EP3119763A1 - Dérivés substitués par 3-indole, compositions pharmaceutiques et procédés d'utilisation - Google Patents
Dérivés substitués par 3-indole, compositions pharmaceutiques et procédés d'utilisationInfo
- Publication number
- EP3119763A1 EP3119763A1 EP15714653.1A EP15714653A EP3119763A1 EP 3119763 A1 EP3119763 A1 EP 3119763A1 EP 15714653 A EP15714653 A EP 15714653A EP 3119763 A1 EP3119763 A1 EP 3119763A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- fluoro
- indol
- benzo
- alkyl
- mmol
- 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.)
- Withdrawn
Links
- 238000000034 method Methods 0.000 title claims abstract description 53
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 8
- 150000001875 compounds Chemical class 0.000 claims abstract description 410
- 150000003839 salts Chemical class 0.000 claims abstract description 76
- 239000012453 solvate Substances 0.000 claims abstract description 59
- 230000008569 process Effects 0.000 claims abstract description 32
- 239000003112 inhibitor Substances 0.000 claims abstract description 14
- 238000004519 manufacturing process Methods 0.000 claims abstract description 11
- 208000008589 Obesity Diseases 0.000 claims abstract description 7
- 235000020824 obesity Nutrition 0.000 claims abstract description 7
- 102100040653 Tryptophan 2,3-dioxygenase Human genes 0.000 claims abstract description 3
- 101000892398 Homo sapiens Tryptophan 2,3-dioxygenase Proteins 0.000 claims abstract 2
- -1 arylalkyi Chemical group 0.000 claims description 142
- 125000003118 aryl group Chemical group 0.000 claims description 130
- 229910052736 halogen Inorganic materials 0.000 claims description 127
- 150000002367 halogens Chemical class 0.000 claims description 125
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 116
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 101
- 125000000217 alkyl group Chemical group 0.000 claims description 96
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 91
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 70
- 125000000623 heterocyclic group Chemical group 0.000 claims description 68
- 125000001072 heteroaryl group Chemical group 0.000 claims description 67
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 66
- 125000002877 alkyl aryl group Chemical group 0.000 claims description 64
- 125000005213 alkyl heteroaryl group Chemical group 0.000 claims description 64
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 63
- 229910052757 nitrogen Inorganic materials 0.000 claims description 61
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 60
- 125000001424 substituent group Chemical group 0.000 claims description 55
- 206010028980 Neoplasm Diseases 0.000 claims description 53
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 52
- VMWNQDUVQKEIOC-CYBMUJFWSA-N apomorphine Chemical compound C([C@H]1N(C)CC2)C3=CC=C(O)C(O)=C3C3=C1C2=CC=C3 VMWNQDUVQKEIOC-CYBMUJFWSA-N 0.000 claims description 48
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 48
- 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 46
- 229910052799 carbon Inorganic materials 0.000 claims description 34
- 125000004432 carbon atom Chemical group C* 0.000 claims description 29
- 201000011510 cancer Diseases 0.000 claims description 27
- QLNJFJADRCOGBJ-UHFFFAOYSA-N propionamide Chemical compound CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 claims description 21
- 125000006239 protecting group Chemical group 0.000 claims description 18
- 239000003814 drug Substances 0.000 claims description 11
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 11
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 10
- 230000002265 prevention Effects 0.000 claims description 10
- 125000004043 oxo group Chemical group O=* 0.000 claims description 9
- BUGOPWGPQGYYGR-UHFFFAOYSA-N thiane 1,1-dioxide Chemical compound O=S1(=O)CCCCC1 BUGOPWGPQGYYGR-UHFFFAOYSA-N 0.000 claims description 9
- 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 8
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 8
- 230000001684 chronic effect Effects 0.000 claims description 8
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 8
- 208000023105 Huntington disease Diseases 0.000 claims description 7
- 208000018737 Parkinson disease Diseases 0.000 claims description 7
- 125000005278 alkyl sulfonyloxy group Chemical group 0.000 claims description 7
- 125000005279 aryl sulfonyloxy group Chemical group 0.000 claims description 7
- 239000003085 diluting agent Substances 0.000 claims description 7
- 125000001188 haloalkyl group Chemical group 0.000 claims description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- 208000015122 neurodegenerative disease Diseases 0.000 claims description 7
- 229910052760 oxygen Inorganic materials 0.000 claims description 7
- 208000024827 Alzheimer disease Diseases 0.000 claims description 6
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 6
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 6
- 208000036142 Viral infection Diseases 0.000 claims description 6
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 6
- 229910052794 bromium Inorganic materials 0.000 claims description 6
- 239000000460 chlorine Substances 0.000 claims description 6
- 229910052801 chlorine Inorganic materials 0.000 claims description 6
- 239000003937 drug carrier Substances 0.000 claims description 6
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical group II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 6
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 6
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 6
- 229910052717 sulfur Inorganic materials 0.000 claims description 6
- WTVXIBRMWGUIMI-UHFFFAOYSA-N trifluoro($l^{1}-oxidanylsulfonyl)methane Chemical group [O]S(=O)(=O)C(F)(F)F WTVXIBRMWGUIMI-UHFFFAOYSA-N 0.000 claims description 6
- 230000009385 viral infection Effects 0.000 claims description 6
- IHWDSEPNZDYMNF-UHFFFAOYSA-N 1H-indol-2-amine Chemical compound C1=CC=C2NC(N)=CC2=C1 IHWDSEPNZDYMNF-UHFFFAOYSA-N 0.000 claims description 5
- 208000003174 Brain Neoplasms Diseases 0.000 claims description 5
- 206010006187 Breast cancer Diseases 0.000 claims description 5
- 208000026310 Breast neoplasm Diseases 0.000 claims description 5
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 5
- 206010035226 Plasma cell myeloma Diseases 0.000 claims description 5
- 125000003545 alkoxy group Chemical group 0.000 claims description 5
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 5
- 208000032839 leukemia Diseases 0.000 claims description 5
- 201000001441 melanoma Diseases 0.000 claims description 5
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 5
- 206010009944 Colon cancer Diseases 0.000 claims description 4
- 206010029260 Neuroblastoma Diseases 0.000 claims description 4
- 206010039491 Sarcoma Diseases 0.000 claims description 4
- 239000002671 adjuvant Substances 0.000 claims description 4
- 201000008275 breast carcinoma Diseases 0.000 claims description 4
- 229910052731 fluorine Inorganic materials 0.000 claims description 4
- 208000005017 glioblastoma Diseases 0.000 claims description 4
- 201000003911 head and neck carcinoma Diseases 0.000 claims description 4
- 201000005296 lung carcinoma Diseases 0.000 claims description 4
- 201000000050 myeloid neoplasm Diseases 0.000 claims description 4
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 4
- UDSAJFSYJMHNFI-UHFFFAOYSA-N 2,6-diazaspiro[3.3]heptane Chemical compound C1NCC11CNC1 UDSAJFSYJMHNFI-UHFFFAOYSA-N 0.000 claims description 3
- KVGFRXJPJVMBRI-UHFFFAOYSA-N 3-(1,3-benzodioxol-5-yl)-1h-indole Chemical compound C1=CC=C2C(C3=CC=C4OCOC4=C3)=CNC2=C1 KVGFRXJPJVMBRI-UHFFFAOYSA-N 0.000 claims description 3
- 206010003571 Astrocytoma Diseases 0.000 claims description 3
- 206010005003 Bladder cancer Diseases 0.000 claims description 3
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 3
- 206010027406 Mesothelioma Diseases 0.000 claims description 3
- 208000006265 Renal cell carcinoma Diseases 0.000 claims description 3
- 125000002393 azetidinyl group Chemical group 0.000 claims description 3
- 201000001531 bladder carcinoma Diseases 0.000 claims description 3
- 201000010989 colorectal carcinoma Diseases 0.000 claims description 3
- 208000021045 exocrine pancreatic carcinoma Diseases 0.000 claims description 3
- 208000010570 urinary bladder carcinoma Diseases 0.000 claims description 3
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 claims description 2
- 230000002401 inhibitory effect Effects 0.000 claims description 2
- 125000003386 piperidinyl group Chemical group 0.000 claims description 2
- QHZORGLJTWMYIW-UHFFFAOYSA-N 3-(1-benzofuran-5-yl)-6-chloro-1H-indole Chemical compound C1=C2OC=CC2=CC(C=2C3=CC=C(C=C3NC=2)Cl)=C1 QHZORGLJTWMYIW-UHFFFAOYSA-N 0.000 claims 1
- XGFKUTKVQOMXHC-UHFFFAOYSA-N FC1=CC=C2C(=CNC2=C1)C1=CC2=C(NC(=N2)NS(=O)(=O)C)C=C1 Chemical compound FC1=CC=C2C(=CNC2=C1)C1=CC2=C(NC(=N2)NS(=O)(=O)C)C=C1 XGFKUTKVQOMXHC-UHFFFAOYSA-N 0.000 claims 1
- WVXYAASBXCJBCT-UHFFFAOYSA-N FC1=CC=C2C(=CNC2=C1)C=1C=CC2=C(C(NS2(=O)=O)=O)C1 Chemical compound FC1=CC=C2C(=CNC2=C1)C=1C=CC2=C(C(NS2(=O)=O)=O)C1 WVXYAASBXCJBCT-UHFFFAOYSA-N 0.000 claims 1
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims 1
- 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 abstract description 30
- 239000000543 intermediate Substances 0.000 description 387
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 311
- 239000000203 mixture Substances 0.000 description 237
- 239000007787 solid Substances 0.000 description 210
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 206
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 176
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 172
- 235000019439 ethyl acetate Nutrition 0.000 description 155
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 119
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 100
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 100
- 239000007832 Na2SO4 Substances 0.000 description 99
- 229910052938 sodium sulfate Inorganic materials 0.000 description 99
- 239000000243 solution Substances 0.000 description 95
- 238000007429 general method Methods 0.000 description 85
- 238000000746 purification Methods 0.000 description 85
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 83
- 238000005160 1H NMR spectroscopy Methods 0.000 description 81
- 239000012044 organic layer Substances 0.000 description 77
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 74
- 239000012267 brine Substances 0.000 description 74
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 74
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 67
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 66
- 239000000706 filtrate Substances 0.000 description 64
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 62
- 238000005481 NMR spectroscopy Methods 0.000 description 56
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 56
- 239000011541 reaction mixture Substances 0.000 description 51
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 51
- 238000002953 preparative HPLC Methods 0.000 description 49
- 229940125904 compound 1 Drugs 0.000 description 45
- 239000003208 petroleum Substances 0.000 description 45
- 238000010898 silica gel chromatography Methods 0.000 description 45
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 44
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 43
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 42
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 37
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 35
- 101710136122 Tryptophan 2,3-dioxygenase Proteins 0.000 description 33
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 description 33
- BCMCBBGGLRIHSE-UHFFFAOYSA-N 1,3-benzoxazole Chemical compound C1=CC=C2OC=NC2=C1 BCMCBBGGLRIHSE-UHFFFAOYSA-N 0.000 description 32
- 102000057288 Tryptophan 2,3-dioxygenases Human genes 0.000 description 32
- 239000002904 solvent Substances 0.000 description 30
- 125000005605 benzo group Chemical group 0.000 description 28
- 239000003921 oil Substances 0.000 description 28
- 229910000027 potassium carbonate Inorganic materials 0.000 description 28
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 27
- 235000019198 oils Nutrition 0.000 description 27
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 26
- 238000006243 chemical reaction Methods 0.000 description 25
