmacological agents. Thus, the compounds of this invention may be useful as radioligands in assays for detecting pharmacologically active compounds.
- WO 2013/034738 discloses that inhibitors of PI4KIIIβ activity are useful as medicaments for the treatment of autoimmune and inflammatory disorders, and organ and cell transplant rejection.
- WO 2010/103130 describes a family of oxazolo[5,4-d]pyrimidine, thiazolo[5,4-d]-pyrimidine, thieno[2,3-d]pyrimidine and purine derivatives that are active in a range of assays, including the Mixed Lymphocyte Reaction (MLR) test, and are stated to be effective for the treatment of immune and autoimmune disorders, and organ and cell transplant rejection. WO 2011/147753 discloses the same family of compounds as having significant antiviral activity. Furthermore, WO 2012/035423 discloses the same family of compounds as having significant anticancer activity.
- WO 2013/024291, WO 2013/068458, WO 2014/053581, and copending international patent application PCT/EP2013/077846 (published on 26 Jun. 2014 as WO 2014/096423) describe various series of fused pyrimidine derivatives that are stated to be of benefit as pharmaceutical agents, especially in the treatment of adverse inflammatory, autoimmune and oncological disorders, in the treatment of viral diseases, and in the management of organ and cell transplant rejection.
- Inhibitors of PI4KIIIβ have been identified as molecules with an ideal activity profile for the prevention, treatment and elimination of malaria (cf. C. W. McNamara et al., Nature, 2013, 504, 248-253).
- None of the prior art available to date, however, discloses or suggests the precise structural class of fused bicyclic heteroaromatic derivatives as provided by the present invention as having activity as PI4KIIIβ inhibitors.
- The compounds of the present invention are potent and selective inhibitors of PI4KIIIβ activity, inhibiting the kinase affinity of human PI4KIIIβ (IC50) at concentrations of 50 μM or less, generally of 20 μM or less, usually of 5 μM or less, typically of 1 μM or less, suitably of 500 nM or less, ideally of 100 nM or less, and preferably of 20 nM or less (the skilled person will appreciate that a lower IC50 figure denotes a more active compound). The compounds of the invention may possess at least a 10-fold selective affinity, typically at least a 20-fold selective affinity, suitably at least a 50-fold selective affinity, and ideally at least a 100-fold selective affinity, for human PI4KIIIβ relative to other human kinases.
- Certain compounds in accordance with the present invention are active as inhibitors when subjected to the Mixed Lymphocyte Reaction (MLR) test. The MLR test is predictive of immunosuppression or immunomodulation. Thus, when subjected to the MLR test, certain compounds of the present invention display an IC50 value of 10 μM or less, generally of 5 μM or less, usually of 2 μM or less, typically of 1 μM or less, suitably of 500 nM or less, ideally of 100 nM or less, and preferably of 20 nM or less (again, the skilled person will appreciate that a lower IC50 figure denotes a more active compound).
- The compounds of the invention possess notable advantages in terms of their high potency, demonstrable efficacy at lower doses, and valuable pharmacokinetic and pharmacodynamic properties (including clearance and bioavailability).
- The present invention provides a compound of formula (IA) or (IB) or an N-oxide thereof, or a pharmaceutically acceptable salt or solvate thereof:
- wherein
-
- X represents N or CH;
- T represents N or C—R2;
- U represents oxygen, sulphur or N—R4;
- Q represents a group of formula (Qa), (Qb), (Qc), (Qd) or (Qe):
- in which the asterisk (*) represents the point of attachment to the remainder of the molecule;
-
- V represents —CH2—, —C(CH3)2—, —CH2CH2— or —CH2CH2CH2—;
- W represents the residue of a C3-7 cycloalkyl group;
- Y represents a covalent bond, or a linker group selected from —C(O)—, —S(O)—, —S(O)2—, —C(O)O—, —C(O)N(R5)—, —C(O)C(O)— and —S(O)2N(R5)—, or a linker group of formula (Ya):
- in which the asterisk (*) represents the point of attachment to the remainder of the molecule;
- Z represents hydrogen; or Z represents C1-6 alkyl, C2-6 alkenyl, C3-7 cycloalkyl, C3-7 cycloalkyl(C16)alkyl, C3-7 heterocycloalkyl, C3-7 heterocycloalkyl(C1-6)alkyl, aryl, aryl(C1-6)alkyl, heteroaryl or heteroaryl(C1-6)alkyl, any of which groups may be optionally substituted by one or more substituents;
- A1 represents hydrogen, cyano or trifluoromethyl; or A1 represents C1-6 alkyl, optionally substituted by one or more substituents independently selected from fluoro, —ORa, trifluoromethoxy, —NRbRc, —CO2Rd and —CONRbRc; or A1 represents C3-7 cycloalkyl;
- A2 represents hydrogen or C1-6 alkyl;
- R1 and R2 independently represent hydrogen, halogen, cyano, nitro, hydroxy, trifluoromethyl, trifluoromethoxy, —ORa, —SRa, —SORa, —SO2Ra, —NRbRc, —CH2NRbRc, —NRcCORd, —CH2NRcCORd, —NRcCO2Rd, —NHCONRbRc, —NRcSO2Rc, —N(SO2Rc)2, —NHSO2NRbRc, —CORd, —CO2Rd, —CONRbRc, —CON(ORa)Rb or —SO2NRbRc; or C1-6 alkyl, C3-7 cycloalkyl, C3-7 cycloalkyl(C1-6)alkyl, aryl, aryl(C1-6)alkyl, C3-7 heterocycloalkyl, C3-7 heterocycloalkyl(C1-6)alkyl, C3-7 heterocycloalkenyl, heteroaryl or heteroaryl(C1-6)alkyl, any of which groups may be optionally substituted by one or more substituents;
- R3 represents hydrogen, halogen or C1-6 alkyl;
- R4 represents hydrogen; or R4 represents C1-6 alkyl, aryl, aryl(C1-6)alkyl, heteroaryl or heteroaryl(C1-6)alkyl, any of which groups may be optionally substituted by one or more substituents;
- R5 represents hydrogen; or R5 represents C1-6 alkyl, optionally substituted by one or more substituents independently selected from —ORa and —NRbRc;
- Ra represents hydrogen; or Ra represents C1-6 alkyl, aryl, aryl(C1-6)alkyl, heteroaryl or heteroaryl(C1-6)alkyl, any of which groups may be optionally substituted by one or more substituents;
- Rb and Rc independently represent hydrogen or trifluoromethyl; or C1-6 alkyl, C3-7 cycloalkyl, C3-7 cycloalkyl(C1-6)alkyl, aryl, aryl(C1-6)alkyl, C3-7 heterocycloalkyl, C3-7 heterocycloalkyl(C1-6)alkyl, heteroaryl or heteroaryl(C1-6)alkyl, any of which groups may be optionally substituted by one or more substituents; or
- Rb and Rc, when taken together with the nitrogen atom to which they are both attached, represent azetidin-1-yl, pyrrolidin-1-yl, oxazolidin-3-yl, isoxazolidin-2-yl, thiazolidin-3-yl, isothiazolidin-2-yl, piperidin-1-yl, morpholin-4-yl, thiomorpholin-4-yl, piperazin-1-yl, homopiperidin-1-yl, homomorpholin-4-yl or homopiperazin-1-yl, any of which groups may be optionally substituted by one or more substituents;
- Rd represents hydrogen; or C1-6 alkyl, C3-7 cycloalkyl, aryl, C3-7 heterocycloalkyl or heteroaryl, any of which groups may be optionally substituted by one or more substituents; and
- Re represents C1-6 alkyl, aryl or heteroaryl, any of which groups may be optionally substituted by one or more substituents.
- Where any of the groups in the compounds of formula (IA) or (IB) above is stated to be optionally substituted, this group may be unsubstituted, or substituted by one or more substituents. Typically, such groups will be unsubstituted, or substituted by one or two substituents.
- For use in medicine, the salts of the compounds of formula (IA) or (IB) will be pharmaceutically acceptable salts. Other salts may, however, be useful in the preparation of the compounds of the invention or of their pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds of this invention include acid addition salts which may, for example, be formed by mixing a solution of the compound of the invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulphuric acid, methanesulphonic acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid or phosphoric acid. Furthermore, where the compounds of the invention carry an acidic moiety, e.g. carboxy, suitable pharmaceutically acceptable salts thereof may include alkali metal salts, e.g. sodium or potassium salts; alkaline earth metal salts, e.g. calcium or magnesium salts; and salts formed with suitable organic ligands, e.g. quaternary ammonium salts.
- The present invention includes within its scope solvates of the compounds of formula (IA) or (IB) above. Such solvates may be formed with common organic solvents, e.g. hydrocarbon solvents such as benzene or toluene; chlorinated solvents such as chloroform or dichloromethane; alcoholic solvents such as methanol, ethanol or isopropanol; ethereal solvents such as diethyl ether or tetrahydrofuran; or ester solvents such as ethyl acetate. Alternatively, the solvates of the compounds of formula (IA) or (IB) may be formed with water, in which case they will be hydrates.
- Suitable alkyl groups which may be present on the compounds of the invention include straight-chained and branched C1-6 alkyl groups, for example C1-4 alkyl groups. Typical examples include methyl and ethyl groups, and straight-chained or branched propyl, butyl, pentyl and hexyl groups. Particular alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, 2,2-dimethylpropyl and 3-methylbutyl. Derived expressions such as “C1-6 alkoxy”, “C1-6 alkylthio”, “C1-6 alkylsulphonyl” and “C1-6 alkylamino” are to be construed accordingly.
- Suitable C2-6 alkenyl groups include vinyl, allyl and prop-1-en-2-yl.
- Suitable C3-7 cycloalkyl groups, which may comprise benzo-fused analogues thereof, include cyclopropyl, cyclobutyl, cyclopentyl, indanyl, cyclohexyl and cycloheptyl.
- Suitable aryl groups include phenyl and naphthyl, preferably phenyl.
- Suitable aryl(C1-6)alkyl groups include benzyl, phenylethyl, phenylpropyl and naphthylmethyl.
- Suitable heterocycloalkyl groups, which may comprise benzo-fused analogues thereof, include oxetanyl, azetidinyl, tetrahydrofuranyl, dihydrobenzofuranyl, pyrrolidinyl, indolinyl, thiazolidinyl, imidazolidinyl, tetrahydropyranyl, chromanyl, piperidinyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, piperazinyl, 1,2,3,4-tetrahydro-quinoxalinyl, homopiperazinyl, morpholinyl, benzoxazinyl and thiomorpholinyl.
- Examples of suitable heterocycloalkenyl groups include oxazolinyl.
- Suitable heteroaryl groups include furyl, benzofuryl, dibenzofuryl, thienyl, benzothienyl, dibenzothienyl, pyrrolyl, indolyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[3,2-c]pyridinyl, pyrazolyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[3,4-d]pyrimidinyl, indazolyl, oxazolyl, benzoxazolyl, isoxazolyl, thiazolyl, benzothiazolyl, isothiazolyl, imidazolyl, imidazo[2,1-b]thiazolyl, benzimidazolyl, imidazo[1,2-a]pyridinyl, imidazo[4,5-b]pyridinyl, purinyl, imidazo[1,2-a]pyrimidinyl, imidazo[1,2-a]pyrazinyl, oxadiazolyl, thiadiazolyl, benzothiadiazolyl, triazolyl, benzotriazolyl, tetrazolyl, pyridinyl, quinolinyl, isoquinolinyl, naphthyridinyl, pyridazinyl, cinnolinyl, phthalazinyl, pyrimidinyl, quinazolinyl, pyrazinyl, quinoxalinyl, pteridinyl, triazinyl and chromenyl groups.
- The term “halogen” as used herein is intended to include fluorine, chlorine, bromine and iodine atoms, typically fluorine, chlorine or bromine.
- Where the compounds of formula (IA) or (IB) have one or more asymmetric centres, they may accordingly exist as enantiomers. Where the compounds of the invention possess two or more asymmetric centres, they may additionally exist as diastereomers. The invention is to be understood to extend to all such enantiomers and diastereomers, and to mixtures thereof in any proportion, including racemates. Formula (IA) or (IB) and the formulae depicted hereinafter are intended to represent all individual stereoisomers and all possible mixtures thereof, unless stated or shown otherwise. In addition, compounds of formula (IA) or (IB) may exist as tautomers, for example keto (CH2C═O)⇄enol (CH═CHOH) tautomers or amide (NHC═O)⇄hydroxyimine (N═COH) tautomers. Formula (IA) or (IB) and the formulae depicted hereinafter are intended to represent all individual tautomers and all possible mixtures thereof, unless stated or shown otherwise.
- It is to be understood that each individual atom present in formula (IA) or (IB), or in the formulae depicted hereinafter, may in fact be present in the form of any of its naturally occurring isotopes, with the most abundant isotope(s) being preferred. Thus, by way of example, each individual hydrogen atom present in formula (IA) or (IB), or in the formulae depicted hereinafter, may be present as a 1H, 2H (deuterium) or 3H (tritium) atom, preferably 1H. Similarly, by way of example, each individual carbon atom present in formula (IA) or (IB), or in the formulae depicted hereinafter, may be present as a 12C, 13C or 14C atom, preferably 12C.
- In one embodiment, X represents N. In another embodiment, X represents CH.
- In one embodiment, T represents N. In another embodiment, T represents C—R2.
- In a first embodiment, U represents oxygen. In a second embodiment, U represents sulfur. In a third embodiment, U represents N—R4. In a first embodiment, T represents N and U represents oxygen or N—R4. In a first aspect of that embodiment, T represents N and U represents oxygen. In a second aspect of that embodiment, T represents N and U represents N—R4.
- In a second embodiment, T represents C—R2 and U represents sulfur or N—R4. In a first aspect of that embodiment, T represents C—R2 and U represents sulfur. In a second aspect of that embodiment, T represents C—R2 and U represents N—R4.
- Selected sub-classes of compounds in accordance with the present invention include the compounds of formula (IA-1), (IA-2), (IB-1), (IB-2) and (IB-3):
- wherein X, Q, R1, R2, R3 and R4 are as defined above.
- Particular sub-classes of compounds in accordance with the present invention include the compounds of formula (IA-1), (IA-2), (IB-1) and (IB-2) as defined above.
- In a first embodiment, the invention provides a compound of formula (IA-1) as defined above.
- In a second embodiment, the invention provides a compound of formula (IA-2) as defined above.
- In a third embodiment, the invention provides a compound of formula (IB-1) as defined above.
- In a fourth embodiment, the invention provides a compound of formula (IB-2) as defined above.
- In a fifth embodiment, the invention provides a compound of formula (IB-3) as defined above.
- In a particular embodiment, Q represents a group of formula (Qa) as defined above. In a second embodiment, Q represents a group of formula (Qb) as defined above. In a third embodiment, Q represents a group of formula (Qc) as defined above. In a fourth embodiment, Q represents a group of formula (Qd) as defined above. In a fifth embodiment, Q represents a group of formula (Qe) as defined above.
- Where Q represents a group of formula (Qa) as defined above, this may be a group of formula (Qa-1), (Qa-2), (Qa-3), (Qa-4), (Qa-5) or (Qa-6):
- in which the asterisk (*) represents the point of attachment to the remainder of the molecule; and
- Y, Z, A1 and A2 are as defined above.
- In a first embodiment, Q represents a group of formula (Qa-1) as defined above.
- In a second embodiment, Q represents a group of formula (Qa-2) as defined above.
- In a third embodiment, Q represents a group of formula (Qa-3) as defined above.
- In a fourth embodiment, Q represents a group of formula (Qa-4) as defined above.
- In a fifth embodiment, Q represents a group of formula (Qa-5) as defined above.
- In a sixth embodiment, Q represents a group of formula (Qa-6) as defined above.
- In one embodiment, V represents —CH2— or —C(CH3)2—. In a first aspect of that embodiment, V represents —CH2—. In a second aspect of that embodiment, V represents —C(CH3)2—. Where Q represents a group of formula (Qb) and V represents —CH2— or —C(CH3)2—, the bicyclic moiety containing the integer V is a 2,5-diazabicyclo[2.2.1]-heptane ring system. Where Q represents a group of formula (Qc) or (Qd) and V represents —CH2— or —C(CH3)2—, the bicyclic moiety containing the integer V is a 3,6-diazabicyclo[3.1.1]heptane ring system.
- In another embodiment, V represents —CH2CH2—. Where Q represents a group of formula (Qb) and V represents —CH2CH2—, the bicyclic moiety containing the integer V is a 2,5-diazabicyclo[2.2.2]octane ring system. Where Q represents a group of formula (Qc) or (Qd) and V represents —CH2CH2—, the bicyclic moiety containing the integer V is a 3,8-diazabicyclo[3.2.1]octane ring system.
- In a further embodiment, V represents —CH2CH2CH2—. Where Q represents a group of formula (Qb) and V represents —CH2CH2CH2—, the bicyclic moiety containing the integer V is a 6,8-diazabicyclo[3.2.2]nonane ring system. Where Q represents a group of formula (Qc) or (Qd) and V represents —CH2CH2CH2—, the bicyclic moiety containing the integer V is a 7,9-diazabicyclo[3.3.1]nonane ring system.
- Where Q represents a group of formula (Qe), the C3-7 cycloalkyl group of which W is the residue is spiro-fused to the adjacent six-membered ring containing two nitrogen atoms. The cyclic group of which W is the residue is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Suitably, the cyclic group of which W is the residue is a C4-6 cycloalkyl group. In a particular embodiment, the cyclic group of which W is the residue is cyclobutyl.
- Generally, Y represents a covalent bond, or a linker group selected from —C(O)—, —S(O)—, —S(O)2—, —C(O)O—, —C(O)N(R5)— and —S(O)2N(R5)—, or a linker group of formula (Ya) as defined above.
- Typically, Y represents a covalent bond, or a linker group selected from —C(O)—, —C(O)O— and —C(O)N(R5)—, or a linker group of formula (Ya) as defined above.
- Suitably, Y represents a covalent bond, or a linker group selected from —C(O)— and —C(O)N(R5)—.
- Appositely, Y represents a covalent bond, or a linker group selected from —C(O)—, —S(O)—, —S(O)2—, —C(O)O—, —C(O)N(R5)— and —S(O)2N(R5)—.
- Suitable values of Y include —C(O)—, —S(O)—, —S(O)2—, —C(O)O—, —C(O)N(R5)— and —S(O)2N(R5)—.
- Typical values of Y include —C(O)—, —C(O)N(R5)— and —C(O)C(O)—.
- Selected values of Y include —C(O)— and —C(O)N(R5)—.
- In a first embodiment, Y represents a covalent bond. In a second embodiment, Y represents —C(O)—. In a third embodiment, Y represents —S(O)—. In a fourth embodiment, Y represents —S(O)2—. In a fifth embodiment, Y represents —C(O)O—. In a sixth embodiment, Y represents —C(O)N(R5)—. In a seventh embodiment, Y represents —C(O)C(O)—. In an eighth embodiment, Y represents —S(O)2N(R5)—. In a ninth embodiment, Y represents a group of formula (Ya) as defined above.
- Generally, Z represents hydrogen; or Z represents C1-6 alkyl, C3-7 cycloalkyl, C3-7 cycloalkyl(C1-6)alkyl, C3-7 heterocycloalkyl, C3-7 heterocycloalkyl(C1-6)alkyl, aryl, aryl(C1-6)alkyl, heteroaryl or heteroaryl(C1-6)alkyl, any of which groups may be optionally substituted by one or more substituents.
- Appositely, Z represents C1-6 alkyl, C2-6 alkenyl, C3-7 cycloalkyl, C3-7 cycloalkyl(C1-6)alkyl, C3-7 heterocycloalkyl, C3-7 heterocycloalkyl(C1-6)alkyl, aryl, aryl(C1-6)alkyl, heteroaryl or heteroaryl(C1-6)alkyl, any of which groups may be optionally substituted by one or more substituents.
- Typically, Z represents C1-6 alkyl, C3-7 cycloalkyl, C3-7 cycloalkyl(C1-6)alkyl, C3-7 heterocycloalkyl, C3-7 heterocycloalkyl(C1-6)alkyl, aryl, aryl(C1-6)alkyl, heteroaryl or heteroaryl(C1-6)alkyl, any of which groups may be optionally substituted by one or more substituents.
