NZ623727B2 - Inhibitors of phosphodiesterase type 10a - Google Patents
Inhibitors of phosphodiesterase type 10a Download PDFInfo
- Publication number
- NZ623727B2 NZ623727B2 NZ623727A NZ62372712A NZ623727B2 NZ 623727 B2 NZ623727 B2 NZ 623727B2 NZ 623727 A NZ623727 A NZ 623727A NZ 62372712 A NZ62372712 A NZ 62372712A NZ 623727 B2 NZ623727 B2 NZ 623727B2
- Authority
- NZ
- New Zealand
- Prior art keywords
- ethyl
- quinolinyl
- pyridinyl
- thieno
- phthalazin
- Prior art date
Links
- 230000002401 inhibitory effect Effects 0.000 title claims abstract description 36
- 101710031992 pRL90232 Proteins 0.000 title claims abstract description 11
- 101710035540 plaa2 Proteins 0.000 title claims abstract description 11
- 239000003112 inhibitor Substances 0.000 title abstract description 15
- 150000001875 compounds Chemical class 0.000 claims abstract description 404
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 330
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims abstract description 224
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 184
- 239000001257 hydrogen Substances 0.000 claims abstract description 180
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 118
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 112
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 102
- 150000002431 hydrogen Chemical class 0.000 claims abstract description 87
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 87
- 125000004432 carbon atoms Chemical group C* 0.000 claims abstract description 77
- 201000010099 disease Diseases 0.000 claims abstract description 68
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 57
- 150000002367 halogens Chemical class 0.000 claims abstract description 56
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims abstract description 47
- 239000003814 drug Substances 0.000 claims abstract description 37
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 claims abstract description 29
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims abstract description 27
- 150000002829 nitrogen Chemical group 0.000 claims abstract description 18
- 206010037175 Psychiatric disease Diseases 0.000 claims abstract description 11
- 208000009025 Nervous System Disease Diseases 0.000 claims abstract description 10
- 206010029305 Neurological disorder Diseases 0.000 claims abstract description 10
- 238000004519 manufacturing process Methods 0.000 claims abstract description 6
- -1 saturated carbocyclic radical Chemical class 0.000 claims description 1154
- 150000003254 radicals Chemical class 0.000 claims description 204
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 146
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 127
- 125000005842 heteroatoms Chemical group 0.000 claims description 113
- 150000003839 salts Chemical class 0.000 claims description 95
- 239000011780 sodium chloride Substances 0.000 claims description 95
- 239000000651 prodrug Substances 0.000 claims description 92
- 229940002612 prodrugs Drugs 0.000 claims description 92
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 84
- 229910052731 fluorine Inorganic materials 0.000 claims description 79
- 239000011737 fluorine Substances 0.000 claims description 79
- YCKRFDGAMUMZLT-UHFFFAOYSA-N fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 claims description 79
- VDBNYAPERZTOOF-UHFFFAOYSA-N isoquinolin-1(2H)-one Chemical compound C1=CC=C2C(=O)NC=CC2=C1 VDBNYAPERZTOOF-UHFFFAOYSA-N 0.000 claims description 78
- IJAPPYDYQCXOEF-UHFFFAOYSA-N phthalazin-1(2H)-one Chemical compound C1=CC=C2C(=O)NN=CC2=C1 IJAPPYDYQCXOEF-UHFFFAOYSA-N 0.000 claims description 73
- 150000004677 hydrates Chemical class 0.000 claims description 69
- 150000001204 N-oxides Chemical class 0.000 claims description 67
- 239000000126 substance Substances 0.000 claims description 64
- 125000001072 heteroaryl group Chemical group 0.000 claims description 56
- 125000004076 pyridyl group Chemical group 0.000 claims description 50
- 125000001424 substituent group Chemical group 0.000 claims description 44
- 125000004433 nitrogen atoms Chemical group N* 0.000 claims description 39
- DUPNPBCUJHMSFZ-UHFFFAOYSA-N 5H-thieno[3,2-c]pyridin-4-one Chemical compound O=C1NC=CC2=C1C=CS2 DUPNPBCUJHMSFZ-UHFFFAOYSA-N 0.000 claims description 37
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 claims description 36
- 239000000460 chlorine Substances 0.000 claims description 35
- 229910052801 chlorine Inorganic materials 0.000 claims description 33
- ZAMOUSCENKQFHK-UHFFFAOYSA-N chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 33
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 31
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 claims description 31
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 31
- 125000004429 atoms Chemical group 0.000 claims description 29
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 29
- 125000004430 oxygen atoms Chemical group O* 0.000 claims description 25
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 25
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 24
- 125000000335 thiazolyl group Chemical group 0.000 claims description 23
- 125000001544 thienyl group Chemical group 0.000 claims description 23
- 125000002971 oxazolyl group Chemical group 0.000 claims description 22
- 125000000623 heterocyclic group Chemical group 0.000 claims description 20
- 125000002883 imidazolyl group Chemical group 0.000 claims description 20
- 125000000217 alkyl group Chemical group 0.000 claims description 19
- CZPWVGJYEJSRLH-UHFFFAOYSA-N 289-95-2 Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 18
- 229940035295 Ting Drugs 0.000 claims description 17
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 claims description 17
- 125000002541 furyl group Chemical group 0.000 claims description 17
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 17
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 17
- 201000000980 schizophrenia Diseases 0.000 claims description 17
- 125000003545 alkoxy group Chemical group 0.000 claims description 16
- 239000001301 oxygen Substances 0.000 claims description 15
- MYMOFIZGZYHOMD-UHFFFAOYSA-N oxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims description 15
- 125000004618 benzofuryl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 14
- 125000003709 fluoroalkyl group Chemical group 0.000 claims description 14
- 125000002950 monocyclic group Chemical group 0.000 claims description 14
- 206010057666 Anxiety disease Diseases 0.000 claims description 11
- 150000001413 amino acids Chemical class 0.000 claims description 11
- 239000008194 pharmaceutical composition Substances 0.000 claims description 10
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 9
- 125000004769 (C1-C4) alkylsulfonyl group Chemical group 0.000 claims description 8
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Substances N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 claims description 8
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims description 8
- 125000002837 carbocyclic group Chemical group 0.000 claims description 8
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
- 125000004568 thiomorpholinyl group Chemical group 0.000 claims description 8
- 125000004008 6 membered carbocyclic group Chemical group 0.000 claims description 7
- 206010002855 Anxiety Diseases 0.000 claims description 7
- 206010057668 Cognitive disease Diseases 0.000 claims description 7
- NALBLJLOBICXRH-UHFFFAOYSA-N Dinitrogen monohydride Chemical compound N=[N] NALBLJLOBICXRH-UHFFFAOYSA-N 0.000 claims description 7
- 125000004414 alkyl thio group Chemical group 0.000 claims description 7
- 230000036506 anxiety Effects 0.000 claims description 7
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims description 7
- 150000004657 carbamic acid derivatives Chemical class 0.000 claims description 7
- NGVDGCNFYWLIFO-UHFFFAOYSA-N pyridoxal 5'-phosphate Chemical group CC1=NC=C(COP(O)(O)=O)C(C=O)=C1O NGVDGCNFYWLIFO-UHFFFAOYSA-N 0.000 claims description 7
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 7
- FYNCIYHECMWXPK-UHFFFAOYSA-N 5H-furo[3,2-c]pyridin-4-one Chemical compound O=C1NC=CC2=C1C=CO2 FYNCIYHECMWXPK-UHFFFAOYSA-N 0.000 claims description 6
- 229910004755 ORb Inorganic materials 0.000 claims description 6
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 6
- 125000002911 monocyclic heterocycle group Chemical group 0.000 claims description 6
- 125000002757 morpholinyl group Chemical group 0.000 claims description 6
- 229910052702 rhenium Inorganic materials 0.000 claims description 6
- 201000009031 substance-related disease Diseases 0.000 claims description 6
- AAILEWXSEQLMNI-UHFFFAOYSA-N 1H-pyridazin-6-one Chemical compound OC1=CC=CN=N1 AAILEWXSEQLMNI-UHFFFAOYSA-N 0.000 claims description 5
- 125000002373 5 membered heterocyclic group Chemical group 0.000 claims description 5
- 201000001971 Huntington's disease Diseases 0.000 claims description 5
- 125000002252 acyl group Chemical group 0.000 claims description 5
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 5
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 5
- 125000001041 indolyl group Chemical group 0.000 claims description 5
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 claims description 5
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 claims description 5
- 125000006656 (C2-C4) alkenyl group Chemical group 0.000 claims description 4
- HLTZFJMZKQGXKH-UHFFFAOYSA-N 2-(2-imidazo[1,2-a]pyridin-2-ylethyl)-4-morpholin-4-ylphthalazin-1-one Chemical compound C12=CC=CC=C2C(=O)N(CCC=2N=C3C=CC=CN3C=2)N=C1N1CCOCC1 HLTZFJMZKQGXKH-UHFFFAOYSA-N 0.000 claims description 4
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 4
- 125000003354 benzotriazolyl group Chemical group N1N=NC2=C1C=CC=C2* 0.000 claims description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 4
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 claims description 4
- 125000001624 naphthyl group Chemical group 0.000 claims description 4
- 125000002206 pyridazin-3-yl group Chemical group [H]C1=C([H])C([H])=C(*)N=N1 0.000 claims description 4
- 238000002560 therapeutic procedure Methods 0.000 claims description 4
- MHCVCKDNQYMGEX-UHFFFAOYSA-N 1,1'-biphenyl;phenoxybenzene Chemical group C1=CC=CC=C1C1=CC=CC=C1.C=1C=CC=CC=1OC1=CC=CC=C1 MHCVCKDNQYMGEX-UHFFFAOYSA-N 0.000 claims description 3
- 125000005987 1-oxo-thiomorpholinyl group Chemical group 0.000 claims description 3
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 3
- 125000001054 5 membered carbocyclic group Chemical group 0.000 claims description 3
- 206010001897 Alzheimer's disease Diseases 0.000 claims description 3
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 3
- 241000229754 Iva xanthiifolia Species 0.000 claims description 3
- 235000005911 diet Nutrition 0.000 claims description 3
- 230000037213 diet Effects 0.000 claims description 3
- 125000004785 fluoromethoxy group Chemical group [H]C([H])(F)O* 0.000 claims description 3
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 3
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 claims description 3
- WZSXORXZGIVIER-UHFFFAOYSA-N 5-(1,1-dioxo-1,4-thiazinan-4-yl)-2-(2-quinolin-2-ylethyl)phthalazin-1-one Chemical compound C1=CC=C2C(=O)N(CCC=3N=C4C=CC=CC4=CC=3)N=CC2=C1N1CCS(=O)(=O)CC1 WZSXORXZGIVIER-UHFFFAOYSA-N 0.000 claims description 2
- RWRGYTCBRXICLF-UHFFFAOYSA-N 5-(3-hydroxyphenyl)-2-(2-quinolin-2-ylethyl)phthalazin-1-one Chemical compound OC1=CC=CC(C=2C3=C(C(N(CCC=4N=C5C=CC=CC5=CC=4)N=C3)=O)C=CC=2)=C1 RWRGYTCBRXICLF-UHFFFAOYSA-N 0.000 claims description 2
- 150000007578 6-membered cyclic compounds Chemical class 0.000 claims description 2
- 208000008589 Obesity Diseases 0.000 claims description 2
- 125000005197 alkyl carbonyloxy alkyl group Chemical group 0.000 claims description 2
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims description 2
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 125000002618 bicyclic heterocycle group Chemical group 0.000 claims description 2
- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 claims description 2
- 230000000926 neurological Effects 0.000 claims description 2
- 235000020824 obesity Nutrition 0.000 claims description 2
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 2
- XPPXUDVPZXZMHC-UHFFFAOYSA-N 8-morpholin-4-yl-2-(2-quinolin-2-ylcyclopropyl)isoquinolin-1-one Chemical compound C=12C(=O)N(C3C(C3)C=3N=C4C=CC=CC4=CC=3)C=CC2=CC=CC=1N1CCOCC1 XPPXUDVPZXZMHC-UHFFFAOYSA-N 0.000 claims 4
- PBMFSQRYOILNGV-UHFFFAOYSA-N Pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 claims 3
- XBGKDDYOBIDYGP-UHFFFAOYSA-N 3-morpholin-4-yl-5-(2-quinolin-2-ylcyclopropyl)thieno[3,2-c]pyridin-4-one Chemical compound C1=2C(=O)N(C3C(C3)C=3N=C4C=CC=CC4=CC=3)C=CC=2SC=C1N1CCOCC1 XBGKDDYOBIDYGP-UHFFFAOYSA-N 0.000 claims 2
- DEBVRECAXOMUKB-UHFFFAOYSA-N 8-(1,3,3a,4,6,6a-hexahydrofuro[3,4-c]pyrrol-5-yl)-2-(2-quinolin-2-ylcyclopropyl)isoquinolin-1-one Chemical compound C1=CC=CC2=NC(C3CC3N3C(C4=C(N5CC6COCC6C5)C=CC=C4C=C3)=O)=CC=C21 DEBVRECAXOMUKB-UHFFFAOYSA-N 0.000 claims 2
- PWCXNISNHONFFV-UHFFFAOYSA-N 8-(3-methoxypiperidin-1-yl)-2-(2-quinolin-2-ylcyclopropyl)isoquinolin-1-one Chemical compound C1C(OC)CCCN1C1=CC=CC2=C1C(=O)N(C1C(C1)C=1N=C3C=CC=CC3=CC=1)C=C2 PWCXNISNHONFFV-UHFFFAOYSA-N 0.000 claims 2
- DAVWDBKMWVHGSV-UHFFFAOYSA-N 8-(4-fluorophenyl)-2-(2-quinolin-2-ylcyclopropyl)isoquinolin-1-one Chemical compound C1=CC(F)=CC=C1C1=CC=CC2=C1C(=O)N(C1C(C1)C=1N=C3C=CC=CC3=CC=1)C=C2 DAVWDBKMWVHGSV-UHFFFAOYSA-N 0.000 claims 2
- BEQNPWNIWYZXKT-UHFFFAOYSA-N 8-(4-hydroxypiperidin-1-yl)-2-(2-quinolin-2-ylcyclopropyl)isoquinolin-1-one Chemical compound C1CC(O)CCN1C1=CC=CC2=C1C(=O)N(C1C(C1)C=1N=C3C=CC=CC3=CC=1)C=C2 BEQNPWNIWYZXKT-UHFFFAOYSA-N 0.000 claims 2
- HATHYQZLFTULDK-UHFFFAOYSA-N 8-(4-methoxyphenyl)-2-(2-quinolin-2-ylcyclopropyl)isoquinolin-1-one Chemical compound C1=CC(OC)=CC=C1C1=CC=CC2=C1C(=O)N(C1C(C1)C=1N=C3C=CC=CC3=CC=1)C=C2 HATHYQZLFTULDK-UHFFFAOYSA-N 0.000 claims 2
- VNLWXEZYYWYETD-UHFFFAOYSA-N 8-(4-methoxypiperidin-1-yl)-2-(2-quinolin-2-ylcyclopropyl)isoquinolin-1-one Chemical compound C1CC(OC)CCN1C1=CC=CC2=C1C(=O)N(C1C(C1)C=1N=C3C=CC=CC3=CC=1)C=C2 VNLWXEZYYWYETD-UHFFFAOYSA-N 0.000 claims 2
- WYIOMEWWIORQAU-UHFFFAOYSA-N 8-(4-methylpiperazin-1-yl)-2-(2-quinolin-2-ylcyclopropyl)isoquinolin-1-one Chemical compound C1CN(C)CCN1C1=CC=CC2=C1C(=O)N(C1C(C1)C=1N=C3C=CC=CC3=CC=1)C=C2 WYIOMEWWIORQAU-UHFFFAOYSA-N 0.000 claims 2
- DIUVFUVAQLFMKK-UHFFFAOYSA-N 8-(furan-2-yl)-2-(2-imidazo[1,2-a]pyridin-2-ylethyl)phthalazin-1-one Chemical compound C=12C(=O)N(CCC=3N=C4C=CC=CN4C=3)N=CC2=CC=CC=1C1=CC=CO1 DIUVFUVAQLFMKK-UHFFFAOYSA-N 0.000 claims 2
- VBLCGBMNUHGMPA-UHFFFAOYSA-N 8-[3-(difluoromethyl)pyrrolidin-1-yl]-2-(2-quinolin-2-ylcyclopropyl)isoquinolin-1-one Chemical compound C1C(C(F)F)CCN1C1=CC=CC2=C1C(=O)N(C1C(C1)C=1N=C3C=CC=CC3=CC=1)C=C2 VBLCGBMNUHGMPA-UHFFFAOYSA-N 0.000 claims 2
- PXUKFUXBASUFNE-UHFFFAOYSA-N 8-[3-(fluoromethyl)pyrrolidin-1-yl]-2-(2-quinolin-2-ylcyclopropyl)isoquinolin-1-one Chemical compound C1C(CF)CCN1C1=CC=CC2=C1C(=O)N(C1C(C1)C=1N=C3C=CC=CC3=CC=1)C=C2 PXUKFUXBASUFNE-UHFFFAOYSA-N 0.000 claims 2
- JPRPJUMQRZTTED-UHFFFAOYSA-N 1,3-dioxolanyl Chemical group [CH]1OCCO1 JPRPJUMQRZTTED-UHFFFAOYSA-N 0.000 claims 1
- ZKZYHJUFYIHZIS-UHFFFAOYSA-N 5-morpholin-4-yl-2-(2-quinolin-2-ylethyl)phthalazin-1-one Chemical compound C1=CC=C2C(=O)N(CCC=3N=C4C=CC=CC4=CC=3)N=CC2=C1N1CCOCC1 ZKZYHJUFYIHZIS-UHFFFAOYSA-N 0.000 claims 1
- IVPQULUXGFANGE-UHFFFAOYSA-N 8-(1,1-dioxo-1,4-thiazinan-4-yl)-2-(2-imidazo[1,2-a]pyridin-2-ylethyl)phthalazin-1-one Chemical compound C=12C(=O)N(CCC=3N=C4C=CC=CN4C=3)N=CC2=CC=CC=1N1CCS(=O)(=O)CC1 IVPQULUXGFANGE-UHFFFAOYSA-N 0.000 claims 1
- ANWMTJXMGCVPSL-UHFFFAOYSA-N 8-(1,1-dioxo-1,4-thiazinan-4-yl)-2-(2-quinolin-2-ylethyl)phthalazin-1-one Chemical compound C=12C(=O)N(CCC=3N=C4C=CC=CC4=CC=3)N=CC2=CC=CC=1N1CCS(=O)(=O)CC1 ANWMTJXMGCVPSL-UHFFFAOYSA-N 0.000 claims 1
- VALTXHDNDYAMNE-UHFFFAOYSA-N 8-(2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-c]pyrrol-5-yl)-2-(2-imidazo[1,2-a]pyridin-2-ylethyl)phthalazin-1-one Chemical compound N1=CC2=CC=CC(N3CC4CNCC4C3)=C2C(=O)N1CCC1=CN(C=CC=C2)C2=N1 VALTXHDNDYAMNE-UHFFFAOYSA-N 0.000 claims 1
- HMVCKYIKOYKEAZ-UHFFFAOYSA-N 8-(2,3-difluorophenyl)-2-(2-quinolin-2-ylethyl)phthalazin-1-one Chemical compound FC1=CC=CC(C=2C=3C(=O)N(CCC=4N=C5C=CC=CC5=CC=4)N=CC=3C=CC=2)=C1F HMVCKYIKOYKEAZ-UHFFFAOYSA-N 0.000 claims 1
- SZIBUDQVFZLYQL-UHFFFAOYSA-N 8-(2,4-dimethoxyphenyl)-2-(2-quinolin-2-ylethyl)phthalazin-1-one Chemical compound COC1=CC(OC)=CC=C1C1=CC=CC2=C1C(=O)N(CCC=1N=C3C=CC=CC3=CC=1)N=C2 SZIBUDQVFZLYQL-UHFFFAOYSA-N 0.000 claims 1
- BNGIOLANESYJGX-UHFFFAOYSA-N 8-(2,5-difluorophenyl)-2-(2-quinolin-2-ylethyl)phthalazin-1-one Chemical compound FC1=CC=C(F)C(C=2C=3C(=O)N(CCC=4N=C5C=CC=CC5=CC=4)N=CC=3C=CC=2)=C1 BNGIOLANESYJGX-UHFFFAOYSA-N 0.000 claims 1
- GHCSQONACBFQCS-UHFFFAOYSA-N 8-(2,5-dimethoxyphenyl)-2-(2-quinolin-2-ylethyl)phthalazin-1-one Chemical compound COC1=CC=C(OC)C(C=2C=3C(=O)N(CCC=4N=C5C=CC=CC5=CC=4)N=CC=3C=CC=2)=C1 GHCSQONACBFQCS-UHFFFAOYSA-N 0.000 claims 1
- FUJSQVCEXWRUTI-UHFFFAOYSA-N 8-(2,6-dimethylmorpholin-4-yl)-2-(2-imidazo[1,2-a]pyridin-2-ylethyl)phthalazin-1-one Chemical compound C1C(C)OC(C)CN1C1=CC=CC2=C1C(=O)N(CCC=1N=C3C=CC=CN3C=1)N=C2 FUJSQVCEXWRUTI-UHFFFAOYSA-N 0.000 claims 1
- PIJPDFOZENNOON-UHFFFAOYSA-N 8-(2-chlorophenyl)-2-(2-quinolin-2-ylethyl)phthalazin-1-one Chemical compound ClC1=CC=CC=C1C1=CC=CC2=C1C(=O)N(CCC=1N=C3C=CC=CC3=CC=1)N=C2 PIJPDFOZENNOON-UHFFFAOYSA-N 0.000 claims 1
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- 150000003212 purines Chemical class 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000004353 pyrazol-1-yl group Chemical group [H]C1=NN(*)C([H])=C1[H] 0.000 description 1
- WTKZEGDFNFYCGP-UHFFFAOYSA-N pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 1
- BEJXOECDIXUTLN-UHFFFAOYSA-N pyrido[2,3-c]pyridazine Chemical class N1=NC=CC2=CC=CN=C21 BEJXOECDIXUTLN-UHFFFAOYSA-N 0.000 description 1
- KAESVJOAVNADME-UHFFFAOYSA-N pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 1
- NYCVCXMSZNOGDH-UHFFFAOYSA-M pyrrolidine-1-carboxylate Chemical compound [O-]C(=O)N1CCCC1 NYCVCXMSZNOGDH-UHFFFAOYSA-M 0.000 description 1
- 150000003856 quaternary ammonium compounds Chemical class 0.000 description 1
- WPYJKGWLDJECQD-UHFFFAOYSA-N quinoline-2-carbaldehyde Chemical compound C1=CC=CC2=NC(C=O)=CC=C21 WPYJKGWLDJECQD-UHFFFAOYSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000033764 rhythmic process Effects 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 201000000978 schizoaffective disease Diseases 0.000 description 1
- 201000000261 schizophreniform disease Diseases 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 230000036280 sedation Effects 0.000 description 1
- 230000001624 sedative Effects 0.000 description 1
- 239000000932 sedative agent Substances 0.000 description 1
- 239000012056 semi-solid material Substances 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 230000001340 slower Effects 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000001187 sodium carbonate Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 229940001593 sodium carbonate Drugs 0.000 description 1
- 229910001415 sodium ion Inorganic materials 0.000 description 1
- 239000011343 solid material Substances 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 201000001716 specific phobia Diseases 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000003892 spreading Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 201000006152 substance dependence Diseases 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000002511 suppository base Substances 0.000 description 1
- 230000002459 sustained Effects 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 230000001975 sympathomimetic Effects 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 238000007910 systemic administration Methods 0.000 description 1
- 125000006253 t-butylcarbonyl group Chemical group [H]C([H])([H])C(C(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- NCQZFEAREIAQME-UHFFFAOYSA-N tert-butyl 2-(7-fluoroquinolin-2-yl)acetate Chemical compound C1=CC(F)=CC2=NC(CC(=O)OC(C)(C)C)=CC=C21 NCQZFEAREIAQME-UHFFFAOYSA-N 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 125000004187 tetrahydropyran-2-yl group Chemical group [H]C1([H])OC([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000004523 tetrazol-1-yl group Chemical group N1(N=NN=C1)* 0.000 description 1
- 230000000542 thalamic Effects 0.000 description 1
- 230000004797 therapeutic response Effects 0.000 description 1
- 125000000437 thiazol-2-yl group Chemical group [H]C1=C([H])N=C(*)S1 0.000 description 1
- 125000004495 thiazol-4-yl group Chemical group S1C=NC(=C1)* 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- DBDCNCCRPKTRSD-UHFFFAOYSA-N thieno[3,2-b]pyridine Chemical compound C1=CC=C2SC=CC2=N1 DBDCNCCRPKTRSD-UHFFFAOYSA-N 0.000 description 1
- BEDLZTHJABCULR-UHFFFAOYSA-N thieno[3,2-b]pyridine-2-carbaldehyde Chemical compound C1=CC=C2SC(C=O)=CC2=N1 BEDLZTHJABCULR-UHFFFAOYSA-N 0.000 description 1
- YTPLMLYBLZKORZ-UHFFFAOYSA-N thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 1
- 230000000699 topical Effects 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000002110 toxicologic Effects 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 230000001131 transforming Effects 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- COIOYMYWGDAQPM-UHFFFAOYSA-N tris(2-methylphenyl)phosphane Chemical compound CC1=CC=CC=C1P(C=1C(=CC=CC=1)C)C1=CC=CC=C1C COIOYMYWGDAQPM-UHFFFAOYSA-N 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 239000003039 volatile agent Substances 0.000 description 1
- 230000035513 volume of distribution Effects 0.000 description 1
- 230000002618 waking Effects 0.000 description 1
- XLYOFNOQVPJJNP-ZSJDYOACSA-N water-d2 Chemical compound [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
- 230000002034 xenobiotic Effects 0.000 description 1
- 239000002676 xenobiotic agent Substances 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- PTFCDOFLOPIGGS-UHFFFAOYSA-N zinc dication Chemical compound [Zn+2] PTFCDOFLOPIGGS-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
-
- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/22—Anxiolytics
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/08—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing alicyclic rings
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- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
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- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
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- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
Abstract
The disclosure relates to novel compounds of the formula (I) which are inhibitors of phosphodiesterase type 10A and to their use for the manufacture of a medicament and which thus are suitable for treating or controlling of medical disorders selected from neurological disorders and psychiatric disorders, for ameliorating the symptoms associated with such disorders and for reducing the risk of such disorders. wherein Q is O or S, X1 is N or CH, X2 is N or C-R7; X3 is O, S, -X4=C(R8)-, where C(R8) is bound to the carbon atom which carries R2, or -X5=C(R9)-, where X5 is bound to the carbon atom which carries R2; X4 is N or C-R9; X5 is N; Het is selected from optionally substituted phenyl, monocyclic hetaryl and fused bicyclic hetaryl; R1 is selected inter alia from hydrogen, halogen, OH, C1-C4-alkyl, trimethylsilyl, C1-C4-alkylsulfanyl, C1-C4-alkoxy-C1-C4-alkyl, C1-C4- alkoxy, C1-C4-alkoxy-C1-C4-alkoxy, the moiety Y1-Cyc1; R2 is selected inter alia from hydrogen, halogen, OH, C1-C4-alkyl, trimethylsilyl, C1-C4-alkoxy-C1-C4-alkyl, C1-C4-alkoxy, C1-C4- alkoxy-C1-C4-alkoxy, C2-C4-alkenyloxy, etc; A represents one of the following groups A1, A2, A3, A4 or A5: where * indicates the points of attachment to Het and to the nitrogen atom, respectively; and where R3 to R9, R3e, R3f, A', Y1 and Cyc are defined in the claims. Exemplary compounds are: 3,7-di(pyridin-4-yl)-5-[2-(quinolin-2-yl)ethyl]thieno[2,3-d]pyridazin-4(5H)-one; 8-(furan-3-yl)-2-[2-(quinolin-2-yl)ethyl]phthalazin-1(2H)-one; 2-[2-(imidazo[l,2-a]pyridin-2-yl)ethyl]-8-(morpholin-4-yl)phthalazin-l(2H)-one. ders, for ameliorating the symptoms associated with such disorders and for reducing the risk of such disorders. wherein Q is O or S, X1 is N or CH, X2 is N or C-R7; X3 is O, S, -X4=C(R8)-, where C(R8) is bound to the carbon atom which carries R2, or -X5=C(R9)-, where X5 is bound to the carbon atom which carries R2; X4 is N or C-R9; X5 is N; Het is selected from optionally substituted phenyl, monocyclic hetaryl and fused bicyclic hetaryl; R1 is selected inter alia from hydrogen, halogen, OH, C1-C4-alkyl, trimethylsilyl, C1-C4-alkylsulfanyl, C1-C4-alkoxy-C1-C4-alkyl, C1-C4- alkoxy, C1-C4-alkoxy-C1-C4-alkoxy, the moiety Y1-Cyc1; R2 is selected inter alia from hydrogen, halogen, OH, C1-C4-alkyl, trimethylsilyl, C1-C4-alkoxy-C1-C4-alkyl, C1-C4-alkoxy, C1-C4- alkoxy-C1-C4-alkoxy, C2-C4-alkenyloxy, etc; A represents one of the following groups A1, A2, A3, A4 or A5: where * indicates the points of attachment to Het and to the nitrogen atom, respectively; and where R3 to R9, R3e, R3f, A', Y1 and Cyc are defined in the claims. Exemplary compounds are: 3,7-di(pyridin-4-yl)-5-[2-(quinolin-2-yl)ethyl]thieno[2,3-d]pyridazin-4(5H)-one; 8-(furan-3-yl)-2-[2-(quinolin-2-yl)ethyl]phthalazin-1(2H)-one; 2-[2-(imidazo[l,2-a]pyridin-2-yl)ethyl]-8-(morpholin-4-yl)phthalazin-l(2H)-one.
Description
INHIBITORS OF PHOSPHODIESTERASE TYPE 10A
The present invention relates to novel compounds which are inhibitors of
phosphodiesterase type 10A and to their use for the manufacture of a medicament and
which thus are suitable for treating or controlling of medical disorders selected from
neurological disorders and psychiatric disorders, for ameliorating the symptoms
associated with such disorders and for reducing the risk of such disorders.
Background of the Invention
10
odiesterase type 10A (hereinafter ) is a dual-substrate
phosphodiesterase that can convert both CAMP to AMP and cGMP to GMP. PDE10A is
highly prominent in the mammalian brain. In the rat, as well as in other mammalian
species, PDE10A and the mRNA of PDE10A are highly ed in the GABAergic
15 medium spiny tion neurons (MSNs) ofthe striatal complex (caudate nucleus,
nucleus accumbens, and olfactory tubercle) where the output is ted by the effect
ofPDE10A on cAMP and cGMP signalling cascades (see e.g. C. J. Schmidt et al, The
Journal of Pharmacology and Experimental Therapeutics 325 (2008) 681-690, A. Nishi,
The Journal ofNeuroscience 2008, 28, 10450-10471).
20 MSNs express two functional classes ofneurons: the D1 class expressing D1
dopamine receptors and the D2 class expressing D2 dopamine receptors. The D1 class of
neurons is part of the 'direct' al output pathway, which broadly ons to
facilitate behavioral responses. The D2 class of neurons is part of the 'indirect' striatal
output pathway, which functions to suppress behavioral responses that e with
25 those being facilitated by the 'direct' pathway. PDElOA regulation of cAMP and/or
cGMP signaling in the dendritic tment of these neurons may be involved in
ng the cortico/thalamic input into the MSN. Furthermore, PDEI 0A may be
involved in the regulation of GABA release in the substantia nigra and globus pallidus
(Seeger, T.F. et al. Brain Research, 2003, 985, 1 13-126). Inhibition ofPDEIOA s
30 in striatal activation and behavioral suppression such as dampened locomotion,
inhibition of conditioned avoidance se (CAR), and activity in the rat auditory
2
gating model, suggesting that inhibitors ofphosphodiesterase type 10A represent a
novel class of antipsychotic agents.
The hypotheses around the physiological role ofPDElOA and the therapeutic
utility ofPDElOA inhibitors derive in part from studies with rine (J. A. k
et al. loc. cit.), the first extensively d pharmacological tool compound for this
target. The PDElOA inhibitor papaverine was shown to be active in several
ychotic models. Papaverine potentiated the cataleptic effect of the D2 receptor
antagonist haloperidol in rats, but did not cause catalepsy on its own (WO 03/093499).
Papaverine reduced hyperactivity in rats induced by PCP, while reduction of
10 amphetamine—induced hyperactivity was insignificant (WO 03/093499). These models
suggest that PDElOA inhibition has the classic antipsychotic potential that would be
expected from theoretical considerations. Papaverine, however has significant
limitations in this regard with vely poor potency and selectivity and a very short
exposure half-life after systemic administration. It was found that tion of PDElOA
15 reverses subchronic PCP-induced deficits in attentional set-shifting in rats ting
that PDElOA inhibitors might alleviate cognitive deficits associated with schizophrenia.
(Rodefer et al., Eur. J. Neurosci, 4 (2005) 1070—1076).
The discovery of a new class ofPDE10A inhibitors with improved potency,
selectivity, and pharmacokinetic properties, ed an opportunity to r explore
20 the physiology ofPDE 1 0A and the potential therapeutic utility of inhibiting this
. The new class of inhibitors are exemplified by MP-lO (PF-2545920: 2- {4-[1-
methylpyridineyl— l -H-pyrazol—3—31y]phenoxymethyl} -quino line) and TP- 1 0, i.e. 2-
{4-[pyridineyl-l-(2,2,2-trifluoroethyl)—1-H-pyrazol—3 -3ly]phenoxymethyl} -
quino line. The compounds offer a therapeutic approach to the ent of
25 schizophrenia (see C. J. Schmidt et al., loc cit.; S.M. Grauer eta1., Journal of
acology and Experimental Therapeutics, fast forward DOI 10.1124 JPET
109.155994). Positive signals in rodent models of schizophrenia include the: attenuation
of conditioned avoidance response (CAR), inhibition of hyperactivity caused by
amphetamine—induced dopamine release or phencyclidine (PCP) mediated NMDA
30 receptor blockade, attenuation ofpharmaco logically impaired social or object
recognition, and antagonism of apomorphine—induced climbing. Taken together, these
data suggest a broad suppression of all 3 symptoms clusters (positive symptoms,
3
negative symptoms & cognitive dysfunctions) linked to schizophrenia (see C. J.
Schmidt et a1., loc cit.; S.M. Grauer et al., loc. cit).
Beyond schizophrenia, selective PDE10 inhibitiors may have the ial for the
treatment of Huntington's disease (S. H. Francis et al., l. Rev., 91 (2011) 651-
690) and they may be a therapeutic option for substance abuse disorders (F. Sotty et al.,
J. Neurochem., 109 (2009) 766—775). Furthermore, it has been suggested that PDE10A
inhibitors may be useful for treatment of y and non—insulin dependent es
(see e.g. W0 2005/120514, W0 2005/012485, Cantin et a1, Bioorganic & Medicinal
Chemistry Letters 17 (2007) 2869-2873).
10 In summary, inhibitors of PDElOA offer a promising therapeutic approach to the
treatment or prevention of ogical and psychiatric disorders, in particular
schizophrenia and related disorders, including symptoms linked to schizophrenia such
as cognitive dysfunction.
Several classes of compounds which are inhibitors of PDElOA have been
15 described in the art, the recent compound groups are:
Pyrido[3,2-e]pyridazines - see W0 2007/137819, W0 2007/137820, W0
68246, W0 2009/068320, WO 2009/070583 and W0 2009/070584;
4-substiuted phtha1azines and quinazolines WO 2007/085954, WO 2007/022280,
W0 2007/096743, W0 2007/103370, WO 2008/020302, W0 2008/006372 and W0
20 2009/036766;
4-substiuted cinnazolines - see WO 2006/028957, WO 2007/098169, W0
2007/098214, WO 2007/103554, WO 2009/025823 and WO 2009/025839;
Isoquinolines and isoquinolinones - see W0 2007/100880 and WO 2009/029214
MP10 and MP10 like ds: US 2007/0155779, WO 2008/001182 and WO
25 2008/004117; and
Benzodiazepines - see W0 2007/082546.
For a further review see also T. Chappie et a1. t Opinion in Drug ery
& Development 12(4), (2009) 458-467) and the literature cited therein.
Although some of the compounds of prior art are known to inhibit PDE10A
30 effectively having IC50 values of less than 50 nM, there is still an ongoing need for
compounds which inhibit . In particular, there is an ongoing need for
compounds which have one ofthe ing characteristics:
4
Selective inhibition of PDElOA, in particular Vis-a-vis tion of the
other ten phosphodiesterase families PDEl-9, 11 and their different gene
variants; suitable selectivity with regard to molecular receptors, transporters
channels, enzymes or other biomolecules whose interaction with the
PDElOA ligand might cause undesired side effects;
ii. metabolic stability, in particular omal ity, e.g. measured in vitro,
in liver microsomes from various species (e.g. rat or human) in human cells,
such as hepatocytes;
iii. no or only low inhibition of rome P450 (CYP) enzymes: cytochrome
10 P450 (CYP) is the name for a superfamily ofheme proteins having
enzymatic activity (oxidase). They are also particularly important for the
degradation (metabolism) of foreign substances such as drugs or xenobiotics
in mammalian organisms. The principal representatives ofthe types and
subtypes of CYP in the human body are: CYP 1A2, CYP 2C9, CYP 2D6
15 and CYP 3A4. If CYP 3A4 inhibitors (e.g. grapefruit juice, cimetidine,
erythromycin) are used at the same time as medicinal substances which are
degraded by this enzyme system and thus compete for the same binding site
on the , the degradation fmay be slowed down and thus
effects and side effects of the stered medicinal substance may be
20 undesirably enhanced;
iv. a suitable lity in water (in mg/ml);
suitable pharmacokinetics (time course of the concentration of the
compound of the invention in plasma or in tissue, for example brain). The
pharmacokinetics can be described by the following parameters: half-life,
25 volume of distribution (in 1~kg‘l), plasma clearance (in l-h'l -kg'1), AUC
(area under the curve, area under the concentration—time curve (in ng-h-l'l),
oral bioavailability, (the dose-normalized ratio ofAUC after oral
administration and AUC after intravenous administration), the so-called
brain—plasma ratio (the ratio ofAUC in brain tissue and AUC in plasma);
30 Vi. no or only low blockade of the hERG channel: compounds which block the
hERG l may cause a prolongation of the QT interval and thus lead to
serious bances of cardiac rhythm (for example so-called "torsade de
5
pointes"). The potential of nds to block the hERG channel can be
determined by means of the displacement assay with radio labelled dofetilide
which is described in the literature (G. J. Diaz et al., Journal of
Pharmacological and logical Methods, 50 (2004), 187-199). A
smaller IC50 in this dofetilide assay means a greater probability of potent
hERG blockade. In addition, the blockade of the hERG channel can be
measured by electrophysiological experiments on cells which have been
transfected with the hERG channel, by so-called whole-cell patch clamping
(G. J. Diaz et al., Journal of Pharmacological and Toxicological Methods,
10 50 , 9).
Vii. high free fraction in brain, i.e. the fraction of the compound bound to
proteins should be low.
viii. low ilicity.
15 Brief Description of the Invention
The present invention is thus based on the object of providing compounds which
inhibit PDElOA at low concentrations.
The compounds are further intended to display at least one of the properties i. to
20 viii. ned above, in particular high selectivity with regard to inhibition of
PDElOA, high selectivity Vis-a-Vis other phosphodiesterases such as enhanced
,
metabolic ity, in particular microsomal and/or cytosolic stability, low affinity to
the HERG receptor, low inhibition of cytochrome P450 (CYP) enzymes, suitable
solubility in water and suitable pharmacokinetics.
25 This object and further objects are ed by the compounds of the general
formula I described below, the N—oxides, the prodrugs, the hydrates and the tautomers
thereof and the ceutically suitable salts thereof:
Q R1
(I)
N
2
X: |\ R
k2 (.0
X
wherein
is O or S;
>< is N or CH;
>1, is N or C-R7;
>3, is O, S, -X4=C(R8)-, where C(RS) is bound to the carbon atom which
- 2
carries R or
,
-X5=C(R9)-, where X5 is bound to the carbon atom which carries R2;
is N or C-R9;
is N;
10
is selected from
i. monocyclic hetaryl having 1 or 2 nitrogen atoms and optionally
a further heteroatom selected from O, S and N as ring members,
which is unsubstituted or may carry 1, 2, 3 or 4 identical or
15 different substituents RX,
ii. fused bicyclic hetaryl having 1 or 2 nitrogen atoms and
optionally a further heteroatom selected from O, S and N as ring
members, benzothienyl or benzofuryl, where bicyclic hetaryl,
hienyl and benzofuryl are, independently of each other,
20 unsubstituted or may carry 1, 2, 3 or 4 identical or ent
substituents RX, and
iii. phenyl, which carries a monocyclic hetaryl radical having 1 or 2
nitrogen atoms and optionally a fiarther heteroatom selected
from O, S and N as ring members, which in on to
25 monocyclic hetaryl, may carry 1, 2 or 3 identical or different
substituents RX,
where
RX is selected from the group consisting of H, halogen, alkyl,
C1-C4-alkoxy, C1-C4-fluoroalkyl, C1-C4-fluoroalkoxy, C3-C5-
30 cycloalkyl, alkoxy-C1—C4-alkoxy, C1-C4-alkoxy-C1-C4-
alkyl, OH, hydroxy—Cl—C4—alkyl, 6-cycloalkyl,
benzyloxy, C(O)O—(C1—C4—alkyl), O-(Cl-C4-alkyl)-C02H,
7
N(RX1)(RX2), C(O)N(RX1)(RX2), C1-C4-alkyl-N(RX1)(RX2),
-NRX3-C(O)—N(RX1)(RX2), NRX3-C(O)O-(C1-C4-alkyl),
-N(RX3)-SOg—RX4, phenyl, CN, -SF5, -OSF5, —sosz4, -SR"4 and
trimethylsilyl, where R“, RXZ, RX3 and RX4, independently of
each other are selected from the group consisting of hydrogen,
C1-C4-alkyl, C1—C4-fluoroalky1 and C3-C6-cycloalky1 or RX1 and
RX2 form together with the N atom to which they are attached a
3- to 7-membered, nitrogen heterocycle which may have 1, 2 or
3 further different or identical heteroatoms or heteroatom
10 containing groups ed from the group of O, N, S, SO and
SOZ as ring members and which may carry 1, 2, 3, 4, 5 or 6
substituents selected from C1-C4-alkyl,
or two radicals Rx which are bound at adjacent carbon atoms
may form a fused 5— or 6—membered saturated carbocyclic
15 radical or a fused 5— or 6—membered heterocyclic radical having
1, 2 or 3 heteroatoms as ring members, which are selected from
O, S and N;
is selected from the group consisting of hydrogen, halogen, OH, C1-
20 C4-alkyl, trimethylsilyl, alkylsulfanyl, C1-C4-alkoxy-C1-C4-
alkyl, C1-C4-alkoxy, C1—C4—alkoxy-C1-C4-alkoxy, C1-C4-alkylsulfanyl-
C1-C4-alkoxy, alkenyloxy, fluoroalkyl, C1-C4-
fluoroalkoxy, cyclopropyl, optionally substituted by l, 2 or 3 methyl
groups, fluorinated cyclopropyl, CN, NRXIRXZ, NRXIRXZ-Cl-C4-alkoxy
25 and the moiety Yl-Cyc];
is selected from the group consisting of hydrogen, halogen, OH, C1-
C4-alkyl, trimethylsilyl, C1-C4-alkoxy-C1-C4-alkyl, C1-C4-alkoxy, C1-
C4-a1koxy-C1-C4-alkoxy, alkenyloxy, fluoroalkyl, C1-C4-
30 fluoroalkoxy, cyclopropyl, optionally substituted by l, 2 or 3 methyl
groups, fluorinated cyclopropyl, CN and NRXIRXZ;
8
A represents one of the following groups A1, A2, A3; A4 or A5:
R3e R3f
R4 R3
(A1) (A2) (A3) (A4) (A5)
where * tes the points of attachment to Het and to the nitrogen atom,
tively;
R3, R4, R5, R6 independently of each other are selected from the group consisting
of hydrogen, halogen, C1—C4—alkyl, trimethylsilyl, C1-C4-fluoroalkyl,
10 C1-C4-fluoroalkoxy, C3—C6—cycloalkyl, or the radicals together with the
carbon atoms to which they are bound form a saturated 3- to 6-
membered carbocycle or a saturated 3- to 6-membered heterocycle
having 1 or 2 non-adjacent heteroatoms as ring members, where the
ycle and the heterocycle are unsubstituted or may carry 1, 2, 3
15 or 4 substituents ed from fluorine and methyl or either the
radicals R3, R4 or the radicals R5, R6 together with the carbon atom to
which they are bound form a saturated 3- to 6-membered carbocycle
or a saturated 3- to 6-membered heterocycle having 1 or 2 non-
nt heteroatoms as ring members, where the carbocycle and the
20 heterocycle are unsubstituted or may carry 1, 2, 3 or 4 substituents
selected from fluorine and methyl;
AV is a O, NR3a, CR3bR3C or linear C2-C3-alkandiy1, where one of the
ieties of C2-C3-alkandiyl may be replaced by oxygen or NR”,
25 and where l, 2, 3, or 4 of the hydrogen atoms of Cg-Cg-alkandiyl may
be replaced by a radical R”, where
R3a is hydrogen or C1—C4—alkyl,
9
R3b, R30 independently of each other are ed from the group
consisting of hydrogen, halogen, C1-C4-alkyl or R3b and R30
together form C2-C3-alkandiyl;
R3d is selected from the group consisting of halogen and C1-C4-
alkyl;
independently of each other are selected from the group consisting of
hydrogen and C1-C4-alkyl;
10 is selected from the group consisting of hydrogen, halogen, OH, C1-
C4—alkyl, trimethylsilyl, alkylsulfanyl, C1-C4-alkoxy-C1-C4-
alkyl, C1—C4—alkoxy, C1—C4—alkoxy—C1-C4-alkoxy, C1-C4-alkylsulfanyl-
alkoxy, C2-C4-alkenyloxy, C1—C4-fluoroalkyl, C1-C4-
fluoroalkoxy, cyclopropyl, optionally substituted by l, 2 or 3 methyl
15 groups, fluorinated cyclopropyl, 1RX2, NRXlez-Cl-C4-alkoxy
and the moiety Yz-Cycz;
is selected from the group consisting of hydrogen, halogen, OH, C1-
C4-alkyl, trimethylsilyl, C1-C4-alkoxy-C1-C4-alkyl, alkoxy, C1-
20 oxy-C1-C4—alkoxy, C2-C4-alkenyloxy, C1-C4-fluoroalkyl, C1-C4-
lkoxy, cyclopropyl, optionally substituted by l, 2 or 3 methyl
groups, fluorinated cyclopropyl, CN and NRXIRXZ;
is selected from the group consisting of hydrogen, halogen, OH, C1-
25 C4-alkyl, trimethylsilyl, C1-C4—alkylsulfanyl, C1-C4-alkoxy-C1-C4-
alkyl, C1-C4-alkoxy, C1-C4—alkoxy-C1—C4-alkoxy, C1-C4-alkylsulfanyl-
C1-C4-alkoxy, C2-C4-alkenyloxy, C1-C4-fluoroalkyl, C1-C4-
fluoroalkoxy, cyclopropyl, optionally substituted by l, 2 or 3 methyl
groups, fluorinated cyclopropyl, CN, NRXIRXZ, NRXlez-Cl-C4-alkoxy
30 and the moiety Y3—Cyc3 ;
10
Y1, Y2, Y3 independently of each other are selected from a chemical bond, CH2,
0, O-CH2, NRy, NRy—CHg, NRy-S(O)2, S, S(O), S(O)2, 1,2-ethandiyl,
1,2-ethendiyl or 1,2-ethyndiyl, where Ry is selected from the group
consisting of en, C1—C4—alkyl, C1-C4-alkylcarbonyl, C1-C4-
alkylsulfonyl, C1-C4-fluoroalkylsulfonyl;
Cycl, Cycz, Cyc3 ndently of each other are selected from the group
consisting of phenyl, naphthyl, 4- to 8-membered saturated or partially
unsaturated heteromonocyclic radicals, saturated or partially
10 unsaturated 7- to 10 membered bicyclic radicals, 5- or 6-
membered monocyclic hetaryl, and 8— to 10 membered bicyclic
hetaryl, where the saturated or partially rated heteromonocyclic
and heterobicyclic radicals have 1, 2, 3 or 4 heteroatoms or
heteroatom containing groups as ring s, which are selected
15 from O, S, SO, S02 and N, and where the 5- or 6-membered
monocyclic hetaryl and the 8— to lO-membered ic l have 1,
2, 3 or 4 heteroatoms as ring members, which are selected from O, S
and N,
where phenyl, naphthyl, the saturated or partially unsaturated
20 monocyclic and heterobicyclic radicals and the mono and
bicyclic heteroaromatic radicals are unsubstituted or carry 1, 2, 3, 4 or
5 radicals RC1 or one radical Y'—RC2 and 0, l, 2, 3 or 4 radicals RC1;
where
25 RCl is selected from hydrogen, halogen, OH, CN, N02, C1-C4-alkyl,
C1-C4-alkoxy, C1-C4-alkylsulfanyl, y—Cl-C4-alkyl, C1-C4-
alkoxy-Cl-C4-alkyl, C1-C4-alkoxy-C1-C4-alkoxy, cyano-Cl-C4-
alkyl, C1-C4-fluoroalkyl, C1-C4-fluoroalkoxy, C1-C4-
alkylsulfonyl, C(O)Ra, Z-C(O)ORb, Z-C(O)NR°Rd, S(O)2NR°Rd
30 and Z—NReRf, where
R81 is selected from the group consisting of C1-C4-alkyl and
C1—C4—fluoroalkyl,
1 1
Rb is selected from the group consisting of hydrogen, C1-C4-
alkyl, C2—C4-alkenyl and C1-C4-fluoroalkyl,
RC, Rd is selected from the group consisting of hydrogen, C1-C4-
alkyl, C1—C4—fluoroalkyl, C1-C4-alkoxy and C1-C4-
fluoroalkoxy,
Re, Rf is selected from the group consisting of hydrogen, C1-C4-
alkyl, C1-C4—fluoroalkyl, C1-C4—alkoxy and C1-C4-
fluoroalkoxy,
Z is a nt bond or C1-C4-alkandiyl,
10 or two radicals RCl which are bound at adjacent carbon atoms
may form a fused 5— or 6—membered carbocyclic radical or a
fused 5— or 6—membered heterocyclic l having 1, 2 or 3
heteroatoms as ring members, which are selected from O, S and
N;
15 or two radicals RC] which are bound at the same carbon atom
may form a spiro 5— or ered carbocyclic radical or a
spiro 5- or 6-membered cyclic radical having 1 or 2
heteroatoms as ring members, which are ed from O, S and
N,
20 or two radicals RC1 which are bound at the same carbon atom
may form an oxygen atom,
where the fused and the spiro radicals are unsubstituted or carry
1, 2, 3 or 4 radicals RC3;
25 Y! is a chemical bond, CH2, 0, O-CHz, S(O)2, NRy', NRy'-CH2 or
NRy'-S(O)2, where R)" is selected from the group consisting of
hydrogen, C1-C4-alkyl, C1-C4-alkylcarbonyl, C1-C4-
alkylsulfonyl, C1-C4-fluoroalkylsulfonyl;
30 is a carbocyclic or heterocyclic l selected from the group
consisting ofphenyl, 3- to 7-membered saturated or partially
unsaturated monocarbocyclic radicals, 3- to 7-membered
12
saturated or partially unsaturated heteromonocyclic radicals,
having 1, 2 or 3 heteroatoms as ring members, which are
selected from O, S and N, and 5- or 6-membered heteroaromatic
ls, having 1, 2 or 3 heteroatoms as ring members, which
are selected from O, S and N, where the carbocyclic and the
heterocyclic radical is unsubstituted or carries 1, 2, 3, 4 or 5
radicals RC3;
RC3 is selected from hydrogen, halogen, OH, CN, C1-C4-alky1, C1-
10 C4-alkoxy, hydroxy-Cl-C4-alkyl, C1-C4-alkoxy-C1-C4-alkyl,
cyano—CI—C4—alkyl, C1-C4-fluoroalkyl, C1-C4-fluoroalkoxy, C2-
C6—alkenyl, C(O)Ra, benzyl, Z-C(O)ORb, NR°Rd,
S(O)2NR°Rd and Z-NReRf, where, z, Ra, Rb, R“, Rd, Re and Rf
are as defined above or two radicals RC3 which are bound at the
15 same atom may form an oxygen atom;
provided that for X3 being 0 or S, at least one of the ls R1 and R7 is a
moiety Yl-Cyc1 or YZ-Cycz, respectively;
20 further provided that for X3 being X4=C(R8), one or two of the radicals R1, R7 and
R9 are a moiety Yl-Cycl, YZ-Cyc2 or Y3-Cyc3, respectively;
r provided that for X3 being 9), one or two of the radicals R1, R7 and
R9 are a moiety Yl-Cycl, Yz-Cyc2 or Y3-Cyc3, respectively;
25
and the N—oxides, the prodrugs, the tautomers and the hydrates thereof, and the
ceutically acceptable salts thereof.
The present invention therefore relates to the nds of the general formula 1,
30 their tautomers, the hydrates thereof, the pharmaceutically suitable salts of the
compounds of formula I, the gs of the compounds of formula I and the
13
pharmaceutically suitable salts of said prodrugs, tautomers or es of the compounds
of formula I.
The compounds of the formula I, their salts, their prodrugs, their hydrates and their
ers effectively inhibit PDE10A even at low concentrations. They are additionally
distinguished by a high selectivity in relation to the inhibition of the PDE10A vis-a-vis
tion of other phosphodiesterease, such as PDE3 or PDE4. The compounds of the
invention may additionally have one or more of the properties ii. to viii. ned above.
The compounds of the a I, their salts, their prodrugs, their hydrates and their
tautomers are therefore particularly suitable for treating disorders and conditions in
creatures, especially human creatures, which can be treated or controlled by inhibition of
phosphodiesterase type 10A.
The invention therefore also relates to the use of carboxamide compounds of the
formula I, their tautomers, their hydrates and their pharmaceutically suitable salts for the
manufacture of a medicament, in particular of a ment which is le for the
treatment of a disorder or a condition which can be treated by inhibition of
phosphodiesterase type 10A.
The invention further relates to a medicament, in particular a medicament which is
suitable for the treatment of a disorder or a condition which can be treated by inhibition of
odiesterase type 10A. The medicament comprises at least one compound of the
formula I, as described , or a tautomer, or a hydrate or a prodrug of said compound I,
or a pharmaceutically suitable salt of the compound of the formula I or a pharmaceutically
suitable salt of the tautomer, the hydrate or the prodrug of compound of the formula I.
The invention further relates to the compound of formula I
Q R1
Het A (I)
N
R2
X1
X2 X3
n
Q is O or S;
X1 is N or CH;
X2 is N or C-R7;
(11352636_1):GGG
13a
X3 is O, S, -X4=C(R8)-, where C(R8) is bound to the carbon atom which
carries R2, or
-X5=C(R9)-, where X5 is bound to the carbon atom which carries R2;
X4 is N or C-R9;
X5 is N;
Het is ed from
i. monocyclic C-bound 6-membered hetaryl having 1 or 2 nitrogen
atoms as ring members, which is unsubstituted or may carry 1,
2, 3 or 4 cal or different substituents Rx,
ii. fused bicyclic hetaryl having 1 or 2 nitrogen atoms and
optionally a further heteroatom selected from O, S and N as ring
members, benzothienyl or benzofuryl, where bicyclic hetaryl,
benzothienyl and benzofuryl are, ndently of each other,
unsubstituted or may carry 1, 2, 3 or 4 identical or different
substituents Rx, and
iii. phenyl, which carries a monocyclic hetaryl radical having 1 or 2
nitrogen atoms and optionally a further heteroatom selected
from O, S and N as ring members, which in addition to
monocyclic l, may carry 1, 2 or 3 cal or different
tuents Rx,
where
Rx is selected from the group consisting of H, halogen, C1-C4-alkyl,
C1-C4-alkoxy, C1-C4-fluoroalkyl, C1-C4-fluoroalkoxy, C3-C6-
cycloalkyl, C1-C4-alkoxy-C1-C4-alkoxy, C1-C4-alkoxy-C1-C4-alkyl,
OH, y-C1-C4-alkyl, O-C3-C6-cycloalkyl, benzyloxy, C(O)O-
(C1-C4-alkyl), O-(C1-C4-alkyl)-CO2H, N(Rx1)(Rx2),
Rx1)(Rx2), C1-C4-alkyl-N(Rx1)(Rx2),
-NRx3-C(O)-N(Rx1)(Rx2), NRx3-C(O)O-(C1-C4-alkyl),
-N(Rx3)-SO2-Rx4, phenyl, CN, -SF5, -OSF5, -SO2Rx4, -SRx4 and
trimethylsilyl, where Rx1, Rx2, Rx3 and Rx4, independently of each
other are selected from the group consisting of hydrogen, C1-C4-
(11352636_1):GGG
13b
alkyl, C1-C4-fluoroalkyl and C3-C6-cycloalkyl or Rx1 and Rx2 form
together with the N atom to which they are attached a 3- to 7-
membered, nitrogen heterocycle which may have 1, 2 or 3 further
different or identical heteroatoms or heteroatom containing groups
selected from the group of O, N, S, SO and SO2 as ring members
and which may carry 1, 2, 3, 4, 5 or 6 substituents selected from
alkyl;
or two radicals Rx which are bound at nt carbon atoms may
form a fused 5- or 6-membered saturated carbocyclic l or a
fused 5- or 6-membered heterocyclic radical having 1, 2 or 3
heteroatoms as ring s, which are selected from O, S and N;
R1 is a moiety Y1-Cyc1;
R2 is selected from the group consisting of hydrogen, halogen, OH, C1-C4-
alkyl, trimethylsilyl, alkoxy-C1-C4-alkyl, C1-C4-alkoxy, C1-C4-
alkoxy-C1-C4-alkoxy, C2-C4-alkenyloxy, C1-C4-fluoroalkyl, C1-C4-
fluoroalkoxy, cyclopropyl, optionally substituted by 1, 2 or 3 methyl
, fluorinated cyclopropyl, CN and NRx1Rx2;
A represents one of the following groups A1, A2, A3, A4 or A5:
R3e R3f
R6 R5
R4 A'
* *
* * * * * * * *
R4 R3 R5 R5 R4 R4 R5
(A1 ) (A2 ) (A3 ) (A4 ) (A5 )
where * indicates the points of attachment to Het and to the nitrogen
atom, tively,
R3, R4, R5, R6 independently of each other are selected from the group consisting of
hydrogen, halogen, C1-C4-alkyl, trimethylsilyl, C1-C4-fluoroalkyl, C1-C4-
fluoroalkoxy, C3-C6-cycloalkyl, or the radicals er with the carbon
atoms to which they are bound form a saturated 3- to 6-membered
carbocycle or a saturated 3- to 6-membered heterocycle having 1 or 2
non-adjacent heteroatoms as ring members, where the carbocycle and the
heterocycle are unsubstituted or may carry 1, 2, 3 or 4 substituents
(11352636_1):GGG
13c
ed from ne and methyl or either the radicals R3, R4 or the
radicals R5, R6 together with the carbon atom to which they are bound
form a saturated 3- to 6-membered carbocycle or a saturated 3- to 6-
membered cycle having 1 or 2 non-adjacent heteroatoms as ring
members, where the carbocycle and the heterocycle are unsubstituted or
may carry 1, 2, 3 or 4 substituents selected from fluorine and methyl;
A' is a O, NR3a, CR3bR3c or linear C2-C3-alkandiyl, where one of the CH2-
moieties of C2-C3-alkandiyl may be replaced by oxygen or NR3a, and
where 1, 2, 3, or 4 of the hydrogen atoms of C2-C3-alkandiyl may be
replaced by a radical R3d, where
R3a is hydrogen or C1-C4-alkyl,
R3b, R3c independently of each other are selected from the group
consisting of hydrogen, halogen, C1-C4-alkyl or R3b and R3c
together form C2-C3-alkandiyl;
R3d is selected from the group consisting of halogen and C1-C4-
alkyl;
R3e, R3f independently of each other are selected from the group consisting of
hydrogen and C1-C4-alkyl;
R7 is selected from the group consisting of hydrogen, halogen, OH, C1-C4-
alkyl, trimethylsilyl, C1-C4-alkylsulfanyl, alkoxy-C1-C4-alkyl, C1-
oxy, C1-C4-alkoxy-C1-C4-alkoxy, C1-C4-alkylsulfanyl-C1-C4-
alkoxy, C2-C4-alkenyloxy, C1-C4-fluoroalkyl, C1-C4-fluoroalkoxy,
cyclopropyl, optionally tuted by 1, 2 or 3 methyl groups,
fluorinated cyclopropyl, CN, NRx1Rx2, NRx1Rx2-C1-C4-alkoxy and the
moiety Y2-Cyc2;
R8 is selected from the group consisting of hydrogen, halogen, OH, C1-C4-
alkyl, trimethylsilyl, C1-C4-alkoxy-C1-C4-alkyl, alkoxy, C1-C4-
-C1-C4-alkoxy, C2-C4-alkenyloxy, C1-C4-fluoroalkyl, C1-C4-
fluoroalkoxy, cyclopropyl, optionally substituted by 1, 2 or 3 methyl
, fluorinated cyclopropyl, CN and NRx1Rx2;
(11352636_1):GGG
13d
R9 is selected from the group consisting of hydrogen, halogen, OH, C1-C4-
alkyl, trimethylsilyl, alkylsulfanyl, C1-C4-alkoxy-C1-C4-alkyl, C1-
C4-alkoxy, C1-C4-alkoxy-C1-C4-alkoxy, alkylsulfanyl-C1-C4-
alkoxy, C2-C4-alkenyloxy, C1-C4-fluoroalkyl, C1-C4-fluoroalkoxy,
cyclopropyl, optionally substituted by 1, 2 or 3 methyl groups,
fluorinated cyclopropyl, CN, NRx1Rx2, NRx1Rx2-C1-C4-alkoxy and the
moiety Y3-Cyc3;
Y1, Y2, Y3 ndently of each other are selected from a chemical bond, CH2, O,
O-CH2, NRy, NRy-CH2, O)2, S, S(O), S(O)2, 1,2-ethandiyl, 1,2-
ethendiyl or 1,2-ethyndiyl, where Ry is selected from the group consisting
of hydrogen, C1-C4-alkyl, C1-C4-alkylcarbonyl, C1-C4-alkylsulfonyl, C1-
C4-fluoroalkylsulfonyl;
Cyc1, Cyc2, Cyc3 independently of each other are selected from the group
consisting of phenyl, yl, 4- to ered saturated or partially
unsaturated heteromonocyclic radicals, saturated or partially unsaturated
7- to 10 ed heterobicyclic radicals, 5- or 6-membered monocyclic
hetaryl, and 8- to 10 membered bicyclic hetaryl, where the saturated or
partially unsaturated heteromonocyclic and heterobicyclic radicals have
1, 2, 3 or 4 heteroatoms or heteroatom ning groups as ring
s, which are selected from O, S, SO, SO2 and N, and where the 5-
or 6-membered clic hetaryl and the 8- to 10-membered bicyclic
hetaryl have 1, 2, 3 or 4 heteroatoms as ring members, which are selected
from O, S and N,
where phenyl, naphthyl, the saturated or partially unsaturated
heteromonocyclic and heterobicyclic radicals and the mono- and bicyclic
heteroaromatic radicals are unsubstituted or carry 1, 2, 3, 4 or 5 radicals
RC1 or one radical Y'-RC2 and 0, 1, 2, 3 or 4 radicals RC1; where
RC1 is selected from hydrogen, halogen, OH, CN, NO2, C1-C4-alkyl, C1-
C4-alkoxy, C1-C4-alkylsulfanyl, hydroxy-C1-C4-alkyl, C1-C4-
alkoxy-C1-C4-alkyl, C1-C4-alkoxy-C1-C4-alkoxy, cyano-C1-C4-
alkyl, C1-C4-fluoroalkyl, C1-C4-fluoroalkoxy, C1-C4-alkylsulfonyl,
C(O)Ra, Z-C(O)ORb, NRcRd, S(O)2NRcRd and Z-NReRf,
where
(11352636_1):GGG
13e
Ra is selected from the group consisting of C1-C4-alkyl and C1-
oroalkyl,
Rb is selected from the group consisting of hydrogen, C1-C4-
alkyl, C2-C4-alkenyl and C1-C4-fluoroalkyl,
Rc, Rd is selected from the group consisting of hydrogen, C1-C4-
alkyl, C1-C4-fluoroalkyl, C1-C4-alkoxy and C1-C4-
fluoroalkoxy,
Re, Rf is selected from the group consisting of hydrogen, C1-C4-
alkyl, C1-C4-fluoroalkyl, C1-C4-alkoxy and C1-C4-
fluoroalkoxy,
Z is a covalent bond or C1-C4-alkandiyl,
or two radicals RC1 which are bound at adjacent carbon atoms may
form a fused 5- or 6-membered carbocyclic radical or a fused 5- or
6-membered cyclic radical having 1, 2 or 3 heteroatoms as
ring members, which are selected from O, S and N;
or two radicals RC1 which are bound at the same carbon atom may
form a spiro 5- or 6-membered carbocyclic radical or a spiro 5- or
6-membered cyclic radical having 1 or 2 heteroatoms as ring
members, which are selected from O, S and N,
or two ls RC1 which are bound at the same carbon atom may
form an oxygen atom,
where the fused and the spiro radicals are unsubstituted or carry 1,
2, 3 or 4 radicals RC3;
Y' is a chemical bond, CH2, O, O-CH2, S(O)2, NRy', NRy'-CH2 or
NRy'-S(O)2, where Ry' is selected from the group ting of
hydrogen, alkyl, alkylcarbonyl, C1-C4-alkylsulfonyl,
C1-C4-fluoroalkylsulfonyl;
RC2 is a carbocyclic or heterocyclic radical selected from the group
consisting of phenyl, 3- to 7-membered saturated or partially
unsaturated monocarbocyclic ls, 3- to 7-membered saturated
or partially unsaturated heteromonocyclic radicals, having 1, 2 or 3
heteroatoms as ring members, which are selected from O, S and N,
and 5- or 6-membered heteroaromatic radicals, having 1, 2 or 3
(11352636_1):GGG
13f
heteroatoms as ring members, which are selected from O, S and N,
where the carbocyclic and the heterocyclic radical is unsubstituted
or carries 1, 2, 3, 4 or 5 radicals RC3;
RC3 is selected from hydrogen, halogen, OH, CN, C1-C4-alkyl, C1-C4-
alkoxy, hydroxy-C1-C4-alkyl, C1-C4-alkoxy-C1-C4-alkyl, cyano-C1-
C4-alkyl, C1-C4-fluoroalkyl, C1-C4-fluoroalkoxy, C2-C6-alkenyl,
C(O)Ra, , Z-C(O)ORb, Z-C(O)NRcRd, S(O)2NRcRd and ZNReRf
, where, Z, Ra, Rb, Rc, Rd, Re and Rf are as defined above or
two radicals RC3 which are bound at the same atom may form an
oxygen atom;
provided that for X3 being X4=C(R8), one or two of the radicals R1, R7 and R9 are a
moiety Y1-Cyc1, Y2-Cyc2 or Y3-Cyc3, respectively;
further provided that for X3 being X5=C(R9), one or two of the radicals R1, R7 and R9
are a moiety Y1-Cyc1, Y2-Cyc2 or 3, respectively;
and the N-oxides, the prodrugs, the tautomers and the hydrates thereof, and the
pharmaceutically acceptable salts thereof;
wherein prodrugs are derivatives of the compounds of a I carrying an OH or
NH2-group, where one of the hydrogen atoms of the OH or NH2-group is substituted
by a alkylcarbonyl group, by benzoyl, or by an acyl group derived from an
amino acid, which is linked to the oxygen or nitrogen of the OH or NH2-group via
the carbonyl group of the amino acid; or wherein prodrugs are alkylcarbonyloxyalkyl
carbonates or carbamates of compounds I carrying an OH- or NH2-group in which
one of the hydrogen atoms of the OH- or oup has been replaced by a group of
the formula -O-CHRp-O-C(=O)-Rq in which Rp and Rq are independently of
one another C1-C4-alkyl;
except for the following compounds:
ylphenyl[2-(2-pyridinyl)ethyl]-thieno[2,3-d]pyrimidin(3H)-one,
yl[2-(4-pyridinyl)ethyl]-thieno[2,3-d]pyrimidin(3H)-one,
5-(4-Methylphenyl)[2-(2-pyridinyl)ethyl]-thieno[2,3-d]pyrimidin(3H)-one,
(11352636_1):GGG
13g
5-(2-Furanyl)[1-methyl(3-pyridinyl)ethyl]-thieno[2,3-d]pyrimidin(3H)-one,
5-(2-Thienyl)[1-methyl(3-pyridinyl)ethyl]-thieno[2,3-d]pyrimidin(3H)-one,
5-(3,4-Dimethylphenyl)[2-(2-pyridinyl)ethyl]-thieno[2,3-d]pyrimidin(3H)-one,
5-(4-Methylphenyl)[2-(4-pyridinyl)ethyl]-thieno[2,3-d]pyrimidin(3H)-one,
5-Phenyl[2-(2-pyridinyl)ethyl]-thieno[2,3-d]pyrimidin(3H)-one, and
5-Phenyl[2-(4-oxophenylthieno[2,3-d]pyrimidin-(3H)yl)ethyl]-thieno[2,3-
d]pyrimidin(3H)-one.