- DNUTZBZXLPWRJG-UHFFFAOYSA-M piperidine-1-carboxylate Chemical compound [O-]C(=O)N1CCCCC1 DNUTZBZXLPWRJG-UHFFFAOYSA-M 0.000 description 25
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 24
- 125000003037 imidazol-2-yl group Chemical group [H]N1C([*])=NC([H])=C1[H] 0.000 description 24
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 23
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 23
- 239000007821 HATU Substances 0.000 description 22
- 150000002460 imidazoles Chemical class 0.000 description 22
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 21
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 21
- 238000012746 preparative thin layer chromatography Methods 0.000 description 19
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 18
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 18
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 18
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 18
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 18
- 125000004287 oxazol-2-yl group Chemical group [H]C1=C([H])N=C(*)O1 0.000 description 17
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 14
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 14
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 14
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 13
- 238000010511 deprotection reaction Methods 0.000 description 13
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 13
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 11
- 239000002253 acid Substances 0.000 description 11
- 230000015556 catabolic process Effects 0.000 description 11
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 11
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 10
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 10
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 10
- 150000001721 carbon Chemical group 0.000 description 10
- RWTNPBWLLIMQHL-UHFFFAOYSA-N fexofenadine Chemical group C1=CC(C(C)(C(O)=O)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 RWTNPBWLLIMQHL-UHFFFAOYSA-N 0.000 description 10
- 239000010410 layer Substances 0.000 description 10
- 229920006395 saturated elastomer Polymers 0.000 description 10
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 10
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 9
- 229910000029 sodium carbonate Inorganic materials 0.000 description 9
- 150000001412 amines Chemical class 0.000 description 8
- 229910000024 caesium carbonate Inorganic materials 0.000 description 8
- 125000005842 heteroatom Chemical group 0.000 description 8
- 125000002962 imidazol-1-yl group Chemical group [*]N1C([H])=NC([H])=C1[H] 0.000 description 8
- 239000000651 prodrug Substances 0.000 description 8
- 229940002612 prodrug Drugs 0.000 description 8
- 239000000741 silica gel Substances 0.000 description 8
- 229910002027 silica gel Inorganic materials 0.000 description 8
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 8
- GEYOCULIXLDCMW-UHFFFAOYSA-N 1,2-phenylenediamine Chemical compound NC1=CC=CC=C1N GEYOCULIXLDCMW-UHFFFAOYSA-N 0.000 description 7
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 7
- JUIKUQOUMZUFQT-UHFFFAOYSA-N 2-bromoacetamide Chemical compound NC(=O)CBr JUIKUQOUMZUFQT-UHFFFAOYSA-N 0.000 description 7
- 241000713772 Human immunodeficiency virus 1 Species 0.000 description 7
- 230000001965 increasing effect Effects 0.000 description 7
- 238000004949 mass spectrometry Methods 0.000 description 7
- HNQIVZYLYMDVSB-UHFFFAOYSA-N methanesulfonimidic acid Chemical compound CS(N)(=O)=O HNQIVZYLYMDVSB-UHFFFAOYSA-N 0.000 description 7
- 238000002360 preparation method Methods 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- ZHGNHOOVYPHPNJ-UHFFFAOYSA-N Amigdalin Chemical compound FC(F)(F)C(=O)OCC1OC(OCC2OC(OC(C#N)C3=CC=CC=C3)C(OC(=O)C(F)(F)F)C(OC(=O)C(F)(F)F)C2OC(=O)C(F)(F)F)C(OC(=O)C(F)(F)F)C(OC(=O)C(F)(F)F)C1OC(=O)C(F)(F)F ZHGNHOOVYPHPNJ-UHFFFAOYSA-N 0.000 description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 6
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- WCNFFKHKJLERFM-UHFFFAOYSA-N thiomorpholinyl sulfone group Chemical group N1(CCSCC1)S(=O)(=O)N1CCSCC1 WCNFFKHKJLERFM-UHFFFAOYSA-N 0.000 description 1
- ZCAGUOCUDGWENZ-UHFFFAOYSA-N thiomorpholinyl sulfoxide group Chemical group N1(CCSCC1)S(=O)N1CCSCC1 ZCAGUOCUDGWENZ-UHFFFAOYSA-N 0.000 description 1
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- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
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- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
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Definitions
- the present invention relates to novel 3-(indol-3-yl)-pyridine derivatives, including pharmaceutically acceptable enantiomers, salts and solvates thereof.
- Compounds of the invention are inhibitors of TDO2 (tryptophan 2,3-dioxygenase) and are useful as therapeutic compounds, particularly in the treatment and/or prevention of cancers.
- tryptophan an essential amino acid, is catabolized in the local microenvironment of tumors, immune- privileged sites, or sites of inflammation (Mellor AL and Munn DH., Nat Rev Immunol, 2008, 8, 74-80).
- cancer cells In these tissues, cancer cells, immune cells, or specialized epithelial cells (e.g., syncytiotrophoblasts in the placenta) create an immunosuppressive environment in tumors that shuts down antitumor immune responses in tumors and in tumor-draining lymph nodes by inducing T-cell anergy and apoptosis through depletion of tryptophan and accumulation of immunosuppressive tryptophan catabolites (Munn DH et al., J Exp Med., 1999, 189, 1363-1372; Fallarino F et al., Cell Death Differ., 2002, 9, 1069-1077).
- epithelial cells e.g., syncytiotrophoblasts in the placenta
- tryptophan 2,3-dioxygenase which is considered responsible for regulating systemic tryptophan levels in the liver
- TDO2 tryptophan 2,3-dioxygenase
- bladder carcinoma hepatocarcinoma, melanoma, mesothelioma, neuroblastoma, sarcoma, breast carcinoma, leukemia, renal cell carcinoma, colorectal carcinoma, head and neck carcinoma, lung carcinoma, brain tumor, glioblastoma, astrocytoma, myeloma, and pancreatic carcinoma
- pancreatic carcinoma Pancreatic carcinoma
- TDO2 expression in tumor cells prevents tumor surveillance by the immune system and thus prevents tumor rejection by locally degrading tryptophan (Opitz CA et al., Nature, 201 1 , 478(7368), 197-203).
- the first evidence for this was provided through inhibition of TDO2 by a small molecule which inhibited tumor growth in a P815 mastocytoma tumor model with a prophylactic vaccination approach (Pilotte L et al., Proc Natl Acad Sci U S A, 2012, 109(7), 2497- 502).
- P815mTDO2 expressing tumors were rejected less in comparison to P815 tumors transfected with an empty vector, clearly demonstrating a growth benefit for TDO2 expressing tumors.
- TDO2 inhibitor Inhibition with a TDO2 inhibitor strongly decreased tumor growth in P815mTDO2 implanted tumors. Anti-tumor activity with the TDO2 inhibitor was equally observed in the P815 control implanted tumors negative for TDO2, thus providing evidence for an effect of TDO2 expressed in the immune system of the animal.
- TDO2 In line with its expression profile in liver, TDO2 was found predominantly in
- HCC hepatocellular carcinoma
- RNA expression is a good indication for therapeutic evaluation of TDO2 inhibitors (Pilotte L et al., Proc Natl Acad Sci U S A, 2012, 109(7), 2497-502). The above thus provides a clear rationale for TDO2 activity modulation in the control of liver tumor development.
- TDO2 is expressed in neurons, microglia and astrocytes and the potential benefit of TDO2 inhibition in the context of glioma was shown in another animal model.
- Platten and collaborators demonstrated that the tryptophan catabolite kynurenine produced by TDO expressed in the tumor cells suppresses antitumour immune responses and promotes tumor-cell survival and motility through the AHR in an autocrine/paracrine fashion (Opitz CA et al., Nature, 201 1 , 478(7368), 197-203).
- the TDO-AHR pathway is active in human brain tumors and is associated with malignant progression and poor survival.
- TDO2 imRNA tumor types in which TDO2 imRNA was found are breast carcinoma, bladder, renal cell, pancreatic, colorectal, head & neck carcinoma and lung carcinoma as well as melanoma thus broadening the scope of TDO2 targeting beyond HCC and glioma (Pilotte L et al., Proc Natl Acad Sci U S A, 2012, 109(7), 2497-502).
- the enhanced Tryptophan degradation observed in patients with gynecological cancers ovarian carcinoma, cervical cancer, endometrial cancer
- provides additional rationale for TDO2 targeting in those cancers Sperner-Schweger B et al, Immunology, 201 1 , 216 (3); 296-301 ).
- IDO1 indoleamine 2,3-dioxygenase
- tryptophan catabolism is induced by inflammatory mediators, notably IFN- gamma, it is thought to represent an endogenous mechanism that restricts excessive immune responses, thereby preventing immunopathology.
- IFN- gamma inflammatory mediators
- suppression of antitumor immune responses in precancerous lesions and established cancers by tryptophan catabolism promotes tumor growth, which would make such catabolism an attractive target for therapeutic intervention (Dolusic E and Frederick R., Expert Opin Ther Pat., 2013, 23(10), 1367-81 ).
- TDO2 expression has been demonstrated in neurons, brain vasculature and additionally in the case of schizophrenia in astroglial cells (Miller C et al., 2004, Neurobiology Dis, 15(3):618-29).
- the kynurenine pathway is now considered as a therapeutic target in cognitive diseases like bipolar disorder or Tourette syndrome and neurodegenerative disorders like Alzheimer, motor neuron disease like Amyotrophic lateral sclerosis, Multiple sclerosis, Huntington or Parkinson's disease (Stone TW, 2013, Br J of Pharmacol, 169(6): 121 1 -27; Wu et al, 2013, Plos One, 8(4):e59749; Fuvesi et al, 2012, J Neural Transm, 1 19(2):225-34; Widner et al, 2002, J Neural Transm, 109(2):181 -9; Comings et al, 1996, Pharmacogenetics,
- TDO2 inhibitors were proposed in WO2010/008427 and by Dolusic, E. et al.
- the present invention provides new TDO2 inhibitors which may be administered to a mammalian subject having a condition or disease where it is desirable to modulate, and in particular decrease, activity of TDO2, including, without limitation, patients diagnosed with cancer, or any subject being at risk of developing a cancer. Also provided are compositions containing these compounds and uses thereof.
- a compound of Formula I is provided or a pharmaceutically acceptable salt, solvent or solvate thereof, where A1 , A2, A3, Y1 , Y2, Y4, R1 , R2, R3, X1 and X3 are as defined herein.
- a first one of A 1 , A 2 and A 3 is N, a second one of A 1 , A 2 and A 3 is C and the third one of A 1 , A 2 and A 3 is N or O.
- a 2 is N and one of A 1 and A 3 is N or S and the other is C.
- a 1 or A 3 is S, A 1 -Y 1 or A 3 -Y 3 is SO 2 .
- a 2 is C and one of A 1 and A 3 is N and the other is N or O.
- a 1 or A 3 is O, and C is substituted with CR 6 R 7 R 8 as defined herein and one of R 6 , R 7 , R 8 is a 1 .
- A1 or A3 is O, and C is substituted with CR 6 R 7 R 8 and R 6 , R 7 or R 8 is heterocyclyl or C1 -heterocycyl, the heterocyclyl is piperidine, pyrrolidine, piperazine, morpholine, or 2,6-diazaspiro[3.3]heptane, any of which may be optionally substituted with one or more of C1 -C3 alkyl, amino, hydroxyl, halogen, COCH 3 , COOH, or SO 2 CH 3 .
- one of A 1 , A 2 or A 3 is S or A 1 -Y 1 , A 2 -Y 2 , or A 3 -Y 3 is SO 2 ; one of A 1 , A 2 or A 3 is N or C and one of A 1 , A 2 and A 3 is C.
- X 1 and X 2 are independently H or F.
- R 1 , R 2 and R 3 represent each independently H, halogen or methyl, or may each be H.
- a pharmaceutical composition which comprises a compound according to Formula I is provided, or a pharmaceutically acceptable enantiomer, salt or solvate thereof, and at least one pharmaceutically acceptable carrier, diluent, excipient and/or adjuvant.
- a medicament which comprises a compound according to Formula I, or a pharmaceutically acceptable enantiomer, salt or solvate thereof.
- a compound of Formula I, or a pharmaceutically acceptable enantiomer, salt or solvate thereof is provided, for use in the treatment and/or prevention of cancer, neurodegenerative disorders such as Parkinson's disease, Alzheimer's disease and Huntington's disease, chronic viral infections such as HCV and HIV, depression, and obesity, or for use as TDO2 inhibitor.