- More typically, Z represents C3-7 cycloalkyl, C3-7 heterocycloalkyl, aryl or heteroaryl, any of which groups may be optionally substituted by one or more substituents.
- Suitably, Z represents aryl or heteroaryl, either of which groups may be optionally substituted by one or more substituents.
- In a first embodiment, Z represents hydrogen. In a second embodiment, Z represents optionally substituted C1-6 alkyl. In a third embodiment, Z represents optionally substituted C2-6 alkenyl. In a fourth embodiment, Z represents optionally substituted C3-7 cycloalkyl. In a fifth embodiment, Z represents optionally substituted C3-7 cycloalkyl(C1-6)alkyl. In a sixth embodiment, Z represents optionally substituted C3-7 heterocycloalkyl. In a seventh embodiment, Z represents optionally substituted C3-7 heterocycloalkyl(C1-6)alkyl. In an eighth embodiment, Z represents optionally substituted aryl. In a ninth embodiment, Z represents optionally substituted aryl(C1-6)alkyl. In a tenth embodiment, Z represents optionally substituted heteroaryl. In an eleventh embodiment, Z represents optionally substituted heteroaryl(C1-6)alkyl.
- In a particular embodiment, Z is other than hydrogen.
- Typical values of Z include methyl, ethyl, isopropenyl, cyclopropyl, indanyl, cyclopropylmethyl, cyclopentylethyl, dihydrobenzofuranyl, pyrrolidinyl, indolinyl, dihydrobenzofuranylmethyl, morpholinylmethyl, morpholinylethyl, phenyl, benzyl, phenylethyl, furyl, benzofuryl, thienyl, indolyl, pyrazolyl, indazolyl, isoxazolyl, thiazolyl, benzothiazolyl, imidazolyl, benzimidazolyl, imidazo[1,2-c]pyridinyl, benzothiadiazolyl, pyridinyl, quinolinyl, isoquinolinyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinoxalinyl, indolylmethyl, thiazolylmethyl, imidazo[2,1-b]thiazolylmethyl, pyridinylmethyl, furylethyl, benzimidazolylethyl and pyridinylethyl, any of which groups may be optionally substituted by one or more substituents.
- Illustrative values of Z include phenyl, pyridinyl and pyrazinyl, any of which groups may be optionally substituted by one or more substituents.
- Suitable values of Z include phenyl and pyridinyl, either of which groups may be optionally substituted by one or more substituents.
- In one embodiment, Z is unsubstituted. In another embodiment, Z is substituted by one or more substituents, typically by one, two or three substituents, suitably by one or two substituents. In one aspect of that embodiment, Z is monosubstituted. In another aspect of that embodiment, Z is disubstituted. In a further aspect of that embodiment, Z is trisubstituted.
- Typical examples of optional substituents on Z include one or more substituents independently selected from halogen, cyano, nitro, C1-6 alkyl, trifluoromethyl, cyano-(C1-6)alkyl, (C3-7)heterocycloalkyl, halo(C3-7)heterocycloalkyl, (C1-6)alkyl(C3-7)hetero-cycloalkyl, (C2-6)alkoxycarbonyl(C3-7)heterocycloalkyl, dihalo(C3-7)heterocycloalkyl, (C3-7)heterocycloalkyl(C1-6)alkyl, (C1-6)alkyl(C3-7)heterocycloalkyl(C1-6)alkyl, heteroaryl, hydroxy, oxo, C1-6 alkoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy (C3-7)heterocycloalkoxy, (C2-6)alkoxycarbonyl(C3-7)heterocycloalkoxy, (C3-7)heterocycloalkyl(C1-6)alkoxy, aryloxy, haloaryloxy, (C1-6)alkoxyaryloxy, C1-3 alkylenedioxy, dihalo(C1-3)alkylenedioxy, arylcarbonyloxy, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, amino, C1-6 alkylamino, di(C1-6)alkylamino, di(C1-6)-alkylamino(C1-6)alkyl, arylamino, C2-6 alkylcarbonylamino, C2-6 alkoxycarbonylamino, C1-6 alkylsulfonylamino, formyl, C2-6 alkylcarbonyl, C3-6 cycloalkylcarbonyl, C3-6 heterocycloalkylcarbonyl, carboxy, C2-6 alkoxycarbonyl, aryloxycarbonyl, amino-carbonyl, C1-6 alkylaminocarbonyl, di(C1-6)alkylaminocarbonyl, aminosulfonyl, C1-6 alkylaminosulfonyl and di(C1-6)alkylaminosulfonyl.
- Selected examples of optional substituents on Z include one or more substituents independently selected from C1-6 alkyl, trifluoromethyl, (C3-7)heterocycloalkyl, dihalo(C3-7)heterocycloalkyl, C1-6 alkoxy, trifluoromethoxy and di(C1-6)alkylamino.
- Suitable examples of optional substituents on Z include one or more substituents independently selected from C1-6 alkyl, dihalo(C3-7)heterocycloalkyl, C1-6 alkoxy, trifluoromethoxy and di(C1-6)alkylamino.
- Typical examples of specific substituents on Z include fluoro, chloro, bromo, cyano, nitro, methyl, ethyl, isopropyl, tert-butyl, trifluoromethyl, cyanomethyl, azetidinyl, pyrrolidinyl, piperazinyl, morpholinyl, fluoroazetidinyl, fluoropyrrolidinyl, methyl-piperazinyl, tert-butoxycarbonylpiperazinyl, difluoroazetidinyl, difluoropyrrolidinyl, difluoropiperidinyl, pyrrolidinylmethyl, pip eridinylmethyl, morpholinylmethyl, methyl-piperazinylmethyl, pyrazolyl, imidazolyl, hydroxy, oxo, methoxy, ethoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, oxetanyloxy, azetidinyloxy, tetrahydrofuranyloxy, pyrrolidinyloxy, tert-butoxycarbonylazetidinyloxy, tert-butoxy-carbonylpyrrolidinyloxy, tetrahydrofuranylmethoxy, morpholinylethoxy, phenoxy, chlorophenoxy, methoxyphenoxy, methylenedioxy, ethylenedioxy, difluoromethylene-dioxy, benzoyloxy, methylthio, methylsulfinyl, methylsulfonyl, amino, methylamino, tert-butylamino, dimethylamino, dimethylaminomethyl, phenylamino, acetylamino, methoxycarbonylamino, methylsulfonylamino, formyl, acetyl, cyclopropylcarbonyl, azetidinylcarbonyl, pyrrolidinylcarbonyl, piperidinylcarbonyl, piperazinylcarbonyl, morpholinylcarbonyl, carboxy, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, aminosulfonyl, methylaminosulfonyl and dimethylaminosulfonyl.
- Selected examples of specific substituents on Z include methyl, trifluoromethyl, azetidinyl, difluoroazetidinyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy and dimethylamino.
- Suitable examples of specific substituents on Z include methyl, difluoroazetidinyl, methoxy, ethoxy, trifluoromethoxy and dimethylamino.
- Selected values of Z include phenoxymethyl, chlorophenoxymethyl, methoxyphenoxymethyl, tert-butoxycarbonylmethyl, benzyloxycarbonylmethyl, phenoxyethyl, isopropenyl, cyclopropyl, indanyl, cyclopropylmethyl, cyclopentylethyl, (methyl)(oxo)pyrrolidinyl, dihydrobenzofuranyl, methylindolinyl, dihydrobenzofuranyl-methyl, morpholinylmethyl, morpholinylethyl, phenyl, nitrophenyl, methylphenyl, ethylphenyl, cyanomethylphenyl, morpholinylphenyl, pyrazolylphenyl, imidazolylphenyl, methoxyphenyl, difluoromethoxyphenyl, trifluoromethoxyphenyl, morpholinylethoxy-phenyl, ethylenedioxyphenyl, difluoromethylenedioxyphenyl, benzoyloxyphenyl, dimethylaminophenyl, acetylaminophenyl, aminocarbonylphenyl, (chloro)(methyl)-phenyl, dimethylphenyl, (methyl)(trifluoromethyl)phenyl, bis(trifluoromethyl)phenyl, (fluoropyrrolidinyl)(methyl)phenyl, (methyl)(pyrrolidinylmethyl)phenyl, (methyl)-(morpholinylmethyl)phenyl, (methyl)(methylpiperazinylmethyl)phenyl, (fluoro)-(methoxy)phenyl, (chloro)(methoxy)phenyl, (cyano)(methoxy)phenyl, (methoxy)-(methyl)phenyl, (methoxy)(trifluoromethyl)phenyl, dimethoxyphenyl, (difluoromethoxy)-(methyl)phenyl, (methyl)(trifluoromethoxy)phenyl, (methyl)(oxetanyloxy)phenyl, (azetidinyloxy)(methyl)phenyl, (tert-butoxycarbonylazetidinyloxy)(methyl)phenyl, (methyl)(tetrahydrofuranylmethoxy)phenyl, (methyl)(morpholinylethoxy)phenyl, (dimethylaminomethyl)(methyl)phenyl, trimethoxyphenyl, benzyl, cyanobenzyl, methylbenzyl, methoxybenzyl, methylenedioxybenzyl, dimethylaminobenzyl, dimethoxy-benzyl, phenylethyl, fluorophenylethyl, methylphenylethyl, (hydroxy)(phenyl)ethyl, methoxyphenylethyl, methylfuryl, methoxybenzofuryl, thienyl, indolyl, methylindolyl, pyrazolyl, methylpyrazolyl, dimethylpyrazolyl, indazolyl, methylindazolyl, dimethyl-isoxazolyl, thiazolyl, methylthiazolyl, tert-butylthiazolyl, ethoxycarbonylthiazolyl, benzothiazolyl, methoxybenzothiazolyl, methylimidazolyl, benzimidazolyl, methyl-benzimidazolyl, trifluoromethylbenzimidazolyl, piperidinylmethylbenzimidazolyl, morpholinylmethylbenzimidazolyl, imidazo[1,2-a]pyridinyl, benzothiadiazolyl, pyridinyl, chloropyridinyl, methylpiperazinylpyridinyl, methoxypyridinyl, dimethylpyridinyl, (methyl)(trifluoromethyl)pyridinyl, (azetidinyl)(methyl)pyridinyl, (methyl)(pyrrolidinyl)-pyridinyl, (methyl)(piperazinyl)pyridinyl, (fluoroazetidinyl)(methyl)pyridinyl, (fluoropyrrolidinyl)(methyl)pyridinyl, (methyl)(methylpiperazinyl)pyridinyl, (tert-butoxycarbonylpiperazinyl)(methyl)pyridinyl, (difluoroazetidinyl)(methyl)pyridinyl, (difluoropyrrolidinyl)(methyl)pyridinyl, (difluoropiperidinyl)(methyl)pyridinyl, (methyl)-(pyrrolidinylmethyl)pyridinyl, (methyl)(morpholinylmethyl)pyridinyl, (methyl)(methyl-piperazinylmethyl)pyridinyl, (hydroxy)(methyl)pyridinyl, (dimethyl)(oxo)pyridinyl, (chloro)(methoxy)pyridinyl, (methoxy)(methyl)pyridinyl, (methoxy)(trifluoromethyl)-pyridinyl, dimethoxypyridinyl, (ethoxy)(methyl)pyridinyl, (isopropoxy)(methyl)pyridinyl, (difluoromethoxy)(methyl)pyridinyl, (methyl)(trifluoroethoxy)pyridinyl, (methyl)-(tetrahydrofuranyloxy)pyridinyl, (methyl)(pyrrolidinyloxy)pyridinyl, (tert-butoxy-carbonylazetidinyloxy)(methyl)pyridinyl, (tert-butoxycarbonylpyrrolidinyloxy)(methyl)-pyridinyl, (methyl)(methylamino)pyridinyl, (dimethylamino)(methyl)pyridinyl, quinolinyl, isoquinolinyl, methoxypyridazinyl, pyrimidinyl, (difluoroazetidinyl)(methyl)-pyrimidinyl, methoxypyrimidinyl, (methoxy)(methyl)pyrimidinyl, (dimethylamino)-(methyl)pyrimidinyl, pyrazinyl, methoxypyrazinyl, (methoxy)(methyl)pyrazinyl, quinoxalinyl, indolylmethyl, thiazolylmethyl, methylthiazolylmethyl, imidazo[2,1-b]-thiazolylmethyl, pyridinylmethyl, furylethyl, benzimidazolylethyl and pyridinylethyl. Additional values include (isopropoxy)(methyl)phenyl and (dimethylamino)(methyl)-pyrazinyl.
- Representative values of Z include methoxyphenyl, dimethylaminophenyl, (methoxy)(methyl)phenyl, (isopropoxy)(methyl)phenyl, (methyl)(trifluoromethoxy)-phenyl, (azetidinyl)(methyl)pyridinyl, (difluoroazetidinyl)(methyl)pyridinyl, (methoxy)-(trifluoromethyl)pyridinyl, dimethoxypyridinyl, (ethoxy)(methyl)pyridinyl, (dimethylamino)(methyl)pyridinyl and (dimethylamino)(methyl)pyrazinyl.
- Typical values of Z include methoxyphenyl, dimethylaminophenyl, (methoxy)(methyl)phenyl, (methyl)(trifluoromethoxy)phenyl, (difluoroazetidinyl)-(methyl)pyridinyl, dimethoxypyridinyl and (ethoxy)(methyl)pyridinyl.
- In a first embodiment, Z represents methoxyphenyl, especially 4-methoxyphenyl.
- In a second embodiment, Z represents dimethylaminophenyl, especially 4-(dimethylamino)phenyl.
- In a third embodiment, Z represents (methoxy)(methyl)phenyl. In a first aspect of that embodiment, Z represents 4-methoxy-2-methylphenyl. In a second aspect of that embodiment, Z represents 4-methoxy-3-methylphenyl.
- In a fourth embodiment, Z represents (difluoromethoxy)(methyl)phenyl, especially 4-(difluoromethoxy)-2-methylphenyl.
- In a fifth embodiment, Z represents (methyl)(trifluoromethoxy)phenyl, especially 2-methyl-4-(trifluoromethoxy)phenyl.
- In a sixth embodiment, Z represents imidazo[1,2-a]pyridinyl, especially imidazo-[1,2-a]pyridin-8-yl.
- In a seventh embodiment, Z represents (difluoroazetidinyl)(methyl)pyridinyl, especially 6-(3,3-difluoroazetidin-1-yl)-2-methylpyridin-3-yl.
- In an eighth embodiment, Z represents (methoxy)(methyl)pyridinyl. In a first aspect of that embodiment, Z represents 6-methoxy-2-methylpyridin-3-yl. In a second aspect of that embodiment, Z represents 6-methoxy-5-methylpyridin-3-yl.
- In a ninth embodiment, Z represents dimethoxypyridinyl, especially 2,6-dimethoxypyridin-3-yl.
- In a tenth embodiment, Z represents (ethoxy)(methyl)pyridinyl, especially 6-ethoxy-2-methylpyridin-3-yl.
- In an eleventh embodiment, Z represents (isopropoxy)(methyl)pyridinyl, especially 6-isopropoxy-2-methylpyridin-3-yl.
- In a twelfth embodiment, Z represents (difluoromethoxy)(methyl)pyridinyl, especially 6-(difluoromethoxy)-2-methylpyridin-3-yl.
- In a thirteenth embodiment, Z represents (isopropoxy)(methyl)phenyl, especially 4-isopropoxy-2-methylphenyl.
- In a fourteenth embodiment, Z represents (azetidinyl)(methyl)pyridinyl, especially 6-(azetidin-1-yl)-2-methylpyridin-3-yl.
- In a fifteenth embodiment, Z represents (methoxy)(trifluoromethyl)pyridinyl, especially 5-methoxy-6-(trifluoromethyl)pyridin-2-yl.
- In a sixteenth embodiment, Z represents (dimethylamino)(methyl)pyridinyl, especially 6-(dimethylamino)-2-methylpyridin-3-yl.
- In a seventeenth embodiment, Z represents (dimethylamino)(methyl)pyrazinyl, especially 5-(dimethylamino)-3-methylpyrazin-2-yl.
- Generally, A1 represents hydrogen, cyano or trifluoromethyl; or A1 represents C1-6 alkyl, optionally substituted by one or more substituents independently selected from —ORa, —NRbRc, —CO2Rd and —CONRbRc; or A1 represents C3-7 cycloalkyl.
- Typically, A1 represents hydrogen or cyano; or A1 represents C1-6 alkyl, optionally substituted by one or more substituents independently selected from —ORa, —CO2Rd and —CONRbRc; or A1 represents C3-7 cycloalkyl.
- Suitably, A1 represents hydrogen; or A1 represents C1-6 alkyl, optionally substituted by —ORa.
- Appositely, A1 represents hydrogen or C1-6 alkyl.
- In a first embodiment, A1 represents hydrogen. In a second embodiment, A1 represents cyano. In a third embodiment, A1 represents trifluoromethyl. In a fourth embodiment, A1 represents C1-6 alkyl, optionally substituted by one or more substituents independently selected from fluoro, —ORa, trifluoromethoxy, —NRbRc, —CO2Rd and —CONRbRc. In a first aspect of that embodiment, A1 represents C1-6 alkyl, optionally substituted by one or more substituents independently selected from —ORa, —NRbRc, —CO2Rd and —CONRbRc. In a second aspect of that embodiment, A1 represents C1-6 alkyl, optionally substituted by one or more substituents independently selected from —ORa, —CO2Rd and —CONRbRc. In a third aspect of that embodiment, A1 represents C1-6 alkyl, optionally substituted by one or more substituents independently selected from —ORa and —NRbRc. In a fourth aspect of that embodiment, A1 represents unsubstituted C1-6 alkyl, typically methyl, ethyl, isopropyl or isobutyl, especially methyl or ethyl. In a fifth aspect of that embodiment, A1 represents C1-6 alkyl monosubstituted by —ORa, —CO2Rd or —CONRbRc. In a sixth aspect of that embodiment, A1 represents C1-6 alkyl monosubstituted by —ORa or —NRbRc. In a seventh aspect of that embodiment, A1 represents C1-6 alkyl monosubstituted by —ORa, especially hydroxyethyl. In an eighth aspect of that embodiment, A1 represents C1-6 alkyl disubstituted by two substituents independently selected from —ORa and —NRbRc. In a fifth embodiment, A1 represents C3-7 cycloalkyl, especially cyclopropyl.
- Selected values of A1 include hydrogen, cyano, methyl, ethyl, isopropyl, isobutyl, —CH2ORa, —CH2CH2ORa, —CH2CO2Rd, —CH2CONRbRc and cyclopropyl.
- Illustrative values of A1 include hydrogen, methyl, ethyl and —CH2CH2ORa.
- Particular values of A1 include hydrogen, methyl, ethyl and hydroxyethyl.
- Apposite values of A1 include hydrogen, methyl and ethyl.
- A first particular value of A1 is hydrogen.
- A second particular value of A1 is methyl.
- A third particular value of A1 is ethyl.
- A fourth particular value of A1 is hydroxyethyl, especially 2-hydroxyethyl.
- In a particular embodiment, A2 represents hydrogen. In another embodiment, A2 represents C1-6 alkyl, especially methyl.
- Selected values of A2 include hydrogen and methyl.
- Suitably, R1 represents hydrogen, halogen, cyano, nitro, hydroxy, trifluoromethyl, trifluoromethoxy, —ORa, —SO2Ra, —NRbRc, —CH2NRbRc, —NRcCORd, —CH2NRcCORd, —NRcCO2Rd, —NHCONRbRc, —NRcSO2Re, —NHSO2NRbRc, —CORd, —CO2Rd, —CONRbRc, —CON(ORa)Rb or —SO2NRbRc; or R1 represents C1-6 alkyl, aryl or heteroaryl, any of which groups may be optionally substituted by one or more substituents.
- Typically, R1 represents hydrogen, —NRbRc or —NRcCORd; or R1 represents C1-6 alkyl, which group may be optionally substituted by one or more substituents.
- Suitable values of R1 include hydrogen and —NRbRc.