The invention further relates to the compound which is selected from the group consisting
of
idinyl)[2-(quinolinyl)ethyl]thieno[2,3-d]pyridazin-4(5H)-one;
5-(pyridinyl)[2-(quinolinyl)ethyl]phthalazin-1(2H)-one;
5-(pyrimidinyl)[2-(quinolinyl)ethyl]phthalazin-1(2H)-one;
5-(1-methyl-1H-pyrazolyl)[2-(quinolinyl)ethyl]phthalazin-1(2H)-one;
5-(1,1-dioxidothiomorpholinyl)[2-(quinolinyl)ethyl]phthalazin-1(2H)-one;
2-[2-(imidazo[1,2-a]pyridinyl)ethyl](pyridinyl)phthalazin-1(2H)-one;
2-[2-(imidazo[1,2-a]pyridinyl)ethyl](pyrimidinyl)phthalazin1(2H)-one;
2-[2-(imidazo[1,2-a]pyridinyl)ethyl](morpholinyl)phthalazin-1(2H)-one;
2-[2-(imidazo[1,2-a]pyridinyl)ethyl](tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-
yl)phthalazin-1(2H)-one;
2-[2-(imidazo[1,2-a]pyridinyl)ethyl](pyrimidinyl)phthalazin-1(2H)-one;
2-[2-(imidazo[1,2-a]pyridinyl)ethyl](morpholinyl)phthalazin-1(2H)-one;
3-methyl(pyridinyl)(2-(quinolinyl)ethyl)thieno[3,2-c]pyridin-4(5H)-one;
5-(3-hydroxyphenyl)[2-(quinolinyl)ethyl]phthalazin-1(2H)-one;
7-(pyridinyl)[2-(quinolinyl)ethyl]furo[3,2-c]pyridin-4(5H)-one;
anti imidinyl)[2-(quinolinyl)cyclopropyl]isoquinolin-1(2H)-one;
syn 5-(pyrimidinyl)[2-(quinolinyl)cyclopropyl]isoquinolin-1(2H)-one;
anti 5-(pyridinyl)[2-(quinolinyl)cyclopropyl]isoquinolin-1(2H)-one;
syn idinyl)[2-(quinolinyl)cyclopropyl]isoquinolin-1(2H)-one;
anti 5-(pyridinyl)[2-(quinolinyl)cyclopropyl]isoquinolin-1(2H)-one;
syn 5-(pyridinyl)[2-(quinolinyl)cyclopropyl]isoquinolin-1(2H)-one;
anti 5-(morpholinyl)(2-(quinolinyl)cyclopropyl]isoquinolin-1(2H)-one;
syn 5-(morpholinyl)(2-(quinolinyl)cyclopropyl]isoquinolin-1(2H)-one;
(11352636_1):GGG
13h
pholinyl)[2-(quinolinyl)ethyl]phthalazin-1(2H)-one;
2-[2-(1H-benzimidazolyl)ethyl](pyridinyl)phthalazin-1(2H)-one;
4-(pyridinyl)[2-(quinolinyl)ethyl]phthalazin-1(2H)-one;
5-(1,4-dihydropyrimidinyl)[2-(5,6,7,8-tetrahydroimidazo[1,2-a]pyridin
yl]phthalazin-1(2H)-one2-[2-(imidazo[1,2-a]pyridinyl)ethyl](pyridin
yl)phthalazin-1(2H)-one;
5-(pyridinyl)[2-(quinolinyl)ethyl]phthalazin-1(2H)-one;
and the enantiomers thereof, the N-oxides thereof, the prodrugs thereof, the tautomers
thereof and the hydrates thereof, and the ceutically acceptable salts thereof, wherein
prodrugs are derivatives of the compounds of formula I ng an OH or NH2-group,
where one of the hydrogen atoms of the OH or NH2-group is substituted by a C1-C4-
alkylcarbonyl group, by benzoyl, or by an acyl group derived from an amino acid, which is
linked to the oxygen or en of the OH or NH2-group via the carbonyl group of the
amino acid; or wherein prodrugs are alkylcarbonyloxyalkyl carbonates or carbamates of
compounds I carrying an OH- or NH2-group in which one of the hydrogen atoms of the
OH- or oup has been replaced by a group of the formula -C(=O)-O-CHRp-OC
(=O)-Rq in which Rp and Rq are ndently of one another C1-C4-alkyl.
The invention r relates to the use of at least one compound as claimed in the
invention for the manufacture of a medicament for treating a medical disorder, selected
from neurological and psychiatric disorders which can be treated by inhibition of
phosphodiesterase type 10A.
Detailed Description of the Invention
The terms "compound of the formula I" and "compounds I" are used as synonyms.
The term "prodrugs" means nds which are metabolized in vivo to the
compounds I of the invention. Typical examples of prodrugs are described in C.G.
Wermuth (editor): The Practice of Medicinal Chemistry, Academic Press, San Diego,
1996, pages 671-715. These include for example phosphates, carbamates, amino acids,
(11352636_1):GGG
14
esters, amides, peptides, ureas and the like. Suitable prodrugs in the present case may be
for example tives of those compounds I ng an OH or oup, where the
OH or NHz-group forms an ester/amide/peptide linkage, i.e. where one of the hydrogen
atoms ofthe OH or NHz-group is substituted by a C1-C4-alkylcarbonyl group, e.g. by
acetyl, propionyl, n-propylcarbonyl, isopropylcarbonyl, n—butylcarbonyl or tert-
butylcarbonyl (pivaloyl), by benzoyl, or by an acyl group d from an amino acid,
e.g. glycine, alanine, , phenylalanine and the like, which is linked to the oxygen or
nitrogen of the OH or oup via the carbonyl group of the amino acid. Further
suitable prodrugs are alkylcarbonyloxyalkyl carbonates or carbamates of compounds I
10 carrying an OH— or NHz-group in which one of the hydrogen atoms of the OH- or NH2-
group has been ed by a group of the a —C(=O)-O-CHRp-O-C(=O)-R01 in
which Rp and Rq are independently of one another C1—C4-alkyl. Such carbonates and
carbamates are described for example in J. Alexander, R. Cargill, S. R. Michelson, H.
, J. Medicinal Chem. 1988, 31(2), 318—322. These groups can then be
15 eliminated under lic conditions and result in compounds 1. Therefore, said
prodrugs and their pharmaceutically acceptable salts are also part of the invention.
The term "pharmaceutically acceptable salts" refers to cationic or anionic salts
compounds, wherein the counter ion is derived from pharmaceutically acceptable non-
toxic bases or acids including inorganic or c bases and inorganic or organic acids.
20 When the compound of formula I or its prodrug or N—oxide is acidic, salts may be
ed from ceutically acceptable non-toxic bases, including inorganic and
organic bases. Salts derived from inorganic bases include salts, wherein the counter ion
is aluminium, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium,
manganic, manganous, potassium, sodium, zinc ion and the like. Particularly preferred
25 are the ammonium, calcium, ium, potassium, and sodium ions. Salts derived
from pharmaceutically acceptable organic non-toxic bases include salts of primary,
secondary, and tertiary amines, substituted amines including naturally occurring
substituted amines, cyclic amines, and basic ion exchange resins, such as arginine,
e, caffeine, e, dibenzylethylene-diamine, diethylamine, 2-diethylamino-
30 ethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N—ethyl-morpholine,
N—ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine,
lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins,
15
procaine, purines, omine, triethylamine, trimethylamine, tripropylamine,
tromethamine, and the like.
When the compound of formula I or its prodrug or N—oxide is basic, salts may be
prepared from pharmaceutically acceptable xic acids, including inorganic and
organic acids. Such acids include acetic, roacetic acid, benzenesulfonic, benzoic,
camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic,
hydrochloric, onic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric,
pamoic, pantothenic, oric, succinic, sulfiiric, tartaric, p-toluenesulfonic acid, and
the like. Particularly red are citric, hydrobromic, hydrochloric, maleic,
10 phosphoric, sulfuric, fumaric, and tartaric acids. It will be understood that, as used
herein, references to the compounds of formula I are meant to also include the
pharmaceutically acceptable salts.
The compounds of the invention may be in the form of a mixture of
diastereomers, or of a mixture of diastereomers in which one of the two diastereomers is
15 enriched, or of essentially diastereomerically pure compounds (diastereomeric excess
de > 90%). The compounds are ably in the form of essentially diastereomerically
pure nds (diastereomeric excess de > 90%). The compounds I of the ion
may furthermore be in the form of a mixture of enantiomers (for example as racemate),
of a mixture of enantiomers in which one of the two enantiomers is enriched, or
20 essentially in enantiomerically pure compounds (enantiomeric excess ee > 90%). It is
preferred to employ the nds enantiomerically pure or diastereomerically pure.
The present invention moreover relates to compounds as defined herein, wherein
one or more ofthe atoms depicted in formula I have been replaced by its stable,
preferably non-radioactive e (e.g., en by deuterium, 12C by 13C, 14N by 15N,
25 16O by 18O) and preferably wherein at least one hydrogen atom has been replaced by a
deuterium atom. Of course, the compounds according to the invention contain more of
the respective isotope than this lly occurs and thus is anyway present in the
compounds I.
The compounds of the formula I and their salts in the solid form may exist in
30 more than one crystal structure (polymorphism), and may also be in the form of
hydrates or other solvates. The present invention includes any polymorph of the
compound I or its salt as well as any hydrate or other solvate.
16
In the context of the present description, unless stated otherwise, the terms
", "alkenyl", "alkoxy , alkenyloxy", "fluoroalkyl", alkoxy , cycloalkyl",
"fluorinated cycloalkyl", ene", "alkandiyl", "hetaryl" and radicals derived
therefrom, such as "alkylcarbonyl", "alkylsulfanyl", "alkylsulfonyl",
"fluoroalkylsulfonyl", "hydroxylalkyl", "cyanoalkyl", "alkoxylalkyl", "alkoxyalkoxy",
sulfanylalkyl", "alkylsulfanylalkoxy" and "hetarylmethyl" ent groups of
individual radicals. The groups of noncyclic radicals "alkyl", "alkenyl", "alkoxy",
"alkenyloxy", "fluoroalkyl", "fluoroalkoxy", "alkylene", "alkandiyl", and the groups of
10 ls derived therefrom always include both unbranched and branched "alkyl",
"alkenyl", "alkoxy", "alkenyloxy", "fluoroalkyl", "fluoroalkoxy", "alkylene" and
"alkandiyl", respectively.
The prefix Cn-Cm- indicates the respective number of carbons in the hydrocarbon
unit. Unless indicated otherwise, fluorinated substituents preferably have one to five
15 identical or different fluorine atoms.
The term "halogen" ates in each case, e, bromine, chlorine or iodine,
specifically fluorine, chlorine or bromine.
Examples of other meanings are:
Alkyl, and the alkyl moieties for example in alkylcarbonyl, alkylsulfanyl,
20 alkylsulfonyl, alkylsulfanylalkyl and alkylsulfaylalkoxy: saturated, straight-chain or
branched hydrocarbon radicals having one or more C atoms, e. g. l to 4 carbon atoms,
e. g. C1-C4-a1kyl such as , ethyl, , l-methylethyl, n-butyl, l-methylpropyl,
2—methylpropyl and l l -dimethylethyl.
,
Fluoroalkyl and the fluoroalkyl moieties for example in lkylsulfonyl: an
25 alkyl radical having ordinarily l to 4 C atoms, in particular 1 or 2 C-atoms (C1-C2-
lkyl) as mentioned above, whose hydrogen atoms are partly or completely
replaced by fluorine atoms such as fluoromethyl, difluoromethyl, trifluoromethyl, 2-
fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 2-fluoro
ethyl, 2,2—difluoro—1-methylethyl, 2,2-trifluoro-l-methylethyl, opropyl, 3-
30 fluoropropyl, 2,2—difluoropropyl, 2,3-difluoropropyl, 3,3,3-trifluoropropyl, 2,3,3,3-
pentafluoropropyl, heptafluoropropyl, 1—(fluoromethyl)fluoroethyl, 4-fluorobutyl,
and nonafluorobutyl.
17
Cycloalkyl, and the cycloalkyl moieties for example in cycloalkoxy or cycloalkyl-
C1-C4-alkyl: clic, saturated hydrocarbon groups having three or more C atoms,
e. g. 3, 4, 5, 6 or 7 carbon ring members, such as cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl and cycloheptyl.
nated cycloalkyl: monocyclic, saturated hydrocarbon groups having three or
more C atoms, e.g. 3, 4, 5, 6 or 7 carbon ring s, such as cyclopropyl, utyl,
cyclopentyl, cyclohexyl and cycloheptyl, wherein at least one, e. g. l, 2, 3, 4, 5 or 6 of
the hydrogen atoms are replaced by fluorine atoms, examples including 1-
fluorocyclopropyl, rocyclopropyl, 2,2-difluorocyclopropyl, 1,2-
10 difluorocyclopropyl, 2,3—difluorocyclopropyl, etc..
Cycloalkoxy: a cycloalkyl radical as defined above which is linked Via an oxygen
atom, e. g. cyclopropyloxy, cyclobutyloxy, cyclopentyloxy or cyclohexyloxy.
Cycloalkylalkyl: a cycloalkyl radical as defined above which is linked via an
alkylene group, in particular via a methylene, 1,1—ethylene or 1,2-ethylene group, e. g.
15 cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl or cyclohexylmethyl.
Alkenyl, and alkenyl es for example in alkenyloxy: monounsaturated,
straight-chain or branched hydrocarbon radicals having two or more C atoms, e.g. 2 to 4
carbon atoms and one C=C-double bond in any position, e. g. C2-C4-alkenyl such as
ethenyl, l-propenyl, 2-propenyl, l-methylethenyl, l-butenyl, 2-butenyl, 3-butenyl, 1-
20 methyl- 1 nyl, 2-methyl- l -propenyl, l -methylpropenyl and 2-methyl
propenyl.
Alkoxy or alkoxy es for example in alkoxyalkyl and alkoxyalkoxy:
an alkyl radical as defined above having preferably 1 to 4 C atoms, which is
connected to the remainder ofthe molecule via an O atom: e.g. methoxy, ethoxy, n-
25 propoxy, l-methylethoxy, butoxy, ylpropoxy, 2-methylpropoxy or 1,1-
dimethylethoxy.
Fluoroalkoxy: alkoxy as described above, in which the hydrogen atoms of these
groups are partly or completely replaced by e atoms, i.e. for example C1-C4-
lkoxy, in particular C1—C2-fluoroalkoxy, such as fluoromethoxy,
30 difluoromethoxy, trifluoromethoxy, 2—fluoroethoxy, 2,2-difluoroethoxy,
2,2,2-trifluoroethoxy, pentafluoroethoxy, 2-fluoropropoxy, opropoxy,
2,2-difluoropropoxy, 2,3-difluoropropoxy, 3,3,3—trifluoropropoxy, 2,2,3,3,3-
18
pentafluoropropoxy, heptafluoropropoxy, l-(fluoromethyl)fluoroethoxy, specifically
fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-fluoroethoxy, or 2,2,2-
trifluoroethoxy.
Hydroxyalkyl: an alkyl radical ordinarily having 1 to 4 C atoms, in which one
hydrogen atom is replaced by an OH radical. Examples thereof are CHz-OH, l-
hydroxyethyl, 2-hydroxyethy1, 1 —hydroxypropyl, 2-hydroxypropyl, 1 -methyl
hydroxyethyl, l-methyl-Z-hydroxyethyl, 3-hydroxypropy1, 2—hydroxybuty1, 3-
hydroxybutyl, 4-hydroxybutyl, 1-methylhydroxypropyl, 1 ,1-dimethy1hydroxyetyl,
1-methy1hydroxypropyl etc.
10 lkyl: an alkyl radical ordinarily having 1 to 4 C atoms, in which one
hydrogen atom is replaced by a CN radical. Examples thereof are CHg-CN, 1-
cyanoethyl, 2-cyanoethyl, l—cyanopropyl, 2—cyanopropyl, l-methyl- l -cyanoethyl, l-
methylcyanoethyl, 3-cyanopropyl, 2—cyanobutyl, 3-cyanobutyl, 4-cyanobutyl, l-
methylcyanopropyl, l l -dimethyl—2—cyanoetyl, yl— l -cyanopropyl etc.
,
15 Alkoxyalkyl: an alkyl l ordinarily having 1 to 4 C atoms, in which one
hydrogen atom is replaced by an alkoxy radical rily having 1 to 4 C atoms.
Examples thereof are CHz-OCHg, sz, n—propoxymethyl, CH2-OCH(CH3)2,
xymethyl, (l-methylpropoxy)methyl, (2—methylpropoxy)methyl, CH2-OC(CH3)3,
2-(methoxy)ethyl, 2-(ethoxy)ethyl, 2—(n—propoxy)ethyl, 2-(l-methylethoxy)ethyl,
20 2-(n-butoxy)ethyl, 2-(l-methylpropoxy)ethyl, 2-(2-methylpropoxy)ethyl,
2-(l,l-dimethylethoxy)ethyl, 2-(methoxy)propyl, 2-(ethoxy)propyl, 2-(n-
propoxy)propyl, 2-(l-methylethoxy)propyl, 2-(n—butoxy)propyl, 2-(1-
propoxy)propyl, 2-(2-methylpropoxy)propyl, 2-(1,l-dimethylethoxy)propyl, 3-
(methoxy)propyl, 3-(ethoxy)propyl, ropoxy)propyl, 3-(l-methylethoxy)propyl, 3-
25 (n-butoxy)propy1, 3 -( l -methy1propoxy)propyl, 3-(2-methy1propoxy)propyl, 3 -(1 , 1 -
dimethylethoxy)propyl, 2-(methoxy)butyl, oxy)butyl, 2-(n—propoxy)butyl, 2-(1 -
methylethoxy)butyl, utoxy)butyl, 2-(1-methy1propoxy)butyl, 2-(2-
methylpropoxy)butyl, 2-(1, 1-dimethylethoxy)butyl, 3-(methoxy)butyl, 3-(ethoxy)buty1,
3 -(n-propoxy)butyl, 3 —(1—methylethoxy)butyl, utoxy)butyl, 3 -(1-
30 methylpropoxy)butyl, 3—(2—methylpropoxy)butyl, 3—(1,l-dimethylethoxy)butyl, 4-
(methoxy)butyl, 4-(ethoxy)butyl, 4—(n—propoxy)butyl, 4-(l-methylethoxy)butyl, 4-(n-
19
butoxy)butyl, 4-(l-methylpropoxy)butyl, 4-(2-methylpropoxy)butyl, 4-(l ,ldimethylethoxy
)butyl, etc.
Alkoxyalkoxy: an alkyl radical as defined above ordinarily having 1 to 4 C
atoms both in the alkoxy and the alkyl moiety which is connected to the remainder of
the molecule via an O atom: Examples thereof are CHg, OCHz-OCsz, n-
propoxymethoxy, OCHz-OCH(CH3)2, n—butoxymethoxy, (1—methylpropoxy)methoxy,
(2-methylpropoxy)methoxy, OCH2-0C(CH3)3, 2-(methoxy)ethoxy, 2—(ethoxy)ethoxy,
2-(n-propoxy)ethoxy, 2-(1-methylethoxy)ethoxy, 2-(n—butoxy)ethoxy,
2-(1-methylpropoxy)ethoxy, ethylpropoxy)ethoxy, 2-(1 l -dimethyl-
,
10 ethoxy)ethoxy, etc.
arbonyl: alkyl as defined above preferably having 1 to 4 C atoms, which is
connected via a carbonyl group to the remainder of the molecule, e.g. acetyl, propionyl,
butyryl, isobutyryl, oyl, pivaloyl and the like.
Alkylsulfanyl and the alkylsulfanyl radicals in alkylsulfanylalkyl and
15 alkylsulfanylalkoxy: alkyl as defined above ably having 1 to 4 C atoms, which is
connected via an S atom to the remainder of the molecule, e.g. methylsulfanyl,
ethylsulfanyl, n-propylsulfanyl and the like.
Alkylsulfonyl: alkyl as defined above preferably having 1 to 4 C atoms, which is
connected via an 802 group to the remainder of the molecule, e.g. methylsulfonyl,
20 ethylsulfonyl, n-propylsulfonyl and the like.
Fluoroalkylsulfanyl: lkyl as defined above preferably having 1 to 4 C
atoms, which is connected via an S atom to the remainder of the molecule, e.g.
fluoromethylsulfanyl, difluoromethylsulfanyl, trifluoromethylsulfanyl, 2-
fluoroethylsulfanyl, 2,2-difluoroethylsulfanyl, 2,2,2-trifluoroethylsulfanyl,
25 pentafluoroethylsulfanyl, opropylsulfanyl, 3-fluoropropylsulfanyl, 2,2-
difluoropropylsulfanyl, 2,3-difluoropropylsulfanyl, and heptafluoropropylsulfanyl.
Fluoroalkylsulfonyl: fluoroalkyl as defined above preferably having 1 to 4 C
atoms, which is connected via an SO; group to the remainder of the molecule, e. g.
fluoromethylsulfonyl, difluoromethylsulfonyl, trifluoromethylsulfonyl, 2-
30 fluoroethylsulfonyl, 2,2—difluoroethylsulfonyl, 2,2,2—trifluoroethylsulfonyl,
uoroethylsulfonyl, 2—fluoropropylsulfonyl, 3—fluoropropylsulfonyl, 2,2-
difluoropropylsulfonyl, 2,3-difluoropropylsulfonyl, and heptafluoropropylsulfonyl.
20
Alkylsulfanylalkyl: an alkyl radical ordinarily having 1 to 4 C atoms, in which
one en atom is replaced by an alkylsulfanyl radical ordinarily having 1 to 4 C
atoms. Examples thereof are CH2—SCH3, CH2-SC2H5, n-propylsulfanylmethyl,
CH2-SCH(CH3)2, n-butylsulfanylmethyl, (1—methylpropsulfanyl)methyl, (2-
methylpropsulfanyl)methyl, CH2—0C(CH3)3, 2—(methylsulfanyl)ethyl, 2-
(ethylsulfanyl)ethyl, 2-(n-propylsulfanyl)ethyl, ethy1ethylsu1fanyl)ethyl,
utylsulfanyl)ethyl, ethylpropylsulfanyl)ethyl, 2—(2-
methylpropylsulfanyl)ethyl, 2-(1 , l -dimethylethylsulfanyl)ethyl,
2-(methylsulfanyl)propyl, 2-(ethylsulfanyl)propyl, 2-(n-propylsulfanyl)propyl,
10 2-(1-methylethylsulfanyl)propyl, 2-(n—butylsulfanyl)propyl, 2-(1-
methylpropylsulfanyl)propyl, 2—(2—methylpropylsulfanyl)propyl,
2-(1,l-dimethylethylsulfanyl)propyl, 3—(methylsulfanyl)propyl, 3-(ethylsulfanyl)propyl,
3-(n-propylsulfanyl)propyl, 3—(1—methylethylsulfanyl)propyl, 3-(n-butylsulfanyl)propyl,
3-(1-methylpropylsulfanyl)propyl, 3—(2—methylpropylsulfanyl)propyl, 3-(1 , l -
15 dimethylethylsulfanyl)propyl, 2-(methylsulfanyl)butyl, 2-(ethylsulfanyl)butyl, 2-(npropylsulfanyl
)butyl, 2—(1-methylethylsulfanyl)butyl, 2-(n-butylsulfanyl)butyl, 2-(1-
methylpropylsulfanyl)butyl, 2-(2-methylpropylsulfanyl)butyl, 2-(1 ,l-
dimethylethylsulfanyl)butyl, 3-(methylsulfanyl)butyl, 3-(ethylsulfanyl)butyl, 3-(npropylsulfanyl
)butyl, ethylethylsulfanyl)butyl, utylsulfanyl)butyl, 3-(1-
20 methylpropylsulfanyl)butyl, 3-(2-methylpropylsulfanyl)butyl, 3-(l,l-dimethylethylsulfanyl
)butyl, 4-(methylsulfanyl)butyl, 4-(ethylsulfanyl)butyl, 4-(n-
propylsulfanyl)butyl, 4-(l-methylethylsulfanyl)butyl, 4-(n-butylsulfanyl)butyl, 4-(lmethylpropylsulfanyl
)butyl, ethylpropylsulfanyl)butyl, 4-(1 ,ldimethylethylsulfanyl
)butyl, etc.
25 "Alkylen" or "Alkandiyl": a ted hydrocarbon chain having rily from 1
to 4 carbon atoms, such as methylen (-CH2-), 1,2-ethylen (—CHzCH2—), 1,1-ethandiy1
(-CH(CH3)-), 1,2-propandiyl, 1,3-propandiyl, 1,4-butandiyl, 1,2-butandiyl, 1,3-
butandiyl, l-methyl- 1 ,2-propandiyl, 2-methyl-1,3-propandiyl, l-methyl- l , 1 -ethandiyl,
l-methyl— l ,2—propandiyl etc.
30 Saturated or partially unsaturated 4 to 7-membered monocarbocyclic radicals
include cycloalkyl as defined above and lkenyl having ordinarily from 4 to 7
carbon atoms as ring members, e.g. l—cyclobuten—l—yl, 2-cyclobutenyl, l-cyclopentenyl,
21
2-cyclopentenyl, l-cyclohexenyl, 2—cyclohexenyl, 3-cyclohexenyl, l-cycloheptenyl, 2-
cycloheptenyl, 3-cycloheptenyl.
Saturated or partially unsaturated 7 to 10-membered ocyclic radicals
include bicyclic carbocyclic radicals which ordinarily have from 7 to 10 carbon atoms
as ring s and which are saturated or which have one or more, e.g. one or two
C=C double bonds, or which e a monounsaturated carbocycle where the double
bond is part of a fused benzene ring, e.g. bicyclo[2,2,1]heptyl, bicyclo[2,2,1]—2-
heptyl, bicyclo[2,2,1]heptyl, bicyclo[3,3,0]octyl, bicyclo[3,3,0]—2-octy1,
bicyclo[3,3,0]octyl, bicyclo[2,2,2]octyl, bicyclo[2,2,2]octyl, bicyclo[3,2,1]
10 octyl, bicyclo[3 ,2, l ]—2—octyl, bicyclo[3,2,1]—6—octyl, bicyclo[3 ,2, l ]octyl,
bicyclo[4,3,0]—l—nonyl, bicyclo[4,3,0]—2—nonyl, bicyclo[4,3,0]—3-nonyl, bicyclo[4,3,0]—
7-nonyl, bicyclo[4,3,0]—8—nonyl, bicyclo[4,4,0]—1—decyl, bicyclo[4,4,0]—2-decyl,
bicyclo[4,4,0]—3-decyl, bicyclo[2,2,1]-hepten—l-yl, bicyclo[2,2, l ]-heptenyl,
bicyclo[2,2, l ]-hepten—5-yl, bicyclo[2,2, l ]—hept—2—en—7-yl, bicyclo[2,2,2]—octen— l -
15 yl, bicyclo[2,2,2]-octenyl, o[2,2,2]—oct—2-en—5-yl, bicyclo[2,2,2]-octen
yl, bicyclo[3,3,0]—2-octen—l-yl, bicyclo[3,3,0]—2—octen—2-yl, bicyclo[3,3,0]—2-octen—3-yl,
o[3,3,0]—2-octen—4-yl, bicyclo[3,3,0]—2—octen—5-yl, bicyclo[3,3,0]—2-octen—6-yl,
bicyclo[3,3,0]—2-octen—7-yl, bicyclo[3,3,0]—2-octenyl, inden— l -yl, 2-yl, inden-
4-yl, inden—6-yl, tetrahydro- l -naphthyl, tetrahydronaphthyl, tetrahydro-S-naphthyl,
20 tetrahydronaphthyl, etc..
Heterocyclyl: a heterocyclic radical which may be saturated or partly rated
and which may be a monocyclic heterocyclic radical ordinarily having 3, 4, 5, 6, 7 or 8
ring atoms or a bicyclic radical rily having 7, 8, 9 or 10 ring atoms, where
ordinarily l, 2, 3 or 4, in particular 1, 2 or 3, of the ring atoms are heteroatoms such as
25 N, S or O, or heteroatom groups such as S(=O) or S(=O)2 besides carbon atoms as ring
members.
Examples of saturated heteromonocycles are in particular:
- Saturated heteromonocyclic radical which rily has 3, 4, 5, 6 or 7 ring
atoms, where ordinarily 1, 2 or 3 of the ring atoms are heteroatoms such as
30 N, S or O, besides carbon atoms as ring members. These include for
example:
C-bonded, 3- or 4—membered saturated rings such as
22
2-0Xiranyl, 2-oxetanyl, 3—0xetanyl, idinyl, 3-thiethanyl, idinyl,
2-azetidinyl.
C-bonded, 5-mernbered saturated rings such as
tetrahydrofiJran-Z-yl, tetrahydrofiaran—3—y1, tetrahydrothien—Z-yl,
tetrahydrothien—3-yl, tetrahydropyrrol—Z-yl, tetrahydropyrrol—S-yl,
tetrahydropyrazo , tetrahydropyrazo 1y1, tetrahydroisoxazol—3-yl,
tetrahydroisoxazol—4—yl, tetrahydroisoxazol-S-yl, 1,2—oxathi01anyl, 1,2-
oxathiolanyl, athiolanyl, tetrahydroisothiazo1y1,
tetrahydroisothiazolyl, tetrahydroisothiazo1y1, 1,2-dithiolan—3-yl, 1,2-
10 dithio 1any1, tetrahydroimidazol—2-yl, tetrahydroimidazol—4-y1,
tetrahydrooxazo 1—2—yl, tetrahydrooxazo , tetrahydrooxazol—S-yl,
tetrahydrothiazol—Z—yl, ydrothiazo , ydrothiazo 1y1, 1,3-
dioxolan—Z-yl, 1,3—dioxolan—4—y1, 1,3—oxathi01anyl, 1,3-0xathi01an—4-yl,
1,3-oxathiolanyl, 1,3—dithiolan—2—yl, 1,3-dithi01an—4-yl, 1,3,2-
15 dioxathiolan—4-yl.
C-bonded, bered saturated rings such as:
tetrahydropyran—2-yl, tetrahydropyran—3-yl, tetrahydropyran—4-yl, piperidin-
2-y1, piperidinyl, piperidin—4-yl, tetrahydrothiopyran—Z-yl,
tetrahydrothiopyran—3-yl, tetrahydrothiopyran—4-yl, 1,3-di0xan—2-y1, 1,3-
20 dioxan—4-yl, 1,3-dioxan—5—yl, 1,4-di0xan—2-yl, thian—2-yl, 1,3-dithian—
4-yl, 1,3-dithian—5-yl, 1,4—dithian—2-yl, 1,3-oxathiany1, 1,3-oxathianyl,
1,3-oxathiany1, 1,3—oxathian-6—yl, 1,4-oxathiany1, 1,4-0xathian—3-yl,
1,2-dithian—3-yl, 1,2-dithian—4-yl, hexahydropyrimidin—Z-yl,
hexahydropyrirnidin—4-yl, hexahydropyrimidin—S-yl, hexahydropyrazin—Z-yl,
25 hexahydropyridazin—3-yl, hexahydropyridazin—4-yl, tetrahydro-1,3-oxazin-
2-y1, tetrahydro- 1 ,3-0xazin—4-yl, tetrahydro-l ,3—0xazin—5-y1, tetrahydro- 1 ,3-
oxazin—6-yl, tetrahydro-1,3-thiazinyl, tetrahydro-l ,3-thiaziny1,
tetrahydro- 1 azinyl, tetrahydro- 1 ,3-thiaziny1, tetrahydro- 1 ,4-
thiazin-Z-yl, tetrahydro- 1 ,4-thiazinyl, tetrahydro- 1 ,4-0xazin—2-yl,
30 tetrahydro— 1 ,4—oxazin—3—yl, tetrahydro— 1 ,2—0xazin—3 -y1, tetrahydro- 1 ,2-
oxazin—4-yl, tetrahydro—l ,2—oxazin—5—yl, tetrahydro- 1 ,2-oxazinyl.
N—bonded, 5-membered saturated rings such as:
23
tetrahydropyrrol— l -yl, tetrahydropyrazo l- l -yl, tetrahydroisoxazo lyl,
tetrahydroisothiazol-2—yl, tetrahydroimidazol— l -yl, tetrahydrooxazol—3-yl,
tetrahydrothiazol—3-yl.
N—bonded, 6-membered saturated rings such as:
piperidin— l -yl, hexahydropyrimidinyl, hexahydropyrazin- l -yl,
hexahydro-pyridazin— 1 —yl, tetrahydro- l ,3-oxazin—3 -y1, tetrahydro- 1 ,3 -
thiazinyl, tetrahydro— 1 ,4—thiazin—4—yl, tetrahydro— 1 ,4-oxazin—4-yl,
tetrahydro- 1 ,2-oxazinyl.
Unsaturated heteromonocyclic radicals which ordinarily have 4, 5, 6 or 7
10 ring atoms, where ordinarily 1, 2 or 3 of the ring atoms are heteroatoms
such as N, S or O, besides carbon atoms as ring s. These include for
example:
C-bonded, 5-membered, partially unsaturated rings such as:
2,3-dihydrofuran—2—yl, hydrofi1ran—3-yl, 2,5-dihydrofi1ran—2-yl,
15 2,5-dihydrofuran—3-yl, hydrofuran—2-yl, 4,5-dihydrofi1ran—3-yl, 2,3-
dihydrothien—Z-yl, 2,3-dihydrothien—3—yl, hydrothien—2-yl, 2,5-
dihydrothien—3-yl, 4,5-dihydrothien—2-yl, 4,5-dihydrothien—3-yl, 2,3-
dihydro-lH-pyrrol—2-yl, 2,3-dihydro-lH-pyrrol—3-yl, 2,5-dihydro-1H-
pyrrol—2-yl, 2,5-dihydro—lH-pyrrol—3-yl, 4,5-dihydro-lH-pyrrol—2-yl, 4,5-
20 dihydro-lH-pyrrol—3-yl, 3,4—dihydro-2H-pyrrol—2-yl, 3,4-dihydro-2H-
—3-yl, 3,4-dihydro—5H—pyrrol—2-yl, 3,4-dihydro-5H-pyrrol—3-yl, 4,5-
o- l H-pyrazo l—3—yl, 4,5-dihydro- l H-pyrazo lyl, 4,5 -dihydro- l H-
pyrazol—S-yl, 2,5-dihydro-1H-pyrazol—3-yl, 2,5-dihydro-lH-pyrazol—4-yl,
2,5-dihydro-lH—pyrazol—S-yl, 4,5-dihydroisoxazol—3-yl, 4,5-
25 dihydroisoxazol—4-yl, 4,5-dihydroisoxazol—5—yl, 2,5-dihydroisoxazol—3-yl,
2,5-dihydroisoxazol—4-yl, 2,5—dihydroisoxazolyl, 2,3-dihydroisoxazol—3-
yl, 2,3-dihydroisoxazolyl, 2,3-dihydroisoxazolyl, 4,5-
dihydroisothiazol—3-yl, 4,5-dihydroisothiazolyl, 4,5-dihydroisothiazol—5-
yl, 2,5-dihydroisothiazol—3-yl, 2,5-dihydroisothiazolyl, 2,5-
30 dihydroisothiazol—S—yl, 2,3—dihydroisothiazolyl, 2,3-dihydroisothiazol—4-
yl, 2,3-dihydroisothiazol—5—yl, 4,5—dihydro-lH-imidazol—Z-yl, hydrolH-imidazol
—4-yl, 4,5—dihydro—1H—imidazol—S-yl, 2,5-dihydro-lH-imidazol—
24
2-yl, 2,5-dihydro-1H-imidazol—4-yl, 2,5-dihydro-lH-imidazol-S-yl, 2,3-
dihydro-lH-imidazol—Z—yl, 2,3—dihydro-1H-imidazol—4-y1, 4,5-
dihydrooxazol—2-y1, 4,5-dihydr00xaz01—4-y1, 4,5-dihydrooxazol—5-yl, 2,5-
dihydrooxazol—Z-yl, hydr00xazol—4-y1, 2,5-dihydrooxazol—5-yl, 2,3-
dihydrooxazol—Z-yl, hydr00xazolyl, 2,3-dihydrooxazol—5-yl, 4,5-
dihydrothiazol—2-yl, 4,5-dihydr0thiazol—4-yl, 4,5—dihydrothiazol—5-yl, 2,5-
dihydrothiazol—Z-yl, 2,5—dihydr0thiazol—4-yl, 2,5—dihydr0thiazol—5-yl, 2,3-
dihydrothiazol-Z-yl, 2,3-dihydrothiazolyl, 2,3-dihydrothiazol—5-yl, 1,3-
dioxolyl, 1,3-dioxolyl, 1,3-dithioly1, 1,3-dithiolyl, 1,3-oxathi01-
10 2—y1, 1,3—oxathiol—4-yl, athiolyl.
C-bonded, ered, partially unsaturated rings such as:
2H-3,4-dihydropyran—6—yl, 2H—3,4—dihydropyran—5-yl, 2H-3,4-
dihydropyran—4-y1, 2H—3,4—dihydr0pyran—3 -y1, 2H-3,4-dihydr0pyran—2-yl,
2H-3 ,4-dihydrothiopyran—6—yl, 2H—3,4—dihydr0thi0pyran—5-yl, 2H-3 ,4-
15 dihydrothiopyran—4-yl, 2H—3,4—dihydrothi0pyran—3-y1, 2H-3,4-
dihydrothiopyran—2—yl, 1 ,2,3,4—tetrahydropyridinyl, 1 ,2,3 ,4-
tetrahydropyridin-S-yl, 1 ,2,3,4—tetrahydropyridinyl, 1 ,2,3 ,4-tetra-
hydropyridinyl, 1,2,3,4—tetrahydropyridiny1, 2H-5,6-dihydropyran—2-
yl, 2H-5,6-dihydropyran—3—yl, 2H-5,6-dihydropyran—4-yl, -
20 dihydropyran—S-yl, —dihydropyran—6-yl, 2H-5,6-dihydr0thiopyran—2-
yl, 2H-5,6-dihydrothiopyran—3—yl, 2H-5,6-dihydrothiopyran—4-yl, 2H-5,6-
dihydrothiopyran—S-yl, 2H—5,6—dihydrothiopyran—6-yl, 1,2,5,6-
tetrahydropyridinyl, 1,2,5,6-tetrahydropyridiny1, 1,2,5,6-
ydropyridinyl, 1,2,5,6-tetrahydropyridiny1, 1,2,5,6-tetra-
25 hydropyridin-é-yl, 2,3,4,5—tetrahydr0pyridinyl, 2,3,4,5-tetrahydropyridin-
3-y1, 2,3,4,5-tetrahydr0pyridin—4-yl, 2,3,4,5—tetrahydr0pyridinyl, 2,3,4,5-
tetrahydropyridinyl, anyl, 4H-pyrany1, 4H—pyrany1, 4H-
thiopyran—2-yl, 4H-thiopyran—3-yl, 4H-thiopyrany1, 1,4-dihydropyridin—2-
yl, 1,4—dihydropyridinyl, 1,4-dihydropyridiny1, 2H—pyran—2-yl, 2H-
30 pyran—3—y1, 2H—pyran—4—yl, 2H—pyran—5—yl, 2H-pyran—6-yl, 2H—thi0pyran—2-
yl, opyran—3—yl, 2H—thiopyran—4—yl, 2H-thiopyran—5-yl, 2H-thi0pyran—
6-y1, 1,2-dihydr0pyridin—2—yl, 1,2—dihydropyridinyl, 1,2-dihydr0pyridin—
25
4-y1, 1,2-dihydropyridin—5—yl, hydropyridinyl, 3,4-dihydropyridin—
2-yl, 3,4-dihydropyridin—3—yl, 3,4—dihydropyridinyl, 3,4-dihydropyridin—
5-y1, 3,4-dihydropyridin—6-yl, 2,5—dihydropyridinyl, 2,5-dihydropyridin—
3-y1, hydropyridin—4-yl, 2,5—dihydropyridinyl, 2,5-dihydropyridin—
6-y1, 2,3-dihydr0pyridin—2-yl, 2,3—dihydropyridinyl, 2,3-dihydropyridin—
4-y1, 2,3-dihydr0pyridin—5—yl, 2,3-dihydropyridin—6-yl, 2H—5,6-dihydro-1,2-
0xazin—3-yl, 2H—5,6-dihydr0—1,2-0xazin—4-yl, 2H—5,6-dihydr0-1,2-oxazin
yl, 2H-5,6-dihydro-1,2-oxazinyl, 2H-5,6-dihydro-1,2-thiaziny1,
2H-5,6-dihydro-1,2-thiazinyl, 2H-5,6-dihydro-1 ,2-thiaziny1, 2H—5 ,6-
10 dihydro— 1 ,2—thiazinyl, 4H-5,6-dihydro-1 ,2-oxazinyl, 4H-5 ,6-dihydro-
1,2—0xazin—4—yl, 4H—5,6—dihydro—1,2—0xazinyl, 4H-5 ,6-dihydr0-1,2-
oxazin—6-y1, 4H—5,6—dihydro—1,2—thiazin—3—yl, 4H-5,6-dihydro-1,2-thiazin—4-
yl, -dihydro—1,2—thiazin—5—yl, 4H—5,6-dihydr0-1,2-thiazinyl, 2H-
3,6-dihydro-1,2—oxazin—3—y1, 2H—3,6—dihydr0-1,2-oxazinyl, 2H-3,6-
15 dihydro-1,2-oxazinyl, 2H—3,6—dihydr0-1,2-0xazin—6-y1, 2H-3,6-dihydr0-
1,2-thiaziny1, 2H-3,6-dihydro—1,2—thiazin—4-y1, 2H-3,6-dihydr0-1,2-
thiazin-S-yl, -dihydro-1,2—thiazin—6-y1, 2H-3,4-dihydr0-1,2-oxazin
yl, 2H-3,4-dihydro-1,2-0xazin—4-yl, 2H-3,4-dihydr0-1,2-oxazinyl, 2H-
3,4-dihydr0-1,2-oxazin-6—yl, 2H-3,4-dihydro-1,2-thiaziny1, -
20 o- 1 ,2-thiazinyl, -dihydro-1,2-thiaziny1, 2H-3 ,4-dihydr0-
1,2-thiaziny1, 2,3,4,5—tetrahydropyridazin—3-y1, 5-
tetrahydropyridazin-4—yl, 2,3,4,5—tetrahydropyridazin—5-y1, 2,3,4,5-
tetrahydropyridazin—6-yl, 3,4,5,6—tetrahydropyridazin—3-y1, 3,4,5,6-
tetrahydropyridazin—4-yl, 1 ,2,5,6-tetrahydr0pyridazin—3-y1, 1 ,2,5 ,6-
25 tetrahydropyridazinyl, 1 ,2,5,6-tetrahydr0pyridazin—5-y1, 1 ,2,5 ,6-
tetrahydropyridazinyl, 1 -tetrahydr0pyridazin—3-y1, 1 ,2,3 ,6-
tetrahydropyridazinyl, 4H-5,6-dihydro-1 ,3-oxazinyl, 4H—5 ,6-dihydro-
1,3-0xazin—4-yl, 4H-5,6-dihydro-1,3-oxaziny1, 4H-5,6-dihydro-1,3-
oxazin—6-yl, 4H—5 ,6-dihydro- 1 ,3-thiaziny1, 4H-5,6-dihydr0-1,3-thiazin—4-
30 yl, 4H—5,6—dihydro—1,3—thiazin—5—yl, 4H—5,6-dihydr0-1,3-thiaziny1, 3,4,5-
6-tetrahydropyrimidin—Z—yl, 3,4,5,6—tetrahydr0pyrimidin—4-yl, 3,4,5,6-tetra—
hydropyrimidin—S—yl, 3,4,5,6—tetrahydropyrimidin—6-y1, 1,2,3,4-
26
tetrahydropyrazinyl, l ,2,3,4-tetrahydropyrazinyl, l ,2,3 ,4-
tetrahydropyrimidin—2—yl, l ,2,3,4-tetrahydropyrimidin—4-yl, l ,2,3 ,4-
tetrahydropyrimidin—S—yl, l,2,3,4-tetrahydropyrimidin—6-yl, 2,3-dihydr0-l,4-
thiazinyl, 2,3-dihydr0—l,4—thiazin—3-yl, 2,3-dihydro-l,4-thiazin—5-yl, 2,3-
o- l ,4-thiazin-6—yl, 2H-l ,3—0xazinyl, 2H- 1 ,3-oxazinyl, 2H- 1 ,3-
oxazin-S-yl, 2H— 1 ,3-0xazin—6-yl, 2H—1,3-thiazin—2-yl, 2H—1,3-thiazin—4-yl,
2H—1,3-thiazinyl, 2H—1,3-thiazinyl, 4H-l ,3-oxazinyl, 4H—1,3-
oxazin—4-yl, 4H- 1 ,3-oxazinyl, 4H-1,3-oxazinyl, 4H—1,3-thiazin—2-yl,
4H-1,3-thiazinyl, 4H-1,3-thiazinyl, 4H-l ,3-thiazinyl, 6H—1,3-
10 oxazin—2-yl, 6H— 1 ,3-oxazinyl, 6H-1,3-oxazinyl, 6H-1,3-0xazin—6-yl,
6H— 1 ,3—thiazin—2—yl, 6H—1,3—oxazin—4—yl, 6H-l ,3-0xazinyl, 6H— 1 ,3-
nyl, 2H— 1 ,4—oxazin—2—yl, 2H— 1 ,4—0xazin—3-yl, 2H- 1 ,4-0xazin—5-yl,
2H- 1 ,4-oxazinyl, 2H—1,4—thiazin—2—yl, 2H- 1 ,4-thiazinyl, 2H- 1 ,4-
thiazin-S-yl, 2H- 1 ,4-thiazin—6—yl, 4H—1,4-0xazin—2-yl, 4H- 1 ,4-oxazinyl,
15 4H-l,4-thiazinyl, 4H-1,4—thiazin—3—yl, l,4-dihydr0pyridazin—3-yl, 1,4-
dihydropyridazinyl, hydropyridazinyl, 1,4-dihydr0pyridazin
yl, 1,4-dihydr0pyrazinyl, 1,2-dihydropyrazinyl, 1,2-dihydr0pyrazin
yl, l,2-dihydr0pyrazin—5-yl, 1,2-dihydropyrazinyl, 1,4-dihydr0pyrirnidin-
2-yl, l,4-dihydropyrimidin—4-yl, 1,4-dihydropyrirnidin—5-yl, 1,4-
20 dihydropyrimidin—6-yl, 3,4—dihydropyrimidin—2-yl, 3,4-dihydropyrirnidin
yl, 3,4-dihydropyrimidin—5-yl or 3,4-dihydropyrimidin—6-yl.
N—bonded, 5-membered, lly unsaturated rings such as:
2,3-dihydro- l H-pyrrol— l -yl, 2,5-dihydro- l H-pyrrol- l -yl, hydr0-1H-
pyrazo l- l -yl, 2,5 -dihydr0— l H-pyrazo l— l -yl, 2,3 —dihydro- l H-pyrazo l- l -yl,
25 2,5-dihydroisoxazolyl, 2,3—dihydr0isoxazo1y1, 2,5-dihydroisothiazol—2-
yl, 2,3-dihydr0isoxazol—2-yl, 4,5-dihydro- l azol— 1 -y1, 2,5-dihydro-
lH-imidazol— l -yl, hydro- 1 H-imidazol- l -yl, hydrooxazol—3-yl,
2,3-dihydrothiazol—3-yl.
N—bonded, 6—membered, lly unsaturated rings such as:
30 l ,2,3 ,4—tetrahydropyridin—1—yl, 1 ,2,5 ,6—tetrahydr0pyridin— l -yl, l ,4-
dihydropyridin— l —yl, l ,2—dihydropyridin— l —yl, 2H-5 ,6-dihydr0- l ,2-0xazin—2-
yl, 2H-5,6-dihydro—l,2—thiazin—2—yl, 2H—3,6-dihydr0-l,2-0xazin—2-yl, 2H-
27
3,6-dihydro- l ,2-thiazin—2—yl, 2H-3,4-dihydro- l ,2-oxazinyl, -
dihydro-l,2-thiazin-2—yl, 2,3,4,5-tetrahydropyridazinyl, l,2,5,6-
ydropyridazin-l—yl, l,2,5,6-tetrahydropyridazin—2-yl, l,2,3,6-
tetrahydropyridazin—l-yl, 3,4,5,6-tetrahydropyrimidin—3-yl, l,2,3,4-
tetrahydropyrazin- l -yl, 1 ,2,3 ,4—tetrahydropyrimidin— l -yl, l ,2,3 ,4-tetrahydro-
pyrimidinyl, 2,3—dihydro-1,4—thiazinyl, 2H—1,2-oxazin—2-yl, 2H—1,2-
thiazinyl, 4H—l,4—oxazin—4-yl, 4H—1,4-thiazinyl, hydropyridazin-
l-yl, 1,4-dihydropyrazinyl, 1,2-dihydropyrazin-l-yl, 1,4-
dihydropyrimidin- l -yl or 3,4-dihydropyrimidinyl.
10 Examples of saturated or partially unsaturated bicycles are in particular
radicals corresponding to saturated or partially unsaturated ocyclic radicals,
wherein l, 2 or 3 CH or CH2 moieties have been replaced by N, NH, O, S, S(=O) or
S(=O)2, such as 2-oxa—6-azaspiro-[3,4]octyl, 2-azabicyclo[2.2.l]heptyl, 5-
yclo[2.2.l]heptyl, 2,5-diazabicyclo[2.2.l]heptyl, 3-azabicyclo[3.2.l]octyl, 8-
15 azabicyclo [3 .2. l]octyl, 3 , abicyclo[3 .2. l]octyl, dihydroindo lyl,
dihydroindolizynyl, dihydroisoindolyl, oquinolinyl, dihydroisoquinolinyl,
chromenyl and chromanyl.
Hetaryl: a 5- or 6-membered aromatic heteromonocyclic radical (also termed 5- or
6-membered monocyclic hetaryl) which ordinarily has 1, 2, 3 or 4 heteroatoms as ring
20 members, which are selected from O, S and N, and which has in particular 1, 2, 3 or 4
nitrogen atoms or a heteroatom selected from oxygen and sulfur and, if appropriate, 1 or
2 nitrogen atoms as ring members besides carbon atoms as ring members and a 8- to 10-
ed aromatic heterobicyclic radical (also termed 8- to lO-membered bicyclic
hetaryl) which ordinarily has 1, 2, 3 or 4 heteroatoms as ring members, which are
25 selected from O, S and N, and which has in particular 1, 2, 3 or 4 nitrogen atoms or a
heteroatom selected from oxygen and sulfur and, if appropriate, 1 or 2 nitrogen atoms as
ring members besides carbon atoms as ring members: for example
C-bonded, 5-membered monocyclic hetaryl having 1, 2 or 3 or 4 nitrogen atoms
or a heteroatom selected from oxygen and sulfur and, if appropriate, having 1, 2
30 or 3 nitrogen atoms as ring members, such as:
l, 3-furyl, 2—thienyl, nyl, pyrrol—2—yl, pyrrol—3-yl, l—3-yl,
pyrazol—4-yl, isoxazol—3—yl, isoxazol—4—yl, isoxazol-S-yl, isothiazol—3-yl,
28
isothiazol—4-yl, isothiazol—S-yl, imidazol—2-yl, imidazol—4-yl, oxazol—2-yl, oxazol—
4-yl, —S-yl, thiazol—2—yl, thiazol—4-yl, thiazol-S-yl, 1,2,3-oxadiazolyl,
1,2,3-oxadiazol—5-yl, 1,2,4—oxadiazol—3-yl, l,2,4,—oxadiazol—5-yl, 1,3,4-oxadiazol-
2-yl, 1,2,3-thiadiazol—4-yl, thiadiazol—5-yl, 1,2,4-thiadiazol—3-yl, 1,2,4-
thiadiazol—S-yl, 1,3,4-thiadiazolylyl, 1,2,3-triazol—4-yl, 1,2,4-triazolyl,
tetrazol—S-yl.
C-bonded, 6-membered monocyclic hetaryl having 1, 2 or 3 nitrogen atoms as
ring members, such as:
pyridinyl, pyridinyl, pyridinyl, pyridazinyl, pyridazinyl, pyrimidin-
10 2—yl, pyrimidin—4—yl, pyrimidin-S-yl, pyrazinyl, 1,3,5-triazinyl, 1,2,4-triazin-
3-yl, 1,2,4—triazin—5—yl, 1,2,4—triazin—6—yl, 1,2,4,5-tetrazin—3-yl.
N—bonded, 5-membered heteroaromatic radicals having 1, 2, 3 or 4 nitrogen atoms
as ring members, such as:
pyrrol— 1 -yl, pyrazol— 1 -yl, imidazol— 1 —y1, 1,2,3—triazol— l -yl, 1,2,4-triazolyl,
15 tetrazol— 1 -yl.
bicyclic 8 to lO-membered hetaryl, hetaryl which has one of the aforementioned
5- or 6-membered aromatic rings and a r aromatic carbocycle or 5- or
6-membered heterocycle fused thereto, for example a fused benzene, thiophene,
furane, pyrrole, pyrazole, imidazole, pyridine or pyrimidine ring. These bicyclic
20 hetaryl include for e inyl, isoquinolinyl, cinnolinyl, indolyl,
indolizynyl, isoindolyl, indazolyl, benzofuryl, benzothienyl, b]thiazolyl,
benzoxazolyl, benzthiazolyl, benzimidazolyl, imidazo[l,2-a]pyridineyl,
thieno [3 yridine-5 -yl, imidazo—[2,1-b]-thiazolyl and 1 ,2,4-triazo lo [ 1 ,5 -
dineyl.
25 Hetarylalkyl: a hetaryl radical as defined above which is linked via an alkylene
group, in particular via a methylene, 1,1—ethylene or hy1ene group, to the
remainder of the molecule.
The expression "optionally tuted" in the context of the present invention
means that the tive moiety is unsubstituted or has 1, 2 or 3, in particular 1,
30 substituents Which are selected from halogen, C1-C4-alkyl, C1-C4-haloalkyl, OH, SH,
CN, CF3, O-CFg, COOH, O—CHz—COOH, C1—C6—alkoxy, haloalkoxy, C1-C6-
alkylthio, C3-C7-cycloalkyl, COO—Cl—C6—alkyl, CONHZ, CONH-Cl-Cg-alkyl, SOZNH-
29
C1-C6-alkyl, CON-(Cl-Cg-alkylh, SOzN—(Cl-C6-alkyl)2, NH-SOz-Cl-C6-alkyl, NH-COC1-C6-alkyl
, -CG-alkyl, O-phenyl, O-CHg-phenyl, CONH-phenyl, SOZNH-
phenyl, CONH-hetaryl, SOZNH-hetaryl, SOg-phenyl, NH-SOz-phenyl, NH-CO-phenyl,
NH-SOz-hetaryl and NH-CO-hetaryl, where phenyl and hetaryl in the last 11 radicals
mentioned are unsubstituted or may have 1, 2 or 3 substituents which are ed from
halogen, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy and C1-C4-haloalkoxy.
In relation to their use as inhibitors of PDEIOA, the variables Het, A, A', Q, X1,
X2, X3, Y1, Y2, Y3, R1, R2, R3, R4, R5, R6, R7, R8, R9, Cycl, Cyc2 and Cyc3 preferably
have the following meanings, where these represent, both considered on their own and
10 in combination with at least one other or all, special configurations of the compounds of
the formula I:
In a particular embodiment, Het is unsubstituted or may carry 1, 2, 3 or 4 identical
or different tuents Rx. In this regard, Rx is selected from the group consisting of H,
halogen, C1-C4-alkyl, C1-C4-alkoxy, C1—C4—fluoroalkyl, C1-C4-fluoroalkoxy, C3-C6-
15 lkyl, C1-C4-alkoxy-C1-C4-alkoxy, C1—C4—alkoxy-C1-C4-alkyl, OH, y—Cl-
C4-alkyl, O-Cg-C6-cycloalkyl, benzyloxy, C(O)O-(C1-C4-alkyl), C4-alkyl)-C02H,
N(RX1)(RX2), RX1)(R"2), C1-C4-alkyl-N(RX1)(RX2), -NRX3-C(O)-N(RX1)(RX2),
NRX3-C(O)O-(C1-C4-alkyl), -N(RX3)-SOz-RX4, phenyl, CN, -SF5, -OSF5, -SOZRX4, -SR"4
and trimethylsilyl, where R“, sz, RX3 and RX4, independently of each other are selected
20 from the group consisting of hydrogen, alkyl, C1-C4-fluoroalkyl and C3-C6-
cycloalkyl or RX1 and sz form together with the N atom to which they are attached a 3-
to 7-membered, nitrogen heterocycle which may have 1, 2 or 3 further different or
identical atoms or heteroatom containing groups selected from the group of O, N,
S, SO and 802 as ring members and which may carry 1, 2, 3, 4, 5 or 6 substituents
25 selected from C1-C4-alkyl.
Het is preferably selected from the group consisting of C-bound 6-membered
monocyclic hetaryl, which has 1 or 2 nitrogen atoms as ring members, and C-bound,
fused bicyclic hetaryl, which has 1 or 2 nitrogen atoms as ring members and ally
a further heteroatom selected from O, S and N as ring member, where monocyclic
30 hetaryl and bicyclic hetaryl may be unsubstituted or may carry 1, 2, 3 or 4 substituents
RX, in particular 0, l or 2 substituents Rx. In this regard, RX is preferably selected from
n, alkyl, C1-C2-fluoroalkyl, C1—C4—alkoxy, C1-C2-fluoralkoxy, phenyl, C3-
30
C6-cycloalkyl, optionally substituted by l, 2 or 3 methyl groups, and fluorinated C3-C6-
cycloalkyl. In this regard, Rx is in particular selected from e, chlorine, methyl,
fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy,
difluoromethoxy, trifluoromethoxy, phenyl, cyclopropyl, optionally substituted by l, 2
or 3 methyl groups, and fluorinated cyclopropyl.
In a particular embodiment of the invention, Het is selected from fiased bicyclic
hetaryl, which has 1 or 2 nitrogen atoms as ring s and ally a further
heteroatom selected from O, S and N as ring member and which may be unsubstituted
or may carry 1, 2, 3 or 4 substituents RX, in ular 0, 1 or 2 substituents RX. In this
10 regard, RX is ably selected from halogen, C1-C4-alkyl, C1-C2-fluoroalkyl, C1-C4-
, C1-C2-fluoralkoxy, C3—C6—cycloalkyl, optionally substituted by l, 2 or 3 methyl
groups, and fluorinated C3—C6—cycloalkyl. In this regard, RX is in particular selected from
fluorine, chlorine, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy,
fluoromethoxy, difluoromethoxy, romethoxy, ropyl, optionally substituted
15 by l, 2 or 3 methyl groups, and fluorinated cyclopropyl.
In another particular embodiment of the invention, Het is selected from 6-
membered monocyclic hetaryl, which may be unsubstituted or may carry 1, 2, 3 or 4
substituents RX, in particular 0, l or 2 substituents RX. In this regard, RX is preferably
selected from halogen, C1-C4-alkyl, C1—C2-fluoroalkyl, C1-C4-alkoxy, C1-C2-
20 fluoralkoxy, phenyl, C3-C6-cycloalkyl, optionally substituted by l, 2 or 3 methyl
groups, and ated C3-C6-cycloalkyl. In this regard, RX is in particular selected from
fluorine, chlorine, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy,
fluoromethoxy, omethoxy, romethoxy, cyclopropyl, optionally substituted
by l, 2 or 3 methyl groups, and fluorinated cyclopropyl or one Rx may also be phenyl,
25 ular preference is given to those Het radicals, which have at least one imino-
nitrogen as ring member, which is located in the position adjacent to the carbon atom
which is bound to A. Particular preference is given to those Het radicals, which have at
least one imino-nitrogen as ring member, which is located in the position adjacent to the
carbon atom which is bound to tA and which are ed from the group consisting of
30 d 6-membered monocyclic hetaryl, which has 1 or 2 nitrogen atoms as ring
members, uryl and C—bound, fused bicyclic hetaryl, which has 1 or 2 nitrogen
atoms as ring members and optionally a further heteroatom selected from O, S and N as
31
ring , where monocyclic hetaryl, benzofuryl and bicyclic hetaryl may be
unsubstituted or may carry 1, 2, 3 or 4 substituents RX, in particular 0, l or 2 tuents
RX. In this , Rx is preferably ed from halogen, C1-C4-alkyl, C1-C2-
fluoroalkyl, C1-C4-alkoxy, C1-C2—fluoralkoxy, , C3-C6-cycloalkyl, optionally
substituted by l, 2 or 3 methyl groups, and fluorinated C3-C6-cycloalkyl. In this regard,
Rx is in particular selected from e, ne, methyl, fluoromethyl,
difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy,
trifluoromethoxy, phenyl, cyclopropyl, optionally substituted by 1, 2 or 3 methyl
groups, and fluorinated cyclopropyl.
10 Particular examples of Het are selected from the group consisting of 2-benzo furyl,
2-pyridyl, 2-pyrimidinyl, 4—pyrimidinyl, 2—pyrazinyl, 3-pyridazinyl, 2-quinolinyl, 3-
nolinyl, 2-quinazolinyl, 2—quinoxalinyl, 1,5—naphthyridin—2-yl, 1,8-naphthyridin-
2-yl, benzothiazol— l -yl, benzoxazol— 1 —yl, benzimidazol—2-yl, l-methylbenzimidazol—2-
yl, imidazo[l ,2-a]pyridineyl, thieno[3,2—b]pyridineyl, imidazo-[2, l -b]-thiazolyl
15 and l,2,4-triazolo[l,5-a]pyridineyl, where the entioned radicals are
unsubstituted or may carry 1, 2 or 3 radicals RX as defined above, which are in particular
selected from the group consisting of fluorine, chlorine, methyl, fluoromethyl,
difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy,
romethoxy, cyclopropyl, optionally substituted by l, 2 or 3 methyl groups, and
20 fluorinated cyclopropyl.
In a particular ment ofthe invention, Het has at least one imino-nitrogen as
ring member, which is located in the position adjacent to the carbon atom which is
bound to A and Het is selected from the group consisting of fiased bicyclic hetaryl,
which has 1 or 2 nitrogen atoms as ring members and optionally a further heteroatom
25 selected from O, S and N as ring , where bicyclic hetaryl may be unsubstituted
or may carry 1, 2, 3 or 4 substituents RX, in particular 0, 1 or 2 substituents RX. In this
regard, RX is preferably selected from halogen, C1-C4-alkyl, C1-C2-fluoroalkyl, C1-C4-
alkoxy, C1-C2-fluoralkoxy, cycloalkyl, optionally substituted by 1, 2 or 3 methyl
groups, and ated C3-C6-cycloalkyl. In this regard, Rx is in particular selected from
30 fluorine, chlorine, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy,
fluoromethoxy, difluoromethoxy, trifluoromethoxy, cyclopropyl, ally substituted
by l, 2 or 3 methyl groups, and fluorinated cyclopropyl. Particular examples of Het of
32
this embodiment are 2-quinolinyl, 3—isoquinolinyl, 2-quinazolinyl, 2-quinoxalinyl, 1,5-
naphthyridin—2-yl, l ,8-naphthyridin—2—yl, benzothiazol— l -yl, benzoxazo l- l -yl,
benzimidazol—2-yl, l-methylbenzimidazol—2—yl, imidazo[ l ,2-a]pyridineyl, thieno[3 ,2-
b]pyridine-5 -yl, imidazo- [2, l -b]—thiazolyl and l,2,4-triazo lo [ l ,5 idineyl,
where the aforementioned radicals are unsubstituted or may carry 1, 2 or 3 radicals RX
as defined above, which are in particular selected from the group consisting of fluorine,
chlorine, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy,
fluoromethoxy, difluoromethoxy, trifluoromethoxy, cyclopropyl, optionally tuted
by 1, 2 or 3 methyl groups, and fluorinated cyclopropyl.