- a method of treating and/or preventing of cancer is provided, for use in the treatment and/or prevention of cancer, neurodegenerative disorders such as Parkinson's disease, Alzheimer's disease and Huntington's disease, chronic viral infections such as HCV and HIV, depression, and obesity, or for use as TDO2 inhibitor.
- the method comprises administering a compound of Formula I, or a pharmaceutically acceptable salt thereof.
- a process for manufacturing a compound of Formula I or a pharmaceutically acceptable enantiomer, salt or solvate thereof comprises:
- X 1 and X 2 represent each independently H, halogen, alkyl, haloalkyl
- Z 1 represents H or an amino protecting group
- Y represents an halogen, an alkylsulfonyloxy having 1 -6 carbon atoms or arylsulfonyloxy having 6-10 carbon atoms; with a compound of Formula (ii)
- R 1 , R 2 , R 3 , A 1 , A 2 , A 3 , Y 1 , Y 2 and Y 3 are as defined herein; and Z 2 and Z 3 represent H or alkyl groups, with the possibility for Z 2 and Z 3 to form a ring; so as to obtain a compound of Formula (iii),
- X 1 and X 2 represent each independently H, halogen, alkyl, or haloalkyl
- R 1 , R 2 and R 3 represent each independently H, halogen, C1 -C6 alkyl, alkoxy, or haloalkyl, optionally substituted by one or more substituents selected from halogen, hydroxyl, OR 4 , COOR 4 , CONR 4 R 5 , NR 4 COR 5 , NR 4 R 5 , SO 2 R 4 , SO 2 NR 4 R 5 , NR 4 SO 2 R 5 , SO 2 R 4 , aryl, CO-alkyl, or C1 -C6 alkyl which is optionally substituted by one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R 4 and R 5 represent each independently a hydrogen atom or a group, optionally substituted, selected from C1 -C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, or amino;
- a 1 , A 2 and A 3 represent each independently C, N, S or O, wherein when A 1 , A 2 or A 3 is S, A 1 -Y 1 , A 2 -Y 2 or A 3 -Y 3 is optionally SO 2 ; each of Y 1 , Y 2 and Y 3 is either absent or represent independently
- R 9 and R 10 represent each independently a hydrogen atom or a group, optionally substituted, selected from C1 -C6.
- R 11 represents a hydrogen atom or a group, optionally substituted, selected from C1 -C6 alkyl, aryl, arylalkyi, alkylaryl, heteroaryl, heteroarylalkyi, alkylheteroaryl, hydroxyl, or amino; v) C1 -C10 alkyl, linear or branched; optionally substituted with up to three substituents selected from halogen, hydroxyl, OR 9 , COOR 9 , CONR 9 R 10 , NR 9 COR 10 , NR 9 R 10 , SO 2 R 9 , SO 2 NR 9 R 10 , NR 9 SO 2 R 10 , SOR 9 , aryl, or CO-alkyl, wherein R 9 and R 10 represent each independently a hydrogen atom or a group, optionally substituted, selected from C1 -C6 alkyl, aryl, arylalkyi, alkylaryl, heteroaryl, heteroarylalkyi, alkylhetero
- heterocyclyl substituted, selected from C1 -C6 alkyl, heterocyclyl, aryl, arylalkyi, alkylaryl, heteroaryl, heteroarylalkyi, alkylheteroaryl, or amino; vi) heterocyclyl or C1 -C2 alkyl - heterocyclyl; wherein the heterocyclyl is optionally substituted with up to three substituents halogen, hydroxyl, oxo, OR 9 , COOR 9 , CONR 9 R 10 , NR 9 COR 10 , NR 9 R 10 , SO 2 R 9 , SO 2 NR 9 R 10 , NR 9 SO 2 R 10 , SO 2 R 9 , aryl, CO-alkyl, or alkyl, the alkyl group being optionally substituted by one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R 9 and R 10 represent each independently a hydrogen atom or a group, optionally substituted, selected from C1
- X 1 and X 2 represent each independently H, halogen, alkyl, haloalkyi, preferably H or F;
- R 1 , R 2 and R 3 represent each independently H, halogen, C1 -C6 alkyl, alkoxy, haloalkyi, optionally substituted by one or more substituents selected from the group comprising halogen, hydroxyl, OR 4 , COOR 4 , CONR 4 R 5 , NR 4 COR 5 , NR 4 R 5 , SO 2 R 4 , SO 2 NR 4 R 5 , NR 4 SO 2 R 5 , SO 2 R 4 , aryl, CO-alkyl, alkyl, the alkyl group being optionally substituted by one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R 4 and R 5 represent each independently a hydrogen atom or a group, optionally substituted, selected from C1 -C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino;
- R 1 , R 2 and R 3 represent each independently H, halogen or alkyl, preferably R 1 , R 2 and R 3 represent each independently H, halogen or methyl, preferably R 1 , R 2 and R 3 represent each H; A 1 , A 2 and A 3 represent each independently C, N or O; each of Y 1 , Y 2 and Y 3 is either absent or represent independently
- R 6 , R 7 and R 8 represent each independently:
- R 9 and R 10 represent each independently a hydrogen atom or a group, optionally substituted, selected from C1 -C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino, CO-alkyl, SO 2 R 11 , wherein R 11 represents a hydrogen atom or a group, optionally substituted, selected from C1 -C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino;
- C1 -C10 alkyl linear or branched, preferably methyl, ethyl or propyl
- NR 9 COR 10 NR 9 R 10 , SO 2 R 9 , SO 2 NR 9 R 10 , NR 9 SO 2 R 10 , SOR 9 , aryl, CO- alkyl
- R 9 and R 10 represent each independently a hydrogen atom or a group, optionally substituted, selected from C1 -C6 alkyl, heterocyclyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino; heterocyclyl, preferably selected from piperidine, pyrrolidine, piperazine, morpholine; optionally substituted with up to three substituents selected from the group comprising halogen, hydroxyl, OR 9 , COOR 9 , CONR 9 R 10 , NR 9 COR 10 , NR 9 R 10 , SO 2 R 9 , SO 2 NR 9 R 10 , NR 9 SO 2 R 10 , SO 2 R 9 , aryl, CO- alkyl,
- R 11 represents a group selected from amine, alkyl, heterocyclyl (preferably piperidine, pyrrolidine, piperazine or tetrahydrothiopyrandioxide); optionally substituted with up to three substituents selected from the group comprising halogen, hydroxyl, OR 9 , COOR 9 , CONR 9 R 10 , NR 9 COR 10 , NR 9 R 10 , SO 2 R 9 , SO 2 NR 9 R 10 , NR 9 SO 2 R 10 , SOR 9 , aryl, CO-alkyl, alkyl, the alkyl group being optionally substituted by one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R 9 and R 10 represent each independently a hydrogen atom or a group, optionally substituted, selected from C1 -C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl
- ring being preferably selected from: cycloalkyl, optionally substituted with up to three substituents selected from the group comprising halogen, hydroxyl, OR 9 , COOR 9 , CONR 9 R 10 , NR 9 COR 10 , NR 9 R 10 , SO 2 R 9 , SO 2 NR 9 R 10 , NR 9 SO 2 R 10 , SO 2 R 9 , aryl, CO-alkyl, alkyl, the alkyl group being optionally substituted by one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R 9 and R 10 represent each independently a hydrogen atom or a group, optionally substituted, selected from C1 -C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino; hetero
- R 12 and R 13 represent each independently a hydrogen atom or a group, optionally substituted, selected from C1 -C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino; dotted lines stand for single or double bonds; provided that A 1 , A 2 and A 3 are not all C; provided that when one of A 1 , A 2 and A 3 is N, the two others are not both C; provided that compound of Formula I is not 3-(benzofuran-5-yl)-6-chloro-1 /-/-indole or 3- (benzo[d][1 ,3]dioxol-5-yl)-1 H-indole.
- the fused heterocycle which substitutes the indole ring in Formula I is aromatic. In another embodiment, the fused heterocycle which substituted the indole ring in Formula I is partially aromatic. In a further embodiment, the heterocycle which substituted the indole ring in Formula I is non-aromatic.
- X 1 and X 2 represent each independently H or halogen, preferably H or F. According to a specific embodiment, X 1 represents H and X 2 represents F. According to a preferred embodiment, in Formula I, R 1 , R 2 and R 3 represent each H.
- X 1 and X 2 represent each independently H or halogen and R 1 , R 2 and R 3 represent each H; preferably X 1 represents H and X 2 represents F and R 1 , R 2 and R 3 represent each H
- a first one of A 1 , A 2 and A 3 is N
- a second one of A 1 , A 2 and A 3 is C
- the third one of A 1 , A 2 and A 3 is N or O.
- a 2 is N and one of A 1 and A 3 is N or S r and the other is C. According to one embodiment, in Formula I, A 2 is C and one of A 1 and A 3 is N and the other is N or O.
- a 1 or A 3 is O, and C is substituted with CR 6 R 7 R 8 and R 6 , R 7 or R 8 is heterocyclyl or C1 -heterocycyl
- the heterocyclyl is piperidine, pyrrolidine, piperazine, morpholine, or2,6-diazaspiro[3.3]heptane, any of which may be optionally substituted with one or more of C1 -C3 alkyl, amino, hydroxyl, halogen, COCH 3 , COOH, or SO 2 CH 3 .
- a 1 or A 3 is S, A 1 -Y 1 or A 3 -Y 3 is SO 2 .
- one of A 1 , A 2 or A 3 is S or A 1 -Y 1 , A 2 -Y 2 , or A 3 -Y 3 is SO 2 ; one of A 1 , A 2 or A 3 is N or C and one of A 1 , A 2 and A 3 is C.
- preferred com ounds of Formula I are those of Formula 11-1
- a 1 and A 3 are not both C.
- one of A 1 and A 1 is S and the other is C, A 1 -Y 1 or A 3 -Y 3 is optionally SO 2 , and the C is optionally substituted with oxo.
- preferred com ounds of Formula I are those of Formula II-2
- ⁇ A 1 , A 3 ⁇ are not ⁇ C, N ⁇ , ⁇ N, C ⁇ or ⁇ C, C ⁇ .
- preferred compounds of Formula I are those of Formula 11-1 a
- preferred com ounds of Formula I are those of Formula 11-1 b
- preferred compounds of Formula I are those of Formula ll-2a
- a 1 is not C.
- preferred compounds of Formula I are those of Formula ll-2b
- a 3 is not C.