- In a first embodiment, R1 represents hydrogen. In a second embodiment, R1 represents cyano. In a third embodiment, R1 represents —ORa. In a fourth embodiment, R1 represents —SRa. In a fifth embodiment, R1 represents —SO2Ra. In a sixth embodiment, R1 represents —NRbRc. In a seventh embodiment, R1 represents —NRcCORd. In an eighth embodiment, R1 represents optionally substituted C1-6 alkyl. In one aspect of that embodiment, R1 represents optionally substituted methyl.
- Examples of typical substituents on R1 include one or more substituents independently selected from halogen, cyano, nitro, C1-6 alkyl, trifluoromethyl, aryl(C1-6)alkyl, hydroxy, C1-6 alkoxy, difluoromethoxy, trifluoromethoxy, aryloxy, C1-4 alkylenedioxy, C1-6 alkoxy(C1-6)alkyl, C1-6 alkylthio, C1-6 alkylsulphonyl, oxo, amino, C1-6 alkylamino, di(C1-6)alkylamino, C2-6 alkylcarbonylamino, C2-6 alkoxycarbonylamino, aryl(C1-6)alkoxycarbonylamino, C1-6 alkylaminocarbonylamino, arylaminocarbonylamino, C1-6 alkylsulphonylamino, formyl, C2-6 alkylcarbonyl, carboxy, C2-6 alkoxycarbonyl, aminocarbonyl, C1-6 alkylaminocarbonyl, di(C1-6)alkylaminocarbonyl, aminosulphonyl, C1-6 alkylaminosulphonyl and di(C1-6)alkylaminosulphonyl.
- Specific examples of typical substituents on R1 include one or more substituents independently selected from fluoro, chloro, bromo, cyano, nitro, methyl, ethyl, tert-butyl, trifluoromethyl, benzyl, hydroxy, methoxy, difluoromethoxy, trifluoromethoxy, phenoxy, methylenedioxy, ethylenedioxy, methoxymethyl, methylthio, methylsulphonyl, oxo, amino, methylamino, dimethylamino, acetylamino, methoxycarbonylamino, ethoxycarbonylamino, benzyloxycarbonylamino, ethylaminocarbonylamino, butylaminocarbonylamino, phenylaminocarbonylamino, methylsulphonylamino, formyl, acetyl, carboxy, methoxycarbonyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, aminosulphonyl, methylaminosulphonyl and dimethylaminosulphonyl.
- Generally, R2 represents hydrogen, cyano, hydroxy, trifluoromethyl, —NRcCO2Rd, —CORd, —CO2Rd, —CONRbRc or —CON(ORa)Rb; or R2 represents C1-6 alkyl, C3-7 cycloalkyl, aryl, C3-7 heterocycloalkyl, C3-7 heterocycloalkenyl or heteroaryl, any of which groups may be optionally substituted by one or more substituents.
- Typically, R2 represents hydrogen, —CO2Rd, —CONRbRc or —CON(ORa)Rb; or R2 represents C3-7 heterocycloalkenyl, which group may be optionally substituted by one or more substituents.
- In a first embodiment, R2 represents hydrogen. In a second embodiment, R2 represents cyano. In a third embodiment, R2 represents hydroxy. In a fourth embodiment, R2 represents trifluoromethyl. In a fifth embodiment, R2 represents —NRcCO2Rd. In a sixth embodiment, R2 represents —CORd. In a seventh embodiment, R2 represents —CO2Rd. In an eighth embodiment, R2 represents —CONRbRc. In a ninth embodiment, R2 represents —CON(ORa)Rb. In a tenth embodiment, R2 represents optionally substituted C1-6 alkyl. In a first aspect of that embodiment, R2 represents unsubstituted C1-6 alkyl. In a second aspect of that embodiment, R2 represents monosubstituted C1-6 alkyl. In a third aspect of that embodiment, R2 represents disubstituted C1-6 alkyl. In an eleventh embodiment, R2 represents optionally substituted C3-7 cycloalkyl. In a first aspect of that embodiment, R2 represents unsubstituted C3-7 cycloalkyl. In a second aspect of that embodiment, R2 represents monosubstituted C3-7 cycloalkyl. In a third aspect of that embodiment, R2 represents disubstituted C3-7 cycloalkyl. In a twelfth embodiment, R2 represents optionally substituted aryl. In a first aspect of that embodiment, R2 represents unsubstituted aryl. In a second aspect of that embodiment, R2 represents monosubstituted aryl. In a third aspect of that embodiment, R2 represents disubstituted aryl. In a thirteenth embodiment, R2 represents optionally substituted C3-7 heterocycloalkyl. In a first aspect of that embodiment, R2 represents unsubstituted C3-7 heterocycloalkyl. In a second aspect of that embodiment, R2 represents monosubstituted C3-7 heterocycloalkyl. In a third aspect of that embodiment, R2 represents disubstituted C3-7 heterocycloalkyl. In a fourteenth embodiment, R2 represents optionally substituted C3-7 heterocycloalkenyl. In a first aspect of that embodiment, R2 represents unsubstituted C3-7 heterocycloalkenyl. In a second aspect of that embodiment, R2 represents monosubstituted C3-7 heterocycloalkenyl. In a third aspect of that embodiment, R2 represents disubstituted C3-7 heterocycloalkenyl. In a fifteenth embodiment, R2 represents optionally substituted heteroaryl. In a first aspect of that embodiment, R2 represents unsubstituted heteroaryl. In a second aspect of that embodiment, R2 represents monosubstituted heteroaryl. In a third aspect of that embodiment, R2 represents disubstituted heteroaryl.
- Where R2 represents optionally substituted C1-6 alkyl, suitable values include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl, any of which groups may be optionally substituted by one or more substituents. Selected values include methyl, hydroxymethyl, chloropropyl and isobutyl. Particular values include methyl and isobutyl, especially methyl.
- Where R2 represents optionally substituted C3-7 cycloalkyl, a suitable value is cyclohexyl, optionally substituted by one or more substituents.
- Where R2 represents optionally substituted aryl, a suitable value is phenyl, optionally substituted by one or more substituents. Selected values include phenyl, fluorophenyl, chlorophenyl and methoxyphenyl.
- Where R2 represents optionally substituted C3-7 heterocycloalkyl, typical values include azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl, any of which groups may be optionally substituted by one or more substituents.
- Where R2 represents optionally substituted C3-7 heterocycloalkenyl, a typical value is oxazolinyl, optionally substituted by one or more substituents. Suitable values include oxazolinyl, methyloxazolinyl, isopropyloxazolinyl and dimethyloxazolinyl.
- Where R2 represents optionally substituted heteroaryl, typical values include pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, tetrazolyl and triazinyl, any of which groups may be optionally substituted by one or more substituents. Suitable values include oxadiazolyl and pyridinyl, either of which groups may be optionally substituted by one or more substituents. Selected values include methyloxadiazolyl, isopropyloxadiazolyl, tert-butyloxadiazolyl and pyridinyl.
- In a selected embodiment, R2 represents hydrogen, cyano, hydroxy, trifluoro-methyl, —NRcCO2Rd, —CORd, —CO2Rd, —CONRbRc or —CON(ORa)Rb; or R2 represents C1-6 alkyl, cyclohexyl, phenyl, oxazolinyl, oxadiazolyl or pyridinyl, any of which groups may be optionally substituted by one or more substituents.
- In a typical embodiment, R2 represents hydrogen, —CO2Rd, —CONRbRc or —CON(ORa)Rb; or R2 represents oxazolinyl, which group may be optionally substituted by one or more substituents.
- Typical examples of optional substituents on R2 include one or more substituents independently selected from halogen, cyano, nitro, C1-6 alkyl, trifluoromethyl, hydroxy, C1-6 alkoxy, difluoromethoxy, trifluoromethoxy, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, amino, C1-6 alkylamino, di(C1-6 )alkylamino, C2-6 alkylcarbonylamino, C2-6 alkoxycarbonylamino, C1-6 alkylsulfonylamino, formyl, C2-6 alkylcarbonyl, carboxy, C2-6 alkoxycarbonyl, aminocarbonyl, C1-6 alkylaminocarbonyl, di(C1-6)alkylaminocarbonyl, aminosulfonyl, C1-6 alkylaminosulfonyl and di(C1-6)alkylaminosulfonyl.
- Typical examples of specific substituents on R2 include one or more substituents independently selected from fluoro, chloro, bromo, cyano, nitro, methyl, ethyl, isopropyl, tert-butyl, trifluoromethyl, hydroxy, methoxy, isopropoxy, difluoromethoxy, trifluoro-methoxy, methylthio, methylsulfinyl, methylsulfonyl, amino, methylamino, dimethyl-amino, acetylamino, methoxycarbonylamino, methylsulfonylamino, formyl, acetyl, carboxy, methoxycarbonyl, aminocarbonyl, methylaminocarbonyl, dimethylamino-carbonyl, aminosulfonyl, methylaminosulfonyl and dimethylaminosulfonyl.
- Typical values of R2 include hydrogen, cyano, hydroxy, trifluoromethyl, —NRcCO2Rd, —CORd, —CO2Rd, —CONRbRc, —CON(ORa)Rb, methyl, hydroxymethyl, chloro-propyl, isobutyl, cyclohexyl, phenyl, fluorophenyl, chlorophenyl, methoxyphenyl, oxazolinyl, methyloxazolinyl, isopropyloxazolinyl, dimethyloxazolinyl, methyl-oxadiazolyl, isopropyloxadiazolyl, tert-butyloxadiazolyl and pyridinyl.
- Suitable values of R2 include hydrogen, —CO2Rd, —CONRbRc, —CON(ORa)Rb and oxazolinyl.
- Typically, R3 represents hydrogen or C1-6 alkyl.
- In a first embodiment, R3 represents hydrogen. In a second embodiment, R3 represents halogen, especially fluoro or chloro. In a first aspect of that embodiment, R3 represents fluoro. In a second aspect of that embodiment, R3 represents chloro. In a third embodiment, R3 represents C1-6 alkyl, especially methyl.
- Typical values of R3 include hydrogen and methyl.
- Typically, R4 represents hydrogen; or R4 represents C1-6 alkyl, aryl or heteroaryl, any of which groups may be optionally substituted by one or more substituents.
- Suitably, R4 represents hydrogen; or R4 represents C1-6 alkyl, which group may be optionally substituted by one or more substituents.
- In a first embodiment, R4 represents hydrogen. In a second embodiment, R4 represents optionally substituted C1-6 alkyl. In a first aspect of that embodiment, R4 represents unsubstituted C1-6 alkyl. In a second aspect of that embodiment, R4 represents monosubstituted C1-6 alkyl. In a third aspect of that embodiment, R4 represents disubstituted C1-6 alkyl. In a third embodiment, R4 represents optionally substituted aryl. In a first aspect of that embodiment, R4 represents unsubstituted aryl. In a second aspect of that embodiment, R4 represents monosubstituted aryl. In a third aspect of that embodiment, R4 represents disubstituted aryl. In a fourth embodiment, R4 represents optionally substituted aryl(C1-6)alkyl. In a first aspect of that embodiment, R4 represents unsubstituted aryl(C1-6)alkyl. In a second aspect of that embodiment, R4 represents monosubstituted aryl(C1-6)alkyl. In a third aspect of that embodiment, R4 represents disubstituted aryl(C1-6)alkyl. In a fifth embodiment, R4 represents optionally substituted heteroaryl. In a first aspect of that embodiment, R4 represents unsubstituted heteroaryl. In a second aspect of that embodiment, R4 represents monosubstituted heteroaryl. In a third aspect of that embodiment, R4 represents disubstituted heteroaryl. In a sixth embodiment, R4 represents optionally substituted heteroaryl(C1-6)alkyl. In a first aspect of that embodiment, R4 represents unsubstituted heteroaryl(C1-6)alkyl. In a second aspect of that embodiment, R4 represents monosubstituted heteroaryl(C1-6)alkyl. In a third aspect of that embodiment, R4 represents disubstituted heteroaryl(C1-6)alkyl.
- Where R4 represents optionally substituted C1-6 alkyl, suitable values include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl, any of which groups may be optionally substituted by one or more substituents. Selected values include methyl, ethyl, n-propyl, isopropyl and isobutyl, especially methyl.
- Where R4 represents optionally substituted aryl, a suitable value is phenyl, optionally substituted by one or more substituents. Selected values include phenyl, fluorophenyl, chlorophenyl and methoxyphenyl. A particular value is fluorophenyl.
- Where R4 represents optionally substituted aryl(C1-6)alkyl, a suitable value is benzyl, optionally substituted by one or more substituents. Selected values include benzyl, fluorobenzyl, chlorobenzyl and methoxybenzyl. A particular value is fluoro-benzyl.
- Where R4 represents optionally substituted heteroaryl, typical values include pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, tetrazolyl and triazinyl, any of which groups may be optionally substituted by one or more substituents. Suitable values include oxadiazolyl and pyridinyl, either of which groups may be optionally substituted by one or more substituents. Selected values include methyloxadiazolyl, isopropyloxadiazolyl, tert-butyloxadiazolyl and pyridinyl.
- Where R4 represents optionally substituted heteroaryl(C1-6)alkyl, a suitable value is pyridinylmethyl, optionally substituted by one or more substituents.
- In a typical embodiment, R4 represents hydrogen; or R4 represents C1-6 alkyl, phenyl, benzyl, oxadiazolyl, pyridinyl or pyridinylmethyl, any of which groups may be optionally substituted by one or more substituents.
- In a suitable embodiment, R4 represents hydrogen; or R4 represents C1-6 alkyl or phenyl, either of which groups may be optionally substituted by one or more substituents.
- In a selected embodiment, R4 represents hydrogen; or R4 represents C1-6 alkyl, which group may be optionally substituted by one or more substituents.
- Typical examples of optional substituents on R4 include one or more substituents independently selected from halogen, cyano, nitro, C1-6 alkyl, trifluoromethyl, hydroxy, C1-6 alkoxy, difluoromethoxy, trifluoromethoxy, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, amino, C1-6 alkylamino, di(C1-6)alkylamino, C2-6 alkylcarbonylamino, C2-6 alkoxycarbonylamino, C1-6 alkylsulfonylamino, formyl, C2-6 alkylcarbonyl, carboxy, C2-6 alkoxycarbonyl, aminocarbonyl, C1-6 alkylaminocarbonyl, di(C1-6)alkylaminocarbonyl, aminosulfonyl, C1-6 alkylaminosulfonyl and di(C1-6)alkylaminosulfonyl.
- Typical examples of specific substituents on R4 include one or more substituents independently selected from fluoro, chloro, bromo, cyano, nitro, methyl, ethyl, isopropyl, tert-butyl, trifluoromethyl, hydroxy, methoxy, isopropoxy, difluoromethoxy, trifluoro-methoxy, methylthio, methylsulfinyl, methylsulfonyl, amino, methylamino, dimethyl-amino, acetylamino, methoxycarbonylamino, methylsulfonylamino, formyl, acetyl, carboxy, methoxycarbonyl, aminocarbonyl, methylaminocarbonyl, dimethylamino-carbonyl, aminosulfonyl, methylaminosulfonyl and dimethylaminosulfonyl.
- Typical values of R4 include hydrogen, methyl, phenyl, fluorophenyl, chloro-phenyl, methoxyphenyl, benzyl, methyloxadiazolyl, isopropyloxadiazolyl, tert-butyl-oxadiazolyl, pyridinyl and pyridinylmethyl.
- Suitably, R4 represents hydrogen or C1-6 alkyl.
- In one embodiment, R4 represents hydrogen. In another embodiment, R4 represents C1-6 alkyl, especially methyl.
- Appositely, R4 represents methyl.
- Suitably, R5 represents hydrogen or C1-6 alkyl.
- Suitable values of R5 include hydrogen and methyl.
- In one embodiment, R5 represents hydrogen. In another embodiment, R5 represents C1-6 alkyl, optionally substituted by one or more substituents independently selected from —ORa and —NRbRc. In one aspect of that embodiment, R5 represents unsubstituted C1-6 alkyl, especially methyl. In another aspect of that embodiment, R5 represents C1-6 alkyl monosubstituted by —ORa or —NRbRc. In a further aspect of that embodiment, R5 represents C1-6 alkyl disubstituted by two substituents independently selected from —ORa and —NRbRc.
- Typical examples of suitable substituents on Ra, Rb, Rc, Rd or Re, or on the heterocyclic moiety —NRbRc, include halogen, C1-6 alkyl, C1-6 alkoxy, difluoromethoxy, trifluoromethoxy, alkoxy(C1-6)alkyl, C1-6 alkylthio, C1-6 alkylsulphinyl, C1-6 alkylsulphonyl, hydroxy, hydroxy(C1-6)alkyl, amino(C1-6)alkyl, cyano, trifluoromethyl, oxo, C2-6 alkylcarbonyl, carboxy, C2-6 alkoxycarbonyl, C2-6 alkylcarbonyloxy, amino, C1-6 alkylamino, di(C1-6)alkylamino, phenylamino, pyridinylamino, C2-6 alkylcarbonylamino, C2-6 alkylcarbonylamino(C1-6)alkyl, C2-6 alkoxycarbonylamino, C1-6 alkylsulphonylamino, aminocarbonyl, C1-6 alkylaminocarbonyl and di(C1-6)alkylaminocarbonyl.
- Typical examples of specific substituents on Ra, Rb, Rc, Rd or Re, or on the heterocyclic moiety —NRbRc, include fluoro, chloro, bromo, methyl, ethyl, isopropyl, methoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, methoxymethyl, methylthio, ethylthio, methylsulphinyl, methylsulphonyl, hydroxy, hydroxymethyl, hydroxyethyl, aminomethyl, cyano, trifluoromethyl, oxo, acetyl, carboxy, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, acetoxy, amino, methylamino, ethylamino, dimethylamino, phenylamino, pyridinylamino, acetylamino, acetylaminomethyl, tert-butoxycarbonylamino, methylsulphonylamino, aminocarbonyl, methylaminocarbonyl and dimethylaminocarbonyl.
- Typically, Ra represents hydrogen; or Ra represents C1-6 alkyl, aryl(C1-6)alkyl or heteroaryl(C1-6)alkyl, any of which groups may be optionally substituted by one or more substituents.
- Suitably, Ra represents C1-6 alkyl, aryl(C1-6)alkyl or heteroaryl(C1-6)alkyl, any of which groups may be optionally substituted by one or more substituents.
- Apposite values of Ra include hydrogen; and methyl, ethyl, benzyl or isoindolyl-propyl, any of which groups may be optionally substituted by one or more substituents.
- Selected values of Ra include methyl, ethyl, benzyl and isoindolylpropyl, any of which groups may be optionally substituted by one or more substituents.
- Selected examples of suitable substituents on Ra include C1-6 alkoxy and oxo.
- Selected examples of specific substituents on Ra include methoxy and oxo.
- In one embodiment, Ra represents hydrogen. In another embodiment, Ra represents optionally substituted C1-6 alkyl. In one aspect of that embodiment, Ra ideally represents unsubstituted C1-6 alkyl, especially methyl. In another aspect of that embodiment, Ra ideally represents substituted C1-6 alkyl, e.g. methoxyethyl. In another embodiment, Ra represents optionally substituted aryl. In one aspect of that embodiment, Ra represents unsubstituted aryl, especially phenyl. In another aspect of that embodiment, Ra represents monosubstituted aryl, especially methylphenyl. In another embodiment, Ra represents optionally substituted aryl(C1-6)alkyl, ideally unsubstituted aryl(C1-6)alkyl, especially benzyl. In a further embodiment, Ra represents optionally substituted heteroaryl. In a further embodiment, Ra represents optionally substituted heteroaryl(C1-6)alkyl, e.g. dioxoisoindolylpropyl.
- Specific values of Ra include methyl, methoxyethyl, benzyl and dioxoisoindolyl-propyl.
- Appositely, Ra represents hydrogen or C1-6 alkyl.
- Individual values of Ra include hydrogen and methyl.