10 Particular preference is given to compounds, where Het is 2-quinolinyl, 1,8-
naphthyridin—2-yl, benzothiazol—l—yl, benzoxazol— l —yl, benzimidazol—Z-yl, l-
methylbenzimidazol—2-yl, imidazo[1,2—a]pyridine—2—yl, thieno[3,2-b]pyridineyl, and
in particular 2-quinolinyl or imidazo[1,2—a]pyridine—2-yl, where these radicals are
unsubstituted or may carry 1, 2 or 3 radicals Rx as defined above, which are in particular
15 selected from the group consisting of fluorine, chlorine, methyl, ethyl,
difluoromethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy,
romethoxy, cyclopropyl, optionally substituted by l, 2 or 3 methyl groups, and
ated ropyl.
In particular ments of the invention, the variable X1 is CH. In these
20 particular embodiments, X2 is preferably C-R7, where R7 is as defined above and in
particular H or YZ-Cycz. In these ular embodiments, X3 is preferably S or
C(R9)=C(R8).
In further particular embodiments of the invention, the variable X1 is N. In these
particular embodiments, X2 is preferably C-R7, where R7 is as defined above and in
25 particular H or z. In these particular embodiments, X3 is preferably S or
C(R9)=C(R8).
In particular embodiments ofthe invention, the variable X2 is C-R7. In these
particular embodiments R7 is as defined above and in particular H or Yz-Cycz. In these
embodiments, X1 is CH or preferably N. In these particular embodiments, X3 is
30 ably 5 or C(R9)=C(R8).
33
In r particular embodiments ofthe invention, the variable X2 is N. In this
embodiment, X1 is preferably CH. In these particular embodiments, X3 is preferably
C(R9)=C(R8).
In particular embodiments ofthe invention X3 is O, S, -X4=C(R8)-, Where C(RS) is
bound to the carbon atom which carries R2.
In particular ments of the invention X3 is S. In these embodiments, X1 is
CH or preferably N and X2 is preferably C-R7, where R7 is as defined above and in
particular H or Yz-Cycz.
In particular embodiments of the invention X3 is O. In these embodiments, X1 is N
10 or preferably CH, X2 is preferably C—R7, where R7 is as defined above and in particular
H or 2 and R1 is as defined above and in particular H or Yl-Cycl.
In further particular ments of the invention, the variable X3 is
C(R9)=C(R8). In these embodiments, X1 is CH or preferably N and X2 is preferably C-
R7, where R7 is as defined above and in particular H or YZ-Cycz.
15 In further particular embodiments of the invention, the variable X3 is N=C(R9). In
these embodiments, X1 is CH or ably N and X2 is preferably C-R7, where R7 is as
defined above and in particular H and R1 is as defined above and in ular Yl-Cycl.
In the embodiments ofthe invention, where X3 is N=C(R9), R9 is preferably H.
In further particular embodiments of the invention, the variable X3 is N=C(R8). In
20 these embodiments, X1 is preferably CH and X2 is preferably C-R7, where R7 is as
defined above and in particular H or YZ-Cycz.
In the embodiments ofthe invention, where X2 is C-R7, R7 is preferably H or Y2-
Cyc2.
In the embodiments ofthe invention, where X3 is C(R9)=C(R8), R9 is preferably H
25 or Y3-Cyc3, while R8 is preferably en.
In the embodiments ofthe invention, where X3 is N=C(R8), R8 is preferably H.
In the embodiments ofthe invention, where X2 is C-R7, and where X3 is
C(R8), R7 is preferably H or YZ-Cycz, R9 is preferably H or Y3-Cyc3, while R8 is
ably hydrogen, where preferably either R7 is Yz-Cyc2 or R9 is Y3-Cyc3 While one
30 of R7 and R9 is different from Yz—Cyc2 or Y3—Cyc3, respectively, or both R7 and R9 are
different from Yz-Cyc2 or Y3—Cyc3.
34
In this , those ls R], R7 and R9, which are different from Yl-Cycl,
YZ-Cycz, Y3-Cyc3 , respectively, are in particular selected, independently of each other,
from the group consisting of hydrogen, fluorine, C1-C4-alkyl, fluorinated C1-C2-alkyl,
C1-C4-alkoxy, fluorinated C1-C2-alkoxy, cyclopropyl, optionally substituted by l, 2 or 3
methyl groups, and fluorinated cyclopropyl. Those radicals R1, R7 and R9, which are
different from Yl-Cycl, YZ-Cycz, Y3-Cyc3, respectively, are most preferably hydrogen.
In particular preferred embodiments of the invention, R1 is Yl-Cycl. In these
embodiments X1 is CH or preferably N and X2 is preferably C-R7, where R7 is as
defined above and in particular H or YZ-Cycz. In these embodiments, particular
10 preference is given to compounds, where X3 is S or X3 is C(R9)=C(R8), where R9 is
ably H or Y3—Cyc3, while R8 is preferably en.
Y3-Cyc3, while R8 is preferably hydrogen.
In other particular preferred embodiments of the invention, R1 is different from
Yl-Cyc1 and in particular hydrogen. In these embodiments X1 is CH or ably N. In
15 these embodiments X2 is preferably C—R7, where R7 is as defined above and in particular
YZ-Cyc2 and X3 is S or X2 is preferably C-R7, where R7 is as defined above and in
particular H or Yz-Cyc2 and X3 is X3 is C(R9)=C(R8), where R9 is preferably H or
3, while R8 is preferably hydrogen.
In the moiety Yl-Cycl, Y1 is ably selected from O, NH and a chemical
20 bond. In particular Y1 is a chemical bond.
In the moiety Yz-Cycz, Y2 is preferably selected from O, NH and a chemical
bond. In particular Y2 is a chemical bond.
In the moiety Y3-Cyc3, Y3 is preferably selected from O, NH and a chemical
bond. In particular Y3 is a al bond.
25 Preferably, Cyc1 is selected from the groups of
(i) saturated 4-, 5-, 6-, 7- or 8—membered heteromonocycles or a saturated 7-, 8-,
9- or lO-membered heterobicycle, where the heteromonocycle and the heterobicycle
have one nitrogen or oxygen atom as ring member and may have one fiirther heteroatom
or atom group as ring member, which is selected from the group consisting of O,
30 S, S(=O), S(=O)2 and N, where the saturated monocycle and the saturated
heterobicycle are unsubstituted or carry 1, 2, 3, 4 or 5, in particular 1, 2, or 3 ls
RC1 or one radical Y'-RC2 and 0, l, 2, 3 or 4, in ular 0, l or 2 radicals RC1, where
35
RC1, RC2 and Y' are as defined herein and where Y', if t, is preferably a chemical
bond or O; and
(ii) phenyl or a 5- or 6 membered monocyclic hetaryl, which has one heteroatom,
selected from O, S and N as ring member and optionally one or two further heteroatoms
as ring members, and which is in particular selected from the group consisting of
pyridyl, pyrimidinyl, furyl, thienyl, pyrrolyl, olyl, pyrazolyl, oxazolyl and
thiazolyl, 9- or lO-membered bicyclic l which has one heteroatom, ed from
O, S and N as ring member and optionally one or two further heteroatoms as ring
members, and which is in particular selected from the group consisting of indolyl,
10 quinolinyl, isoquinolinyl, quinazolinyl, benzimidazolyl, benzotriazolyl, benzopyrazolyl
and benzo furyl, where phenyl and hetaryl are unsubstituted or carry 1, 2, 3, 4 or 5, in
particular 1, 2, or 3 radicals RC1 or one l Y'—RC2 and 0, l, 2, 3 or 4, in particular 0,
l or 2 radicals RC1, where RC1, RC2 and Y' are as defined herein and where Y', if present,
is preferably a chemical bond or O.
15 In this regard, RC1 is preferably selected from the group consisting of fluorine,
chlorine, CN, methyl, difluoromethyl, trifluoromethyl, methoxy and NH2, or, if Cyc1 is
, two radicals RC1 which are bound to adjacent carbon atoms, together with the
phenyl ring to which they are bound, form a bicyclic heterocyclic radical, which is
selected from 5- or 6-indolyl, 5- or 6-benzimidazolyl, 5- or 6-benzopyrazolyl, 5- or 6-
20 benzotriazolyl, 5- or 6-benzofuranyl, 2,3—dihydrobenzofuran—5-yl, 2,3-
obenzofuran—6-yl, l,3-dihydroindol—2-on—5-yl, l,3-dihydroindol—2-on—6-yl, 5- or
6-quinolinyl, 5- or 6-isoquinolinyl, 5— or 6-quinazolinyl, 2-aminoquinazolinyl, and 2-
aminoquinazolinyl.
In this regard, RCZ is ably selected from the group consisting of phenyl, C3-
25 Cs-cycloalkyl, optionally substituted by 1, 2, or 3 methyl groups, ated C3-C6-
lkyl, and 5- or 6-membered ted heteromonocyclic radicals, having 1, 2 or 3
heteroatoms as ring members, which are selected from O, S and N, where phenyl the
saturated heteromonocyclic radical is unsubstituted or carries 1, 2 or 3 radicals RC3,
which are preferably selected from fluorine, chlorine, CN, methyl, difluoromethyl,
30 trifluoromethyl, methoxy and NH2.
In particular, Cyc1 is selected from the groups of
36
(i) saturated 4-, 5-, 6- or ered heteromonocycles, where the
heteromonocycle has one nitrogen or oxygen atom as ring member and may have one
further heteroatom or heteroatom group as ring member, which is selected from the
group consisting of O, S, S(=O), S(=O)2 and N, where the saturated heteromonocycle
and the saturated heterobicycle are unsubstituted or carry 1, 2, or 3 radicals RC1, where
RCl is as defined herein; and
(ii) phenyl or a 5- or 6 membered l, selected from pyridyl, pyrimidinyl,
furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl and lyl, where phenyl and
the 5- or 6 membered hetaryl are unsubstituted or carry 1, 2, 3, 4 or 5, in particular 1, 2,
10 or 3 radicals RC1 or one radical Y‘-RC2 and 0, 1, 2, 3 or 4, in particular 0, 1 or 2 radicals
RC1, where RC1, RC2 and Y' are as defined herein and where Y', if present, is preferably
a chemical bond or O.
In particular embodiments of the invention, Cyc1 is selected from the group
consisting of saturated 4-, 5-, 6- or 7—membered heteromonocycles or a ted 7-, 8-,
15 9- or 10-membered heterobicycle, where the heteromonocycle and the heterobicycle
have one nitrogen or oxygen atom as ring member and may have one r heteroatom
or heteroatom group as ring , which is selected from the group consisting of O,
S, S(=O), S(=O)2 and N, where the saturated heteromonocycle and the ted
heterobicycle are unsubstituted or carry 1, 2, 3, 4 or 5, in particular 1, 2, or 3 radicals
20 RC1 or one radical Y'-RC2 and 0, 1, 2, 3 or 4, in particular 0, 1 or 2 radicals RC1, where
RC1, RC2 and Y' are as defined herein and where Y', if present, is preferably a chemical
bond or O.
In special embodiments ofthe invention, Cycl is selected from the group
consisting of saturated 4-, 5-, 6- or ered heteromonocycles, where the
25 heteromonocycle has one nitrogen or oxygen atom as ring member and may have one
further heteroatom or heteroatom group as ring member, which is selected from the
group consisting of O, S, S(=O), S(=O); and N, where the saturated heteromonocycle
and the saturated heterobicycle are tituted or carry 1, 2, or 3 radicals RC1, where
RC1 is as defined herein.
30 In this particular and special embodiment, Y1 is preferably selected from O, NH
and a chemical bond, with particular preference given to Y1 being a chemical bond.
37
In this particular and special embodiment Yl-Cyc1 is e.g. selected from the group
consisting of l-piperidinyl, 4,4-difluoropiperidinyl, 4-piperidinyl, l-methyl
piperidinyl, l-piperazinyl, 4-methylpiperazinyl, morpholin—4-yl, 2-oxaazaspiro-
ctyl, 2,5-diazabicyclo[2.2.I]heptan—2—yl, 3,8-diazabicyclo[3.2.l]octan—8-yl,
thiomorpholinyl, l-oxothiomorpholin-4—yl, N-(oxetan—3-yl)amino, l,l-
dioxothiomorpholinyl and oxetan—3—ylamino and especially from the group
consisting of l-piperidinyl, 4,4-difluoropiperidinyl, 4-piperidinyl, 1—methy1—4-
piperidinyl, 1-piperazinyl, 4-methylpiperazinyl, morpholinyl, thiomorpholinyl,
l-oxothiomorpholinyl, N-(oxetanyl)amino, 1, 1 -dioxothiomorpholinyl and
10 oxetan—3-ylamino.
In other ular embodiments of the invention, Cyc1 is phenyl or a 5- or 6
membered heteroaromatic radical, which has one heteroatom, selected from O, S and N
as ring member and optionally one or two further heteroatoms as ring s, and
which is in particular ed from the group consisting of l, pyrimidinyl, fiiryl,
15 thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl and thiazolyl, where phenyl and the 5-
or 6 membered heteroaromatic radical are tituted or either carry, independently
of each other, carry 1, 2, 3, 4 or 5, in particular 1, 2, or 3 radicals RC1 or one radical Y'-
RC2 and 0, l, 2, 3 or 4, in particular 0, l or 2 radicals RC1, where RC1, RC2 and Y' are as
defined herein and where Y', if present, is preferably a chemical bond or O.
20 In special embodiments ofthe ion, Cycl is selected from the group
consisting of phenyl or a 5- or 6 membered l, selected from pyridyl, pyrimidinyl,
furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, yl and thiazolyl, where phenyl and
the 5- or 6 ed hetaryl are unsubstituted or carry 1, 2, 3, 4 or 5, in particular 1, 2,
or 3 radicals RCl or one radical Y'—RC2 and 0, l, 2, 3 or 4, in particular 0, l or 2 radicals
25 RC1, where RC1, RC2 and Y' are as defined herein and where Y', if present, is preferably
a al bond or O.
In particular Cyc1 is selected from the group consisting of phenyl and 5- or 6-
membered hetaryl selected from the group consisting of pyridyl, pyrimidinyl, furyl,
thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl and lyl, where phenyl and
30 hetaryl are unsubstituted or carry 1, 2 or 3 radicals RC1 which are selected from the
group consisting of fluorine, chlorine, CN, methyl, difluoromethyl, trifluoromethyl,
methoxy and NH2, or, if Cyc1 is Pheny1, two radicals RC1 which are bound to adjacent
38
carbon atoms, together with the phenyl ring to which they are bound, form a ic
heterocyclic radical, which is selected from 5- or 6-indolyl, 5- or 6-benzimidazolyl, 5-
or 6-benzopyrazolyl, 5- or otriazolyl, 5- or 6-benzofuranyl, 2,3-
dihydrobenzofiaran—S-yl, 2,3-dihydrobenzofi1ran—6-yl, l,3-dihydroindolonyl, 1,3-
dihydroindol—2-on—6-yl, 5- or 6-quinolinyl, 5— or 6-isoquinolinyl, 5- or 6-quinazolinyl,
2-aminoquinazolinyl, and 2-aminoquinazolinyl. Amongst these, particular
preference is given to compounds, where Y1 is a chemical bond. Amongst these,
particular preference is given to compounds, where Cyc1 is selected from the group
consisting of phenyl and 5- or ered hetaryl selected from the group consisting of
10 pyridyl, pyrimidinyl, fiiryl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl and
thiazolyl, where phenyl and hetaryl are unsubstituted or carry 1, 2 or 3 radicals RC1
which are selected from the group ting of fluorine, chlorine, CN, methyl,
difluoromethyl, trifluoromethyl, methoxy and NH2.
Preferably, Cyc2 and Cyc3 are, independently from each other, selected from the
15 groups of
(i) ted 4-, 5-, 6-, 7- or 8-membered heteromonocycles or a saturated 7-, 8-,
9- or lO-membered heterobicycle, where the heteromonocycle and the heterobicycle
have one en or oxygen atom as ring member and may have one fiarther heteroatom
or heteroatom group as ring member, which is ed from the group consisting of O,
20 S, S(=O), S(=O)2 and N, where the saturated heteromonocycle and the saturated
heterobicycle are unsubstituted or carry 1, 2, 3, 4 or 5, in particular 1, 2, or 3 radicals
RC1 or one radical Y'-RC2 and 0, l, 2, 3 or 4, in ular 0, l or 2 radicals RC1, where
RC1, RC2 and Y' are as defined herein and where Y', if present, is preferably a chemical
bond or O; and
25 (ii) phenyl or a 5- or 6 membered monocyclic hetaryl, which has one atom,
selected from O, S and N as ring member and optionally one or two r heteroatoms
as ring members, and which is in particular ed from the group consisting of
pyridyl, pyrimidinyl, fiiryl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl and
thiazolyl, 9- or lO-membered bicyclic hetaryl which has one heteroatom, selected from
30 O, S and N as ring member and optionally one or two further heteroatoms as ring
members, and which is in particular ed from the group consisting of indolyl,
quinolinyl, isoquinolinyl, quinazolinyl, benzimidazolyl, benzotriazolyl, benzopyrazolyl
39
and benzo fiaryl, where phenyl and hetaryl are unsubstituted or carry 1, 2, 3, 4 or 5, in
ular 1, 2, or 3 radicals RC1 or one radical Y'—RC2 and 0, 1, 2, 3 or 4, in particular 0,
1 or 2 radicals RC1, where RC1, RC2 and Y' are as defined herein and where Y', if present,
is ably a chemical bond or O.
In this regard, RCl is preferably selected from the group consisting of fluorine,
chlorine, CN, methyl, difluoromethyl, trifluoromethyl, y and NH2, or, if Cyc2 or
Cyc3 are phenyl, two radicals RC1 which are bound to adjacent carbon atoms, together
with the phenyl ring to which they are bound, form a bicyclic heterocyclic radical,
which is selected from 5- or 6-indolyl, 5- or 6-benzimidazolyl, 5- or 6-benzopyrazoly1,
10 5- or 6—benzotriazolyl, 5- or 6-benzofuranyl, 2,3-dihydrobenzofuran-S-yl, 2,3-
dihydrobenzofuran—6—yl, 1,3—dihydroindol—2—on—5—yl, 1,3-dihydroindol—2-on—6-yl, 5- or
olinyl, 5- or 6-isoquinolinyl, 5— or 6—quinazolinyl, 2-aminoquinazolinyl, and 2-
aminoquinazolinyl.
In this regard, RC2 is preferably ed from the group consisting of , C3-
15 C6-cycloalkyl, optionally substituted by 1, 2, or 3 methyl groups, fluorinated C3-C6-
lkyl, and 5- or 6-membered saturated heteromonocyclic radicals, having 1, 2 or 3
heteroatoms as ring members, which are selected from O, S and N, where phenyl the
saturated heteromonocyclic radical is unsubstituted or carries 1, 2 or 3 radicals RC3,
which are ably selected from e, chlorine, CN, methyl, difluoromethyl,
20 trifluoromethyl, methoxy and NH2.
In particular, Cyc2 and Cyc3 are, independently from each other, selected from the
groups of
(i) saturated 4-, 5-, 6- or 7-membered heteromonocycles, where the
heteromonocycle has one nitrogen or oxygen atom as ring member and may have one
25 further heteroatom or heteroatom group as ring member, which is selected from the
group consisting of O, S, S(=O), S(=O); and N, where the saturated heteromonocycle
and the saturated bicycle are unsubstituted or carry 1, 2, or 3 radicals RC1, where
RC1 is as defined herein; and
(ii) phenyl or a 5— or 6 membered hetaryl, selected from pyridyl, pyrimidinyl,
30 furyl, l, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl and thiazolyl, where phenyl and
the 5- or 6 membered hetaryl are unsubstituted or carry 1, 2, 3, 4 or 5, in particular 1, 2,
or 3 radicals RC1 or one radical Y‘—RC2 and 0, 1, 2, 3 or 4, in particular 0, 1 or 2 radicals
40
RC1, where RC1, RC2 and Y' are as defined herein and where Y', if present, is preferably
a chemical bond or O.
In ular embodiments ofthe invention, Cyc2 and Cyc3 are, independently
from each other, selected from the group consisting of ted 4-, 5-, 6- or 7-
membered heteromonocycles or a saturated 7-, 8-, 9- or lO-membered heterobicycle,
where the heteromonocycle and the heterobicycle have one en or oxygen atom as
ring member and may have one further heteroatom or heteroatom group as ring
member, which is selected from the group consisting of O, S, S(=O), S(=O)2 and N,
where the saturated heteromonocycle and the saturated heterobicycle are unsubstituted
10 or carry 1, 2, 3, 4 or 5, in particular 1, 2, or 3 ls RC1 or one radical Y'-RC2 and 0, 1,
2, 3 or 4, in particular 0, l or 2 radicals RC1, where RC1, RC2 and Y’ are as defined herein
and where Y', if present, is preferably a chemical bond or O.
In special embodiments ofthe invention, Cyc2 and Cyc3 are, independently from
each other, selected from the group consisting of saturated 4-, 5-, 6- or 7-membered
15 heteromonocycles, where the heteromonocycle has one nitrogen or oxygen atom as ring
member and may have one further heteroatom or heteroatom group as ring member,
which is selected from the group consisting of O, S, S(=O), S(=O)2 and N, where the
saturated heteromonocycle and the saturated bicycle are unsubstituted or carry 1,
2, or 3 radicals RC1, where RC1 is as defined herein.
20 In this particular and special ments Y2 and Y3 are, independently from
each other preferably selected from O, NH and a chemical bond, with particular
preference given to Y2 and Y3 being a chemical bond.
In this particular and special embodiments Cyc2 and Cyc3 are, independently from
each other, e. g. selected from the group consisting of l-piperidinyl, 4,4-difluoro-l-
25 dinyl, 4-piperidinyl, 1 -methyl—4—piperidinyl, 1 -piperazinyl, 4-methy1— 1 -
piperazinyl, linyl, 2-oxaazaspiro-[3,4]octy1, 2,5—
diazabicyclo[2.2.1]heptanyl, 3,8-diazabicyclo[3.2.1]octanyl, thiomorpholinyl,
1-oxothiomorpholinyl, N-(oxetanyl)amino, 1,1-dioxothiomorpholinyl and
—3—ylamino and especially from the group consisting of 1-piperidinyl, 4,4-
30 difluoro- l -piperidinyl, 4—piperidinyl, 1 l—4—piperidinyl, l -piperazinyl, 4-methyl- l -
piperazinyl, morpholin-4—yl, thiomorpholin—4—yl, 1—oxothiomorpholin—4-yl, N-(oxetan—
3-yl)amino, l,l-dioxothiomorpholin—4—yl and oxetan—3-ylamino.
41
In other particular ments of the invention, YZ-Cyc2 and Y3-Cyc3 are,
independently of each other, phenyl or a 5— or 6 membered heteroaromatic l,
which has one heteroatom, selected from O, S and N as ring member and optionally one
or two fiirther heteroatoms as ring members, and which is in particular selected from the
group consisting of pyridyl, pyrimidinyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl,
oxazolyl and thiazolyl, where phenyl and the 5— or 6 ed heteroaromatic radical
are unsubstituted or either carry, independently of each other, carry 1, 2, 3, 4 or 5, in
particular 1, 2, or 3 ls RC1 or one radical Y'-RC2 and 0, 1, 2, 3 or 4, in particular 0,
1 or 2 radicals RC1, where RC1, RC2 and Y' are as defined herein and where Y', if present,
10 is ably a chemical bond or O.
In special embodiments of the invention, YZ—Cyc2 and Y3-Cyc3 are, independently
from each other, selected from the group consisting of phenyl or a 5- or 6 membered
l, selected from pyridyl, pyrimidinyl, fiiryl, thienyl, pyrrolyl, imidazolyl,
pyrazolyl, oxazolyl and thiazolyl, where phenyl and the 5- or 6 membered hetaryl are
15 unsubstituted or carry 1, 2, 3, 4 or 5, in particular 1, 2, or 3 radicals RC1 or one radical
Y'-RC2 and 0, l, 2, 3 or 4, in particular 0, 1 or 2 radicals RC1, where RC1, RC2 and Y' are
as defined herein and where Y', if present, is preferably a chemical bond or O.
In particular YZ-Cyc2 and 3 are, independently from each other, selected
from the group consisting of phenyl and 5- or 6-membered hetaryl selected from the
20 group consisting of pyridyl, pyrimidinyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl,
oxazolyl and thiazolyl, where phenyl and hetaryl are unsubstituted or carry 1, 2 or 3
radicals RC1 which are selected from the group consisting of fluorine, chlorine, CN,
methyl, difluoromethyl, romethyl, methoxy and NH2, or, if one or both of Y2-
Cyc2 and 3 are phenyl, two radicals RCl which are bound to adjacent carbon
25 atoms, er with the phenyl ring to which they are bound, form a bicyclic
heterocyclic radical, which is selected from 5- or lyl, 5- or 6—benzimidazoly1, 5-
or 6-benzopyrazolyl, 5- or 6-benzotriazolyl, 5- or 6-benzofurany1, 2,3-
dihydrobenzofuran—S-yl, 2,3-dihydrobenzofuranyl, 1,3-dihydroindolony1, 1,3-
dihydroindol—2—on—6-yl, 5— or 6-quinolinyl, 5- or 6-isoquinoliny1, 5- or 6-quinazolinyl,
30 2-aminoquinazolinyl, and 2—amino—6—quinazolinyl. Amongst these, particular
preference is given to compounds, where Yz—Cyc2 and Y3-Cyc3 are, ndently from
each other, selected from the group consisting of phenyl and 5- or 6-membered hetaryl
42
selected from the group consisting of pyridyl, dinyl, furyl, thienyl, pyrrolyl,
olyl, pyrazolyl, oxazolyl and thiazolyl, where phenyl and hetaryl are
unsubstituted or carry 1, 2 or 3 radicals RC] which are selected from the group
consisting of fluorine, ne, CN, methyl, omethyl, trifluoromethyl, methoxy
and NH2.
With regard to Cycl, Cyc2 and Cyc3, and in particular with regard to the
aforementioned ular or special embodiments of Cycl, Cyc2 and Cyc3 RC1 is
,
preferably selected from the group consisting of fluorine, chlorine, CN, ,
difluoromethyl, trifluoromethyl, methoxy and NH2.
10 With regard to Cycl, Cyc2 and Cyc3, and in particular with regard to the
aforementioned particular or special embodiments of Cycl, Cyc2 and Cyc3, RC2 is
preferably selected from the group consisting ofphenyl, C3-C6-cycloalkyl, optionally
substituted by l, 2, or 3 methyl groups, fluorinated C3-C6-cycloalkyl, and 5- or 6-
ed saturated heteromonocyclic radicals, having 1, 2 or 3 heteroatoms as ring
15 members, which are selected from O, S and N, where phenyl the saturated
heteromonocyclic radical is unsubstituted or carries 1, 2 or 3 radicals RC3 , which are
preferably selected from fluorine, chlorine, CN, methyl, difluoromethyl,
trifluoromethyl, methoxy and NH2.
Irrespectively from the entioned embodiments, R2 is preferably selected
20 from the group consisting of hydrogen, fluorine, C1-C4-alkyl, C1-C2-fluoroalkyl, C1-C4-
alkoxy, fluoroalkoxy, cyclopropyl, ally substituted by l, 2 or 3 methyl
groups, and fluorinated cyclopropyl.
Irrespectively from the aforementioned embodiments, R2 is in particular
hydrogen.
25 Irrespectively from the aforementioned embodiments, Q is in particular oxygen.
Particular embodiments of the invention relate to the compounds of the following
formulae 1-1 and 1-2:
0 1
R
Het—A\
I}! l \ R2 (M)
N\
8
R7
43
O R1
Het—A\N
l \ R2 (I-2)
\
8
R7
where Het, A, R1, R2 and R7 are as defined here and in the claims.
Other particular embodiments of the invention relate to the compounds of the
following ae 1-3 and 1-4:
0 R
Het—A\ R2
I? 0-3)
N \
R8
R7 R9
o R1
Het—A\ R2
N (I-4)
\ R8
R7 R9
where Het, A, R1, R2, R7, R8 and R9 are as defined here and in the claims.
Further particular embodiments of the invention relate to the compounds of the
following formulae 1-5 and 1-6:
0 R
Het—A\ R2
“I1 \
| 0-5)
N \ /
N R8
44
(l-6)
where Het, A, R1, R2, R7 and R8 are as defined here and in the claims.
ular embodiments of the invention relate to the compounds of the following
formulae 1-7 and 1-8:
0 R1
Het—A\
I}! l \ R2 (I-7)
7
R
0 R1
N
l \ R2 (I-8)
0
R7
where Het, A, R1, R2 and R7 are as defined here and in the claims.
Further particular embodiments of the invention relate to the compounds of the
10 following formulae 1-9 and 1-10:
0 R
Het—A\ R2
“I1 \
| 0-9)
N \ / N
45
o R
Het—A\ R2
N \
l (I-10)
\ / N
R7 R9
where Het, A, R1, R2, R7 and R9 are as defined here and in the claims.
In a particular embodiment of the invention, A in formula I is Al, A2, A3 or A4.
In a particular embodiment of the invention, A in formula I, and likewise in
formulae 1—1, 1—2, 1—3, 1-4, 1-5, 1-6, 1-7, 1-8, 1-9 and 1-10 is a bivalent radical A1.
ence is given to compounds of the formula I, and likewise to compounds of
formulae 1-1, 1—2, 1—3, 1—4, 1—5, 1-6, 1—7, 1-8, 1—9 and 1—10, where R3, R4 are selected from
hydrogen and fluorine and in particular to those compounds, where both R3 and R4 are
10 hydrogen. Preference is given to compounds of the a I, where R5 and R6 are,
independently of each other, selected from the group consisting of hydrogen, fluorine
and methyl, and in particular to those compounds, where both R5 and R6 are en.
In another particular embodiment of the invention, A in a I, and likewise in
formulae 1-1, 1-2, 1-3, 1-4, 1-5, 1-6, 1-7, 1-8, 1-9 and 1-10, is a bivalent radical A2.
15 In another particular embodiment of the ion, A in formula I, and likewise in
formulae 1-1, 1-2, 1-3, 1-4, 1-5, 1-6, 1—7, 1—8, 1-9 and 1-10, is a bivalent radical A3.
Preference is given to compounds ofthe formula I, and likewise to compounds of
formulae 1-1, 1—2, 1—3, 1—4, 1—5, 1-6, 1—7, 1-8, 1—9 and 1—10, where R4, R5 are selected from
hydrogen and fluorine. In particular, both R4 and R5 are hydrogen.
20 In another particular embodiment of the invention, A in formula I, and likewise in
formulae 1-1, 1-2, 1-3, 1-4, 1-5, 1-6, 1-7, 1—8, 1-9 and 1-10, is a bivalent radical A4.
Preference is given to nds of the formula I, and se to compounds of
formulae 1-1, 1-2, 1-3, 1-4, 1-5, 1-6, 1-7, 1-8, 1-9 and 1-10, where R4, R5 are selected from
hydrogen and e and in particular to those compounds, where both R4 and R5 are
25 hydrogen. In the bivalent radical A4 the moiety A' is ably CR3bR3c, where R3b and
R30 are independently of each other selected from the group consisting of hydrogen,
fluorine and methyl or together form CHZCHZ and where R3b and R3b are independently
of each other in ular selected from the group consisting of hydrogen and fluorine.
46
Particular preference is given to compounds of the formula I, and likewise to
nds of formulae 1-1, 1-2, 1—3, 1—4, 1-5, 1-6, 1-7, 1-8, 1-9 and 1-10, where A is a
bivalent radical A4, where the moiety A' is CR3bR3C, where R3b and R30 are as defined
herein and where R3b and R3C are in particular, independently of each other, selected
from the group ting of hydrogen, fluorine and methyl or together form CH2CH2
and ally where both R3b and R30 are hydrogen or fluorine.
In another particular ment of the ion, A in formula I and likewise in
formulae 1-1, 1-2, 1-3, 1-4, 1-5, 1-6, 1-7, 1-8, 1-9 and 1-10 is a bivalent radical A4, where A'
is O.
10 In another particular embodiment of the invention, A in formula I, and likewise in
formulae 1-1, 1—2, 1—3, 1—4, 1—5, 1—6, 1—7, 1—8, 1—9 and 1—10, is a bivalent radical A4, where
A' is NR3a with R3a being as defined above in particular hydrogen or C1-C4-alkyl.
In r particular embodiment, A in formula I, and likewise in formulae 1-1, I-
2, 1-3, 1-4, 1-5, 1-6, 1-7, 1-8, 1-9 and 1—10, is a bivalent radical A4, where A' is linear C2-
15 Cg-alkanediyl, where one of the CHz—moieties of C2-C3-alkandiyl may be replaced by
oxygen or NR3a, and where l, 2, 3, or 4 of the hydrogen atoms of C2-C3-alkandiyl may
be replaced by a l R3d. R3d is eably selected from halogen and C1-C4-alkyl.
In another particular embodiment of the invention, A in formula I, and likewise in
formulae 1-1, 1-2, 1-3, 1-4, 1-5, 1-6, 1-7, 1-8, 1-9 and 1-10 is a bivalent radical A5.
20 Preference is given to compounds ofthe formula I, and likewise to compounds of
ae 1-1, 1-2, 1-3, 1-4, 1-5, 1-6, 1—7, 1-8, 1-9 and 1-10, where R4, R5 are selected from
hydrogen and methyl and in particular to those compounds, where both R4 and R5 are
hydrogen. Preference is given to compounds of the formula I, where R36 and R3f are,
independently of each other, selected from the group consisting of hydrogen and
25 methyl, and in particular to those compounds, where both R36 and R3f are en.
A particular preferred embodiment of the invention relates to the compounds of
formula I-1.A, described below, to the N-oxides, the prodrugs, the hydrates and the
tautomers thereof and to the pharmaceutically suitable salts thereof:
0 R1
Hetml
N
l \ R2 (I1.A)_
R7
47
where Het, R1, R2, R5, R6 and R7 are as defined here and in the claims.
Another particular red embodiment of the ion relates to the
compounds of formula I-2.A, described below, to the N—oxides, the prodrugs, the
hydrates and the tautomers thereof and to the pharmaceutically suitable salts thereof:
0 R1
HetDC
N
I \ R2 (I 2.A)_
R R
\ 8
R7
where Het, R1, R2, R5, R6 and R7 are as defined here and in the claims.
Another particular preferred embodiment of the invention relates to the
compounds of formula 1—1 .B, described below, to the N-oxides, the prodrugs, the
hydrates and the tautomers thereof and to the pharmaceutically suitable salts thereof:
10
R30 R3b
0 R1
Het N
R5 I l \ R2 _
N\
8
R7
where Het, R1, R2, R3b, R“, R5 and R7 are as defined here and in the claims and
where R5 is in particular hydrogen.
Another particular preferred embodiment of the invention relates to the
15 compounds of formula I-2.B, described below, to the es, the prodrugs, the
es and the tautomers thereof and to the pharmaceutically suitable salts thereof:
R30 3b
R
O 1
R
Het N
R5 | \ R2 (I-2.B)
\
8
R7
where Het, R1, R2, R3b, R3c, R5 and R7 are as defined here and in the claims and
where R5 is in ular hydrogen. In formulae I—l.B and I-2.B, the variables R3b and
48
R30 are independently of each other in particular selected from the group ting of
hydrogen, fluorine and methyl or together form CHZCHZ. Particular preference is given
to compounds of the ae 1-1 .B and I-2.B, where both R3b and R30 are hydrogen or
fluorine.
5 Another particular preferred embodiment of the invention relates to the
nds of formula I-l .C, described below, to the N-oxides, the prodrugs, the
hydrates and the tautomers thereof and to the pharmaceutically suitable salts thereof:
RE>1 0 R1
_
Het N _
I l \ R2 (I1.C)
N\
8
R7
where Het, R1, R2, R5 and R7 are as defined here and in the claims and where R5 is
10 in particular en.
Another particular preferred embodiment of the invention relates to the
nds of formula I-2.C, described below, to the N—oxides, the prodrugs, the
hydrates and the tautomers thereof and to the pharmaceutically suitable salts thereof:
Fabio 1
R
Het—N
I \ R2 (I-2.C)
\
8
R7
15 where Het, R1, R2, R5 and R7 are as defined here and in the claims and where R5 is
in particular hydrogen.
A particular preferred embodiment of the invention relates to the compounds of
formula I-l .D, described below, to the N—oxides, the prodrugs, the hydrates and the
tautomers thereof and to the pharmaceutically suitable salts thereof:
0 R1
!
l \ R2 (I-1.D)
N \
R3 R3f 8
R7
20
49
where Het, R1, R2, R36, R3f and R7 are as defined here and in the claims and where
R3‘3 and R3f are in particular both hydrogen.
Another particular preferred embodiment of the invention s to the
compounds of formula I-2.D, described below, to the N-oxides, the prodrugs, the
5 hydrates and the tautomers thereof and to the pharmaceutically suitable salts thereof:
0 R1
Het
N
| |\ R2 (I-2.D)
\
R3 R3f S
R7
where Het, R1, R2, R36, R3f and R7 are as defined here and in the claims and where
R36: and R3f are in particular both hydrogen.
Particular embodiments of the invention relate to compounds of the formulae 1-1,
10 1-2, I-l.A, I-2.A, 1-1 .B, I-2.B, I-l.C, I-2.C, I-1.D, and I-2.D described above, to the N-
oxides, the prodrugs, the hydrates and the tautomers thereof and to the ceutically
suitable salts thereof, where R1 is a l Yl—Cyc1 and R7 is as defined above and in
particular selected from the group ting of hydrogen, fluorine, C1-C4-alkyl, C1-C2-
fluoroalkyl, C1-C4-alkoxy, C1-C2-fluoroalkoxy, ropyl, optionally substituted by l,
15 2 or 3 methyl groups, fluorinated cyclopropyl and z, especially from the group
consisting of hydrogen and Yz-Cycz.
Further particular embodiments of the invention relate to nds of the
formulae 1- 1, 1-2, 1-1 .A, I-2.A, 1-1 .B, I-2.B, I-1.C, I-2.C, I-l .D, and I-2.D, described
above, to the N—oxides, the gs, the hydrates and the tautomers thereof and to the
20 pharmaceutically suitable salts thereof, where R1 is selected from the group consisting
of hydrogen, fluorine, C1-C4-a1kyl, C1-C2-fluoroalkyl, C1—C4—alkoxy, C1-C2-
fluoroalkoxy, cyclopropyl, optionally substituted by l, 2 or 3 methyl groups and
fluorinated cyclopropyl and R7 is a moiety YZ-Cycz. In these embodiments R1 is in
particular hydrogen.
25 A further particular preferred embodiment of the ion relates to the
compounds of formula I—3.A, described below, to the N-oxides, the prodrugs, the
es and the tautomers thereof and to the pharmaceutically suitable salts thereof:
50
o R
Het R2
mlN (I 3.A)_
R R N\
R8
R7 R9
where Het, R1, R2, R5, R6, R7, R8 and R9 are as defined here and in the claims.
Another particular preferred embodiment of the invention relates to the
compounds of formula I-4.A, described below, to the N-oxides, the prodrugs, the
hydrates and the tautomers thereof and to the pharmaceutically suitable salts f:
1
o R
Het R2
xN (I 4.A)_
R R \ R8
R7 R9
where Het, R1, R2, R5, R6, R7, R8 and R9 are as defined here and in the claims.
Another particular preferred embodiment of the invention s to the
compounds of formula I-3.B, described below, to the N—oxides, the prodrugs, the
10 hydrates and the tautomers thereof and to the pharmaceutically suitable salts thereof:
3C
R 3b
R
1
O R
R2
Het
N
R5 (I _3. B)
|
N \
R8
R7 R9
where Het, R1, R2, R3b, R3°, R7, R8 and R9 are as defined here and in the claims
and where R5 is in particular hydrogen.
15 Another particular preferred embodiment of the invention relates to the
nds of formula I—4.B, described below, to the es, the prodrugs, the
hydrates and the tautomers thereof and to the pharmaceutically suitable salts thereof:
51
R R3b
1
o R
R2
Het
N
R5 (I-4.B)
\ R8
R7 R9
where Het, R1, R2, R3b, R3°, R7, R8 and R9 are as defined here and in the claims
and where R5 is in particular hydrogen.
In formulae I-3.B and 1-43, the variables R3b and R“ are independently of each
other in particular selected from the group consisting of hydrogen, fluorine and methyl
or together form CHZCHZ. Particular preference is given to compounds ofthe formulae
I-3.B and I-4.B, where both R3b and R30 are hydrogen or fluorine.
Another particular preferred embodiment ofthe invention relates to the
compounds of formula I-3.C, described below, to the N-oxides, the prodrugs, the
10 hydrates and the tautomers thereof and to the ceutically suitable salts thereof:
5 O R
N )
where Het, R1, R2, R5, R7, R8 and R9 are as defined here and in the claims and
where R5 is in particular hydrogen.
r particular preferred embodiment of the invention relates to the
15 nds of formula I-4.C, described below, to the es, the prodrugs, the
hydrates and the tautomers thereof and to the pharmaceutically suitable salts thereof:
R5 O R
:3: R2
Het
N (I-4.C)
\ R8
R7 R9
where Het, R1, R2, R5, R7, R8 and R9 are as defined here and in the claims and
where R5 is in particular hydrogen.
52
A further particular preferred embodiment of the invention relates to the
nds of formula I-3.D, described below, to the N—oxides, the prodrugs, the
es and the tautomers thereof and to the pharmaceutically suitable salts thereof:
0 R1
Het R2
f:11N (I-3.D)
\ 8
R3 R3f R
R7 R9
5 where Het, R1, R2, R33, R”, R7, R8 and R9 are as defined here and in the claims
and where R36 and R3f are in particular both hydrogen.
Another particular preferred embodiment of the invention relates to the
compounds of formula I—4.D, described below, to the N—oxides, the prodrugs, the
es and the tautomers thereof and to the ceutically suitable salts thereof:
0 R1
Het R2
R393 \Nl (I-4.D)
R8
R7 R9
10
where Het, R1, R2, R36, R“, R7, R8 and R9 are as d here and in the claims
and where R3‘3 and R3f are in particular both hydrogen.
Particular embodiments ofthe invention relate to compounds of the formulae 1-3,
1-4, I-3.A, I-4.A, I-3.B, I-4.B, I-3.C, I-3.D, I-4.C, and I-4.D, described above, to the N-
15 oxides, the prodrugs, the hydrates and the tautomers thereof and to the pharmaceutically
suitable salts thereof, where R1 is a radical Yl—Cycl and R7, R8 and R9 are as defined
above and where R7 is in particular selected from the group consisting of hydrogen,
fluorine, C1-C4-a1kyl, C1-C2-fluoroalkyl, C1-C4-alkoxy, C1-C2—fluoroalkoxy,
cyclopropyl, optionally tuted by 1, 2 or 3 methyl groups, fluorinated cyclopropyl
20 and Y2-Cyc2, especially from the group consisting of en and Yz-Cyc2 and where
R9 is in particular selected from the group consisting of hydrogen, e, C1-C4-alkyl,
C1-C2-fluoroalkyl, C1—C4—alkoxy, C1-C2-fluoroalkoxy, cyclopropyl, optionally
substituted by l, 2 or 3 methyl groups, fluorinated cyclopropyl and Y3-Cyc3, especially
from the group consisting of hydrogen and Y3—Cyc3, provided that none or only one of
53
R7 and R9 is a moiety Y3-Cyc3, or Y3—Cyc3, tively. R7 and R9 are in ular
hydrogen.
Further particular embodiments of the invention relate to compounds of the
formulae 1-3, 1-4, I-3.A, I-4.A, I-3.B, I-4.B, I-3.C, I-4.C, I-3.D and I-4.D, bed
above, to the N—oxides, the prodrugs, the hydrates and the tautomers thereof and to the
ceutically suitable salts thereof, where R1 is selected from the group consisting
of hydrogen, fluorine, C1-C4-alkyl, C1—C2-fluoroalkyl, alkoxy, C1-C2-
fluoroalkoxy, cyclopropyl, optionally substituted by l, 2 or 3 methyl groups and
fluorinated cyclopropyl and where R7 and R9 are selected, independently of each other,
10 from the group consisting of hydrogen, fluorine, C1-C4-alkyl, C1-C2-fluoroalkyl, C1-C4-
alkoxy, C1-C2-fluoroalkoxy, cyclopropyl, ally substituted by l, 2 or 3 methyl
groups, fluorinated cyclopropyl and Yz—Cyc2 or Y3—Cyc3 , respectively, provided that
either R7 is Yz-Cyc2 or R9 is Y3—Cyc3. In these embodiments R1 is in particular
hydrogen. In these embodiments the radical R7 or R9, which is different from Yz-Cyc2
15 or Y3-Cyc3 is in particular hydrogen.
, respectively,
A further particular preferred embodiment of the invention relates to the
compounds of formula 1-5.A, described below, to the N—oxides, the prodrugs, the
hydrates and the ers thereof and to the pharmaceutically suitable salts thereof:
0 R
Het R2
9QN \
| " 5""_
\ /
N R8
R7
20
where Het, R1, R2, R5, R6, R7 and R8 are as defined here and in the claims.
r particular preferred embodiment of the invention relates to the
compounds of a I-6.A, described below, to the N-oxides, the prodrugs, the
hydrates and the tautomers thereof and to the ceutically suitable salts thereof:
54
o R
Het R2
ECN \
l (I 6.A)_
R R \ N/ R8
R7
where Het, R1, R2, R5, R6, R7 and R8 are as defined here and in the .
A further particular preferred ment of the invention relates to the
compounds of formula I-5.B, described below, to the N-oxides, the prodrugs, the
5 hydrates and the tautomers thereof and to the pharmaceutically le salts thereof:
3b
30
R R
1
o R
R2
Het \
R5 I}! (I-5.B)
N \ /
N R8
R7
where Het, R1, R2, R3b, R30, R5, R7 and R8 are as defined here and in the claims
and where R5 is in ular hydrogen.
A further particular preferred embodiment of the invention relates to the
10 compounds of formula I-6.B, described below, to the N—oxides, the prodrugs, the
hydrates and the tautomers thereof and to the pharmaceutically suitable salts thereof:
(I—6.B)
where Het, R1, R2, R33, R3b, R5, R7 and R8 are as defined here and in the claims
15 and where R5 is in particular hydrogen. In formulae I-S.B and I-6.B, the variables R3b
and R3C are independently of each other in particular selected from the group consisting
of en, fluorine and methyl or together form CHZCHZ. Particular preference is
given to compounds ofthe formulae I-5.B and I-6.B, where both R3b and R30 are
hydrogen or fluorine.
55
A further particular preferred embodiment of the invention relates to the
compounds of formula 1-5.C, described below, to the es, the prodrugs, the
hydrates and the tautomers thereof and to the pharmaceutically suitable salts thereof:
R5 O R
:5: R2
Het I?! \
l (I-5.C)
N \ N/ R8
R7
5
where Het, R1, R2, R5, R7 and R8 are as defined here and in the claims and where
R5 is in particular hydrogen.
A further particular preferred embodiment of the invention relates to the
nds of formula I-6.C, described below, to the N—oxides, the prodrugs, the
10 hydrates and the tautomers thereof and to the pharmaceutically suitable salts thereof:
(I-6.C)
where Het, R1, R2, R5, R7 and R8 are as defined here and in the claims and where
R5 is in particular hydrogen.
15 A further particular preferred ment of the invention relates to the
compounds of formula I-5.D, described below, to the N—oxides, the prodrugs, the
es and the tautomers thereof and to the pharmaceutically suitable salts f:
1
o R
Het R2
fl |\ ("5-0)
N /
R3e \
Raf N R8
R7
where Het, R1, R2, R36, R“, R7, R8 and R9 are as d here and in the claims
20 and in particular, R36: and R3f are both hydrogen.
56
r particular red embodiment ofthe invention relates to the
compounds of formula I-6.D, described below, to the N—oxides, the prodrugs, the
hydrates and the tautomers f and to the pharmaceutically suitable salts f:
(I-6.D)
where Het, R1, R2, R33, R”, R7, R8 and R9 are as defined here and in the claims
and in particular, R36 and R3f are both hydrogen.
Particular embodiments of the invention relate to compounds of the formulae 1-5,
1-6, I-5.A, I-6.A, I-5.B, I—6.B, 1—5.C, I—6.C, I—5.D and I-6.D, described above, to the N-
oxides, the prodrugs, the hydrates and the tautomers thereof and to the pharmaceutically
10 suitable salts thereof, where R1 is a radical Yl—Cyc1 and R7 is as defined above and in
particular selected from the group consisting of hydrogen, e, C1-C4-alkyl, C1-C2-
fluoroalkyl, C1-C4-alkoxy, C1-C2-fluoroalkoxy, cyclopropyl, optionally substituted by l,
2 or 3 methyl groups, fluorinated cyclopropyl and YZ-Cycz, especially from the group
consisting of hydrogen and Yz-Cycz.
15 Further particular embodiments of the invention relate to compounds of the
formulae 1-5, 1-6, 1-5.A, I-6.A, 1-5.B, I—6.B, I-5.C, I-6.C, I-5.D, and I-6.D, bed
above, to the N—oxides, the prodrugs, the hydrates and the tautomers thereof and to the
pharmaceutically le salts thereof, where R1 is ed from the group consisting
of hydrogen, fluorine, alkyl, C1-C2-fluoroalkyl, C1-C4-alkoxy, C1-C2-
20 fluoroalkoxy, cyclopropyl, optionally substituted by l, 2 or 3 methyl groups and
fluorinated cyclopropyl and R7 is a moiety Yz-Cycz. In these embodiments R1 is in
particular hydrogen.
A particular red embodiment of the invention relates to the compounds of
formula I-7.A, described below, to the N-oxides, the prodrugs, the hydrates and the
25 tautomers thereof and to the pharmaceutically suitable salts thereof:
57
o R1
HetXI
N
I \ R2 (I 7.A)_
R7
where Het, R1, R2, R5, R6 and R7 are as defined here and in the claims.
Another particular red embodiment of the invention relates to the
compounds of formula I-8.A, described below, to the N-oxides, the prodrugs, the
hydrates and the tautomers thereof and to the pharmaceutically suitable salts thereof:
0 R1
Hetx
N
I \ R2 (I 8.A)_
R R \ 0
R7
where Het, R1, R2, R5, R6 and R7 are as defined here and in the claims.
Another particular preferred embodiment ofthe invention relates to the
10 compounds of a I-7.B, described below, to the N—oxides, the prodrugs, the
hydrates and the tautomers thereof and to the pharmaceutically le salts f:
R30 R3b
0 R1
Het N
R5 (I 7.3)_
I I \ R2
N\
0
R7
where Het, R1, R2, R3b, R3°, R5 and R7 are as defined here and in the claims and
where R5 is in particular hydrogen.
15 Another particular preferred embodiment of the invention relates to the
nds of formula I-8.B, described below, to the N-oxides, the prodrugs, the
hydrates and the tautomers thereof and to the pharmaceutically suitable salts thereof:
58
R30 R3b
O R1
Het N
R5 I \ R2 (I 8.8)_
\
o
R7
where Het, R1, R2, R3b, R3°, R5 and R7 are as defined here and in the claims and
where R5 is in particular hydrogen.
In formulae I-7.B and I-8.B, the variables R3b and R“ are independently of each
other in particular selected from the group consisting of hydrogen, fluorine and methyl
or er form CHZCHZ. Particular preference is given to compounds ofthe formulae
I-7.B and I-8.B, where both R3b and R30 are hydrogen or fluorine.
Another particular preferred embodiment of the invention relates to the
compounds of formula I-7.C, described below, to the es, the prodrugs, the
10 es and the tautomers thereof and to the pharmaceutically suitable salts thereof:
REgj O R1
_
Het I}! l \ R2 (I-7.C)
N\
0
R7
where Het, R1, R2, R5 and R7 are as defined here and in the claims and where R5 is
in particular hydrogen.
15 Another particular preferred embodiment of the ion relates to the
compounds of a I-8.C, described below, to the N—oxides, the prodrugs, the
hydrates and the tautomers thereof and to the pharmaceutically suitable salts thereof:
R5 O R1
\
0
R7
where Het, R1, R2, R5 and R7 are as defined here and in the claims and where R5 is
20 in particular hydrogen.
59
A particular red embodiment of the invention relates to the compounds of
formula I-7.D, described below, to the N—oxides, the prodrugs, the hydrates and the
ers thereof and to the pharmaceutically suitable salts f:
0 R1
Hetfill
N
l \ R2 (I-7.D)
3e \
R O
R3f
7
R
5 where Het, R1, R2, R31: R3e and R7 are as defined here and in the claims where R3e
and R3f are both in particular hydrogen.
Another particular preferred embodiment of the invention relates to the
compounds of a I—8.D, described below, to the N-oxides, the prodrugs, the
hydrates and the tautomers thereof and to the pharmaceutically suitable salts thereof:
10
0 R1
Het
Rae R3f \ O
R7
where Het, R1, R2, R3f, R36 and R7 are as defined here and in the claims where R3‘3
and R3f are both in ular hydrogen.
Particular embodiments ofthe invention relate to compounds of the formulae 1-7,
15 1-8, I-7.A, I-8.A, I-7.B, I-8.B, I-7.C, I-8.C, I-7.D, and I-8.D described above, to the N-
oxides, the prodrugs, the hydrates and the tautomers thereof and to the pharmaceutically
suitable salts thereof, where R1 is a radical Yl—Cycl and R7 is as defined above and in
particular selected from the group ting of hydrogen, fluorine, C1—C4-alkyl, C1-C2-
fluoroalkyl, C1-C4-alkoxy, C1-C2-fluoroalkoxy, ropyl, optionally substituted by 1,
20 2 or 3 methyl groups, fluorinated cyclopropyl and YZ-Cycz, ally from the group
consisting of hydrogen and YZ-Cycz.
Further particular embodiments of the invention relate to nds of the
formulae 1-7, 1-8, I-7.A, I—8.A, I—7.B, I—8.B, I—7.C, I—8.C, I-7.D and I-8.D, described
above, to the N—oxides, the prodrugs, the hydrates and the tautomers thereof and to the
25 pharmaceutically suitable salts thereof, where R1 is selected from the group consisting
60
of hydrogen, fluorine, C1-C4-alkyl, C1—C2-fluoroalkyl, C1-C4-alkoxy, C1-C2-
fluoroalkoxy, cyclopropyl, optionally substituted by l, 2 or 3 methyl groups and
fluorinated cyclopropyl and R7 is a moiety YZ—Cycz. In these embodiments R1 is in
particular hydrogen.
5 A further particular preferred embodiment ofthe invention relates to the
compounds of formula I-9.A, described below, to the N-oxides, the gs, the
es and the tautomers thereof and to the pharmaceutically suitable salts thereof:
0 R
Hetml R
N \
| (I 9.A)_
R R N\ /N
7 9
R R
where Het, R1, R2, R5, R6, R7 and R9 are as defined here and in the claims.
10 r particular preferred ment of the invention relates to the
compounds of formula I-lO.A, described below, to the es, the prodrugs, the
hydrates and the tautomers thereof and to the pharmaceutically suitable salts thereof:
1
o R
Het R2
ECN \
l (I 10.A)_
R7 R9
where Het, R1, R2, R5, R6, R7, and R9 are as defined here and in the claims.
15 Another particular preferred embodiment of the invention relates to the
compounds of formula I-9.B, described below, to the es, the prodrugs, the
hydrates and the tautomers thereof and to the pharmaceutically suitable salts f:
30
R 3b
R
1
o R
2
R
Het
N \
5
R | | (I-9.B)
N \ / N
R7 R9
61
where Het, R1, R2, R3b, R“, R7, and R9 are as defined here and in the claims and
where R5 is in particular hydrogen.
r particular preferred embodiment of the invention relates to the
5 compounds of formula I-lO.B, described below, to the N—oxides, the prodrugs, the
hydrates and the ers thereof and to the pharmaceutically le salts thereof:
(I-10.B)
where Het, R1, R2, R3b, R3c, R7, and R9 are as defined here and in the claims and
where R5 is in particular hydrogen.
10 In formulae I-9.B and I-lOB, the variables R3b and R30 are independently of each
other in particular selected from the group consisting of hydrogen, fluorine and methyl
or together form CHZCHZ. Particular preference is given to compounds ofthe formulae
I-3.B and I-4.B, where both R3b and R30 are hydrogen or fluorine.
Another particular preferred embodiment of the invention relates to the
15 compounds of formula I-9.C, described below, to the N—oxides, the prodrugs, the
es and the tautomers f and to the pharmaceutically suitable salts thereof:
R5 O R
:3: R2
Het
[TI \
| )
N \ / N
R7 R9
where Het, R1, R2, R5, R7, and R9 are as defined here and in the claims and where
R5 is in particular hydrogen.
20 Another particular preferred ment of the invention relates to the
compounds of formula I—lO.C, described below, to the N-oxides, the prodrugs, the
hydrates and the tautomers thereof and to the pharmaceutically suitable salts thereof:
62
(I-10.C)
where Het, R1, R2, R5, R7, and R9 are as defined here and in the claims and where
R5 is in particular hydrogen.
A r particular preferred embodiment of the invention relates to the
5 compounds of formula I-9.D, bed below, to the N-oxides, the prodrugs, the
hydrates and the tautomers thereof and to the pharmaceutically suitable salts thereof:
0 R
2
Het R
\
I [Tl I (I-9.D)
N\ /N
R3 R3f
R7 R9
where Het, R1, R2, Rh, R3f, R7, and R9 are as defined here and in the claims and
where R3‘3 and R3f are in particular both hydrogen.
10 Another particular preferred embodiment of the invention relates to the
compounds of formula I-lO.D, described below, to the N—oxides, the prodrugs, the
hydrates and the tautomers thereof and to the pharmaceutically le salts thereof:
(I-10.D)
where Het, R1, R2, R36, R3f, R7, and R9 are as defined here and in the claims and
15 where R36 and R3f are in particular both hydrogen.
Particular embodiments of the invention relate to compounds of the formulae 1-9,
1-10, I-9.A, I—lO.A, I—9.B, , I—9.C, 1—10.C, I—9.D and I-lOD, described above, to
the N—oxides, the prodrugs, the hydrates and the tautomers thereof and to the
pharmaceutically suitable salts thereof, where R1 is a radical Yl-Cyc1 and R7, and R9 are
20 as defined above and where R7 is in particular selected from the group consisting of
63
en, fluorine, C1-C4-alkyl, C1—C2—fluoroalkyl, C1-C4-alkoxy, C1-C2-fluoroalkoxy,
cyclopropyl, optionally substituted by l, 2 or 3 methyl groups, fluorinated cyclopropyl
and YZ-Cycz, ally from the group consisting of hydrogen and Yz-Cyc2 and Where
R9 is in particular selected from the group consisting of hydrogen, e, C1-C4-alkyl,
C1-C2-fluoroalkyl, C1-C4-alkoxy, C1-C2-fluoroalkoxy, ropyl, optionally
substituted by l, 2 or 3 methyl groups, fluorinated cyclopropyl and Y3-Cyc3, especially
from the group consisting of hydrogen and Y3-Cyc3, provided that none or only one of
R7 and R9 is a moiety Y3-Cyc3, or Y3-Cyc3, respectively. R7 and R9 are in ular
hydrogen.
10 Further particular embodiments of the invention relate to compounds of the
formulae 1-9, 1-10, I-9.A, 1—10.A, I-9.B, 1-10.B, I-9.C, 1-10.C, I-9.D and I-lO.D,
described above, to the N—oxides, the prodrugs, the hydrates and the tautomers thereof
and to the pharmaceutically le salts thereof, Where R1 is selected from the group
consisting of hydrogen, fluorine, C1—C4—alkyl, C1—C2-fluoroalkyl, C1-C4-alkoxy, C1-C2-
15 lkoxy, cyclopropyl, optionally substituted by l, 2 or 3 methyl groups and
ated cyclopropyl and where R7 and R9 are ed, independently of each other,
from the group consisting of hydrogen, fluorine, C1-C4-alkyl, C1-C2-fluoroalkyl, C1-C4-
alkoxy, C1-C2-fluoroalkoxy, cyclopropyl, optionally substituted by l, 2 or 3 methyl
groups, fluorinated cyclopropyl and YZ-Cyc2 or Y3-Cyc3 , respectively, provided that
20 either R7 is YZ-Cyc2 or R9 is Y3-Cyc3. In these embodiments R1 is in particular
hydrogen. In these embodiments the radical R7 or R9, which is different from 2
or Y3-Cyc3 is in particular en.
, respectively,
In formulae 1-1, 1-2, 1-3, 1-4, 1-5, 1-6, 1-7, 1-8, 1-9, 1-10, I-l.A, I-l.B, I-2.A, I-2.B,
I-l.C, I-2.C, I-1.D, I-2.D, I-3.A, I-4.A, I-3.B, I-4.B, I-3.C, I-4.C, I-3.D, I-4.D, I-5.A, I-
25 6.A, I-5.B, I-6.B, I-5.C, I-6.C, I-5.D, I-6.D, I—7.A, I-8.A, I—7.B, I—8.B, I-7.C, I-8.C, I-
7.D, I-8.D, I-9.A, , I-9.B, I-lO.B, I-9.C, I-10.C, I-9.D and I—10.D, R2 is preferably
selected from the group consisting of hydrogen, fluorine, C1-C4-alkyl, C1-C2-
fluoroalkyl, C1-C4-alkoxy, C1-C2-fluoroalkoxy, cyclopropyl, optionally substituted by 1,
2 or 3 methyl groups, and fluorinated cyclopropyl. R2 is in particular hydrogen.
30 Preference is given to compounds of the formulae 1-1, 1-2, 1-3, 1-4, 1-5, 1-6, 1-7, I-
8, 1-9, 1-10, I-1.A, I-l.B, I-2.A, I-2.B, I-1.C, I-2.C, I-3.A, I-4.A, I-3.B, I-4.B, I-3.C, I-
4.C, I-5.A, I-6.A, I-5.B, I-6.B, I—S.C, I—6.C, I—7.A, I—8.A, I-7.B, I-8.B, I-7.C, I-8.C, I-
64
9.A, I-lO.A, I-9.B, I-lO.B, I-9.C and I—10.C, where R3b, R“, R5 and R6, ifpresent, are,
independently of each other, selected from the group consisting of hydrogen, fluorine
and methyl, and in particular to those compounds, where both R5 and R6 are hydrogen.
In ae 1-3, 1-4, 1-5, 1-6, I-3.A, I-4.A, I-3.B, I-4.B, I-3.C, I-4.C, I-3.D, I-4.D,
I-5.A, I-6.A, I-5.B, I-6.B, I-5.C, I—6.C, I—5.D, I-6.D, R8 is in ular hydrogen.
With regard to formulae I—l 1-1 .A, 1-1 .B, I-
, 1-2, 1-3, 1—5, 1—4, 1-6, 1—7, 1-8, 1—9, 1-10;
2.A, I-2.B, I-l.C, I-2.C, I-l.D, I-2.D, I-3.A, I-4.A, I—3.B, I-4.B, I—3.C, I—4.C, I-3.D, I-
4.D, I-5.A, I-6.A, I-5.B, I-6.B, I-5.C, I-6.C, I-5.D, I-6.D, I-7.A, I-8.A, I-7.B, I-8.B, I-
7.C, I-8.C, I-7.D, I-8.D, I-9.A, 1-10.A, I-9.B, I-lO.B, I-9.C, I-lO.C, I-9.D and I-lO.D, the
10 variable Het is as defined above and ably selected from the group consisting of C-
bound 6-membered monocyclic hetaryl, which has 1 or 2 nitrogen atoms as ring
members, and C-bound, fused bicyclic l, which has 1 or 2 nitrogen atoms as ring
members and optionally a further heteroatom selected from O, S and N as ring member,
where monocyclic hetaryl and bicyclic hetaryl may be unsubstituted or may carry 1, 2, 3
15 or 4 substituents RX, in ular 0, l or 2 substituents RX. In this regard, RX is
preferably selected from halogen, C1-C4-alkyl, C1-C2-fluoroalkyl, C1-C4-alkoxy, C1-C2-
fluoralkoxy, phenyl, C3-C6-cycloalkyl, optionally substituted by l, 2 or 3 methyl
groups, and fluorinated C3-C6-cycloalkyl. In this regard, RX is in ular selected from
fluorine, chlorine, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy,
20 ethoxy, difluoromethoxy, trifluoromethoxy, phenyl, cyclopropyl, optionally
substituted by l, 2 or 3 methyl groups, and fluorinated cyclopropyl.
In formulae 1-1, 1-2, 1-3, 1-4, 1-5, 1-6, 1-7, 1-8, 1-9, 1-10, 1-1 .A, 1-1 .B, I-2.A, I-2.B,
I-l.C, I-2.C, I-l.D, I-2.D, I-3.A, I-4.A, I-3.B, I-4.B, I-3.C, I-4.C, I-3.D, I-4.D, I-5.A, I-
6.A, I-5.B, I-6.B, I-5.C, I-6.C, I-5.D, I-6.D, I-7.A, I-8.A, I-7.B, I-8.B, I-7.C, I-8.C, I-
25 7.D, I-8.D, I-9.A, I-lO.B, I-9.A, ,I-9.C,I-10.C,I-9.D and I-lO.D, Het is in
particular selected from the group consisting of fused bicyclic hetaryl, which has 1 or 2
en atoms as ring s and optionally a fiarther heteroatom selected from O, S
and N as ring member and which may be unsubstituted or may carry 1, 2, 3 or 4
substituents RX, in particular 0, 1 or 2 substituents Rx. In this , Rx is preferably
30 selected from halogen, C1—C4—alkyl, C1-C2-fluoroalkyl, alkoxy, C1-C2-
fluoralkoxy, C3-C6-cycloalkyl, optionally substituted by l, 2 or 3 methyl groups, and
fluorinated C3-C6-cycloalkyl. In this regard, Rx is in particular selected from fluorine,
65
chlorine, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy,
fluoromethoxy, difluoromethoxy, trifluoromethoxy, cyclopropyl, optionally tuted
by l, 2 or 3 methyl groups, and fluorinated cyclopropyl.