- preferred compounds of Formula I are those of Formula 11-1 a1
- Y 1 represents H and Y 3 is as defined in Formula I, preferably, Y 3 represents:
- R 6 , R 7 and R 8 represent each independently:
- NR 9 COR 10 NR 9 R 10 , SO 2 R 9 , SO 2 NR 9 R 10 , NR 9 SO 2 R 10 , SOR 9 , aryl, CO-alkyl, wherein R 9 and R 10 represent each independently a hydrogen atom or a group, optionally substituted, selected from C1 -C6 alkyl, heterocyclyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino;
- heterocyclyl preferably selected from piperidine, pyrrolidine, piperazine, morpholine; optionally substituted with up to three substituents selected from the group comprising halogen, hydroxyl, OR 9 , COOR 9 , CONR 9 R 10 , NR 9 COR 10 , NR 9 R 10 , SO 2 R 9 , SO 2 NR 9 R 10 , NR 9 SO 2 R 10 , SO 2 R 9 , aryl, CO- alkyl, alkyl, the alkyl group being optionally substituted by one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R 9 and R 10 represent each independently a hydrogen atom or a group, optionally substituted, selected from C1 -C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino; • -CO-R 11 wherein R 11 represents a group selected from amine, alkyl
- NR 9 SO 2 R 10 SOR 9 , aryl, CO-alkyl, alkyl, the alkyl group being optionally substituted by one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R 9 and R 10 represent each independently a hydrogen atom or a group, optionally substituted, selected from C1 -C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino;
- preferred compounds of Formula I are those of Formula 11-1 a2
- R 6 , R 7 and R 8 represent each independently:
- NR 9 COR 10 NR 9 R 10 , SO 2 R 9 , SO 2 NR 9 R 10 , NR 9 SO 2 R 10 , SOR 9 , aryl, CO-alkyl, wherein R 9 and R 10 represent each independently a hydrogen atom or a group, optionally substituted, selected from C1 -C6 alkyl, heterocyclyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino;
- heterocyclyl preferably selected from piperidine, pyrrolidine, piperazine, morpholine; optionally substituted with up to three substituents selected from the group comprising halogen, hydroxyl, OR 9 , COOR 9 , CONR 9 R 10 , NR 9 COR 10 , NR 9 R 10 , SO 2 R 9 , SO 2 NR 9 R 10 , NR 9 SO 2 R 10 , SO 2 R 9 , aryl, CO- alkyl, alkyl, the alkyl group being optionally substituted by one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R 9 and R 10 represent each independently a hydrogen atom or a group, optionally substituted, selected from C1 -C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino;
- amine alkyl, heterocyclyl (preferably piperidine, pyrrolidine, piperazine or tetrahydrothiopyrandioxide); optionally substituted with up to three substituents selected from the group comprising halogen, hydroxyl, OR 9 , COOR 9 , CONR 9 R 10 , NR 9 COR 10 , NR 9 R 10 , SO 2 R 9 , SO 2 NR 9 R 10 ,
- NR 9 SO 2 R 10 SOR 9 , aryl, CO-alkyl, alkyl, the alkyl group being optionally substituted by one or more groups selected from halogen, hydroxyl, amino or COOH;
- R 9 and R 10 represent each independently a hydrogen atom or a group, optionally substituted, selected from C1 -C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino; • R 6 , R 7 and the carbon atom to which they are attached form together a ring, said ring being preferably an heterocyclyl, preferably selected from morpholine, piperazine or piperidine; optionally substituted with up to three substituents selected from the group comprising halogen, hydroxyl, OR 9 , COOR 9 , CONR 9 R 10 , NR 9 COR 10 , NR 9 R 10 , SO 2 R 9 , SO 2 NR 9 R 10
- preferred compounds of Formula I are those of Formula 11-1 b1
- Il-1 b1 and pharmaceutically acceptable enantiomers, salts and solvates thereof, wherein X 1 , X 2 , R 1 , R 2 , R 3 , Y 1 and Y 3 are as defined in Formula I.
- Y 3 represents H and Y 1 is as defined in Formula I, preferably, Y 1 represents:
- R 6 , R 7 and R 8 represent each independently:
- NR 9 COR 10 NR 9 R 10 , SO 2 R 9 , SO 2 NR 9 R 10 , NR 9 SO 2 R 10 , SOR 9 , aryl, CO-alkyl, wherein R 9 and R 10 represent each independently a hydrogen atom or a group, optionally substituted, selected from C1 -C6 alkyl, heterocyclyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino;
- heterocyclyl preferably selected from piperidine, pyrrolidine, piperazine, morpholine; optionally substituted with up to three substituents selected from the group comprising halogen, hydroxyl, OR 9 , COOR 9 , CONR 9 R 10 , NR 9 COR 10 , NR 9 R 10 , SO 2 R 9 , SO 2 NR 9 R 10 , NR 9 SO 2 R 10 , SO 2 R 9 , aryl, CO- alkyl, alkyl, the alkyl group being optionally substituted by one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R 9 and R 10 represent each independently a hydrogen atom or a group, optionally substituted, selected from C1 -C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino;
- R 11 represents a group selected from amine, alkyl, heterocyclyl (preferably piperidine, pyrrolidine, piperazine or tetrahydrothiopyrandioxide); optionally substituted with up to three substituents selected from the group comprising halogen, hydroxyl, OR 9 , COOR 9 , CONR 9 R 10 , NR 9 COR 10 , NR 9 R 10 , SO 2 R 9 , SO 2 NR 9 R 10 ,
- NR 9 SO 2 R 10 SOR 9 , aryl, CO-alkyl, alkyl, the alkyl group being optionally substituted by one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R 9 and R 10 represent each independently a hydrogen atom or a group, optionally substituted, selected from C1 -C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino;
- N-1 b2 and pharmaceutically acceptable enantiomers, salts and solvates thereof, wherein X 1 , X 2 , R 1 , R 2 , R 3 , Y 2 and Y 3 are as defined in Formula I.
- Y 3 represents H and Y 2 is as defined in Formula I, preferably, Y 2 represents:
- R 6 , R 7 and R 8 represent each independently:
- NR 9 COR 10 NR 9 R 10 , SO 2 R 9 , SO 2 NR 9 R 10 , NR 9 SO 2 R 10 , SOR 9 , aryl, CO-alkyl, wherein R 9 and R 10 represent each independently a hydrogen atom or a group, optionally substituted, selected from C1 -C6 alkyl, heterocyclyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino;
- heterocyclyl preferably selected from piperidine, pyrrolidine, piperazine, morpholine; optionally substituted with up to three substituents selected from the group comprising halogen, hydroxyl, OR 9 , COOR 9 , CONR 9 R 10 , NR 9 COR 10 , NR 9 R 10 , SO 2 R 9 , SO 2 NR 9 R 10 , NR 9 SO 2 R 10 , SO 2 R 9 , aryl, CO- alkyl, alkyl, the alkyl group being optionally substituted by one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R 9 and R 10 represent each independently a hydrogen atom or a group, optionally substituted, selected from C1 -C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino; • -CO-R 11 or -SO 2 R 11 wherein R 11 represents a group compris
- NR 9 SO 2 R 10 SOR 9 , aryl, CO-alkyl, alkyl, the alkyl group being optionally substituted by one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R 9 and R 10 represent each independently a hydrogen atom or a group, optionally substituted, selected from C1 -C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino;
- preferred compounds of Formula I are those of Formula Il-2a1
- Il-2a1 and pharmaceutically acceptable enantiomers, salts and solvates thereof, wherein X 1 , X 2 , R 1 , R 2 , R 3 , Y 1 and Y 2 are as defined in Formula I.
- Y 1 represents H and Y 2 is as defined in Formula I, preferably, Y 2 represents:
- R 6 , R 7 and R 8 represent each
- R 11 represents a hydrogen atom or a group, optionally substituted, selected from C1 -C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino, CO-alkyl, SO 2 R 11 , wherein R 11 represents a hydrogen atom or a group, optionally substituted, selected from C1 -C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino;
- NR 9 COR 10 NR 9 R 10 , SO 2 R 9 , SO 2 NR 9 R 10 , NR 9 SO 2 R 10 , SOR 9 , aryl, CO-alkyl, wherein R 9 and R 10 represent each independently a hydrogen atom or a group, optionally substituted, selected from C1 -C6 alkyl, heterocyclyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino;
- heterocyclyl preferably selected from piperidine, pyrrolidine, piperazine, morpholine; optionally substituted with up to three substituents selected from the group comprising halogen, hydroxyl, OR 9 , COOR 9 , CONR 9 R 10 , NR 9 COR 10 , NR 9 R 10 , SO 2 R 9 , SO 2 NR 9 R 10 , NR 9 SO 2 R 10 , SO 2 R 9 , aryl, CO- alkyl, alkyl, the alkyl group being optionally substituted by one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R 9 and R 10 represent each independently a hydrogen atom or a group, optionally substituted, selected from C1 -C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino;
- amine, alkyl, heterocyclyl preferably piperidine, pyrrolidine, piperazine or tetrahydrothiopyrandioxide
- preferred compounds of Formula I are those of Formula Il-2a2 2
- Il-2a2 and pharmaceutically acceptable enantiomers, salts and solvates thereof, wherein X 1 , X 2 , R 1 , R 2 , R 3 and Y 2 are as defined in Formula I.
- Y 2 represents:
- R 6 , R 7 and R 8 represent each
- amine alkyl, heterocyclyl (preferably piperidine, pyrrolidine, piperazine or tetrahydrothiopyrandioxide); optionally substituted with up to three substituents selected from the group comprising halogen, hydroxyl, OR 9 , COOR 9 , CONR 9 R 10 , NR 9 COR 10 , NR 9 R 10 , SO 2 R 9 , SO 2 NR 9 R 10 ,
- NR 9 SO 2 R 10 SOR 9 , aryl, CO-alkyl, alkyl, the alkyl group being optionally substituted by one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R 9 and R 10 represent each independently a hydrogen atom or a group, optionally substituted, selected from C1 -C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino.
- preferred compounds of Formula I are those of Formula Il-2b1
- Il-2b1 and pharmaceutically acceptable enantiomers, salts and solvates thereof, wherein X 1 , X 2 , R 1 , R 2 , R 3 , Y 2 and Y 3 are as defined in Formula I.
- Y 3 represents H and Y 2 is as defined in Formula I, preferably, Y 2 represents:
- R 6 , R 7 and R 8 represent each independently:
- R 11 represents a hydrogen atom or a group, optionally substituted, selected from C1 -C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino, CO-alkyl, SO 2 R 11 , wherein R 11 represents a hydrogen atom or a group, optionally substituted, selected from C1 -C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino;
- R 9 and R 10 represent each independently a hydrogen atom or a group, optionally substituted, selected from C1 -C6 alkyl, heterocyclyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino;
- heterocyclyl preferably selected from piperidine, pyrrolidine, piperazine, morpholine; optionally substituted with up to three substituents selected from the group comprising halogen, hydroxyl, OR 9 , COOR 9 , CONR 9 R 10 , NR 9 COR 10 , NR 9 R 10 , SO 2 R 9 , SO 2 NR 9 R 10 , NR 9 SO 2 R 10 , SO 2 R 9 , aryl, CO- alkyl, alkyl, the alkyl group being optionally substituted by one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R 9 and
- R 10 represent each independently a hydrogen atom or a group, optionally substituted, selected from C1 -C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino.
- preferred compounds of Formula I are those of Formula Il-2b2
- Il-2b2 and pharmaceutically acceptable enantiomers, salts and solvates thereof, wherein X 1 , X 2 , R 1 , R 2 , R 3 and Y 2 are as defined in Formula I, wherein the dotted line is an absent or a bond.
- R 6 , R 7 and R 8 represent each independently:
- heterocyclyl or C1 -heterocycl preferably selected from piperidine, pyrrolidine, piperazine, morpholine or 2,6-diazaspiro[3.3]heptane; optionally substituted with up to three substituents selected from the group comprising halogen, hydroxyl, OR 9 , COOR 9 , CONR 9 R 10 , NR 9 COR 10 , NR 9 R 10 , SO 2 R 9 , SO 2 NR 9 R 10 , NR 9 SO 2 R 10 , SO 2 R 9 , aryl, CO- alkyl, alkyl, the alkyl group being optionally substituted by one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R 9 and R 10 represent each independently a hydrogen atom or a group, optionally substituted, selected from C1 -C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroary
- R 11 represents a group selected from amine, alkyl, heterocyclyl (preferably piperidine, pyrrolidine, piperazine or tetrahydrothiopyrandioxide); optionally substituted with up to three substituents selected from the group comprising halogen, hydroxyl, OR 9 , COOR 9 , CONR 9 R 10 , NR 9 COR 10 , NR 9 R 10 , SO 2 R 9 , SO 2 NR 9 R 10 , NR 9 SO 2 R 10 , SOR 9 , aryl, CO-alkyl, alkyl, the alkyl group being optionally substituted by one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R 9 and R 10 represent each independently a hydrogen atom or a group, optionally substituted, selected from C1 -C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalky
- one ore more of the heterocycles is substituted with at least one of H or a group selected from SO2CH3, C1 -C3 lower akyl, preferably CH 3 , or COOH.
- preferred com ounds of Formula I are those of Formula Il-2b3
- Il-2b3 and pharmaceutically acceptable enantiomers, salts and solvates thereof wherein X 1 , X 2 , R 1 , R 2 , R 3 , Y 1 , and Y 2 and Y 3 are as defined in Formula I.
- R 1 , R 2 or R 3 are each independently H, halogen, or C1 -C6 alkyl, preferably, C1 alkyl.
- X 1 and X 2 are independently H or halogen.
- the compounds of Table 1 were named using ChemBioDraw ® Ultra version 12.0 (PerkinElmer).