- In a particular aspect, Rb represents hydrogen or trifluoromethyl; or C1-6 alkyl, C3-7 cycloalkyl, C3-7 cycloalkyl(C1-6)alkyl, aryl, aryl(C1-6)alkyl, C3-7 heterocycloalkyl, C3-7 heterocycloalkyl(C1-6)alkyl, heteroaryl or heteroaryl(C1-6)alkyl, any of which groups may be optionally substituted by one or more substituents.
- Selected values of Rb include hydrogen; or C1-6 alkyl, aryl(C1-6)alkyl, C3-7 heterocycloalkyl or C3-7 heterocycloalkyl(C1-6)alkyl, any of which groups may be optionally substituted by one or more substituents.
- Typical values of Rb include hydrogen and C1-6 alkyl.
- Illustratively, Rb represents hydrogen or trifluoromethyl; or methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-methylpropyl, tert-butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, phenyl, benzyl, phenylethyl, azetidinyl, tetrahydrofuryl, tetrahydrothienyl, pyrrolidinyl, piperidinyl, homopiperidinyl, morpholinyl, azetidinylmethyl, tetrahydrofurylmethyl, pyrrolidinylmethyl, pyrrolidinylethyl, pyrrolidinylpropyl, thiazolidinylmethyl, imidazolidinylethyl, piperidinylmethyl, pip eridinylethyl, tetrahydroquinolinylmethyl, piperazinylpropyl, morpholinylmethyl, morpholinylethyl, morpholinylpropyl, pyridinyl, indolylmethyl, pyrazolylmethyl, pyrazolylethyl, imidazolylmethyl, imidazolylethyl, benzimidazolylmethyl, triazolylmethyl, pyridinylmethyl or pyridinylethyl, any of which groups may be optionally substituted by one or more substituents.
- Representative values of Rb include hydrogen; or methyl, ethyl, n-propyl, benzyl, pyrrolidinyl or morpholinylpropyl, any of which groups may be optionally substituted by one or more substituents.
- Selected examples of suitable substituents on Rb include C1-6 alkoxy, C1-6 alkylthio, C1-6 alkylsulphinyl, C1-6 alkylsulphonyl, hydroxy, cyano, C2-6 alkoxycarbonyl, di-(C1-6)alkylamino and C2-6 alkoxycarbonylamino.
- Selected examples of specific substituents on Rb include methoxy, methylthio, methylsulphinyl, methylsulphonyl, hydroxy, cyano, tert-butoxycarbonyl, dimethylamino and tert-butoxycarbonylamino.
- Specific values of Rb include hydrogen, methyl, methoxyethyl, methylthioethyl, methylsulphinylethyl, methylsulphonylethyl, hydroxyethyl, cyanoethyl, dimethylamino-ethyl, tert-butoxycarbonylaminoethyl, dihydroxypropyl, benzyl, pyrrolidinyl, tert-butoxycarbonylpyrrolidinyl and morpholinylpropyl.
- Apposite values of Rb include hydrogen and methyl.
- In one embodiment, Rb represents hydrogen. In another embodiment, Rb represents C1-6 alkyl, especially methyl.
- Selected values of Rc include hydrogen; or C1-6 alkyl, C3-7 cycloalkyl or C3-7 heterocycloalkyl, any of which groups may be optionally substituted by one or more substituents.
- In a particular aspect, Rc represents hydrogen, C1-6 alkyl or C3-7 cycloalkyl.
- Representative values of Rc include hydrogen; or methyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyranyl and piperidinyl, any of which groups may be optionally substituted by one or more substituents.
- Selected examples of suitable substituents on Rc include C2-6 alkylcarbonyl and C2-6 alkoxycarbonyl.
- Selected examples of specific substituents on Rc include acetyl and tert-butoxycarbonyl.
- Specific values of Rc include hydrogen, methyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyranyl, acetylpiperidinyl and tert-butoxycarbonylpiperidinyl,
- Suitably, Rc represents hydrogen or C1-6 alkyl. In one embodiment, Rc is hydrogen. In another embodiment, Rc represents C1-6 alkyl, especially methyl or ethyl, particularly methyl. In a further embodiment, Rc represents C3-7 cycloalkyl, e.g. cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
- Alternatively, the moiety —NRbRc may suitably represent azetidin-1-yl, pyrrolidin-1-yl, oxazolidin-3-yl, isoxazolidin-2-yl, thiazolidin-3-yl, isothiazolidin-2-yl, piperidin-1-yl, morpholin-4-yl, thiomorpholin-4-yl, piperazin-1-yl, homopiperidin-1-yl, homomorpholin-4-yl or homopiperazin-1-yl, any of which groups may be optionally substituted by one or more substituents.
- Selected examples of suitable substituents on the heterocyclic moiety —NRbRc include C1-6 alkyl, C1-6 alkylsulphonyl, hydroxy, hydroxy(C1-6)alkyl, amino(C1-6)alkyl, cyano, oxo, C2-6 alkylcarbonyl, carboxy, C2-6 alkoxycarbonyl, amino, C2-6 alkylcarbonyl-amino, C2-6 alkylcarbonylamino(C1-6)alkyl, C2-6 alkoxycarbonylamino, C1-6 alkyl-sulphonylamino and aminocarbonyl.
- Selected examples of specific substituents on the heterocyclic moiety —NRbRc include methyl, methylsulphonyl, hydroxy, hydroxymethyl, aminomethyl, cyano, oxo, acetyl, carboxy, ethoxycarbonyl, amino, acetylamino, acetylaminomethyl, tert-butoxy-carbonylamino, methylsulphonylamino and aminocarbonyl.
- Specific values of the moiety —NRbRc include azetidin-1-yl, hydroxyazetidin-1-yl, hydroxymethylazetidin-1-yl, (hydroxy)(hydroxymethyl)azetidin-1-yl, aminomethyl-azetidin-1-yl, cyanoazetidin-1-yl, carboxyazetidin-1-yl, aminoazetidin-1-yl, aminocarbonylazetidin-1-yl, pyrrolidin-1-yl, aminomethylpyrrolidin-1-yl, oxopyrrolidin-1-yl, acetylaminomethylpyrrolidin-1-yl, tert-butoxycarbonylaminopyrrolidin-1-yl, oxo-oxazolidin-3-yl, hydroxyisoxazolidin-2-yl, thiazolidin-3-yl, oxothiazolidin-3-yl, dioxo-isothiazolidin-2-yl, piperidin-1-yl, hydroxypiperidin-1-yl, hydroxymethylpiperidin-1-yl, aminopiperidin-1-yl, acetylaminopiperidin-1-yl, tert-butoxycarbonylaminopiperidin-1-yl, methylsulphonylaminopiperidin-1-yl, morpholin-4-yl, piperazin-1-yl, methylpiperazin-1-yl, methylsulphonylpiperazin-1-yl, oxopiperazin-1-yl, acetylpiperazin-1-yl, ethoxycarbonylpiperazin-1-yl and oxohomopiperazin-1-yl.
- Suitably, Rd represents hydrogen; or C1-6 alkyl, aryl or heteroaryl, any of which groups may be optionally substituted by one or more substituents.
- Selected examples of suitable values for Rd include hydrogen, methyl, ethyl, isopropyl, 2-methylpropyl, tert-butyl, cyclopropyl, cyclobutyl, phenyl, thiazolidinyl, thienyl, imidazolyl and thiazolyl, any of which groups may be optionally substituted by one or more substituents.
- Selected examples of suitable substituents on Rd include halogen, C1-6 alkyl, C1-6 alkoxy, oxo, C2-6 alkylcarbonyloxy and di(C1-6)alkylamino.
- Selected examples of particular substituents on Rd include fluoro, methyl, methoxy, oxo, acetoxy and dimethylamino.
- In one embodiment, Rd represents hydrogen. In another embodiment, Rd represents optionally substituted C1-6 alkyl. In one aspect of that embodiment, Rd ideally represents unsubstituted C1-6 alkyl, e.g. methyl, ethyl, isopropyl, 2-methylpropyl or tert-butyl, especially methyl or ethyl, particularly methyl. In another aspect of that embodiment, Rd ideally represents substituted C1-6 alkyl, e.g. substituted methyl or substituted ethyl, including acetoxymethyl, dimethylaminomethyl and trifluoroethyl. In another embodiment, Rd represents optionally substituted aryl. In one aspect of that embodiment, Rd represents unsubstituted aryl, especially phenyl. In another aspect of that embodiment, Rd represents monosubstituted aryl, especially methylphenyl. In a further aspect of that embodiment, Rd represents disubstituted aryl, e.g. dimethoxyphenyl. In a further embodiment, Rd represents optionally substituted heteroaryl, e.g. thienyl, chlorothienyl, methylthienyl, methylimidazolyl or thiazolyl. In another embodiment, Rd represents optionally substituted C3-7 cycIoalkyl, e.g. cyclopropyl or cyclobutyl. In a further embodiment, Rd represents optionally substituted C3-7 heterocycloalkyl, e.g. thiazolidinyl or oxothiazolidinyl.
- Selected examples of specific values for Rd include hydrogen, methyl, ethyl, acetoxymethyl, dimethylaminomethyl, ethyl, trifluoroethyl, isopropyl, 2-methylpropyl, tert-butyl, cyclopropyl, cyclobutyl, phenyl, dimethoxyphenyl, thiazolidinyl, oxothiazolidinyl, thienyl, chlorothienyl, methylthienyl, methylimidazolyl and thiazolyl.
- Appositely, Rd represents hydrogen or C1-6 alkyl.
- Individual values of Rd include hydrogen, methyl and ethyl.
- A particular value of Rd is ethyl.
- Suitably, Re represents C1-6 alkyl or aryl, either of which groups may be optionally substituted by one or more substituents.
- Selected examples of suitable substituents on Re include C1-6 alkyl, especially methyl.
- In one embodiment, Re represents optionally substituted C1-6 alkyl, ideally unsubstituted C1-6 alkyl, e.g. methyl or propyl, especially methyl. In another embodiment, Re represents optionally substituted aryl. In one aspect of that embodiment, Re represents unsubstituted aryl, especially phenyl. In another aspect of that embodiment, Re represents monosubstituted aryl, especially methylphenyl. In a further embodiment, Re represents optionally substituted heteroaryl.
- Selected values of Re include methyl, propyl and methylphenyl.
- One sub-class of compounds according to the invention is represented by the compounds of formula (IIA-1) or (IIB-1), and pharmaceutically acceptable salts and solvates thereof:
- wherein
- A11 represents hydrogen, cyano, C1-6 alkyl, —CH2ORa, —CH2CH2ORa, —CH2CO2Rd, —CH2CONRbRc or C3-7 cycloalkyl;
- R11 represents hydrogen or amino; and
- X, T, U, Z, R3, Ra, Rb, Rc and Rd are as defined above.
- Appositely, A11 represents hydrogen or C1-6 alkyl.
- In a first embodiment, A11 represents hydrogen. In a second embodiment, A11 represents cyano. In a third embodiment, A11 represents C1-6 alkyl, typically methyl, ethyl, isopropyl or isobutyl, especially methyl or ethyl. In a fourth embodiment, A11 represents —CH2ORa. In a fifth embodiment, A11 represents —CH2CH2ORa. In a sixth embodiment, A11 represents —CH2CO2Rd. In a seventh embodiment, A11 represents —CH2CONRbRc. In an eighth embodiment, A11 represents C3-7 cycloalkyl, especially cyclopropyl.
- Selected values of A11 include hydrogen, cyano, methyl, ethyl, isopropyl, isobutyl, —CH2ORa, —CH2CH2ORa, —CH2CO2Rd, —CH2CONRbRc and cyclopropyl.
- Illustrative values of A11 include hydrogen, methyl, ethyl and —CH2CH2ORa.
- Particular values of A11 include hydrogen, methyl, ethyl and 2-hydroxyethyl.
- Apposite values of A11 include hydrogen, methyl and ethyl.
- A first particular value of A11 is hydrogen.
- A second particular value of A11 is methyl.
- A third particular value of A11 is ethyl.
- A fourth particular value of A11 is 2-hydroxyethyl.
- In a first embodiment, R11 is hydrogen. In a second embodiment, R11 is —NH2.
- Another sub-class of compounds according to the invention is represented by the compounds of formula (IIA-2) or (IIB-2), and pharmaceutically acceptable salts and solvates thereof:
- wherein X, T, U, Z, A11, R3 and R11 are as defined above.
- Specific novel compounds in accordance with the present invention include each of the compounds whose preparation is described in the accompanying Examples, and pharmaceutically acceptable salts and solvates thereof.
- The compounds in accordance with the present invention are beneficial in the treatment and/or prevention of various human ailments. These include inflammatory, autoimmune and oncological disorders; viral diseases and malaria; and organ and cell transplant rejection.
- Inflammatory and autoimmune disorders include systemic autoimmune disorders, autoimmune endocrine disorders and organ-specific autoimmune disorders. Systemic autoimmune disorders include systemic lupus erythematosus (SLE), psoriasis, vasculitis, polymyositis, scleroderma, multiple sclerosis, ankylosing spondylitis, rheumatoid arthritis and Sjögren's syndrome. Autoimmune endocrine disorders include thyroiditis. Organ-specific autoimmune disorders include Addison's disease, haemolytic or pernicious anaemia, glomerulonephritis (including Goodpasture's syndrome), Graves' disease, idiopathic thrombocytopenic purpura, insulin-dependent diabetes mellitus, juvenile diabetes, uveitis, inflammatory bowel disease (including Crohn's disease and ulcerative colitis), pemphigus, atopic dermatitis, autoimmune hepatitis, primary biliary cirrhosis, autoimmune pneumonitis, autoimmune carditis, myasthenia gravis and spontaneous infertility.
- Oncological disorders, which may be acute or chronic, include proliferative disorders, especially cancer, in animals, including mammals, especially humans. Particular categories of cancer include haematological malignancy (including leukaemia and lymphoma) and non-haematological malignancy (including solid tumour cancer, sarcoma, meningioma, glioblastoma multiforme, neuroblastoma, melanoma, gastric carcinoma and renal cell carcinoma). Chronic leukaemia may be myeloid or lymphoid. Varieties of leukaemia include lymphoblastic T cell leukaemia, chronic myelogenous leukaemia (CML), chronic lymphocytic/lymphoid leukaemia (CLL), hairy-cell leukaemia, acute lymphoblastic leukaemia (ALL), acute myelogenous leukaemia (AML), myelodysplastic syndrome, chronic neutrophilic leukaemia, acute lymphoblastic T cell leukaemia, plasmacytoma, immunoblastic large cell leukaemia, mantle cell leukaemia, multiple myeloma, acute megakaryoblastic leukaemia, acute megakaryocytic leukaemia, promyelocytic leukaemia and erythroleukaemia. Varieties of lymphoma include malignant lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, lymphoblastic T cell lymphoma, Burkitt's lymphoma, follicular lymphoma, MALT1 lymphoma and marginal zone lymphoma. Varieties of non-haematological malignancy include cancer of the prostate, lung, breast, rectum, colon, lymph node, bladder, kidney, pancreas, liver, ovary, uterus, cervix, brain, skin, bone, stomach and muscle.
- Viral diseases include infections caused by various families of virus, including the Retroviridae, Flaviviridae, Picornaviridae. Various genera within the Retroviridae family include Alpharetrovirus, Betaretrovirus, Gammaretrovirus, Deltaretrovirus, Epsilonretrovirus, Lentivirus and Spumavirus. Members of the Lentivirus genus include human immunodeficiency virus 1 (HIV-1) and human immunodeficiency virus 2 (HIV-2). Various genera within the Flaviviridae family include Flavivirus, Pestivirus, Hepacivirus and Hepatitis G Virus. Members of the Flavivirus genus include Dengue fever virus, yellow fever virus, West Nile encephalitis virus and Japanese encephalitis virus. Members of the Pestivirus genus include bovine viral diarrhoea virus (BVDV), classical swine fever virus and border disease virus 2 (BDV-2). Members of the Hepacivirus genus include hepatitis C virus (HCV). Members of the Hepatitis G Virus genus include hepatitis G virus. Various genera within the Picornaviridae family include Aphthovirus, Avihepatovirus, Cardiovirus, Enterovirus, Erbovirus, Hepatovirus, Kobuvirus, Parechovirus, Sapelovirus, Senecavirus, Teschovirus and Tremovirus. Members of the Enterovirus genus include poliovirus, coxsackie A virus, coxsackie B virus and rhinovirus.
- Organ transplant rejection includes the rejection of transplanted or grafted organs or cells (both allografts and xenografts), including graft-versus-host reaction disease. The term “organ” as used herein means all organs or parts of organs in mammals, particularly humans, including kidney, lung, bone marrow, hair, cornea, eye (vitreous), heart, heart valve, liver, pancreas, blood vessel, skin, muscle, bone, intestine and stomach. The term “rejection” as used herein means all reactions of the recipient body or the transplanted organ which ultimately lead to cell or tissue death in the transplanted organ, or adversely affect the functional ability and viability of the transplanted organ or the recipient. In particular, this means acute and chronic rejection reactions.
- Cell transplant rejection includes the rejection of cell transplants and xeno- transplantation. The major hurdle for xenotransplantation is that even before the T lymphocytes (responsible for the rejection of allografts) are activated, the innate immune system (especially T-independent B lymphocytes and macrophages) is activated. This provokes two types of severe and early acute rejection, referred to as hyperacute rejection and vascular rejection respectively. Conventional immunosuppressant drugs, including cyclosporine A, are ineffective in xenotransplantation. The compounds in accordance with the present invention are not liable to this drawback. The ability of the compounds of this invention to suppress T-independent xeno-antibody production as well as macrophage activation may be demonstrated by their ability to prevent xenograft rejection in athymic, T-deficient mice receiving xenogenic hamster-heart grafts.
- The present invention also provides a pharmaceutical composition which comprises a compound in accordance with the invention as described above, or a pharmaceutically acceptable salt or solvate thereof, in association with one or more pharmaceutically acceptable carriers.
- Pharmaceutical compositions according to the invention may take a form suitable for oral, buccal, parenteral, nasal, topical, ophthalmic or rectal administration, or a form suitable for administration by inhalation or insufflation.
- For oral administration, the pharmaceutical compositions may take the form of, for example, tablets, lozenges or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methyl cellulose); fillers (e.g. lactose, microcrystalline cellulose or calcium hydrogenphosphate); lubricants (e.g. magnesium stearate, talc or silica); disintegrants (e.g. potato starch or sodium glycollate); or wetting agents (e.g. sodium lauryl sulphate). The tablets may be coated by methods well known in the art. Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents, emulsifying agents, non-aqueous vehicles or preservatives. The preparations may also contain buffer salts, flavouring agents, colouring agents or sweetening agents, as appropriate.
- Preparations for oral administration may be suitably formulated to give controlled release of the active compound.
- For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner.
- The compounds of formula (IA) or (IB) may be formulated for parenteral administration by injection, e.g. by bolus injection or infusion. Formulations for injection may be presented in unit dosage form, e.g. in glass ampoules or multi-dose containers, e.g. glass vials. The compositions for injection may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising, preserving and/or dispersing agents. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use.
- In addition to the formulations described above, the compounds of formula (IA) or (IB) may also be formulated as a depot preparation. Such long-acting formulations may be administered by implantation or by intramuscular injection.
- For nasal administration or administration by inhalation, the compounds according to the present invention may be conveniently delivered in the form of an aerosol spray presentation for pressurised packs or a nebuliser, with the use of a suitable propellant, e.g. dichlorodifluoromethane, fluorotrichloromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas or mixture of gases.
- The compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient. The pack or dispensing device may be accompanied by instructions for administration.
- For topical administration the compounds of use in the present invention may be conveniently formulated in a suitable ointment containing the active component suspended or dissolved in one or more pharmaceutically acceptable carriers. Particular carriers include, for example, mineral oil, liquid petroleum, propylene glycol, polyoxyethylene, polyoxypropylene, emulsifying wax and water. Alternatively, the compounds of use in the present invention may be formulated in a suitable lotion containing the active component suspended or dissolved in one or more pharmaceutically acceptable carriers. Particular carriers include, for example, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, benzyl alcohol, 2-octyldodecanol and water.