In another particular embodiments of formulae 1-1, 1-2, 1-3, 1-4, 1-5, 1-6, 1-7, 1-8, I-
9, 1-10, 1-1 .A, 1-1 .B, I-2.A, I-2.B, I-1.C, I-2.C, I-1.D, I-2.D, I-3.A, I-4.A, I-3.B, I-4.B, I-
3.C, I-4.C, I-3.D, I-4.D, I-5.A, I—6.A, I-5.B, I-6.B, I-5.C, I—6.C, I—5.D, I-6.D, I-7.A, 1-
SA, I-7.B, I-8.B, I-7.C, I-8.C, I-7.D, I-8.D, I—9.A, 1-10.A, I—9.B, I—lO.B, I—9.C, I-10.C, I-
9.D and 1-10.D Het is selected from 6-membered monocyclic hetaryl, which may be
unsubstituted or may carry 1, 2, 3 or 4 substituents Rx, in particular 0, 1 or 2 substituents
10 RX. In this regard, Rx is preferably selected from n, C1-C4-alkyl, C1-C2-
fluoroalkyl, C1—C4—alkoxy, C1—C2—fluoralkoxy, phenyl, cycloalkyl, ally
substituted by l, 2 or 3 methyl groups, and fluorinated C3-C6-cycloalkyl. In this regard,
Rx is in particular selected from fluorine, chlorine, methyl, fluoromethyl,
difluoromethyl, romethyl, methoxy, fluoromethoxy, difluoromethoxy,
15 trifluoromethoxy, cyclopropyl, optionally substituted by l, 2 or 3 methyl groups, and
fluorinated cyclopropyl or one Rx may also be phenyl.
Particular preference is given to those compounds of 1-1, 1-2, 1-3, 1-4, 1-5, 1-6, 1-7,
1-8, 1-9, 1-10, 1-1 .A, 1-1 .B, I-2.A, I-2.B, I-1.C, I-2.C, I-l .D, I-2.D, I-3.A, I-4.A, I-3.B, I-
4.B, I-3.C, I-4.C, I-3.D, I-4.D, I-S.A, I—6.A, I-5.B, I-6.B, I-S.C, I-6.C, I-5.D, I-6.D, I-
20 7.A, I-8.A, I-7.B, I-8.B, I-7.C, I-8.C, I—7.D, I-8.D, I-9.A, I-lO.A, I-9.B, I-lO.B, I-9.C, I-
lO.C, I-9.D and I-lO.D, to the N—oxides, the gs, the hydrates and the tautomers
thereof and to the ceutically suitable salts thereof, where the Het radical has at
least one imino-nitrogen as ring member, which is located in the position adjacent to the
carbon atom which is bound to the group CR5. Amongst these, particular preference is
25 given to those, where the Het l has at least one imino-nitrogen as ring member,
which is located in the position adjacent to carbon atom bound to the group CR5 and
which is ed from the group consisting of C-bound 6-membered monocyclic
hetaryl, which has 1 or 2 nitrogen atoms as ring members, and C-bound, fused bicyclic
hetaryl, which has 1 or 2 nitrogen atoms as ring members and ally a fiarther
30 heteroatom selected from O, S and N as ring member, where monocyclic l and
ic hetaryl may be unsubstituted or may carry 1, 2, 3 or 4 substituents RX, in
particular 0, l or 2 substituents Rx. In this regard, RX is preferably selected from
66
n, C1-C4-alkyl, C1-C2-fluoroalkyl, C1-C4-a1koxy, C1-C2-fluoralkoxy, phenyl, C3-
C6-cycloalkyl, ally substituted by 1, 2 or 3 methyl groups, and ated C3-C6-
cycloalkyl. In this regard, Rx is in particular selected from fluorine, chlorine, methyl,
fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy,
difluoromethoxy, trifluoromethoxy, phenyl, cyclopropyl, optionally substituted by l, 2
or 3 methyl groups, and fluorinated cyclopropyl.
Particular examples of Het in ae 1-], 1-2, 1—3, 1—4, 1-5, 1-6, 1—7, 1-8, 1-9, 1-10,
I-1.A, I-1.B, I-2.A, I-2.B, I-1.C, I-2.C, I-1.D, I-2.D, I-3.A, I-4.A, I-3.B, I-4.B, I-3.C, I-
4.C, I-3.D, I-4.D, I-5.A, I-6.A, I-5.B, I-6.B, I-5.C, I-6.C, I-5.D, I-6.D, I-7.A, I-8.A, I-
10 73, I—8.B, I—7.C, I—8.C, I—7.D, I—8.D, I—9.A, 1—10.A, I—9.B, 1-10.B, I-9.C, I-lO.C, I-9.D
and I-lO.D are ed from the group consisting of 2-benzofuryl, 2-pyridyl, 2-
pyrimidinyl, 4-pyrimidinyl, 2—pyrazinyl, 3—pyridazinyl, 2-quinolinyl, 3-isoquinolinyl, 2-
quinazolinyl, 2-quinoxalinyl, 1,5—naphthyridin—2—yl, 1,8-naphthyridinyl,
benzothiazol—l-yl, azol—l-yl, benzimidazol—2—yl, l-methylbenzimidazolyl,
15 imidazo[l ,2-a]pyridineyl, thieno[3,2—b]pyridine—5-yl, imidazo-[2, l -b]-thiazolyl
and l,2,4-triazolo[l,5-a]pyridineyl, where the aforementioned radicals are
unsubstituted or may carry 1, 2 or 3 ls Rx as defined above, which are in
particular ed from the group consisting of fluorine, chlorine, methyl, fluoromethyl,
omethyl, trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy,
20 trifluoromethoxy, cyclopropyl, optionally substituted by l, 2 or 3 methyl groups, and
fluorinated cyclopropyl.
In a particular embodiment ofthe compounds of formulae 1-1, 1-2, 1-3, 1-4, 1-5, I-
6, 1-7,I-8,I-9,I-10,I-l.A,I-l.B,I-2.A,I-2.B,I-1.C,I—2.C,I-l.D,I-2.D,I-3.A,I-4.A,I-
3.B, I-4.B, I-3.C, I-4.C, I-3.D, I—4.D, I—5.A, I—6.A, I—5.B, I-6.B, I-5.C, I-6.C, I-5.D, I-
25 6.D, I-7.A, I-8.A, I-7.B, I-8.B, I—7.C, I—8.C, I-7.D, I-8.D, I-9.A, I—lO.A, I-9.B, I-lO.B, I-
9.C, I-lO.C, I-9.D and I-lO.D Het has at least one imino—nitrogen as ring member, which
is located in the position adjacent to carbon atom bound to the group CR5 and Het is
selected from the group consisting of fused bicyclic hetaryl, which has 1 or 2 nitrogen
atoms as ring members and optionally a further heteroatom selected from O, S and N as
30 ring member, where bicyclic hetaryl may be unsubstituted or may carry 1, 2, 3 or 4
tuents RX, in ular 0, l or 2 tuents Rx. In this regard, RX is preferably
selected from halogen, C1-C4—alkyl, C1—C2—fluoroalkyl, C1-C4-alkoxy, C1-C2-
67
fluoralkoxy, C3-C6-cycloalkyl, optionally tuted by l, 2 or 3 methyl groups, and
fluorinated C3-C6-cycloalkyl. In this regard, Rx is in particular selected from fluorine,
chlorine, methyl, fluoromethyl, difluoromethyl, romethyl, methoxy,
fluoromethoxy, difluoromethoxy, trifluoromethoxy, cyclopropyl, ally substituted
by l, 2 or 3 methyl groups, and fluorinated cyclopropyl. ular examples of Het of
this embodiment are olinyl, 3—isoquinolinyl, 2-quinazolinyl, 2-quinoxalinyl, 1,5-
naphthyridin—2-yl, 1,8-naphthyridinyl, benzothiazol— l -y1, benzoxazo 1y1,
benzimidazolyl, 1-methylbenzimidazol—2-yl, imidazo[l ,2-a]pyridineyl, thieno[3 ,2-
b]pyridineyl, o-[2, l -b]-thiazolyl and 1,2,4-triazolo [l ,5-a]pyridineyl,
10 Where the aforementioned radicals are unsubstituted or may carry 1, 2 or 3 radicals Rx
as defined above, Which are in particular selected from the group consisting of fluorine,
chlorine, methyl, fluoromethyl, omethyl, trifluoromethyl, methoxy,
fluoromethoxy, difluoromethoxy, trifluoromethoxy, cyclopropyl, optionally substituted
by l, 2 or 3 methyl groups, and fluorinated cyclopropyl.
15 ular preference is given to compounds, Where Het in formulae 1-1, 1-2, 1-3,
1-4, 1-5, 1-6, 1-7, 1-8, 1-9, 1-10, I-l.A, I-l.B, I—2.A, I-2.B, I-l.C, I-2.C, I-l.D, I-2.D, I-
3.A, I-4.A, I-3.B, I-4.B, I-3.C, I-4.C, I-3.D, I—4.D, I-5.A, I-6.A, I-SB, I-6.B, 1-5.C, I-
6.C, I-SD, I-6.D, I-7.A, I-8.A, I-7.B, I-8.B, I-7.C, I-8.C, I-7.D, I-8.D, I-9.A, I-lO.A, I-
9.B, I-lO.B, I-9.C, , I-9.D and I—lO.D is selected from the group consisting of 2-
20 quinolinyl, 1,8-naphthyridinyl, benzothiazol—l-yl, benzoxazol—l-yl, benzimidazol—2-
yl, l-methylbenzimidazolyl, imidazo[l,2—a]pyridineyl, thieno[3,2-b]pyridineyl,
and in particular 2-quinolinyl or o[l ,2-a]pyridineyl, where these radicals are
unsubstituted or may carry 1, 2 or 3 radicals Rx as defined above, which are in particular
selected from the group ting of fluorine, chlorine, methyl, fluoromethyl,
25 difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy,
trifluoromethoxy, cyclopropyl, optionally substituted by l, 2 or 3 methyl groups, and
fluorinated cyclopropyl.
With regard to formulae 1-1, 1-2, 1-3, 1-4, 1-5, 1-6, 1-7, 1-8, 1-9, 1-10, 1-1 .A, I-1.B, I-
2.A, I—2.B, I—l.C, I—2.C, I—1.D, I—2.D, I—3.A, I—4.A, I—3.B, I-4.B, I-3.C, I-4.C, I-3.D, I-
30 4.D, I-5.A, I-6.A, 1—5.B, I—6.B, I—S.C, I—6.C, I—5.D, I—6.D, I-7.A, I-8.A, I-7.B, I-8.B, I-
7.C, I-8.C, I-7.D, I-8.D, I—9.A, I—lO.A, I—9.B, 1—10.B, I-9.C, 1-10.C, I-9.D and 1-10.D, the
68
variables Y1, Y2, Cyc1 and Cyc2 are as defined above and in ular have the
red meanings.
In particular, Cycl, ent in formulae I-l, I-2, 1-3, 1-4, 1-5, 1-6, 1-7, 1-8, 1-9, I-
10, 1-1 .A, I-1.B, I-2.A, I-2.B, I-1.C, I-2.C, I-1.D, I-2.D, I-3.A, I-4.A, I-3.B, I-4.B, I-3.C,
I-4.C, I-3.D, I-4.D, I-5.A, I-6.A, I—5.B, I—6.B, I-5.C, I-6.C, I-5.D, I-6.D, I-7.A, I-8.A, I-
7.B, I-8.B, I-7.C, I-8.C, I-7.D, I-8.D, I-9.A, I—10.A, I—9.B, I-10.B, I-9.C, I-10.C, I-9.D
and I-10 D is selected from the groups of
(i) saturated 4-, 5-, 6- or 7-membered heteromonocycles, where the
heteromonocycle has one en or oxygen atom as ring member and may have one
10 further heteroatom or heteroatom group as ring , which is selected from the
group consisting of O, S, S(=O), S(=O); and N, where the saturated heteromonocycle
and the saturated heterobicycle are unsubstituted or carry 1, 2, or 3 radicals RC1, where
RC1 is as defined herein; and
(ii) phenyl or a 5- or 6 membered hetaryl, selected from pyridyl, pyrimidinyl,
15 furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl and thiazolyl, where phenyl and
the 5- or 6 membered hetaryl are unsubstituted or carry 1, 2, 3, 4 or 5, in particular 1, 2,
or 3 radicals RC1 or one radical Y'—RC2 and 0, 1, 2, 3 or 4, in particular 0, 1 or 2 radicals
RC1, where RC1, RC2 and Y' are as defined herein and where Y', if t, is preferably
a chemical bond or O.
20 In particular embodiments ofthe compounds of formulae 1-1, I-2, L3, L4, 1-5, 1-6,
1-7, 1-8, 1-9, I-10, I-1.A, I-1.B, I-2.A, I-2.B, I-1.C, I-2.C, I-1.D, I-2.D, I-3.A, I-4.A, I-
3.B, I-4.B, I-3.C, I-4.C, I-3.D, I-4.D, I-5.A, I-6.A, I-5.B, I-6.B, I-5.C, I-6.C, I-SD, I-
6.D, I-7.A, I-8.A, I-7.B, I-8.B, I-7.C, I—8.C, I-7.D, I-8.D, I-9.A, , I-9.B, I-10.B, I-
9.C, I-10.C, I-9.D and I-10.D, Cyc], ifpresent, is selected from the group consisting of
25 saturated 4-, 5-, 6- or 7-membered heteromonocycles or a saturated 7-, 8-, 9- or 10-
membered heterobicycle, where the heteromonocycle and the heterobicycle have one
nitrogen or oxygen atom as ring member and may have one further heteroatom or
heteroatom group as ring member, which is selected from the group consisting of O, S,
S(=O), S(=O)2 and N, where the ted heteromonocycle and the saturated
30 heterobicycle are unsubstituted or carry 1, 2, 3, 4 or 5, in particular 1, 2, or 3 radicals
RC1 or one radical Y'-RC2 and 0, 1, 2, 3 or 4, in particular 0, 1 or 2 radicals RC1, where
69
RC1, RC2 and Y' are as defined herein and where Y', if present, is preferably a chemical
bond or O.
In special embodiments ofthe compounds of formulae 1-1, 1-2, 1-3, 1-4, 1-5, 1-6, I-
7, 1-8,I-9,I-10,I-1.A,I-1.B,I-2.A,I-2.B,I-1.C,I-2.C,I-1.D,I-2.D,I-3.A,I-4.A,I-3.B,
I-4.B, I-3.C, I-4.C, I-3.D, I-4.D, I-5.A, I-6.A, I-5.B, I-6.B, I-5.C, I-6.C, I-5.D, I-6.D, I-
7.A, I-8.A, I-7.B, I-8.B, I-7.C, I—8.C, I-7.D, I-8.D, I-9.A, I-lO.A, I—9.B, I-10.B, I-9.C, I-
lO.C, I-9.D and I-10.D, Cycl, ifpresent, is selected from the group consisting of
saturated 4-, 5-, 6- or 7-membered heteromonocycles, where the heteromonocycle has
one nitrogen or oxygen atom as ring member and may have one further heteroatom or
10 heteroatom group as ring , which is ed from the group consisting of O, S,
S(=O), S(=O)2 and N, where the saturated heteromonocycle and the saturated
heterobicycle are tituted or carry 1, 2, or 3 ls RC1, where RC1 is as defined
herein.
In these particular and special embodiments of the compounds of formulae 1-1, I-
15 2, 1—3, 1—4, 1—5, 1-6, 1—7, 1-8, 1—9, 1—10, I-1.A, 1—1.3, I—2.A, 1—2.3, I-1.C, I-2.C, I-1.D, 1—
2D, I-3.A, I-4.A, I-3.B, I-4.B, I-3.C, I-4.C, I—3.D, I-4.D, I-5.A, I-6.A, I-5.B, I-6.B, I-
5.C, I-6.C, I-5.D, I-6.D, I-7.A, I-8.A, I-7.B, I—8.B, I-7.C, I-8.C, I-7.D, I-8.D, I-9.A, I-
10.A, I-9.B, I-lOB, I-9.C, , I-9.D and I—10.D, Y1, ifpresent, is preferably selected
from O, NH and a chemical bond, with particular preference given to Y1 being a
20 chemical bond.
In these particular and special embodiments of the compounds of formulae 1-1, I-
2, 1-3, 1-4, 1-5, 1-6, 1-7, 1-8, 1-9, 1-10, I—1.A, I—l.B, I-2.A, I-2.B, I-l.C, I-2.C, I-l.D, I-
2D, I-3.A, I-4.A, 1—3.3, 1—4.3, I-3.C, I-4.C, I-3.D, I-4.D, I-5.A, I-6.A, 1—5.3, I-6.B, 1—
5.C, I-6.C, I-5.D, I-6.D, I-7.A, I-8.A, I—7.B, I—8.B, I-7.C, I-8.C, I-7.D, I-8.D, I-9.A, I-
25 10.A, I-9.B, I-lO.B, I-9.C, I-lO.C, I—9.D and I—lO.D, Yl-Cycl. ifpresent, is e.g. selected
from the group consisting of l-piperidinyl, 4,4-difluoropiperidiny1, 4-piperidinyl, 1-
methylpiperidinyl, 1-piperazinyl, 4-methylpiperaziny1, morpholiny1, 6-
azaspiro-[3,4]octyl, 2,5-diazabicyclo[2.2.1]heptanyl, 3,8-diazabicyclo[3.2. l]octan
yl, thiomorpholinyl, 1—oxothiomorpholinyl, tanyl)amino, 1,1-
30 dioxothiomorpholin—4—yl and oxetan—3—ylamino and especially from the group
consisting of l-piperidinyl, 4,4—difluoro—1—piperidinyl, 4-piperidinyl, l-methyl
piperidinyl, l-piperazinyl, 4-methyl—1—piperazinyl, lin—4-yl, thiomorpholinyl,
70
l-oxothiomorpholin—4-yl, N—(oxetan—3—y1)amino, 1, l -dioxothiomorpholinyl and
oxetan—3-ylamino.
In other particular embodiments of the compounds of formulae 1-1, 1-2, 1-3, 1-4, I-
5, 1-6, 1-7, 1-8, 1-9, 1-10, I-l.A, I-l.B, I-2.A, I-2.B, I-l.C, I-2.C, I-l.D, I-2.D, I-3.A, I-
4.A, I-3.B, I-4.B, I-3.C, I-4.C, I-3.D, I-4.D, I—5.A, I-6.A, I—5.B, I-6.B, I-5.C, I-6.C, I-
5.D, I-6.D, I-7.A, I-8.A, I-7.B, I-8.B, I-7.C, I-8.C, I-7.D, I—8.D, I-9.A, 1-10.A, I-9.B, I-
10.B, I-9.C, I-lO.C, I-9.D and 1—10.D, Cycl, ifpresent, is phenyl or a 5- or 6 ed
heteroaromatic radical, which has one heteroatom, selected from O, S and N as ring
member and optionally one or two further heteroatoms as ring members, and which is in
10 ular selected from the group consisting of pyridyl, pyrimidinyl, fiaryl, thienyl,
pyrrolyl, imidazolyl, pyrazolyl, oxazolyl and thiazolyl, where phenyl and the 5- or 6
membered heteroaromatic radical are unsubstituted or either carry, independently of
each other, carry 1, 2, 3, 4 or 5, in particular 1, 2, or 3 radicals RC1 or one radical Y'-RC2
and 0, l, 2, 3 or 4, in particular 0, l or 2 radicals RC1, where RC1, RC2 and Y' are as
15 defined herein and where Y', if t, is preferably a chemical bond or O.
In other l embodiments ofthe compounds of formulae 1-1, 1-2, 1-3, 1-4, 1-5,
1-6, 1-7, 1-8, 1-9, 1-10, I-l.A, I-l.B, I-2.A, I-2.B, I-l.C, I-2.C, I-l.D, I-2.D, I-3.A, I-4.A,
I-3.B, I-4.B, I-3.C, I-4.C, I-3.D, I-4.D, I-5.A, I-6.A, I-5.B, I-6.B, 1-5.C, I-6.C, I-SD, I-
6.D, I-7.A, I-8.A, I-7.B, I-8.B, I-7.C, I—8.C, I-7.D, I-8.D, I-9.A, I-lO.A, I-9.B, I-lO.B, I-
20 9.C, I-lO.C, I-9.D and , Cyc], ifpresent, is selected from the group consisting of
phenyl or a 5- or 6 membered hetaryl, selected from pyridyl, pyrimidinyl, furyl, thienyl,
pyrrolyl, olyl, pyrazolyl, oxazolyl and thiazolyl, where phenyl and the 5- or 6
ed hetaryl are unsubstituted or carry 1, 2, 3, 4 or 5, in particular 1, 2, or 3
radicals RCl or one radical Y'-RC2 and 0, 1, 2, 3 or 4, in particular 0, l or 2 radicals RC1,
25 where RC1, RC2 and Y' are as defined herein and where Y', if present, is preferably a
chemical bond or 0.
More ularly, Cycl, if present in formulae 1-], 1-2, 1-3, 1-4, 1-5, 1-6, 1-7, 1-8, I-
9, 1-10, I-l.A, I-1.B, I-2.A, I-2.B, I-1.C, I-2.C, I-1.D, I-2.D, I-3.A, I-4.A, I-3.B, I-4.B, I-
3.C, I—4.C, I—3.D, I—4.D, I—5.A, I—6.A, I—5.B, I—6.B, I—5.C, I-6.C, I-5.D, I-6.D, I-7.A, I-
30 8.A, I-7.B, I-8.B, I—7.C, I—8.C, I—7.D, I—8.D, I—9.A, I—lO.A, I-9.B, 1-10.B, I-9.C, 1-10.C, I-
9.D and I-lO.D, is selected from the group consisting of phenyl and 5- or 6-membered
hetaryl ed from the group consisting of pyridyl, pyrimidinyl, furyl, thienyl,
71
pyrrolyl, olyl, pyrazolyl, oxazolyl and thiazolyl, where phenyl and hetaryl are
unsubstituted or carry 1, 2 or 3 radicals RC] which are selected from the group
consisting of fluorine, chlorine, CN, methyl, difluoromethyl, romethyl, methoxy
and NH2, or, if Cyc1 is phenyl, two radicals RCl which are bound to adjacent carbon
atoms, together with the phenyl ring to which they are bound, form a bicyclic
cyclic radical, which is selected from 5- or 6-indolyl, 5- or 6-benzimidazolyl, 5-
or 6-benzopyrazolyl, 5- or 6-benzotriazolyl, 5- or 6-benzofuranyl, 2,3—
dihydrobenzofuran—S-yl, 2,3-dihydrobenzofuranyl, l,3-dihydroindolonyl, 1,3-
oindolonyl, 5- or 6-quinolinyl, 5- or 6-isoquinolinyl, 5- or 6-quinazolinyl,
10 2-amino—5—quinazolinyl, and 2-aminoquinazolinyl. Amongst these, particular
preference is given to compounds, where Y1 is a chemical bond. Amongst these,
particular preference is given to compounds, where Cyc1 in formulae 1-1, 1-2, 1-3, 1-4, I-
5, 1-6, 1-7, 1-8, 1-9, 1-10, I-l.A, I—l.B, I—2.A, I—2.B, I—l.C, I-2.C, I-l.D, I-2.D, I-3.A, I-
4.A, I-3.B, I-4.B, I-3.C, I-4.C, l-3.D, I-4.D, I—5.A, l—6.A, I-5.B, I-6.B, I-5.C, I-6.C, I-
15 5.D, I-6.D, I-7.A, I-8.A, I-7.B, I-8.B, I—7.C, I—8.C, I-7.D, I-8.D, I-9.A, I-lO.A, I-9.B, I-
lO.B, I-9.C, I-lO.C, I-9.D and , is selected from the group consisting of phenyl
and 5- or 6-membered hetaryl selected from the group ting of pyridyl,
pyrimidinyl, furyl, thienyl, yl, imidazolyl, pyrazolyl, yl and thiazolyl,
where phenyl and hetaryl are unsubstituted or carry 1, 2 or 3 radicals RC1 which are
20 ed from the group consisting of fluorine, chlorine, CN, methyl, difluoromethyl,
trifluoromethyl, methoxy and NH2.
In particular, Cyc2 and Cyc3, if present in formulae 1-1, 1-2, 1-3, 1-4, 1-5, 1-6, 1-7, I-
8, 1-9, 1-10, 1-1 .A, 1-1 .B, I-2.A, I-2.B, I-1.C, I-2.C, I-l .D, I-2.D, I-3.A, I-4.A, I-3.B, l-
4.B, l-3.C, l-4.C, I-3.D, I-4.D, I-5.A, I-6.A, I-5.B, I-6.B, 1-5.C, I-6.C, 1-5.D, I-6.D, I-
25 7.A, I-8.A, I-7.B, I-8.B, I-7.C, I-8.C, I—7.D, I-8.D, l-9.A, I—lO.A, I-9.B, I-lO.B, I-9.C, I-
lO.C, I-9.D and I-lO.D, are, independently from each other, selected from the groups of
(i) saturated 4-, 5-, 6- or 7-membered heteromonocycles, where the
heteromonocycle has one nitrogen or oxygen atom as ring member and may have one
further heteroatom or heteroatom group as ring member, which is selected from the
30 group consisting of O, S, S(=O), S(=O); and N, where the saturated heteromonocycle
and the saturated heterobicycle are unsubstituted or carry 1, 2, or 3 radicals RC1, where
RC1 is as defined herein; and
72
(ii) phenyl or a 5- or 6 membered hetaryl, selected from pyridyl, pyrimidinyl,
fiiryl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl and thiazolyl, where phenyl and
the 5- or 6 membered hetaryl are unsubstituted or carry 1, 2, 3, 4 or 5, in particular 1, 2,
or 3 radicals RCl or one radical Y'—RCZ and 0, l, 2, 3 or 4, in particular 0, l or 2 radicals
RC1, where RC1, RCZ and Y' are as defined herein and where Y', if present, is preferably
a chemical bond or O.
In particular embodiments of the compounds of formulae I-l, I—2, I-3, I-4, I-5, I-7,
1-8, I-9,I1.A, I-1.B, I-2.A, I-2.B, I-1.C, I-2.C, I-1.D, I-2.D, I-3.A, I-4.A, I-3.B, I-
43, I-3.C, I-4.C, I-3.D, I-4.D, I-5.A, I-6.A, I-5.B, I-6.B, I-5.C, I-6.C, I-5.D, I-6.D, I-
10 7.A, I—8.A, I—7.B, I—8.B, I—7.C, I—8.C, I—7.D, I—8.D, I—9.A, I-10.A, I-9.B, I-10.B, I-9.C, I-
NC, I-9.D and I—10.D, Y2—Cy02 and Y3—Cyc3, if present, are, ndently from each
other, selected from the group consisting of saturated 4-, 5-, 6- or ered
heteromonocycles or a saturated 7—, 8—, 9— or 10—membered heterobicycle, where the
heteromonocycle and the heterobicycle have one nitrogen or oxygen atom as ring
15 member and may have one further atom or heteroatom group as ring member,
which is ed from the group ting of O, S, S(=O), S(=O)2 and N, where the
saturated heteromonocycle and the saturated bicycle are unsubstituted or carry 1,
2, 3, 4 or 5, in particular 1, 2, or 3 radicals RC1 or one radical Y'-RC2 and 0, l, 2, 3 or 4,
in particular 0, l or 2 radicals RC1, where RC1, RC2 and Y' are as defined herein and
20 where Y', if present, is preferably a chemical bond or O.
In special embodiments ofthe compounds of formulae I-l, I-2, L3, L4, 1-5, 1-6, I-
7, 1-8, 1-9, 1-10, 1-1 .A, 1-1 .B, I-2.A, I-2.B, I-1.C, I-2.C, I-l .D, I-2.D, I-3.A, I-4.A, I-3.B,
I-4.B, I-3.C, I-4.C, I-3.D, I-4.D, I-5.A, I-6.A, I-5.B, I-6.B, 1-5.C, I-6.C, 1-5.D, I-6.D, I-
7.A, I-8.A, I-7.B, I-8.B, I-7.C, I-8.C, I-7.D, I-8.D, I-9.A, I-lO.A, I-9.B, , I-9.C, I-
25 lO.C, I-9.D and I-lO.D, YZ-Cyc2 and Y3-Cyc3, if present, are, independently from each
other, selected from the group consisting of saturated 4-, 5-, 6- or 7-membered
heteromonocycles, where the heteromonocycle has one en or oxygen atom as ring
member and may have one further heteroatom or heteroatom group as ring member,
which is ed from the group consisting of O, S, S(=O), S(=O)2 and N, where the
30 saturated heteromonocycle and the saturated heterobicycle are unsubstituted or carry 1,
2, or 3 radicals RC1, where RC1 is as defined herein.
73
In this particular and special embodiments of the compounds of formulae 1-1, 1-2,
1-3, 1-4, 1-5, 1-6, 1-7, 1-8, 1-9, 1-10, I—1.A, I-1.B, I-2.A, I-2.B, I-l.C, I-2.C, I-l.D, I-2.D, I-
3.A, I-4.A, I-3.B, I-4.B, I-3.C, I-4.C, I-3.D, I-4.D, I-5.A, I-6.A, I-5.B, I-6.B, I-S.C, I-
6.C, I-5.D, I-6.D, I-7.A, I-8.A, I-7.B, I-8.B, I-7.C, I-8.C, I-7.D, I-8.D, I-9.A, I-lO.A, I-
9.B, I-lO.B, I-9.C, I-lO.C, I-9.D and I-lO.D, Yz-Cyc2 and Y3-Cyc3, ifpresent, are,
independently from each other preferably selected from O, NH and a chemical bond,
with ular preference given to Y2 and Y3 being a chemical bond.
In this particular and special embodiments of the compounds of formulae 1-1, 1-2,
1-3, 1-4, 1-5, 1-6, 1-7, 1-8, 1-9, 1-10,I-1.A,I-1.B,I-2.A,I-2.B,I-1.C,I-2.C,I-1.D,I-2.D,I-
10 3.A, I-4.A, I-3.B, I-4.B, I-3.C, I—4.C, I—3.D, I-4.D, I-5.A, I-6.A, I-5.B, I-6.B, I-5.C, I-
6.C, I-5.D, I-6.D, I—7.A, I—8.A, I—7.B, I—8.B, I—7.C, I—8.C, I-7.D, I-8.D, I-9.A, 1-10.A, I-
9.B, I-lO.B, I-9.C, I-lO.C, I—9.D and I—10.D, YZ—Cyc2 and Y3-Cyc3, ifpresent, are,
independently from each other, e.g. selected from the group consisting of l-piperidinyl,
4,4-difluoro-l-piperidinyl, 4-piperidinyl, 1—methyl—4-piperidinyl, l-piperazinyl, 4-
15 methyl-l-piperazinyl, morpholinyl, 2—oxa—6—azaspiro-[3,4]octyl, 2,5-
diazabicyclo[2.2. l]heptan—2-yl, 3,8-diazabicyclo[3 .2. l]octan—8-yl, thiomorpholinyl,
l-oxothiomorpholin—4-yl, tan—3-yl)amino, l, l thiomorpholinyl and
oxetan—3-ylamino and especially from the group consisting of l-piperidinyl, 4,4-
difluoro- l -piperidinyl, 4-piperidinyl, l —methylpiperidinyl, l -piperazinyl, 4-methyl- l -
20 piperazinyl, morpholinyl, thiomorpholin—4-yl, 1-oxothiomorpholin—4-yl, N—(oxetan—
mino, oxothiomorpholin—4-yl and oxetan—3-ylamino.
In other particular embodiments of the compounds of formulae 1-1, 1-2, 1-3, 1-4, I-
5, 1-6, 1-7, 1-8, 1-9, 1-10, I-l.A, I-1.B, I-2.A, I-2.B, I-l.C, I-2.C, I-l.D, I-2.D, I-3.A, I-
4.A, I-3.B, I-4.B, I-3.C, I-4.C, I-3.D, I-4.D, I—5.A, I-6.A, I—5.B, I-6.B, I-5.C, I-6.C, I-
25 5.D, I-6.D, I-7.A, I-8.A, I-7.B, I-8.B, I-7.C, I-8.C, I-7.D, I—8.D, I-9.A, I-lO.A, I-9.B, I-
lO.B, I-9.C, I-lO.C, I-9.D and , Yz-Cyc2 and Y3-Cyc3, ifpresent, are,
independently of each other, phenyl or a 5- or 6 membered aromatic radical,
which has one heteroatom, selected from O, S and N as ring member and optionally one
or two further atoms as ring members, and which is in particular selected from the
30 group consisting of pyridyl, pyrimidinyl, furyl, l, pyrrolyl, imidazolyl, pyrazolyl,
oxazolyl and thiazolyl, where phenyl and the 5— or 6 ed heteroaromatic radical
are unsubstituted or either carry, independently of each other, carry 1, 2, 3, 4 or 5, in
74
particular 1, 2, or 3 radicals RCl or one l Y'—RC2 and 0, l, 2, 3 or 4, in particular 0,
l or 2 radicals RC1, where RC1, RC2 and Y' are as defined herein and where Y', if present,
is preferably a chemical bond or O.
In special ments ofthe compounds of formulae 1-1, 1-2, 1-3, 1-4, 1-5, 1-6, I-
7, 1-8, 1-9, 1-10, I-l.A, I-l.B, I-2.A, I-2.B, I-1.C, I-2.C, I-l.D, I-2.D, I-3.A, I-4.A, I-3.B,
I-4.B, I-3.C, I-4.C, I-3.D, I-4.D, I-5.A, I-6.A, I-5.B, I-6.B, I-5.C, I—6.C, I-5.D, I-6.D, I-
7.A, I-8.A, I-7.B, I-8.B, I-7.C, I—8.C, I-7.D, I-8.D, I-9.A, 1—10.A, I—9.B, , I-9.C, I-
10.C, I-9.D and I-10.D, 2 and Y3-Cyc3, if present, are, independently from each
other, selected from the group consisting ofphenyl or a 5- or 6 membered hetaryl,
10 selected from pyridyl, pyrimidinyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl,
oxazolyl and thiazolyl, where phenyl and the 5— or 6 membered hetaryl are
unsubstituted or carry 1, 2, 3, 4 or 5, in particular 1, 2, or 3 ls RC1 or one radical
Y'-RC2 and 0, l, 2, 3 or 4, in particular 0, 1 or 2 radicals RC1, where RC1, RC2 and Y’ are
as defined herein and where Y', if present, is preferably a chemical bond or O.
15 In ular, Yz-Cyc2 and Y3-Cyc3, ifpresent in formulae 1-1, 1-2, 1-3, 1-4, 1-5, I-
6, 1-7, 1-8, 1-9, 1-10, 1-1 .A, 1-1 .B, I-2.A, I-2.B, I—1.C, I-2.C, I-l .D, I-2.D, I-3.A, I-4.A, I-
3.B, I-4.B, I-3.C, I-4.C, I-3.D, I-4.D, I-5.A, I—6.A, I-5.B, I-6.B, 1-5.C, I-6.C, I-SD, I-
6.D, I-7.A, I-8.A, I-7.B, I-8.B, I-7.C, I-8.C, I-7.D, I-8.D, I-9.A, I-lO.A, I-9.B, I-lO.B, I-
9.C, I-lO.C, I-9.D and I-lO.D, YZ-Cyc2 and Y3-Cyc3, are, ndently from each
20 other, selected from the group consisting ofphenyl and 5- or 6-membered hetaryl
selected from the group consisting of pyridyl, pyrimidinyl, fiaryl, thienyl, pyrrolyl,
imidazolyl, pyrazolyl, oxazolyl and thiazolyl, where phenyl and hetaryl are
unsubstituted or carry 1, 2 or 3 radicals RC] which are selected from the group
ting of fluorine, chlorine, CN, methyl, difluoromethyl, trifluoromethyl, methoxy
25 and NH2, or, if one or both of Yz—Cyc2 and Y3-Cyc3 are phenyl, two radicals RCl which
are bound to adjacent carbon atoms, together with the phenyl ring to which they are
bound, form a bicyclic heterocyclic l, which is selected from 5- or 6-indoly1, 5- or
6-benzimidazolyl, 5- or 6-benzopyrazolyl, 5- or 6-benzotriazolyl, 5- or 6-benzofi1rany1,
2,3-dihydrobenzofuran—5—yl, hydrobenzofi1ran—6-yl, 1,3-dihydroindol—2-on—5-yl,
30 l,3-dihydroindol—2—on—6—yl, 5— or 6—quinolinyl, 5— or 6-isoquinolinyl, 5- or 6-
quinazolinyl, 2-amino-5—quinazolinyl, and 2—amino—6-quinazolinyl. Amongst these,
particular preference is given to nds, where YZ-Cyc2 and Y3-Cyc3 are,
75
independently from each other, selected from the group consisting of phenyl and 5- or
6-membered hetaryl selected from the group consisting of pyridyl, pyrimidinyl, furyl,
thienyl, pyrrolyl, imidazolyl, lyl, oxazolyl and thiazolyl, where phenyl and
hetaryl are unsubstituted or carry 1, 2 or 3 radicals RCl which are selected from the
group consisting of fluorine, chlorine, CN, methyl, difluoromethyl, trifluoromethyl,
methoxy and NH2.
Particular embodiment of the invention relates to the compounds of formula I, to
the N-oxides, the prodrugs, the hydrates and the tautomers thereof and to the
pharmaceutically suitable salts thereof, where the compounds of the formula I are
10 selected from the group ting of:
3,7-di(pyridin—4—yl)—5—[2—(quinolin—2—yl)ethyl]thieno[2,3-d]pyridazin-4(5H)-one;
7-(pyridin—4-yl)-5—[2—(quinolin—2—yl)ethyl]thieno[2,3-d]pyridazin—4(5H)-one;
3-(pyridinyl)[2-(quinolin—2—yl)ethyl]thieno[2,3-d]pyridazin—4(5H)-one;
3-(pyridinyl)[2-(pyridin—2—yl)ethyl]thieno[2,3-d]pyridazin-4(5H)-one;
15 (pyridinyl)[2-(pyridin—2—yl)ethyl]thieno[2,3-d]pyridazin-4(5H)-one;
quinolinyl)ethyl][4-(trifluoromethyl)phenyl]thieno[2,3-d]pyridazin-
4(5H)-one;
3-(4-methylphenyl)[2-(quino1inyl)ethyl]thieno[2,3-d]pyridazin-4(5H)-one;
3-[4-(propan—2-yl)phenyl][2—(quinolinyl)ethyl]thieno[2,3-d]pyridazin—
20 4(5H)-one;
3-(4-ethylphenyl)[2-(quino1iny1)ethyl]thieno[2,3-d]pyridazin-4(5H)-one;
4- {4-oxo[2-(quinolin-2—yl)ethy1]—4,5—dihydrothieno[2,3-d]pyridazin—3-
yl}benzonitrile;
3-(4-methoxyphenyl)[2—(quino1inyl)ethyl]thieno[2,3-d]pyridazin—4(5H)-one;
25 3-(4-fluorophenyl)[2-(quinolin—2—yl)ethyl]thieno[2,3-d]pyridazin-4(5H)-one;
3-(4-ethoxyphenyl)[2-(quinolin—2-yl)ethy1]thieno[2,3—d]pyridazin-4(5H)-one;
3-[4-(dimethylamino)phenyl][2-(quinolin—2-y1)ethy1]thieno[2,3-d]pyridazin-
one;
(4— {4—oxo—5- ino lin—2-yl)ethyl]-4,5-dihydrothieno [2,3 -d]pyridazin-3 -
30 yl}phenyl)acetonitrile;
3-(4-hydroxyphenyl)—5—[2—(quinolin—2—yl)ethyl]thieno[2,3-d]pyridazin—4(5H)-one;
3-(2-chlorophenyl)[2—(quino1in—2—yl)ethyl]thieno[2,3-d]pyridazin-4(5H)-one;
76
3 -(2-rnethylphenyl)-5 -[2-(quin01in—2-y1)ethy1]thieno[2,3 -d]pyridazin-4(5H)-one;
3 -(2-ethy1phenyl)-5 -[2-(quin01iny1)ethy1]thieno[2,3 -d]pyridazin-4(5H)-one;
3 -(2-flu0ropheny1)-5 - [2-(quin01in—2-y1)ethyl]thieno [2,3 -d]pyridazin-4(5H)-one;
3-(2-methoxypheny1)-5 - [2—(quin01in—2-yl)ethy1]thieno [2,3 -d]pyridazin—4(5H)-one;
3 hoxypheny1)-5 - [2-(quin01in—2-yl)ethy1]thieno [2,3 -d]pyridazin-4(5H)-one;
3 -(2-hydroxyphenyl)-5 -[2-(quin0lin—2-yl)ethy1]thien0[2,3 —d]pyridazin—4(5H)-one;
5 - [2-(quin0 liny1)ethyl]—3—[2-(triflu0r0methy1)phenyl]thieno ]pyridazin-
4(5H)-one;
3 - [3 oxymethyl)phenyl][2-(quino lin—2-y1)ethy1]thieno ]pyridazin-
10 4(5H)—one;
3 -(3 -methoxyphenyl)—5 — [2—(quin0 lin—2—yl)ethy1]thien0 [2,3 -d]pyridazin—4(5H)-one;
3 -(3 -ethoxypheny1)—5 — [2—(quino1in—2—yl)ethyl]thien0 [2,3 -d]pyridazin-4(5H)-one;
3 - [3 -(dimethylamino)pheny1]—5—[2—(quin0lin—2—y1)ethy1]thien0[2,3-d]pyridazin-
4(5H)-one;
15 3 - [4-OX0(2-quino 1iny1—ethy1)—4,5—dihydr0-thien0 [2,3 idazin—3 -y1} -
benzonitrile;
3 -(3 -fluor0phenyl)-5 - [2-(quino1inyl)ethy1]thieno [2,3 -d]pyridazin-4(5H)-one;
3 -(3 -hydroxyphenyl)-5 - [2-(quino1iny1)ethy1]thieno [2,3 -d]pyridazin—4(5H)-one;
N,N—dimethy1—3 - {4-0X0 [2-(quino1iny1)ethy1] -4,5 -dihydr0thieno [2,3 -
20 d]pyridazin—3-y1}benzamide;
3 -(3 -rnethylphenyl)-5 - [2-(quin01in—2-yl)ethy1]thieno [2,3 -d]pyridazin-4(5H)-one;
5 - ino 1iny1)ethy1] -3—(thi0phen—2-yl)thieno [2,3 -d]pyridazin—4(5H)-one;
3 -(1-methy1—1H-indol—5 -y1)(2-quin01iny1-ethy1)-5H-thieno [2,3 -d]pyridazin-
4-one;
25 3 -(1H-ind01—6-y1)-5 - [2-(quin01in—2-yl)ethyl]thieno [2,3 —d]pyridazin-4(5H)-one;
3 -(pyrimidin—5 -y1)-5 - [2-(quin0 lin—2—yl)ethyl]thien0 [2,3 -d]pyridazin-4(5H)-one;
3 -(2-methoxypyridin-3 -yl)[2-(quino liny1)ethy1]thieno [2,3-d]pyridazin—
4(5H)-one;
3 —(pyridin—3 —y1)—5 — [2—(quino yl)ethyl]thieno [2 ,3 idazin—4(5H)-0ne;
30 3 -(4-methoxypyridin—3 —y1)—5—[2—(quinolin—2—yl)ethy1]thien0[2,3-d]pyridazin—
4(5H)-one;
3 -(furan—3 -y1)-5 - [2-(quino1in—2—y1)ethyl]thieno[2,3-d]pyridazin-4(5H)-one;
77
3 -(quin01in-3 -y1)-5 - [2-(quino1in—2—y1)ethy1]thieno [2,3 -d]pyridazin—4(5H)-one;
3 -(isoquinolinyl)-5 - [2-(quin01inyl)ethy1]thieno [2,3 -d]pyridazin-4(5H)-one;
3 -(isoquinolin-5 -y1)-5 - [2-(quin01iny1)ethy1]thieno [2,3 -d]pyridazin-4(5H)-one;
3 -(1H-ind01y1)-5 -(2-quin01iny1—ethyl)—5H-thieno [2,3 idazin—4-one;
3 -(2,3-dihydrobenzo furan—S-yl)—5—(2-quin0 liny1—ethy1)-5H-thieno [2,3-
d]pyridazin—4-one;
3 -(quin0 1111-5 -y1)-5 - [2-(quin0 lin—2—yl)ethyl]thien0 [2,3 -d]pyridazin—4(5H)-one;
3 -(3,5-dimethyl-1,2-oxazolyl)[2-(quino1iny1)ethy1]thieno[2,3 -
d]pyridazin—4(5H)-one;
10 3 thoxypyridin-3 -yl)—5-[2-(quino liny1)ethy1]thien0 [2,3-d]pyridazin—
4(5H)-one;
3 -(2,3-dihydr0-1 ,4—benzodioxin—6—yl)—5—[2—(quin01iny1)ethyl]thieno[2,3 -
d]pyridazin—4(5H)-one;
3 -(2-methy1pyridinyl)-5—[2—(quino1in—2—y1)ethyl]thieno [2,3-d]pyridazin-4(5H)-
15 one;
3 -(5 -meth0xypyridin-3 -y1)[2-(quino1in—2-y1)ethy1]thieno [2,3-d]pyridazin—
4(5H)-one;
3 - rph01inyl)pyridiny1][2—(quino y1)ethy1]thieno [2,3 -
d]pyridazin—4(5H)-0ne;
20 3 -(1 ,3-benz0di0X01-5 -y1)[2—(quin01in—2-y1)ethyl]thieno [2,3-d]pyridazin-4(5H)-
one;
3 -(quino 1iny1)-5 - [2-(quin01in—2-yl)ethy1]thieno [2,3 -d]pyridazin—4(5H)-one;
3 -(1-methy1—1H-pyrazo1-4—yl)—5-[2—(quinolin—2-y1)ethy1]thieno[2,3-d]pyridazin-
4(5H)-one;
25 3 -[1-(2-methy1propy1)-1H-pyrazol—4-yl]—5-[2-(quin01in—2—y1)ethy1]thieno[2,3 -
d]pyridazin—4(5H)-one;
tert-butyl 2- {4-oxo-5 - [2-(quino lin—2-yl)ethyl]-4,5 rothieno [2,3-d]pyridazin—
3 -y1}-1H-pyrrole- l-carboxylate;
3 —(2—methoxypyrimidin—5-yl)—5-[2-(quin0 lin—2-y1)ethy1]thien0 [2,3 -d]pyridazin—
30 4(5H)-one;
5 - [2-(quino liny1)ethy1] 3 ,4—triflu0r0phenyl)thien0 [2,3-d]pyridazin-4(5H)-
one;
78
3-(4-fluoron1ethylphenyl)-5—[2—(quino1iny1)ethyl]thieno[2,3-d]pyridazin—
4(5H)-one;
3-(4-fluoromethylphenyl)-5—[2-(quino1iny1)ethy1]thieno[2,3-d]pyridazin—
4(5H)-one;
hlorofluoropheny1)[2-(quinolin—2-y1)ethy1]thieno [2,3-d]pyridazin—
4(5H)-one;
hlorofluoropheny1)[2—(quinolin—2-yl)ethyl]thieno[2,3-d]pyridazin—
4(5H)-one;
3-(3,4-dimethylphenyl)[2-(quinolin—2-yl)ethy1]thieno[2,3-d]pyridazin-4(5H)-
10 one;
3-(2,4-dimethylpheny1)—5—[2—(quinolin—2—yl)ethy1]thieno[2,3-d]pyridazin-4(5H)-
one;
3-(2,4-difluoropheny1)-5—[2—(quino1in—2—yl)ethyl]thieno[2,3-d]pyridazin-4(5H)-
one;
15 3-(2,4-din1ethoxyphenyl)[2-(quino1in—2—y1)ethyl]thieno [2,3-d]pyridazin-4(5H)-
one;
3-(2,5-din1ethoxyphenyl)[2-(quino1in—2-y1)ethy1]thieno[2,3-d]pyridazin-4(5H)-
one;
3-(2,3-difluorophenyl)[2-(quino1iny1)ethy1]thieno[2,3-d]pyridazin-4(5H)-
20 one;
3-(3,4-din1ethoxyphenyl)[2—(quino1iny1)ethy1]thieno[2,3-d]pyridazin-4(5H)-
one;
3-(3,4-difluorophenyl)[2-(quino1in—2-yl)ethy1]thieno[2,3-d]pyridazin-4(5H)-
one;
25 3-(5-fluoromethoxyphenyl)—5-[2-(quinoliny1)ethy1]thieno [2,3-d]pyridazin-
4(5H)-one;
3-(4-fluoromethoxyphenyl)[2-(quinoliny1)ethy1]thieno[2,3-d]pyridazin-
4(5H)-one;
3—(3,5—din1ethoxyphenyl)[2-(quinoliny1)ethy1]thieno[2,3-d]pyridazin-4(5H)-
30 one;
3-(2,5-difluoropheny1)—5—[2—(quinolin—2—yl)ethyl]thieno[2,3-d]pyridazin-4(5H)-
one;
79
3 -(2,3-din1ethoxyphenyl)[2—(quino1iny1)ethy1]thieno [2,3-d]pyridazin-4(5H)-
one;
3 -(3 -fluorornethoxyphenyl)—5-[2—(quino liny1)ethy1]thieno [2,3-d]pyridazin-
4(5H)-one;
3 -(2-fluorornethoxyphenyl)—5-[2—(quino y1)ethy1]thieno [2,3-d]pyridazin-
4(5H)-one;
3 -(3 ,5-difluorophenyl)-5 -[2—(quino linyl)ethyl]thieno [2,3 idazin-4(5H)—
one;
3 -(3 -fluoromethoxyphenyl)[2-(quino liny1)ethy1]thieno [2,3-d]pyridazin-
10 4(5H)—one;
3-(2-methoxy—5—methy1phenyl)—5—[2—(quino lin—2-y1)ethy1]thieno [2,3 -d]pyridazin—
4(5H)-one;
3 -(2,5-dichloropheny1)—5 —[2—(quino1in—2—yl)ethyl]thieno [2,3 -d]pyridazin-4(5H)-
one;
15 3 -(naphtha1en—2-y1)-5 - [2-(quinolin—2—y1)ethy1]thieno [2,3 -d]pyridazin-4(5H)-one;
3 -pheny1-5 -[2-(quino1iny1)ethy1]thieno[2,3-d]pyridazin—4(5H)-one;
3 nzo furan—2-y1)-5 - [2-(quino1in—2—y1)ethy1]thieno [2,3 idazin—4(5H)-
one;
3 -(1H-indazol—5 -y1)-5 - [2-(quino1iny1)ethy1]thieno [2,3 -d]pyridazin-4(5H)-one;
20 3 -(1 -methyl- 1 H-pyrazo1yl)—5—[2—(quino1iny1)ethy1]thieno[2,3-d]pyridazin-
4(5H)-one;
3 -(4,5-difluorornethoxypheny1)—5—[2-(quinoliny1)ethy1]thieno[2,3 -
d]pyridazin—4(5H)-one;
3 -(2-fluorornethy1pheny1)—5-[2-(quino liny1)ethy1]thieno [2,3-d]pyridazin—
25 4(5H)-one;
3-(2-fluoromethoxyphenyl)—5-[2—(quinoliny1)ethy1]thieno [2,3—d]pyridazin-
4(5H)-one;
3 1 {4-oxo-5 -[2-(quinolinyl)ethyl]-4,5 -dihydrothieno [2,3-d]pyridazin—
3 —y1}benzonitrile;
30 5 - [2-(6-fluoroquino lin—2—y1)ethyl]—3—(pyridin—4—yl)thieno [2,3 -d]pyridazin-4(5H)-
one;
80
5 - [2,2-difluor0(quino yl)ethy1](pyridinyl)thieno [2,3 idazin—
4(5H)-one;
3 -(pyridin—4-y1)-5 - [2-(thien0[3 ,2-b]pyridin—5-y1)ethy1]thieno[2,3-d]pyridazin—
4(5H)-one;
5 - [2-(imidazo [1 ,2-a]pyridin—2—yl)ethyl]—3-(pyridin—4—y1)thieno [2,3 -d]pyridazin—
4(5H)-one;
5 - [2-(7-flu0roimidazo [1 ,2-a]pyridin—2-yl)ethyl]-3 -(pyridinyl)thieno [2,3 -
dazin—4(5H)-one;
8-(pyridinyl)[2-(quinolinyl)ethyl]phthalazin-1(2H)-one;
10 2—[2-(quinoliny1)ethyl][4-(trifluoromethy1)phenyl]phtha1azin-1(2H)-0ne;
8-(4-methylpheny1)—2—[2—(quino lin—2—yl)ethy1]phthalazin- 1 (2H)-0ne;
8-[4-(propan—2-y1)pheny1]—2—[2—(quinolin—2—yl)ethyl]phthalazin- 1 (2H)-0ne;
8-(4-ethy1phenyl)[2—(quino1in—2—y1)ethyl]phtha1azin—1(2H)-0ne;
4- {4-oxo-3 -[2-(quino linyl)ethy1]—3 ,4—dihydrophthalazin-5 -y1}benzonitrile;
15 ethoxyphenyl)[2-(quino1in—2—y1)ethy1]phthalazin- 1 (2H)-one;
8-(4-flu0rophenyl)[2-(quinolin-2—y1)ethy1]phthalazin- 1 (2H)-one;
(4- {4-oxo [2-(quino linyl)ethyl]-3 ,4—dihydrophthalazin-5 -
y1}phenyl)acetonitrile;
8-(4-hydroxyphenyl)[2-(quin0liny1)ethyl]phthalazin- 1 (2H)-one;
20 8-(2-chlorophenyl) [2-(quino1in—2-y1)ethy1]phthalazin- 1 (2H)-one;
8-(2-rnethy1pheny1)[2-(quin01in—2-y1)ethy1]phthalazin- 1 (2H)-one;
8-(2-ethy1pheny1)[2-(quin01iny1)ethyl]phthalazin- 1 (2H)-one;
8-(2-fluoropheny1)[2-(quin01in—2-y1)ethyl]phthalazin- 1 (2H)-one;
8-(2-methoxyphenyl)[2-(quin01in—2—yl)ethy1]phthalazin- 1 (2H)-one;
25 8-(3 -methoxyphenyl)[2-(quin0lin—2-yl)ethyl]phthalazin-1(2H)-one;
3 - {4-ox0-3 -[2-(quin01in—2—yl)ethyl]—3 ,4-dihydrophthalazin—5 —y1}benzonitrile;
8-(3-fluorophenyl)[2-(quino linyl)ethyl]phtha1azin- 1 (2H)-one;
8-(3 -hydroxyphenyl)[2-(quinolinyl)ethy1]phtha1azin-1 (2H)-one;
N,N—dimethy1—3 — {4-oxo[2-(quino yl)ethy1] -3 ,4-dihydr0phthalazin-5 -
30 y1}benzamide;
8-(3 -methy1pheny1)—2—[2—(quino1in—2—yl)ethy1]phthalazin- 1 (2H)-0ne;
2-[2-(quino1iny1)ethy1]—8—(thi0phen—2—yl)phtha1azin—1(2H)-0ne;
8 1
8-(1-methy1—1H-indol—5-y1)-2—[2—(quino1iny1)ethy1]phthalazin—1(2H)-0ne;
8-(3 ,S-dimethyl-1H-pyrazol—4—y1)—2-[2-(quino1iny1)ethy1]phthalazin-1(2H)-0ne;
8-(1H-ind01y1)[2-(quin0lin—2—y1)ethyl]phthalazin—1(2H)-one;
8-(1H-indo1—6-y1)[2-(quin01in—2-y1)ethyl]phthalazin—1(2H)-one;
8-(pyrimidin—5-y1)[2-(quin01in-2—yl)ethyl]phthalazin-1(2H)-one;
8-(2-methoxypyridiny1)[2-(quin0[iny1)ethy1]phthalazin- 1 (2H)-one;
8—(pyridin—3 -y1)[2-(quin0[in—2—yl)ethyl]phtha1azin-1 (2H)—0ne;
8-(furan-3 -y1)[2-(quinolin—2-yl)ethyl]phthalazin-1(2H)-one;
8-(quino 1in-3 -[2-(quinolin—2-yl)ethyl]phtha1azin- 1 (2H)-one;
10 8—(1H—indo1—4—y1)—2—[2—(quino[inyl)ethyl]phthalazin- 1 (2H)-0ne;
8-(2,3-dihydr0— 1 —benzofi1ran—5—yl)—2—[2—(quino liny1)ethyl]phthalazin- 1 (2H)-
one;
8-(3 ,4-dihydr0-2H-1 ,5-benzodi0xepin—7—yl)—2—[2-(quin01iny1)ethy1]phthalazin-
1 (2H)-one;
15 8-(1-benzofuran—S-y1)[2-(quino1in—2—y1)ethy1]phthalazin-1(2H)-0ne;
nethoxypyridin-3 -y1)[2-(quinolin—2—y1)ethyl]phthalazin— 1 (2H)-one;
8-(2,3-dihydr0-1 ,4-benzodioxiny1)—2—[2—(quino1iny1)ethy1]phthalazin— 1 (2H)-
one;
8-(2-methy1pyridinyl)[2—(quino1iny1)ethy1]phthalazin- 1 (2H)-one;
20 8-(5-meth0xypyridiny1)-2—[2—(quino1iny1)ethyl]phthalazin— 1 (2H)-one;
8-(5 -flu0r0pyridin—3 -y1)[2—(quin01in—2-y1)ethy1]phthalazin- 1 (2H)-one;
8-(1 ,3-benzodioxo 1—5 -y1)-2—[2—(quin01in-2—y1)ethyl]phthalazin-1(2H)-0ne;
8-(1-methy1—1H-pyrazo1—4—y1)—2-[2—(quin0lin—2-yl)ethy1]phthalazin-1(2H)-0ne;
8-[ 1 -(2-methy1propyl)- 1H-pyrazol—4-yl]—2-[2-(quin01iny1)ethy1]phthalazin—
25 1 (2H)-one;
utyl 2- {4-0x0-3 - [2-(quin0 lin—2-yl)ethyl]-3 ,4-dihydr0phthalazin—5 -y1}-1H—
pyrrolecarboxylate;
8-(3 ofluorophenyl)[2-(quinoliny1)ethy1]phtha1azin-1(2H)-one;
8-(2—chloro—4—fluorophenyl)[2-(quinolin—2-y1)ethy1]phthalazin- 1 (2H)-0ne;
30 8-(3 ,4-dimethylpheny1)—2—[2—(quino lin—2—yl)ethy1]phthalazin- 1 (2H)-0ne;
8-(2,4-dimethoxypheny1)—2—[2—(quino yl)ethyl]phthalazin- 1 (2H)-0ne;
8-(2,5-dimethoxypheny1)—2—[2—(quino1in—2—y1)ethyl]phthalazin- 1 (2H)-0ne;
82
8-(2,3-difluor0pheny1)[2-(quin01iny1)ethy1]phthalazin-1(2H)-0ne;
8-(3 ,4-dimethoxypheny1)-2—[2—(quin01iny1)ethy1]phthalazin- 1 (2H)-one;
8-(3 ,4-difluoropheny1) [2—(quin01iny1)ethy1]phtha1azin- 1 (2H)-one;
8-(5-flu0r0methoxypheny1)—2-[2—(quin0 lin—Z-yl)ethy1]phtha1azin- 1 ne;
8-(4-fluorometh0xyphenyl)—2-[2-(quin0 liny1)ethy1]phtha1azin- 1 (2H)-one;
8-(3,5-dimeth0xyphenyl)—2—[2-(quin0[in—2—y1)ethy1]phthalazin-1(2H)-one;
8-(2,5-diflu0r0pheny1)[2—(quin0[inyl)ethy1]phthalazin-1(2H)-0ne;
8-(3 -fluoromethoxyphenyl)[2-(quinoliny1)ethy1]phtha1azin-1(2H)-one;
8-(2-fluoromethoxyphenyl)[2-(quinoliny1)ethy1]phtha1azin-1(2H)-one;
10 8—(3,5—difluoropheny1)[2-(quino[inyl)ethy1]phthalazin-1(2H)-0ne;
8-(3-flu0r0—5—methoxyphenyl)—2—[2—(quin0lin—2—y1)ethy1]phtha1azin- 1 (2H)-0ne;
8-(naphthaleny1)—2—[2—(quinolin—2—yl)ethy1]phtha1azin-1(2H)-0ne;
y1—2-[2-(quino1111—2—y1)ethy1]phthalazin— 1 (2H)-0ne;
8-(1-benzofuran—Z-y1)[2-(quino1in—2—y1)ethy1]phtha1azin-1(2H)-one;
15 8-(1-rnethy1—1H-pyrazo1yl)-2—[2—(quino1in—2-y1)ethy1]phtha1azin-1(2H)-0ne;
8-(4,5-diflu0romethoxyphenyl)-2—[2—(quin0liny1)ethy1]phtha1azin- 1 (2H)-
one;
8-(2-fluor0rnethy1pheny1)—2-[2-(quinoliny1)ethy1]phtha1azin— 1 (2H)-one;
8-(2-flu0r0meth0xyphenyl)—2—[2-(quino1iny1)ethy1]phtha1azin- 1 (2H)-one;
20 2- [2-(irnidazo [1 ,2-a]pyridin—2—yl)ethyl](pyridin—3 -y1)phtha1azin—1(2H)-one;
2- [2-(irnidazo [1 ,2-a]pyridin—2—yl)ethyl](pyridin—4-y1)phtha1azin—1(2H)-0ne;
2- [2-(imidazo [1 yridin—2-yl)ethyl]-8—(3-methoxypyridin—4-y1)phtha1azin—
1 ne;
imidazo[1 ,2-a]pyridin—2-yl)ethyl]-8—(pyrimidin—5 -y1)phtha1azin-1(2H)-one;
25 2- [2-(imidazo [1 ,2-a]pyridin—2-yl)ethyl](1-methy1—1H—pyrazol—3 -y1)phtha1azin-
1 (2H)-one;
8-(furan-3 -y1) [2-(imidazo[1 ,2-a]pyridiny1)ethy1]phtha1azin—1(2H)-one;
2-[2-(imidazo[1,2-a]pyridinyl)ethyl](2-oxo-2,3-dihydro-1H-ind01
y1)phtha1azin-1(2H)—one;
30 8-(3 ,4-dihydro—2H—chromen—6—yl)—2—[2—(imidazo [1 ,2-a]pyridin—2-
y1)ethy1]phtha1azin— 1 (2H)—one;
83
8-(1 , 1 -dioxidothiomorpho1in—4—y1)—2-[2-(quino1iny1)ethy1]phthalazin- 1 (2H)-
one;
2- [2-(imidazo [1 yridin—2-yl)ethyl]-8—(morpho1iny1)phtha1azin-1(2H)-0ne;
8-(1 , 1-dioxidothiomorpholin—4-y1)—2—[2-(imidazo [1 ,2-a]pyridin—2-
y1]phtha1azin— 1 (2H)—0ne;
2- [2-(imidazo [1 ,2-a]pyridin—2—yl)ethyl]—8—(tetrahydr0— 1 H—furo [3 ,4-c]pyrr01-
5(3H)-y1)phtha1azin—1(2H)—0ne;
8-(5 ,5-difluorohexahydrocyclopenta[c]pyrrol—2( 1 H)-y1)[2-(imidazo [1 ,2-
a]pyridinyl)ethyl]phthalazin-1(2H)-one;
10 2— [2—(imidazo [1 ,2—a]pyridin—2-yl)ethyl](piperaziny1)phtha1azin-1(2H)-0ne;
8-(4,4-difluoropiperidin—1—y1)—2—[2—(imidazo[ 1 ,2-a]pyridin—Z-y1)ethy1]phtha1azin-
1 (2H)-one;
8- [4-(ch10romethy1)(hydroxymethyl)piperidin— 1 -y1] [2-(irnidaz0 [1 ,2-
a]pyridiny1)ethy1]phtha1azin— 1 ne;
15 2- [2-(irnidazo [1 ,2-a]pyridinyl)ethy1]—8—(piperidin—1-y1)phtha1azin-1(2H)-0ne;
8-(2,3-dihydro-4H- 1 zoxazin—4—y1)—2—[2-(imidazo [1 ,2—a]pyridin—2-
y1)ethy1]phtha1azin— 1 (2H)-one;
2- [2-(irnidazo [1 ,2-a]pyridin—2-yl)ethy1][4-(triflu0r0rnethy1)piperidin— 1 -
y1]phtha1azin—1(2H)-one;
20 2- [2-(irnidazo [1 ,2-a]pyridin—2—yl)ethyl](4-methy1piperaziny1)phtha1azin-
1 (2H)-one;
8-(1 ,3-dihydro-2H-isoind01—2-y1)-2—[2-(imidazo [1 ,2-a]pyridin
y1)ethy1]phtha1azin— 1 (2H)—0ne;
8-(7-benzy1—2,7-diazaspir0[4.4]n0nyl)-2—[2-(imidazo [1 ,2-a]pyridin—2-
25 yl)ethy1]phtha1azin— 1 (2H)-0ne;
8-( { [(3 aR,4S,6aS)benzyloctahydrocyclopenta[c]pyrr01y1]methyl} amino)
idazo[1 ,2-a]pyridin-Z-yl)ethyl]phthalazin-1(2H)-one;
tert-butyl (3 R)-3 -( {3 -[2-(imidazo[1 ,2-a]pyridiny1)ethy1] oxo-3 ,4-
dihydrophthalazin—S —y1} amino)pyrrolidinecarb0xy1ate;
30 8-(2,6-dimethy1morpho1in—4—yl)—2—[2—(imidazo[ 1 ,2-a]pyridin
y1]phtha1azin— 1 (2H)—one;
84
2- [2-(in1idazo [1 ,2-a]pyridin—2—yl)ethy1](1,4-oxazepan—4-y1)phtha1azin—1(2H)-
one;
tert-butyl 4- {3 - [2-(irnidazo[1 yridiny1)ethy1] oxo-3 ,4-
dihydrophthalazin—S -y1} -3 ,6—dihydropyridine- 1 (2H)-carboxy1ate;
5 -(pyridin—4-y1) [2-(quino1in—2—y1)ethyl]phtha1azin— 1 (2H)-one;
5 -(pyrimidin—5 -y1)[2-(quino1inyl)ethyl]phthalazin-1(2H)-one;
5 -(1-methy1—1H—pyrazo1yl)[2-(quinolin—2-y1)ethy1]phthalazin—1(2H)-one;
5 -(1,1-dioxidothiomorpholinyl)[2-(quino1iny1)ethy1]phthalazin-1(2H)-
one;
10 2— [2—(in1idazo [1 ,2-a]pyridin—2-yl)ethyl](pyridin-3 -y1)phtha1azin—1(2H)-one;
2- [2-(imidazo [1 ,2—a]pyridin—2—yl)ethyl]—5—(pyrimidin-5 -y1)phtha1azin1 (2H)-one;
2- [2-(imidazo [1 ,2—a]pyridin—2—y1)ethyl]—5—(morpho1iny1)phtha1azin-1(2H)-one;
2- [2-(imidazo [1 yridin—2—y1)ethy1]—5—(tetrahydro- 1 H-furo [3 ,4-c]pyrro 1-
5 (3H)-y1)phtha1azin— 1 (2H)-one;
15 2- [2-(in1idazo [1 ,2-a]pyridinyl)ethy1]—4—(pyrin1idin-5 -y1)phtha1azin-1(2H)-one;
2- [2-(in1idazo [1 ,2-a]pyridin—2-yl)ethyl]—4—(morpho1iny1)phtha1azin-1(2H)-one;
3 -(3 -n1ethoxypyridiny1)[2-(quino1in—2-y1)ethy1]thieno [3 ,2-c]pyridin—4(5H)-
one;
3 -(3 -hydroxypyridiny1)[2—(quino1iny1)ethy1]thieno [3 ,2-c]pyridin—4(5H)-
20 one;
3 -(1-n1ethy1—1H-pyrazo1y1)—5—[2-(quino1iny1)ethy1]thieno[3 ,2-c]pyridin—
4(5)H-one;
3 -(pyridin—4-y1)-5 - [2-(quino1in—2-y1)ethyl]thieno [3 ,2-c]pyridin—4(5H)-one;
3 -(pyrirnidin—5 -y1)-5 ino1in—2-y1)ethyl)thieno [3 yridin-4(5H)-one;
25 3 -(2-oxoindo liny1)-5 - [2-(quinolinyl)ethy1]thieno [3 yridin-4(5H)-one;
3 -(3 -hydroxypheny1)-5 - [2-(quino linyl)ethy1]thieno [3 ,2-c]pyridin-4(5H)-one;
5 - [2-(5-ethy1pyridinyl)ethyl](pyridiny1)thieno [3 ,2-c]pyridin-4(5H)-one;
5 - idazo[1 ,2-a]pyridinyl)ethyl](pyridiny1)thieno [3 ,2-c]pyridin-
4(5H)—one;
30 3 -(morpholin—4—y1)—5 — [2—(quinolin—2—yl)ethy1]thieno [3 ,2-c]pyridin-4(5H)-one;
tert-buty1(4-oxo—5 —(2—quino1in—2—yl)ethyl)—4,5 -dihydrothieno [3 ,2-c]pyridin—3 -
y1)-5 ,6-dihydropyridine— 1 (2H) carboxylate;
85
5 -(2-(quino1iny1)ethy1)(1 ,2,3 rahydropyridin—4-y1)thieno [3 ,2-c]pyridin—
4(5H)-one;
tert-butyl(4-oxo-5 -(2-quinoliny1)ethyl)—4,5 -dihydrothieno [3 ,2-c]pyridin—3 -
y1)-piperidine-1 carboxylate;
5 3 -(piperidin—4-y1)-5 - ino1iny1)ethyl]thieno [3 ,2-c]pyridin-4(5H)-one;
3 -methy1—7-(pyridiny1)(2-(quino lin—2—yl)ethyl)thieno [3 ,2-c]pyridin—4(5H)-
one;
3 diny1)-5 - [2-(5 ,6,7,8-tetrahydroquino lin-2 -y1)ethy1]thieno [2,3 -
d]pyridazin-4(5H)-one;
10 (R)—tert—buty1 3 —(3 —(2—(imidazo[1 yridin—2-y1)ethy1)oxo-3 ,4-
dihydrophthalazin—S—y1amino)pyrrolidine— 1 —Carboxylate;
2- idazo [1 ,2—a]pyridin—2—yl)ethyl]—8—[(3 rolidin-3 -y1arnino]phthalazin-
1 (2H)-one;
5 -(3 -hydroxypheny1)-2— [2-(quino1in—2—y1)ethyl]phthalazin- 1 (2H)-one;
1 5 (E)—8-(pyridinyl)(2-(quino1in—2—y1)viny1)isoquinolin- 1 (2H)-one;
anti (rac) 8-(pyridiny1)(2-(quino1in—2—y1)cyclopropy1)isoquinolin- 1 (2H)-one;
anti (+)(pyridiny1)(2-(quino1in—2—y1)cyclopropyl)isoquino lin- 1 (2H)-one;
anti (-)(pyridin—4-y1)(2-(quino1in—2—y1)cyclopropy1)isoquinolin-1(2H)-one;
8-(pyridin—4-y1)(2-quino1in—2—y1—ethy1)isoquino lin- 1 (2H)-one;
20 anti (rac) 3 -(pyridiny1)(2—(quino1iny1)cyclopropy1)thieno [3 ,2-c]pyridin-
4(5H)-one;
anti (+) 3-(pyridiny1)-5—(2—(quino1in-2—yl)cyclopropy1)thieno[3 ,2-c]pyridin-
4(5H)-one;
anti (-) 3-(pyridin—4-y1)-5—(2-(quinolin—2-yl)cyclopropy1)thieno[3 ,2-c]pyridin-
25 4(5H)—one;
(E)—8-pyridin—4-y1—2-(2-quino linyl—vinyl)-2H-phthalazin- 1 —one;
anti (rac) 8-pyridinyl(2-quinolinyl-cyclopropy1)-2H-phtha1azinone;
anti (+) 8-pyridinyl(2-quino linyl-cyclopropy1)-2H-phtha1azinone;
anti (—) 8-pyridiny1—2—(2-quino lin—2-yl-cyclopropy1)-2H-phthalazinone;
3 0 and the N—oxides, the prodrugs, the tautomers and the hydrates thereof, and the
pharmaceutically acceptable salts thereof.