- the compounds of Formula I and subformulae thereof may contain an asymmetric center and thus may exist as different stereoisomeric forms. Accordingly, the present invention includes all possible stereoisomers and includes not only racemic compounds but the individual enantiomers and their non-racemic mixtures as well.
- a compound is desired as a single enantiomer, such may be obtained by stereospecific synthesis, by resolution of the final product or any convenient intermediate, or by chiral chromatographic methods as each are known in the art. Resolution of the final product, an intermediate, or a starting material may be performed by any suitable method known in the art.
- the compounds of the invention may be in the form of "pharmaceutically acceptable salts".
- Pharmaceutically acceptable salts of the compounds of Formula I include the acid addition and base salts thereof. Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, lactobionate, benzenesulfonate, laurate, adipate, aspartate, benzoate, besylate, bicarbonate/carbonate,
- methylnitrate calcium edetate, mucate, napsylate, chloride, clavulanate, N oleate, edetate, estolate, pantothenate, polygalacuronate, salicylate, glutamate,
- naphthylate 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate and xinofoate salts.
- Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, ornithine, N,N-dibenzyethelenediamine, piperazine, tri(hydroxymethyl_aminomethane, tetramethylammonium hydroxide, - methylgucamine, ammonium salt, potassium, sodium, tromethamine, 2- (diethylamino)ethanol, ethanolamine, morpholine, 4-(2-hydroxyethyl)morpholine and zinc salts. Hemisalts of acids and bases may also be formed, for example, hemisulphate and hemicalcium salts. Preferred, pharmaceutically acceptable salts include
- hydrochloride/chloride hydrobromide/bromide, bisulphate/sulphate, nitrate, citrate, and acetate.
- the compounds of the invention may also form internal salts, and such compounds are within the scope of the invention.
- the compounds of the invention contain a hydrogen-donating heteroatom (e.g. NH)
- the invention also covers salts and/or isomers formed by transfer of said hydrogen atom to a basic group or atom within the molecule.
- compositions of Formula I may be prepared by one or more of these methods:
- the salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent.
- the degree of ionization in the salt may vary from completely ionized to almost non- ionized.
- the compounds of the present invention may be administered in the form of
- salts which are as defined above. These salts may be prepared by standard procedures, e.g. by reacting a free acid with a suitable organic or inorganic base. Where a basic group is present, such as amino, an acidic salt, i.e.
- hydrochloride hydrobromide, acetate, palmoate, and the like, can be used as the dosage form.
- esters can be employed, e.g. acetate, maleate, pivaloyloxymethyl, and the like, and those esters known in the art for modifying solubility or hydrolysis characteristics for use as sustained release or prodrug formulations.
- the compounds of the invention include compounds of Formula I as hereinbefore defined, including all polymorphs and crystal habits thereof, prodrugs and isomers thereof (including optical, geometric and tautomeric isomers) and isotopically- labeled compounds of Formula I.
- pharmaceutically acceptable salts are preferred, it should be noted that the invention in its broadest sense also included non-pharmaceutically acceptable salts, which may for example be used in the isolation and/or purification of the compounds of the invention.
- salts formed with optically active acids or bases may be used to form diastereoisomeric salts that can facilitate the separation of optically active isomers of the compounds of Formula I above.
- the invention also generally covers all pharmaceutically acceptable predrugs and prodrugs of the compounds of Formula I.
- the invention further relates to a first process for manufacturing of compounds of Formula I
- X 1 and X 2 are as defined in Formula I;
- Z 1 represents H or an amino protecting group such as for example an arylsulphonyl, a te/t-butoxy carbonyl, a methoxymethyl, a para-methoxy benzyl, a benzyl or any other suitable protecting group known to those skilled in the art
- Y represents an halogen (preferably iodine, bromine or chlorine), an alkylsulfonyloxy having 1 -6 carbon atoms (preferably methylsulfonyloxy or trifluoromethylsulfonyloxy) or arylsulfonyloxy having 6-10 carbon atoms (preferably phenyl- or p-tolylsulfonyloxy), or any leaving group known to those skilled in the art with a compound of Formula (ii)
- R 1 , R 2 , R 3 , A 1 , A 2 , A 3 , Y 1 , Y 2 and Y 3 are as defined in Formula I;
- Z 2 and Z 3 represent H or alkyl groups, with the possibility for Z 2 and Z 3 to form a ring; so as to obtain a compound of Formula (iii),
- step (a1 ) of the process of the invention may be performed with or without a catalyst such as but not limited to Pd 2 (dba) 3 , Pd(PPh 3 ) 4 , dichlorobis(triphenylphosphine)palladium(ll) or 1 ,1 '-bis(diphenylphosphino)ferrocene- dichloro palladium(ll), Pd(OAc)2, or Pd/C in the presence or absence of an additional ligand, such as but not limited to X-Phos, S-Phos, P(oTol) 3 , PPh 3 , BINAP, P(iBu) 3 or any other suitable phosphine ligand known to those skilled in the art.
- a catalyst such as but not limited to Pd 2 (dba) 3 , Pd(PPh 3 ) 4 , dichlorobis(triphenylphosphine)palladium(ll) or 1 ,1 '-bis(dipheny
- step (a1 ) of the process of the invention may be performed in the presence of bases such as but not limited to K 3 PO 4 , K 2 CO 3 , Na 2 CO 3 .
- step (a1 ) of the process of the invention may be performed in the presence of a suitable solvent such as but not limited to dioxane, THF, DMF, water or mixtures thereof, preferably in a mixture of dioxane or THF and water.
- step (a1 ) of the process of the invention may be performed at a temperature ranging from 20 °C to about 180 °C, with or without microwave irradiation, for a period ranging from 10 minutes to a few hours, e.g. 10 minutes to 24 h.
- the deprotection (b1 ) may be performed, depending on the nature of the group Z 1 , by treatment with bases, such as but not limited to sodium hydroxide, potassium hydroxide, potassium carbonate.
- the deprotection may be performed in the presence or absence of a suitable solvent such as but not limited to methanol, ethanol, isopropanol, terf-butanol, THF, DMF, Dioxane, water or a mixture thereof.
- a suitable solvent such as but not limited to methanol, ethanol, isopropanol, terf-butanol, THF, DMF, Dioxane, water or a mixture thereof.
- the deprotection may be performed at a temperature ranging from 20 °C to 100 °C, preferably at about 85 °C, for a few hours, e.g. one hour to 24 h.
- the deprotection (b1 ) may be performed, depending on the nature of the group Z 1 in the presence of strong acids, such as but not limited to HCI, TFA, HF, HBr.
- the deprotection may be performed in the presence or absence of a suitable solvent such as methanol, ethanol, isopropanol, te/t-butanol, THF, DMF, Dioxane, water or a mixture thereof.
- the deprotection may be performed at a temperature between about 20 °C to about 100 °C, for a period comprised between 10 minutes and a few hours, e.g. 10 minutes to 24 h.
- the invention further relates to a second process of manufacturing of compounds of Formula I
- Y 1 , Y 2 and Y 3 represent respectively Y 1 , Y 2 and Y 3 as defined in Formula I with the condition that at least one of Y 1 , Y 2 and Y 3 is H;
- Z 1 represents H or an amino protecting group such as for example an arylsulphonyl, a te/t-butoxy carbonyl, a methoxymethyl, a para-methoxy benzyl, a benzyl or any other suitable protecting group known to those skilled in the art; so as to obtain a compound of Formula (v)
- alkylation step (a2) is performed in presence of a compound of Formula (vi) Y 4 -X
- Y 4 represent Y 1 , Y 2 or ⁇ 3 , as defined in Formula I, with the condition that Y 4 is not H or absent;
- X represents an halogen (preferably iodine, bromine or chlorine), alkylsulfonyloxy having 1 -6 carbon atoms (preferably methylsulfonyloxy or trifluoro- methylsulfonyloxy) or arylsulfonyloxy having 6-10 carbon atoms (preferably phenyl- or p-tolylsulfonyloxy), or any other leaving group known to those skilled in the art.
- halogen preferably iodine, bromine or chlorine
- alkylsulfonyloxy having 1 -6 carbon atoms preferably methylsulfonyloxy or trifluoro- methylsulfonyloxy
- arylsulfonyloxy having 6-10 carbon atoms (preferably phenyl- or p-tolylsulfonyloxy), or any other leaving group known to those skilled in the art.
- step (a2) of the process of the invention may be performed in the presence of bases such as but not limited to potassium carbonate, sodium carbonate, cesium carbonate, potassium hydroxide, sodium hydroxide, sodium te/t-butoxide, potassium te/t-butoxide, sodium hydride, lithium diisopropyl amide, buthyl lithium.
- bases such as but not limited to potassium carbonate, sodium carbonate, cesium carbonate, potassium hydroxide, sodium hydroxide, sodium te/t-butoxide, potassium te/t-butoxide, sodium hydride, lithium diisopropyl amide, buthyl lithium.
- step (a2) of the process of the invention may be performed in the presence of a suitable solvent such as but not limited to DMF, methanol, ethanol, isopropanol, te/t-butanol, THF, dioxane, dichloromethane, water.
- a suitable solvent such as but not limited to DMF, methanol, ethanol, isopropanol, te/t-butanol, THF, dioxane, dichloromethane, water.
- step (a2) of the process of the invention may be performed in the presence or absence of catalytic amounts of appropriate iodide salts, such as but not limited to tetrabutylammonium iodide.
- step (a2) of the process of the invention may be performed at a temperature ranging from 20 °C to about 180 °C, with or without microwave irradiation.
- step (a2) of the process of the invention may be performed for a period ranging from 10 minutes and a few hours, e.g. 10 minutes to 24 h.
- the deprotection step (b2) may be performed in conditions described above for deprotection (b1 ).
- the invention further relates to a third process of manufacturing of compounds of Formula Il-2a1 wherein Y 1 is H:
- Z 1 represents H or an amino protecting group such as for example an arylsulphonyl, a te/t-butoxy carbonyl, a methoxymethyl, a para-methoxy benzyl, a benzyl or any other suitable protecting group known to those skilled in the art; with a compound of Formula (viii)
- Y represents an hydroxyl, halogen (preferably iodine, bromine or chlorine), alkylsulfonyloxy having 1 -6 carbon atoms (preferably methylsulfonyloxy or trifluoromethylsulfonyloxy) or arylsulfonyloxy having 6-10 carbon atoms (preferably phenyl- or p-tolylsulfonyloxy), or any other leaving group known to those skilled in the art; so as to obtain a compound of Formula (ix) 2
- step (a3) of the process of the invention may be performed in the presence of a suitable amide coupling reagent, such as but not limited to HATU, DCC, DIC, BOP, PyBOP, in the presence or absence of additional additives such as but not limited to HOBt.
- a suitable amide coupling reagent such as but not limited to HATU, DCC, DIC, BOP, PyBOP, in the presence or absence of additional additives such as but not limited to HOBt.
- step (a3) of the process of the invention may be performed in the presence of bases such as but not limited to triethylamine,
- step (a3) of the process of the invention may be performed in the presence of a suitable solvent such as but not limited to
- step (a3) further comprises adding a suitable acid, such as but not limited to acetic acid, wherever necessary to complete cyclization.
- step (a3) of the process of the invention may be performed at a temperature ranging from 20 °C to about 180 °C, with or without microwave irradiation.
- step (a3) of the process of the invention may be performed for a period ranging from 10 minutes and a few hours, e.g. 10 minutes to 24 h.
- the deprotection step (b3) may be performed in conditions described above for deprotection (b1 ).