- For ophthalmic administration the compounds of use in the present invention may be conveniently formulated as micronized suspensions in isotonic, pH-adjusted sterile saline, either with or without a preservative such as a bactericidal or fungicidal agent, for example phenylmercuric nitrate, benzylalkonium chloride or chlorhexidine acetate. Alternatively, for ophthalmic administration compounds may be formulated in an ointment such as petrolatum.
- For rectal administration the compounds of use in the present invention may be conveniently formulated as suppositories. These can be prepared by mixing the active component with a suitable non-irritating excipient which is solid at room temperature but liquid at rectal temperature and so will melt in the rectum to release the active component. Such materials include, for example, cocoa butter, beeswax and polyethylene glycols.
- The quantity of a compound of use in the invention required for the prophylaxis or treatment of a particular condition will vary depending on the compound chosen and the condition of the patient to be treated. In general, however, daily dosages may range from around 10 ng/kg to 1000 mg/kg, typically from 100 ng/kg to 100 mg/kg, e.g. around 0.01 mg/kg to 40 mg/kg body weight, for oral or buccal administration, from around 10 ng/kg to 50 mg/kg body weight for parenteral administration, and from around 0.05 mg to around 1000 mg, e.g. from around 0.5 mg to around 1000 mg, for nasal administration or administration by inhalation or insufflation.
- The compounds of formula (IA) or (IB) above may be prepared by a process which comprises reacting a compound of formula Q-H with a compound of formula (IIIA) or (IIIB):
- wherein X, T, U, Q, R1 and R3 are as defined above, and L1 represents a suitable leaving group.
- The leaving group L1 is typically a halogen atom, e.g. chloro.
- The reaction will generally be carried out in the presence of a base, typically an organic amine such as triethylamine or N,N-diisopropylethylamine. The reaction is conveniently effected at ambient or elevated temperature in a suitable solvent, e.g. a lower alkanol such as ethanol or n-butanol, a cyclic ether solvent such as tetrahydrofuran, 2-methyltetrahydrofuran or 1,4-dioxane, or a dipolar aprotic solvent such as N,N-dimethyl-formamide.
- Alternatively, the leaving group L1 may be hydroxy (—OH), in which case the reaction may be accomplished at a suitable temperature (ambient or elevated) in a solvent such as acetonitrile or N,N-dimethylformamide, ideally in the presence of a coupling agent such as benzotriazol-1—yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP) or (benzotriazol-1—yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP), and a base, e.g. an organic base such as 1,8—diazabicyclo[5.4.0]undec-7—ene (DBU).
- In another procedure, the compounds of formula (IA) or (IB) above wherein Y represents —C(O)—, —S(O)2—or —C(O)O— may be prepared by a process which comprises reacting a compound of formula L2—C(O)—Z, L2—S(O)2—Z or L2—C(O)O—Z respectively with a compound of formula (IVA-1), (IVA-2), (IVA-3), (IVA-4), (IVA-5), (IVB-1), (IVB-2), (IVB-3), (IVB-4) or (IVB-5):
- wherein X, T, U, V, W, Z, A1, A2, R1 and R3 are as defined above, and L2 represents a suitable leaving group.
- The leaving group L2 is typically a halogen atom, e.g. chloro.
- The reaction is conveniently effected at ambient temperature in a suitable solvent, e.g. an ethereal solvent such as 1,4-dioxane, or a chlorinated solvent such as dichloro-methane, typically in the presence of a base. A suitable base for use in the reaction may be an organic base such as N,N-diisopropylethylamine, or an inorganic base such as potassium carbonate.
- Alternatively, the leaving group L2 may be 2-methyl-3-(trifluoromethylsulfonyl)-1H-imidazol-3-ium-1-yl, in which case the reaction may conveniently be effected at ambient temperature in an organic solvent such as acetonitrile.
- In a variant procedure, the compounds of formula (IA) or (IB) above wherein Y represents —C(O)— may be prepared by a process which comprises reacting a compound of formula (IVA-1), (IVA-2), (IVA-3), (IVA-4), (IVA-5), (IVB-1), (IVB-2), (IVB-3), (IVB-4) or (IVB-5) as defined above with a compound of formula Z—CO2H. Similarly, the compounds of formula (IA) or (IB) above wherein Y represents —C(O)C(O)— may be prepared by a process which comprises reacting a compound of formula (IVA-1), (IVA-2), (IVA-3), (IVA-4), (IVA-5), (IVB-1), (IVB-2), (IVB-3), (IVB-4) or (IVB-5) as defined above with a compound of formula Z—C(O)CO2H.
- The reaction is conveniently effected at ambient temperature in a suitable solvent, e.g. a dipolar aprotic solvent such as N,N-dimethylformamide, typically in the presence of a coupling reagent and a base. A suitable coupling reagent for use in the reaction may be O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU). A suitable base for use in the reaction may be an organic base such as N,N-diisopropyl-ethylamine.
- In another procedure, the compounds of formula (IA) or (IB) above wherein Y represents —C(O)NH— may be prepared by a process which comprises reacting a compound of formula (IVA-1), (IVA-2), (IVA-3), (IVA-4), (IVA-5), (IVB-1), (IVB-2), (IVB-3), (IVB-4) or (IVB-5) as defined above with an isocyanate derivative of formula Z—N═C═O, wherein Z is as defined above.
- The reaction is conveniently effected at a suitable temperature, e.g. ambient temperature or a temperature in the region of 0° C., in a suitable solvent or mixture of solvents. Such solvent or solvents may typically be selected as appropriate from an ethereal solvent such as 1,4-dioxane or tetrahydrofuran, a chlorinated solvent such as dichloromethane, a nitrile-containing solvent such as acetonitrile, and a dipolar aprotic solvent such as N,N-dimethylformamide. The reaction may optionally be performed in the presence of a base, e.g. an organic base such as diisopropylamine, N,N-diisopropylethyl-amine or triethylamine.
- Alternatively, the compounds of formula (IA) or (IB) above wherein Y represents —C(O)NH— may be prepared by a process which comprises reacting a compound of formula (IVA-1), (IVA-2), (IVA-3), (IVA-4), (IVA-5), (IVB-1), (IVB-2), (IVB-3), (IVB-4) or (IVB-5) as defined above with a compound of formula Z—NH2, wherein Z is as defined above, in the presence of triphosgene or 1,1′-carbonyldiimidazole.
- The reaction is conveniently effected at ambient temperature in a suitable solvent, e.g. a chlorinated solvent such as dichloromethane, or a dipolar aprotic solvent such as N,N-dimethylformamide, typically in the presence of a base, e.g. an organic base such as N,N-diisopropylethylamine.
- Alternatively, the compounds of formula (IA) or (IB) above wherein Y represents —C(O)NH— may be prepared by a two-step process which comprises: (i) reacting a compound of formula Z—NH2, wherein Z is as defined above, with phenyl chloroformate; and (ii) reacting the material thereby obtained with a compound of formula (IVA-1), (IVA-2), (IVA-3), (IVA-4), (IVA-5), (IVB-1), (IVB-2), (IVB-3), (IVB-4) or (IVB-5) as defined above.
- Step (i) of the above process is conveniently effected at a suitable temperature, e.g. ambient temperature or a temperature in the region of 0° C., in a suitable solvent, e.g. a cyclic ether solvent such as tetrahydrofuran or a chlorinated solvent such as dichloro-methane, typically in the presence of a base, e.g. an organic base such as pyridine or triethylamine. Step (ii) is conveniently effected at ambient or elevated temperature in a suitable solvent, e.g. a sulfoxide solvent such as dimethyl sulfoxide, or a nitrile-containing solvent such as acetonitrile, or a C1-4 alkanol such as ethanol, or a chlorinated solvent such as dichloromethane, typically in the presence of a base, e.g. an organic base such as N,N-diisopropylethylamine.
- In a further procedure, the compounds of formula (IA) or (IB) above wherein Y represents —S(O)2NH— may be prepared by a two-step process which comprises: (i) reacting a compound of formula (IVA-1), (IVA-2), (IVA-3), (IVA-4), (IVA-5), (IVB-1), (IVB-2), (IVB-3), (IVB-4) or (IVB-5) as defined above with methyl trifluoromethanesulfonate; and (ii) reacting the material thereby obtained with a compound of formula Z—NH2, wherein Z is as defined above.
- Step (i) of the above process is conveniently effected at a temperature in the region of 0° C. in a suitable solvent, typically a chlorinated solvent such as dichloromethane. Step (ii) is conveniently effected at an elevated temperature in a suitable solvent, e.g. a nitrile-containing solvent such as acetonitrile.
- In a further procedure, the compounds of formula (IA) or (IB) above wherein Y represents a covalent bond, and Z represents optionally substituted C1-6 alkyl, optionally substituted C3-7 cycloalkyl(C1-6)alkyl, optionally substituted C3-7 heterocycloalkyl(C1-6)-alkyl, optionally substituted aryl(C1-6)alkyl or optionally substituted heteroaryl(C1-6)alkyl, may be prepared by a process which comprises reacting a compound of formula (IVA-1), (IVA-2), (IVA-3), (IVA-4), (IVA-5), (IVB-1), (IVB-2), (IVB-3), (IVB-4) or (IVB-5) as defined above with a compound of formula Z1-L3 wherein Z1 represents C1-6 alkyl, C3-7 cycloalkyl(C1-6)alkyl, aryl(C1-6)alkyl, C3-7 heterocycloalkyl(C1-6)alkyl or heteroaryl(C1-6)-alkyl, any of which groups may be optionally substituted by one or more substituents, and L3 represents a suitable leaving group.
- The leaving group L3 is typically a halogen atom.
- The reaction is conveniently effected at ambient temperature in a suitable solvent, e.g. a dipolar aprotic solvent such as N,N-dimethylformamide, or a chlorinated solvent such as dichloromethane, typically in the presence of a base. A suitable base for use in the reaction may be an organic base such as triethylamine, or an inorganic base such as caesium carbonate.
- In a variant procedure, the compounds of formula (IA) or (IB) above wherein Y represents a covalent bond, and Z represents optionally substituted C1-6 alkyl, optionally substituted C3-7 cycloalkyl(C1-6)alkyl, optionally substituted C3-7 heterocycloalkyl(C1-6)-alkyl, optionally substituted aryl(C1-6)alkyl or optionally substituted heteroaryl(C1-6)alkyl, may be prepared by a two-step process which comprises: (i) reacting a compound of formula (IVA-1), (IVA-2), (IVA-3), (IVA-4), (IVA-5), (IVB-1), (IVB-2), (IVB-3), (IVB-4) or (IVB-5) as defined above with a compound of formula Z2—CHO, wherein Z2—CH2— corresponds to a group of formula Z1— as defined above; and (ii) reacting the material thereby obtained with a reducing agent.
- Steps (i) and (ii) of the above process are conveniently effected at ambient temperature in a suitable solvent, e.g. a C1-4 alkanol such as methanol. Step (i) is typically performed in the presence of a base, e.g. an organic base such as triethylamine. The reducing agent for use in step (ii) may suitably be an alkali metal borohydride such as sodium borohydride.
- The compounds of formula (IA) or (IB) above wherein Y represents a linker group of formula (Ya) as defined above may be prepared by a process which comprises reacting a compound of formula (IVA-1), (IVA-2), (IVA-3), (IVA-4), (IVA-5), (IVB-1), (IVB-2), (IVB-3), (IVB-4) or (IVB-5) as defined above with a compound of formula (V):
- wherein Z and R5 are as defined above, and L4 represents a suitable leaving group.
- The leaving group L4 is typically a C1-4 alkoxy group, e.g. ethoxy.
- The reaction is conveniently effected at ambient temperature in a suitable solvent, e.g. a lower alkanol such as ethanol, typically in the presence of a base, e.g. an organic base such as triethylamine.
- The intermediates of formula (IVA-1), (IVA-2), (IVA-3), (IVA-4), (IVA-5), (IVB-1), (IVB-2), (IVB-3), (IVB-4) or (IVB-5) above may be prepared by reacting a compound of formula (IIIA) or (IIIB) as defined above with a compound of formula (VIA), (VIB), (VIC), (VID) or (VIE):
- wherein V, W, A1 and A2 are as defined above, and RP represents hydrogen or an N-protecting group; followed, as necessary, by removal of the N-protecting group RP.
- In one embodiment, the N-protecting group RP is typically tert-butoxycarbonyl (BOC).
- In another embodiment, the N-protecting group RP is typically benzyl.
- The reaction between compound (IIIA) or (IIIB) and compound (VIA), (VIB), (VIC), (VID) or (VIE) is conveniently accomplished under conditions analogous to those described above for the reaction between the compound of formula Q-H and compound (IIIA) or (IIIB).
- Where the N-protecting group RP is BOC, subsequent removal of the BOC group may typically be accomplished by treatment with an acid, e.g. a mineral acid such as hydrochloric acid or sulphuric acid, or an organic acid such as trifluoroacetic acid. Alternatively, the BOC group may be removed by treatment with trimethylsilyl trifluoromethanesulfonate and 2,6—lutidine, typically at ambient temperature in a suitable solvent, e.g. a chlorinated solvent such as dichloromethane. Alternatively, the BOC group may be removed by treatment with trimethylsilyl iodide, typically at ambient temperature in a suitable solvent, e.g. a chlorinated solvent such as chloroform.
- Where the N-protecting group RP is benzyl, subsequent removal of the benzyl group may typically be accomplished by catalytic hydrogenation. Suitably, transfer hydrogenation conditions will be employed. A suitable hydrogenation catalyst of use in this procedure may be a transition metal catalyst such as palladium on carbon. The reaction will conveniently be performed at an elevated temperature in the presence of a hydrogen donor such as ammonium formate.
- The intermediates of formula (IIIA) or (IIIB) above wherein L1 is chloro may be prepared by treating a compound of formula (VIIA) or (VIIB):
- wherein X, T, U, R1 and R3 are as defined above; with a chlorinating agent.
- A suitable chlorinating agent for use in the above procedure is phosphorus oxychloride.
- The reaction is conveniently effected by mixing the reagents at an elevated temperature, typically in the presence of a base, e.g. an organic amine such as N,N-diisopropylethylamine or N,N-dimethylaniline.
- As will be appreciated, the intermediates of formula (IVA-1), (IVA-2), (IVA-3), (IVA-4), (IVA-5), (IVB-1), (IVB-2), (IVB-3), (IVB-4) and (IVB-5) correspond to compounds in accordance with the present invention wherein Y represents a covalent bond and Z is hydrogen. Similarly, the intermediates of formula (VIA), (VIB), (VIC), (VID) or (VIIE) wherein RP is hydrogen correspond to intermediates of formula Q-H wherein Y represents a covalent bond and Z is hydrogen. Likewise, the intermediates of formula (VIA), (VIB), (VIC), (VID) or (VIE) wherein RP is BOC correspond to intermediates of formula Q-H wherein Y represents —C(O)O— and Z is tert-butyl. Furthermore, the intermediates of formula (VIA), (VIB), (VIC), (VID) or (VIE) wherein RP is benzyl correspond to intermediates of formula Q-H wherein Y represents a covalent bond and Z is benzyl. The intermediates of formula (VIIA) and (VIIB) correspond to intermediates of formula (IIIA) or (IIIB) wherein L1 is hydroxy.
- Where they are not commercially available, the starting materials of formula (V), (VIA), (VIB), (VIC), (VID), (VIE), (VIIA) and (VIIB) may be prepared by methods analogous to those described in the accompanying Examples, or by standard methods well known from the art.
- It will be understood that any compound of formula (IA) or (IB) initially obtained from any of the above processes may, where appropriate, subsequently be elaborated into a further compound of formula (IA) or (IB) by techniques known from the art. By way of example, a compound comprising a N—BOC moiety may be converted into the corresponding compound comprising a N—H moiety by treatment with an acid, e.g. a mineral acid such as hydrochloric acid, or an organic acid such as trifluoroacetic acid.
- A compound wherein R1 represents halogen, e.g. chloro, may be converted into the corresponding compound wherein R1 represents amino (—NH2) in a two-step procedure which comprises: (i) treatment with benzylamine or 4-methoxybenzylamine; and (ii) removal of the benzyl or 4-methoxybenzyl moiety from the material thereby obtained by catalytic hydrogenation or by treatment with an acid, e.g. a mineral acid such as sulfuric acid, or an organic acid such as trifluoroacetic acid.
- A compound wherein R1 represents —SRa may be converted into the corresponding compound wherein R1 represents —SO2Ra by treatment with an oxidising agent, typically 3-chloroperoxybenzoic acid (MCPBA).
- A compound wherein R1 represents —SO2Ra, e.g. methylsulfonyl, may be converted into the corresponding compound wherein R1 represents —ORa by treatment with a sodium salt of formula NaORa. Similarly, a compound wherein R1 represents —SO2Ra, e.g. methylsulfonyl, may be converted into the corresponding compound wherein R1 represents cyano by treatment with a cyanide salt, e.g. an alkali metal cyanide salt such as sodium cyanide. Likewise, a compound wherein R1 represents —SO2Ra, e.g. methylsulfonyl, may be converted into the corresponding compound wherein R1 represents —NRbRc by treatment with an amine of formula H—NRbRc. By analogy, a compound wherein R1 represents —SO2Ra, e.g. methylsulfonyl, may be converted into the corresponding compound wherein R1 represents —NH2 by treatment with ammonium hydroxide.
- A compound wherein R2 represents —CO2Rd, in which Rd is other than hydrogen, may be converted into the corresponding compound wherein R2 represents carboxy (—CO2H) by treatment with a base, typically an alkali metal hydroxide such as sodium hydroxide.
- A compound wherein R2 represents carboxy (—CO2H) may be converted into the corresponding compound wherein R2 represents —CONRbRc or —CON(ORa)Rb by treatment with the appropriate reagent of formula H—NRbRc or H—N(ORa)Rb respectively. The reaction may typically be performed in the presence of a coupling agent such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) and an additive such as 1-hydroxybenzotriazole hydrate (HOBT), optionally in the presence of a base, e.g. an organic base such as N,N-diisopropylethylamine. Alternatively, the reaction may be performed in the presence of a coupling agent such as O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU) and a base, e.g. an organic base such as N,N-diisopropylethylamine.
- A compound wherein R2 represents carboxy (—CO2H) may be converted into the corresponding compound wherein R2 represents —CONH2 by treatment with ammonium chloride, typically in the presence of a coupling agent such as EDC and an additive such as HOBT, suitably in the presence of a base, e.g. an organic base such as diisopropylamine or N,N-diisopropylethylamine. A compound wherein R2 represents —CONH2 may be converted into the corresponding compound wherein R2 represents cyano (—CN) by treatment with phosphorus oxychloride. Alternatively, a compound wherein R2 represents —CONH2 may be converted into the corresponding compound wherein R2 represents cyano in a two-step procedure which comprises: (i) treatment with cyanuric chloride; and (ii) treatment of the material thereby obtained with water.
- A compound wherein R2 represents carboxy (—CO2H) may be converted into the corresponding compound wherein R2 represents hydrogen by heating in the presence of a base, e.g. an organic amine such as triethylamine.
- A compound wherein R2 represents carboxy (—CO2H) may be converted into the corresponding compound wherein R2 represents hydroxymethyl (—CH2OH) in a two-step procedure which comprises: (i) treatment with ethyl chloroformate and triethylamine; and (ii) treatment of the material thereby obtained with a reducing agent, typically an alkali metal borohydride such as sodium borohydride.
- A compound wherein R2 represents carboxy (—CO2H) may be converted into the corresponding compound wherein R2 represents hydroxy in a two-step procedure which comprises: (i) treatment with diphenyl phosphoryl azide; and (ii) treatment of the material thereby obtained with water.
- A compound wherein R2 represents carboxy (—CO2H) may be converted into the corresponding compound wherein R2 represents —NHCO2Rd, wherein Rd is other than hydrogen, in a two-step procedure which comprises: (i) treatment with diphenyl phosphoryl azide; and (ii) treatment of the material thereby obtained with the appropriate reagent of formula Rd—OH.