86
Further particular embodiments ofthe invention relate to the compounds of
formula I, where the nds ofthe formula I are selected from the group consisting
of:
7-(pyridin—4-yl)-5 - [2-(quinolinyl)ethyl]furo[3 ,2-c]pyridin-4(5H)-one;
3 -(pyridinyl)-5 -(2-(quino1in—2—y1)ethyl)fi1ro[3 ,2—c]pyridin-4(5H)-one;
5 -(2-( l H—benzo dazo1yl)ethyl)(pyridiny1)furo [3 ,2-c]pyridin—4(5H)-
one;
5 -(2-(imidazo [1 ,2-a]pyridinyl)ethyl)(pyridiny1)furo [3 ,2-c]pyridin-4(5H)-
one;
10 3 —(pyrimidin—5 —yl)—5 uino linyl)ethyl)furo [3 ,2-c]pyridin—4(5H)-one;
4-(pyridin—4—yl)—6—(2—(quinolin—2—yl)allyl)pyrido [2 ,3 -d]pyridazin-5 (6H)-one;
syn 8-(pyridin—4-yl)—2—(2—(quinolin—2—yl)cyclopropyl)isoquino lin- l (2H)-one;
syn 3 -(pyridin—4-yl)-5 -(2—(quinolin—2—yl)cyclopropyl)thieno [3 ,2-c]pyridin—4(5H)-
one;
15 anti 3 dazin—4-yl)-5 -(2-(quinolin—2—yl)cyclopropyl)furo [3 ,2-c]pyridin-4(5H)-
one;
syn 3 -(pyridazinyl)-5 -(2-(quinolin-2—yl)cyclopropyl)furo [3 ,2-c]pyridin-4(5H)-
one;
anti 3 -(pyridinyl)-5 -(2-(quino1inyl)cyclopropyl)furo [3 ,2-c]pyridin-4(5H)-
20 one;
syn 3 -(pyridinyl)-5 -(2-(quinolin-2—yl)cyclopropyl)furo [3 ,2-c]pyridin-4(5H)-
one;
anti 8-(oxetan—3 -ylamino)(2—(quino1inyl)cyclopropyl)isoquino lin- l (2H)-one;
syn 8-(oxetan—3-ylamino)(2-(quinoliny1)cyclopropyl)isoquinolin- l (2H)-one;
25 anti 8-(pyridazin—4-y1)(2—(quinolinyl)cyclopropy1)isoquinolin- 1 (2H)-one;
syn 8-(pyridazinyl)(2-(quinolin—2-yl)cyclopropyl)isoquinolin-1(2H)-one;
anti 8-(6-fluoropyridinyl)(2-(quinoliny1)cyclopropyl)isoquinolin-1(2H)-
one;
syn 8—(6—fluoropyridin—3-yl)—2-(2-(quinoliny1)cyclopropyl)isoquinolin-1(2H)-
30 one;
anti uoropyridin—4—yl)—2—(2—(quino lin—2—yl)cyclopropyl)isoquino lin- 1 (2H)-
one;
87
syn 8-(2-fluoropyridin—4-y1)—2—(2—(quino1iny1)cyclopropy1)isoquino 1in- 1 (2H)-
one;
anti 8-(pyridin-3 -y1)(2-(quino1iny1)cyclopropy1)isoquino1in- 1 (2H)-one;
syn idin—3 -y1)(2—(quinolinyl)cyclopropy1)isoquino1in- 1 (2H)-one;
anti 8-(pyrirnidin-5 -(2—(quino1inyl)cyclopropy1)isoquino 1in- 1 (2H)-one;
syn 8-(pyrimidin—5 -y1)(2—(quino linyl)cyclopropy1)isoquino lin- 1 (2H)-one;
anti 8-(1-methy1—1H—pyrazol—4—yl)(2-(quinolin-2—y1)cyclopropyl)isoquino1in-
1 (2H)-one;
syn 8-(1-methyl- 1H-pyrazolyl)(2-(quinolin-2 -y1)cyclopropy1)isoquino1in-
10 1 (2H)-one;
anti 8-(3 -fluoropyridin—4—y1)—2—(2—(quinolin—2—y1)cyclopropyl)isoquinolin- 1 (2H)-
one;
syn 8-(3 -fluoropyridin—4—y1)—2—(2—(quinolin—2—yl)cyclopropyl)isoquinolin- 1 (2H)-
one;
15 anti uoropyridiny1)(2—(quino1in—2-y1)cyclopropy1)isoquino 1in- 1 (2H)-
one;
syn 8-(2-fluoropyridin—4-y1)(2-(quino1in—2-y1)cyclopropy1)isoquino 1in- 1 (2H)-
one;
anti 8-((3 S)hydroxypiperidin—1-y1)(2-(quinolin
20 y1)cyclopropy1)isoquino1in- 1 (2H)—one;
syn 8-((3 S)-3 -hydroxypiperidin—1—y1)—2—(2-(quinolin—2-
y1)cyclopropyl)isoquino1in- 1 (2H)—one;
anti 8-(3 -rnethoxypiperidin-1 —y1)(2-(quino 1iny1)cyclopropy1)isoquino 1in-
1 (2H)-one;
25 syn 8-(3-methoxypiperidiny1)(2-(quinoliny1)cyclopropyl)isoquino1in-
1 ne;
anti 8-morpholino(2-(quinolinyl)cyclopropyl)isoquino1in-1(2H)-one;
syn 8-morpho lino(2-(quinolin—2-yl)cyclopropyl)isoquino1in- 1 (2H)-one;
anti 1-(1—oxo—2—(2—(quinolin-Z-yl)cyclopropy1)-1 ,2-dihydroisoquino 1in
30 y1)piperidineoarbonitrile;
syn 1-( 1 -oxo(2—(quino1in—2—y1)cyclopropyl)— 1 ,2-dihydroisoquino 1in
y1)piperidinecarbonitrile;
88
anti 8-((3R,4R)fluorohydr0xypiperidinyl)(2-(quin01in
yl)cyc10pr0pyl)isoquino lin- 1 (2H)-0ne;
syn 8-((3R,4R)fluorohydr0xypiperidin—1-y1)(2-(quin01in
10propyl)isoquino lin- 1 (2H)—0ne;
anti 8-((3 S)hydroxypyrr01idin— 1 -y1)(2-(quin01in—2-
y1)cyc10propyl)isoquinolin- 1 (2H)—0ne;
syn 8-((3 S)-3 -hydr0xypyrrolidinyl)—2-(2—(quin01in—2—
y1)cyclopropyl)isoquinolin- 1 (2H)-one;
anti 8-((3 R)-3 xypyrrolidinyl)(2-(quinolin
10 y1)cyclopropy1)isoquino lin- 1 (2H)—one;
syn )—3 —hydroxypyrrolidin—1—yl)—2—(2—(quin01in—2-
yl)cyc10propyl)isoquino lin— 1 (2H)—0ne;
anti 8-(methy1(oxetan—3—y1)amino)—2—(2—(quino1iny1)cyclopr0pyl)isoquinolin-
1 (2H)-one;
15 syn 8-(niethy1(oxetany1)amino)—2—(2—(quin01iny1)cyclopropyl)isoquino lin-
1 (2H)-one;
anti 8-(4-niethoxypiperidin-1 -(2—(quino 1iny1)cyc10pr0py1)is0quino lin-
1 (2H)-one;
syn 8-(4-niethoxypiperidiny1)—2-(2-(quino1iny1)cyc10pr0py1)is0quino lin-
20 1 (2H)-one;
anti 8-(4-hydroxypiperidin— 1 —y1)—2—(2-(quinoliny1)cyc10pr0py1)is0quino lin-
1 (2H)-one;
syn 8-(4-hydroxypiperidin-1 -y1)—2-(2—(quino1in—2-y1)cyc10pr0py1)isoquinolin-
1 (2H)-one;
25 anti 8-(1 -acetylpiperidin-4—ylamin0)—2—(2-quinolin—2-cyclopropy1)isoquino lin-
1 (2H)-one;
syn 8-(1-acetylpiperidin—4-ylamino)(2-quino1incyclopropy1)isoquinolin-
1 (2H)-one;
anti 8-(piperidiny1amino)(2-(quin0liny1)cyclopr0pyl)isoquin0lin-1(2H)-
30 one;
syn 8-(piperidin—4—y1amino)—2—(2—(quin0lin—2—yl)cyclopr0pyl)isoquino lin- 1 (2H)-
one;
89
anti 2-(2-(quino1iny1)cyc10pr0pyl)—8-(tetrahydro-2H-pyran—4-y1)isoquinolin-
1 (2H)-one;
syn 2-(2-(quino1iny1)cyclopr0pyl)(tetrahydro-2H-pyran—4-y1)is0quino1in-
1 ne;
anti 2-(2-(quino1iny1)cyclopr0pyl)—8-(2—0xa-6—azaspiro[3 .4]octan
y1)isoquin01in-1(2H)-0ne;
syn 2-(2-(quin01iny1)cyc10pr0pyl)—8-(2-0xa—6—azaspir0[3 .4]0ctan—6-
y1)isoquino lin- 1 (2H)-one;
anti 8-(dihydro- 1 H-furo [3 ,4-c]pyrrol-5(3H,6H,6aH)-y1)(2-(quino 1in
10 y1)cyclopropy1)isoquino 1in- 1 (2H)—one;
syn 8-(dihydro— 1 H—furo [3 ,4-c]pyrro1-5(3H,6H,6aH)-y1)(2-(quino 1in
yl)cyclopropy1)isoquino1in— 1 (2H)—0ne;
anti 8-(4,4-difluoropiperidin— 1 —y1)—2—(2—(quino 1iny1)cyc10pr0pyl)isoquino 1in-
1 (2H)-one;
15 syn -difluoropiperidiny1)—2—(2—(quino 1iny1)cyc10propyl)isoquino 1in-
1 (2H)-one;
anti 8-n10rpholino(2-(quinoliny1)cyclopropy1)isoquino1in- 1 (2H)-0ne;
syn 8-n10rpho1in0(2-(quinolin—2-y1)cyclopropyl)is0quino 1in- 1 (2H)-0ne;
anti 8-(3 0r0methyl)pyrr0lidin— 1 -y1)(2-(quin01in—2-
20 y1)cyclopropyl)isoquino1in- 1 (2H)—0ne;
syn 8-(3 -(difluorornethyl)pyrr01idin— 1 —y1)(2-(quino 1in
lopropyl)isoquino1in- 1 (2H)—0ne;
anti 8-((1R,5 S)—3 -oxa—8-azabicyclo [3 .2. 1 ]octany1)(2-(quino y1)cyc10-
propyl)isoquin01in- 1 (2H)-0ne;
25 syn 8-((1R,5 S)oxaazabicyclo [3 .2. ny1)—2—(2—(quino 1iny1)cyclo-
propy1)is0quin0 lin- 1 (2H)-0ne;
anti 8-(4-methylpiperazinyl)(2-(quinoliny1)cyc10propy1)isoquino1in-
1 (2H)-one;
syn 8—(4—methy1piperazin— 1 -yl)—2-(2-(quino lin—2-y1)cyc10pr0py1)is0quin0 1in-
30 1 (2H)-one;
anti 8-(3 -(fluor0methy1)pyrrolidin— 1 —yl)—2—(2—(quin01in—2-
yl)cyclopropyl)isoquino1in- 1 (2H)—0ne;
90
syn 8-(3 -(fluoron1ethy1)pyrrolidin— 1 -y1)(2-(quino1in
lopropy1)isoquino lin- 1 (2H)—one;
anti 8-((1R,5 S)—8-oxa—3 -azabicyclo[3.2.1]octan—3 -(2-(quino 1in
y1)cyclopropy1)isoquino lin- 1 (2H)—one;
syn 8-((1R,5 S)oxa—3 -azabicyclo[3.2.1]octan-3 -y1)(2-(quino 1in
y1)cyclopropy1)isoquino lin- 1 (2H)—one;
anti 8-(4-fluoropheny1)-2—(2-(quinolin—2—yl)cyclopropy1)isoquinolin-1(2H)-one;
syn 8-(4-fluorophenyl)(2-(quinolin—2-yl)cyclopropy1)isoquinolin-1(2H)-one;
anti 8-(furanyl)(2-(quinolinyl)cyclopropy1)isoquinolin-1 (2H)-one;
10 syn 8—(furan—3 -y1)(2—(quino linyl)cyc lopropy1)isoquino lin- 1 (2H)-one;
anti 8-(4,5 —dihydrofuran—3—yl)—2—(2—(quino lin—2—y1)cyclopropy1)isoquino lin- 1 (2H)-
one;
syn 8-(4,5 -dihydro furan—3—yl)—2—(2—(quino lin—2—y1)cyclopropy1)isoquino lin- 1 (2H)-
one;
15 anti 8-(4-n1ethoxypheny1)—2-(2-(quino1in—2—y1)cyclopropy1)isoquino lin- 1 (2H)-one;
syn 8-(4-n1ethoxypheny1)(2-(quino1in—2—y1)cyclopropy1)isoquino lin- 1 (2H)-one;
anti 6-fluoroquinoliny1)cyclopropy1)morpholinoisoquinolin— 1 (2H)-
one;
syn 2-(2-(6-fluoroquinoliny1)cyclopropy1)niorpholinoisoquino lin- 1 (2H)-
20 one;
anti 2-(2-(6-fluoroquino1in-2—y1)cyclopropy1)—8-(pyridin—3 -y1)isoquino lin- 1 (2H)-
one;
syn 2-(2-(6-fluoroquino1in—2-y1)cyclopropyl)(pyridin—3 -y1)isoquino lin- 1 (2H)-
one;
25 anti 2-(2-(6-fluoroquino1iny1)cyclopropyl)—8-(pyrimidiny1)isoquinolin-
1 (2H)-one;
syn 2-(2-(6-fluoroquinolinyl)cyclopropyl)(pyrimidiny1)isoquinolin-
1 (2H)-one;
anti 2-(2—(6—fluoroquino [inyl)cyclopropyl)(pyridiny1)isoquino lin- 1 (2H)-
30 one;
syn 2-(2-(6-fluoroquinolin—2—y1)cyclopropyl)—8—(pyridin—4-y1)isoquinolin- 1 (2H)-
one;
91
anti 4-fluoro(pyridin—4-y1)—2—(2—(quino1iny1)cyclopropy1)isoquino lin- 1 (2H)-
one;
syn 4-fluoro(pyridiny1)—2—(2-(quino1iny1)cyclopropy1)isoquino lin- 1 (2H)-
one;
anti 4-chloro(pyrimidin-5—y1)(2—(quino1iny1)cyclopropy1)isoquinolin-
1 (2H)-one;
syn 4-chloro(pyrimidin—5-yl)—2-(2—(quinoliny1)cyclopropyl)isoquinolin-
1 ne;
anti 4-(pyridinyl)(2-(quinolinyl)cyclopropyl)pyrido ]pyridazin-
10 5(6H)—one;
syn4-(pyridin—4—y1)—6—(2—(quinolin—2—yl)cyclopropyl)pyrido[2,3-d]pyridazin-
5(6H)-one;
anti 2-(2-(6-fluoroquino 1in—2—y1)cyclopropyl)—8-(pyridin—4-y1)phthalazin— 1 (2H)-
one;
15 syn 2-(2-(6-fluoroquino1inyl)cyclopropyl)—8-(pyridin—4-y1)phtha1azin— 1 (2H)-
one;
anti 7-fluoro(pyridin—4-y1)—5-(2-(quino1iny1)cyclopropy1)thieno[3 ,2-
c]pyridin-4(5H)-one;
syn 7-fluoro(pyridiny1)-5—(2-(quino1iny1)cyclopropyl)thieno[3 ,2-
20 c]pyridin-4(5H)-one;
anti 3-(2-fluoropyridiny1)—5—(2-(6—fluoroquino1iny1)cyclopropy1)thieno[3 ,2-
c]pyridin-4(5H)-one;
syn 3-(2-fluoropyridin—4-y1)—5-(2-(6—fluoroquino1iny1)cyclopropy1)thieno[3 ,2-
c]pyridin-4(5H)-one;
25 anti 5-(2-(6-fluoroquino1inyl)cyclopropyl)(pyridin—4—y1)thieno[3 ,2-
c]pyridin-4(5H)-one;
syn 5-(2-(6-fluoroquino linyl)cyclopropyl)(pyridinyl)thieno [3 ,2-c]pyridin-
4(5H)-one;
anti 3—(pyrimidin—5—y1)—5-(2-(quino[inyl)cyclopropyl)thieno[3 ,2—c]pyridin—
30 one;
syn 3-(pyrimidin—5—yl)—5—(2—(quinolin—2—yl)cyclopropyl)thieno[3 ,2-c]pyridin—
4(5H)-one;
92
anti 3-(pyrin1idiny1)(2-(quin01iny1)cyc10pr0py1)thieno[3 ,2-c]pyridin—
4(5H)-one;
syn 3-(pyrirnidin—5-y1)(2—(quin01iny1)cyc10propy1)thieno[3 ,2-c]pyridin—
4(5H)-one;
anti 3-(pyrirnidiny1)-5—(2-(quin01in—2—yl)cyclopr0py1)thieno[3 ,2-c]pyridin—
4(5H)-one;
syn 3-(pyrimidin—5-y1)(2-(quin0[inyl)cyc10pr0pyl)thien0[3 ,2-c]pyridin—
one;
anti 3-(6-fluoropyridinyl)(2-(quinoliny1)cyc10propy1)thieno[3,2-
10 c]pyridin-4(5H)—one;
syn 3-(6-flu0ropyridin—3—y1)—5—(2—(quin0lin—2—yl)cyclopropyl)thien0[3 ,2-c]pyridin-
4(5H)-one;
anti 3-(2-methy1pyrimidin—5—y1)—5—(2—(quin0lin—2-y1)cyc10pr0pyl)thien0[3 ,2-
c]pyridin-4(5H)-one;
15 syn 3-(2-methylpyrimidiny1)—5—(2—(quinoliny1)cyc10pr0pyl)thieno[3 ,2-
c]pyridin-4(5H)-0ne;
anti 3 -(pyridazin—4-yl)-5 -(2-(quinolin—2—yl)cyclopr0pyl)thieno [3 yridin—
4(5H)-one;
syn 3 -(pyridaziny1)-5 -(2-(quino1iny1)cyclopropyl)thieno [3 ,2-c]pyridin—
20 4(5H)-one;
anti 3-(2-fluoropyridiny1)—5—(2—(quin01iny1)cyclopropyl]thieno[3 ,2-
c]pyridin-4(5H)-one;
syn 3-(2-fluoropyridin—4-y1)—5-(2—(quin0liny1)cyclopropy1]thieno[3 ,2-c]pyridin-
4(5H)-one;
25 anti 3 -(rnorph01iny1)-5 [2—(quin0 linyl)cyclopr0pyl]thieno [3 ,2-c]pyridin—
4(5H)-one;
syn 3-(morpholin—4-yl)-5[2-(quinolinyl)cyclopropy1]thieno[3,2-c]pyridin-
one;
anti 3—(pyridin—3—y1)—5—[2-(thieno[3,2-b]pyridiny1)cyc10pr0py1]thien0[3 ,2-
30 din-4(5H)—one;
syn 3-(pyridin—3-y1)—5—[2—(thieno[3,2—b]pyridin—5-y1)cyclopr0pyl]thieno[3 ,2-
c]pyridin-4(5H)-one;
93
anti 3-(pyridiny1)[2-(quino1in—2-y1)cyclopropyl]thieno[3 ,2-c]pyridin—4(5H)-
one;
syn idin—3-y1)[2-(quinolin-2—y1)cyclopropy1]thieno[3 ,2-c]pyridin—4(5H)-
one;
anti 3-(pyrirnidiny1)-5—[2-(quino1inyl)cyclopropy1]thieno [2,3-d]pyridazin—
4(5H)-one;
syn 3-(pyrin1idin—5-y1)[2—(quino[inyl)cyclopropyl]thieno[2,3—d]pyridazin—
4(5H)-one;
anti 3-(pyridinyl)[2-(thieno[3,2-b]pyridiny1)cyclopropy1]thieno[2,3-
10 d]pyridazin—4(5H)—one;
syn -(pyridin—4—yl)—5—[2—(thieno[3,2—b]pyridin—5—y1)cyclopropy1]thieno[2,3-
d]pyridazin—4(5H)-one;
anti 3-(pyridiny1)[2—(thieno[3,2—b]pyridiny1)cyclopropyl]thieno[3 ,2-
din-4(5H)-one;
15 syn 3-(pyridin—4-yl)[2-(thieno[3,2—b]pyridin—5-y1)cyclopropyl]thieno[3 ,2-
c]pyridin-4(5H)-one;
anti 3-(pyridiny1)[2-(quino1iny1)cyclopropy1]thieno[3 ,2-c]pyridin—4(5H)-
one;
syn 3-(pyridin—4-y1)[2-(quinoliny1)cyclopropyl]thieno[3 ,2-c]pyridin—4(5H)-
20 one;
anti 3-(pyridiny1)[2-(quinoliny1)cyclopropy1]thieno[2,3-d]pyridazin—
4(5H)-one;
syn 3-(pyridin—4-y1)[2—(quinolinyl)cyclopropyl]thieno[2,3-d]pyridazin—
4(5H)-one;
25 anti 5-(pyrimidiny1)[2-(quino lin—2-yl)cyclopropy1]isoquino lin- 1 (2H)-one;
syn 5 -(pyrin1idin—5 -y1)[2-(quinolinyl)cyclopropy1]isoquinolin-1(2H)-one;
anti 5 -(pyridiny1)[2-(quinolinyl)cyclopropy1]isoquinolin-1(2H)-one;
syn 5 -(pyridinyl)[2-(quinolinyl)cyclopropy1]isoquinolin-1(2H)-one;
anti idiny1)[2-(quinolinyl)cyclopropy1]isoquinolin-1(2H)-one;
30 syn 5-(pyridin—3—y1)—2—[2—(quinolin—2—yl)cyclopropy1]isoquinolin-1(2H)-one;
anti 5 -(morpholin—4—y1)—2—(2—(quinolin—2—yl)cyclopropyl]isoquinolin- 1 (2H)-one;
syn 5 -(morpho1iny1)—2—(2—(quino1in—2—yl)cyclopropyl]isoquino lin- 1 (2H)-one;
94
anti o(pyrirnidin—5—y1)—2—(2-(quino1iny1)cyclopropyl)isoquino lin-
1 (2H)-one;
syn 4-fluoro(pyrirnidin—5—y1)(2-(quino liny1)cyclopropy1)isoquino lin-
1 (2H)-one;
idin—4-y1) [2-(quino1iny1)ethyl]pyrido [3 ,4-d]pyridazin—1(2H)-one;
5 - idazo [1 ,2-a]pyridin—2-yl)ethyl](1-methy1—1H—imidazol—4-y1)-3 -
(pyridiny1)thieno [2,3 -d]pyridazin-4(5H)—one;
5 - [2-(imidazo [1 ,2-a]pyridinyl)ethyl](1-methy1-1H-pyrazoly1)-3 -(pyridin-
4-y1)thieno [2,3 -d]pyridazin-4(5H)-one;
10 5 — [2—(imidazo [1 ,2-a]pyridin—2-yl)ethyl](pyridin-3 -y1)-3 -(pyridin—4-
y1)thieno [2,3-d]pyridazin—4(5H)—one;
5 - [2-(6-chloroquino lin—2—y1)ethy1]—3—(pyridin—4—y1)thieno [3 ,2-c]pyridin-4(5H)-
one;
5 - [2-(3-n1ethquuino 1iny1)ethy1]—3—(pyridin—4-yl)thieno [3 ,2-c]pyridin—4(5H)-
15 one;
5 - [2-(8-fluoroquino 1iny1)ethyl]-3—(pyridinyl)thieno [3 ,2-c]pyridin-4(5H)-
one;
5 - [2-(6-fluoroquino 1iny1)ethyl]—3-(pyridin-3 -y1)thieno [3 yridin-4(5H)-
one;
20 5 - [2-(6-fluoroquino liny1)ethy1]—3-(pyridinyl)thieno [3 ,2-c]pyridin-4(5H)-
one;
5 - [2-(in1idazo [1 ,2-a]pyridin—2-yl)ethyl](pyridin—3 -y1)thieno [3 ,2-c]pyridin-
4(5H)-one;
3 din—4-y1)-5 - [2-(quinoxalin—2-yl)ethyl]thieno [2,3 -d]pyridazin-4(5H)-one;
25 5 - [2-(1 ,5 -naphthyridiny1)ethyl](pyridinyl)thieno [2,3 -d]pyridazin-4(5H)-
one;
5 -[2-(1H-indazoly1)ethyl](pyridinyl)thieno[2,3 -d]pyridazin-4(5H)-one;
3 -(1-rnethy1-1 H-pyrazo lyl)[2-(quino liny1)ethy1]thieno [2,3-d]pyridazin-
4(5H)-one;
30 3 yrazol—3 —y1)—5 —[2—(quinolin—2—yl)ethy1]thieno[2,3 -d]pyridazin-4(5H)-one;
5 -[2-(1H-benzimidazol—1—y1)ethy1]—3—(pyridin—4—yl)thieno[2,3-d]pyridazin-4(5H)-
one;
95
5 -[2-( 1 H-benzimidazo1y1)ethy1]—3-(pyridin—4-y1)thieno[2,3-d]pyridazin-4(5H)-
one;
5 -[2-(6-chloroquino1iny1)ethyl](pyridiny1)thieno[2,3 -d]pyridazin-4(5H)-
one;
3 -(pyridin—3 -y1ethyny1)-5 -[2-(quino1inyl)ethy1]thieno [2,3 -d]pyridazin-4(5H)-
one;
3 -(pyridin—4-y1ethynyl)[2-(quino lin—2—yl)ethyl]thieno [2,3 -d]pyridazin-4(5H)-
one;
5 - [2-(3 ,5 -dimethylpyridinyl)ethyl](pyridinyl)thieno [2 ,3 -d]pyridazin—
10 4(5H)—one;
5 - [2-(7-fluoroquino lin—2—y1)ethyl]—3—(pyridin—4—yl)thieno [2,3 -d]pyridazin-4(5H)-
one;
5 - [2-(pyrazin—2-y1)ethyl] —3—(pyridin—4—yl)thieno [2,3 -d]pyridazin-4(5H)-one;
2- [2-(1 ,6-naphthyridiny1)ethy1]—8—(pyridin—4-y1)isoquinolin-1(2H)-one;
15 2-[2-(8-fluoroquino1iny1)ethy1]—8—(pyridin—4-y1)isoquinolin- 1 (2H)-one;
8-(pyridin—4-y1)[ 1 -(quino1iny1)propan—2-y1]isoquinolin— 1 (2H)-one;
2-[2-(3-n1ethy1quinoliny1)ethy1](pyridin—4-y1)isoquino1in- 1 (2H)-one;
2- [2-(in1idazo [1 ,2-a]pyridin—2-yl)ethy1]—8-(1 H-pyrazol—3 tha1azin-1(2H)-one;
8-(morpholin—4-y1) [2-(quinoliny1)ethy1]phtha1azin- 1 (2H)-one;
20 2-[2-(in1idazo[1,2-a]pyridin—2—yl)ethyl](1-oxa-4,9-diazaspiro[5.6]dodec
y1)phtha1azin— 1 (2H)-one;
2- [2-(in1idazo [1 ,2-a]pyridin—2-yl)ethyl]-8—(2-oxaazaspiro [3 .5 ]non
y1)phtha1azin— 1 (2H)-one;
8- [(3 R)hydroxypiperidiny1][2-(imidazo [1 ,2—a]pyridin
25 y1]phtha1azin— 1 ne;
8- [(3 S)-3 -hydroxypiperidin—1—yl][2—(imidazo[1 ,2-a]pyridin
y1)ethy1]phthalazin-1(2H)-one;
2-[2-(imidazo[1,2-a]pyridinyl)ethyl](2-oxaazaspiro[3.3]hept
y1)phtha1azin— 1 ne;
30 2- [2-(imidazo [1 yridin—2—yl)ethyl]—8—(1 ,2—oxazo1idiny1)phtha1azin- 1 (2H)-
one;
96
8-(hexahydrocyclopenta[b] [1 zin—4(4aH)-y1) [2-(irnidazo [1 ,2-a]pyridin—2-
y1)ethy1]phtha1azin— 1 (2H)-one;
2- [2-(imidazo [1 ,2-a]pyridin—2-yl)ethyl](tetrahydrofuran—3 -y1)phtha1azin- 1 (2H)-
one;
2- [2-(imidazo [1 yridin—2-yl)ethyl]-8—(3-oxaazabicyclo [3 .2. 1 ]oct
y1)phtha1azin— 1 (2H)-0ne;
2-[2-(imidazo[1,2-a]pyridin—2-yl)ethyl](2-oxaazaspir0[3.4]0ct
y1)phthalazin-1(2H)-one;
imidazo[1 ,2-a]pyridin—2-yl)ethyl](2,2,6,6-tetrafluoromorpholin
10 ha1azin— 1 (2H)-one;
8-(4-hydroxypiperidin—1—y1)—2—[2—(imidaz0[1 ,2—a]pyridin-Z-y1)ethy1]phthalazin-
1 (2H)-one;
2- [2-(imidazo [1 ,2-a]pyridin—2—yl)ethyl]—8—(2—methylpyrirnidin-5 -y1)phtha1azin-
1 (2H)-one;
15 8-(2-cyclopropy1pyrimidiny1)—2—[2—(imidazo [1 ,2-a]pyridin-2—
y1)ethy1]phtha1azin— 1 (2H)-one;
2- [2-(irnidazo [1 ,2-a]pyridin—2-yl)ethy1]—8—(pyridaziny1)phtha1azin-1(2H)-0ne;
8-(5 -flu0r0pyridin—3 -y1) idazo [1 ,2-a]pyridiny1)ethy1]phtha1azin— 1 (2H)-
one;
20 8- [2-(3-fluoropheny1)morpholin—4—y1][2-(imidazo [1 ,2-a]pyridin
y1)ethy1]phtha1azin— 1 (2H)-one;
2- [2-(imidazo [1 ,2-a]pyridin—2—yl)ethyl](2-methoxypyrimidin-5 -y1)phtha1azin-
1 (2H)-one;
2- [2-(imidazo [1 ,2-a]pyridin—2—yl)ethyl]—8-[2-(trifluoromethy1)pyridin
25 y1]phtha1azin—1(2H)-one;
2-[2-(imidazo[1,2-a]pyridin—2-yl)ethyl](8-oxaazabicyc10[3.2.1]oct
y1)phthalazin-1(2H)-one;
2-[2-(imidazo[1 ,2-a]pyridin—2-yl)ethyl][2-(trifluoromethy1)morpho1in
y1]phtha1azin—1(2H)-one;
30 8-(2,2—dimethy1morpho1in—4—yl)—2—[2—(imidazo [1 ,2-a]pyridin
y1)ethy1]phtha1azin— 1 (2H)—one;
97
8- [2-(4-ch10ropheny1)morpho1in—4—y1][2-(imidazo [1 yridin
y1)ethy1]phtha1azin— 1 ne;
8- [2-(3 ,4-difluoropheny1)morph01iny1][2-(imidazo [1 ,2-a]pyridin
y1)ethy1]phtha1azin— 1 (2H)-one;
2-[2-(imidazo[1 yridin—2—yl)ethyl]—8-(piperidin—4-y1)phtha1azin-1(2H)-one;
2- [2-(imidazo [1 yridin—2—yl)ethyl]—8-(tetrahydr0—2H-pyran—4-y1)phtha1azin-
1 (2H)-one;
8-(2,6-diazabicyclo[3 .2. 1]octyl)[2-(imidazo[1 ,2-a]pyridin
y1)ethy1]phtha1azin- 1(2H)-one;
10 8— [(1 8,5 S)—3 ,6—diazabicyclo[3 .2.0]heptyl][2-(imidazo [1 ,2-a]pyridin—2-
y1)ethy1]phtha1azin— 1 (2H)—one;
8-(furan—2-y1) [2—(imidazo[1 ,2—a]pyridin—2—yl)ethy1]phtha1azin-1(2H)-0ne;
2- [2-(imidazo [1 ,2-a]pyridin—2—y1)ethyl]—8—(1—methy1—1H-pyrazo1y1)phtha1azin-
1 (2H)-one;
15 8-(hexahydropyrro10[3 ,4-c]pyrr01—2(1H)—yl)—2-[2-(irnidaz0[1 ,2-a]pyridin
y1)ethy1]phtha1azin— 1 (2H)-one;
8-(2,7-diazaspiro[4.4]non—2—yl)[2-(imidazo[1,2-a]pyridin
y1)ethy1]phtha1azin— 1 (2H)-0ne;
8-[(1S,4S)—2,5-diazabicyc10[2.2.1]hepty1]—2-[2-(irnidazo[1,2-a]pyridin—2-
20 y1)ethy1]phtha1azin— 1 (2H)-one;
8-(2,7-diazaspiro [3 .5 ]n0n—7—y1)—2—[2-(imidazo [1 ,2-a]pyridin
y1)ethy1]phtha1azin— 1 (2H)-one;
8-(2,6-diazaspiro [3 .5 ]n0n—6-y1)—2-[2—(imidazo[1 ,2-a]pyridin
y1]phtha1azin— 1 (2H)-0ne;
25 8-(piperidin—4-y1)[2-(5,6,7,8-tetrahydroimidazo[1 ,2-a]pyridin—2-
yl)ethy1]phtha1azin— 1 (2H)-0ne;
8- [2-(aminomethyl)chloropyrrolidinyl][2-(imidazo [1 ,2-a]pyridin—2-
y1)ethy1]phtha1azin- 1(2H)-one;
2— [2—(imidazo [1 ,2—a]pyridin—2-yl)ethyl]-4,8-di(pyridiny1)phtha1azin-1(2H)-one;
30 2- idazo [1 ,2—a]pyridin—2—yl)ethyl]—8—[(3aR,4S,7R,7aS)-0ctahydro-1H—4,7-
epiminoisoindo1y1]phtha1azin— 1 (2H)—one;
98
8- [5 -(4-ch10r0pheny1)-2,5-diazabicyclo[2.2. 1]hepty1] [2-(irnidazo [1 ,2-
din-Z-y1)ethy1]phtha1azin- 1 (2H)—0ne;
4-br0m0[2-(imidazo [1 yridin—2-yl)ethy1] -8 -(pyridin—4-y1)phtha1azin—
1 (2H)-one;
2- [2-(imidazo [1 ,2-a]pyridin—2-yl)ethyl][(3aS,8aS)-octahydropyrr010[3 ,4-
c]azepin—2(1H)-y1]phtha1azin—1(2H)—0ne;
2- idazo [1 ,2-a]pyridin—2-yl)ethyl][(3aS,8aR)—0ctahydr0pyrro10[3 ,4-
c]azepin-2(1H)-y1]phthalazin-1(2H)-one;
tert-butyl (3 aR,4S,7R,7aS){3-[2-(imidazo[1,2-a]pyridiny1)ethy1]oxo-3,4-
10 dihydrophthalazin—S-y1}octahydro-ZH-4,7—epiminoisoindo16carboxy1ate;
8-(hexahydro—5H—furo[2,3—c]pyrrol—S—yl)—2—[2—(imidazo [1 ,2-a]pyridin—2-
y1)ethy1]phtha1azin— 1 (2H)—one;
2- [2-(imidazo [1 ,2-a]pyridin—2—y1)ethyl]—8—( 1 ,2,3 ,6-tetrahydr0pyridin
y1)phtha1azin— 1 (2H)-one;
15 2- [2-(irnidazo [1 ,2-a]pyridinyl)ethy1]—8—[(3 S)-tetrahydrofuran—3 -
y1arnino]phtha1azin—1(2H)-one;
2- [2-(irnidazo [1 ,2-a]pyridin—2-yl)ethy1]—8—[(3 R)-tetrahydr0furan—3 -
y1amino]phtha1azin— 1 (2H)-one;
8- {[5 -(hydr0xyrnethy1)- 1 ,4-dioxan—2-yl]methoxy} [2-(irnidazo [1 ,2-a]pyridin
20 y1]phtha1azin— 1 (2H)-one;
2- [2-(irnidazo [1 ,2-a]pyridin—2—y1)ethyl]—8-(oxetan—3 -y10xy)phtha1azin—1(2H)-0ne;
2- [2-(imidazo [1 ,2-a]pyridin—2-yl)ethyl]—8-(pyridin—4-y1methoxy)phtha1azin—
1 (2H)-one;
2- [2-(imidazo [1 ,2-a]pyridin—2-yl)ethyl]—8—(morph01iny1methy1)phtha1azin—
25 1 (2H)-one;
2- [2-(imidazo [1 ,2-a]pyridin—2-yl)ethyl](pyridin-3 -y10xy)phtha1azin—1(2H)-one;
2- idazo [1 ,2-a]pyridinyl)ethyl][(oxetan-3 -y1methy1)amino]phtha1azin—
1 (2H)-one;
2— [2—(imidazo [1 ,2-a]pyridin—2-yl)ethyl](tetrahydr0-2H-pyran—4-
30 y1amino)phtha1azin— 1 (2H)—one;
2- [2-(imidazo [1 ,2—a]pyridin—2—y1)ethyl]—8—[( 1 —methy1azetidin-3 -
y1)amino]phtha1azin— 1 (2H)-one;
99
2- [2-(irnidazo [1 ,2-a]pyridin—2—yl)ethy1](1 ,3 -oxazol—2-y1arnino)phtha1azin-
1 (2H)-one;
2- [2-(imidazo [1 ,2-a]pyridin—2—yl)ethyl][methy1(oxetan—3 -y1)amino]phtha1azin-
1 (2H)-one;
2- idazo [1 ,2-a]pyridin—2-yl)ethyl]—8-(piperidin—4-y1amino)phtha1azin-1(2H)-
one;
8-[(1-acety1piperidin—3 -y1)amino]—2-[2-(imidazo[1 ,2-a]pyridin
y1)ethy1]phthalazin-1(2H)-one;
8-[(1-acety1piperidin—4-yl)amino][2-(imidazo[1 yridin
10 y1)ethy1]phtha1azin—1(2H)—one;
2- [2-(imidazo [1 ,2—a]pyridin—2—yl)ethyl]—8—(tetrahydrofuran—3 -y1amino)phtha1azin-
1 (2H)-one;
2- [2-(imidazo [1 ,2-a]pyridin—2—y1)ethy1]—8—(tetrahydro-2H-pyran—3 -
y1arnino)phtha1azin— 1 (2H)-one;
15 2- [2-(irnidazo [1 ,2-a]pyridin—2-yl)ethy1]—8—(piperidin—3 -y1arnino)phtha1azin-1(2H)-
one;
2- [2-(irnidazo [1 ,2-a]pyridin—2-yl)ethyl]—8— {methy1[(3 -methyloxetan-3 -
y1)rnethy1]arnino } phthalazin- 1 (2H)—one;
2- [2-(irnidazo [1 yridin—2—yl)ethy1](oxetan—3 -y1arnino)phtha1azin—1(2H)-
20 one;
8- { [(3 aS ,4S ,6aS)-octahydrocyclopenta[c]pyrro1y1methy1]amino} [2-(5 ,6,7,8-
tetrahydroimidazo[ 1 ,2-a]pyridin—2—y1)ethy1]phthalazin— 1 (2H)-one;
5 holin—4-y1) [2-(quinoliny1)ethyl]phtha1azin- 1 (2H)-one;
2-[2-(1H-benzimidazo1y1)ethy1](pyridiny1)phthalazin-1(2H)-one;
25 4-(pyridin—3 -y1) [2-(quino1in—2—yl)ethyl]phtha1azin- 1 (2H)-one;
5 -(1 ,4-dihydropyrimidinyl)—2-[2—(5 ,6,7,8-tetrahydroimidazo[1 ,2-a]pyridin—2-
y1)ethy1]phthalazin-1(2H)-one2-[2-(imidazo[1 yridiny1)ethy1] -5 -(pyridin
y1)phtha1azin-1(2H)-one;
5 —(pyridin—3 — [2—(quino [inyl)ethyl]phtha1azin- 1 (2H)-one;
30 2- [2-(imidazo [1 ,2—a]pyridin—2—yl)ethyl]—8— { [(3—methyloxetan-3 -y1)methy1]amino} -
phthalazin-1(2H)-one;
4-(pyridin—4-y1) [2—(quino1in—2—y1)ethyl]pyrido [2,3 -d]pyridazin—5 (6H)-one;
100
4-(morpholin—4-yl)[2-(quinolin—2-yl)ethyl]pyrido[2,3-d]pyridazin-5(6H)-one;
4-(oxetan—3-ylamino)[2-(quinolinyl)ethyl]pyrido[2,3-d]pyridazin—5(6H)-
one;
2- [2-(6-methoxypyridin—2-yl)ethyl](pyridin—4-yl)isoquino lin- l ne;
2- [2-(1 ,3 -benzothiazo l-2—yl)ethyl](pyridinyl)isoquino lin- l (2H)-one;
2-[2-(5-methylpyridin—2-y1)ethy1](pyridinyl)isoquinolin-1(2H)-one;
5-[(E)(6-methoxyquinolin—2—yl)ethenyl](pyridinyl)thieno[3,2-c]pyridin—
one;
8-(pyridinyl)[(E)(quinazolinyl)ethenyl]isoquinolin-1 ne;
10 5—[(E)—2-(6—chloroquinolinyl)ethenyl](pyridinyl)thieno[3,2-c]pyridin-
4(5H)-one;
5-[(E)(3 -methquuinolin—2—yl)ethenyl]—3—(pyridin—4-yl)thieno[3,2-c]pyridin-
4(5H)-one;
8-(pyridin—4-yl) [(E)-2—(quinolin—2—yl)ethenyl]isoquino lin- l (2H)-one;
15 5 - [(E)(l zothiazolyl)ethenyl]—3—(pyridin—4-yl)thieno [3 ,2-c]pyridin-
4(5H)-one;
3-(pyridinyl)[(E)(quinolinyl)ethenyl]thieno[3,2-c]pyridin-4(5H)-one;
and the omers, the N-oxides, the prodrugs, the tautomers and the hydrates
thereof, and the pharmaceutically acceptable salts thereof.
20 The compounds of the invention of the general formula I and the starting
materials used to prepare them can be prepared in analogy to known processes of
c chemistry as are described in standard works of organic chemistry, e. g. —
Weyl, "Methoden der Organischen Chemie", Thieme-Verlag, Stuttgart, Jerry March
"Advanced Organic Chemistry", 5th edition, Wiley & Sons and the literature cited
25 therein, and R. Larock, "Comprehensive Organic Transformations", 2Ild edition,
Weinheim, 1999 and the literature cited therein. The compounds of the invention of the
general formula I are advantageously prepared by the methods described below and/or
in the experimental section.
nds of the formula I, wherein Q is oxygen, can be prepared e. g. by
30 reacting a compound of the formula II
O R1a
Het—A\ (n)
T | \ R2
X§X23 X3":l
wherein
X2a is N or C-R7a;
X3a is s, o, N=C(R8), C(R93)=C(R8) or );
Het, A, X1, R2, R6 and R8 are as defined for formulae I, 1-1 .A, I-1.B, I-2.A, I-2.B,
I-1.C, I-2.C, I-1.D, I-2.D, I-3.A, I-4.A, I-3.B, I-4.B, I-3.C, I-4.C, I-3.D,
I-4.D, I-5.A, I-6.A, I-5.B, I-6.B, I-5.C, I-6.C, I-5.D, I-6.D, I-7.A, I-8.A,
I—7.B, I—8.B, I—7.C, I—8.C, I—7.D, I—8.D, I-9.A, I-lO.A,I-9.B, 1-10.B, I-
9.C, I-lO.C, I—9.D or 1—10.D;
10 R”, R”, R921 independently of each other, are selected from the group
consisting of hydrogen, halogen, C1-C4-alkyl, trimethylsilyl, C1-C4-
alkylsulfanyl, alkoxy—C1—C4-alkyl, C1-C4-alkoxy, C1-C4-alkoxy-
C1-C4-alkoxy, C1-C4-alkylsulfanyl-C1-C4-alkoxy, C2-C4-alkenyloxy,
C1-C4-fluoroalkyl, C1-C4-fluoroalkoxy, CN,NRX1RX2, NRXlez-Cl-C4-
15 alkoxy;
ed that l or 2 of the ls Rla, R7a and Rga, in particular exactly one of
these radicals is bromine or iodine, while the others are ent from bromine or
iodine;
with a nd of formula III,
20
M-Y-Cyc (111)
where Y has one of the meanings given for Y1, Y2, and Y3 and Cyc has one of the
meanings given herein for Cyc], Cycz, and Cyc3 and wherein
25 M is a Li, B(ORBI)(ORBZ) radical or an Sn(Rsn)3 radical, where RBl and R132
are, independently of each other, hydrogen or C1-C4-alkyl or RBl and R132
together form a C2—C6—alkandiyl moietyl, e.g. ethan-l,2-diyl, propan—l,3-diyl
or l,l ,2,2-tetramethylethan—1,2—diyl, and wherein R811 is C1-C6-alkyl or C3-
C6-cycloalkyl or phenyl.
102
Amongst the compounds of formula III, where Y is a chemical bond, particular
ence is given to the compounds of formula 111a and, if RBl and R132 are hydrogen,
the trimers thereof.
31
R —O\
/B—Y—Cyc (”13)
RBZ—O
The reaction ofthe nd II with the compound 111 can be performed by
analogy to known coupling reactions in the presence of suitable transition metal
catalysts, in particular palladium catalysts. Typical reactions conditions are those of
Stille coupling (see e.g. Stille et al. Angew. Chem. Int. Ed. Engl. 1986, 25,508;
J. Eluguero et al.; Synthesis 1997, 5, 563—566) or Suzuki coupling (see e.g. A. Suzuki et
10 a1, Chem. Rev. 1995, 95, 2457—2483, N. Zhe et al.; J. Med. Chem. 2005, 48 (5),
609; Young et al.; J. Med. Chem. 2004, 47 (6), 1547-1552; C. Slee et al.; Bioorg.
Med. Chem. Lett. 2001, 9, 253).
In a similar manner, compounds of the formula I, where Y1, Y2 or Y3 is NH or
were Cycl-Yl, Cycz-Y2 or Cyc3-Y3 (Y1, Y2 or Y3 are single bonds) an N—bound
15 heterocycle (Y1, Y2 or Y3 are single bonds) can be prepared by reacting a compound of
the formula II, as defined above, with a compound of the formula III'
H-Y-Cyc (111')
where Y and Cyc are as defined for formula III. The reaction of II with 111' is
ably carried out in an aprotic solvent, such as dimethylsulfoxide, acetonitrile, N-
20 methylpyrrolidone, dimethylformamide, dimethylacetamide, ethyl urea, or
mixtures thereof or mixtures f with halogenated hydrocarbons such as
dichloromethane. The reaction is preferably carried out in the presence of a suitable
base, e.g. an alkalimetal carbonate such as lithium carbonate, sodium carbonate,
potassium carbonate or caesium carbonate or an metal alkoxide.
25 Compounds of the formula I, where Q is O, can also be prepared e. g. by reacting a
compound of the formula 11a
0 1b
R
Het
\A\ ( Ila )
N
1 | \ R2
X§ 2b X3b
103
wherein
X2b is N or C-R7b;
X3b is s, o, N=C(R8), C(Rgb)=C(R8) or N=C(R9);
Het, A, X1, R2 and R8 are as defined for formulae I, 1-1 .A, 1-1 .B, I-2.A, I-2.B, I-
l.C, I-2.C, I-l.D, I-2.D, I-3.A, I-4.A, I-3.B, I-4.B, I-3.C, I-4.C, I-3.D,
I-4.D, I-5.A, I—6.A, I-5.B, I-6.B, I-5.C, I—6.C, I—5.D, I-6.D, I-7.A, I-8.A,
I-7.B, I-8.B, I-7.C, I-8.C, I—7.D, I-8.D, I—9.A, I—lO.A,I—9.B, I-lO.B, I-
9.C,I-10.C,I-9.D or 1-10.D;
Rlb, R713, R9b independently of each other, are selected from the group
10 consisting of hydrogen, alkyl, trimethylsilyl, C1-C4-
ulfanyl, C1-C4-alkoxy-C1-C4-alkyl, alkoxy, C1-C4-alkoxy-
C1-C4—alkoxy, alkylsulfanyl—C1-C4-alkoxy, C2-C4-alkenyloxy,
C1-C4-fluoroalkyl, C1—C4—fluoroalkoxy, CN,NRX1RX2, NRXlez-Cl-C4-
alkoxy or a moiety M;
15 provided that l or 2 of the radicals Rlb, R7b and Rgb, in particular exactly one of
these radicals is moiety M, while the others are different from M, where M is as
defined for formula III and in particular a B(ORB1)(ORB2) radical;
with a compound of formula IIIb,
20 Hal-Y-Cyc (IIIb)
where Y and Cyc are as defined herein and wherein Hal is bromine or .
The reaction of the compound IIa with the compound IIIb can be performed by
analogy tot the reaction of compound II with compound III.
25 The compounds 11, Ha, III, III', 111a and IIIb are known or can be prepared by
standard methods of organic chemistry.
Compounds of the formula I, where Yl-Cycl, YZ-Cyc2 or 3 is a N-bound
radical can be obtained by a coupling reaction between the compound II and the
corresponding amine in the presence of a palladium catalyst in terms of a Buchwald-
30 Hartwig reaction. Suitable ium catalyst are for example tris-(dibenzylidene-
acetone)dipalladium(0) (Pd2(dba)3), [1,1—bis(diphenylphosphino)ferrocene]dichloropalladium
(II) (PdC12(dppf)) or palladium acetate (Pd(OAc)2). The reaction is usually
104
carried out in the presence of a bstituted)phosphine, e.g. a triarylphosphine such as
triphenylphosphine, tritolylphosphine or 2,2'-bis(diphenylphosphino)-1,1'-binaphthalene
(BINAP), tri(cyclo)alkylphosphine such as tris—n-butylphosphine, ertbutyl
hine or tris(cyclohexylphosphine), or ohexyl-(Z',4',6'-tri-iso-propyl—
biphenylyl)-phosphane (X-Phos). Usually, the reaction is performed in the presence
of a base such as an alkaline alkoxide, earth alkine alkoxide, alkaline carbonate or earth
ne carbonate such as or sodium tert—butoxide or cesium carbonate.
Compounds of the formula I (or likewise the compounds 11), where Q is O and A
is a radical A1 can be prepared according to the following reaction schemes 1 and 2 by
10 successively reacting compounds of the formulae V or Va, respectively with a le
hydroxy compound IV, in terms of a Mitsunobu reaction.
Schemel:
6
R R5 0 R1 R4 R3 O R1
Hetitem ”TiaHet
HN
MT |\ R2
R R3 X§X2 X3 R R X§X2
X3
(IV) (V) (I)
15
Scheme2:
(IV) (Va) (II)
In schemes 1 and 2, X1, X2, X3, X23, X”, R], R”, R2, R3, R4, R5, R6 and Het are as
20 defined above. Compounds of the formulae V and Va, respectively, can be prepared in
analogy to known methods, e. g. as described in Natl. Symposium Vacuum Technol,
Chicago, (Trans), 161-3; 1956, Journal of Organic Chemistry, , 3849-3 855;
2009, or Journal of Heterocyclic Chemistry, 8(1), 57—60; 1971.
105
Alternatively, compounds ofthe formula I (or likewise the compounds II), where
Q is O and A is a radical A1 can be prepared by hydrogenation of nds of the
formula I (or likewise the nds II), where A is A3.
Compounds of the formula I (or se the compounds II), where Q is O and A
is a radical A3 can be prepared according to the following reaction schemes 3 and 4 by
sively reacting compounds of the formulae V or Va, respectively with a suitable
halocompound VI.
Scheme 3:
R5 0 R1 R4 0 R1
HetM‘g‘Hal Het
+ HN | \ R2 —> \ 2
4 X1\ ’LYA'T‘
3 1 l R
R \XZ X R5 X§X2 X3
10 (VI) (V) (I)
Scheme 4:
R5 0 R13 R4 O R1a
HetNyHal
+ HTJfiRZ —> HetQ/5 'l‘
l \ R2
R X§X23 X3a R X1§X28 X3a
(VI) (Va) (II)
In schemes 3 and 4, X1, X2, X3, X23, X33, R1, R13, R2, R4, R5 and Het are as defined
15 above. Hal is halogen, preferably bromine or iodine. The reaction is usually performed
in the presence of a base. Suitable bases are alkali metal carbonates and hydrogen
carbonates or earth metal carbonates and hydrogencarbonates such as cesium carbonate.
Compounds of the formula I (or likewise the compounds II), where Q is O and A
is a radical A4 can be ed according to the following reaction schemes 5 and 6 by
20 successively reacting compounds of the formulae V or Va, respectively with a suitable
halocompound VII.
Scheme 5:
O 1
R
Het
A. 4
R5 AI R
WHEN + HN \
1, I R2 _> O
5
Het R4 X§X2 X3 R N
x1\< R
(VII) X2 /
(V) \
(I)
X3 R2
Scherne6:
O R1a
Het A' R4
5
R:{§.HalAl + '3‘ |\ Rz_,R5 o
\ 3a
R4 \X2a X Xl/N R1 a Het
\\2a /
(VII) (Va) (n) x 3\
X3 R2
In schemes 5 and 6, X1, X2, X3, X23, X33, R1, R”, R2, R4, R5, A’ and Het are as
defined above. Hal is halogen, preferably bromine or iodine. The reaction is usually
performed in the presence of a base. Suitable bases are alkali metal carbonates and
hydrogen carbonates or earth metal carbonates and hydrogencarbonates such as cesium
carbonate.
10 Alternatively, compounds ofthe formula I (or likewise the nds II), where
Q is O and A is a radical A4 with A' being a CR3bR3c (R3b and R30 are as defined above)
can be ed by cyclopropanation of compounds of the formula I (or likewise the
compounds II), where A is A3, in terms of a Simmon—Smith reaction. Compounds of the
formula I (or likewise the compounds 11), where Q is O and A is a radical A4 with A'
15 being a O can be prepared by epoxidation of compounds ofthe formula I (or likewise
the compounds 11), where A is A3, using hydrogen peroxide.
Compounds of the formula I (or likewise the compounds 1]), where A is a l
A4 can be ed in the form of enantiomers, for example as racemate, in the form of
a mixture of enanantiomers, as pure enantiomers or in the form of diastereomers.
20 nds of the formula I (or likewise the compounds 11), where Q is O and A
is a radical A5 can be prepared according to the following on schemes 7 and 8 by
reacting compounds of the formulae V or Va, respectively with a suitable
mpound VIII under basic conditions for a longer period.
107
Scheme7
3e 5
R36 R3f O R1 R R3f R
Het R4
4 o
R5 Het R _.
Hal
+ HI}! I \ R2 _> o /
R36 N 1
X1 R5 3fX1/ R
3
Ht R4 \X2 x N
R1 R
X1] \\)(2 /
\\ \
(VIII) (V) x2 /3\ x3 R2
(I)
X R2 (I)
A : A4
A=A5
Scheme8
5
0 RS‘a Ref Het R5
3e R16‘ flR4 R 3f
R Het 4
R 0
5
R
Hal + W l \ R2 _> O _> R38 R3fN 1,
X1\ 5
3a R
N XI’ R
Het R4 \Xza X
x1< R13 \\X2a /
\ l
(VII) (Va) (II) X2a / \ X3:11 2
x33 R2 (II)
A=A4
A=A5
In schemes 7 and 8, X1, X2, X3, Xza, X3a, R1, R”, R2, R36, R“, R4, R5, and Het are
as defined above. Hal is halogen, preferably bromine or iodine. The reaction is usually
10 med in the presence of a base. Suitable bases are alkali metal carbonates and
hydrogen ates or earth metal carbonates and encarbonates such as cesium
carbonateApart from that, compounds of the formula I and likewise compounds ofthe
formula II, where Q is S can be prepared by successively reacting compounds of the
formulae I and II, where Q is O with a suitable sulfurizing agent, such as Lawenson's
15 reagent or P285.
The N—oxides of compound I may be prepared from the compounds of formula 1
according to conventional oxidation methods, for e by treating said compounds
with an organic d; such as metachloroperbenzoic acid or 3-chloroperbenzoic acid
[Journal of Medicinal Chemistry 38(11), 1892-1903 (1995), WO 03/64572]; or with
20 inorganic oxidizing agents; such as hydrogen peroxide [cf. l of Heterocyclic
Chemistry 18 (7), 1305—1308 (1981)] or oxone [cf. Journal ofthe American al
Society 123(25), 5962—5973 (2001)]. The oxidation may lead to pure mono-N—oxides or
to a mixture of different N—oxides, which can be separated by conventional methods;
such as chromatography.
108
nds of the formula Ila can be prepared from compounds of the formula II
by suitable metal-halogen exchange reactions.
The nds of the formulae III, IIIa, IV, V and Va are well known in the art
or can be prepared by anology to well established reactions of organic synthetic
chemistry or by analogy to the methods as bed in standard works of organic
chemistry, e.g. —Weyl, "Methoden der Organischen Chemie", -Verlag,
Stuttgart, Jerry March "Advanced Organic Chemistry", 5th edition, Wiley & Sons and
the literature cited therein, and R. Larock, "Comprehensive Organic ormations",
2nd edition, im, 1999 and the literature cited therein. Compounds of the formula
10 VI can be prepared in analogy to known methods, e.g in terms of a Wittig reaction.
Compounds of the formula VII can be prepared in analogy to known methods. E. g.,
compounds of the formula VII, where A' is CR3bR3C can be prepared by
cyclopropanation of compounds VI in terms of a Simmon—Smith reaction.
The reactions are usually performed in an organic t, including aprotic
15 organic solvent, e.g. substituted amides, lactames and ureas; such as
dimethylformamide, dimethylacetamide, N—methylpyrrolidone, tetramethyl urea, cyclic
ethers; such as dioxane, tetrahydrofurane, halogenated hydrocarbons; such as
romethane, and mixtures thereof as well as mixtures thereof with C1-C6-alkanols
and/or water.
20 The ons described above will be usually med at temperatures ranging
from -10°C to 100°C, depending on the reactivity of the used compounds.
The reaction mixtures are worked up in a conventional way, e.g. by mixing with
water, ting the phases and, where appropriate, ing the crude products by
chromatography. The intermediates and final products in some cases result in the form
25 of colorless or pale brownish, viscous oils which are freed of volatiles or purified under
reduced pressure and at moderately elevated temperature. If the intermediates and final
products are obtained as solids, the purification can also take place by recrystallization
or digestion.
Due to their capability of inhibiting PDE10A at low concentrations, the
30 compounds of the formula 1, their N—oxides, their hydrates, their tautomers and their
prodrugs and the pharmaceutically acceptable salts thereof, are particularly suitable for
treating disorders or ions, which can be treated by inhibition ofphosphodiesterase
109
type 10A. The terms "treating" and ment" in terms of the present invention have to
be understood to e both curative treatment of the cause of a disease or disorder,
the treatment of the symptoms associated with a disease or disorder, i.e. controlling the
e or disorder or ameliorating the conditions or symptoms associated with a
disease or disorder, and prophylactic treatment, i.e. a treatment for reducing the risk of a
disease or disorder.
Neurological and psychiatric disorders or conditions which can be treated by
inhibition of PDElOA, including curative treatment, control or amelioration and
prophylaxis, include CNS disorders, in particular schizophrenia, depression, bipolar
10 disorders, cognitive dysfunctions associated with phrenia, cognitive ctions
associated with Alzheimer's disease, Huntington's disease (Huntington chorea), anxiety
and substance-related disorders, especially substance use disorder, substance tolerance
conditions associated with substance withdrawal. Disorders or conditions which can be
treated by inhibition of PDElOA, including curative treatment, control or amelioration
15 and laxis, also include treatment of diet induced obesity.
Thus, the invention relates to the use of compounds of formula 1, their N—oxides,
their hydrates, their tautomers and their prodrugs and the pharmaceutically acceptable
salts thereof, for ent of disorders or conditions, which can be treated by inhibition
phodiesterase type 10A, i.e. the invention relates to the use of such compounds
20 for curative treatment of such a disease or disorder, controlling such a disease or
disorder, ameliorating the ms associated with such a disease or disorder and
reducing the risk for such a disease or disorder.
The present invention also relates to a method for the ent of a l
disorder, selected from neurological and psychiatric disorders which can be d by
25 tion ofphosphodiesterase type 10A, said method comprising administering an
effective amount of at least one compound, selected from the group of compounds of
formula 1, their N-oxides, their hydrates, their tautomers, their prodrugs and the
pharmaceutically acceptable salts thereof, to a mammal in need thereof.
The present ion in ular relates to:
30 o a method for treating, controlling, ameliorating or reducing the risk of
schizophrenia in a mammalian;
110
o a method for treating, controlling, ameliorating or reducing the risk of
cognitive disturbances associated with schizophrenia in a mammalian;
o a method for treating, controlling, rating or ng the risk of
sion in a mammalian;
o a method for treating, controlling, ameliorating or reducing the risk of
bipolar disorders in a mammalian;
o a method for treating or ameliorating the symptoms associated with
substance use ers in a mammalian;
o a method for treating or ameliorating the symptoms associated with diet-
10 induced y in a mammalian;
o a method for treating, controlling, ameliorating or reducing the risk of
cognitive disturbances associated with Alzheimer's e in a mammalian;
o a method for treating, lling, ameliorating or reducing the risk of
behavioral symptoms in Alzheimer's disease;
15 0 a method for ng, controlling, ameliorating or reducing the risk of
anxiety in a mammalian;
o a method for treating, controlling, ameliorating or reducing the risk of
Huntington's disease in a mammalian;
which methods comprising administering an effective amount of at least one
20 compound, selected from the group of compounds of a 1, their N—oxides, their
hydrates, their tautomers, their prodrugs and the pharmaceutically acceptable salts
thereof, to a mammal in need thereof.