- the invention further relates to a fourth process for manufacturing of compounds of Formula I
- Z 1 represents H or an amino protecting group such as for example an arylsulphonyl, a te/t-butoxy carbonyl, a methoxymethyl, a para-methoxy benzyl, a benzyl or any other suitable protecting group known to those skilled in the art
- Z 2 and Z 3 represent H or alkyl groups, with the possibility for Z 2 and Z 3 to form a ring;
- R 1 , R 2 , R 3 , A 1 , A 2 , A 3 , Y 1 , Y 2 and Y 3 are as defined in Formula I;
- Y represents an halogen (preferably iodine, bromine or chlorine), an alkylsulfonyloxy having 1 -6 carbon atoms (preferably methylsulfonyloxy or trifluoromethylsulfonyloxy) or arylsulfonyloxy having 6-10 carbon atoms
- halogen preferably iodine, bromine or chlorine
- alkylsulfonyloxy having 1 -6 carbon atoms preferably methylsulfonyloxy or trifluoromethylsulfonyloxy
- arylsulfonyloxy having 6-10 carbon atoms
- step (b4) of the process of the invention may be performed with or without a catalyst such as but not limited to Pd2(dba)3, Pd(PPh 3 ) 4 , dichlorobis(triphenylphosphine)palladium(ll) or 1 ,1 '-bis(diphenylphosphino)ferrocene- dichloro palladium(ll), Pd(OAc) 2 , or Pd/C in the presence or absence of an additional ligand, such as but not limited to X-Phos, S-Phos, P(oTol) 3 , PPh 3 , BINAP, P(iBu) 3 or any other suitable phosphine ligand known to those skilled in the art.
- a catalyst such as but not limited to Pd2(dba)3, Pd(PPh 3 ) 4 , dichlorobis(triphenylphosphine)palladium(ll) or 1 ,1 '-bis(diphenylphosphin
- step (a4) of the process of the invention may be performed in the presence of bases such as but not limited to K 3 PO 4 , K 2 CO 3 , Na 2 CO 3 .
- step (a4) of the process of the invention may be performed in the presence of a suitable solvent such as but not limited to dioxane, THF, DMF, water or mixtures thereof, preferably in a mixture of dioxane or THF and water.
- a suitable solvent such as but not limited to dioxane, THF, DMF, water or mixtures thereof, preferably in a mixture of dioxane or THF and water.
- step (a4) of the process of the invention may be performed at a temperature ranging from 20 °C to about 180 °C, with or without microwave irradiation, for a period ranging from 10 minutes to a few hours, e.g. 10 minutes to 24 h.
- the deprotection step (b4) may be performed in conditions described above for deprotection (b1 ).
- compounds of Formula I can be converted to alternative compounds of Formula I, employing suitable interconversion techniques well known by a person skilled in the art.
- Compounds of the Formula I and related formulae can furthermore be obtained by liberating compounds of the Formula I from one of their functional derivatives by treatment with a solvolysing or hydrogenolysing agent.
- Preferred starting materials for the solvolysis or hydrogenolysis are those which conform to the Formula I and related formulae, but contain corresponding protected amino and/or hydroxyl groups instead of one or more free amino and/or hydroxyl groups, preferably those which carry an amino-protecting group instead of an H atom bonded to an N atom, in particular those which carry an R * -N group, in which R * denotes an amino- protecting group, instead of an HN group, and/or those which carry a hydroxyl-protecting group instead of the H atom of a hydroxyl group, for example those which conform to the Formula I, but carry a -COOR ** group, in which R ** denotes a hydroxyl-protecting group, instead of a -COOH group.
- amino-protecting group is known in general terms and relates to groups which are suitable for protecting (blocking) an amino group against chemical reactions, but which are easy to remove after the desired chemical reaction has been carried out elsewhere in the molecule. Typical of such groups are, in particular, unsubstituted or substituted acyl, aryl, aralkoxymethyl or aralkyl groups. Since the amino-protecting groups are removed after the desired reaction (or reaction sequence), their type and size are furthermore not crucial; however, preference is given to those having 1 -20, in particular 1 -8, carbon atoms.
- acyl group is to be understood in the broadest sense in connection with the present process.
- acyl groups derived from aliphatic, araliphatic, aromatic or heterocyclic carboxylic acids or sulfonic acids, and, in particular, alkoxy-icarbonyl, aryloxycarbonyl and especially aralkoxycarbonyl groups.
- acyl groups are alkanoyl, such as acetyl, propionyl and butyryl; aralkanoyl, such as phenylacetyl; aroyl, such as benzoyl and tolyl; aryloxyalkanoyl, such as POA; alkoxycarbonyl, such as methoxy-icarbonyl, ethoxycarbonyl, 2,2,2- trichloroethoxycarbonyl, BOC (terf-butoxycarbonyl) and 2-iodoethoxycarbonyl; aralkoxycarbonyl, such as CBZ ("carbobenzoxy”), 4-methoxybenzyloxycarbonyl and FMOC; and arylsulfonyl, such as Mtr.
- Preferred amino-protecting groups are BOC and Mtr, further-iimore CBZ, Fmoc, benzyl and acetyl.
- hydroxyl-protecting group is likewise known in general terms and relates to groups which are suitable for protecting a hydroxyl group against chemical reactions, but are easy to remove after the desired chemical reaction has been carried out elsewhere in the molecule. Typical of such groups are the above-mentioned unsubstituted or substituted aryl, aralkyl or acyl groups, furthermore also alkyl groups.
- the nature and size of the hydroxyl-protecting groups are not crucial since they are removed again after the desired chemical reaction or reaction sequence; preference is given to groups having 1 -20, in particular 1 -10, carbon atoms.
- hydroxyl- protecting groups are, inter alia, benzyl, 4-methoxybenzyl, p-nitrobenzoyl, p- toluenesulfonyl, terf-butyl and acetyl, where benzyl and terf-butyl are particularly preferred.
- the compounds of the Formula I and related formulae are liberated from their functional derivatives - depending on the protecting group used - for example strong inorganic acids, such as hydrochloric acid, perchloric acid or sulfuric acid, strong organic carboxylic acids, such as trichloroacetic acid, TFA or sulfonic acids, such as benzene- or p-toluenesulfonic acid.
- strong inorganic acids such as hydrochloric acid, perchloric acid or sulfuric acid
- strong organic carboxylic acids such as trichloroacetic acid, TFA or sulfonic acids, such as benzene- or p-toluenesulfonic acid.
- Suitable inert solvents are preferably organic, for example carboxylic acids, such as acetic acid, ethers, such as tetrahydrofuran or dioxane, amides, such as DMF, halogenated hydrocarbons, such as dichloromethane, furthermore also alcohols, such as methanol, ethanol or isopropanol, and water. Mixtures of the above-mentioned solvents are furthermore suitable. TFA is preferably used in excess without addition of a further solvent, and perchloric acid is preferably used in the form of a mixture of acetic acid and 70% perchloric acid in the ratio 9:1 .
- the reaction temperatures for the cleavage are advantageously between about 0 and about 50°C, preferably between 15 and 30°C (room temperature).
- the BOC, OtBu and Mtr groups can, for example, preferably be cleaved off using TFA in dichloromethane or using approximately 3 to 5N HCI in dioxane at 15-30°C, and the FMOC group can be cleaved off using an approximately 5 to 50% solution of dimethylamine, diethylamine or piperidine in DMF at 15-30°C.
- Protecting groups which can be removed hydrogenolytically can be cleaved off, for example, by treatment with hydrogen in the presence of a catalyst (for example a noble-metal catalyst, such as palladium, advantageously on a support, such as carbon).
- a catalyst for example a noble-metal catalyst, such as palladium, advantageously on a support, such as carbon.
- Suitable solvents are those indicated above, in particular, for example, alcohols, such as methanol or ethanol, or amides, such as DMF.
- the hydrogenolysis is generally carried out at temperatures between about 0 and 100°C and pressures between about 1 and 200 bar, preferably at 20-30°C and 1 -10 bar. Hydrogenolysis of the CBZ group succeeds well, for example, on 5 to 10% Pd/C in methanol or using ammonium formate (instead of hydrogen) on Pd/C in methanol/DMF at 20-30°C.
- suitable inert solvents are hydrocarbons, such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons, such as trichloroethylene, 1 ,2- dichloroethane, tetrachloromethane, trifluoromethylbenzene, chloroform or
- amides such as acetamide, dimethylacetamide, A/-methylpyrrolidone (NMP) or dimethyhformamide (DMF); nitriles, such as acetonitrile; sulfoxides, such as dimethyl sulfoxide (DMSO); carbon disulfide; carboxylic acids, such as formic acid or acetic acid; nitro compounds, such as nitromethane or nitrobenzene; esters, such as ethyl acetate, or mixtures of the said solvents.
- NMP NMP
- DMF dimethyhformamide
- nitriles such as acetonitrile
- sulfoxides such as dimethyl sulfoxide (DMSO)
- carbon disulfide such as carboxylic acids, such as formic acid or acetic acid
- nitro compounds such as nitromethane or nitrobenzene
- esters such as ethyl acetate, or mixtures of the said solvent
- Esters can be hydrolysed, for example, using HCI, H 2 SO 4 , or using LiOH, NaOH or KOH in water, water/THF, water/THF/ethanol or water/dioxane, at temperatures between 0 and 100°C.
- Free amino groups can furthermore be acylated in a conventional manner using an acyl chloride or anhydride or alkylated using an unsubstituted or substituted alkyl halide, advantageously in an inert solvent, such as dichloromethane or THF and/or in the presence of a base, such as triethylamine or pyridine, at temperatures between -60°C and +30°C.
- an inert solvent such as dichloromethane or THF
- a base such as triethylamine or pyridine
- the invention is further directed to the use of the compounds of the invention or pharmaceutically acceptable enantiomers, salts and solvates thereof as TDO2 inhibitors.
- the invention relates to the use of compounds of Formula I and subformulae in particular those of Table 1 above, or pharmaceutically acceptable enantiomers, salts and solvates thereof, as TDO2 inhibitors. Accordingly, in another aspect, the invention relates to the use of these compounds or enantiomers, salts and solvates thereof for the synthesis of pharmaceutical active ingredients, such as TDO2 inhibitors.
- the invention relates to the use of compounds of Formula I and subformulae in particular those of Table 1 above, or pharmaceutically acceptable enantiomers, salts and solvates thereof, for increasing immune recognition and destruction of the cancer cells.
- the compounds of the invention are therefore useful as medicaments, in particular in the prevention and/or treatment of cancer.
- compounds of the invention or pharmaceutically acceptable enantiomers, salts or solvates thereof are for use in the treatment and/or prevention of cancer, neurodegenerative disorders such as Parkinson's disease, Alzheimer's disease and Huntington's disease, chronic viral infections such as HCV and HIV, depression, and obesity.
- the invention further relates to a method for treatment or prevention of cancer, neurodegenerative disorders such as Parkinson's disease, Alzheimer's disease and Huntington's disease, chronic viral infections such as HCV and HIV, depression, and obesity, which comprises administering to a mammalian species in need thereof a therapeutically effective amount of the compound according to the invention or a pharmaceutically acceptable enantiomers, salts or solvates thereof.
- the cancer may be metastatic or non-metastatic.
- the cancer may be may be familial or sporadic.
- the cancer is selected from the group consisting of: leukemia and multiple myeloma. Additional cancers that can be treated using the methods of the invention include, for example, benign and malignant solid tumours and benign and malignant non-solid tumours.
- solid tumours include, but are not limited to: biliary tract cancer, brain cancer (including glioblastomas and medulloblastomas), breast cancer, cervical cancer, choriocarcinoma, colon cancer, endometrial cancer, esophageal cancer, gastric cancer, intraepithelial neoplasms (including Bowen's disease and Paget's disease), liver cancer, lung cancer, neuroblastomas, oral cancer (including squamous cell carcinoma), ovarian cancer (including those arising from epithelial cells, stromal cells, germ cells and mesenchymal cells), pancreatic cancer, prostate cancer, rectal cancer, renal cancer (including adenocarcinoma and Wilms tumour), sarcomas (including leiomyosarcoma, rhabdomyosarcoma, liposarcoma, fibrosarcoma and osteosarcoma), skin cancer (including melanoma, Kaposi's sarcoma, basocellular
- non-solid tumours include but are not limited to hematological neoplasms.
- a hematologic neoplasm is a term of art which includes lymphoid disorders, myeloid disorders, and AIDS associated leukemias.
- Lymphoid disorders include but are not limited to acute lymphocytic leukemia and chronic lymphoproliferative disorders (e.g., lymphomas, myelomas, and chronic lymphoid leukemias). Lymphomas include, for example, Hodgkin's disease, non- Hodgkin's lymphoma lymphomas, and lymphocytic lymphomas). Chronic lymphoid leukemias include, for example, T cell chronic lymphoid leukemias and B cell chronic lymphoid leukemias.