- A compound wherein R2 represents carboxy (—CO2H) may be converted into the corresponding compound wherein R2 represents a 3-substituted 1,2,4—oxadiazol-5—yl moiety in a two-step procedure which comprises: (i) treatment with an appropriately-substituted N′—hydroxyamidine derivative, typically in the presence of a coupling agent such as O-(7—azabenzotriazol-1—yl)-N,N,N′, N′-tetramethyluronium hexafluorophosphate (HATU), suitably in the presence of a base, e.g. an organic base such as N,N-diisopropyl-ethylamine; and (ii) treatment of the material thereby obtained with a strong base, suitably a strong inorganic base, e.g. an alkali metal tert-butoxide such as potassium tert-butoxide.
- A compound wherein R2 represents 4,5-dihydrooxazol-2-yl may be prepared from the corresponding compound wherein R2 represents —CONRbRc, in which Rb represents —CH2CH2OH and Rc represents hydrogen, by heating with a condensing agent such as N,N′-diisopropylcarbodiimide, typically in the presence of copper(II) trifluoromethane-sulfonate.
- A compound wherein R4 represents hydrogen may be converted into the corresponding compound wherein R4 represents C1-6 alkyl, e.g. methyl, by treatment with a C1-6 alkyl halide, e.g. iodomethane, usually in the presence of a base, suitably an inorganic base, e.g. potassium carbonate.
- Where a mixture of products is obtained from any of the processes described above for the preparation of compounds according to the invention, the desired product can be separated therefrom at an appropriate stage by conventional methods such as preparative HPLC; or column chromatography utilising, for example, silica and/or alumina in conjunction with an appropriate solvent system.
- Where the above-described processes for the preparation of the compounds according to the invention give rise to mixtures of stereoisomers, these isomers may be separated by conventional techniques. In particular, where it is desired to obtain a particular enantiomer of a compound of formula (IA) or (IB) this may be produced from a corresponding mixture of enantiomers using any suitable conventional procedure for resolving enantiomers. Thus, for example, diastereomeric derivatives, e.g. salts, may be produced by reaction of a mixture of enantiomers of formula (IA) or (IB), e.g. a racemate, and an appropriate chiral compound, e.g. a chiral base. The diastereomers may then be separated by any convenient means, for example by crystallisation, and the desired enantiomer recovered, e.g. by treatment with an acid in the instance where the diastereomer is a salt. In another resolution process a racemate of formula (IA) or (IB) may be separated using chiral HPLC. Moreover, if desired, a particular enantiomer may be obtained by using an appropriate chiral intermediate in one of the processes described above. Alternatively, a particular enantiomer may be obtained by performing an enantiomer-specific enzymatic biotransformation, e.g. an ester hydrolysis using an esterase, and then purifying only the enantiomerically pure hydrolysed acid from the unreacted ester antipode. Chromatography, recrystallisation and other conventional separation procedures may also be used with intermediates or final products where it is desired to obtain a particular geometric isomer of the invention.
- During any of the above synthetic sequences it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W. Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 3rd edition, 1999. The protecting groups may be removed at any convenient subsequent stage utilising methods known from the art.
- The following Examples illustrate the preparation of compounds according to the invention.
- The compounds in accordance with this invention potently inhibit the activity of human PI4KIIIβ.
- Compounds were assayed utilizing reagents from Invitrogen and Promega.
- Compounds were screened in 1% DMSO (final) as 3-fold serial dilutions from a starting concentration of 20 μM. The 2.5× PI4Kβ reagent, the 2.5× PI Lipid Kinase Substrate/ATP mixture and the 5× compounds were prepared in 20 mM Tris pH 7.5, 0.5 mM EGTA, 2 mM DTT, 5 mM MgCl2, 0.4% Triton. The final 25 μL Kinase Reaction consisted of: 4 nM PI4Kβ, 100 μM PI Lipid Kinase Substrate (both Invitrogen), and compound. The final ATP concentration in the assay was 10 μM. The detection reagents consisted of ADP-GIo™ Reagent and ADP-Glo™ Detect Reagent (Promega).
- Briefly, compound was added to PI4Kβ followed by addition of ATP/PI Lipid Kinase Substrate mixture. The reaction mixture was incubated for 60 minutes at room temperature. The ADP-Glo™ Reagent was added and the plate was incubated for 40 minutes at room temperature, followed by addition of ADP-Glo™ Detect Reagent. The plate was incubated for a further 120 minutes and read on a Luminescence plate reader. The data was fitted with XLfit from IDBS using model number 205.
- Compounds were assayed using a PI4Kbeta Adapta assay. Compounds were screened in 1% DMSO (final) as 3-fold serial dilutions from a starting concentration of 10 μM. The 2× PI4KB (PI4K beta)/PI Lipid Kinase Substrate mixture was prepared in 50 mM HEPES pH 7.5, 0.1% CHAPS, 1 mM EGTA, 4 mM MgCl2. The final 10 μL Kinase Reaction consisted of 7.5-60 ng PI4Kβ, and 100 μM PI Lipid Kinase Substrate in 32.5 mM HEPES pH 7.5, 0.05% CHAPS, 0.5 mM EGTA, 2 mM MgCl2. The final ATP concentration in the assay was 10 μM. The detection mix consisted of EDTA (30 mM), Eu-anti-ADP antibody (6 nM) and ADP tracer. The detection mix contained the EC60 concentration of tracer for 5-150 μM ATP.
- Briefly, ATP was added to compound, followed by addition of a PI4Kβ/PI Lipid Kinase Substrate mixture. The plate was shaken for 30 seconds to mix, then briefly centrifuged. The reaction mixture was incubated for 60 minutes at room temperature. The detection mix was added, then the plate was shaken and centrifuged. The plate was incubated for 60 minutes at room temperature and read on a fluorescence plate reader. The data was fitted with XLfit from IDBS using model number 205.
- When tested in the above assay (Procedure A or Procedure B), the compounds of the accompanying Examples were all found to possess IC50 values for inhibition of the activity of human PI4KIIIβ of 50 μM or better.
- Certain compounds in accordance with this invention are potent inhibitors when measured in the MLR test described below.
- Human peripheral blood mononuclear cells (PBMCs) were isolated from buffy coats, obtained from healthy blood donors by Ficoll (Lymphoprep, Axis-Shield PoC AS, Oslo, Norway) density-gradient centrifugation. The cells at the Ficoll-plasma interface were washed three times and used as “Responder” cells. RPMI 1788 (ATCC, N° CCL-156) cells were treated with mitomycin C (Kyowa, Nycomed, Brussels, Belgium) and used as “Stimulator” cells. Responder cells (0.12×106), Stimulator cells (0.045×106) and compounds (in different concentrations) were cocultured for 6 days in RPMI 1640 medium (BioWhittaker, Lonza, Belgium) supplemented with 10% fetal calf serum, 100 U/ml Geneticin (Gibco, LifeTechnologies, UK). Cells were cultured in triplicate in flat-bottomed 96-well microtiter tissue culture plates (TTP, Switzerland). After 5 days, cells were pulsed with 1 μCi of methyl-3H thymidine (MP Biomedicals, USA), harvested 18 h later on glass filter paper and counted. Proliferation values were expressed as counts per minute (cpm), and converted to % inhibition with respect to a blank MLR test (identical but without added compound). The IC50 was determined from a graph with at least four points, each derived from the mean of 2 experiments. The IC50 value represents the lowest concentration of test compound (expressed in μM) that resulted in a 50% inhibition of the MLR.
- Certain compounds of the accompanying Examples were found to generate IC50 values in the MLR test of 10 μM or better.
-
-
THF: tetrahydrofuran MeOH: methanol DMF: N,N-dimethylformamide DMSO: dimethyl sulfoxide DCM: dichloromethane DIPEA: N,N-diisopropylethylamine EtOH: ethanol EtOAc: ethyl acetate MeCN: acetonitrile MCPBA: 3-chloroperoxybenzoic acid TFA: trifluoroacetic acid Et2O: diethyl ether NMP: 1-methyl-2-pyrrolidinone DBU: 1,8- DIC: N,N′-diisopropylcarbodiimide diazabicyclo[5.4.0]undec-7-ene BOP: (Benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate PyBOP: (Benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate TBTU: O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate h: hour r.t.: room temperature MS: Mass Spectrometry M: mass LCMS: Liquid Chromatography Mass Spectrometry ES+: Electrospray Positive Ionisation HPLC: High Performance Liquid Chromatography TLC: thin layer chromatography RT: retention time -
- High pH (approximately pH 9.5)
- Column: Waters XBridge, C18, 2.1×20 mm, 2.5 μm
- Solvent A: 10 mM ammonium formate in water+0.1% ammonia solution
- Solvent B: acetonitrile+5% solvent A+0.1% ammonia solution
- Gradient Program:
-
Time A % B % 0.00 95.0 5.0 1.50 5.0 95.0 2.50 5.0 95.0 3.00 95.0 5.0 -
- High pH (approximately pH 9.5)
- Column: Waters XBridge, C18, 2.1×20 mm, 2.5 μm
- Solvent A: 10 mM ammonium formate in water+0.1% ammonia solution
- Solvent B: acetonitrile+5% solvent A+0.1% ammonia solution
- Gradient Program:
-
Time A % B % 0.00 95.0 5.0 4.00 5.0 95.0 5.00 5.0 95.0 5.10 95.0 5.0 - A mixture of dimethyl 4-aminothiophene-2,3-dicarboxylate (1.08 g, 5 mmol), chloroformamidine hydrochloride (1.44 g, 12.5 mmol) and dimethyl sulfone (2.35 g, 25 mmol) was finely ground with a pestle and mortar, and the mixture was heated at 130° C. for 40 minutes, then cooled to r.t. Water was poured into the reaction mixture, and concentrated ammonia solution was added to basify the reaction solution (ice bath). The precipitate was collected, washed with water and dried in vacuo to provide the title compound (1.1 g, 97%) as a yellow solid. 13C NMR (75 MHz, DMSO-d6) δ 161.1, 156.8, 151.3, 151.2, 131.8, 123.1, 113.5, 52.6. MS m/z (%) 226 [M+H]+.
- Methyl 2-amino-4-(piperazin-1-yl)thieno[3,4-d]pyrimidine-5-carboxylate
- To a suspension of Intermediate 1 (6.78 g, 30.11 mmol), piperazine (7.7 g, 90.23 mmol) and BOP (13.3 g, 30.11 mmol) in DMF (100 mL) was added DBU (6.7 mL, 45.16 mmol). The reaction mixture was stirred at r.t. for 16 h. The solvent was evaporated in vacuo, then the residue was purified by silica gel chromatography (DCM:MeOH:NH3—MeOH 100:10:1), to provide the title compound (3.6 g, 41%) as a yellow solid. δH (300 MHz, DMSO-d6) 7.42 (s, 1H), 6.16 (s, 2H), 3.84 (s, 3H), 3.52 (s, 4H), 2.76 (s, 4H). MS m/z (%) 294 [M+H]+.
- To a solution of Intermediate 2 (0.82 g, 2.79 mmol) in DMF (10 mL) were added di-tert-butyl dicarbonate (0.73 g, 3.35 mmol) and triethylamine (0.47 mL, 3.35 mmol). The reaction mixture was stirred at room temperature for 5 h, then partitioned between DCM and water. The layers were separated, and the aqueous layer was extracted twice with DCM. The combined organic phases were dried with anhydrous MgSO4. The solvent was evaporated in vacuo, and the residue was precipitated in a mixture of EtOAc and hexane, to provide the title compound (0.96 g, 87%) as a yellow solid. MS m/z (%) 394 [M+H]+.
- To a suspension of Intermediate 3 (1.1 g, 2.79 mmol) in a mixture of MeOH and water (10:1, 11 mL) was added 40% aqueous NaOH solution (0.95 mL, 13.97 mmol). The reaction mixture was heated at reflux for 3 h, then concentrated and dissolved in water (5 mL). Concentrated HCl was added dropwise to acidify the solution to pH 4-5 (ice bath). The resulting precipitate was collected, washed with water and dried in vacuo to provide the title compound (0.73 g, 68%) as a yellow solid. MS m/z (%) 380 [M+H]+.
- A solution of Intermediate 4 (76 mg, 0.2 mmol) and triethylamine (84 μL, 0.6 mmol) in DMF (6 mL) was heated at 100° C. for 2 h. The reaction mixture was concentrated to dryness giving the title compound (66 mg, 98%) as a yellowish solid. MS m/z (%) 336 [M+H]+.
- Intermediate 5 (66 mg, 0.2 mmol) was dissolved in a mixture of 4 M HCl in 1,4-dioxane (1 mL) and MeOH (1 mL). The reaction mixture was stirred at room temperature for 3 h, then evaporated to dryness and co-evaporated twice with ammonia in MeOH, to provide the title compound (47 mg, 100%) as a yellow solid. MS m/z (%) 236 [M+H]+.
- A mixture of methyl 4—aminothiophene-3-carboxylate (1.0 g, 6.4 mmol), chloro-formamidine hydrochloride (1.83 g 15.9 mmol) and dimethyl sulfone (2.99 g, 31.8 mmol) was finely ground with a pestle and mortar, and the mixture was heated at 130° C. for 40 minutes. Water was poured into the reaction mixture, and concentrated ammonia solution was added to basify the reaction solution (ice bath). The precipitate was collected, washed with water and dried in vacuo, to provide the title compound (0.99 g, 92%) as a yellow solid. 13C NMR (75 MHz, DMSO-d6) δ 159.7, 151.4, 148.8, 127.4, 123.7, 108.4. MS m/z (%) 168 [M+H]+.
- Intermediate 4 (76 mg, 0.2 mmol) was dissolved in a mixture of 4M HCl in 1,4-dioxane (1 mL) and MeOH (1.25M, 1 mL). The reaction mixture was stirred at room temperature for 1.5 h, then evaporated to dryness, and twice co-evaporated with ammonia in MeOH. The resulting crude material was suspended in DMF (10 mL) and treated with 4-methoxyphenyl isocyanate (26 μL, 0.2 mmol). The reaction mixture turned clear, and was stirred at room temperature for 2 h. The reaction mixture was concentrated, and the residue was precipitated in a small amount of water. The precipitate was collected, and washed with water and EtOH, then dried in vacuo, to yield the title compound (73 mg, 85% overall) as a yellow solid. δH (300 MHz, DMSO-d6) 8.49 (s, 1H), 8.09 (s, 2H), 7.29 (d, 2H, J 9.0 Hz), 7.07 (s, 1H), 6.79 (d, 2H, J 9.0 Hz), 3.96 (m, 4H), 3.69 (s, 3H), 3.59 (m, 4H). MS m/z (%) 429 [M+H]+.
- To a solution of Intermediate 8 (214 mg, 0.5 mmol), TBTU (241 mg, 0.75 mmol) and DIPEA (260 μL, 1.5 mmol) in DMF (10 mL) was added 2-hydroxyethylamine (92 μL, 1.5 mmol). The reaction mixture was stirred for 6 h, then concentrated to dryness in vacuo. The residue was purified by silica gel chromatography (DCM:MeOH 9:1, then DCM:MeOH:NH3—MeOH 100:10:1) to provide the title compound (166 mg, 70%) as a yellow solid. 13C NMR (75 MHz, DMSO-d6) δ 161.7, 160.5, 158.4, 155.2, 154.6, 154.5, 134.3, 133.3, 121.6 (2C), 114.4, 113.5 (2C), 108.8, 59.3, 55.1, 48.1 (2C), 43.0 (2C), 42.7. MS m/z (%) 472 [M+H]+.
- 4M HCl in 1,4-dioxane (14.7 mL, 59.1 mmol) was added dropwise to a solution of cyanamide (1.86 g, 44.3 mmol) in 1,4-dioxane (5 mL). A thick white precipitate formed. The reaction mixture was left to stir for 1 h, then evaporated to dryness. The resulting crude material (2.03 g, 17.6 mmol) was treated with ethyl 4-amino-3-methylisoxazole-5-carboxylate (3.0 g, 17.6 mmol) in diethylene glycol dimethyl ether (10 mL), then the reaction mixture was heated at 180° C. (reflux) and maintained at this temperature for 5 minutes. A brown tar formed on the bottom of the flask. The reaction mixture was cooled to r.t. and the solvent was decanted away. The resulting crude material (3.70 g, 17 mmol) was treated with 2M NaOH in water (15 mL, 150 mmol) and heated at 70° C., then cooled to r.t. The reaction mixture was cooled in an ice-bath, and acidified to pH 2 with concentrated HCl. The resulting precipitate was collected, washed with diethyl ether, and dried in vacuo, to give the title compound (2.7 g, 93%). δH (400 MHz, DMSO-d6) 11.41 (s, 1H), 6.54 (s, 2H), 2.33 (s, 3H).
- Intermediate 10 (2.70 g, 16 mmol) was slurried in phosphorus oxychloride (33 mL) and DIPEA (5.3 mL) was added. The mixture was heated at reflux for 5 h. Upon cooling, the reaction mixture was concentrated in vacuo. The brown oil was partitioned between EtOAc and water. The organic layer was dried over Na2SO4 and concentrated. The resulting crude brown oil was dissolved in DMF (10 mL) and DIPEA (1.3 mL) was added, followed by (S)-tert-butyl 3-ethylpiperazine-1-carboxylate (0.96 g, 4.17 mmol). The reaction mixture was stirred at 70° C. overnight. The resulting solution was concentrated in vacuo, and the residue was purified by silica gel chromatography (gradient 40-100% EtOAc in isohexane). The resulting crude material was dissolved in EtOH, then 4M HCl in 1,4—dioxane (10 mL) was added. The reaction mixture was stirred for 2 h, then concentrated in vacuo, to give the title compound (1.0 g, 19% overall) as a sticky brown solid. LCMS (ES+) MH+ 263, RT 0.76 minutes (method 1).
- Iodomethane (0.75 mL, 12 mmol) was added to a suspension of ethyl 4-nitro-1H-pyrazole-3-carboxylate (2 g, 10.80 mmol) and potassium carbonate (2.24 g, 16.2 mmol) in acetonitrile (50 mL). The reaction mixture was stirred overnight, then concentrated in vacuo. The residue was partitioned between DCM and brine, then separated. The organic layer was passed through a phase separator cartridge, then evaporated. The resulting crude material was purified by silica gel chromatography (gradient 5—30% EtOAc in isohexane). The title compound (1.31 g, 60.9%) was obtained as a white solid. δH (400 MHz, DMSO-d6) 8.94 (s, 1H), 4.36 (q, 2H, J 7.1 Hz), 3.95 (s, 3H), 1.30 (t, 3H, J 7.1 Hz).
- Tin(II) chloride dihydrate (7.42 g, 32.9 mmol) was added to a solution of Intermediate 12 (1.31 g, 6.58 mmol) in EtOH (50 mL). The reaction was heated at 50° C. with stirring for 3.5 h, then cooled to room temperature and concentrated in vacuo. The residue was diluted with DCM and treated with 2M aqueous NaOH solution. A viscous thick precipitate formed. The mixture was filtered through celite, and the two layers were separated. The aqueous layer was extracted with DCM (twice). The combined organic layers were passed through a phase separator cartridge, then evaporated. The resulting crude material was purified by silica gel chromatography (gradient 25-75% EtOAc in isohexane). The title compound (0.32 g, 29%) was isolated as a dark blue/black oil. δH (400 MHz, DMSO-d6) 7.12 (s, 1H), 4.66 (s, 2H), 4.23 (q, 2H, J 7.1 Hz), 3.76 (s, 3H), 1.27 (t, 3H, J 7.1 Hz).
- 5-Amino-2-methylpyrazolo[4,3-d]pyrimidin-7-ol
- Prepared from Intermediate 13 (0.32 g, 1.9 mmol), 4M HCl in 1,4-dioxane (1.6 mL, 6.4 mmol), cyanamide (200 mg, 4.76 mmol), 1,4-dioxane (5 mL), diethylene glycol dimethyl ether (10 mL) and 2M aqueous NaOH solution (15 mL) according to the procedure described for Intermediate 10, except that during the final step the title compound precipitated from the aqueous solution at pH 7. The title compound (162 mg, 52%) was obtained as a brown solid. δH (400 MHz, DMSO-d6) 10.59 (s, 1H), 7.70 (s, 1H), 5.93 (s, 2H), 3.94 (s, 3H).