The t treated in the present methods is generally a mammal, preferably a
human being, male or female, in whom tion of PDElOA is desired. The terms
25 "effective amoun " and "therapeutically effective amount" mean the amount ofthe
subject compound that will elicit the biological or medical response of a tissue, system,
animal or human that is being sought by the researcher, veterinarian, medical doctor or
other clinician. It is recognized that one skilled in the art may affect the neurological
and psychiatric disorders by treating a patient presently ed with the disorders or
30 by prophylactically ng a patient afflicted with the disorders with an effective
amount of the compound of the present invention. As used herein, the terms "treatment"
and "treating" refer to all processes, wherein there may be a slowing, interrupting,
1 1 1
arresting, controlling, or stopping of the progression of the disorders described herein,
but does not necessarily indicate a total elimination of all disorder symptoms, as well as
the prophylactic therapy of the ned ions, ularly in a patient who is
predisposed to such disease or disorder. The term "composition" as used herein is
intended to encompass a product comprising the specified ingredients in the specified
s, as well as any product which results, directly or indirectly, from combination
ofthe specified ingredients in the specified amounts. Such term in relation to
pharmaceutical composition, is intended to encompass a product comprising the active
ingredient(s), and the inert ingredient(s) that make up the carrier, as well as any product
10 which results, directly or indirectly, from ation, complexation or aggregation of
any two or more of the ingredients, or from dissociation of one or more of the
ingredients, or from other types ofreactions or ctions of one or more of the
ingredients. Accordingly, the pharmaceutical compositions of the t invention
encompass any composition made by ng a compound of the present invention
15 and a pharmaceutically acceptable carrier. By "pharmaceutically acceptable" it is meant
the carrier, t or excipient must be compatible with the other ingredients of the
formulation and not rious to the recipient thereof.
The terms "administration of and or "administering a" compound should be
understood to mean providing a compound of the invention or a prodrug of a compound
20 ofthe invention to the individual in need of treatment.
A preferred ment ofthe present invention provides a method for treating
schizophrenia, comprising: administering to a patient in need thereof an ive
amount of at least one compound, selected from the group of compounds of formula 1,
their N—oxides, their hydrates, their tautomers, their prodrugs and the pharmaceutically
25 acceptable salts thereof.
In another preferred ment, the present invention provides a method for
treating cognitive disturbances associated with schizophrenia, comprising:
administering to a t in need thereof an effective amount of at least one compound,
selected from the group of compounds of formula 1, their N-oxides, their hydrates, their
30 tautomers, their prodrugs and the pharmaceutically able salts thereof
At present, the fourth edition of the Diagnostic and Statistical Manual of Mental
Disorders (DSM-IV) (1994, American Psychiatric Association, Washington, DC),
1 12
provides a stic tool including schizophrenia and other tic disorders. These
include: disorders having psychotic symptoms as the g feature. The term
psychotic refers to delusions, prominent hallucinations, disorganized ,
disorganized or catatonic behavior. The disorder includes: paranoid, anized,
catatonic, undifferentiated, and residual schizophrenia, schizophreniform disorder,
schizoaffective disorder, delusional disorder, brief psychotic disorder, shared psychotic
er, psychotic disorder due to a general l ion, substance-induced
psychotic er, and psychotic disorder not otherwise specified. The skilled artisan
will recognize that there are alternative nomenclatures, nosologies, and classification
10 systems for neurological and psychiatric disorders, and particular schizophrenia, and
that these systems evolve with medical scientific progress. Thus, the term
"schizophrenia" is intended to include like disorders that are described in other
diagnostic sources.
In another preferred embodiment, the present invention provides a method for
15 treating substance-related disorders, comprising: administering to a patient in need
thereof an effective amount of at least one compound, selected from the group of
compounds of formula 1, their es, their es, their tautomers, their prodrugs
and the pharmaceutically able salts thereof.
In another preferred embodiment, the present invention provides a method for
20 treating anxiety, comprising: administering to a patient in need thereof an effective
amount of at least one compound, selected from the group of compounds of formula 1,
their N—oxides, their hydrates, their tautomers, their prodrugs and the pharmaceutically
acceptable salts thereof. At present, the fourth n of the Diagnostic and Statistical
Manual of Mental Disorders (DSM-IV) (1994, American Psychiatric Association,
25 Washington, DC), provides a diagnostic tool ing y and related disorders.
These include: panic disorder with or without agoraphobia, agoraphobia without history
ofpanic disorder, specific phobia, social phobia, obsessive-compulsive er, post-
tic stress disorder, acute stress disorder, generalized anxiety disorder, anxiety
disorder due to a general medical condition, substance-induced anxiety disorder and
30 anxiety disorder not otherwise specified. As used herein the term "anxiety" es
treatment of those anxiety disorders and related disorder as described in the DSM-IV.
The skilled artisan will recognize that there are alternative nomenclatures, nosologies,
1 13
and classification systems for neurological and psychiatric ers, and particular
anxiety, and that these systems evolve with medical scientific progress. Thus, the term
"anxiety" is intended to include like ers that are described in other diagnostic
sources.
In another preferred embodiment, the present invention provides a method for
treating depression, comprising: administering to a patient in need thereof an effective
amount of at least one compound, selected from the group of compounds of formula 1,
their N-oxides, their hydrates, their tautomers, their prodrugs and the pharmaceutically
acceptable salts thereof. At present, the fourth edition of the Diagnostic and Statistical
10 Manual of Mental Disorders (DSM-IV) (1994, American atric Association,
gton, DC), provides a diagnostic tool ing depression and d
disorders. Depressive ers include, for example, single episodic or ent major
sive disorders, and dysthymic disorders, depressive neurosis, and neurotic
depression; holic depression including anorexia, weight loss, insomnia and early
15 morning waking, and psychomotor retardation; atypical depression (or reactive
depression) including increased appetite, hypersomnia, psychomotor ion or
irritability, anxiety and phobias; seasonal affective disorder; or bipolar disorders or
manic depression, for example, bipolar] disorder, bipolar II disorder and cyclothymic
er. As used herein the term "depression" includes treatment of those depression
20 disorders and related er as described in the DSM-lV.
In another preferred embodiment, the present invention provides a method for
treating nce-related disorders, especially substance dependence, substance abuse,
substance tolerance, and substance withdrawal, comprising: administering to a patient in
need thereof an effective amount at least one compound, selected from the group of
25 compounds of formula 1, their N—oxides, their hydrates, their tautomers, their prodrugs
and the pharmaceutically acceptable salts thereof. At present, the fourth edition of the
Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) (1994, American
Psychiatric Association, Washington, DC), provides a stic tool including
disorders related to taking a drug of abuse ding alcohol), to the side effects of a
30 medication, and to toxin exposure. Substances e alcohol, amphetamine and
similarly acting sympathomimetics, caffeine, cannabis, cocaine, hallucinogens,
inhalants, nicotine, opioids, phencyclidine (PCP) or similarly acting
1 14
arylcyclohexylamines, and sedatives, hypnotics, or anxiolytics. Also, polysubstance
dependence and other n substance-related disorders are included. The skilled
artisan will recognize that there are alternative nomenclatures, nosologies, and
classification systems for neurological and psychiatric disorders, and particular
substance-related disorders, and that these systems evolve with medical scientific
ss. Thus, the term "substance-related disorder" is intended to include like
ers that are described in other diagnostic s.
In the treatment, prevention, control, amelioration, or reduction of risk of
conditions which require inhibition of PDE10A an appropriate dosage level will
10 generally be about 0.01 to 500 mg per kg patient body weight per day which can be
administered in single or multiple doses. Preferably, the dosage level will be about 0.1
to about 250 mg/kg per day; more preferably about 0.5 to about 100 mg/kg per day. A
le dosage level may be about 0.01 to 250 mg/kg per day, about 0.05 to 100 mg/kg
per day, or about 0.1 to 50 mg/kg per day. Within this range the dosage may be 0.05 to
15 0.5, 0.5 to 5 or 5 to 50 mg/kg per day. For oral administration, the compositions are
preferably provided in the form of tablets containing 1.0 to 1000 milligrams of the
active ingredient, particularly 1.0, 5.0, 10.0, 15.0, 20.0, 25.0, 50.0, 75.0, 100.0, 150.0,
200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0, and 1000.0 milligrams of
the active ingredient for the symptomatic adjustment of the dosage to the patient to be
20 treated. The compounds may be administered on a regimen of l to 4 times per day,
ably once or twice per day. When ng, preventing, controlling, rating,
or reducing the risk of neurological and psychiatric disorders or other diseases for which
compounds of the present invention are indicated, generally satisfactory results are
obtained when the compounds ofthe present invention are administered at a daily
25 dosage of from about 0.1 milligram to about 100 milligram per kilogram of animal body
weight, preferably given as a single daily dose or in divided doses two to six times a
day, or in sustained release form. For most large s, the total daily dosage is
from about 1.0 milligrams to about 1000 milligrams, preferably from about 1 milligram
to about 50 milligrams, in the case of a 70 kg adult human, the total daily dose will
30 generally be from about 7 rams to about 350 milligrams. This dosage regimen
may be adjusted to provide the optimal therapeutic response. It will be understood,
however, that the specific dose level and frequency of dosage for any particular patient
1 15
may be varied and will depend upon a variety of factors including the activity of the
specific compound employed, the metabolic stability and length of action of that
compound, the age, body weight, general health, sex, diet, mode and time of
administration, rate of excretion, drug combination, the severity of the ular
condition, and the host undergoing therapy.
The compounds of the present invention may be administered by conventional
routes of administration, including parenteral (e.g., intramuscular, intrapentoneal,
intravenous, ICV, intracisternal injection or infiision, subcutaneous ion, or
implant), oral, by inhalation spray, nasal, vaginal, rectal, sublingual, or l routes of
10 administration.
The compounds according to the present invention are further useful in a method
for the prevention, treatment, control, ration, or reduction of risk of the
aforementioned diseases, disorders and conditions in combination with other agents.
The nds of the present invention may be used in combination with one or
15 more other drugs in the treatment, prevention, control, amelioration, or ion of risk
of diseases or conditions for which compounds of Formula I or the other drugs may
have utility, where the combination ofthe drugs together are safer or more effective
than either drug alone. Such other drug(s) may be administered, by a route and in an
amount commonly used therefore, poraneously or tially with a compound
20 of Formula I. When a compound of formula I is used contemporaneously with one or
more other drugs, a ceutical composition in unit dosage form containing such
other drugs and the compound of formula I is preferred. However, the combination
therapy may also include therapies in which the nd of formula I and one or more
other drugs are administered on different overlapping schedules. It is also contemplated
25 that when used in combination with one or more other active ingredients, the
compounds of the present invention and the other active ingredients may be used in
lower doses than when each is used singly. Accordingly, the ceutical
compositions of the present invention include those that contain one or more other
active ingredients, in on to a compound of a I. The above combinations
30 include combinations of a compound ofthe present invention not only with one other
active compound, but also with two or more other active compounds.
1 16
Likewise, compounds of the present invention may be used in combination with
other drugs that are used in the prevention, treatment, control, amelioration, or reduction
ofrisk of the es or conditions for which compounds of the present invention are
useful. Such other drugs may be stered, by a route and in an amount commonly
used therefore, contemporaneously or sequentially with a compound of the present
invention. When a compound ofthe t invention is used contemporaneously with
one or more other drugs, a pharmaceutical composition containing such other drugs in
addition to the compound of the present ion is preferred. Accordingly, the
pharmaceutical compositions ofthe present invention include those that also n
10 one or more other active ingredients, in addition to a compound of the present
invention.
The weight ratio of the compound of the compound of the present invention to the
second active ingredient may be varied and will depend upon the effective dose of each
ingredient. Generally, an effective dose of each will be used. Thus, for example, when a
15 compound of the present invention is combined with another agent, the weight ratio of
the compound of the present invention to the other agent will generally range from
about 1000: l to about , preferably about 200:1 to about 1:200. Combinations of
a nd of the present invention and other active ingredients will generally also be
within the aforementioned range, but in each case, an ive dose of each active
20 ingredient should be used. In such combinations the compound of the present invention
and other active agents may be administered separately or in ction. In addition,
the administration of one element may be prior to, rent to, or subsequent to the
stration of other agent(s).
The present invention also relates to pharmaceutical compositions (i.e.
25 medicaments) which comprise at least one compound of the present invention and,
where appropriate, one or more suitable excipients.
These excipients/drug carriers are chosen according to the pharmaceutical form
and the desired mode of administration.
The compounds of the present invention can be used to manufacture
30 pharmaceutical compositions for parenteral (e.g., intramuscular, intrapentoneal,
intravenous, ICV, intracistemal injection or infusion, subcutaneous injection, or
implant), oral, sublingual, intratracheal, intranasal, l, transdermal, vaginal or
1 17
rectal administration, and be administered to animals or humans in unit dose forms,
mixed with conventional pharmaceutical carriers, for the prophylaxis or treatment of the
above impairments or diseases.
In the pharmaceutical compositions, the at least one compound of the present
invention may be formulated alone or together with fiarther active compounds, in
suitable dosage unit formulations containing conventional ents, which generally
are non-toxic and/or pharmaceutically acceptable. Carriers or excipients can be solid,
semisolid or liquid materials which serve as vehicles, carriers or medium for the active
compound. le excipients are listed in the specialist medicinal monographs. In
10 addition, the formulations can se pharmaceutically acceptable carriers or
ary auxiliary substances, such as glidants; wetting ; emulsifying and
suspending agents; preservatives; antioxidants; antiirritants; chelating agents; coating
auxiliaries; emulsion stabilizers; film formers; gel s; odor g agents; taste
corrigents; resin; hydrocolloids; solvents; solubilizers; neutralizing ; diffusion
15 accelerators; pigments; quaternary ammonium compounds; refatting and overfatting
agents; raw materials for ointments, creams or oils; silicone derivatives; spreading
auxiliaries; stabilizers; ants; suppository bases; tablet auxiliaries, such as binders,
fillers, glidants, disintegrants or coatings; propellants; drying agents; opacifiers;
thickeners; waxes; plasticizers and white mineral oils. A formulation in this regard is
20 based on specialist knowledge as described, for example, in r, H. P., Lexikon der
Hilfsstoffe fur Pharmazie, Kosmetik und angrenzende Gebiete lopedia of
auxiliary substances for pharmacy, cosmetics and related fields], 4th edition, Aulendorf:
ECV-Editio-Kantor-Verlag, 1996.
Suitable unit dose forms include forms for oral administration, such as tablets,
25 gelatin capsules, powders, granules and solutions or suspensions for oral , forms
for sublingual, buccal, intratracheal or intranasal administration, aerosols, implants,
forms of subcutaneous, intramuscular or intravenous administration and forms of rectal
administration.
The compounds of the invention can be used in creams, nts or s for
30 topical administration.
1 18
If a solid composition is ed in the form of tablets, the main ingredient is
mixed with a pharmaceutical carrier such as gelatin, starch, lactose, magnesium te,
talc, silicon dioxide or the like.
The s may be coated with sucrose, a cellulose derivative or another suitable
substance or be treated otherwise in order to display a prolonged or delayed ty and
in order to release a predetermined amount of the active basic ingredient continuously.
A preparation in the form of gelatin capsules is obtained by mixing the active
ingredient with an extender and taking up the resulting mixture in soft or hard gelatin
capsules.
10 A preparation in the form of a syrup or elixir or for administration in the form of
drops may comprise active ingredients together with a sweetener, which is preferably
calorie-free, methylparaben or propylparaben as antiseptics, a flavoring and a suitable
coloring.
The water-dispersible powders or granules may comprise the active ingredients
15 mixed with dispersants, wetting agents or suspending agents such as
polyvinylpyrrolidones, and ners or taste improvers.
Rectal administration is achieved by the use of suppositories which are prepared
with binders which melt at the rectal temperature, for example cocobutter or
polyethylene s. Parenteral administration is effected by using aqueous
20 sions, isotonic salt solutions or sterile and injectable solutions which comprise
pharmacologically suitable dispersants and/or wetting , for example propylene
glycol or polyethylene glycol.
The active basic ingredient may also be formulated as microcapsules or
mes/centrosomes, if suitable with one or more carriers or additives.
25 In addition to the compounds of the general formula I, their prodrugs, their N-
, their tautorners, their hydrates or their pharmaceutically suitable salts, the
compositions ofthe invention may comprise further active basic ingredients which may
be beneficial for the ent of the impairments or diseases indicated above.
The present invention thus further relates to pharmaceutical compositions in
30 which a plurality of active basic ingredients are present together, where at least one
thereof is a compound of the invention.
1 19
When producing the pharmaceutical compositions, the compounds according to
the invention are optionally mixed or diluted with one or more rs.
The compounds of the invention also include those compounds in which one or
more atoms have been replaced by their , non-radioactive es, for example, a
hydrogen atom by deuterium.
Stable isotopes (e.g., deuterium, 13’C, 15 N, 18O) are nonradioactive isotopes which
contain one additional neutron than the ly abundant isotope of the respective
atom. Deuterated compounds have been used in ceutical research to investigate
the in vivo metabolic fate of the compounds by evaluation of the mechanism of action
10 and metabolic pathway of the non deuterated parent compound (Blake et al. J. Pharm.
Sci. 64, 3, 367-391 (1975)). Such metabolic studies are important in the design of safe,
effective therapeutic drugs, either because the in vivo active compound administered to
the patient or because the metabolites ed from the parent compound prove to be
toxic or carcinogenic (Foster et al., Advances in Drug ch Vol. 14, pp. 2-36,
15 Academic press, London, 1985; Kato et al., J. Labelled Comp. Radiopharmaceut.,
:927-932 (1995); Kushner et al., Can. J. Physiol. Pharmacol., 77, 79-88 (1999).
Incorporation of a heavy atom particularly substitution of deuterium for en,
can give rise to an isotope effect that could alter the pharmacokinetics of the drug. This
effect is usually insignificant if the label is placed at a metabolically inert position of the
20 molecule.
Stable isotope labeling of a drug can alter its physico-chemical properties such as
pKa and lipid solubility. These changes may influence the fate of the drug at different
steps along its passage through the body. Absorption, distribution, metabolism or
excretion can be changed. Absorption and distribution are processes that depend
25 primarily on the molecular size and the lipophilicity ofthe substance. These effects and
alterations can affect the pharmacodynamic response of the drug molecule if the
isotopic substitution affects a region involved in a -receptor interaction.
Drug metabolism can give rise to large isotopic effect if the ng of a
chemical bond to a deuterium atom is the rate limiting step in the process. While some
30 ofthe physical properties of a stable isotope—labeled le are different from those
ofthe unlabeled one, the chemical and biological properties are the same, with one
important exception: because of the increased mass of the heavy isotope, any bond
120
ing the heavy isotope and another atom will be stronger than the same bond
between the light isotope and that atom. In any reaction in which the breaking of this
bond is the rate limiting step, the on will proceed slower for the molecule with the
heavy isotope due to "kinetic isotope effect". A reaction involving breaking a C--D
bond can be up to 700 percent slower than a similar reaction involving breaking a C--H
bond. If the C--D bond is not involved in any of the steps leading to the metabolite,
there may not be any effect to alter the behavior of the drug. If a deuterium is placed at
a site involved in the metabolism of a drug, an isotope effect will be observed only if
ng of the C--D bond is the rate limiting step. There is evidence to t that
10 whenever cleavage of an aliphatic C--H bond occurs, usually by oxidation catalyzed by
a mixed-function oxidase, replacement of the en by deuterium will lead to
able e effect. It is also important to understand that the incorporation of
deuterium at the site of metabolism slows its rate to the point where another metabolite
produced by attack at a carbon atom not substituted by ium becomes the major
15 pathway a process called "metabolic switching".
Deuterium tracers, such as deuterium—labeled drugs and doses, in some cases
edly, of thousands of milligrams of deuterated water, are also used in healthy
humans of all ages, including neonates and pregnant women, without reported incident
(e.g. Pons G and Rey E, rics 1999 104: 633; Coward W A et al., Lancet 1979 7:
20 13; Schwarcz H P, Control. Clin. Trials 1984 5(4 Suppl): 573; Rodewald L E et al., J.
Pediatr. 1989 114: 885; Butte N F et al. Br. J. Nutr. 1991 65: 3; MacLennan A H et al.
Am. J. Obstet l. 1981 139: 948). Thus, it is clear that any deuterium released, for
instance, during the metabolism of compounds of this invention poses no health risk.
The weight percentage of hydrogen in a mammal (approximately 9%) and natural
25 abundance of deuterium (approximately 0.015%) indicates that a 70 kg human normally
contains nearly a gram of deuterium. Furthermore, replacement of up to about 15% of
normal hydrogen with ium has been effected and maintained for a period of days
to weeks in mammals, including rodents and dogs, with minimal observed adverse
effects (Czajka D M and Finkel A J, Ann. NY. Acad. Sci. 1960 84: 770; Thomson J F,
30 Ann. New York Acad. Sci 1960 84: 736; Czakja D M eta1., Am. J. l. 1961 201:
357). Higher deuterium concentrations, usually in excess of 20%, can be toxic in
animals. However, acute replacement of as high as 15%-23% of the hydrogen in
121
humans' fluids with deuterium was found not to cause toxicity j evic N et al. in
"Dosimetry & Treatment Planning for Neutron Capture Therapy", Zamenhof R, Solares
G and Harling O Eds. 1994. Advanced Medical Publishing, Madison Wis. pp. 125-134;
es Metab. 23: 251 (1997)).
Increasing the amount of deuterium present in a compound above its natural
abundance is called ment or deuterium-enrichment. Examples of the amount of
enrichment include from about 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 16, 21, 25, 29, 33, 37,
42, 46, 50, 54, 58, 63, 67, 71, 75, 79, 84, 88, 92, 96, to about 100 mol %.
The hydrogens present on a particular c nd have different ties
10 for ge with ium. Certain hydrogen atoms are easily exchangeable under
physiological conditions and, if replaced by deuterium atoms, it is expected that they
will readily exchange for protons after administration to a patient. Certain hydrogen
atoms may be exchanged for deuterium atoms by the action of a deuteric acid such as
D2S04/D20. Alternatively, deuterium atoms may be incorporated in various
15 combinations during the synthesis of compounds ofthe invention. Certain hydrogen
atoms are not easily exchangeable for deuterium atoms. However, deuterium atoms at
the remaining positions may be incorporated by the use of deuterated ng materials
or intermediates during the construction of compounds of the invention.
Deuterated and deuterium-enriched compounds of the invention can be prepared
20 by using known methods described in the literature. Such methods can be carried out
utilizing corresponding deuterated and optionally, other isotope-containing reagents
and/or intermediates to synthesize the compounds delineated herein, or invoking
standard synthetic protocols known in the art for introducing ic atoms to a
chemical structure. Relevant procedures and intermediates are disclosed, for instance in
25 Lizondo, J et al., Drugs Fur, , 1116 (1996); Brickner, S J et al., JMed Chem,
39(3), 673 (1996); Mallesham, B et al., Org Lett, 5(7), 963 (2003); PCT publications
W01997010223, WO2005099353, W01995007271, W02006008754; US Patent Nos.
7538189; 7534814; 7531685; 7528131; 1; 7514068; 3; and US Patent
Application Publication Nos. 20090137457; 20090131485; 20090131363;
30 20090118238; 20090111840; 20090105338; 05307; 20090105147;
20090093422; 88416; 20090082471, the methods are hereby incorporated by
reference.
122
The following examples are intended for further illustration of the present
invention.
Abbreviations which have been used in the descriptions of the s and the
Examples that follow are: BINAP for 2,2'—bis (diphenylphosphino)-l,l'—binaphthyl;
DCM for dichloromethane; DEAD for diethyl azodicarboxylate; DIAD for diisopropyl
azodicarboxylate; DMF for dimethylformamide; EA for ethyl acetate; EDCI l-ethyl
(3-dimethylaminopropyl)carbodiimide; Et for ethyl; EX. for EXAMPLE; HMPA for
hexamethylphosphoramide; HOBT for hydroxybenzotriazole; i-Pr for isopropyl; LDA
for lithium diisopropylamide; MeOH for methanol; PE for petroleum ether; Pd2(dba)3
10 for tris (dibenzylideneacetone)dipalladium(0); PdClz(dppf) for 1,1'-bis
(diphenylphosphino)ferrocene—palladium (ID—dichloride; Rt for retension time; TEA for
triethylamine; THF for ydrofuran; TMEDA for N,N,N’,N’-tetramethyl 1,2-
ethanediamine; TMSCl for hylsilyl chloride.
15 LC-MS measurements were run on Agilent 1200 HPLC/6100 SQ .
The compounds I of the invention were d in some cases by preparative
HPLC. The compounds I then result as the salts.
Preparation Examples
20
1. Preparation of intermediates
The starting materials used in the examples are either cially available or
can be synthesized by the average skilled person trained in organic chemistry following
e laboratory practice as outlined, for example in the examples below.
25
a) Preparation of compounds of the general formula Het—Al—OH
a1) 2-Quinolinyl-ethanol
\
/
N
OH
30 al . l) Quinolin—2-yl-acetic acid ethyl ester
123
To a suspension ofvacuum dried Zn dust (6.0 g, 93.8 mmol) in dry THF (100
mL) was added TMSCl (0.5 mL) dropwise over 5 min under N2 atmosphere and under
stirring. The e was d for 30 min and warmed to 45°C. Ethyl bromoacetate
(5.2 mL, 46.9 mmol) was added dropwise Via a e. After addition, the mixture was
stirred at the same temperature for 1 h. After sedation at room temperature for 2 h, a
clear orange solution was formed. The orange solution (50 mL) was carefully sucked
into a syringe through a long needle and added to a mixture of 2—bromoquinoline (2.0 g,
9.6 mmol) and PdC12(dppf) (200 mg, 0.27 mmol) in a three-neck flask. The mixture was
refluxed under N2 for 3 h. The reaction was red with LC-MS. Ethyl acetate (200
10 mL) was added to dilute the mixture and water (50 mL) was added to quench the
reaction. The mixture was filtered through a celite pad. The ion was partitioned
n brine and ethyl acetate. The organic layer was ted, washed with brine
(100 mL), dried over sodium sulfate and concentrated. The residue was purified with
silica column (PE/EA=3: l) to give the title compound as orange oil (1.0 g, 48%). LC-
15 MS (ESI+): m/e 216 (M+H)+, R: 0.62 min.
al .2) 2-Quinolinyl-ethanol
To a cold (0 0C) solution of the compound from Example a1 . la (10 g, 45 mmol) in
THE (200 mL) was added LiAlH4 (2.65 mg, 70 mmol) in small portions over a period
20 of 5 min. The resulting mixture was stirred for 1h. Water was added dropwise very
slowly. Then more water and EA were added. The organic phase was ted, dried
and concentrated. The residue was purified by silica gel chromatography (PE/EA=2: l)
to give the title compound as a yellow solid (2.5 g, 30%). LC-MS (ESI+): m/e 174
(M+H)+, R: 0.75 min.
25
a2) 2-(6-Fluoroquinolinyl)-ethanol
Fm/N
OH
6-Fluoro—2-methquuinoline (1.00 g, 6.20 mmol) and sodium hydroxide were each
added sequentially to the mixture ofHCHO in water. Then 2 mL ofEtOH were added
30 to the mixture. The resulting solution was stirred at about 85 °C overnight. The organic
layer was extracted with EA (3 x 10 mL), collected and dried with anhydrous Na2804,
124
d and concentrated to afford a pink oil. The crude material was purified by
chromatography on silica-gel (eluent: PE/EA=6/1) and then r purified by combi-
fiash chromatography (NH4HC03/Hgo, MeOH/HZO=40%~60%) to give 360 mg of the
title t (yield: 30.3%).
LC-MS: m/e (M+H): 192.7, R: 1.63 min.
a3) 2-Thieno[3,2-b]pyridin-5—yl—ethanol
NH2 NH2 ””2 N 000“
/ / N COOCH
| 213.1} (TL 213.2) I L3)- qj/ 3
a3.4) qj/
S S 8
S /
o 0 /
OH s
H
1 o 4 5
‘CH3 2 3
10
OH CN
Cl
N N
5 fl / \ OH
I a3.6) / \ a3.8) N\
l a3.7) N\
/ I /
/ I
3 / O
s / /
s s
6 7 8 9
N\
9 fl / O‘CHS N\ OH
I a3.10)
—> /
O I
/
3 /
s
10 11
a3.l) Compound (2)
15 To a suspension of LiAlH4 (1.39 g, 36.58 mmol) in anhydrous THF (30 mL) was
added a solution of methyl 3-aminothiophene 2-carboxylate (compound 1, 5.00 g, 31.81
mmol) dropwise at 0 0C. The reaction mixture was stirred at room temperature
overnight. Water (4 mL) was added dropwise to quench the reaction. The mixture was
stirred for 30 min. and then more water was added (10 mL). The solid was filtered off
20 and then washed with NaOH solution (50 mL, 5 N). The filtrate was concentrated in
vacuo and the residue was dissolved in EtOAc (200 mL). The solution was dried over
NaZSO4, d and concentrated in vacuo. The crude solid was used in the next step
without fiirther purification (2.71 g, yield 66%). LC—MS (ESI+): m/e 130 (M+H)+, R:
1.57 min.
25
125
a3.2) Compound (3)
A mixture of compound 2 (8.14 g, 63.00 mmol) and MnOz (32.8 g, 0.378 mol) in
EtOAc (100 mL) was stirred at 30°C for 48 h. The mixture was filtered and the filtrate
was concentrated in vacuo. The residue was used in the next step without further
purification (6.82 g, yield 85%). LC—MS (ESI+): m/e 128 (M+H)+, R: 1.55 min.
a1.3) Compound (4)
To a solution of compound 3 (6.82 g, 53.62 mmol) in EtOH (70 mL) was added a
e of pyruvic acid (9.44 g, 0.107 mol) and NaOH (10.7 g, 0.268 mol) in H20 (70
10 mL) in one portion. The mixture was heated at 60 °C for 2 h, then cooled and extracted
with EtzO/EtOAc (l: l, 30 mL). The aqueous layer was acidified with HCl (2 N) to pH
= 3 at 0°C and the water was removed under d pressure. The residue was co-
evaporated with toluene (50 mL><3) and then used in the next step without further
purification. LC-MS (ESI+): m/e 180 (M+H)+, Rt: 1.50 min.
15
a3.4) Compound (5)
To a mixture of crude nd 4 (7 g, 39 mmol) in methanol (60 mL) was
added thionyl chloride (10 mL) se at 0°C. The reaction mixture was then heated
at 65 °C for 3 h. The excess of solvent was removed under reduced pressure. The
20 residue was diluted with EtOAc (100 mL) and washed with ted NaHC03 aqueous
solution (30 mL><4) and brine (30 mL). The organic layer was dried over Na2S04,
filtered and concentrated in vacuo. The residue was purified on a silica column
(PE/EtOAc = 5: 1, V/V) to afford the title product as an off-white solid (715 mg, total
yield 9.5%). LC-MS (ESI+): m/e 194 (M+H)+, R,: 1.78 min.
25
a3.5) Compound (6)
To a on of compound 5 (100 mg, 0.52 mmol) in THF (2 mL) was added
LiBH4 (11 mg) in one portion. The mixture was allowed to stir at room temperature
overnight. The reaction was quenched with saturated NH4C1 solution, and then extracted
30 with EtOAc (20 mL). The organic layer was washed with brine (10 mL), dried over
Na2S04, d and concentrated in vacuo. The yellow residue was used in the next
step without fiirther purification. LC—MS : m/e 166 (M+H)+, R: 1.44 min.
126
a3.6) Compound (7)
A e of compound 6 (100 mg, crude) and thionyl chloride (1 mL) in DCM (3
mL) was stirred at room temperature for 3 h. The mixture was trated in vacuo.
The residue was diluted with EtOAc (20 mL) and washed with saturated NaHC03
solution (6 mLX4) and brine (6 mL). The organic layer was dried over Na2SO4, filtered
and concentrated in vacuo. The red residue was used in the next step without further
ation. LC-MS (ESI+): m/e 184 (M+H)+, Rt: 1.88 min.
10 a3.7) Compound (8)
A mixture of compound 7 (580 mg, 3.157 mmol) and NaCN (170 mg, 3.473
mmol) in EtOH (12 mL) and H20 (4 mL) was stirred at 50 0C for 60 h. The mixture was
diluted with EtOAc (50 mL) and washed with brine (15 mL><4). The organic layer was
dried over , filtered and concentrated in vacuo. The e was purified on a
15 silica column (PE/EtOAc = 10: 1, v/v) to afford the title product as an off-white solid
(280 mg, yield 51%). LC-MS (ESI+): m/e 175 (M+H)+, Rt: 1.89 min.
a3.8) Compound (9)
A mixture of compound 8 (200 mg, 1.148 mmol), sodium hydroxide (459 mg,
20 11.48 mmol) in EtOH (4 mL) and water (0.5 mL) was stirred at 700C overnight. The
solvent was concentrated, the residue was adjusted to pH=3. The solution was
concentrated. The t was used in the next step without r purification
LC-MS (ESI+): m/e 194 (M+H)+, Rt: 1.16 min
25 a3.9) Compound (10)
To a mixture of 2-(thieno[3,2-b]pyridinyl)acetic acid from Example a3.8 (77
mg, 0.399 mmol) in MeOH (5 mL) was added S002 (0.5 mL, 6.85 mmol) dropwise at
0 0C. The reaction mixture was d at room temperature for 5h. The excess of solvent
was removed under reduced pressure. The residue was diluted with EtOAc (100 mL)
30 and washed with saturated NaHC03 aqueous solution (5 mL><2) and brine (30 mL). The
organic layer was dried over NaZSO4, filtered and concentrated in vacuo. The residue
127
was purified by Pre-TLC (PE/EtOAc = 2:1, v/v) to afford the title product as an oil (55
mg, yield 65%).
LC-MS (ESI+): m/e 208 (M+H)+, Rt: 1.69 min.
a3. 10) 2-Thieno [3 ,2-b]pyridin—5-y1—ethanol
To a on of methyl 2—(thieno[3,2-b]pyridinyl)acetate (70 mg, 0.338 mmol)
from Example a3.9) in THF (4 mL) was added LiBH4 (8.09 mg, 0.372 mmol) in one
portion. The mixture was allowed to stir at room temperature overnight. The reaction
was quenched with saturated NH4Cl solution, and then extracted with EtOAc (3>< 10
10 mL). The organic layer was washed with brine (10 mL), dried over NaZSO4, filtered and
concentrated in vacuo. The yellow residue was used in the next step without further
purification.
LC-MS (ESI+): rn/e 180 (M+H)+, Rt: 157 min
15 a4) 2-(Imidazo[ 1 ,2-a]pyridinyl)ethanol
a4. 1) Ethyl 2-(imidazo[1,2-a]pyridin—2-yl)acetate
A mixture of ethyl 4-chloro-3—oxobutanoate (15 g, 91 mmol) and pyridinamine
(8.58 g, 91 mmol) in THF (80 mL) was refluxed overnight. Then, the reaction mixture
20 was concentrated and the residue purified by silica gel chromatography =1 :1) to
afford ethyl 2-(imidazo[1,2-a] pyridine—2-y1)acetate (5 g, yield 26.9 %).
LC-MS (ESI+): m/e 205 (M+H)+, Rt: 0.54 min.
a4.2) 2-(Imidazo[1 ,2-a]pyridinyl)ethanol
25 To a solution of ethyl 2-(imidazo[1,2-a]pyridinyl)acetate (3.1 g, 15.18 mmol)
in THF (30 mL), LiBH4 (0.661 g, 30.4 mmol) was added and the mixture was stirred at
room ature overnight. Saturated NH4C1 was added dropwise to quench the
reaction. The solution was extracted with EA (3X 100 mL). The organic phase was
collected, dried over , filtered and trated. The title compound was used
30 t fiirther purification in the next step.
LC-MS (ESI+): rn/e 163 (M+H)+, Rt: 135 min
128
a5) 2-(7-Fluoroimidazo[1 ,2-a]pyridin-2—y1)ethanol
a5. 1) 4-Fluoropyridin—2-amine
A mixture ofN—(diphenylmethylene)—4-fluoropyridin—Z—amine (2.0 g, 7.24 mmol)
in THF (50 mL) and 1N HCl (aq) (50 mL) was stirred at about room ature
overnight. The aqueous layer was adjusted to pH>10 with 5N NaOH. The aqueous layer
was extracted with ethyl acetate (3x50 mL), concentrated. The mixture was purified by
column chromatography (PE/EA=4/1) to give the title compound (300 mg, yield: 37%).
10 LC-MS: m/e 113 (M+H); 6 min. lH NMR(CDC13) : 4.62 (s, 2H), 6.16 (dd,
J=10.8 Hz, 2.4, 1H) 6.38-6.42 (m, 1H), 8.00 (dd, J=9.2 Hz, 6 Hz, 1H).
a5 .2) Ethyl 2-(7-fluoroimidazo[1,2-a]pyridin—2—yl)acetate
A mixture of 4-fluoropyridinamine (1.0 g, 8.92 mmol) and ethyl 4-chloro
15 oxobutanoate (1.46 mL, 10.7 mmol) in THF (20 mL) was stirred at about reflux
overnight. The residue was concentrated and was chromatographed on the C18 ISCO
Combiflash system using the following gradient: A: Water (0.1% NH4HC03); B:
Methanol; 10%B to 60% B over 20 min to give 350 mg product as brown oil (350 mg,
yield: 17.6%).
20 LC-MS: m/e 223 (M+H); Rt:1.62 min; 1H NMR (CDC13): 1.29 (t, 3H), 3.84 (s,
2H), 4.21 (q, 2H), 7.66-7.69 (m, 1H), 7.19 (dd, J=8.2, 2.4 Hz, 1H), 7.56 (s, 1H), 8.01-
8.04 (m, 1H).
a5 .3) 2-(7-Fluoroimidazo[1,2-a]pyridinyl)ethanol
25 LiAlH4 (0.171 g, 4.50 mmol) was added to the solution of ethyl 2-(7-
fluoroimidazo[1,2-a]pyridinyl)acetate (0.5 g, 2.25 mmol) in THF (15 mL) and the
reaction was stirred for about 2 h. The reaction was quenched with H20 and
concentrated. The residue was d with methanol (3 mL) and filtered. The e
was purified by C18 ISCO Combiflash system using the following gradient: A: Water
30 (0.1% NH4HC03); B: ol; 10%B to 50%B over 20 min (100 mg, yield:24.6%).
129
a6) 2-(5,6,7,8-Tetrahydroquinolin—2—yl)ethanol
\
l
/
N
OH
a6. 1) Ethyl 2-(5 ,6,7,8-tetrahydroquinolinyl)acetate
A solution of 7.56 g (74.7 mmol) of diisopropylamine in 100 mL of water-free
THF was cooled to -30°C and n—BuLi (31.9 g, 15% solution in n-hexane, 74.7 mrnol
mmol) was added via a syringe. The mixture was allowed to stir for 30 min. After
cooling to -70°C, 8.68 g (74.7 mmol) tetramethylethylenediamine in 20mL ofTHF were
added and the mixture was allowed at —70°C for 1 h. Then, 5 g (34.00 mmol) of 2-
-5,6,7,8-tetrahydroquinoline and 3.87 g (35,7 mmol) of ethyl carbonochloridate
10 were added. The mixture was d to warm to room temperature within 2 h while
being stirring. The reaction mixture was poured onto conc. cold aqueous um
chloride solution and extracted with EA (3 times). The combined organic phase was
once extracted with a saturated um de solution, washed with a saturated
sodium bicarbonate solution and dried (magnesium sulfate). After removal of the
15 solvent, the crude product was purified by flash column chromatography (eluent:
heptane/EA 1/2) to provide 2.16 g (29%) of the title compound).
a6.2) 2-(5,6,7,8-Tetrahydroquinolin—2—yl)ethanol
Under N2, 4.56 mL (4.56 mmol) of lithium aluminium hydride (1M in THF) was
20 cooled to 0°C and ethyl 2-(5,6,7,8-tetrahydroquinolin—2-yl)acetate (1 g, 4.56 mmol)
dissolved in a small quantity ofTHF was slowly added. The e was allowed to stir
for 1.5 h. To the reaction mixture 173 mg ofH20 in THF,173 mg of 10%ige NaOH and
3x 173 mg ofH20 were added. The mixture was then stirred for 30 min. ium
sulfate was added. After removal of the solvent, the crude product (0.78 g, 96%) was
25 purified by chromatography (eluent: EA/heptane 3/ 1) to give the title compound.
a7) 2-( l H—benzo [d]imidazo l—2—yl)ethanol
H
I
61W“
130
Commercially available from Sigma-Aldrich.
a8) 1-(quinolinyl)propan—2-ol
\
CH3
/
N
OH
5 GAS-No.2 1565388, commercially available from e (Ukraine, Kiew,
order number EN300-95420.
a9) 2—(8—fluoroquinolin—2—yl)ethanol
\
/
N OH
F
10 To a solution of formaldehyde and paraformaldehyde (0.187 g, 6.20 mmol) in 2
mL ofwater was added -fluoromethquuinoline (1 g, 6.20 mmol) and then sodium
ide (0.37 g, 9.31 mmol) dissolved in 2 mL of water. Then 2-3 mL of l
were added. The mixture ws stirred at 85°C for 48 hours. After cooling to room
temperature, the reaction mixture was poured onto ice-water. The on mixture was
15 mixed with DCM and water. The organic phase was washed with water, dried and
concentrated. The residue was purified by chromatography (eluent: DCM/methanol) to
give 0.316 g (26.6%) of the title compound as bright yellow oily compound.
a10) 2-(7-fluoroquinolinyl)ethanol
m/
F N OH
20
a10. 1) tert—butyl 2—(7—fluoroquinolin—2—yl) acetate
To a solution of diisopropylamine (0.753 g, 7.45 mmol) in THF was added at
-78°C l lithium (0.437 g, 6.82 mmol, 2.5 molar) over a period of 15 min. Then
25 the mixture was stirred for further 30 min at -78°C. A solution of 7-fluoro
131
methquuinoline (1 g, 6.20 mmol) in 2 mL ofTHF was added at -78°C. After stirring for
a filrther hour solution of di—tert-butyl dicarbonate (1.49 g, 6.82 mmol) in 1 mL of THF
was added. The reaction mixture was allowed to warm up to room temperature over a
period of 2 h. The reaction mixture was mixed with water and EA. The aqueous phase
was extracted with EA. The combined organic phases were dried and concentrated to
give the title compound (790 mg, 48.7%) as red oil.
a10.2) 2-(7-fluoroquino linyl)ethanol
To 3.03 mL of lithiumaluminiumhydride in THF (1 molar, 115 mg, 3.03 mmol)
10 was added the compound of example a10.1 at 0°C. Then the mixture was stirred for 2 h
at 0°C and then stirred at room temperature for 20 h. The reaction e was mixed
with water and 10% by weight aq. NaOH solution. The mixture was stirred for 30 min,
dried and concentrated to give 250 mg of the title compound (43.2%).
15 a1 1) 2-(1 ,6-naphthyridinyl)ethanol
N OH
The title compound was ed in analogy to the method described in example
a9).
20 a12) 2-(1 ,5-naphthyridinyl)ethanol
/N \
\ /
N OH
The title compound was prepared in analogy to the method described in example
a9).
25 a1 3) 2-( l o[d]imidazo le—2—yl)ethanol
132
(INM/OHN
|
H
cially available from Matrix Scientific, catalogue number 27653
al4) 2-(1H-benzo[d]imidazol—1 hanol
Commercially available from Matrix ific, catalogue number 054768.
b) Preparation of compounds ofthe general formula Het-Al-OS(O)2CF3
10 bl) Trifluoromethanesulfonic acid 2,2-difluoro—2-quinolin—2-yl ethyl ester
\
O
/ II
N
F F O’beF3
bl.l) Difluoroquinolin—2-yl acetic acid ethyl ester
2-Bromoquinoline (5.0 g, 24.0 mmol), ethyl 2-bromodifluoroacetate (5.8 g, 28.8
mmol) and copper powder (3.5 g, 55.2 mmol) in DMSO (20 mL) were stirred at 55°C
15 for 5 hours. The solid was filtered off, water (100 mL) and EA (150 mL) were added.
The organic layer was separated, dried over sodium sulfate and concentrated to give the
title compound as a yellow oil (4.2 g, 70%), which was used in the next step without
further purification. LC-MS (ESI+): m/e 252 (M+H)+, R: 0.93 min.
20 b1.2) 2,2-Difluoroquinolinylethanol
To a solution of difluoroquinolin—Z—yl acetic acid ethyl ester (2 g, 7.9 mmol) in
ethanol (20 mL) was added NaBH4 (317 mg, 1.0 mmol) at 0°C under N2. The mixture
was stirred for 1 hour and then at room ature for 1.5 hours. The solution was
quenched with dilute HCl (0.1 N, 20 mL). The mixture was neutralized with saturated
133
NaHC03 solution and extracted with EtOAc (3* 100 mL). The combined organic layer
was dried over sodium sulfate. The solvent was evaporated and the residue was purified
by column chromatography on silica gel (PE: EA=10: l) to give the title compound as a
yellow solid (0.7 g, 44%). LC-MS (1331+); m/e 210 (M+H)+, Rt: 0.75 min.
bl .3) Trifluoromethanesulfonic acid 2,2-difluoro—2-quinolin—2—yl ethyl ester
To a on of 2,2-difluoroquinolin—2-ylethanol (300 mg, 1.4 mmol) and
triethylamine (217 mg, 2.1 mmol) in ous DCM (5 mL) was added dropwise
trifluoromethanesulphonic ide (606 mg, 2.1 mol) at -70 0C. The reaction
10 mixture was stirred for 1 hour. The resulting solution was warmed slowly to room
ature and stirred for 1 hour. The solid was removed by filtration. Water (5 mL)
and DCM (30 mL) were added, the organic layer was separated, dried over sodium
sulfate and evaporated to give the crude title compound as an orange oil (450 mg, 92%),
which was used in the next step without further purification. LC-MS (ESI+): m/e 342
15 (M+H)+, R: 1.01 min.
0) Preparation of compounds ofthe l a Het-A4-Br
cl) syn(2-Bromocyclopropyl)quinoline
20
cl . l) (Z)(2-Bromovinyl)quinoline
A sion of 24.97 g (57.3 mmol) of (bromomethyl)triphenylphosphonium
bromide in 160 mL ofTHF was chilled to -70°C under argon. Then, 6.43 g (57.3 mmol)
ofpotassium tert-butoxide were added portionwise and the suspension was allowed to
25 stir at this temperature for 1 h. A solution of 7.5 g of (47.7 mmol) quinoline
carbaldehyde in 40 mL ofTHF was slowly added dropwise. The mixture was allowed to
stir at -75°C for further 5 hours and then warmed to room temperature overnight. 160
mL ofPE were added. The precipitate formed was sucked off. The mother liquid was
evaporated and the residue was stirred with diisopropyl ether. The residue formed was
134
sucked off. Purification by chromatography (heptane/EA 3/1) d 6.6 g (59.1%) of
the title compound.
cl .2) syn romocyclopropyl)quinoline
A solution of lzinc in hexane (5.54 g, 44.9 mL, 44.9 mmol) was chilled to
0°C under argon. Trifluoroacetic acid (5.11 g, 3.46 mL, 44.9 mmol) was added
dropwise over 20 minutes. The mixture was stirred for further 20 minutes at 0° C. Then,
a solution of diiodomethane (12.01 g, 3.62 mL, 44.9 mmol) in dichloromethane was
added at 0°C over a period of 20 minutes. A solution of (Z)(2-bromovinyl)quino line
10 (2.1 g, 8.97 mmol) in DCM was added dropwise and the e was d over night
at room temperature. The total amount ofDCM was 350 mL. The reaction mixture was
quenched by addition of saturated aqueous ammonium chloride and then extracted with
DCM. The organic phase was washed with water. The combined organic phases were
ated. The residue was stirred with EA. Active charcoal was added and the
15 mixture was stirred for some further s. The solids were filtered off and the filtrate
was concentrated. Purification by chromatography (CombiFlash Rf, normal phase
chromatography, gradient elution using cyclohexane in EA up to a concentration of
15%) d 0.78 g (34.8%) of the title compound.
20 c2) syn 2-(2-bromocyclopropyl)—6—fluoroquinoline
F
c2. 1) (Z)(2-bromovinyl)fluoroquino line
To as suspension of (bromomethyl)triphenylphosphonium bromide (14.94 g, 34.3
mmol) in 100 mL of THF was added potassium tert-butoxide (3.84 g, 34.3 mmol)
25 portionwise under Ar. Then the reaction mixture was stirred for 1 h at this temperature.
6-Fluoroquinolinecarbaldehyde (5 g, 28.5 mmol) in 40 mL ofTHFwas added. The
resulting reaction mixture was stirred for 5 h at -75°C and allowed to warm up
overnight. The reaction mixture was diluted with petrol ether and the solid was sucked
off. The mother liquid was concentrated, diisopropyl ether was added and the formed
30 itate was sucked off. The mother liquidwas purified by column chromatography
135
hexane/EA) to give 4.7 g (65.3%) of the title compound as brown solid. LC-MS:
m/e 254.0.
c2.2) syn romocyclopropyl)fluoroquinoline
The title compound was prepared in analogy to the method described for example
c1.2. LC-MS: 268.0
03) syn romocyclopropyl)thieno[3,2-b]pyridine
S
\ Br
\l/
N H
H
10 The title compound was prepared in analogy to the method described in example
c1.2 starting from (Z)(2-bromovinyl)thieno[3,2—b]pyridine. LC-MSM m/e 255.9
(M+H)+
d) Preparation of nds ofthe general formula Het-A3-Br
15
d1) (Z)(2-bromovinyl)methy1quinoline
To a suspension of (bromomethyl)triphenylphosphonium bromide (3.06 g, 7.01
mmol) in 30 mL of THF, potassium tert-butoxide (0.78 g, 7.01 mmol) was added
20 portionwise at -75°C under argon. After completion ofthe addition, the mixture was
d for 1 h a -75°C. Then, a solution of 3—methquuinolinecarbaldehyde (1 g, 5.84
mmol) in 20 mL of THF was added. The reaction mixture was stirred for 5 h at -75°C
and then allowed to warm up to room temperature overnight. For work-up, the reaction
mixture was diluted with diisopropyl ether (1 :1) and the precipitate formed was sucked
25 off. The filtrate was concentrated and triturated in diisopropyl ether. The precipitate was
sucked off. The filtrate was purified by column chromatography (normal phase, eluent:
136
cyclohexane/EA) to give 492.5 mg (34%) of the title compound as yellow solid. LC-
MS: m/e 248.0 ; Rt 1.561 min.
d2) (Z)(2-bromovinyl)methoxyquinoline
o
H3C’ \ Br
/
N H
H
The title compound was prepared in analogy to the method described in example
d1 but using 6-methoxyquinolinecarbaldehyde instead of 3-methquuinoline
carbaldehyde. LC—MS: m/e 265.1 ; R 1.78 min
10 d3) (Z)(2-bromovinyl)—6—chloroquinoline
Cl
\ Br
/
N H
H
The title compound was prepared in analogy to the method described in example
dl but using 6-chloroquinolinecarbaldehyde instead of 3-methquuinoline
carbaldehyde.LC-MS: m/e 268.1 Rt 4.609 min.
15
d4) (Z)(2-bromovinyl)thieno[3,2—b]pyridine
The title compound was prepared in analogy to the method described in example
d1 but using thieno[3,2-b]pyridinecarbaldehyde. LC-MS: m/e 239.9.
20
11. Preparation of compounds of the formula I
11.1 Preparation of nds of the formula I in which A is Al, X1 is N, and X3 is S
137
EXAMPLE 1 : 3 ,7-Di(pyridin-4—yl)—5—[2-(quinolinyl)ethyl]thieno[2,3-d]pyridazin-
4(5H)-one
1.1 4-Bromothiophenecarboxylic acid
To a mixture ofMg (1.4 g, 60 mmol) and 12 (0.1 g) in ous THF (2 mL) was
added dropwise a solution of 2—bromo—propane (7.4 g, 60 mmol) in anhydrous THF (60
mL) at room temperature under nitrogen during a period of 30 min. After the addition,
the mixture was d until the most of magnesium was consumed. The resulting
Grignard reagent was added dropwise to a solution of 3,4-dibromo-thiophene (12.1 g,
10 50 mmol) in anhydrous THF (60 mL) at 0 0C under nitrogen within about 30 min. The
mixture was allowed to stir at 0 °C for 1.5 h. Excessive CO2 was purged into the
mixture at -30 0C and the reaction mixture was stirred until the temperature rose to room
temperature. Then the reaction was quenched with water (30 mL) and basified with 8%
aq. NaOH solution to pH 11 and was washed with ethyl acetate (3 ><60 mL). The
15 aqueous layer was acidified with 5% aq. HCl to pH l~2, the precipitate was filtered and
was dried to give the title compound as off-white solid (5.8 g, yield 56%).
LC-MS (ESI+): m/e 209 (M+H)+, Rt: 0.69 min.
1.2 4-Bromoisonicotinoylthiophenecarboxylic acid
20 To a solution of diisoproplyamine (5.3 g, 53 mmol) in anhydrous THF (40 mL) at
—30°C was added n—BuLi (23.2 mL, 58 mmol, 2.5M in hexanes) dropwise. The e
was stirred at the same temperature for 0.5 h, then cooled to -78 0C and HMPA (0.86 g,
4.8 mmol) was added slowly. Then the solution of 4-bromothiophenecarboxylic acid
(5.0 g, 24 mmol) in anhydrous THF (50 mL) was added slowly. The mixture was stirred
25 at the same temperature for l h, N—methoxy—N—methyl—4-pyridinecarboxamide (8.0 g, 48
mmol) was added dropwise into the stirring mixture at —78°C. The reaction mixture was
stirred for another 1 h at room ature and was then quenched with H20 (10 mL).
The aqueous layer was acidified with 5% aq. HCl to pH l~2, the precipitate was
138
collected by filtration. The filter cake was washed with DCM (10*50 mL). The title
compound was ved in DCM; the solid insoluble in DCM was the side product.
The filtrate was extracted with DCM (3 X200 mL). The organic layers were dried over
Na2SO4 and concentrated under d pressure. The crude product was washed with
DCM to give the title compound (0.8 g, yield 10.7 %) as a yellow solid.
LC-MS (ESI+): m/e 312 (M+H)+, Rt: 1.45 min.
1.3 Ethyl 4-bromoisonicotinoylthiophenecarboxy1ate
To a solution of the compound from example 1.2 (2.5 g, 8 mmol) and CszC03 (5.2 g, 16
10 mmol) in CH3CN (500 mL) was added CH3CHZI (3.0 g, 19.2 mmol) dropwise . The
mixture stirred at 30 0C for 48 h. The mixture was filtered and trated to give the
title compound as yellow oil (2 g, 73.5% yield).
LC-MS (ESI+): m/e 340 (M+H)+, Rt: 0.81 min
15 1.4 Ethyl 2-isonicotinoyl(pyridin—4—yl)thiophenecarboxylate
A mixture of the compound from example 1.3 (500 mg, 1.47 mmol), 4-pyridineboronic
acid (271 mg, 2.21 mmol), Na2C03 (390 mg, 3.68 mmol) and Pd(dppf)C12 (122 mg,
0.15 mmol) in dioxane/HZO (3:1) (12 mL) was stirred at 100°C under argon for 2 h. The
mixture was concentrated and the residue was purified by PLC to give the title
20 product as white solid (318 mg, 64 % .
LC-MS (ESI+): m/e 339 (M+H)+, 11,; 0.61 min
1 .5 3 ,7-Di(pyridinyl)thieno[2,3-d]pyridazin—4(5H)-one
A mixture of the compound from example 1.4 (200 mg, 0.59 mmol) in
25 NHzNHz-HzO (2 mL) and EtOH (10 mL) was stirred at room temperature for 30 min.
The mixture was filtered and the solid was dried to obtain the title compound as a white
solid (150 mg, 83.1%). LC-MS (ESI+): m/e 307 (M+H)+, R: 1.56 min.
1 .6 3 ,7—Di(pyridin—4—yl)—5—[2—(quinolinyl)ethy1]thieno[2,3-d]pyridazin-4(5H)—one
30 To a solution of 3,7—di(pyridin—4—yl)thieno[2,3—d]pyridazin—4(5H)-one from
example 1.5 (100 mg, 0.32 mmol), 2—quinolin—2—yl—ethanol from example a1 (58 mg,
0.33 mmol) and PPh3 (256 mg, 0.98 mmol) in DCM (10 mL), DIAD (198 mg, 0.98
139
mmol) was added dropwise. The mixture was stirred at room temperature for 3h,
concentrated and the residue was purified by Prep-HPLC to give the title compound as
white solid (26 mg, 17.6% yield).
LC-MS (ESI+): m/e 462 (M+H)+, R: 2.00 min; 1H-NMR(DMSO-d, 400MHz): 5
3.46 (t, J: 7.2 Hz, 2H), 4.71 (t, J= 7.2 Hz, 2H), 7.49-7.51 (m, 3H), 7.54-7.57 (m, 1 H),
7.62 (dd, J: 4.4, 1.6 Hz, 2H), .72 (m, 1 H), 7.84 (d, J= 8.4 Hz, 1H), 7.94 (d, J:
7.2 Hz, 1H), 8.28-8.30 (m, 2H), 8.60 (dd, J= 4.6, 1.6 Hz, 2H), 8.70 (dd, J: 4.6, 1.6 Hz,
2H).
10 EXAMPLE 2: 7-(Pyridin—4-yl)[2-(quinolinyl)ethyl]thieno[2,3-d]pyridazin—
4(5H)—one
\ o
/
N
N \
s
/
|
\
N
2.1 2-Isonicotinoylthiophenecarboxylic acid
To a solution of diisopropylamine (5.2 g, 51.5 mmol) in anhydrous THF (40 mL)
15 at —30°C was added n-BuLi (23.2 mL, 56.2 mmol, 2.5M in THF) dropwise. The mixture
was stirred at the same temperature for 0.5 h, then cooled to -78°C and HMPA (0.8 g,
4.7 mmol) was added slowly. Then a solution of thiophenecarboxylic acid (3.0 g,
23.4 mmol) in anhydrous THF (50 mL) was added slowly. The mixture was d at
the same temperature for l h, N—methoxy—N-methyl—4-pyridinecarboxamide (5.0 g, 46.9
20 mmol) was added drop wise into the stirring e at —78°C. The reaction mixture
was stirred for another 1 h at room temperature and was then quenched with H20 (10
mL). The aqueous layer was acidified with 5% aq. HCl to pH 1~2, the precipitate was
collected by filtration. The filter cake wash with DCM and the filtrate was extracted
with DCM (3 X200 mL). The organic layers were dried over NaZSO4 and trated
25 under reduced pressure. The crude product was washed with DCM to give the title
product (2.2 g, yield 40 %) as a white solid.
LC-MS (ESI+): m/e 234 (M+H)+, Rt: 0.57 min.
140
2.2 Ethyl 2-isonicotinoylthiophene—3—carboxy1ate
To a solution of icotinoylthiophenecarboxylic acid (2.2 g, 9.4 mmol)
from e 2.1 and CS2CO3 (6.2 g, 18.9 mmol) in CH3CN (500 mL) was added
CH3CH21 (2.9 g, 18.9 mmol) dropwise. The mixture was d at 30 0C for 48 h. The
mixture was filtered and concentrated to give the title compound as yellow oil (2.1 g,
85.5% yield).
LC-MS (ESI+): m/e 340 (M+H)+, Rt: 0.81 min
2.3 7-(Pyridinyl)thieno[3,2-d]pyridazin-4(5H)-one
10 The mixture of ethyl 2-isonicotinoylthiophenecarboxylate (200 mg, 0.77
mmol) from example 2.2 in NHzNH2~HzO (2 mL) and EtOH (10 mL) was d at
room temperature for 30 min. The mixture was filtered and the solid dried to obtain the
title compound (150 mg, 85.1% yield).
LC-MS (ESI+): m/e 230 , Rt: 1.52 min.
15
2.4 7-(Pyridinyl)[2-(quinolinyl)ethyl]thieno[2,3-d]pyridazin—4(5H)-one
To a solution of 7-(pyridinyl)thieno[3,2-d]pyridazin—4(5H)-one (100 mg, 0.44
mmol) from example 2.3, 2-quinoliny1—ethanol from example a1 (83 mg, 0.48 mmol)
and PPh3 (343 mg, 1.31 mmol) in DCM (10 mL), DEAD (228 mg, 1.31 mmol) was
20 added dropwise. The mixture stirred at room temperature for 3 h, concentrated and the
purified by Prep-HPLC to give the title compound as a white solid (20 mg, 11.8%
yield).
LC-MS (ESI+): m/e 385 (M+H)+, Rt: 1.87 min; lH-NMR(DMSO-d6, 400 MHz):
8 3.49 (t, J: 7.2 Hz, 2H), 4.76 (t, J: 7.2 Hz, 2H), 7.49—7.57 (m, 2H), 7.58 (dd, J: 4.4,
25 1.6 Hz, 2H), 7.67-7.72 (m, 1 H), 7.78 (d, J: 5.2 Hz, 1H), 7.85 (d, J: 8.0 Hz, 1H), 7.93
(d, J: 7.6 Hz, 1H), 8.21 (d, J= 5.2 Hz, 1H), 7.93 (d, J: 8.8 Hz, 1H), 8.66 (dd, J: 4.2,
1.6 Hz, 2H).
EXAMPLE 3: 3—(Pyridin—4—yl)[2-(quinolinyl)ethy1]thieno[2,3-d]pyridazin—4(5H)—
30 0116
141
N
/ \
\ O /
/
N
3.1 4-Bromoformyl-thiophene—3—carboxylic acid
To a solution of (i—Pr)2NH (1.09 g, 10.8 mmol) in anhydrous THF (15 mL) was
added dropwise n-BuLi (5.0 mL, 12.5 mmol, 2.5M in hexane) at -30°C. The mixture
was d at the same temperature for 0.5 h. Then, the mixture was cooled to -78°C
and the solution of 4-bromothiophenecarboxylic acid from example 1.1 (1.0 g, 4.85
mmol) and HMPA (0.17 g, 0.95 mmol) in anhydrous THF (20 mL) was added slowly.
The mixture was stirred at the same ature for l h, anhydrous DMF (0.6 g, 8.22
mmol) was added dropwise into the stirring mixture at —78°C. The reaction mixture was
10 stirred for another 45 min at room ature and then quenched with water. The
aqueous layer was acidified with 5% aq. HCl to pH 1~2, the precipitate was collected
by filtration, the filtrate was extracted with DCM (3 X50 mL). The organic layers were
dried over Na2S04 and concentrated under reduced pressure. The crude product was
washed with CHzClz to give the title t (0.68 g, 60.2 %) as a solid.
15 LC-MS: m/e : 235.7; R: 0.64 min.
3.2 4-Bromoformyl-thiophene—3—carboxylic acid ethyl ester
4-Bromoformyl-thiophene—3—carboxylic acid (0.16 g, 0.68 mmol), K2C03
(0.188 g, 1.36 mmol), and 4 mL of ous DMF were stirred at room temperature
20 for 10 min, then iodoethane was added (0.128 g, 0.8 mmol) dropwise. The reaction
solution was stirred at 50 0C for 3h. The reaction mixture was cooled, extracted with EA
(3 x 50 mL), concentrated and the residue was purified by TLC (PE/EA =8/ 1) to give
0.4 g of the title compound (yield: 63.5%).
LC-MS: m/e (M+H)+: 263.7, R: 0.88 min.
25
3.3 3-Bromo—5H—thieno[2,3-d]pyridazinone
4-Bromo-2—formy1—thiophenecarboxylic acid ethyl ester (1.0 g, 3.8 mmol),
NHZNHZ'HZO (0.27 g, 4.58 mmol) and 20 mL of EtOH were refluxed under nitrogen
142
for 5h. The reaction mixture was cooled and precipitate formed, then filtered to give the
title compound (0.2 g, yield: 23%).
LC-MS: m/e (M+H)+: 231.7, R: 1.29 min
3.4 3-Bromo[2-(quinolin—2-y1)ethyl]thieno[2,3-d]pyridazin—4(5H)-one
To a stirred solution of PPh3 (977 mg, 3.73 mmol) and DEAD (1.13 mL) in 15
mL ofanhydrous THF was added a solution of 3-bromo-5H-thieno[2,3-d]pyridazin
one (429 mg, 1.86 mmol) and 2-quinolinyl-ethanol from example al (355 mg, 2.05
mmol) in 15 mL of ous THF while being cooled with an th. Then the
10 resulting mixture was stirred in nitrogen atmosphere at 45°C overnight. The reaction
mixture was concentrated and the product was recrystalized from EA to give the title
nd (370 mg, 53.6%).
LC-MS: m/e (M+H)+: 386.7, R: 2.02 min
15 3.5 idinyl)[2-(quinolin-2—yl)ethyl]thieno[2,3-d]pyridazin—4(5H)-one
3-Bromo[2-(quinolinyl)ethyl]thieno[2,3-d]pyridazin—4(5H)-one (130 mg,
0.33 mmol), pyridineylboronic acid (45.7 mg, 0.37 mmol), Pd(dppt)C12 (15 mg) and
K2C03 (93 mg, 0.67 mmol) were dissolved in dioxane/HZO (3/1, 2.8 mL). The mixture
was stirred in nitrogen atmosphere at 120°C for 1h in a microwave tube. The solution
20 was concentrated and purified by TLC eOH =10/ 1) and recrystalized from
MeOH to give the title product (90 mg, 69.4%).
LC-MS: m/e (M+H)+: 385.7, R: 1.90 min. 1H NMR (DMSO, 400MHz) 5: 8.48-
8.45 (m, 3H), 8.25 (d, J: 8.4Hz, 1H), 8.02 (s, 1H), 7.93-7.88 (m, 2H), 7.72 (t, J: 8.4Hz,
1H), 7.58 (t, J=7.2Hz, 1H), 7.48-7.42 (m, 3H), 4.72 (t, J: 7.0 Hz, 2H), 3.49 (t, J: 7.0
25 Hz, 2H)
EXAMPLE 4: 3-(Pyridinyl)[2-(pyridinyl)ethyl]thieno[2,3-d]pyridazin-4(5H)-
0116
N
/ \
\ O /
\ /
N
143
4.1 3-Bromo(2-pyridinyl-ethyl)—5H-thieno[2,3-d]pyridazin—4-one
The title compound was prepared in analogy to the process described in Example
3.4 starting from 3-bromo-5H-thieno[2,3-d]-pyridazin—4-one and dinyl-ethanol.
Yield: 76.3%.
LC-MS: m/e (M+H)+: 336.7, Rt: 1.51 min
4.2 3-(Pyridin—4-yl)[2-(pyridinyl)ethyl]thieno[2,3-d]pyridazin-4(5H)-one
The title compound was prepared in analogy to the process bed in Example
3.5 starting from o(2-pyridinyl-ethyl)-5H-thieno[2,3-d]pyridazinone
10 and pyridineylboronic acid. Yield: 33.1%.