- the invention also provides for a method for delaying in patient the onset of cancer comprising the administration of a pharmaceutically effective amount of a compound of Formula I or pharmaceutically acceptable enantiomer, salt and solvate thereof to a patient in need thereof.
- the patient is a warm-blooded animal, more preferably a human.
- the compounds of the invention are especially useful in the treatment and/or prevention of cancer.
- the compounds of the invention are especially useful in the treatment and/or prevention of cancer.
- the invention further provides the use of a compound of Formula I or a pharmaceutically acceptable enantiomer, salt and solvate thereof for the manufacture of a medicament for treating and/or preventing cancer.
- a method for modulating TDO2 activity in a patient, preferably a warm blooded animal, and even more preferably a human, in need of such treatment, which comprises administering to said patient an effective amount of compound of the present invention, or a
- the invention also provides pharmaceutical compositions comprising a compound of Formula I or a pharmaceutically acceptable enantiomer, salt and solvate thereof and at least one pharmaceutically acceptable carrier, diluent, excipient and/or adjuvant.
- the invention also covers pharmaceutical compositions which contain, in addition to a compound of the present invention, a pharmaceutically acceptable enantiomer, salt and solvate thereof as active ingredient, additional therapeutic agents and/or active ingredients.
- Another object of this invention is a medicament comprising at least one compound of the invention, or a pharmaceutically acceptable enantiomer, salt and solvate thereof, as active ingredient.
- a compound of Formula I or a pharmaceutically acceptable enantiomer, salt and solvate thereof for the manufacture of a medicament for modulating TDO2 activity in a patient, in need of such treatment, which comprises administering to said patient an effective amount of compound of the present invention, or a pharmaceutically acceptable enantiomer, salt and solvate thereof.
- the compounds of the invention may be formulated as a pharmaceutical preparation comprising at least one compound of the invention and at least one pharmaceutically acceptable carrier, diluent, excipient and/or adjuvant, and optionally one or more further pharmaceutically active compounds.
- such a formulation may be in a form suitable for oral administration, for parenteral administration (such as by intravenous, intramuscular or subcutaneous injection or intravenous infusion), for topical administration (including ocular), for administration by inhalation, by a skin patch, by an implant, by a suppository, etc.
- parenteral administration such as by intravenous, intramuscular or subcutaneous injection or intravenous infusion
- topical administration including ocular
- suitable administration forms - which may be solid, semi-solid or liquid, depending on the manner of administration - as well as methods and carriers, diluents and excipients for use in the preparation thereof, will be clear to the skilled person;
- Such preparations include tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols, ointments, cremes, lotions, soft and hard gelatin capsules, suppositories, drops, sterile injectable solutions and sterile packaged powders (which are usually reconstituted prior to use) for administration as a bolus and/or for continuous
- compositions which may be formulated with carriers, excipients, and diluents that are suitable per se for such formulations, such as lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, polyethylene glycol, cellulose, (sterile) water, methylcellulose, methyl- and propylhydroxybenzoates, talc, magnesium stearate, edible oils, vegetable oils and mineral oils or suitable mixtures thereof.
- carriers, excipients, and diluents that are suitable per se for such formulations, such as lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrol
- the formulations can optionally contain other substances that are commonly used in pharmaceutical formulations, such as lubricating agents, wetting agents, emulsifying and suspending agents, dispersing agents, desintegrants, bulking agents, fillers, preserving agents, sweetening agents, flavoring agents, flow regulators, release agents, etc..
- the compositions may also be formulated so as to provide rapid, sustained or delayed release of the active compound(s) contained therein.
- the pharmaceutical preparations of the invention are preferably in a unit dosage form, and may be suitably packaged, for example in a box, blister, vial, bottle, sachet, ampoule or in any other suitable single-dose or multi-dose holder or container (which may be properly labeled); optionally with one or more leaflets containing product information and/or instructions for use.
- the active compound of the invention may be administered as a single daily dose, divided over one or more daily doses, or essentially continuously, e.g. using a drip infusion.
- groups may be substituted, such groups may be substituted with one or more substituents, and preferably with one, two or three substituents.
- Substituents may be selected from but not limited to, for example, the group comprising halogen, hydroxyl, oxo, nitro, amido, carboxy, amino, cyano haloalkoxy, and haloalkyl.
- halogen means fluoro (F), chloro (CI), bromo (Br), or iodo (I).
- alkyl by itself or as part of another substituent refers to a hydrocarbyl radical of Formula CnH 2 n + i wherein n is a number greater than or equal to 1 .
- Alkyl groups may contain 1 to 10 carbons (inclusive), i.e., C1 , C2, C3, C4, C5, C6, C7, C8, C9 or C10, i.e., C1 -C10 alkyl.
- alkyl groups of this invention comprise from 1 to 6 carbon atoms, preferably from 1 to 4 carbon atoms, more preferably from 1 to 3 carbon atoms.
- Alkyl groups may be linear or branched and may be substituted as indicated herein.
- Suitable alkyl groups include methyl, ethyl, n-propyl, i-propyl, n- butyl, i-butyl, s-butyl and t-butyl, pentyl and its isomers (e.g. n-pentyl, iso-pentyl), and hexyl and its isomers (e.g. n-hexyl, iso-hexyl).
- haloalkyi alone or in combination, refers to an alkyl radical having the meaning as defined above wherein one or more hydrogens are replaced with a halogen as defined above.
- Non-limiting examples of such haloalkyi radicals include fluoromethyl, difluoromethyl, trifluoro methyl and the like.
- the haloalkyi is a C1 to C6 alkyl group substituted with at least one halogen.
- the haloalkyi is a C1 to C4 alkyl group substituted with at least one halogen. Each halogen substitution may be independently selected.
- cycloalkyi is a cyclic alkyl group, that is to say, a monovalent, saturated, or unsaturated hydrocarbyl group having 1 or 2 cyclic structures.
- Cycloalkyi includes monocyclic or bicyclic hydrocarbyl groups. Cycloalkyi groups may comprise 3 or more carbon atoms in the ring and generally, according to this invention comprise from 3 to 10, more preferably from 3 to 8 carbon atoms still more preferably from 3 to 6 carbon atoms. Examples of cycloalkyi groups include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, with cyclopropyl being particularly preferred.
- heteroatom referns to a sulfur, nitrogen or oxygen atom.
- heterocyclyl where at least one carbon atom in a cycloalkyi group is replaced with a heteroatom, the resultant ring is referred to herein as "heterocyclyl".
- heterocyclyl or “heterocycle” as used herein by itself or as part of another group refer to non-aromatic, fully saturated or partially unsaturated cyclic groups (for example, 3 to 7 member monocyclic, 7 to 1 1 member bicyclic, or containing a total of 3 to 10 ring atoms) which have at least one heteroatom in at least one carbon atom- containing ring.
- Each ring of the heterocyclic group containing a heteroatom may have 1 , 2, 3 or 4 heteroatoms selected from nitrogen, oxygen and/or sulfur atoms, where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen
- heteroatoms may optionally be quaternized.
- the heterocycle may contain 3 to 7 carbon atoms (inclusive), or an integer therebetween. Any of the carbon atoms of the
- heterocyclic group may be substituted by oxo (for example piperidone,
- heterocyclic group may be attached at any heteroatom or carbon atom of the ring or ring system, where valence allows.
- heterocycles may be fused, bridged and/or joined through one or more spiro atoms.
- Non limiting exemplary heterocyclic groups include piperidinyl, azetidinyl, tetrahydropyranyl, piperazinyl, imidazolinyl, morpholinyl, oxetanyl, pyrazolidinyl imidazolidinyl, isoxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, indolyl, indolinyl, isoindolinyl, tetrahydrofuranyl, tetrahydroquinolinyl, thiomorpholinyl, thiomorpholinylsulfoxide, thiomorpholinylsulfone, pyrrolizinyl.
- aryl refers to a polyunsaturated, aromatic hydrocarbyl group having a single ring (i.e. phenyl) or multiple aromatic rings fused together (e.g. naphtyl) or linked covalently, typically containing 5 to 12 atoms; preferably 6 to 10, wherein at least one ring is aromatic.
- the aromatic ring may optionally include one to two additional rings (either cycloalkyl, heterocyclyl or heteroaryl) fused thereto.
- Aryl is also intended to include the partially hydrogenated derivatives of the carbocyclic (carbon-containing ring) systems enumerated herein.
- Non- limiting examples of aryl comprise phenyl, biphenylyl, biphenylenylnaphthalenyl, indenyl.
- heteroaryl refers but is not limited to 5 to 12 carbon-atom aromatic rings or ring systems containing 1 to 2 rings which are fused together or linked covalently, typically containing 5 to 6 atoms; at least one of which is aromatic, in which one or more carbon atoms in one or more of these rings is replaced by oxygen, nitrogen and/or sulfur atoms where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quaternized.
- Such rings may be fused to an aryl, cycloalkyl, heteroaryl or heterocyclyl ring.
- Non-limiting examples of such heteroaryl include: pyridazinyl, pyridinyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, oxatriazolyl, thiatriazolyl, pyrimidyl, pyrazinyl, oxazinyl, dioxinyl, thiazinyl, triazinyl, indolyl, indolizinyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, isobenzothiophenyl, indazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quin
- arylalkyl refers to any group -alkyl-aryl.
- alkylaryl refers to any group -aryl-alkyl.
- heteroarylalkyl refers to any group -alkyl-heteroaryl.
- alkylheteroaryl refers to any group -heteroaryl-alkyl.
- alkoxy refers to any group O-alkyl.
- haloalkoxy refers to any group O-haloalkyl.
- amino refers to a -NH2 group or any group derived thereof by substitution of one nor two hydrogen atom by an organic aliphatic or aromatic group.
- groups derived from -NH2 are "alkylamino" groups, i.e. N-alkyl groups, comprising monoalkylamino and dialkylamino.
- alkylamino i.e. N-alkyl groups, comprising monoalkylamino and dialkylamino.
- amino include NH2, NHMe or NMe2.
- amino-protecting group refers to a protecting group for an amine function. According to a preferred embodiment, the amino-protecting group is selected in the groups comprising: arylsulphonyl, te/t-butoxy carbonyl, methoxymethyl, para-methoxy benzyl or benzyl.
- the term "leaving group” refers to a molecular fragment that departs with a pair of electrons in heterolytic bond cleavage.
- the leaving group is selected in the groups comprising: halogen, preferably iodine, bromine or chlorine; alkylsulfonyloxy having 1 -6 carbon atoms, preferably methylsulfonyloxy or trifluoromethylsulfonyloxy; or arylsulfonyloxy having 6-10 carbon atoms, preferably phenyl- or p-tolylsulfonyloxy.
- solvate is used herein to describe a compound in this invention that contains stoichiometric or sub-stoichiometric amounts of one or more pharmaceutically acceptable solvent molecule, e.g., ethanol. Typically, a solvate does not significantly alter the physiological activity or toxicity of the compounds, and as such may function as pharmacological equivalents to non-solvate compounds of Formula I and its subformula as defined herein.
- solvent molecule e.g., ethanol.
- solvate is a combination, physical association and/or solvation of a compound of the present invention with a solvent molecule. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding.
- solvate can be isolated, such as when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid.
- solvate encompasses both solution-phase and isolatable solvates.
- Solvate may encompass solvates of salts of the compounds of Formula I.
- hydrate refers to when the solvent molecule is water and may be an inorganic salt containing nH 2 O, wherein n is the number of water molecules per formula unit of the salt. N may be 1 ⁇ 2, 1 1 ⁇ 2 , or an integer from 1 to 10. A hydrate which has lost water
- the compounds of the invention include compounds of Formula I as hereinbefore defined, including all polymorphs and crystal habits thereof, prodrugs and prodrugs thereof and isotopically- labeled compounds of Formula I.
- the invention also generally covers all pharmaceutically acceptable predrugs and prodrugs of the compounds of Formula I.