- tert-Butyl (3S)-4-(5-amino-2-methylpyrazolo[4,3-d]pyrimidin-7-yl)-3-methylpiperazine-1-carboxylate
- DBU (0.22 mL, 1.5 mmol) was added to a suspension of Intermediate 14 (162 mg, 0.98 mmol), (S)-tert-butyl 3-methylpiperazine-1-carboxylate (218 mg, 1.09 mmol) and PyBOP (679 mg, 1.30 mmol) in MeCN (5 mL). The reaction mixture was heated at 60° C. for 4 days, then cooled to room temperature and concentrated in vacuo. The residue was partitioned between EtOAc and water, filtered to remove a small quantity of insoluble material, and separated. The organic layer was washed with brine, dried with MgSO4 and evaporated. The resulting crude material was purified by NH-silica gel chromatography (gradient 50-100% EtOAc in isohexane). The title compound (61 mg, 17.9%) was isolated as a colourless oil. δH (400 MHz, DMSO-d6) 7.75 (s, 1H), 5.52 (s, 2H), 3.96-4.04 (m, 2H), 4.00 (s, 3H), 3.81-3.86 (m, 1H), 3.09-3.30 (m, 3H), 3.06-3.21 (m, 1H), 1.43 (s, 9H), 1.17 (d, 3H, J 6.7 Hz).
- 4M HCl in 1,4-dioxane (2 mL) was added to Intermediate 15 (61 mg, 0.18 mmol). The reaction mixture was stirred for 2.5 h, then concentrated in vacuo. The residue was dissolved in water, then washed with DCM (twice). The aqueous solution was basified to pH 14 with 2M aqueous NaOH solution, then extracted with 10% MeOH in DCM (5 times). The organic extracts were combined, passed through a phase separator cartridge and evaporated, to give the title compound (36 mg, 83%) as a brown gum. LCMS (ES+) [M+H]+248, RT 0.55 minutes (method 1).
- To a solution of methyl 1,3-dimethyl-4-nitro-1H-pyrazole-5-carboxylate (0.3 g, 1.5 mmol) in MeOH (3 mL) was added Raney nickel (50% in water, 20 mg). The solution was stirred overnight under a hydrogen atmosphere. The reaction mixture was filtered through Celite, and washed with MeOH. The solvent was evaporated in vacuo, yielding the title compound (0.206 g, 81%), an off-white solid. 13C NMR (CDCl3, 75 MHz) δ 160.5, 133.8, 130.5, 117.1, 50.9, 39.0, 9.8. MS (m/z) 170 [M+H]+.
- To a solution of Intermediate 17 (206 mg, 1.2 mmol) in acetone (10 mL) was added benzoyl isothiocyanate (172 μL, 1.3 mmol). The solution was stirred for 1 h, then extracted with EtOAc and brine. The organic layer was dried over MgSO4. The solvents were evaporated in vacuo. The resulting crude material was dissolved in acetone (15 mL), MeOH (15 mL) and water (2.5 mL). Potassium carbonate (330 mg, 2.4 mmol) was added, and the mixture was stirred at reflux for 2 h. The reaction mixture was cooled and placed in an ice bath. Acetic acid was added until pH 7. The precipitated solids were isolated by filtration and dried, to give the title compound (140 mg, 26% overall) as a yellow solid. 13C NMR (DMSO-d6, 75 MHz) δ 174.1, 153.8, 133.0, 129.8, 123.4, 38.6, 11.7. MS (m/z) 197 [M+H]+.
- Prepared from methyl 4-amino-1-methyl-1H-pyrazole-5-carboxylate (1 g, 6.4 mmol) according to the procedure described for Intermediate 18 to give the title compound (289 mg, 25%) as a yellow solid. 13C NMR (DMSO-d6, 75 MHz) δ 173.4, 152.8, 130.8, 123.7, 122.1, 38.3. MS (m/z) 183 [M+H]+.
- To a solution of Intermediate 18 (131 mg, 0.67 mmol) in EtOH (3 mL) was added aqueous NaOH solution (1.73N, 782 μL), followed by iodomethane (44 μL, 0.70 mmol). The reaction mixture was stirred at r.t. and monitored by TLC. After completion, a 2N solution of sulfuric acid was added dropwise until pH 7. The mixture was cooled (0° C.), and the precipitated solids were isolated by filtration and dried, to give the title compound (130 mg, 33%) as a yellow solid. 13C NMR (DMSO-d6, 75 MHz) δ 154.2, 153.0, 139.2, 138.1, 123.6, 37.8, 13.0, 10.4. MS (m/z) 211 [M+H]+.
- Prepared from Intermediate 19 (289 mg, 1.6 mmol) according to the procedure described for Intermediate 20 to give the title compound (243 mg, 78%) as a yellow solid. 13C NMR (DMSO-d6, 75 MHz) δ 153.9, 140.1, 131.3, 123.7, 123.3, 38.4, 13.1. MS (m/z) 197 [M+H]+.
- To a cooled (ice bath) solution of the appropriate amine (1 mmol) in THF (50 mL) was added pyridine (1.1 equivalents), followed by phenyl chloroformate (1 equivalent) dropwise. The reaction mixture was allowed to warm to room temperature. When LCMS confirmed complete conversion of the amine to the desired carbamate, the reaction mixture was quenched with water. The title compound was then either collected by filtration, or extracted into DCM, phase separated and concentrated in vacuo, and used without further purification.
-
LCMS Data Int. Name RT [M + H[+ Method 22 Phenyl N-(6-ethoxy-2-methylpyridin-3-yl)carbamate 1.45 273 1 23 Phenyl N-[2-methyl-4-(trifluoromethoxy)phenyl]- 2.26 312 1 carbamate 24 Phenyl N-(2,6-dimethoxypyridin-3-yl)carbamate 1.44 275 1 25 Phenyl N-[6-(3,3-difluoroazetidin-1-yl)-2-methyl- 1.34 320 1 pyridin-3-yl]carbamate 26 Phenyl N-(4-methoxy-2-methylphenyl)carbamate 1.87 258 2 27 Phenyl N-(4-methoxy-3-methylphenyl)carbamate 2.02 258 2 28 Phenyl N-[6-(dimethylamino)-2-methylpyridin-3-yl]- 1.79 272 2 carbamate 29 Phenyl N-[6-(azetidin-1-yl)-2-methylpyridin-3-yl]- 1.58 284 2 carbamate 30 Phenyl N-[5-methoxy-6-(trifluoromethyl)pyridin-2- 2.14 313 2 yl]carbamate 31 Phenyl N-(4-isopropoxy-2-methylphenyl)carbamate 2.20 286 2 - Iodomethane (0.98 mL, 16 mmol) was added to a suspension of 2,4-dichloro-5H-pyrrolo[3,2-d]pyrimidine (3 g, 15.8 mmol) and cesium carbonate (5.14 g, 15.8 mmol) in DMF (50 mL). The reaction mixture was stirred for 1.5 h, then water was added. The resulting thick white precipitate was filtered off, then washed with water and isohexane. The residue was concentrated by evaporation to provide the title compound (2.58 g, 81%) as a white solid. LCMS (ES+) [M+H]+ 202, 204, RT 1.13 minutes (method 1).
- DIPEA (4.5 mL, 26 mmol) was added to a solution of Intermediate 32 (2.58 g, 12.76 mmol) and (S)-tert-butyl 3-methylpiperazine-1-carboxylate (2.67 g, 13.3 mmol) in DMF (50 mL). The reaction mixture was heated to 110° C. and stirred for 4 days. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was dissolved in EtOAc (50 mL), washed with saturated aqueous NaHCO3 solution (50 mL) and brine (2×50 mL), then dried over Na2SO4 and evaporated. The crude residue was purified by silica gel chromatography (gradient of 30-70% EtOAc in isohexane) to provide the title compound (3.93 g, 84%) as a brown viscous foaming gum. LCMS (ES+) [M+H]+ 366, 368, RT 1.51 minutes (method 1).
- A solution of Intermediate 33 (3.93 g, 10.75 mmol) in 4-methoxybenzylamine (7 mL) was heated at 170° C. under microwave irradiation for 2 h. The reaction mixture was diluted with EtOAc (50 mL) and water (50 mL), then separated. The organic phase was washed with water (50 mL) and brine (50 mL), then dried (Na2SO4) and evaporated onto silica. The crude residue was purified by NH-silica gel (gradient of 10-45% EtOAc in isohexane) to provide the title compound (2.64 g, 53%) as a cream-coloured foaming gum. LCMS (ES+)[M+H]+ 467, RT 1.60 minutes (method 1).
- Intermediate 34 (2.64 g, 5.65 mmol) was dissolved in TFA (50 mL) and the reaction mixture was heated at 50° C. overnight with stirring. The reaction mixture was cooled to room temperature and concentrated in vacuo. The resulting dark pink/brown sticky gum was triturated with diethyl ether and filtered, then washed with diethyl ether and concentrated by evaporation, to provide the title compound (2.80 g, quantitative) as a cream-coloured solid. LCMS (ES+) [M+H]+ 247, RT 0.90 minutes (method 1).
- Intermediate 21 (3 g, 15.3 mmol) was suspended in POCl3 (10.6 g, 8.00 mL, 68.9 mmol) with N,N-diethylaniline (1.15 g, 1.23 mL, 7.72 mmol). The reaction mixture was heated at 110° C. for 1 h, then cooled and stirred at r.t. overnight. The residue was concentrated to dryness, then partitioned between DCM and brine. The organic layers were phase separated, then concentrated. The resulting sticky yellow gum was taken up in 2-methyltetrahydrofuran (60 mL), then (S)-tert-butyl 3-methylpiperazine-1-carboxylate (1.9 g, 9.32 mmol) and DIPEA (1.21 g, 1.63 mL, 9.32 mmol) were added. The reaction mixture was heated at reflux for 4 days. The reaction was partitioned into water, then the organic layers were dried over Na2SO4 and concentrated in vacuo. The resulting yellow semi-solid was purified by column chromatography (SiO2, 100% EtOAc) to give the title compound (1.5 g, 26%) as a yellow solid. LCMS (ES+) [M+H]+ 379, RT 2.09 minutes (method 1).
- Intermediate 36 (1.5 g, 4.0 mmol) in DCM (100 mL) was treated with MCPBA (2.0 g, 7.9 mmol). The reaction mixture was stirred overnight, then partitioned between DCM and saturated aqueous NaHCO3 solution. The organic layers were separated and dried over Na2SO4, then concentrated in vacuo, to give the title compound (1.38 g, 85%) as a yellow solid. LCMS (ES+) [M+H]+ 411, RT 1.57 minutes (method 1).
- Intermediate 37 (1.38 g, 3.36 mmol) was dissolved in 1,4-dioxane (20 mL) and loaded into a pressure vessel with 15% aqueous NH4OH solution (20 mL). The mixture was heated at 100° C. for 2 h, then at 110° C. and left for 4 h. The reaction mixture was stirred at r.t. overnight, then heated again with fresh ammonia solution for 2 h at 110° C. The reaction mixture was concentrated, then partitioned between DCM and water. The organic layers were phase separated and concentrated. The residue was purified by column chromatography (SiO2, gradient of 100% EtOAc to 20% MeOH in EtOAc) to give the title compound (450 mg, 38.5%). LCMS (ES+) [M+H]+ 348, RT 1.41 minutes (method 1).
- 1-Methyl-7- [(2S)-2-methylpiperazin-1-yl]pyrazolo[4,3 -d]pyrimidin-5-amine dihydrochloride
- Intermediate 38 (5 g, 14.39 mmol) in 4N HCl in dioxane (100 mL) was stirred overnight at r.t. The resultant solid was collected by filtration to yield the title compound (4.5 g, 98%) as a buff-coloured solid. LCMS (ES+) [M+H]+ 248, RT 0.61 minutes (method 1).
- tert-Butyl (35)-4-[1,3-dimethyl-5-(methylsulfanyl)-1H-pyrazolo[4,3-d]pyrimidin-7-yl]-3-methylpiperazine-1-carboxylate
- To a stirred solution of Intermediate 20 (1.3 g, 6.19 mmol) in POCl3 (20 mL) were added DMF (0.1 mL) and pyridine (0.1 mL). The reaction mixture was heated at 100° C. for 2 h, then evaporated in vacuo. The crude residue was neutralized with saturated aqueous NaHCO3 solution. The aqueous layer was extracted with EtOAc (2×20 mL), then the organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was taken up in EtOH (25 mL) in a sealed tube, then (S)-tert-butyl 3-methyl-piperazine-1-carboxylate (1.41 g, 7.05 mmol) and DIPEA (2.3 mmol, 14.1 mmol) were added. The reaction mixture was heated at 100° C. for 16 h, then cooled to r.t. and concentrated in vacuo. The crude residue was purified by column chromatography (normal phase; silica 100-200 mesh; 50% EtOAc in hexanes) to afford the title compound (1.3 g, 84%) as a yellow solid. LCMS (ES+) [M+H]+ 393, RT 3.01 minutes (method 2).
- Prepared from Intermediate 40 (1.1 g, 2.8 mmol) according to the procedure described for Intermediate 37 to give the title compound (1.1 g, 93%) as a pale yellow solid. LCMS (ES+) [M+H]+ 425, RT 2.41 minutes (method 2).
- To a stirred solution of Intermediate 41 (1 g, 2.35 mmol) in 1,4-dioxane (50 mL) in a sealed tube was added 15% aqueous NH4OH solution (50 mL). The mixture was cooled to −20° C. and ammonia gas was bubbled through for 20 minutes. The reaction mixture was heated at 100° C. for 16 h. After cooling, the white solid that had precipitated was filtered and dried under vacuum to afford the title compound (0.60 g, 71%) as a white solid. LCMS (ES+) [M+H]+ 362, RT 2.29 minutes (method 2).
- To a stirred solution of Intermediate 42 (0.45 g, 1.24 mmol) in DCM (2 mL) was added TFA (2 mL) at 0° C. The reaction mixture was stirred at r.t. for 30 minutes, then concentrated in vacuo. The crude residue was co-evaporated with 7N ammonia in methanol to afford the title compound (quantitative), which was used without further purification. LCMS (ES+) [M+H]+ 262, RT 1.93 minutes (method 2).
- Methyl 2-amino-4-{4-[(4-methoxyphenyl)carbamoyl]piperazin-1-yl}thieno[3,4-d]-pyrimidine-5-carboxylate
- To a suspension of Intermediate 2 (117 mg, 0.4 mmol) in 1,4-dioxane (12 mL) was added 4-methoxyphenyl isocyanate (63 μL, 0.48 mmol) at room temperature. The reaction mixture was stirred for 3 h, then partitioned between DCM and water. The organic phase was dried with anhydrous MgSO4, then the solvent was evaporated in vacuo. The residue was purified by silica gel chromatography (DCM:MeOH 15:1) to provide the title compound (160 mg, 90%) as a yellow solid. δH (300 MHz, CDCl3+CD3OD) 7.33 (s, 1H), 7.23 (d, 2H, J 9.0 Hz), 6.82 (d, 2H, J 9.0 Hz), 3.92 (s, 3H), 3.76 (s, 3H), 3.75 (m, 4H), 3.62 (m, 4H). MS m/z (%) 443 [M+H]+.
- Prepared from Intermediate 2 (88 mg, 0.3 mmol) and 4-methoxy-2-methylphenyl isocyanate (49 μL, 0.36 mmol) according to the procedure described for Example 1 to give the title compound (81 mg, 59%) as a yellow solid. δH (300 MHz, CDCl3+CD3OD) 7.35 (s, 1H), 7.04 (m, 1H), 6.68 (m, 2H), 3.94 (s, 3H), 3.76 (s, 3H), 3.75 (m, 4H), 3.62 (m, 4H), 2.22 (s, 3H). MS m/z (%) 457 [M+H]+.
- Prepared from Intermediate 2 (70 mg, 0.24 mmol) and 4-(dimethylamino)phenyl isocyanate (41 mg, 0.25 mmol) according to the procedure described for Example 1 to give the title compound (58 mg, 53%) as a yellow solid. 13C NMR (75 MHz, CDCl3 +CD3OD) δ 165.2, 164.05, 162.5, 160.4, 159.0, 151.4, 132.8, 130.0, 126.8 (2C), 121.4, 118.1, 117.4 (2C), 56.2, 51.9 (2C), 47.0 (2C), 44.7 (2C). MS m/z (%) 456 [M+H]+.
- To a solution of Example 1 (160 mg, 0.36 mmol) in absolute EtOH (10 mL) was added sodium hydride (60% in mineral oil, 15 mg, 0.36 mmol) under nitrogen. The reaction mixture was stirred at r.t. for 18 h under nitrogen, then partitioned between DCM and water and separated. The aqueous layer was extracted with DCM (twice). The combined organic phases were dried with anhydrous MgSO4, concentrated, and purified by silica gel chromatography (DCM:MeOH 10:1), to provide the title compound (85 mg, 52%) as a yellow solid. 13C NMR (75 MHz, CDCl3) δ 160.9, 160.4, 158.1, 156.1, 155.8, 153.8, 132.0, 127.6, 122.8 (2C), 117.6, 114.3, 114.2 (2C), 62.2, 55.6, 48.5 (2C), 43.6 (2C), 14.4. MS m/z (%) 457 [M+H]+.
- Intermediate 6 was suspended in DMF (10 mL) and treated with 4-methoxy-2-methylphenyl isocyanate (27 μL, 0.2 mmol). The solution turned clear and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated in vacuo, and purified by silica gel chromatography (DCM:MeOH 19:1, then DCM: MeOH:NH3—MeOH 100:10:1), to provide the title compound (45 mg, 55%) as a yellow solid. δH (300 MHz, CDCl3+CD3OD) 8.26 (d, 1H, J 3.0 Hz), 7.08-7.23 (m, 2H), 6.69-6.77 (m, 2H), 4.23 (m, 4H), 3.79 (m, 4H), 3.77 (s, 3H), 2.24 (s, 3H). MS m/z (%) 399 [M+H]+.
- To a suspension of Intermediate 7 (0.3 g, 1.8 mmol), piperazine (0.309 g, 3.6 mmol) and BOP (1.03 g, 2.3 mmol) in DMF (20 mL) was added DBU (0.4 mL, 2.7 mmol). The reaction mixture was stirred at room temperature for 16 h. The solvent was evaporated in vacuo and the residue was purified by silica gel chromatography (DCM: MeOH:NH3—MeOH 100:10:1). The resulting crude material (70 mg, 0.3 mmol) was suspended in DMF (2 mL) and 4-(dimethylamino)phenyl isocyanate (51 mg, 0.31 mmol) was added. The reaction mixture was stirred at r.t. for 2 h, then concentrated in vacuo and purified by silica gel chromatography (DCM:MeOH 19:1, then DCM:MeOH:NH3—MeOH 100:10:1), to provide the title compound (22 mg, 18% overall) as a white solid. 13C NMR (75 MHz, CDCl3+CD3OD) δ 158.9, 158.0, 155.5, 153.6, 146.7, 130.2, 124.0, 122.1 (2C), 117.2, 112.9 (2C), 105.3, 45.8 (2C), 43.0 (2C), 40.8 (2C). MS m/z (%) 398 [M+H]+.
- Prepared from Intermediate 8 (98 mg, 0.23 mmol), TBTU (110 mg, 0.34 mmol), concentrated ammonia solution (70 μL, 0.91 mmol) and DIPEA (59 μL, 0.343 mmol) in DMF (4 mL) according to the procedure described for Intermediate 9 to give the title compound (20 mg, 20%) as a yellow solid. δH (300 MHz, DMSO-d6) 8.45 (m, 1H), 7.96 (s, 1H), 7.81 (s, 1H), 7.33 (d, 2H, J 6.9 Hz), 7.21 (s, 1H), 6.81 (d, 2H, J 6.9 Hz), 6.44 (s, 2H), 3.70 (s, 3H), 3.56 (m, 8H). MS m/z (%) 428 [M+H]+.