LC-MS: m/e (M+H): 335.7, R: 1.69 min. 1H NMR (DMSO, 400MHz) 5: 8.60 (d,
J: 5.2Hz, 2H), 8.47 (d, J: 4.4Hz, 1H), 8.16 (s, 1H), 7.53-7.48 (m, 2H), 7.43 (d,
J=5.2Hz, 2H), 7.11-7.04 (m, 2H), 4.57 (t, J: 7.6 Hz, 2H), 3.24 (t, J: 7.4 Hz, 2H).
15 EXAMPLE 5: 3,7-Di(pyridinyl)—5—[2—(pyridin—2-yl)ethyl]thieno[2,3-d]pyridazin-
4(5H)—one
5. l 3-Bromopyridinyl-5H-thieno[2,3—d]pyridazin—4-one
The title compound was prepared in analogy to the process described in Example
20 3.3 starting from ethyl 4-bromo-2—isonicotinoyl—thiophene—3-carboxylic acid from
Example 1.3. Yield: 56.8%.
LC-MS: m/e (M+H) +3087, Rt: 1.59 min.
5.2 3-Bromopyridinyl[2-(pyridinyl)ethy1]thieno[2,3-d]pyridazin-
25 4(5H)—one
The title compound was prepared in y to the process described in Example
3.4 starting from 3-bromo—7—pyridin—4—yl—5H—thieno[2,3-d]pyridazinone and 2-
pyridin—2-yl—ethanol. Yield: 70%.
144
LC-MS: m/e (M+H)+: 413.7; R: 1.84 min.
5 .3 3 ,7-Di(pyridinyl)-5 - [2-(pyridinyl)ethyl]thieno [2,3 -d]pyridazin-4(5H)-one
The title compound was prepared in analogy to the process described in Example
3.5 starting from 3-bromopyridinyl-5—[2-(pyridin—2-yl)ethyl]thieno[2,3-
dazin—4(5H)-one and pyridineylboronic acid. Yield: 75.2%.
LC-MS: m/e (M+H)+: 412.7, Rt: 1.71 min; 1H NMR (DMSO, 400MHz) 8: 8.78
(d, J= 5.2Hz, 2H), 8.71 (d, J= 4.4Hz, 2H), 8.56 (d, J= 4.8Hz, 1H), 7.70-7.67 (m, 3H),
7.60 (t, J=7.6Hz, 1H), 7.51 (d, J= 5.2 Hz, 2H), 7.21 (d, J= 7.6 Hz, 1H), .14 (m,
10 1H), 4.75 (t, J= 7.6 Hz, 2H), 3.37 (t, J= 7.4 Hz, 2H).
EXAMPLE 6: 5-[2-(Quinolin—2—yl)ethyl]—3—[4—(trifluoromethyl)phenyl]thieno[2,3-
dazin—4(5H)-one
FFF
\ o
/
N N
I |\
N\
s
15 3-Bromo[2-(quinolinyl)ethyl]thieno[2,3-d]pyridazin—4(5H)-one Example 3.4
(100 mg, 0.26 mmol), 4-(trifluoromethyl)phenylboronic acid (0.26 mmol), Pd(dppf)Clz
(12.7 mg) and K2C03 (72 mg, 0.527 mmol) were dissolved in dioxane/HZO (3/1, 2.8
mL). The mixture was d at 110°C for 0.5 h in a microwave tube. The solution was
concentrated and purified by prep—TLC to give the title product.
20 LC-MS: m/e (M+H)+: 452, R: 2.36,1H NMR (CDC13, 400 MHZ) 8: 3.50 (t, 2H,
J=7.6 Hz), 4.75 (t, 2H, J=7.6 Hz), 7.33 (d, 1H, J=4.4 Hz), 7.48-7.53 (m, 2H), 7.59-7.69
(m, 5H), 7.78 (d,1H, J=7.6 Hz), 8.00 (d, 1H, J=8.0), 8.06 (d, 1H, J=8.0 Hz), 8.23 (s, 1H)
Examples 7 to 92 were prepared analogously to the method described for Example
25
145
LC-MS: 1H NMR (CDC13) 5:
EX. Name m/ e (M+H)+/
Rt [min]
3-(4- 398 /2.32 2.40 (s, 3H), 3.50 (t, 2H, J=7.6 Hz), 4.73 (t,
methylpheny1) 2H, J=7.6 Hz), 7.22 (d, 2H, J=8.0 Hz), 7.32
[2-(quinolin—2- (d, 1H, J=7.6 Hz),7.40 (d, 2H,J=7.6 Hz),
7
y1)ethy1]thieno[2,3- 7.45 (s,1H), 7.49 (t, 1H,J=7.2 Hz),7.67 (t,
d]pyridazin-4(5H)- 1H, J=7.2 Hz), 7.77 (d, 1H, J=7.6 Hz),8.01-
one 8.06 (m, 2H), 8.19 (s,1H)
3-[4-(propan—2- 426 / 2.46 1.29 (d, 6H, J=6.8 Hz), 2.95 (m, 1H), 3.49
y1)pheny1]-5—[2— (t, 2H, J=7.6 Hz), 4.75 (t, 2H, J=8 Hz),
(quinolin 7.27~7.31 (m, 3H), 7.44~7.49 (m, 4H), 7.66
8
y1)ethy1]thieno[2,3- (t, 1H, J=8.4 Hz), 7.75 (d, 1H, J=8 Hz),
d]pyridazin—4(5H)- 8.01~8.04 (m, 2H), 8.18 (s, 1H)
one
412 / 2.34 1.28 (t, 3H, J=7.6 Hz), 2.70 (q, 2H, J=7.6
3-(4-ethy1pheny1)-
Hz), 3.49 (t, 2H, J=7.6 Hz), 4.74 (t, 2H,
5-[2-(quinolin
J=7.6 Hz), 7.25 (d, 2H, J=8.0 Hz), 7.31
_ (d,
9 y1)ethy1]th1eno[2,3-
1H, J=8.4 Hz), 7.44-7.50 (m, 4H), 7.65-7.69
d]pyr1daz1n—4(5H)-_ _
(m, 1H), 7.77 (d, 1H, J=8.4 Hz), 8.00-8.05
one
(m, 2H), 8.19 (s, 1H)
4- [2- 409 /2.11 3.49 (t, 2H, J=7.6 Hz), 4.74 (t, 2H, J=7.6
(quinolin Hz), 7.33 (d, 1H, J=8.0 Hz), 7.50-7.58 (m,
y1]-4,5- 4H), 7.66-7.68 (m, 3H), 7.79 (d, 1H, J=7.6
10
dihydrothieno[2,3- Hz), 7.98 (d, 1H, J=8.0 Hz), 8.07 (d, 1H,
d]pyridazin—3- J=8.0 Hz), 8.25 (s, 1H)
y1}benzonitrile
146
LC-MS: 1H NMR (CDC13) 5:
EX. Name m/ e (M+H)+/
Rt [min]
3-(4- 414 / 2.18 3.50 (t, 2H, J=7.6 Hz), 3.85 (s, 3H), 4.74 (t,
methoxypheny1) 2H, J=7.6 Hz), 6.94 (d, 2H, J=8.4 Hz), 7.31
[2-(quinolin—2- (d, 1H, J=8.4 Hz), 7.42—7.51 (m, 4H), 7.65-
11
y1)ethy1]thieno[2,3- 7.69 (m, 1H), 7.77 (d, 1H, J=8.4 Hz), 8.00-
d]pyridazin-4(5H)- 8.06 (m, 2H), 8.19 (s, 1H)
one
3-(4—fluoropheny1)— 402 / 2.21 3.50 (t, 2H, J=7.6 Hz), 4.74 (t, 2H, J=7.6
5-[2-(quinolin—2— Hz), 7.06—7.11 (m, 2H), 7.32 (d, 1H, J=8.4
12 y1)ethy1]thieno[2,3— Hz), 7.45—7.52 (m, 4H), 7.65-7.69 (m, 1H),
d]pyridazin—4(5H)— 7.78 (d, 1H, J=8.4 Hz), 8.01 (d, 1H, J=8.4
one Hz), 8.06 (d, 1H, J=8.4 Hz), 8.21 (s, 1H)
3-(4- 428 /2.26 1.44 (t, 3H, J=6.8 Hz), 3.49 (t, 2H, J=7.6
ethoxypheny1) Hz), .11 (m, 2H), 4.74 (t, 2H, J=7.6
[2-(quinolin—2- Hz), 6.93 (d, 2H, J=8.4 Hz), 7.32 (d, 1H,
13
y1)ethy1]thieno[2,3- J=8.4 Hz), 7.42~7.51 (m, 4H), 7.67 (t, 1H,
dazin—4(5H)- J=7.6 Hz), 7.77 (d, 1H, J=8 Hz), 8.00~8.06
one (m, 2H), 8.19 (s, 1H)
3-[4- 427 /2.26 2.99 (s, 6H), 3.50 (t, 2H, J=7.6 Hz), 4.75 (t,
(dimethylamino)ph 2H, J=7.6 Hz), 6.77 (d, 2H, J=8.8 Hz), 7.31
eny1][2- (d, 1H, J=8.8 Hz), 7.38 (s, 1H), 7.43-7.51
14 (quinolin (m, 3H), 7.65—7.69 (m, 1H), 7.77 (d, 1H,
y1)ethy1]thieno[2,3- J=8.0 Hz), 8.01-8.05 (m, 2H), 8.16 (s, 1H).
d]pyridazin—4(5H)-
0116
147
LC-MS: 1H NMR ) 5:
EX. Name m/ e (M+H)+/
Rt [min]
(4- {4-oxo[2- 423 /2.10 3.49 (t, 2H, J=7.6 Hz), 3.79 (s, 3H), 4.73 (t,
(quinolin 2H, J=7.6 Hz), 7.31-7.37 (m, 3H), 7.48-7.51
y1]-4,5- (m, 4H), 7.65—7.69 (m, 1H), 7.99 (d, 1H,
15 dihydrothien0[2,3- J=8.4 Hz), 8.05 (d, 1H, J=8.4 Hz), 8.22 (s,
d]pyridazin—3 - 1 H)
y1}pheny1)acetonitr
ile
3-(4-hydr0xy— 400 / 2.00 2.17 (s, 1H), 3.53 (t, 2H, J=7.6 Hz), 4.77 (t,
phenyl)[2- 2H, J=7.6 Hz), 7.80 (d, 2H, J=8.8 Hz),
(quinolin 7.33~7.42 (m, 4H), 7.51 (t, 1H, J=7.2 Hz),
16
y1)ethy1]thieno[2,3- 7.69 (t, 1H, J=7.2 Hz), 7.79 (d, 1H, J=7.6
d]pyridazin—4(5H)- Hz), 8.08 (d, 2H, J=8.4 Hz), 8.22 (s, 1H)
one
3-(2-ch10r0pheny1)- 418 /2.22 3.47 (t, 2H, J=7.6 Hz), 4.71 (t, 2H, J=7.6
5-[2-(quinolin Hz), .36 (m, 4H), .50 (m, 3H),
17 y1)ethy1]thieno[2,3- 7.64-7.68 (m, 1H), 7.76 (d, 1H, J=8.0 Hz),
d]pyridazin—4(5H)- 8.00-8.04 (m, 2H), 8.21 (s, 1H).
one
3-(2- 398 /2.29 2.09 (s, 3H),3.48 (t, 2H, J=7.6 Hz), 4.69 (t,
methylphenyl) 2H, J=7.6 Hz), 7.17-7.33 (m, 5H), 7.37 (s,
[2-(quin01in 1H), 7.49 (t, 1H, J=7.2 Hz), 7.67 (t, 1H,
18
y1)ethy1]thien0[2,3- J=7.2 Hz), 7.76 (d, 1H, J=8.0 Hz), 7.99-
d]pyridazin—4(5H)- 8.05 (m, 2H), 8.22 (s, 1H)
0116
3-(2-ethy1phenyl)- 412/2.36 1.02 (t, 3H, J=7.6 Hz), 2.36~2.49 (m, 2H),
5-[2—(quin0 1111—2— 3.47 (t, 2H, J=7.6 Hz), 4.65~4.71 (m, 2H),
19 y1)ethy1]thieno[2,3— 7.15 (d, 1H, J=7.2 Hz), 7.02~7.38 (m, 6H),
d]pyridazin—4(5H)— 7.49 (m, 1H, J=7.6 Hz), 7.77 (d, 1H, J=8
0116 Hz), 7.99~8.04 (m, 2H), 8.22 (s, 1H)
148
LC-MS: 1H NMR (CDC13) 5:
EX. Name m/ e (M+H)+/
Rt [min]
402 /2.16 3.49 (t, 2H, J=7.6 Hz), 4.73 (t, 2H, J=7.6
3-(2-fluoropheny1)-
Hz), 7.14~7.21 (m, 2H), .31 (In,
5-[2-(quinolin
7.38 (t, 2H, J=7.6 Hz), 7.48 (t, 1H,
_ 1H),
20 y1)ethy1]th1eno[2,3-
J=7.6 Hz), 7.54 (s, 1H), 7.67 (t, 1H, J=7.6
d]pyr1da21n-4(5H)-. .
Hz), 7.76 (d, 1H, J=8 Hz), 8.02 (t, 2H,
one
J=7.6 Hz), 8.20 (s, 1H)
3-(2- 414 / 2.22 3.47 (t, 2H, J=7.2Hz), 3.74(s, 3H), 4.69 (t,
ypheny1)—5— 2H, J=7.6Hz), 6.97~7.02 (m, 2H), 7.28 (t,
[2-(quinolin—2- 2H, J=8.4Hz), 7.38 (t, 1H, J=8Hz), 7.48 (t,
21
y1)ethy1]thieno[2,3- 2H, J=7.6Hz), 7.67 (t, 1H, J=7.6Hz), 7.76
dazin—4(5H)- (d, 1H, J=8Hz), 8.03 (d, 2H, J=8.4Hz), 8.17
one (s, 1H)
3-(2- 428 /2.31 1.18 (t, 3H, J=6.8 Hz), 3.47 (t, 2H, J=7.6
ethoxypheny1) Hz), 4.01~4.06 (m, 2H), 4.69 (t, 2H, J=7.6
[2-(quinolin—2- Hz), 6.96~7.01 (m, 2H), 7.27~7.36 (n1,
22
y1)ethy1]thieno[2,3- 3H), 7.48 (t, 2H, J=8.8 Hz), 7.67 (t, 1H,
d]pyridazin—4(5H)- J=7.2 Hz), 7.76 (d, 1H, J=8.4 Hz), 8.03 ((1,
one 2H, J=8 Hz), 818 (s, 1H)
23 3-(2- 400 / 2.04 3.52 (t, 2H, J=7.6 Hz), 4.83 (t, 2H, J=7.6
hydroxypheny1)-5 - Hz), 7.05 (t, 1H, J=8 Hz), 7.17 (d, 1H,
[2-(quino lin J=7.6 Hz), 7.27~7.38 (m, 3H), 7.48~7.55
y1)ethy1]thieno[2,3- (m, 2H), 7.68 (t, 1H, J=7.6 Hz), 7.78 (d,
d]pyridazin—4(5H)- 1H, J=7.2 Hz), 8.01~8.08 (m, 2H), 8.32 (s,
0116 1H), 8.71 (s, 1H)
149
LC-MS: 1H NMR (CDC13) 5:
EX. Name m/ e (M+H)+/
Rt [min]
24 5-[2-(quinolin 452 /2.30 3.47 (t, 2H, J=7.6 Hz), 4.67 (t, .6
y1)ethy1][2- Hz), 7.25-7.29 (m, 2H), 7.47-7.57 (m, 4H),
(trifluoromethyl)ph 7.66—7.58 (m, 3H), 8.02:8.04 (m, 2H), 8.22
hieno[2,3- (s, 1H)
d]pyridazin-4(5H)-
one
25 3-[3— 428 / 2.16 3.42 (s,1H), 3.49 J=7.6Hz),4.52
xymethy1)ph (s,2H),3.79 (s,3H),4.74(t,2H,J=7.6Hz),7.31
eny1][2- (d,1H,J=8.4Hz), 7.35-7.51 (m,6H),7.65-
(quinolin 7.69 (m,1H), 7.77 (d,1H,J=8.0Hz),7.99-8.05
yl)ethy1]thieno[2,3- (m,2H), 8.20 (s,1H)
d]pyridazin—4(5H)-
one
26 3-(3- 414 / 2.19 3.50 (t, 2H, J=7.6 Hz), 3.83 (s, 3H), 4.74 (t,
methoxypheny1) 2H, J=7.6 Hz), 6.92-6.95 (m, 1H), 7.07-7.12
[2-(quinolin—2- (m, 2H), 7.31-7.35 (m, 2H), 7.47-7.51 (m,
yl)ethy1]thieno[2,3- 2H), 7.66-7.70 (m, 1H), 7.77 (d, 1H, J=8.4
d]pyridazin—4(5H)- Hz), 8.01-8.06 (m, 2H), 8.20 (s, 1H)
one
27 3-(3- 428 /2.27 1.43 (t, 3H, J=6.8 Hz), 3.50 (t, 2H, J=7.2
ethoxypheny1) Hz), 4.06 (q, 2H, J=6.8 Hz), 4.74 (t, 2H,
[2-(quinolin—2- J=7.2 Hz), 6.91—6.94 (m, 2H), 7.07-7.09 (m,
y1)ethy1]thieno[2,3- 2H), 7.29-7.33 (m, 2H), 7.47—7.51 (m, 2H),
d]pyridazin-4(5H)- 7.65-7.78 (m, 2H), 8.01-8.06 (m, 2H), 8.20
one (s, 1H)
150
LC-MS: 1H NMR ) 5:
EX. Name m/ e (M+H)+/
Rt [min]
28 3-[3- 427 / 2.26 2.97 (s, 6H), 3.49 (t, 2H, J=7.2 Hz), 4.73 (t,
(dimethylamino)ph 2H, J=7.6 Hz), 6.77 (dd, 1H, J=2.4 Hz,
eny1][2- J=8.4 Hz), 6.85—6.88 (m, 2H), 7.26-7.32 (m,
(quinolin 2H), 7.47-7.51 (m, 2H), 7.65-7.77 (m, 2H),
y1)ethyl]thieno[2,3- 8.03 (t, 2H, J=7.6 Hz), 8.19 (s, 1H)
d]pyridazin—4(5H)-
one
29 3-[4-Ox0-5—(2— 409 / 2.11 3.49 (t, 2H, J=7.6 Hz), 4.74 (t, 2H, J=7.6
quinolin—2-y1— Hz), 7.35 (d, 1H, J=8.4 Hz), 7.47~7.52 (m,
ethy1)-4,5-dihydro- 3H), 7.65~7.73 (m, 4H), 7.79 (d, 1H, J=8
thieno[2,3- Hz), 7.97 (d, 1H, J=8.4 Hz), 8.08 (d, 1H,
d]pyridazin—3-y1}- J=8.4 Hz), 8.24 (s, 1H)
benzonitrile
30 3-(3-fluoropheny1)- 402 / 2.21 3.49 (t, 2H, J=7.6 Hz), 4.47 (t, 2H, J=7.6
5-[2-(quin01in Hz), 7.06-7.11 (m, 1H), 7.20-7.24 (m, 1H),
y1)ethy1]thieno[2,3- 7.27-7.39 (m, 3H), 7.47-7.51 (m, 2H),
d]pyridazin—4(5H)- .69 (m, 1H), 7.77 (d, 1H, J=8.0 Hz),
one 8.00 (d, 1H, J=8.4 Hz), 8.06 (d, 1H, J=8.4
Hz), 8.21 (s, 1H)
31 3-(3- 400/200 3.51 (t, 2H, J=7.6 Hz), 3.76 (s, 1H), 4.72 (t,
hydroxypheny1)-5 - 2H, J=7.6 Hz), 6.85 (d,1H,J=1.6 Hz, J=8.0
[2-(quino 1111 Hz), 6.99-7.02 (m, 2H), 7.23 (t, 1H, J=8.0
y1]thien0[2,3- Hz), 7.34 (d, 1H, J=8.8 Hz), 7.48-7.53 (m,
d]pyridazin—4(5H)- 2H), 7.66-7.70 (m, 1H), 7.78 (d, 1H, J=8.0
0116 Hz), 8.03-8.08 (m, 2H), 8.21 (s, 1H)
151
LC-MS: 1H NMR (CDC13) 5:
EX. Name m/ e (M+H)+/
Rt [min]
32 N,N—dimethy1—3-{4- 455 / 1.97 3.09 (d, 6H, J=17.6 Hz), 3.50 (t, 2H, J=7.6
[2-(quinolin- Hz), 4.74 (t, 2H, J=7.6 Hz), 7.31 (d, 1H,
2-y1)ethy1]—4,5- J=8.4 Hz), 7.43~7.51 (m, 6H), .69
dihydrothien0[2,3- (m, 1H), 7.78 (d, 1H, J=8.4 Hz), 8.00 (d,
d]pyridazin—3- 1H, J=8.4 Hz), 8.06 (d, 1H, J=8.4 Hz), 8.21
y1}benzamide (s, 1H)
33 3-(3— 398 / 2.08 2.40 (s,3H), 3.49 (t, 2H, J=7.6 Hz), 4.74 (t,
methylphenyl)—5— 2H, J=7.6 Hz), 7.19-7.21 (m, 1H), 7.30-7.33
[2-(quinolin—2- (m, 4H), 7.45 (s, 1H), 7.49 (t, 1H, J=7.6
yl)ethyl]thieno[2,3- Hz), 7.65—7.69 (m, 1H), 7.77 (d, 1H, J=7.6
d]pyridazin—4(5H)- Hz), 8.01 (d, 1H, J=8.4 Hz), 8.04 (d, 1H,
one J=8.4 Hz), 8.19 (s, 1H)
34 5-[2-(quin01in 390/ 1.53 3.92 (t, 2H, J=6.4 Hz), 4.81 (t, 2H, J=6.4
yl)ethy1]—3- Hz), 7.02-7.04 (m, 1H), 7.32 (d, 1H, J=3.6
(thiophen—2- Hz), 7.38 (d,1H, J=3.6 Hz), 7.62 (s, 1H),
yl)thieno[2,3- 7.71 (d, 1H, J=8.4 Hz), 7.82 (t, 1H, J=7.6
d]pyridazin—4(5H)- Hz), 8.01-8.05 (m, 2H), 8.17 (s, 1H), 8.52
one (d, 1H, J=8.4 Hz), 8.64 (d, 1H, J=8.4 Hz)
35 3-(1-methy1—1H- 437 / 2.23 3.49 (t, 2H, J=7.8 Hz), 3.82 (s, 3H), 4.73 (t,
ind01y1)(2- 2H, J=8 Hz), 6.51 (d, 1H, J=2.8 Hz), 7.07
quinolin—2-y1— (d, 1H, J=2.8 Hz), 7.26~7.48 (m, 5H),
ethy1)-5H- 7.65~7.77 (m, 3H), 8.01~8.04 (m, 2H), 8.20
thien0[2,3- (s, 1H)
d]pyridazin—4-one
36 indolyl)- 423 /2.14 3.49 (t, 2H, J=7.6 Hz), 4.74 (t, 2H, J=7.6
quin0 1111—2— Hz), 6.57 (s, 1H), 7.25—7.32 (m, 2H), 7.48-
y1)ethy1]thieno[2,3— 7.52 (m, 2H), 7.59 (s, 1H), 7.65-7.70 (m,
d]pyridazin—4(5H)— 2H), 7.78 (d, 1H, J=8.0 Hz), 8.04 (t, 2H,
0116 J=8.4 Hz), 8.22 (s, 1H), 8.28 (s, 1H)
152
LC-MS: 1H NMR (CDC13) 5:
EX. Name 111/ e (M+H)+/
Rt [min]
37 3-(pyrimidin—5-y1)— 386/ 1.73, 3.50 (t, 2H, J=7.6 Hz), 4.76 (t, 2H, J=7.6
5-[2-(quinolin Hz),7.34 (d, 1H, J=8.4 Hz), 7.49 (t, 1H,
y1)ethy1]thien0[2,3- J=8.0 Hz), 7.61 (s, 1H), 7.66 (t, 1H, J=8.0
d]pyridazin—4(5H)- Hz), 7.78 (d, 2H, J=8.4 Hz), 7.96 (d, 1H,
0116 J=8.4 Hz), 8.07 (d, 1H, J=8.4 Hz), 8.26 (s,
1H), 8.76 (s, 2H), 9.22 (s, 1H)
38 3 -(2— 415/2.06 3.48 (t, 2H, J=7.6Hz), 3.90 (s, 3H), 4.71 (t,
methoxypyridin—3 — 2H, J=7.6 Hz), 6.93-6.96 (m, 1H), 7.30 (d,
y1)[2-(quinolin- 1H, J=8.4 Hz), 7.49 (t, 1H,J=7.6 Hz), 7.56-
2- 7.59 (m, 2H), 7.67 (t, 2H, J=7.6 Hz), 7.77
yl)ethyl]thieno[2,3- (d, 1H, J=8.0 Hz), 8.00-8.05 (m, 2H), 8.19
d]pyridazin—4(5H)- (s, 1H), 8.21 (dd, 1H, J=1.2, J=5.2 Hz)
one
39 3-(pyridin—3-y1) 385 / 1.91 3.49 (t, 2H, J=7.6 Hz), 4.75 (t, 2H, J=7.6
[2-(quinolin—2- Hz), 7.32-7.36 (m, 2H), 7.49 (t, 1H, J=80
yl)ethy1]thieno[2,3- Hz), 7.55 (s, 1H), 7.64-7.69 (m, 1H), 7.77
d]pyridazin—4(5H)- (d, 1H, J=8.0 Hz), 7.88 (d, 1H, J=8.0 Hz),
one 8.06 (d, 1H, J=8.8 Hz), 8.23 (s, 1H), 8.62
(br, 1H), 8.73 (br, 1H).
40 3-(4- 415 / 1.90 3.47 (t, 2H, J=7.6 Hz), 3.79 (s, 3H), 4.70 (t,
ypyridin-3 - 2H, J=7.6 Hz), 6.91 (d, 1H, J=5.6 Hz), 7.30
y1)[2-(quinolin- (d, 1H, J=8 Hz), 7.47~7.51 (m, 2H), 7.68 (t,
2- 1H, J=7.2Hz), 7.77 (d, 1H, J=7.6 Hz),
yl]thieno[2,3- 8.00~8.06 (m, 2H), 8.20 (s, 1H), 8.37 (s,
d]pyridazin—4(5H)- 1H), 8.54 (d, 1H, J=5.6 Hz)
0116
153
LC-MS: 1H NMR (CDC13) 5:
EX. Name 111/ e (M+H)+/
Rt [min]
41 3-(fi11rany1)[2- 374/214 3.53 (t, 2H, J=7.6 Hz), 4.77 (t, 2H, J=7.6
lin Hz), 6.76 (d, 1H, J=1.2 Hz), 7.35 (d, 1H,
y1)ethy1]thien0[2,3- J=8.8 Hz), 7.46~7.52 (m, 3H), 7.68 (t, 1H,
d]pyridazin—4(5H)- J=7.6 Hz), 7.78 (d, 1H, J=8 Hz), 8.02~8.08
0116 (m, 2H), 8.15 (s, 1H), 8.23 (s, 1H)
42 3-(quinolinyl) 435 / 1.93 3.50 (t, 2H, J=7.6 Hz), 4.76 (t, 2H, J=7.6
[2-(qu1nolin—2- Hz), 7.32 (d, 1H, J=8.4 Hz), 7.49 (t, 1H,
y1)ethy1]thieno[2,3— J=7.6 Hz), 7.57 (t, 1H, J=7.6 Hz), 7.65-7.69
d]pyridazin—4(5H)— (m, 4H), 7.85 (d, 1H, J=8.4 Hz), 7.99 ((1,
one 1H, J=8.4 Hz), 8.05 (d, 1H, J=8.4 Hz), 8.14
(d, 1H, J=8.4 Hz), 8.31 (s,1H), 9.06 (s, 1H)
43 3-(isoquinolin 435 / 1.89 3.42 (t, 2H,J=7.6 Hz), 4.62-4.68 (m, 2H),
yl)[2-(quinolin— 7.25 (d, 1H, J=8.0 Hz),7.47-7.68 (m, 7H),
thy1]— 7.76 (d, 1H, J=8.4 Hz), 7.95-8.04 (m, 3H),
thieno[2,3-d]pyri- 8.29 (s, 1H), 8.45 (s, 1H), 8.30 (s, 1H)
dazin—4(5H)-one
44 3-(isoquinolin 435 / 1.87 3.43 (t, 2H, J=7.6 Hz), 4.65 (t, 2H, J=7.6
yl)[2-(quinolin— Hz), 7.25-7.30 (m, 2H), 7.47-7.51 (m, 1H),
2- 7.56 (s, 1H), 7.63-7.68 (m, 3H), 7.76 (d,
y1]thieno[2,3- 1H, J=8.0 Hz), 7.95-8.05 (m, 2H), 8.30 (s,
d]pyridazin—4(5H)- 1H), 8.36 (d, 1H, J=7.0 Hz), 8.30 (s,1H)
one
45 3-(1H-ind01—4-y1)- 423 /2.10 3.47 (t, 2H, J=7.6 Hz), 4.71 (t, 2H, J=7.6
5-(2-quinolin—2-yl— Hz), 6.26 (s, 1H), 7.05 (s, 1H, J=2.4 Hz),
ethy1)-5H- 7.15~7.33 (m, 4H), 7.46 (t, 1H, J=7.2
thieno[2,3- Hz),7.61~7.67 (m, 2H), 7.74 (d, 1H, J=8.4
d]pyridazin—4—one Hz), 8.00 (d, 2H, J=8.4 Hz), 8.22 (s, 1H),
8.49 (s, 1H)
154
LC-MS: 1H NMR (CDC13) 5:
EX. Name m/ e (M+H)+/
Rt [min]
46 3-(2,3- 426 / 2.19 3.26 (t, 2H, J=8.4 Hz), 3.50 (t, 2H, J=7.6
dihydrobenzofuran— Hz), 4.61 (t, 2H, J=8.8 Hz), 4.74 (t, 2H,
5-y1)(2-quinolin- J=7.6 Hz), 6.81 (d, 1H, J=8.4 Hz),
2-y1-ethy1)-5H- 7.23~7.40 (m, 4H), 7.49 (t, 1H, J=7.6 Hz),
thieno[2,3- 7.67 (t, 1H, J=7.6 Hz), 7.77 (d, 1H, J=8
d]pyridazinone Hz), 8.00~8.06 (m, 2H), 8.19 (s, 1H)
47 3-(quinolin—5—y1)—5— 435/ 1.88 3.43 (t, 2H, J=7.6 Hz), 3.98 (s, 3H), 4.74 (t,
[2-(quin0 1111—2— 2H, J=7.6 Hz), .27 (m, 2H), 7.47-7.51
yl)ethy1]thieno[2,3— (m, 2H), 7.55 (s, 1H), 7.64-7.77 (m, 3H),
d]pyridazin—4(5H)- 7.83 (d, 1H, J=8.4 Hz), 7.97 (d, 1H, J=8.4
0116 Hz), 8.01 (d, 1H, J=8.4 Hz), 8.18 (d, 1H,
J=8.8 Hz), 8.29 (S, 1H), 8.90 (d, 1H, J=2.8
Hz)
48 3-(3,5-dirnethy1— 403 /2.01 2.07 (s, 3H), 2.25 (s, 3H), 3.49 (t, 2H, J=7.6
1,2-0xaz01—4-y1) Hz), .75 (m, 2H), 7.35 (t, 2H, J=8.4
[2-(quin01in—2- Hz), 7.49 (t, 1H, J=8 Hz), 7.66 (t, 1H,
y1]thieno[2,3- J=8.4 Hz), 7.77 (d, 1H, J=8.4 Hz), 7.98 (d,
d]pyridazin—4(5H)- 1H, J=8 Hz), 8.06 (d, 1H, J=8.4 Hz), 8.22
one (s, 1H)
49 3-(6- 415 /2.09 3.49 (t, 2H, J=7.6 Hz), 4.65 (t, 2H, J=7.6
methoxypyridin-3 - Hz), 6.79 (d, 1H, J=8.4 Hz), 7.33 (d, 1H,
y1)[2-(quinolin- J=8.8 Hz), 7.47—7.52 (m, 2H), 7.65-7.69 (m,
2- 2H), 7.75-7.79 (m, 2H), 8.00 (d, 1H, J=8.4
yl)ethyl]thieno[2,3- Hz), 8.06 (d, 1H, J=8.4 Hz), 8.22 (s, 1H),
d]pyridazin—4(5H)- 8.28 (d, 1H, J=2.0 Hz)
0116
155
LC-MS: 1H NMR (CDC13) 5:
EX. Name m/ e /
Rt [min]
50 3-(2,3-dihydro-1,4- 442 /2.17 3.50 (t, 2H, J=7.6 Hz), 4.30 (s, 4H), 4.74 (t,
benzodioxiny1)- 2H, J=7.6 Hz), 6.90 (d, 1H, J=8.8 Hz),
5-[2-(quinolin 7.00~7.02 (m, 1H), 7.08 (d, 1H, J=2 Hz),
y1)ethy1]thieno[2,3- 7.32 (d, 1H, J=8 Hz), 7.42 (s, 1H), 7.49 (t,
dazin-4(5H)- 1H, J=8Hz), 7.67 (t, 1H, J=6.8 Hz), 7.77 ((1,
one 1H, J=8 Hz), 8.01~8.06 (m, 2H), 8.18 (s,
1H)
51 3-(2-rnethylpyridin— 399/ 1.97 2.61 (s, 3H), 3.50 (t, 2H, J=7.6 Hz), 4.75 (t,
4-y1)[2- 2H, J=7.6 Hz), 7.22-7.28 (m, 2H), 7.33 (d,
lin 1H, J=8.0 Hz), 7.47-7.51 (m, 1H), 7.56 (s,
yl)ethy1]thieno[2,3- 1H), 7.65-7.69 (m, 1H), 7.78 (d, 1H, J=7.6
d]pyridazin—4(5H)- Hz), 7.98 (d, 1H, J=8.4 Hz), 8.06 (d, 1H,
one J=8.4 Hz), 8.23 (s, 1H), 8.52 (d, 1H, J=5.2
Hz).
52 3-(5- 415 / 1.96 3.50 (t, 2H, J=7.6 Hz), 3.87 (s,3H), 4.75 (t,
methoxypyridin 2H, J=7.6 Hz), 7.45-7.51 (m, 2H), 7.57 (s,
y1)[2-(quinolin- 1H), 7.67 (t, 1H, J=7.6 Hz), 7.77 (d, 1H,
2- J=8.0 Hz), 7.99 (d, 1H, J=8.4 Hz), 8.05 (d,
yl)ethy1]thieno[2,3- 1H, J=8.4 Hz), 8.23 (s,1H), 8.33 (m, 2H)
d]pyridazin—4(5H)-
one
53 3-[6-(morpholin 470 / 2.05 3.50 (t, 2H, J=7.6Hz), 3.58 (t, 4H, J=4.8
yl)pyridiny1]—5- Hz), 3.84 (t, 4H, J=4.8 Hz), 4.75 (t, 2H,
[2-(quino 1in J=7.6 Hz), 6.69 (d, 1H, J=8.8 Hz), 7.32 (d,
y1)ethy1]thieno[2,3- 1H, J=8.4 Hz), 7.44 (s, 1H), 7.49 (t, 1H,
d]pyridazin—4(5H)— J=7.2 Hz), 7.68 (m, 1H, J=8.4 Hz),
0116 7.76~7.79 (m, 2H), 8.00~8.07 (m, 2H),
8.20 (s, 1H), 8.33 (d, 1H, J=2 Hz)
156
LC-MS: 1H NMR (CDC13) 5:
EX. Name m/ e (M+H)+/
Rt [min]
54 3-(1,3-benzodioxol— 428 /2.16 3.50 (t, 2H, J=7.6Hz), 4.74(t, 2H, z),
5-y1)[2- 6.00 (s, 2H), 6.84 (d, 1H, J=8Hz),
(quinolin 6.95~7.01 (m, 2H), 7.33 (d, 1H, J=8.4Hz),
y1]thieno[2,3- 7.42 (s, 1H), 7.49 (t, 1H, J=7.6Hz), 7.67 (t,
d]pyridazin-4(5H)- 1H, J=7.2Hz), 7.77 (d, 1H, J=8.4Hz),
one 8.00~8.06 (m, 2H), 8.19 (s, 1H)
55 3-(quinolin—6—y1)—5— 435 /2.03 3.50 (t, 2H, J=7.6 Hz), 3.95 (d, 2H, J=7.2
[2-(quinolin—2— Hz), 4.75 (t, 2H, J=7.6 Hz), 7.21 (d, 1H,
yl)ethy1]thieno[2,3— J=8.4 Hz), 7.40-7.50 (m, 2H), 7.60 (s, 1H),
d]pyridazin—4(5H)- 7.65—7.69 (m, 1H), 7.77-7.84 (m, 2H), 7.94
one ((1, 1H, J=2.4 Hz),7.99 (d, 1H, J=8.4 Hz),
8.05 (d, 1H, J=8.4 Hz), 8.12 (d, 1H, J=8.4
Hz), 8.17 (d, 1H, J=8.0 Hz), 8.25 (s, 1H),
8.93—8.94 (m, 1H)
56 3-(1-rnethy1—1H- 388 / 1.93 3.52 (t, 2H, J=7.6 Hz), 3.95 (s, 3H), 4.77 (t,
l—4-yl)[2- 2H, J=7.6 Hz), 7.34 (d, 1H, J=8.4 Hz), 7.48-
(quinolin 7.55 (m, 2H), 7.66-7.71 (m, 1H),7.77-7.80
yl)ethy1]thieno[2,3- (m, 2H), 8.02-8.08 (m, 2H), 8.16 (s, 1H),
d]pyridazin—4(5H)- 8.23 (s, 1H)
one
57 3-[1-(2- 430 / 2.17 0.95 (d, 6H, J=6.8 Hz), 2.26 (m, 1H), 3.54
methylpropyl)- 1 H- (t, 2H, J=7.6 Hz), 3.95 (d, 2H, J=7.2 Hz),
pyrazo 1—4-y1][2- 4.78 (t, 2H, J=7.6 Hz), 7.34 (d, 1H, J=8.4
(quinolin Hz), 7.50-7.54 (m, 2H), 7.69 (t, 1H, J=7.6
y1)ethy1]thieno[2,3- Hz), 7.78 (d, 1H, J=8.4 Hz), 7.82 (s,1H),
d]pyridazin—4(5H)— 8.02-8.08 (m, 2H), 8.14 (s, 1H), 8.28 (s,
0116 1H)
157
LC-MS: 1H NMR (CDC13) 5:
EX. Name m/ e (M+H)+/
Rt [min]
58 tert-buty12-{4-0X0- 473 /2.11 1.35 (s, 9H), 3.46 (t, 2H, J=7.6 Hz), 4.68 (t,
5-[2-(quinolin 2H, J=7.6 Hz), 6.23~6.28 (m, 2H), 7.29 (d,
y1)ethy1]-4,5- 1H, J=8.4 Hz), .51 (m, 3H), 7.69 (t,
dihydrothien0[2,3- 1H, J=8 Hz), 7.77 (d, 1H, J=7.6 Hz), 8.05
d]pyridazin—3-yl}- (d, 2H, J=8 Hz), 8.15 (s, 1H)
lH-pyrrole-l-
carboxylate
59 3-(2- 416/ 1.95 3.50 (t, 2H, J=7.6 Hz), 4.07 (s, 3H), 4.75 (t,
methoxypyrimidin— 2H, J=7.6 Hz), 7.35 (d, 1H, J=8.4 Hz), 7.54
5-y1)[2- (s, 1H), 7.67 (t, 2H, J=9.2 Hz), 7.79 (d, 1H,
(quinolin J=7.6 HZ), 7.98 (d, 1H, J=8.4 Hz), 8.07 (d,
yl)ethy1]thieno[2,3- 1H, J=8.4 Hz), 8.24 (s, 1H), 8.67 (s, 2H)
d]pyridazin—4(5H)-
one
60 5-[2-(quinolin 438 / 1.60 3.88 (t, 2H, J=6.0 Hz), 4.76 (t, 2H, J=6.0
y1]—3-(2,3,4- Hz), 6.88-7.02 (m, 2H), 7.55 (s, 1H), 7.68
trifluorophenyl)thie (d, 1H, J=7.6 Hz), 7.82 (t, 1H, J=7.6 Hz),
no[2,3-d]pyridazin- 7.98-8.06 (m, 2H), 8.24 (s, 1H), 8.48 (d,
4(5H)-one 1H, J=8.4 Hz), 8.63 (d,1H,J=8.4 Hz)
61 u0r0 416 / 2.28 2.24 (d, 3H, J=1.6 Hz), 3.42 (t, 2H, J=7.6
methylpheny1)-5 - Hz), 4.66 (t, 2H, J=7.6 Hz), 6.95 (t, 1H,
[2-(quino 1111 J=8.8 Hz), 7.19~7.24 (m, 3H), 7.35 (s, 1H),
y1)ethy1]thien0[2,3- 7.44 (t, 1H, J=6.8 Hz), 7.58~7.62 (m, 1H),
d]pyridazin—4(5H)- 7.70 (d, 1H, J=8.4 Hz), 7.93~7.99 (m, 2H),
0116 8.13 (s, 1H)
158
LC-MS: 1H NMR (CDC13) 5:
EX. Name 111/ e (M+H)+/
Rt [min]
62 3-(4-fluoro 416/ 1.61 3.87 (t, 2H, J=6.0 Hz), 4.73 (t, 2H, J=6.0
methylpheny1) Hz), 6.78-7.03 (m, 3H), 7.38 (s, 1H), 7.68
[2-(quinolin—2- (d, 1H, J=8.4 Hz), 7.82 (t, 1H, J=7.6 Hz),
y1)ethy1]thieno[2,3- 7.98-8.04 (m, 2H), 8.25 (s, 1H), 8.48 (d,
dazin-4(5H)- 1H, J=8.4 Hz), 8.60 (d, 1H, J=8.4 Hz)
one
63 hloro—4— 436 / 2.09 3.50 (t, 2H, J=7.6 Hz), 4.74 (t, 2H, J=7.6
fluoropheny1)—5—[2— Hz), 7.15 (t, 1H, J=8.8 Hz), 7.33-7.38 (m,
(quinolin 2H), 7.47—7.53 (m, 3H), 7.68 (t, 1H, J=7.6
y1)ethy1]thieno[2,3- Hz), 7.79 (d, 1H, J=7.6 Hz), 7.99-8.08 (m,
d]pyridazin—4(5H)- 2H), 8.22 (s, 1H)
one
64 3-(2-chloro 436 / 2.24 3.47 (t, 2H,J=7.6 Hz), 4.71 (t, 2H, J=7.6
fluoropheny1)[2- Hz), 6.99-7.04 (m, 1H), 7.31-7.44 (m, 2H),
(quinolin 7.47-7.51 (m, 2H), .69 (m, 1H), 7.76
y1)ethy1]thieno[2,3- (d, 1H, J=8.0 Hz), 7.98 (d, 1H, J=8.8 Hz),
d]pyridazin—4(5H)- 8.03 (d, 1H, J=8.8 Hz), 8.22 (s, 1H)
one
65 3-(3,4- 412 /2.13, 2.30 (s, 6H), 3.49 (t, 2H, J=7.6 Hz), 4.73 (t,
dimethylpheny1)-5 - 2H, J=7.6 Hz), 7.18 (d, 1H, J=7.6 Hz), 7.24—
[2-(quino 11n 7.27 (m, 2H), 7.31 (d, 1H, J=8.4 Hz), 7.43
y1)ethy1]thieno[2,3- (s, 1H), 7.46-7.50 (m, 1H), 7.65-7.69 (m,
d]pyridazin—4(5H)- 1H), 7.77 (d, 1H, J=8.4 Hz), 8.03 (t, 2H,
0116 J=8.8 Hz), 8.18 (s, 1H).
159
LC-MS: 1H NMR (CDC13) 5:
EX. Name m/ e (M+H)+/
Rt [min]
66 3-(2,4- 412 /2.12 2.05 (s, 3H), 2.36 (s, 3H), 3.47 (t, 2H, J=7.6
dimethylpheny1) Hz), 4.69 (t, 2H, J=7.6 Hz), 7.02~7.08 (In,
[2-(quinolin—2- 4H), 7.29 (d, 1H, J=8.8 Hz), 7.35 (s, 1H),
y1]thieno[2,3- 7.48 (t, 1H, J=7.2 Hz), 7.66 (t, 1H, J=7.2
d]pyridazin-4(5H)- Hz), 7.76 (d, 1H, J=8 Hz), 8.01 (t, 1H,
one J=8.8 Hz), 8.21 (s, 1H)
67 3-(2,4— 420 / 2.19 3.48 (t, 2H, J=7.6 Hz),4.73 (t, 2H, J=7.6
difluoropheny1)—5— Hz), 6.89—6.94 (m, 2H), 7.29-7.36 (m, 2H),
[2-(quinolin—2- 7.47—7.53 (m, 2H), 7.67-7.69 (m, 1H) 7.76
y1]thieno[2,3- (d, 1H, J=8.0 Hz), 8.00 (d, 1H, J=8.4 Hz),
d]pyridazin—4(5H)- 8.04 (d, 1H, J=8.4 Hz), 8.21 (s, 1H)
one
68 3-(2,4- 444 / 2.17 3.47 (t, 2H, J=7.6 Hz), 3.72 (s,3H), 3.84 (s,
dimethoxypheny1)- 3H), 4.69 (t, 2H, J=7.6 Hz), 6.52-6.55 (m,
5-[2-(quinolin 2H), 7.19 (s, 1H, J=8.0 Hz), 7.30 (d, 1H,
y1)ethy1]thieno[2,3- J=8.0 Hz), 7.44 (s, 1H) 7.46-7.50 (m, 1H),
d]pyridazin—4(5H)- 7.65-7.77 (m, 2H), 8.03 (d, 2H, J=8.4 Hz),
one 8.16 (s, 1H)
69 - 444 / 2.16 3.46~3.50 (m, 2H), 3.69 (s, 3H), 3.79 (s,
dimethoxypheny1)- 3H), 4.69 (t, 2H, J=7.6 Hz), 6.87 (d, 1H,
5-[2-(quinolin J=2 Hz), 6.91 (s, 2H), 7.30 (d, 1H, J=8.4
y1)ethy1]thieno[2,3- Hz), 7.49 (t, 2H, J=6.8 Hz), 7.68 (t, 1H,
d]pyridazin—4(5H)- J=8.4 Hz), 7.76 (d, 1H, J=8.4 Hz),
0116 8.02~8.05 (m, 2H), 8.17 (s, 1H)
160
LC-MS: 1H NMR (CDC13) 5:
EX. Name m/ e (M+H)+/
Rt [min]
70 3-(2,3- 420 /2.19 3.50 (t, 2H, J=7.6 Hz), 4.73 (t, 2H,J=7.6
difluoropheny1) Hz), 7.10-7.13 (m, 2H), 7.18-7.23 (m, 1H),
[2-(quinolin—2- 7.31 (d, 1H, J=8.4 Hz), 7.49 (t, 1H, J=7.6
y1)ethy1]thieno[2,3- Hz), 7.57 (s,1H), 7.68 (t, 1H, J=7.6 Hz),
d]pyridazin-4(5H)- 7.77 (d, 1H, J=7.6 Hz), 8.01-8.06 (m, 2H),
one 8.22 (s, 1H)
71 3-(3,4— 444/ 1.95, 3.50 (t, 2H, J=7.6 Hz), 3.88 (s, 3H), 3.92 (s,
dimethoxyphenyl)— 3H), 4.75 (t, 2H, J=7.6 Hz), 6.92 (d, 1H,
5-[2-(quinolin J=8.4 Hz), .11 (m, 2H), 7.32 (d, 1H,
y1)ethy1]thieno[2,3- J=8.4Hz), .51 (m, 2H), 7.68 (t, 1H,
d]pyridazin—4(5H)- J=7.6Hz), 7.77 (d, 1H, J=7.6 Hz), 8.04 (t,
one 2H, J=8.8 Hz), 8.20 (s, 1H)
72 3-(3,4- 420 / 2.22 3.49 (t, 2H, J=7.6 Hz), 4.74 (t, 2H, J=7.6
difluoropheny1) Hz), 7.15-7.21 (m, 2H), 7.28-7.35 (m, 2H),
[2-(quinolin—2- 7.47 (s, 1H), 7.50 (d, 1H, J=7.2 Hz), 7.65-
y1)ethy1]thieno[2,3- 7.69 (m, 1H), 7.78 (d, 1H, J=8.0 Hz), 7.98
d]pyridazin—4(5H)- (d, 1H, J=8.4 Hz), 8.06 (d, 1H, J=8.0 Hz),
one 8.22 (s, 1H)
73 3-(5-fluoro 432 /2.19 3.48 (t, 2H, J=7.6 Hz), 3.71 (s, 1H), 4.71 (t,
methoxyphenyl)-5 - 2H, J=7.6 Hz), 6.87-7.08 (m, 3H), 7.30 (d,
ino lin 1H, J=8.8 Hz), 7.47—7.51 (m, 2H), 7.68 (t,
y1)ethy1]thieno[2,3- 1H, J=7.6 Hz), 7.77 (d, 1H, J=8.4 Hz), 8.03
d]pyridazin—4(5H)- (t, 2H, J=8.0 Hz), 8.18 (s, 1H).
0116
161
LC-MS: 1H NMR (CDC13) 5:
EX. Name m/ e (M+H)+/
Rt [min]
74 3-(4-fluoro 432 /2.01, 3.47 (t,2H, J=7.6Hz),3.72 (s, 3H), 4.70 (t,
methoxypheny1) 2H, J=7.6 Hz), 6.70-6.72 (m, 2H), 7.18-7.22
[2-(quinolin—2- (m, 1H), 7.44 ,7.49 (t, 1H, J=7.6 Hz),
y1)ethy1]thieno[2,3- 7.67 (d, 1H, J=7.6 Hz), 7.77 (d, 1H, J=8.4
d]pyridazin-4(5H)- Hz),7.99 (d, 1H, J=8.4 Hz), 8.02 (t, 2H,
one J=8.8 Hz), 8.17 (s,1H)
75 — 444 / 2.20 3.50 (t, 2H, J=7.6 Hz), 4.74 (t, 2H, J=7.6
dimethoxyphenyl)— Hz), 6.50 (t, 1H, J=2.4 Hz), 6.68 (d, 2H,
5-[2-(quinolin J=2.4 Hz), 7.31 (d, 1H, J=7.6 Hz), 7.46-
yl)ethy1]thieno[2,3- 7.50 (m, 2H), 7.65-7.69 (m, 1H), 7.76 (d,
dazin—4(5H)— 1H, J=8.4 Hz), 8.00-8.05 (m, 2H), 8.19 (5,
one 1H)
76 3-(2,5- 420 /2.19 3.49 (t, 2H, J=6.0 Hz), 4.73 (t, 2H, J=6.0
difluoropheny1) Hz), 7.06-7.11 (n1,3H), 7.31 (d, 1H, J=8.4
[2-(quinolin—2- Hz), 7.48 (t,1H, J=8.4 Hz), 7.56 (s, 1H),
yl)ethy1]thieno[2,3- 7.64-7.69 (m, 1H), 7.76 (d, 1H, J=8.0 Hz),
d]pyridazin—4(5H)— 8.00 (d, 1H, J=8.4 Hz), 8.04 (d, 1H, J=8.4
one Hz), 8.21 (s, 1H)
77 3-(2,3- 444 / 2.15 3.48 (t, 2H, J=7.6 Hz), 3.59 (s, 3H), 3.89 (s,
dimethoxyphenyl)- 3H), 4.71 (t, 2H, J=7.6 Hz), 6.86 (dd, 1H,
5-[2-(quinolin J=1.2 Hz, J=7.6 Hz), 6.97 (d, 1H, J=8.0
y1)ethy1]thieno[2,3- Hz), 7.05-7.09 (m, 1H), 7.30 (d, 1H, J=8.0
d]pyridazin—4(5H)- Hz), 7.47—7.51 (m, 2H), 7.67 (t, 1H, J=7.6
0116 Hz), 7.76 (d, 1H, J=8.0 Hz), 8.00-8.04 (m,
2H), 8.20 (s, 1H)
162
LC-MS: 1H NMR (CDC13) 5:
EX. Name m/ e (M+H)+/
Rt [min]
78 uoro 432 /2.19 3.50 (t, 2H, J=7.6 Hz), 3.93 (s, 3H), 4.74(t,
methoxypheny1) 2H, J=7.6 Hz), 6.99 (t, 1H, J=8.4 Hz), 7.23-
[2-(quinolin—2- 7.27 (m, 2H), 7.33 (d, 1H, J=8.4 Hz), 7.44
y1)ethy1]thieno[2,3- (s, 1H), 7.49 (t, 1H, J=7.6 Hz), .69
d]pyridazin-4(5H)- (m, 1H), 7.78 (d, 1H, J=8.0 Hz), 8.00 ((1,
one 1H, J=8.0 Hz), 8.05 (d, 1H, J=8.4 Hz), 8.19
(s, 1H)
79 3-(2-fluoro—3— 432 / 2.17 3.48 (t, 2H, J=7.6 Hz), 3.92 (s,3H), 4.72
methoxypheny1)-5— (t,2H,J=7.6 Hz), 6.93-7.13 (m, 3H), 7.29 (d,
[2-(quinolin—2- 1H, J=8.0 Hz), 7.46-7.50 (m, 1H), 7.55 (s,
y1)ethy1]thieno[2,3- 1H), 7.65-7.69 (m, 1H), 7.77 (d, 1H, J=8.0
d]pyridazin—4(5H)— Hz), 8.01-8.04 (m, 2H), 8.19 (s, 1H)
one
80 3-(3,5- 420 / 2.24 3.50 (t, 2H, J=7.6 Hz), 4.75 (t, 2H, J=7.6
difluoropheny1) Hz), .85 (m, 1H), 7.01-7.03 (m, 2H),
[2-(quinolin—2- 7.34 (d,1H, J=8.4 Hz), 7.47-7.51 (m, 2H),
y1)ethy1]thieno[2,3- 7.66 (t, 1H, J=8.4 Hz), 7.77 (d, 1H, J=8.4
d]pyridazin—4(5H)— Hz), 7.98 (d, 1H, J=8.4 Hz), 8.06 (d, 1H,
one J=8.4 Hz), 8.21 (s, 1H)
81 3-(3-fluoro 432 /2.23 3.51 (t, 2H, J=7.6 Hz), 3.81 (s, 1H), 4.75 (t,
methoxyphenyl)-5 - 2H, J=7.6 Hz), 6.63-6.67 (m, 1H), 6.79-6.82
[2-(quinolin—2- (m, 1H), 6.87 (s, 1H), 7.33 (d, 1H, J=8.4
y1)ethy1]thieno[2,3- Hz), 7.47-7.51 (m, 2H), 7.67 (t, 1H, J=7.6
d]pyridazin-4(5H)- Hz), 7.78 (d, 1H, J=8.0 Hz), 8.00-8.07 (m,
0116 2H), 8.20 (s, 1H).
163
LC-MS: 1H NMR (CDC13) 5:
EX. Name m/ e (M+H)+/
Rt [min]
82 3-(2-methoxy 428/ 1.61 2.21 (s, 3H), 3.59 (s, 3H), 3.78 (t, 2H, J=6.0
phenyl) Hz), 4.66 (t, 2H, J=6.0 Hz), 6.77 (d, 1H,
[2-(quinolin—2- J=8.4 Hz), 6.94 (s, 1H), 7.07 (d, 1H, J=8.4
y1)ethy1]thieno[2,3- Hz), 7.37 (s, 1H),7.50 (d, 1H, J=8.4 Hz),
d]pyridazin-4(5H)- 7.69 (t, 1H, J=7.6 Hz), .92 (m, 2H),
one 8.05 (s,1H), 8.45 (m, 2H)
83 3-(2,5— 452 / 2.09 3.48 (t, 2H, J=7.6 Hz), 4.72 (t, 2H, J=7.6
dichlorophenyl)—5— Hz), 7.29~7.33 (m, 3H), 7.39 (d, 1H, J=8
[2-(quinolin—2- Hz), 7.48 (t, 2H, J=6.4 Hz), 7.66 (t, 1H,
y1]thieno[2,3- J=7.2 Hz), 7.76 (d, 1H, J=8 Hz), 7.98~8.04
d]pyridazin—4(5H)- (m, 2H), 8.22 (s, 1H)
one
84 3-(naphthalen 434 / 2.11 3.55 (t, 2H, J=7.6 Hz), 4.75 (t, 2H, J=7.6
y1)[2-(quinolin- Hz), 7.35 (d, 1H, J=8.4 Hz), 7.48~7.63 (n1,
2- 5H), 7.71 (t, 1H, J=7.2 Hz), 7.79~7.87 (n1,
yl)ethy1]thieno[2,3- 4H), 7.94 (s, 1H), 8.09 (t, 2H, J=8.4 Hz),
d]pyridazin—4(5H)- 8.23 (s, 1H)
one
85 3-pheny1—5-[2- 384 / 2.19 3.50 (t, 2H, J=7.6 Hz), 4.74 (t, 2H, J=7.6
(quinolin Hz), 7.32 (d, 1H, J=8.4 Hz), 7.39~7.53 (n1,
y1)ethy1]thieno[2,3- 7 H), 7.67 (t, 1H, J=7.6 Hz), 7.77 (d, 1H,
d]pyridazin—4(5H)- J=7.6 Hz), 8.04 (t, 2H, J=8.8 Hz), 8.20 (5,
one 1H)
86 3-(1-benzofuran—2- 423 / 1.70 3.75 (t, 2H, J=6.8 Hz),4.79 (t, 2H, J=6.8
y1)[2-(quinolin- Hz), 7.14-7.18 (m,1H), 7.24 (t, 1H,J=7.2
2- Hz), 7.07 (d,1H, J=8.4 Hz), 7.40-7.61 (m,
y1)ethy1]thieno[2,3— 4H), 7.77-7.85 (m, 2H), 8.00 (s, 1H), 8.10
d]pyridazin—4(5H)- (s, 2H), 8.30-8.34 (m, 2H)
0116
164
LC-MS: 1H NMR (CDC13) 5:
EX. Name m/ e (M+H)+/
Rt [min]
87 3-(1H-indazol—5- 424/200 3.50 (t, 2H, J=7.6 Hz), 4.75 (t, 2H, J=7.6
y1)[2-(quinolin— Hz), 7.32 (d, 1H, J=8.4 Hz), 6.63-6.67 (m,
2- 1H), 6.79-6.82 (m, 1H), 6.87 (s, 1H), 7.33
y1)ethy1]thieno[2,3- (d, 1H, J=8.4 Hz), .51 (m, 2H), 7.67
d]pyridazin-4(5H)- (t, 1H, J=7.6 Hz), 7.78 (d, 1H, J=8.0 Hz),
one 8.00-8.07 (m, 2H), 8.20 (s, 1H).
88 3-(1—methy1—1H— 388 / 1.89 3.49 (t, 2H, J=7.6 Hz), 3.56 (s, 3H), 4.73 (t,
l—5-y1)—5—[2— 2H, J=7.6 Hz), 6.31 (d, 1H, J=2.0 Hz), 7.34
(quinolin (d, 1H, J=8.0 Hz), 7.47-7.52 (m, 2H), 7.56
yl)ethy1]thieno[2,3- (s, 1H), 7.64-7.69 (m, 1H), 7.77 (d, 1H,
d]pyridazin—4(5H)- J=8.0 Hz), 7.96 (d, 1H, J=8.8 Hz), 8.06 ((1,
one 1H, J=8.4 Hz), 8.25 (s, 1H)
89 3-(4,5-difluoro 450 / 2.22 3.47 (t, 2H, J=7.6Hz), 3.60 (s, 3H), 4.70 (t,
methoxypheny1) 2H, z), 6.75~6.80 (m, 1H), 7.07 (t,
[2-(quinolin—2- 1H, J=7.6 Hz), 7.30 (d, 1H, J=8.4 Hz),
y1)ethy1]thieno[2,3- 7.45~7.50 (m, 2H), 7.67 (t, 1H, J=7.2 Hz),
d]pyridazin—4(5H)- 7.77 (d, 1H, j=8 Hz), 7.99~8.05 (m, 2H),
one 8.18 (s, 1H)
90 3-(2-fluoro 416 / 1.60 2.26 (s, 3H), 3.77 (t, 2H, J=6.0 Hz), 4.68 (t,
methylpheny1)-5 - 2H, J=6.0 Hz), 6.73 (d, 1H, J=8.4 Hz), 6.83
[2-(quino lin (d, 1H, J=8.0 Hz), 7.05 (t, 1H, J=8.0 Hz),
y1)ethy1]thieno[2,3- 7.44(s,1H),7.60 (d, 1H, J=8.4 Hz), 7.75 (t,1
d]pyridazin—4(5H)- H, J=8.0 Hz),7.90-7.99 (m, 2H), 8.14 (s,
0116 1H), 8.28 (d, 1H, J=8.4 Hz), 8.59 (d, 1H,
J=8.4 Hz)
165
LC-MS: 1H NMR ) 8:
EX. Name m/ e (M+H)+/
Rt [min]
91 3-(2-fluoro 432/218 3.49 (t, 2H, J=7.6 Hz), 3.80 (s, 3H), 4.73 (t,
methoxyphenyl)-5 - 2H, J=7.6 Hz), 6.88-6.93 (m, 2H), 7.08 (t,
[2-(quinolin—2- 1H, J=8.8 Hz), 7.30 (d, 1H, J=8.4 Hz), 7.46-
yl)ethyl]thieno[2,3- 7.51 (m, 1H), 7.65-7.69 (m, 1H), 7.55 (s,
d]pyridazin-4(5H)- 1H), 7.65-7.69 (m, 1H), 7.76 (d, 1H, J=8.4
one Hz), 8.03 (t, 2H, J=8.0 Hz), 8.20 (s, 1H).
92 y1—4— {4—oxo— 423 / 1.54 1.99 (s, 3H), 3.84 (t, 2H, J=6.0 Hz), 4.73
5-[2-(quinolin—2— (t,2H,J=6.0 Hz), 7.15 (d, 1H, J=8.0 Hz),
yl)ethyl]—4,5- 7.39-7.46 (m, 3H), 7.77 (d, 1H, J=8.4 Hz),
dihydrothieno [2 ,3 - 7.87 (t, 1H, J=8.0 Hz), 8.02-8.09 (m, 2H),
d]pyridazin—3- 8.32 (s, 1H), 8.36 (d, 1H, J=8.4 Hz), 8.69
yl}benzonitrile (d, 1H, J=8.4 Hz)
E 93: 5-[2-(6-F1uoroquinoliny1)ethy1](pyridinyl)thieno[2,3-
d]pyridazin—4(5H)-one
93. 1 3-Bromo(2-(6-fluoroquino1in-2—yl)ethyl)thieno[2,3-d]pyridazin—4(5H)-one
2-(6-Fluoroquinolinyl)ethanol (182 mg, 0.952 mmol) from Example a2) and 3-
bromo-5H-thieno[2,3-d]pyridazin-4(5H)-one (200 mg, 0.865 mmol) from Example 3.3
were dissolved in THF (10 mL) and stirred for about 10 min. Then Ph3P (342 mg, 1.305
mmol) and DEAD (226 mg, 1.298 mmol) were each added sequentially rapidly to the
10 solution. The reaction mixture was stirred under nitrogen atmosphere overnight. The
reaction solution was concentrated and d by TLC (PE/EA=1/ l). The crude
product was recrystallized from methanol (130 mg, yield: 37.1%). LC-MS: m/e
(M+H)+; Rt : 1.90 min.
166
93.2 5-[2-(6-Fluoroquinolinyl)ethyl]—3—(pyridinyl)thieno[2,3-d]pyridazin-4(5H)-
one
3-Bromo(2-(6-fluoroquinolin-2—yl)ethyl)thieno[2,3-d]pyridazin—4(5H)-one (66
mg, 0.163 mmol) was dissolved in dioxane (2.1 mL) and H20 (0.7 mL), nyl
boronic acid (20.07 mg, 0.163 mmol), K2CO3 (45.1 mg, 0.327 mmol) and Pd(dppf)C12
(7.23 mg, 9.80 umol) were each added sequentially to the suspension. The suspension
was heated in a microwave tube at about 110 °C for 1 h. The crude product was purified
by TLC (EA) to give the title compound (45 mg, yield: .
10 LC—MS: m/e (M+H)+: 403.7, Rt: 1.81 min; lH NMR(CDC13, 400 MHz) 8: 8.65
(d, J = 6.0 Hz, 2H), 8.24 (s, 1H), 8.02—7.96 (m, 2H), 7.61 (s, 1H), 7.46-7.42 (m, 3H),
7.41-7.38 (m, 1H), 7.34 (d, J = 8.4 Hz, 1H), 4.75 (t, J = 7.4 Hz, 2H), 3.48 (t, J = 7.4 Hz,
2H).
15 EXAMPLE 94: 5-[2,2-Difluoro(quinolin—2—yl)ethyl](pyridinyl)thieno[2,3-
d]pyridazin—4(5H)-one
N
/ \
\ O /
/
N N
I
F
\
F |
N \
S
94.1 3-Bromo(2,2-difluoro-2—(quinolin-2—yl)ethyl)thieno[2,3-d]pyridazin—4(5H)-one
A mixture of 3-bromothieno[2,3-d]pyridazin—4(5H)-one (10mg, 0.043 mmol)
20 from Example 3.3, trifluoromethanesulfonic acid 2,2-difluoroquinolinyl ethyl
ester (14.77 mg, 0.043 mmol) from Example b1 and CszC03 (28.2 mg, 0.087 mmol) in
DMF (0.5 mL) was d at room temperature for 5 h. The solution was purified by
Pre-TLC (PE/EA =1/2) to give a dark yellow oil (4 mg, yield 22%).
LC-MS : m/e 422 (M+H)+, Rt: 1.96 min.
25
94.2 5-[2,2—Difluoro—2—(quinolin—2—yl)ethyl]—3—(pyridinyl)thieno[2,3-d]pyridazin—
4(5H)—one
A mixture of 3-bromo—5—(2,2—difluoro—2— (quinolinyl)ethyl)thieno[2,3-
d]pyridazin—4(5H)-one (0.118 mmol), pyridin—4—yl boronic acid (0.118 mmol), Na2C03
167
(31.4 mg, 0.296 mmol) and PdC12(dppf)—CH2C12 adduct (9.67 mg, 0.012 mmol) in
dioxane (1.5 mL) and water (0.5 mL) was stirred at 100 °C for 2h. The solvent was
evaporated and the residue was purified by C =1/ 1) to give a crude
yellow solid. The solid was dissolved in DCM (1.5 mL) and filtered. The white solid
obtained was the title compound (40 mg, yield 80%).