- prodrug as used herein means the pharmacologically acceptable derivatives of compounds of Formula I, such as for example esters, whose in vivo biotransformation product generates the biologically active drug. Prodrugs are generally characterized by increased bio-availability and are readily metabolized into biologically active compounds in vivo.
- predrug means any compound that will be modified to form a drug species, wherein the modification may take place either inside or outside of the body, and either before or after the predrug reaches the area of the body where administration of the drug is indicated.
- patient refers to a warm-blooded animal, more preferably a human, who/which is awaiting the receipt of, or is receiving medical care or is/will be the object of a medical procedure.
- human refers to a subject of both genders and at any stage of development (i.e. neonate, infant, juvenile, adolescent, adult).
- treat are meant to include alleviating, attenuating or abrogating a condition or disease and/or its attendant symptoms.
- prevent refers to a method of delaying or precluding the onset of a condition or disease and/or its attendant symptoms, barring a patient from acquiring a condition or disease, or reducing a patient's risk of acquiring a condition or disease.
- therapeutically effective amount means the amount of active agent or active ingredient that is sufficient to achieve the desired therapeutic or prophylactic effect in the patient to which/whom it is administered.
- administration means providing the active agent or active ingredient, alone or as part of a pharmaceutically acceptable composition, to the patient in whom/which the condition, symptom, or disease is to be treated or prevented.
- pharmaceutically acceptable is meant that the ingredients of a pharmaceutical composition are compatible with each other and not deleterious to the patient thereof.
- pharmaceutical vehicle means a carrier or inert medium used as solvent or diluent in which the pharmaceutically active agent is formulated and/or administered.
- Non-limiting examples of pharmaceutical vehicles include creams, gels, lotions, solutions, and liposomes.
- the words “comprise”, “comprises”, and “comprising” are to be interpreted inclusively rather than exclusively.
- the works “consist”, “consisting”, and its variants, are to be interpreted exclusively, rather than inclusively.
- the term “about” means a variability of 10 % from the reference given, unless otherwise specified.
- MS mass spectrometry
- the microwave chemistry was performed on a single mode microwave reactor Initiator Microwave System EU from Biotage.
- Preparative High Performance Liquid Chromatography (HPLC) purifications were performed with a mass directed autopurification Fractionlynx from Waters equipped with a XbridgeTM Prep C18 OBD column 19x150 mm 5 ⁇ , unless otherwise reported. All HPLC purifications were performed with a gradient of CH 3 CN /H 2 O/NH 4 HCO 3 (5 imM), CH 3 CN /H 2 O/TFA (0.1 %), or CH 3 CN /H 2 O/NH 3 H 2 O (0.1 %).
- triphenylphosphine psi is pound per square inch; PPM is parts per million; qd po means daily by mouth; rt is room temperature; RT is retention time; TLC is thin layer chromatography; TFA is trifluoroacetic acid; TEA is triethylamine.
- reaction mixture was stirred for 1 hour and quenched with saturated aqueous NaHCO 3 (30 mL).
- the aqueous layer was extracted with DCM (70 mLx2).
- the combined organic layers were washed with brine (20 mL), dried over anhydrous
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Abstract
La présente invention concerne des composés de formule (I) ou des énantiomères, sels ou solvates pharmaceutiquement acceptables de ceux-ci. L'invention concerne en outre l'utilisation des composés de formule I en tant qu'inhibiteurs de la TDO2. L'invention concerne également l'utilisation des composés de formule I pour le traitement du VIH, de la dépression et de l'obésité. L'invention se rapporte en outre à un procédé destiné à fabriquer les composés de formule (I).
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201461996975P | 2014-03-18 | 2014-03-18 | |
EP14160578 | 2014-03-18 | ||
BE2014/0776A BE1021253B1 (fr) | 2014-03-18 | 2014-11-06 | Nouveaux derives substitues de 3-indol, compositions pharmaceutiques et methode d'utilisation |
PCT/IB2015/051957 WO2015140717A1 (fr) | 2014-03-18 | 2015-03-17 | Dérivés substitués par 3-indole, compositions pharmaceutiques et procédés d'utilisation |
Publications (1)
Publication Number | Publication Date |
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EP3119763A1 true EP3119763A1 (fr) | 2017-01-25 |
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Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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EP15714653.1A Withdrawn EP3119763A1 (fr) | 2014-03-18 | 2015-03-17 | Dérivés substitués par 3-indole, compositions pharmaceutiques et procédés d'utilisation |
Country Status (4)
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EP (1) | EP3119763A1 (fr) |
JP (1) | JP2017507983A (fr) |
CA (1) | CA2942761A1 (fr) |
WO (1) | WO2015140717A1 (fr) |
Families Citing this family (28)
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CA2948842C (fr) | 2014-05-15 | 2019-09-24 | Iteos Therapeutics | Derives de pyrrolidine -2,5-dione, compositions pharmaceutiques et procedes pour une utilisation en tant qu'inhibiteursde de ido1 |
EA034691B1 (ru) | 2014-06-19 | 2020-03-06 | Ариад Фармасьютикалз, Инк. | Гетероарильные соединения для ингибирования киназ |
JP2018052817A (ja) * | 2015-01-21 | 2018-04-05 | 大日本住友製薬株式会社 | 新規ベンズイミダゾール誘導体およびその医薬用途 |
SG11201706992TA (en) | 2015-03-17 | 2017-09-28 | Pfizer | Novel 3-indol substituted derivatives, pharmaceutical compositions and methods for use |
WO2017025868A1 (fr) | 2015-08-10 | 2017-02-16 | Pfizer Inc. | Dérivés substitués par un 3-indole, compositions pharmaceutiques et leurs procédés d'utilisation |
US11623958B2 (en) | 2016-05-20 | 2023-04-11 | Harpoon Therapeutics, Inc. | Single chain variable fragment CD3 binding proteins |
EP3269714A1 (fr) | 2016-07-13 | 2018-01-17 | Netherlands Translational Research Center B.V. | Inhibiteurs de tryptophane 2,3-dioxygénase |
EP3515914A4 (fr) | 2016-09-24 | 2020-04-15 | BeiGene, Ltd. | Nouvelles imidazo[1,5-a]pyridines substituées en position 5 ou 8 en tant qu'indoleamine et/ou tryptophane 2,3-dioxygénases |
JP7090347B2 (ja) | 2017-05-12 | 2022-06-24 | ハープーン セラピューティクス,インク. | メソテリン結合タンパク質 |
EP4245375A3 (fr) | 2017-05-30 | 2023-12-06 | Bristol-Myers Squibb Company | Compositions comprenant une combinaison d'un anticorps anti-lag-3, d'un inhibiteur de voie pd-1 et d'un agent immunothérapeutique |
AU2018346955A1 (en) | 2017-10-13 | 2020-04-30 | Harpoon Therapeutics, Inc. | B cell maturation antigen binding proteins |
TWI796596B (zh) | 2018-02-13 | 2023-03-21 | 美商基利科學股份有限公司 | Pd‐1/pd‐l1抑制劑 |
JP7242702B2 (ja) | 2018-04-19 | 2023-03-20 | ギリアード サイエンシーズ, インコーポレイテッド | Pd-1/pd-l1阻害剤 |
CN108586432B (zh) * | 2018-05-31 | 2020-08-25 | 温州医科大学 | 一种3-(吲哚-5-基)-吲唑衍生物及其应用 |
EP4234030A3 (fr) | 2018-07-13 | 2023-10-18 | Gilead Sciences, Inc. | Inhibiteurs de pd-1/pd-l1 |
JP7425049B2 (ja) | 2018-09-25 | 2024-01-30 | ハープーン セラピューティクス,インク. | Dll3結合タンパク質および使用方法 |
CN112955435A (zh) | 2018-10-24 | 2021-06-11 | 吉利德科学公司 | Pd-1/pd-l1抑制剂 |
WO2021024020A1 (fr) | 2019-08-06 | 2021-02-11 | Astellas Pharma Inc. | Polythérapie impliquant des anticorps dirigés contre la claudine 18.2 et inhibiteurs de point de contrôle immunitaire pour le traitement du cancer |
EP4144731A4 (fr) | 2020-04-30 | 2023-10-25 | Medshine Discovery Inc. | Composés contenant du benzosultame |
JP2023532768A (ja) | 2020-07-07 | 2023-07-31 | バイオエヌテック エスエー | Hpv陽性癌の治療用rna |
WO2022135666A1 (fr) | 2020-12-21 | 2022-06-30 | BioNTech SE | Programme de traitement faisant intervenir des protéines cytokines |
WO2022135667A1 (fr) | 2020-12-21 | 2022-06-30 | BioNTech SE | Arn thérapeutique pour le traitement du cancer |
TW202245808A (zh) | 2020-12-21 | 2022-12-01 | 德商拜恩迪克公司 | 用於治療癌症之治療性rna |
EP4370552A1 (fr) | 2021-07-13 | 2024-05-22 | BioNTech SE | Agents de liaison multispécifiques contre cd40 et cd137 en polythérapie du cancer |
TW202333802A (zh) | 2021-10-11 | 2023-09-01 | 德商拜恩迪克公司 | 用於肺癌之治療性rna(二) |
WO2023097007A1 (fr) * | 2021-11-24 | 2023-06-01 | Remix Therapeutics Inc. | Composés et procédés de modulation de l'épissage |
WO2023170606A1 (fr) | 2022-03-08 | 2023-09-14 | Alentis Therapeutics Ag | Utilisation d'anticorps anti-claudine-1 pour augmenter la disponibilité des lymphocytes t |
WO2023225244A1 (fr) * | 2022-05-20 | 2023-11-23 | Biogen Ma Inc. | Composés hétérocycliques pour le traitement de la maladie de huntington |
Family Cites Families (8)
Publication number | Priority date | Publication date | Assignee | Title |
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CN101265259A (zh) * | 2003-03-27 | 2008-09-17 | 兰肯瑙医学研究所 | 新型ido抑制剂及其使用方法 |
JP2007520558A (ja) | 2004-02-04 | 2007-07-26 | スミスクライン・ビーチャム・コーポレイション | キナーゼ阻害剤として有用なピリミジノン化合物 |
WO2007050963A1 (fr) * | 2005-10-27 | 2007-05-03 | Lankenau Institute For Medical Research | Nouveaux inhibiteurs de l'ido et leurs procedes d'utilisation |
US8389568B2 (en) * | 2007-03-16 | 2013-03-05 | Lankenau Institute For Medical Research | IDO inhibitors and methods of use thereof |
US20110159017A1 (en) | 2008-04-11 | 2011-06-30 | Ludwig Institute For Cancer Research Ltd. | Trytophan catabolism in cancer treatment and diagnosis |
WO2010136491A1 (fr) | 2009-05-27 | 2010-12-02 | F. Hoffmann-La Roche Ag | Composés bicycliques indole-pyrimidine inhibiteurs de pi3k sélectifs pour p110 delta et leurs procédés d'utilisation |
CA2903463A1 (fr) | 2013-03-11 | 2014-10-09 | The Regents Of The University Of Michigan | Inhibiteurs de bromodomaines bet et methodes therapeutiques les utilisant |
NZ710034A (en) | 2013-03-14 | 2020-06-26 | Boehringer Ingelheim Int | Substituted 2-aza-bicyclo[2.2.1]heptane-3-carboxylic acid (benzyl-cyano-methyl)-amides inhibitors of cathepsin c |
-
2015
- 2015-03-17 EP EP15714653.1A patent/EP3119763A1/fr not_active Withdrawn
- 2015-03-17 CA CA2942761A patent/CA2942761A1/fr not_active Abandoned
- 2015-03-17 WO PCT/IB2015/051957 patent/WO2015140717A1/fr active Application Filing
- 2015-03-17 JP JP2016557605A patent/JP2017507983A/ja active Pending
Also Published As
Publication number | Publication date |
---|---|
CA2942761A1 (fr) | 2015-09-24 |
JP2017507983A (ja) | 2017-03-23 |
WO2015140717A9 (fr) | 2016-03-24 |
WO2015140717A1 (fr) | 2015-09-24 |
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