- Prepared from Intermediate 8 (129 mg, 0.3 mmol), TBTU (145 mg, 0.45 mmol), DIPEA (207 μL, 1.2 mmol) and N,O-dimethylhydroxylamine hydrochloride (35 mg, 0.36 mmol) in DMF (4 mL) according to the procedure described for Intermediate 9 to give the title compound (73 mg, 51%) as a yellow solid. δH (300 MHz, CDCl3+CD3OD) 7.29 (s, 1H), 7.27 (d, 2H, J 6.6 Hz), 6.82 (d, 2H, J 6.6 Hz), 3.92 (m, 4H), 3.67 (m, 10H), 3.41 (s, 3H). MS m/z (%) 472 [M+H]+.
- A mixture of Intermediate 9 (95 mg, 0.2 mmol), copper(II) trifluoromethane-sulfonate (22 mg, 0.06 mmol) and DIC (38 μL, 0.24 mmol) in anhydrous DMF (4 mL) was stirred at room temperature for 16 h, then heated at 110° C. for 20 minutes. The reaction mixture was concentrated, then purified by silica gel chromatography (DCM: MeOH 19:1, then DCM:MeOH:NH3-MeOH 100:10:1), to provide the title compound (42 mg, 46%) as a brown solid. 13C NMR (75 MHz, DMSO-d6) δ 162.0, 159.1, 158.1, 155.2, 154.9, 154.5, 133.2, 126.9, 121.6 (2C), 114.9, 113.5 (2C), 109.1, 68.4, 55.1, 55.0, 48.2 (2C), 43.2 (2C). MS m/z (%) 454 [M+H]+.
- Intermediate 11 (70 mg, 0.21 mmol) was suspended in MeCN (5 mL) and Intermediate 22 (56.86 mg, 0.21 mmol) was added, followed by DIPEA (73 μL, 0.42 mmol). The reaction mixture was stirred at 70° C. for 1 h. Upon cooling, the reaction mixture was concentrated in vacuo, and the residue was purified by HPLC. Upon freeze-drying, the title compound (30 mg, 32.61%) was obtained as a white solid. δH (400 MHz, DMSO-d6) 8.15 (s, 1H), 7.41 (d, 1H, J 8.6 Hz), 6.59 (d, 1H, J 8.4 Hz), 6.21 (s, 2H), 4.45-4.80 (m, 2H), 4.26 (q, 2H, J 7.0 Hz), 4.13-4.21 (m, 2H), 3.18-3.25 (m, 1H), 3.01-3.11 (m, 1H), 2.37 (s, 3H), 2.27 (s, 3H), 1.77-1.69 (m, 2H), 1.33-1.28 (m, 3H), 0.84-0.90 (m, 3H). LCMS (ES+) MH+ 441, RT 1.80 minutes (method 2).
- Prepared from Intermediate 11 (70 mg, 0.21 mmol), Intermediate 23 (65.01 mg, 0.21 mmol) and DIPEA (0.13 mL, 0.42 mmol) in MeCN (5 mL) according to the procedure described for Example 10 to give the title compound (100 mg, 100%) as a white solid. δH (400 MHz, DMSO-d6) 8.23 (s, 1H), 7.30 (m, 1H), 7.18 (m, 2H), 6.21 (s, 2H), 4.50-4.85 (m, 2H), 4.20-4.13 (m, 2H), 3.18-3.29 (m, 1H), 3.01-3.16 (m, 1H), 2.37 (s, 3H), 2.22 (s, 3H), 1.65-1.86 (m, 2H), 0.87 (t, 3H, J 7.3 Hz). LCMS (ES+) MH+ 480, RT 2.30 minutes (method 2).
- Prepared from Intermediate 11 (70 mg, 0.21 mmol), Intermediate 24 (57 mg, 0.21 mmol) and DIPEA (73 μL, 0.42 mmol) in MeCN (5 mL) according to the procedure described for Example 10 to give the title compound (40.4 mg, 44%) as a white solid. δH (400 MHz, DMSO-d6) 7.83 (s, 1H), 7.62 (d, 1H, J 8.2 Hz), 6.35 (d, 1H, J 8.2 Hz), 6.20 (s, 2H), 4.50-4.81 (m, 2H), 4.10-4.20 (m, 2H), 3.89 (s, 3H), 3.85 (s, 3H), 3.14-3.24 (m, 1H), 2.97-3.11 (m, 1H), 2.36 (s, 3H), 1.63-1.83 (m, 2H), 0.87 (t, 3H, J 7.3 Hz). LCMS (ES+) MH+ 443, RT 1.87 minutes (method 2).
- DIPEA (0.03 mL, 0.2 mmol) was added to a suspension of Intermediate 16 (36 mg, 0.15 mmol) and Intermediate 23 (65 mg, 0.21 mmol) in MeCN (5 mL). The reaction mixture was stirred overnight, then concentrated in vacuo. The residue was diluted with DCM and washed with brine, then passed through a phase separator cartridge and evaporated. The crude material was purified by NH-silica gel chromatography (gradient 1-10% MeOH in EtOAc). The residue was freeze-dried from MeCN/water over 3 days to give the title compound (23.9 mg, 29%) as a white powder. δH (400 MHz, DMSO-d6) 8.17 (s, 1H), 7.78 (s, 1H), 7.32 (d, 1H, J 8.7 Hz), 7.21-7.23 (m, 1H), 7.13-7.17 (m, 1H), 5.65 (s, 2H), 5.36 (br m, 2H), 4.14-4.19 (m, 1H), 4.03 (s, 3H), 3.99-4.01 (m, 1H), 3.38 (br m, 1H), 3.26-3.27 (m, 1H), 3.03-3.12 (m, 1H), 2.23 (s, 3H), 1.26 (d, 3H, J 6.6 Hz). LCMS (ES+) [M+H]+ 465, RT 1.88 minutes (method 2).
- To a suspension of Intermediate 20 (125 mg, 0.59 mmol) in phosphorus oxychloride (1.2 mL) was added N,N-dimethylaniline (25 μL). The suspension was stirred at 110° C. and monitored by TLC. After completion (the suspension turned into a solution), the reaction mixture was cooled and evaporated in vacuo. The residue was extracted with EtOAc and brine, and the organic solvent was dried over MgSO4. The resulting crude material (90 mg, 0.39 mmol) was dissolved in THF and treated with triethylamine (82 μL, 0.59 mmol), followed by (S)-tert-butyl 3-methylpiperazine-1-carboxylate (87 mg, 0.43 mmol). The reaction mixture was stirred for 24 h at r.t., after which time the mixture was evaporated in vacuo, then extracted using DCM and brine. The crude residue was purified using silica gel chromatography (EtOAc:cyclohexane 4:1). The resulting isolated solids (124 mg, 0.33 mmol) were dissolved in DCM (4 mL) and MCPBA (165 mg, 0.67 mmol) was added at 0° C. The reaction mixture was stirred at r.t. for 2 h, whereupon 2N aqueous Na2SO3 solution (3 mL) was added. The mixture was extracted using EtOAc and 2N aqueous NaOH solution, then brine. The organic solvents were dried over MgSO4, then evaporated in vacuo. The crude residue was dissolved in 1,4-dioxane (8 mL) and 25% aqueous ammonium hydroxide solution (2 mL) was added. The mixture was heated overnight at 110° C. in a sealed vessel, then cooled and extracted using EtOAc and brine. The solvents were evaporated in vacuo. The residue (68 mg, 0.19 mmol) was dissolved in chloroform (2 mL) and trimethylsilyl iodide (96 μL, 0.66 mmol) was added. Progress of the reaction was followed by TLC. After completion, the solution was evaporated, and the residue was dissolved in DCM (4 mL). To a first aliquot (2 mL) of the DCM solution were added DIPEA (155 μL, 0.95 mmol) and Intermediate 25 (33 mg, 0.1 mmol). The reaction mixture was stirred overnight at r.t. The solution was evaporated in vacuo, and the residue was purified by silica gel chromatography (gradient 2-8% MeOH in DCM). The title compound (32 mg, 22% overall) was isolated as a white solid. 13C NMR (DMSO-d6, 75 MHz) δ 158.0, 156.8, 156.3, 154.5, 152.8, 144.7, 138.3, 137.1, 125.7, 121.4, 117.1 (t, J cF 271.8 Hz), 104.8, 62.1 (2C, t, J CF 25.2 Hz), 51.3, 47.9, 44.1, 43.4, 38.7, 20.9, 14.4, 10.7. MS (m/z) 487 [M+H]+.
- To a second aliquot (2 mL) of the DCM solution prepared in Example 14 were added DIPEA (155 μL, 0.95 mmol) and 4-methoxy-2-methylphenyl isocyanate (14 μL, 0.1 mmol) at r.t. The solution was evaporated in vacuo, and the residue was purified by silica gel chromatography (gradient 2-8% MeOH in DCM), to give the title compound (25 mg, 20% overall) as a white solid. 13C NMR (DMSO-d6, 75 MHz) δ 156.9, 156.8, 156.3, 154.5, 143.9, 137.4, 135.7, 130.7, 128.1, 121.2, 115.3, 111.1, 56.0, 51.3, 47.9, 44.2, 43.4, 38.9, 18.2, 14.6, 10.8. MS (m/z) 425 [M+H]+.
- Prepared from Intermediate 21 (234 mg, 1.2 mmol) according to the procedure described for Example 14, using Intermediate 25 (163 mg, 0.5 mmol) in the final step. The crude residue was purified by silica gel chromatography (gradient 2-8% MeOH in DCM) to give the title compound (49 mg, 7% overall) as a white solid. 13C NMR (DMSO-d6, 75 MHz) δ 158.8, 156.8 (t, J CF 2.8 Hz), 156.3, 154.6, 152.8, 147.8, 137.1, 130.4, 125.7, 121.0, 117.1 (t, J CF 271.8 Hz), 104.8, 62.2 (2C, t, J CF 25.4 Hz), 51.4, 48.0, 44.5, 43.3, 38.8, 20.8, 14.4. MS (m/z) 473 [M+H]+.
- Prepared from Intermediate 21 (234 mg, 1.2 mmol) and 4-methoxy-2-methyl-phenyl isocyanate (69 μL, 0.5 mmol) according to the procedure described for Example 15. The crude residue was purified by silica gel chromatography (gradient 2-8% MeOH in DCM) to give the title compound (45 mg, 9% overall) as a white solid. 13C NMR (DMSO-d6, 75 MHz) δ 158.9, 156.8, 156.4, 154.7, 147.9, 135.6, 130.8, 130.4, 128.2, 121.1, 115.3, 111.1, 55.2, 51.5, 48.1, 44.5, 43.4, 39.1, 18.2, 14.4. MS (m/z) 411 [M+H]+.
- Prepared from Intermediate 35 and Intermediate 26 according to the procedure described for Example 10 yielding the title compound (122 mg, 71%) as a white solid. δH (400 MHz, DMSO-d6) 8.01 (s, 1H), 7.41 (d, 1H, J 3.0 Hz), 7.03 (d, 1H, J 8.6 Hz), 6.78 (d, 1H, J 2.8 Hz), 6.70 (dd, 1H, J 8.6, 2.9 Hz), 6.11 (d, 1H, J 3.0 Hz), 6.04 (br s, 2H), 3.90 (m, 1H), 3.86 (s, 3H), 3.73-3.79 (m, 1H), 3.72 (s, 3H), 3.59-3.64 (m, 1H), 3.49-3.54 (m, 1H), 3.41-3.48 (m, 1H), 3.33-3.40 (m, 1H), 3.16-3.22 (m, 1H), 2.15 (s, 3H), 1.09 (d, 3H, J 6.4 Hz). LCMS (ES−) [M-H]−408, RT 1.57 minutes (method 2).
- Prepared from Intermediate 35 and Intermediate 27 according to the procedure described for Example 10 yielding the title compound (122 mg, 71%) as a white solid. δH (400 MHz, DMSO-d6) 8.34 (s, 1H), 7.40 (d, 1H, J 3.0 Hz), 7.20-7.24 (m, 1H), 7.21 (s, 1H), 6.80-6.83 (m, 1H), 6.10 (d, 1H, J 3.0 Hz), 5.94 (br s, 2H), 3.87 (s, 3H), 3.84 (m, 1H), 3.73 (s, 3H), 3.62-3.68 (m, 2H), 3.42-3.54 (m, 2H), 3.31-3.38 (m, 1H), 3.10-3.18 (m, 1H), 2.11 (s, 3H), 1.06 (d, 3H, J 6.3 Hz). LCMS (ES−) [M-H]−408, RT 1.73 minutes (method 2).
- Prepared from Intermediate 35 and Intermediate 23 (131 mg, 0.42 mmol) according to the procedure described for Example 10 yielding the title compound (183 mg, 93%) as a white solid. δ H (400 MHz, DMSO-d6) 8.24 (s, 1H), 7.47 (d, 1H, J 2.9 Hz), 7.29 (m, 1H), 7.20-7.22 (m, 1H), 7.12-7.15 (m, 1H), 6.53 (br s, 2H), 6.17 (d, 1H, J 2.9 Hz), 4.12 (br s, 1H), 3.90 (br s, 1H), 3.86 (s, 3H), 3.65-3.71 (m, 1H), 3.52-3.58 (m, 1H), 3.33-3.49 (m, 3H), 2.22 (s, 3H), 1.17 (d, 3H, J 6.4 Hz). LCMS (ES−) [M-H]− 462, RT 2.09 minutes (method 2).
- Prepared from Intermediate 11 and Intermediate 26 according to the procedure described for Example 10 yielding the title compound (73 mg, 50%) as a white solid. δH (400 MHz, DMSO-d6) 8.02 (s, 1H), 7.02 (d, J 8.3 Hz, 1H), 6.78 (d, J 2.45 Hz, 1H), 6.71 (dd, J 8.6, 2.7 Hz, 1H), 6.21 (br s, 2H), 4.48-4.83 (m, 2H), 4.17 (m, 2H), 3.72 (s, 3H), 3.18 (d, J 11.2 Hz, 1H), 3.02 (m, 1H), 2.36 (s, 3H), 2.30 (m, 1H), 2.14 (s, 3H), 1.66-1.82 (m, 2H), 0.87 (t, J 7.4 Hz, 3H). LCMS (ES+) [M+H]+ 426.0, RT 2.15 minutes (method 2).
- Prepared from Intermediate 11 and Intermediate 27 according to the procedure described for Example 10 yielding the title compound (80 mg, 52%) as a white solid. δH (400 MHz, DMSO-d6) 8.35 (s, 1H) 7.15-7.27 (m, 2H), 6.82 (d, J 9.2 Hz, 1H), 6.21 (br s, 2H), 4.45-4.80 (m, 2H), 4.18 (m, 2H), 3.73 (s, 3H), 3.15 (d, J 11.74 Hz, 1H), 3.03 (d, J 11.25 Hz, 1H), 2.38 (s, 3H), 2.30 (m, 1H), 2.11 (s, 3H), 1.66-1.82 (m, 2H), 0.84 (t, J 7.4 Hz, 3H). LCMS (ES+) [M+H]+ 426.0, RT 2.29 minutes (method 2).
- Prepared from Intermediate 11 and Intermediate 28 according to the procedure described for Example 10 yielding the title compound (83 mg, 55%) as a white solid. δH (400 MHz, DMSO-d6) 7.99 (s, 1H), 7.21 (d, J 8.3 Hz, 1H), 6.43 (d, J 8.8 Hz, 1H), 6.21 (s, 2H), 4.57-4.80 (m, 3H), 4.16 (m, 2H), 3.17 (m, 2H), 3.10 (m, 1H), 2.99 (s, 6H), 2.36 (s, 3H), 2.21 (s, 3H), 1.66-1.82 (m, 2H), 0.87 (t, J 7.4 Hz, 3H). LCMS (ES+) [M+H]+ 440.0, RT 2.07 minutes (method 2).
- Prepared from Intermediate 11 and Intermediate 29 according to the procedure described for Example 10 yielding the title compound (78 mg, 45%) as a white solid. δH (400 MHz, DMSO-d6) 8.02 (s, 1H), 7.22 (d, J 8.4 Hz, 1H), 6.22 (s, 2H), 6.16 (d, J 8.4 Hz, 1H), 4.80-4.57 (br s, 2H), 4.11-4.23 (m, 2H), 3.84-3.92 (m, 4H), 3.18 (d, J 12.4 Hz, 2H), 3.03 (d, J 11.0 Hz, 1H), 2.36 (s, 3H), 2.25-2.32 (m, 3H), 2.19 (s, 3H), 1.67-1.78 (m, 2H), 0.87 (t, J 7.4 Hz, 3H). LCMS (ES+) [M+H]+ 452.0, RT 1.87 minutes (method 2).
- Prepared from Intermediate 11 and Intermediate 30 according to the procedure described for Example 10 yielding the title compound (92 mg, 50%) as a white solid. δH (400 MHz, DMSO-d6) 9.37 (s, 1H), 7.97 (d, J 9.3 Hz, 1H), 7.80 (d, J 9.4 Hz, 1H), 6.22 (br s, 2H), 4.51-4.81 (m, 2H), 4.24 (m, 2H), 3.89 (s, 3H), 3.16 (d, J 12.0 Hz, 1H), 3.07 (m, 1H), 2.36 (s, 3H), 2.30 (m, 1H), 1.63-1.76 (m, 2H), 0.83 (t, J 7.4 Hz, 3H). LCMS (ES+) [M+H]+ 481.0, RT 2.46 minutes (method 2).
- Prepared from Intermediate 11 and Intermediate 31 according to the procedure described for Example 10 yielding the title compound (88 mg, 58%) as a white solid. δH (400 MHz, DMSO-d6) 8.00 (s, 1H), 6.99 (d, J 8.4 Hz, 1H), 6.75 (d, J 2.6 Hz, 1H), 6.69 (dd, J 8.4, 2.6 Hz, 1H), 6.22 (s, 2H), 4.55 (m, 3H), 4.16 (d, J 13.4 Hz, 2H), 3.18 (m, 1H), 3.03 (m, 1H), 2.36 (s, 3H), 2.30 (m, 1H), 2.12 (s, 3H), 1.65-1.80 (m, 2H), 1.25 (d, J 5.8 Hz, 6H), 0.87 (t, J 7.4 Hz, 3H). LCMS (ES+) [M+H]+ 454.0, RT 2.40 minutes (method 2).
- Prepared from Intermediate 39 and Intermediate 27 according to the procedure described for Example 10 yielding the title compound (69 mg, 36%) as a white solid. δH (400 MHz, DMSO-d6) 8.35 (s, 1H), 7.64 (s, 1H), 7.19-7.25 (m, 2H), 6.81 (d, J 9.2 Hz, 1H), 6.00 (br s, 2H), 4.02-4.15 (m, 1H), 4.01 (s, 3H), 3.85-4.00 (s, 3H), 3.70 (m, 1H), 3.20-3.40 (m, 5H), 2.09 (s, 3H), 1.09 (d, J 6.4 Hz, 3H). LCMS (ES+) [M+H]+ 411.8, RT 1.61 minutes (method 2).
- Prepared from Intermediate 39 and Intermediate 23 according to the procedure described for Example 10 yielding the title compound (111 mg, 51%) as a white solid. δ11 (400 MHz, DMSO-d6) 8.25 (s, 1H), 7.65 (s, 1H), 7.08-7.32 (m, 3H), 5.99 (br s, 2H), 4.02-4.16 (m, 1H), 4.02 (s, 3H), 3.85-4.00 (m, 1H), 3.25-3.49 (m, 5H), 2.15 (s, 3H), 1.09 (d, J 6.3 Hz, 3H). LCMS (ES+) [M+H]+ 465.8, RT 1.83 minutes (method 2).
- Prepared from Intermediate 43 and Intermediate 27 according to the procedure described for Example 10 yielding the title compound (160 mg, 23%) as a white solid. LCMS (ES+) [M+H]+425, RT 2.04 minutes (method 2).
Claims (18)
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US9969748B2 (en) | 2018-05-15 |
AR100894A1 (en) | 2016-11-09 |
WO2015193168A1 (en) | 2015-12-23 |
JP2017518384A (en) | 2017-07-06 |
RU2017101324A3 (en) | 2018-12-27 |
EP3157923A1 (en) | 2017-04-26 |
BR112016029630A2 (en) | 2017-08-22 |
UY36171A (en) | 2016-01-29 |
RU2017101324A (en) | 2018-07-17 |
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