LC-MS (ESI+): m/e 421 (M+H)+, Rt: 2.00 min; 1H NMR (CDCl3, 400MHz) 8:
8.70 (s, 1H), 8.61 (d, J: 8.4 Hz, 1H), 8.50 (dd, J: 4.4 Hz, 1.2Hz, 1H), 8.22 (s, 1H),
8.13 (d, J= 8.4 Hz, 1H), 8.03 (d, J= 8.4 Hz, 1H), 7.88-7.84 (m, 1H), 7.80 (d, J= 8.4
Hz, 1H), 7.76-7.73 (m, 1H), 7.30 (dd, J= 4.4 Hz, 2.0Hz, 2H), 5.15 (t, J= 14 Hz, 2H).
10
EXAMPLE 95: idin—4—yl)—5—[2—(thieno[3,2—b]pyridin—5-yl)ethyl]thieno[2,3-
d]pyridazin—4(5H)—one
N
N \
S
95. l 3-Bromo[2-(thieno [3 ,2-b]pyridin—5—yl)ethyl]thieno [2,3 -d]pyridazin—4(5H)-one
15 To a e of 3-bromothieno[2,3-d]pyridazin-4(5H)-one (100 mg, 0.433 mmol)
from Example 3.3 and triphenylphosphine (227 mg, 0.866 mmol) in THF (2 mL) was
added (E)-diethyl diazene-l,2-dicarboxy1ate (151 mg, 0.866 mmol) se at 0°C.
After the addition, the mixture was stirred for 1h at 0°C. Then 2-(thieno[3,2-b]pyridin—
5-yl)ethanol from Example a3 (78 mg, 0.433 mmol) in THF(1 mL) was added
20 dropwise. The mixture was stirred at room temperature overnight. The solution was
filtered to obtain the title compound (80 mg, yield 47.1 %).
LC-MS (ESI+): m/e 392 (M+H)+, Rt: 1.60 min; 1H NMR (CDC13, 400MHz) 8:
8.67 (d, J: 4.4 Hz, 2H), 8.24 (s, 1H), 8.09 (d, J: 6.4 Hz, 1H), 7.72 (d, J: 4.4 Hz, 1H),
7.60 (s, 1H), 7.49 (d, J= 4.4 Hz, 1H), 7.45 (d, J= 4.8 Hz, 2H), 7.17 (d, J= 6.4 Hz, 1H),
25 4.7 (t, J= 6.4 Hz, 2H), 3.44 (t, J= 6.0 Hz, 2H).
95.2 3-(Pyridin—4—yl)—5—[2—(thieno[3,2—b]pyridin—5—yl)ethyl]thieno[2,3-d]pyridazin-
4(5H)—one
168
A mixture of pyridinylboronic acid (37.6 mg, 0.306 mmol), the compound
from Example 95.1 (80 mg, 0.204 mmol), Na2C03 (54.0 mg, 0.510 mmol) and
PdClz(dppf)-CH2C12 adduct (16.65 mg, 0.020 mmol) in dioxane (3 mL) and water (1
mL) was stirred at 100 °C in a microwave for 10 min. The solvent was evaporated and
the residue was washed with methanol, d, the filtrate was trated and
purified by HPLC to afford the title nd (59 mg, yield 74.1 %) as a white solid.
LC-MS (ESI+): m/e 391 (M+H)+, Rt: 1.86 min.
EXAMPLE 96: 5-[2-(Imidazo[1,2-a]pyridinyl)ethyl](pyridinyl)thieno[2,3-
10 d]pyridazin—4(5H)-one
N
\
, /
N O /
\ \
N\
S
96. l 2-(2-Chloroethyl)imidazo[l ,2-a]pyridine
A mixture of dazo[l,2-a]pyridin—2—yl)ethanol (400mg, 2.466 mmol) from
Example a4) and SOClz (2 mL, 27.4 mmol) in DCM (10 mL) was stirred at room
15 temperature for 2 days. The mixture was concentrated in vacuo. The residue was diluted
with EtOAc (3>< 100 mL) and washed with ted NaHC03 solution (6 mL><4) and
brine (6 mL). The organic layer was dried over NaZSO4, filtered and concentrated in
vacuo. The residue was d by Pre—TLC (PE/EA=1/ 1, v/v) to give the title
compound as an oil (300 mg, yield 70%).
20 LC-MS (ESI+): m/e 181 (M+H)+, R,: 1.68 min.
96.2 3-Bromo[2-(imidazo[1,2-a]pyridinyl)ethy1]-5H—thieno[2,3-d]pyridazin-
4(5H)-one
A mixture of 2-(2-chloroethyl)imidazo[1,2-a]pyridine (90 mg, 0.498 mmol), 3-
25 bromothieno[2,3-d]pyridazin-4(5H)-one from Example 3.4 (115 mg, 0.498 mmol) and
CszCO3 (325 mg, 0.996 mmol) in DMF (3 mL) was stirred at 60 °C for 16h. The solvent
was evaporated. The residue was purified by Pre-TLC (PE/EA=1/2, V/V) to give the title
compound as an oil (140 mg, yield 80%).
LC-MS (ESI+): m/e 374 (M+H)+, Rt: 1.79 min.
169
96.3 5-[2-(Imidazo[ l ,2-a]pyridin—2—yl)ethyl]—3-(pyridinyl)thieno[2,3-d]pyridazin-
4(5H)—one
A mixture of pyridinylboronic acid (29.5 mg, 0.240 mmol), the compound
from Example 96.2 (60 mg, 0.160 mmol), Na2C03 (42.4 mg, 0.400 mmol) and
PdC12(dppf)-CH2C12 adduct (13.06 mg, 0.016 mmol) in e (3 mL) and water (1
mL) was stirred at 100 0C in a microwave for 10 min. The solvent was evaporated and
the residue was purified by Pre-TLC (PE/EA=l/4) and purified by HPLC to afford the
title product as a white solid (45 mg, yield 75%).
10 LC-MS (ESI+): m/e 374 (M+H)+, Rt: 1.70 min; 1H NMR (DMSO-ds, 400MHz):
8.68 (s, 1H), 8.60 (d, J: 6.0 Hz, 2H), 8.46 (d, J: 6.4 Hz, 1H), 8.21 (s,lH), 7.74 (s,
1H), 7.75 (d, J: 6.0 Hz, 2H), 7.46 (d, J: 9.2 Hz, 1H), 7.19-7.15 (m, 1H), .80 (m,
1H), 4.47 (t, J: 7.6 Hz, 2H), 3.13 (t, J: 7.6 Hz, 2H).
15 EXAMPLE 97: 5-[2-(7-Fluoroimidazo[l ,2—a]pyridin—2-yl)ethyl](pyridin
eno[2,3-d]pyridazin—4(5H)-one
N
, /\
F\\®\AN O /
N 'T‘l\
N\
S
97. l 3-Bromo(2-(7-fluoroimidazo[l ,2-a]pyridin—2-yl)ethyl)thieno[2,3-d]pyridazin—
4(5H)—one
20 A mixture of 3-bromothieno[2,3-d]pyridazin-4(5H)-one from Example 3.4 (231
mg, 1 mmol), uoroimidazo[l,2-a]pyridin-2—yl)ethanol from Example a5 (180 mg,
1.00 mmol) and Pth (525 mg, 2.00 mmol) was dissolved in THF (6 mL). Then DEAD
(0.317 mL, 2.00 mmol) in THE (1 mL) was added. The resulting mixture was stirred at
room temperature under nitrogen overnight. The mixture was concentrated and purified
25 on the ISCO ash system using a 40g C-l8 column using the following gradient:
A: Water(0.l%NH4HC03); B: Methanol; 30%B to 80%B over 20 min (160 mg,
yield:l7.7%).
170
LC-MS: m/e 393 (M+H)+; Rt:1.74 min; 1H NMR(DMSO-d6) 8: 3.12(t, 2H), 4.44
(t, 2H), 6.88-6.92 (m, 1H), 7.32 (dd, J=10, 2, 1H), 7.74(s, 1H), 8.17 (s, 1H), 8.52-8.56
(m, 1H), 8.62 (s,1H).
97.2 5-[2-(7-Fluoroimidazo[1,2—a]pyridin—2-yl)ethyl]-3—(pyridinyl)thieno[2,3-
d]pyridazin—4(5H)-one
A mixture of 3-bromo-5—(2-(7—fluoroimidazo[1,2-a]pyridiny1)ethyl)thieno[2,3-
dazin-4(5H)-one (80 mg, 0.203 mmol), pyridiny1boronic acid (37.5 mg, 0.305
mmol), dppf)-CH2C12 adduct (16.61 mg, 0.020 mmol) and C82CO3 (133 mg,
10 0.407 mmol) in 1,4—dioxane (3 mL) and water(1.5mL) was heated under ave at
about 110 °C for about 15min. The mixture was concentrated and was chromatographed
on the ISCO Combiflash system using a 40 g Silicycle SiliaSep Silica gel column C-18
column using the ing gradient: A: Water(0.1%NH4HC03); B: Methanol; 30%B to
80%B over 20 min (15 mg, 18.8%).
15 LC-MS: m/e 392 (M+H); Rt:1.74 min; 1H NMR(CDC13) 8: 3.30 (t, 2H), 4.64 (t,
2H), 6.61-6.65 (m, 1H), 7.15 (dd, J=9.6 Hz, 2.4 Hz, 1H), 7.38 (s, 1H), 7.50 (d, J=6 Hz,
2H), 7.61 (s, 1H), 7.96-7.99 (m, 1H), 8.26 (s, 1H), 8.68 (d, J=6 Hz, 2H).
11.2 ation of compounds of the formula I in which A is Al, X1 is N, R1 is Y1-
20 Cyc1 and x3 is -C(R9)=C(R8)-
EXAMPLE 98: 8-(Pyridin—4-yl)—2-[2-(quinolin—2-yl)ethyl]phthalazin-1(2H)-one
N
|\
/
N '1'
N\
25 98.1 N-tert-Buty1chlorobenzamide
The mixture of 2-chlorobenzoic acid (20 g, 128 mmol), HOBT (34.6 g, 256
mmol), EDCI (48.8 g, 256 mmol), 2—methylpropan—2—amine (9.3 g, 128 mmol) and TEA
(25.9 g, 256 mmol) in THE (600 mL) was stirred at room temperature overnight. After
solvent evaporation, the mixture was diluted with ethyl acetate (600 mL) and washed
171
with water (3 x 300 mL). The c layer was dried over Na2SO4, filtered and
concentrated. The residue was purified by column chromatography on silica gel, g
with EtOAc/PE (1:5) to give the title product as a white solid (23.9 g, yield: 88.5%).
LC-MS: m/e = 212 ; Rt=0.85 min.
98 .2 2-te1t-Butylchloro-3—hydroxy-2,3-dihydroisoindol— 1 -one
N—tert-Butylchlorobenzamide (5.4 g, 25.6 mmol) was dissolved in THF (280
mL) and the on was added with TMEDA (12.4 mL, 81.9 mmol) and then added
with sec-butyllithium—hexane solution (1.0 mol/L, 82.7 mL, 81.9 mmol) dropwise at
10 -78°C for 40 minutes under argon atmosphere, followed by stirring at the same
temperature for 2.5 hours. Then, the mixture was added with DMF (4.36 mL, 56.3
mmol) and warmed from —78°C to room temperature over 2 hours. The reaction mixture
was added with water (200 mL), and extracted with ethyl acetate (100 mL*3). The
c layer was washed with saturated brine and dried over anhydrous sodium e.
15 The solvent was evaporated under reduced pressure and the residue was purified by
crystallization using diisopropyl ether to obtain product 3 (5.0 g, Yield: 81%).
LC-MS: m/e =240 (M+H)+; Rt=l.74 min; 1H NMR (400MHz, DMSO-d6): 5 7.58-
7.54 (m, 1H), 7.49-7.45 (m, 2H), 6.35 (d, J=8.4 Hz, 1H), 5.98 (d, J=8.4 Hz, 1H), 1.52 (s,
9H).
20
98 .3 8-Chloro-2H-phthalazin- 1 —one
The compound from Example 98.2 (5 g, 21 mmol) was suspended in 20 mL acetic
acid under nitrogen. The resulting thick slurry was heated to 90°C. At approximately
80°C, a homogeneous solution was obtained. Hydrazine monohydrate (64%, 3 .2 mL, 63
25 mmol) was added dropwise (exotherm), keeping the internal temperature between 90
and 93°C over approximately 4 h. The resulting suspension was continued to stir at
90°C as the conversion of starting material was monitored by LC (<1%). Water (40 mL)
preheated to 80°C was added, maintaining the mixture at 80-90°C followed by ramping
down to 20°C over approximately 3h time. At this point, the resulting suspension was
30 transferred onto a filter. The filter cake was rinsed with water 3). The wet
product was air-dried overnight to afford the title product (2.6 g, Yield: 69%).
172
LC-MS: m/e =181 (M+H)+; R.=1.51 min; 1H NMR (400MHz, DMSO-d6) 5:
12.61 (s, 1H), 8.32 (s, 1H), .83 (m, 3H).
98 .4 8-Chloro(2-quinolin-2—yl-ethyl)—2H—phthalazinone
To a solution of triphenylphosphine (9.00 g, 34.3 mmol) in THF (100 mL),
DEAD (5.44 mL, 34.3 mmol) was added at 0°C. After stirring for 15 min, 2-(quinolin—
thanol from Example a1 (2.97 g, 17.17 mmol) was added. After another 15 min,
8-chlorophthalazin-1(2H)-one (3.1 g, 17.17 mmol) was added. The mixture was stirred
overnight at room temperature; LC-MS indicated complete conversion to the product. 1
10 N HCl was added (pH= 4). The mixture was extracted with EtOAc (3 x 50 mL), the
EtOAc layers were discarded. The aqueous layer was lized by aq.NaHC03 and
extracted with ethyl acetate (3 x 500 mL). The combined organic layers were washed
with brine, dried over NaZSO4, filtered, and trated under reduced re. The
crude t was suspended in EtOAc. The solid was filtered through a Biichner
15 flannel. The purity of the title product was 95%.
LC-MS: m/e = 336 (M+H)+; Rt=1.54 min; 1H NMR (400MHz, DMSO-d6) 5:
=8.35 (s, 1H), 8.29-8.26 (d, J=8.8Hz, 1H), 7.94—7.90 (m, 2H), 7.88-7.86 (m, 3H), 7.73-
7.69 (m, 1H), 7.57-7.55 (m, 1H), 7.48-7.46 (m, 1H), .55 (t, J=5.4 Hz, 2H), 3.42-
3.38 (t, J=5.4 Hz, 2H).
20
98 .5 8-(Pyridin—4-yl)[2-(quinolin—2—yl)ethyl]phthalazin-1(2H)-one
A reaction tube was charged with pyridin—4-ylboronic acid (0.223 mmol), K2C03
(61.7 mg, 0.447 mmol) under a dry nitrogen atmosphere. A solution of 8-chloro(2-
quinolinyl-ethyl)-2H-phthalazin—1-one (50 mg, 0.186 mmol) in 1,4-dioxane (5 mL)
25 along with PdC12(dppf) (5.45 mg, 7.45 umol) was added. After addition of water (1
mL), the resulting mixture was heated at 100°C overnight. After removal of the solvent
under reduced pressure, the title compound was obtained as a crude product. It was
purified by Prep-HPLC.
LC—MS m/e=379.1 (M+H)+; Rt=1.80 min; 1H NMR (400 MHz, CDC13) 8 ppm
30 8.58 (s, 2 H), 8.18 (s, l H), 8.04 (d, J=8.0 Hz, 1 H), 7.94 (d, J=8.0 Hz, 1H), 7.74-7.78
(m, 3 H), 7.66 (d, J=l.6 Hz, 1 H), 7.46—7.52 (m, 2 H), 7.30 (d, J=8.4 Hz, 1 H), 7.11 (d,
J: 5.2 Hz, 2 H), 4.65 (t, J=7.4 Hz, 2 H), 3.45 (t, J=7.4 Hz, 2 H).
173
Examples 99 to 164 were prepared analogously to the method for Example 98.
EX. Name LC-MS: m/ e (M+H)+ / Rt [min]
99 2- [2-(Quinolinyl)ethy1][4-(trifluoro- 446 / 2.34
methy1)phenyl]phthalazin— 1 (2H)—one
100 8-(4-Methylphenyl)—2—[2-(quino lin—2— 392 / 2.3 0
yl)ethy1]phthalazin-1(2H)-one
101 8- [4-(Propanyl)phenyl][2-(quino 1in- 420 / 2 .45
2—yl)ethyl]phthalazin-1(2H)—one
102 8-(4-Ethylphenyl)—2—[2—(quino lin—2— 406 / 2. 15
yl)ethyl]phthalazin— 1 (2H)—one
103 4- {4-Oxo[2-(quino1in—2—yl)ethyl]—3,4— 403 / 1.96
dihydrophthalazin-S-yl}benzonitrile
104 8-(4-Methoxyphenyl)[2—(quinolin—2— 408 / 2. 19
yl)ethyl]phthalazin— 1 (2H)-one
105 8-(4-Fluorophenyl)[2-(quinolin—2- 396 / 2.22
yl]phthalazin— 1 (2H)—one
106 (4- {4-Oxo[2-(quinolin—2-yl)ethy1]-3,4- 417 / 2.11
dihydrophthalazin—5—yl}phenyl)acetonitrile
107 8-(4-Hydroxyphenyl)—2—[2-(quino1in 394 / 1 .99
yl)ethyl]phthalazin— 1 (2H)-one
108 8-(2-chlorophenyl)—2—[2-(quino1in 412 / 2.06
yl)ethyl]phthalazin— 1 (2H)—one
109 ethy1pheny1)—2-[2—(quinolin 392 / 2.08
yl)ethy1]phthalazin— 1 (2H)—one
110 8-(2-Ethylphenyl)[2-(quinolin 406 / 2.35
yl)ethyl]phthalazin-1(2H)-one
1 1 1 8—(2—Fluorophenyl)—2—[2—(quinolin—2— 396 / 2.20
yl]phthalazin— 1 (2H)—one
1 12 8-(2-Methoxyphenyl)—2—[2—(quino lin—2— 408 / 2.20
yl)ethyl]phthalazin— 1 (2H)—one
174
EX. Name LC-MS: m/ e (M+H)+ / Rt [min]
1 13 8-(3-Methoxypheny1)—2—[2-(quino1in 408 / 2.02
y1)ethy1]phthalazin— 1 (2H)-0ne
114 3-{4-Oxo[2-(quinolinyl)ethyl]—3,4- 403 / 1.96
dihydrophthalazin—S—y1 } benzonitrile
1 15 8-(3 -F1u0r0phenyl)—2-[2—(quin0 lin—2— 396 / 2.04
y1)ethy1]phthalazin-1 (2H)—0ne
1 16 8-(3-Hydroxyphenyl)[2-(quino lin 394 / 1 .87
yl)ethy1]phthalazin-1(2H)-one
1 17 N,N—Dimethy1—3- {4-oxo[2-(quinolin 449 / 1.98
y1)ethy1]—3 ydrophthalazin—5—
yl } benzamide
1 18 8-(3 -Methy1phenyl)—2—[2—(quino1in—2— 392 / 2. 10
y1)ethy1]phthalazin-1 (2H)—one
1 19 2-[2-(Quinoliny1)ethyl]-8—(thiophen—2- 3 84 / 2. 19
y1)phtha1azin- 1 (2H)-one
120 8-(1-Methy1—1H-indoly1)—2-[2— 431 / 2.26
(quino1iny1)ethy1]phthalazin— 1 (2H)-one
121 8-(3,5-Dimethy1—1H-pyrazol—4-y1)—2-[2- 396 / 1.90
(quino1iny1)ethy1]phthalazin— 1 ne
122 Indol—S-y1)-2—[2—(quin01in—2- 417 / 1.97
yl)ethy1]phthalazin— 1 (2H)-0ne
123 8-(1H-Ind01y1)—2—[2-(quin01in 417 / 1.98
yl)ethy1]phtha1azin— 1 (2H)—0ne
124 8-(Pyrimidin-5 -y1)[2—(quin0 lin—2— 3 80 / 1.82
yl)ethy1]phthalazin— 1 (2H)—0ne
125 8-(2-Methoxypyridinyl)[2-(quino lin- 409 / 2 .07
2-y1)ethy1]phthalazin-1(2H)-one
126 8—(Pyridin—3—y1)—2—[2—(quinolin—2— 379 / 1.81
y1]phthalazin— 1 (2H)—one
127 8-(Furan—3-y1)-2—[2—(quinolin—2— 368 / 1.95
y1)ethy1]phthalazin— 1 (2H)—one
175
EX. Name LC-MS: m/ e (M+H)+ / Rt [min]
128 8-(Quino1iny1)[2—(quin01in—2- 439
y1)ethy1]phtha1azin— 1 (2H)-0ne
129 8-(1H-Ind01y1)-2—[2-(quin01in 417 / 2.12
y1)ethy1]phtha1azin- 1 (2H)—0ne
130 8-(2,3-Dihydr0benzofi1ran—5-yl)—2-[2- 420 / 2.19
(quinoliny1)ethyl]phthalazin— 1 (2H)—one
131 8-(3,4-Dihydro-2H-1,5-benzodioxepin 450 / 2.19
y1) [2-(quino [inyl)ethyl]phthalazin-
1(2H)-one
132 8-(1-Benzofuran—5—y1)—2—[2—(quin0lin—2— 418 / 2.25
y1)ethy1]phtha1azin— 1 (2H)—one
133 8-(6-Methoxypyridin—3—y1)—2—[2—(quinolin- 409 / 2.10
2-y1)ethy1]phtha1azin- 1 (2H)—one
134 -Dihydro-1,4-benzodioxin—6—yl)—2- 436 / 1.99
[2-(quino 1iny1)ethyl]phthalazin— 1 (2H)-
one
13 5 8-(2-Methy1pyridin—4-yl)—2-[2-(quino1in 393 / 1 .95
y1)ethy1]phtha1azin— 1 (2H)—one
136 8-(5 -Methoxypyridin—3—y1)—2-[2-(quinolin- 409 / 1 .97
2-y1)ethy1]phtha1azin— 1 (2H)-0ne
137 8-(5 -F1u0ropyridin—3—yl)—2-[2—(quin0lin 397 / 2.00
y1)ethy1]phtha1azin- 1 (2H)—0ne
138 8-(1 ,3-Benzodi0x01—5-y1)—2-[2—(quin0lin—2- 422 / 2.00
y1]phthalazin-1 (2H)—0ne
139 8-(1-Methy1—1H—pyrazol—4—yl)—2-[2- 3 82 / 1.90
(quinolinyl)ethyl]phthalazin- 1 ne
140 2-Methylpropyl)-1H-pyrazoly1] 424 / 2.14
[2—(quino 1111—2—y1)ethyl]phthalazin— 1 (2H)—
one
141 tert-Butyl 2- {4—0x0—3—[2—(quinolin—2— 467 / 2.34
y1)ethy1] -3 ,4-dihydrophthalazin—5—yl} — 1 H-
176
EX. Name LC-MS: m/ e (M+H)+ / Rt [min]
pyrrolecarboxy1ate
142 8-(3-Chlorofluorophenyl)—2-[2- 430/ 2.32
(quino1iny1)ethy1]phthalazin- 1 (2H)—one
143 8-(2-Chloroflu0rophenyl)—2-[2- 430/ 2.28
(quinoliny1)ethy1]phthalazin— 1 (2H)—one
144 8-(3 ,4-dimethylphenyl)—2—[2-(quin0 lin—2- 406 / 2.3 7
yl)ethy1]phthalazin-1(2H)-one
145 8-(2,4-Dimethoxyphenyl)[2-(quino lin- 43 8 / 2 .20
2—y1)ethy1]phthalazin- 1 (2H)—one
146 8-(2,5—Dimethoxyphenyl)—2—[2—(quin0 lin— 43 8 / 2. 18
2-y1)ethy1]phtha1azin— 1 (2H)—one
147 8-(2,3-Difluorophenyl)—2—[2—(quino lin—2— 414 / 2.23
y1)ethy1]phthalazin- 1 (2H)—one
148 8-(3 ,4-Dimethoxyphenyl)-2—[2—(quin0 1in- 43 8 / 2. 1 1
2-y1)ethy1]phtha1azin- 1 (2H)-one
149 8-(3 u0rophenyl)[2-(quino1in 414 / 2.25
y1)ethy1]phtha1azin— 1 (2H)-one
150 8-(5-F1u0r0methoxyphenyl)—2-[2- 426 / 2.21
(quino1iny1)ethy1]phthalazin— 1 (2H)-one
15 1 8-(4-F1uoromethoxyphenyl)—2-[2- 426 / 2.22
(quino1iny1)ethy1]phthalazin- 1 (2H)—one
152 8-(3 ,5-Fimethoxyphenyl)—2-[2—(quin0 lin—2- 43 8 / 2.21
yl)ethy1]phthalazin- 1 ne
153 8-(2,5-Diflu0r0phenyl)—2-[2—(quin0lin 414 / 2.23
y1]phthalazin-1 (2H)-0ne
154 8-(3-F1uoromethoxyphenyl)[2- 426 / 2.20
(quinolin-Z-yl)ethyl]phthalazin-1(2H)-one
155 8—(2—F1u0ro—3—methoxyphenyl)—2—[2— 426 / 2.19
(quino1111—2—y1)ethy1]phthalazin— 1 (2H)—one
156 8-(3 ,5-Difluorophenyl)—2—[2—(quin0 lin—2— 414 / 2.06
y1]phthalazin— 1 (2H)—one
177
EX. Name LC-MS: m/ e (M+H)+ / Rt [min]
157 8-(3 -Fluoromethoxyphenyl)—2-[2- 426 / 2.25
(quinolinyl)ethyl]phthalazin- 1 (2H)—one
l5 8 8-(Naphthalen—2-yl)—2-[2—(quino1in 428 / 2.3 5
yl)ethyl]phthalazin— l (2H)—one
159 8-Phenyl—2-[2-(quinolin—2- 378 / 2.21
yl)ethyl]phthalazin— 1 (2H)—one
160 8-(1-Benzofuranyl)[2-(quinolin 418 / 2 .29
yl)ethyl]phthalazin- l (2H)-one
161 8—( 1 -Methyl— 1 H-pyrazol—5-yl)—2-[2- 3 82 / 1.90
(quinolin—2—yl)ethyl]phthalazin— 1 (2H)—one
hydrochloride
162 8-(4,5-Difluoro-2—methoxyphenyl)—2—[2— 434
(quinolinyl)ethyl]phthalazin— l (2H)—one
163 8-(2-Fluoromethylphenyl)—2—[2— 410 / 2.28
(quinolinyl)ethyl]phthalazin— l ne
164 8-(2-Fluoromethoxyphenyl)—2—[2— 442
(quinolinyl)ethyl]phthalazin— 1 (2H)-one
EXAMPLE 165 : 2- [2-(Imidazo[1 ,2—a]pyridin—2-yl)ethyl] (pyridin-3 -yl)phthalazin-
1 (2H)-one
5 165. 1 ro(2-imidazo[l ,2-a]pyridinyl)ethyl]phthalazin-1(2H)-one
To a solution of triphenylphosphine (5.81 g, 22.15 mmol) in THF (150 mL),
DIAD (7.54 mL, 38.8 mmol) was added at 0°C. After stirring for 15 min, 2-
(imidazo[l,2-a]pyridin—2-yl)ethanol from Example a4 (2.00 g, 11.07 mmol) was added.
After another 15 min, 8—chlorophthalazin—l(2H)—one from Example 98.3 (1.80 g, 11.07
10 mmol) was added. The mixture was stirred ght at room temperature. LC-MS
indicated complete sion to the product. 1 N HCl was added (pH= 4).The mixture
178
was extracted with EtOAc, the EtOAc layers were discarded. The aqueous layer was
lized by aq.NaHCO3 and extracted with ethyl acetate. The combined organic
layers were washed with brine, dried over Na2804, filtered, and concentrated under
d pressure. The crude title product was recrystallized from ethyl e to give
3.1 g : 86%) of a bright beige solid.
165 .2 2-[2-(Imidazo[1,2-a]pyridinyl)ethyl](pyridin—3—yl)phthalazin-1(2H)-one
A reaction tube was charged with 8-chloro(2-imidazo[l ,2-a]pyridin
yl)ethyl]phthalazin-l(2H)-one (80 mg, 0.246 mmol) and a mixture of 1.5 mL of ethanol
10 and 1.5 mL of toluene under argon. To this suspension, pyridinylboronic acid (30.3
mg, 0.246 mmol) and Na2C03 (39.2 mg, 0.369 mmol) were added. Then, tetrakis-
(triphenylphoshine)palladium (28.5 mg, 0.025 mmol) was added. The reaction mixture
was heated in a Biotage microwave at about 130 °C for about 30 min. The reaction was
monitored by TLC ethanol = 9:1). After completion of the reaction, EA was
15 added followed by the addition of 1 N HCl. The mixture was extracted twice with
EtOAc. The aqueous layer was basified with 2N NaOH and extracted three times with
ethyl acetate. The ed organic layers were washed with brine, dried over MgSO4,
filtered, and concentrated under reduced pressure. The crude product was triturated
from ethyl acetate to give the title compound as a white solid (12 mg, 13.26%).
20 LC-MS: m/e = 368.1 (M+H)+
The compound of Examples 2 were prepared in analogy to the method
described in Example 165.2.
EX. Name LC-MS:
m/ e (M+H)+
166 2-[2-(Imidazo[ l ,2-a]pyridinyl)ethyl](pyridin 368.1
yl)phthalazin- l (2H)-one
167 2—[2—(Imidazo[ l ,2—a]pyridin—2—yl)ethyl]—8—(3— 398.1
methoxypyridin—4—yl)phthalazin— l (2H)—one
168 2- [2-(Imidazo[ l ,2—a]pyridin—2—yl)ethyl]—8—(pyrimidin-5 - 3 68.8
yl)phthalazin— 1 (2H)-one
179
EX. Name LC-MS:
m/ e (M+H)+
169 2-[2-(Imidazo[1,2-a]pyridinyl)ethyl]—8-(1-methyl-1H- 3 71.1
pyrazo l-3 -yl)phthalazin-1 (2H)—one
170 8-(Furan—3-yl)[2-(Imidazo[1,2-a]pyridin 3 5 7.1
yl)ethyl]phthalazin— l (2H)—one
171 2- [2-(Imidazo[ l ,2-a]pyridin—2—yl)ethyl]—8—(2-oxo-2 ,3 - 422.1
dihydro- l H-indo lyl)phthalazin- 1 (2H)-one
W
a]pyridin—2—yl)ethyl]phthalazin— l (2H)—one
EXAMPLE 173: 8-(1,1-Dioxidothiomorpholin—4—yl)—2-[2-(quinolinyl)ethyl]—
azin-1(2H)-one
ogséo
A microwave reaction vial was charged with the 8-chloro(2-(quinolin
yl)phthalazin—1(2H)-one from Example 98.4 (100 mg, 0.30 mmol), CS2C03 (194
mg, 0.59 mmol), Pd2(dba)3 (5.45 mg, 5.96 umol) and BINAP (11.13 mg, 0.018 mmol).
The solids were purged with argon for l h. A separate flask was charged with e
(993 ul) and thiomorpholin 1,1—dioxide (48.3 mg, 0.36 mmol), degas with argon for 1 h
10 and then transferred to the microwave reaction vial under inert conditions. The resulting
reaction mixture was heated on microwave at 100 0C for 20 h. The reaction mixture was
poured into water and ted with DCM. The solids were d. The organic layer
was washed with water, dried over MgSO4, filtered and concentrated in vacuo. The
residue was purified on a silica column (eluent: DCM/methanol) and then recrystallized
15 from EA to afford the title product (87 mg, 67.2%).
LC-MS: m/e = 435.1 (M+H)+
EXAMPLE 174: 2-[2-(Imidazo[l ,2—a]pyridin—2—yl)ethyl](morpholin—4-yl)phthalazin-
1 (2H)-on
180
o
A microwave reaction vial was charged with the 8-chloro(2-imidazo[1,2-
a]pyridinyl)ethyl]phthalazin—l(2H)—one from Example 165.1 (100 mg, 0.31 mmol),
CS2CO3 (201 mg, 0.62 mmol), Pd2(dba)3 (5.64 mg, 6.16 umol) and BINAP (11.50 mg,
0.018 mmol). The solids were purged with argon for l h. A separate flask was charged
with toluene (993 pl) and morpholine (32.2 mg, 0.37 mmol), degas with argon for 1 h
and then transferred to the microwave reaction Vial under inert conditions. The resulting
reaction mixture was heated on microwave at 100 °C for 20 h. The reaction mixture was
poured into water and extracted with DCM. The solids were d. The organic layer
10 was washed with water, dried over MgSO4, filtered and concentrated in vacuo. The
e was purified on a silica column (eluent: DCM/methanol) and then recrystallized
from EA to afford the title product (11 mg, 9.52 %).
LC-MS: m/e = 376.1 (M+H)+
15 The compound of Examples 175 to 191 were prepared in analogy to the method
described in Example 174.
EX. Name LC-MS: m/ e (M+H)+
175 8-(1,l-Dioxidothiomorpholin—4-yl)—2-[2- 424. l
(imidazo [l ,2-a]pyridin—2-yl)ethyl]phthalazin—
1(2H)-one
176 2-[2-(Imidazo[1,2-a]pyridin—2-yl)ethyl] 402.2
(tetrahydro- 1 [3 ,4-c]pyrro l-5(3H)-
yl)phthalazin- l (2H)-one hloride
177 8-(5,5-Difluorohexahydrocyclopenta[c]pyrro1- 436.2
2( l H)—yl)—2— [2—(imidazo[l yridin—2—
yl)ethyl]phthalazin— l (2H)—one hydrochloride
178 2- [2-(Imidazo[ l yridin—2—yl)ethyl]—8- 375 .2
(piperazin— l -yl)phthalazin— 1 (2H)—one
181
EX. Narne LC-MS: m/ e (M+H)+
hloride
179 8-(4,4-Difluoropiperidinyl)—2—[2-(imidazo[1 ,2- 410.2
a]pyridinyl)ethyl]phthalazin— 1 (2H)—one
180 8- [4-(Chloromethyl)(hydroxymethyl)piperidin- 451.9
l-yl][2-(imidazo[1 ,2-a]pyridin
yl]phthalazin- l (2H)-one hydrochloride
181 2— [2—(Imidazo [l ,2—a]pyridin—2—yl)ethyl]—8— 374.2
idin— l —yl)phthalazin— l (2H)—one
hydrochloride
182 8-(2,3-Dihydro-4H—l ,4—benzoxazin—4—yl)—2- [2- 424.1
(imidazo[1 ,2-a]pyridin-2—yl)ethyl]phthalazin—
1(2H)-one hydrochloride
183 2- [2-(Irnidazo[ 1 ,2-a]pyridinyl)ethyl] [4- 442.2
(trifluorornethyl)piperidinyl]phthalazin— 1 (2H)-
one hydrochloride
184 2- [2-(Irnidazo[ l ,2-a]pyridin—2-yl)ethyl](4- 389.2
rnethylpiperazin- l -yl)phthalazin— l (2H)-one
hydrochloride
185 8-(1,3-Dihydro-2H—isoindolyl)—2—[2- 408.2
(irnidazo[1 ,2-a]pyridin—2-yl)ethyl]phthalazin—
1 (2H)-one
186 8-(7-Benzyl—2,7-diazaspiro[4.4]nonyl)—2— [2— 505.3
(imidazo [l ,2-a]pyridinyl)ethyl]phthalazin-
1(2H)-one hydrochloride
187 8-( { [(3 aR,4S,6aS)benzyloctahydro- 519.3
cyclopenta[c]pyrrol—4-yl]methyl} amino)—2- [2-
(imidazo [l yridin—2—yl)ethyl]phthalazin-
1(2H)-one hydrochloride
182
EX. Name LC-MS: m/ e (M+H)+
18 8 tert-butyl (3R)-3 -({3—[2—(imidazo[1,2-a]pyridin—2- 475 .2
yl)ethyl] oxo-3 ,4—dihydrophthalazin—5-
yl} amino)pyrrolidine— 1 —carboxylate
189 8-(2,6-Dimethylmorpho1inyl)[2— 404.2
(imidazo [1 ,2-a]pyridinyl)ethyl]phthalazin-
1(2H)-one hydrochloride
190 2-[2-(Imidazo[1,2-a]pyridinyl)ethyl](1,4- 390.2
oxazepan—4—yl)phthalazin-1(2H)—one hydrochloride
191 tert-Butyl 4— {3 —[2—(imidazo[1,2—a]pyridin—2- 472.2
yl)ethyl] —3 ,4—dihydrophthalazin—5—yl} -3 ,6-
opyridine- 1 (2H)—carboxylate
11.3 Preparation of nds ofthe formula I in which A is Al, X1 is N and X3 is
-C(R9)=C(R8)- with R9 being Y3—cyc3
5 EXAMPLE 192: 5-(Pyridin—4-yl)—2-[2-(quinolinyl)ethyl]phthalazin-1(2H)-one
hydrochloride
\ o
/
N r
N \
/
/
192. 1 4-Bromohydroxy-3H-isobenzofiaran— 1 -one
10 To a stirred solution of n-butyllithium 1.6 M in s (17.5 mL, 28.1 mmol)
was added at —20 °C under argon 2,2,6,6-tetramethylpiperidine (4.7 mL, 28.1 mmol) in
anhydrous THF (40 mL). After cooling (—50 °C), 3—bromobenzoic acid (2.54 g, 12.8
mmol) in anhydrous THF (10 mL) was added dropwise and the mixture was stirred for
1 h. The e was then treated with an excess ofDMF (3.7 g, 50.4 mmol). The
15 resulting solution was allowed to warm up to ambient temperature, after which water
183
was added. The aqueous layer was washed with diethyl ether, and then acidified with
4M HCl. The mixture was diluted with diethyl ether and the organic layer was separated
and dried with MgSO4. The residue was d by crystallization using with
PE to give the crude title product (1.18 g, yield: 41 %).
LC-MS: m/e = 229 (M+H)+; Rt=1.47 min.
192.2 5-Brorno-2H—phthalazin— 1 -one
The compound from Example 192.1 (1 g, 4.4 mmol) was suspended in 5 mL
acetic acid under nitrogen. The resulting thick slurry was heated to 90°C. At
10 approximately 80°C, a homogeneous solution was obtained. ine monohydrate
(64%, 0.66 mL, 13.2 mmol) was added dropwise (exotherm), keeping the internal
temperature between 90 and 93°C over approximately 4h. The resulting suspension was
continued to stir at 90°C as the conversion of starting material was monitored by LC
(<l%). Water (10 mL) preheated to 80°C was added, maintaining the mixture at 80-
15 90°C followed by cooling down to 20°C over imately 2h time. At this point, the
resulting suspension was erred onto a filter. The filter cake was rinsed with water
(10 mL*3). The wet product was air-dried overnight to afford the title t (570 mg,
Yield: 58 %).
LC-MS: m/e =227 (M+H)+; Rt=1.65 min, 1H NMR (400MHz, DMSO-d6): 5
20 12.94 (s, 1H), 8.41 (s, 1H), 8.25-8.19 (m, 2H), 7.77-7.73 (m, 1H).
192.3 5 -Bromo[2-(quinoliny1)ethy1]phthalazin-1(2H)-one
To a mixture of PPh3 (699 mg, 2.67 mmol) in THF (50 mL) and DIAD (198 mg,
0.98 mmol), 5-bromo-2H-phthalazinone (300 mg, 1.33 mmol) and then 2-quinolin
25 yl—ethanol from e al (254 mg, 1.46 mmol) were added dropwise at 15°C under
en. The mixture was stirred at room temperature overnight. Water was added and
the mixture was extracted with EtOAc. The organic phase was washed with HCl (1 N).
The aqueous phase was basified and extracted with DCM. The organic phase was
washed with a NaHC03—solution, dried over Na2S04, filtered and concentrated. The
30 crude product was recrystallized from EA and dried to give the title compound as bright
beige solid (300 mg, 59.2% yield).
184
192.4 5 dinyl)[2-(quino1inyl)ethyl]phthalazin-1(2H)-one
hydrochloride
A reaction tube was charged with a solution of 5-bromo[2-(quinolin—2-
yl)ethyl]phthalazin—1(2H)-one (70 mg, 0.184 mmol) in 1.5 mL of ethanol and 1.5 mL of
toluene under argon. To this suspension, pyridinylboronic acid (22.63 mg, 0.184
mmol) and a 2M solution ofNa2C03 (39.2 mg, 0.369 mmol) were added. Then, is-
(triphenylphoshine)palladium (21.27 mg, 0.018 mmol) was added. The reaction mixture
was heated in a Biotage microwave at about 130 °C for about 30 min. The on was
monitored by TLC (DCM/methanol = 9:1). After completion of the reaction, EA was
10 added followed by the addition of 1 N HCl. The mixture was extracted twice with
EtOAc. The organic layer was basified with NaHC03> and ted with brine. The
organic layers were dried over MgSO4, filtered, and concentrated under reduced
pressure. The crude t was dissolved in isopropanol. Isopropanol containing HCl
was added. The precipitate was sucked off and recrystallized from hot isopropanol to
15 give a bright gray solid (55 mg, 72.0%).
LC-MS: m/e = 379.1 (M+H)+
EXAMPLE 193 : 5 -(Pyrimidinyl)[2-(quinolinyl)ethyl]phthalazin-1(2H)-one
hydrochloride
20 The title compound was prepared in analogy to the method described in Example
192. LC—MS: m/e = 380.1 (M+H)+
\ O
/ l
N 1
N\
/
|
NvN
EXAMPLE 194: 5-(1-Methyl-1H-pyrazolyl)[2-(quinolinyl)ethyl]phthalazin-
25 1(2H)-one
185
H3C\N
\
N
The title compound was prepared in analogy to the method bed in Example
192. LC-MS: m/e = 382.2 (M+H)+
EXAMPLE 195: 5-(1,1-Dioxidothiomorpholinyl)[2-(quinolin
yl)ethyl]phthalazin- 1 ne
\ o
/ H
N 1‘
N\
{N}
/s\\
o/ O
The title compound was prepared in analogy to the method bed in Example
173 but using 5-bromo[2-(quino1inyl)ethyl]phthalazin-1(2H)-one instead of 8-
10 chloro(2-(quinolinyl)ethyl)phthalazin-1(2H)-one. LC-MS: m/e = 435.1 (M+H)+.
EXAMPLE 196: 2-[2-(1midazo[1,2—a]pyridin—2-yl)ethyl](pyridinyl)phthalazin-
1 (2H)-one
15 196. 1 5-Bromo[2-(imidazo[1,2-a]pyridinyl)ethyl]phthalazin-1(2H)-one
The title compound was prepared in analogy to the method described in Example
192.3 but using 2—(imidazo[1,2—a]pyridin—2—yl)ethanol from Example a4. Yield: 84%.
196.2 2-[2-(Imidazo[ 1 ,2-a]pyridin—2—yl)ethyl]—5—(pyridin—3 -yl)phthalazin-1(2H)-one
186
The title compound was ed in analogy to the method described in Example
192.4 but using 5-bromo[2-(imidazo[1,2—a]pyridin—2-yl)ethyl]phthalazin—1(2H)-one.
LC-MS: m/e = 368.1 (M+H)+
5 EXAMPLE 197: 2-[2-(Imidazo[1,2-a]pyridin—2—yl)ethyl](pyrimidin—5-
yl)phthalazin1(2H)-on
Q,N\Nj\/\'\ll O \
N\
/
NVN
The title compound was prepared in analogy to the method bed in Example
196 but using 5-(4,4,5,5-tetramethyl-1,3,2-dioxoborolan—2-yl)pyrimidine. Yield: 73.9%.
10 LC—MS: m/e = 368.8 (M+H)+
EXAMPLE 198: 2-[2-(Imidazo[1,2-a]pyridin—2—yl)ethyl](morpholinyl)phthalazin-
one hydrochloride
Q3mIN O
N \
N
[O]
15 The title compound was prepared in analogy to the method described in Example
174 but using 5-bromo[2-(imidazo[1,2-a]pyridin—2-y1)ethy1]phthalazin-1(2H)-one
from Example 196.1 instead of 8-chloro—2—(2-imidazo[1 ,2-a]pyridin—2-
yl)ethyl]phthalazin-1(2H)-one. Yield: 2.1%. LC-MS: m/e = 376.2 (M+H)+
20 EXAMPLE 199: 2—[2—(Imidazo[1,2—a]pyridin—2—yl)ethyl](tetrahydro- 1 H—furo [3 ,4-
c]pyrrol—5(3H)—yl)phthalazin—1(2H)—one hydrochloride
187
QIN\Nj\/\l\lJ O
\
N\
N
H
O
The title compound was prepared in analogy to the method described in Example
176 but using 5-bromo[2-(imidazo[1,2-a]pyridinyl)ethyl]phthalazin-1(2H)-one
from Example 196.1 instead of 8-chloro(2-imidazo[1 ,2-a]pyridin
yl)ethyl]phthalazin—1(2H)—one. Yield: 11.8%. LC—MS: m/e = 402.2 (M—I—H)+
11.4 Preparation of compounds of the formula I in which A is Al, X1 is N, X2 is C-R7
with R7 being z and x3 is -C(R9)=C(R8)-
10 EXAMPLE 200: 2-[2-(Imidazo [1 ,2-a]pyridin—2—yl)ethyl](pyrimidin—5 -yl)phthalazin-
1 (2H)-one
QIN\Nj\/\l\ll O
\
N\
/
I
NVN
200. 1 4-Bromo[2-(imidazo[1 yridin—2-yl)ethyl] lazin- l (2H)-one
To a solution of triphenylphosphine (1165 mg, 4.44 mmol) in THF (60 mL),
15 DIAD (1.5 mL, 7.78 mmol) was added at 0°C under en. After stirring for 30 min,
4-bromophthalazin—1(2H)one (0.5 g, 2.22 mmol) was added. After further stirring, 2-
(2-imidazo[1,2-a]pyridinethanol from Example a4 (396 mg, 2.44 mmol) was added.
The mixture was stirred for 12 h at room temperature. LC-MS ted complete
conversion to the product. EA and water were added. The organic phase was washed
20 with 1 N HCl. The EtOAc layers were discarded. The aqueous layer was neutralized by
aq.NaHC03 and extracted with ethyl acetate. The combined organic layers were washed
with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The
188
crude title product was tallized from diisopropyl ether/ EA (1 :1) to give 710 mg
: 87%) of a white solid.
200.2 2-[2-(Imidazo[1 ,2-a]pyridinyl)ethy1](pyrimidin—5-yl)phthalazin-1(2H)-one
The title compound was prepared in analogy to the method described in Example
168 but using 4-bromo[2-(imidazo[1,2-a]pyridiny1)ethy1]—phthalazin-1(2H)-one.
Yield: 35.1%. LC-MS: m/e = 369.1 (M+H)+
E 201: Imidazo[1,2-a]pyridinyl)ethyl](morpho1inyl)phthalazin-
10 1(2H)-one
The title compound was prepared in analogy to the method described in Example
198 but using 4-bromo-2—[2—(imidazo[1 ,2—a]pyridin—2—yl)ethyl]-phthalazin-1(2H)-one.
Yield: 48.2%. LC-MS: m/e = 376.2 (M+H)+
15
11.5 Preparation of compounds ofthe formula I in which A is Al, X1 is CH, R1 is
Yl-Cyc1 and X3 is S
EXAMPLE 202: 3-(3-Methoxypyridin—4-y1)—5—[2-(quinolinyl)ethyl]thieno[3,2-
20 c]pyridin-4(5H)-one
202.1 (E)—3-(4—Bromothiophen—2—yl)acrylic acid
Piperidine (1.036 mL, 10.47 mmol) was added to a mixture of 4-bromothiophene-
2-carbaldehyde (20 g, 105 mmol) and malonic acid (13.07 g, 126 mmol) at 80°C under
25 nitrogen atmosphere. The reaction mixture was stirred for 2 h at 100°C. The reaction
189
mixture was cooled to room temperature and extracted with EA/water. The organic
phase was washed with 2N NaOH. The s phase was acidified and a precipitate
was formed. The solid was stirred in a mixture of DCM and diisopropyl ether (1 :1). The
solid was sucked off and dried under reduced pressure to give a bright beige solid (12.3
g, 50.4%).
202.2 (E)—3-(4-Bromothiophen—2—yl)acryloyl azide
To a solution of (4-bromothiopheny1)acry1ic acid (9.30 g, 39.9 mmol) in
acetone (100 mL), triethylamine (4.24 g, 41.9 mmol) was added under nitrogen
10 atmosphere. At 0°C, isobutyl chloroforrniate (5.72 g, 41.9 mmol) was slowly added and
then, the mixture was stirred for 1 h. 4.67 g (71.8 mmol) of sodium azide dissolved in
10 mL of water was slowly added at 0°C, the mixture was stirred at 0°C for a further
hour and then warmed up to room ature ght. The reaction mixture was
extracted with EA/water. The organic phase was washed aq. NaHC03 on and then
15 with brine. The organic phase was dried over MgSO4, concentrated to dryness and the
residue was purified by trituration with diisopropyl ether to afford a bright beige solid
(9.00 g, 34.9 mmol). Yield: 87%.
202.3 3-Bromothieno[3,2-c]pyridin—4(5H)—one
20 100 mL of diphenyl ether were warmed to 210°C and then a solution of (E)(4-
bromothiophenyl)acryloyl azide (9.95 g, 38.6 mmol) in 50 mL of diphenyl ether was
added under en. The reaction e was held at this temperature for 15 min.
After cooling to room temperature, the reaction mixture was diluted with 100 mL of
cyclohexane. The precipitate was sucked off and dried in vaccuo to give 6.6 g (yield:
25 74.4%) of the title compound as brown solid.
202.4 3-Brorno[2-(quinolinyl)ethyl]thieno[3,2-c]pyridin-4(5H)-one
The title compound was prepared in analogy to the method described in Example
192.3 but using 3—bromothieno[3,2—c]pyridin—4(5H)—one. Yield: 26.6%. As a byproduct,
30 3-bromo(2-quinolin—2—yl)ethoxy)thieno[3,2-c]pyridine was obtained (yield: 23.3%).
Using a ion® chromatography system (normal phase, eluent cyclohexane/ethyl
acetate), the title compound was obtained as a bright beige solid.
190
202.5 3-(3-Methoxypyridinyl)—5—[2—(quinolinyl)ethyl]thieno[3,2-c]pyridin—
one
A reaction tube was charged with a on of 3-bromo[2-(quinolin
yl]thieno[3,2-c]pyridin-4(5H)—on (100 mg, 0.260 mmol) in 1.5 mL of ethanol and
1.5 mL oftoluene under argon. To this suspension, 3-methoxypyridin—4-y1boronic acid
(39.7 mg, 0.260 mmol) and a 2M on ofNa2C03 (41.3 mg, 0.389 mmol) were
added. Then, tetrakis(triphenylphoshine)palladium (30.0 mg, 0.026 mmol) was added.
The reaction mixture was heated in a Biotage microwave at about 130 °C for about 30
10 min. The reaction was monitored by TLC (DCM/methanol = 9:1). After completion of
the reaction, EA was added followed by the addition of 1 N HCl. The mixture was
extracted twice with EtOAc. The c layer was basified with NaHC03 and extracted
with brine. The organic layers were dried over MgSO4, filtered, and concentrated under
reduced pressure. The crude product was dissolved in isopropanol. Isopropanol
15 containing HCl was added. The precipitate was sucked off and recrystallized from hot
ethyl acetate to give a white solid (32 mg, 29.8%).
LC—MS: m/e = 414.1 (M+H)+
EXAMPLE 203: 3-(3-Hydroxypyridin—4-yl)—5-[2-(quino1iny1)ethy1]thieno[3,2-
20 c]pyridin-4(5H)-one hydrochloride
To 3-(3-methoxypyridinyl)—5-[2-(quinolinyl)ethyl]thieno[3,2—c]pyridin—
4(5H)-one (50.0 mg, 0.121 mmol) in DCM (20 mL) was added 1M BBr3 in DCM
(0.363 mmol, 91 mg). The reaction mixture was stirred for 2 h under nitrogen. The
25 reaction mixture was poured onto water and basified with 1N NaOH, extracted with
DCM and dried. The organic phase was concentrated to dryness and the residue was
purified by column tography (normal phase) on silica using DCM/methanol to
give the title compound (13 mg, 0.030 mmol).
LC-MS: m/e = 400.1 (M+H)+
191
The compounds of Example 204 to 210 were prepared in analogy to the method
described above.
EX. Name LC-MS: m/ e (M+H)+
204 3-( 1 -Methyl- 1 H-pyrazol—5-y1)—5-[2—(quinolin 3 87.1
yl)ethyl]thieno[3 ,2-c]pyridin-4(5)H—one hydrochloride
205 3-(Pyridin—4-yl)[2-(quinolin—2—yl)ethyl]thieno[3,2- 384.1
c]pyridin-4(5H)-one hydrochloride
206 3-(Pyrimidinyl)(2-quinolinyl)ethyl)thieno [3 ,2- 3 85. 1
c]pyridin—4(5H)—one
207 3-(2-Oxoindolin—6—yl)—5—[2—(quinolin—2— 438.1
yl]thieno[3,2—c]pyridin—4(5H)—one
208 3-(3-Hydroxyphenyl)[2—(quinolin—2— 399.1
yl]thieno[3 ,2-c]pyridin-4(5H)—one hydrochloride
209 5-[2-(5-Ethylpyridinyl)ethyl]-3—(pyridin—4— 362.1
yl)thieno[3 ,2-c]pyridin—4(5H)-one hydrochloride
210 5 -[2-(Imidazo[1,2-a]pyridin—2-yl)ethyl]—3—(pyridin 3 73. 1
yl)thieno[3 ,2-c]pyridin-4(5H)—one hydrochloride
EXAVIPLE 211: 3-(Morpholinyl)—5—[2—(quinolin—2-yl)ethyl]thieno[3,2-c]pyridin—
one hydrochloride
\ 05.0)
N N
l \
\
s
21 1.1 3-Morpholinothieno[3,2-c]pyridin-4(5H)-one
3-Bromothieno[3,2-c]pyridin-4(5H)-one from Example 202.3 (411 mg, 1.786
10 mmol) and line 81501 mg, 17.23 mmol) were stirred in a microwave for 3 h at
220°C. The mixture was poured onto water and extracted with DCM. The organic phase
was concentrated and the residue was recrystallized from EA to give 180 mg (yield:
42.6%) of the title compound.
192
21 1.2 3-(Morpholinyl)[2-(quino1in—2-y1)ethyl]thieno[3,2-c]pyridin-4(5H)-one
hydrochloride
The title compound was prepared in analogy to the method described in e
1.6 but using THF as solvent. Yield: 20.5%. LC—MS: m/e = 392.1 (M+H)+
EXAMPLE 212: tert-Buty1(4-oxo-5—(2-quinolinyl)ethy1)—4,5-dihydrothieno [3 ,2-
c]pyridin-3 -yl)-5 ,6-dihydropyridine— 1 (2H) carboxylate
The title compound was prepared in analogy to the method described in Example 202.5.
1 0
EXAMPLE 213 : 5 -(2-(Quinolinyl)ethyl)—3—(1,2,3 ,6-tetrahydropyridin—4-
yl)thieno[3 ,2-c]pyridin-4(5H)-one hloride
Tert-butyl(4-oxo(2-quino1in—2-y1)ethyl)-4,5-dihydrothieno[3,2-c]pyridin—3-
15 yl)-5,6-dihydropyridine-1(2H) carboxylate from e 212 (120 mg, 0.246 mmol) in
1 mL of HCl containing isopropanol was stirred under nitrogen for 12 h at room
temperature. The reaction mixture was extracted with DCM, the aqueous phase was
basified with 1N NaOH and extracted with DCM. The organic phase was dried,
concentrated and the residue was tallized from HCl-isopropanol to give the title
20 compound as hydrochloride salt as yellow solid (90 mg, 86%).
LC-MS: m/e = 388.1 (M+H)+
E 214: tert-Butyl—4—(4—oxo—5—(2—quinolin—2-yl)ethyl)-4,5-dihydrothieno [3 ,2-
c]pyridin-3 -yl)-piperidine— 1 carboxylate
193
N
\ O
/
N N
I \
\
The title compound was prepared in analogy to the method described in Example 202.5
EXAMPLE 215: 3-(Piperidinyl)[2-(quinolinyl)ethyl]thieno[3,2-c]pyridin-
5 4(5H)-one roacetate
H
/
N
\ O
/
N N
I \
\
3
Route a)
Under nitrogen, quinolinyl)ethyl)—3-(1,2,3,6-tetrahydropyridin
yl)thieno[3,2-c]pyridin—4(5H)-one hydrochloride from Example 213 (80 mg, 0.189
10 mmol) in methanol (15 mL) was hydrogenated at room temperature for 12 h. The title
compound was obtained as 2,2,2-trifluoroacetate salt a bright beige solid (4.1 mg,
4.32%) .
LC-MS: m/e = 390.2 (M+H)+
15 Route b)
The title compound was prepared in analogy to the method described in Example
213 starting from tert-butyl—4-(4-oxo(2-quinolinyl)ethy1)—4,5-dihydrothieno[3,2-
c]pyridinyl)-piperidine-l carboxylate from Example 214.
LC-MS: m/e = 390.2 (M+H)+
20
11.6 ation of compounds of the formula I in which A is Al, X1 is CH, R7 is Y2-
Cyc2 and X3 is S
194
EXAMPLE 2 l 6: 3-Methyl(pyridin—4—y1)—5-(2-(quino linyl)ethyl)thieno [3 ,2-
c]pyridin-4(5H)-one
N |\
\
s
/|
\N
216. l 7-Iodomethyl(2-quino linyl)ethyl)thieno [3 ,2-c]pyridin-4(5)H-one
To a mixture of triphenylphosphine (901 mg, 3.44 mmol) and DIAD (1.2 mL,
6.01 mmol) in THF (10 mL), 7—iodo—3—methyl—thieno[3,2-c]pyridin-4(5)H-one (500 mg,
1.72 mmol) was added followed by the addition of 2-(quinolinyl)ethanol from
example al (327 mg, 1.89 mmol) at 15°C under en. The mixture was stirred
ght at room temperature. The mixture was extracted with EtOAc/HZO, the EtOAc
10 layers were washed with 1N HCl and then discharged. The s layer was
lized by aq.NaHC03 and extracted with ethyl acetate. The combined organic
layers were washed with brine, dried over MgSO4, filtered, and concentrated under
reduced pressure. The crude title product was recrystallized from ethyl acetate to give
the title compound as bright beige solid (yield: ). LC-MS: m/e = 447.0 (M+H)+;
15 Rt: 211 min.
2 l 6.2 3 -Methyl(pyridin—4-yl)—5—(2—(quinolinyl)ethyl)thieno [3 ,2-c]pyridin—4(5H)-
one
The title compound was prepared in analogy to the method described in Example
20 1652 but using 7-iodomethyl(2-quinoliny1)ethyl)thieno[3,2-c]pyridin-4(5)H-
one (0.22 mrnol) and pyridin—4-ylboronic acid (0.22 mmol). The title compound was
obtained as white solid (yield: 22.9%).
LC-MS: m/e = 398.1 (M+H)+
25 II.7 Preparation of compounds of the formula I in which A is Al, X1 is N, R1 is Y1-
1
Cyc
195
EXAMPLE 217: 3-(Pyridin—4-yl)—5—[2—(5,6,7,8-tetrahydroquinolin
yl)ethyl]thieno[2,3-d]pyridazin—4(5H)—one hydrochloride
The title compound was prepared in analogy to the method described in e
5 1.6 but starting from 3-(pyridinyl)thieno[2,3-d]pyridazin-4(5H)one (obtainable by
Suzuki coupling of 3-bromo-5H-thieno[2,3-d]pyridazinone from Example 3.3 and
pyridinyl boronic acid as described above) and 2-(5,6,7,8-tetrahydroquinolin—2-
yl)ethanol from example a6). The title compound was obtained as white solid.
LC-MS: m/e = 389.1 (M+H)+
1 0
EXAMPLE 218: (R)-tert-butyl 3-(3—(2—(imidazo[1,2—a]pyridin—2-yl)ethyl)oxo-3,4-
dihydrophthalazin—5-ylamino)pyrrolidine— 1 —carboxylate
o
>70 CH
OHN
A reaction tube was charged with 8—chloro(2-(imidazo[l ,2-a]pyridin
15 yl)ethyl)phthalazin—1(2H)-one (155 mg, 0.48 mmol), BINAP (17.83 mg, 0.029 mmol),
tris(dibenzylideneacetone)dipalladium(0) (8.74 mg, 9.55 umol) and cesium carbonate
(311 mg, 0.955 mmol) in 1591 ul oftoluene. The mixture was stirred for l h under
argon. To this mixture, (R)-tert—buty1 opyrrolidine-l-carboxylate (89 mg, 0.477
mmol) was added. The reaction e was heated in a microwave at 105 °C for 20 h.
20 After completion of the reaction, the on mixture was ted with water and
DCM. The organic layers were washed with water, dried over MgSO4, filtered, and
concentrated under d pressure. The crude product was purified by column
chromatography using a normal phase Companion® system (4 g gold, gradient elution:
DCM to 10% methanol). Yield: 24.73%. LC-MS: m/e = 475.2 (M+H)+.
25
196
EXAMPLE 219: 2-[2-(1midazo[l ,2—a]pyridin—2-yl)ethyl] [(3 R)-pyrrolidin-3 -
ylamino]phthalazin— l (2H)-one dihydrochloride
H
/
13
OHN
A solution of (R)-tert-butyl 3-(3-(2-(imidazo[1,2-a]pyridinyl)ethyl)oxo-3,4-
5 dihydrophthalazin—S-ylamino)pyrrolidinecarboxylate from Example 218 (52 mg,
0.110 mmol) in 20 mL ofDCM was mixed with 1 mL ofHCl containing isopropanol
and the reaction mixture was stirred under en for 12 h at room temperature. The
reaction mixture was mixed with diisopropyl ether and the supernatant was discharged.
Then, the residue was dissolved in isopropanol and diisopropyl ether was added. The
10 supernatant was rged. The precipitate was dried to give 24 mg of a yellow salt as
solid foam. LC—MS: m/e = 357.2 (M+H)+
11.8 Preparation of compounds ofthe formula I in which A is Al, X1 is N, X3 is
-C(R9)=C(R8)- with R9 being Y3—cyc3
1 5
EXAMPLE 220: 5-(3-hydroxyphenyl)—2—[2-(quinolin—2-yl)ethyl]phthalazin— l (2H)-one
\ o
/
N N.
m D
O
The title compound was prepared in y to the method described in Example
1 92.
20
11.9 Preparation of compounds of the formula I in which A is A3, X1 is CH and R1 is
Yl-Cyc1
EXAMPLE 221 : (E)—8-(Pyridin—4—yl)—2—(2—(quino yl)Vinyl)isoquino lin- l (2H)-one
197
221 . 1 8-(Pyridinyl)isoquinolin-1(2H)—one
A reaction tube was charged with 8—bromoisoquinolin-1(2H)—one (1 g, 4.46
mmol) and a mixture of 3 mL of ethanol and 3 mL of toluene under argon. To this, an
s sodium bicarbonate solution (2 M, 710 mg, 3.35 mL, 6.69 mmol) was added
and then pyridinylboronic acid (549 mg, 4.46 mmol). Then, tetrakis(triphenyl—
ne)palladium (516 mg, 4.46 mmol) was added. The on mixture was heated
in a Biotage microwave at 130 °C for 30 min. The reaction was monitored by TLC
(DCM/methanol = 9: 1). After tion of the reaction, the reaction mixture was
10 mixed with water and dichloromethane. The solid was sucked off. The organic phase
was washed with an aqueous NaHC03 solution, brine, dried (MgSO4) and ated.
The residue was taken up with EA and the precipitate was sucked off. The crude
product was purified by chromatography (Campanion normal phase, gradient elution,
using 3-10% DCM in methanol) to yield 465 mg (46.9%) of the title compound.
15
22 1 .2 (E)—8-(pyridinyl)(2-(quinolinyl)vinyl)isoquino lin- 1 (2H)-one
idin—4-yl)isoquinolin—1(2H)—one (40 mg, 0.180 mmol) and (E)—2-(2-
bromovinyl)quino line (50.6 mg, 0.216 mmol) were dissolved in 2 mL ofDMF under
argon. The reaction mixture was stirred for 10 h at 115°C. Then, water and EA were
20 added. The organic phase was washed with water and brine, dried (MgSO4) and
concentrated. The crude product was purified by chromatography (CombiFlash, normal
phase, gradient elution, using 3-5% DCM in methanol) to yield the title compound as
yellow solid (27 mg, 40.0%). LCMS: 3761; Rt = 1.497.
25 11.10 Preparation of compounds of the formula I in which A is A4, X1 is CH and R1 is
Yl-Cyc1
EXAMPLE 222: anti (rac) 8—(Pyridin—4—yl)—2—(2—(quinolinyl)cyclopropyl)iso-
quino lin- 1 (2H)-one
198
idin—4-yl)isoquinolin—l(2H)—one (200 mg, 0.900 mmol) and syn(2-
bromocyclopropyl)quinoline (223 mg, 0.900 mmol) from Example cl) were dissolved
in 10 mL ofDMF under argon. The reaction mixture was stirred for l h at 115°C. Then,
an s solution of sodium chloride and DCM were added. The phases were
separated. The organic phase was washed with brine, dried (MgSO4) and evaporated.
The crude product was taken up in a small amount of EA. The precipitate formed was
sucked off and dried to yield anti (rac) 8-(pyridinyl)(2-(quinolin
yl)cyclopropyl)isoquinolin-l(2H)-one as bright beidge solids (248 mg, 70.8%). LCMS:
10 390.2.
Separation of anti (rac) 8-(pyridin—4—yl)—2—(2—(quinolin—2-
yl)cyclopropyl)isoquino lin- l (2H)-one
230 mg (0.591 mmol) of anti (rac) idin—4-yl)(2-(quinolin
15 yl)cyclopropyl)isoquinolin-l(2H)—one dissolved in 60 ul of roacetic acid were
separated by chromatography (chiral chromatography, Chiralpack AD-H, nheptane
/EtOH) to give 76 mg (33.0%) of compound 222a with positive rotation and 62
mg (27%) of compound 222b with negative rotation.
Compound 222a: (+) 8-(pyridin—4-yl)—2—(2-(quinolin
20 yl)cyclopropyl)isoquino lin- l (2H)-one
[or] = + 87.80 (methanol, 1 ; yellow solid.
Compound 222b: (-) 8-(pyridin-4—yl)(2—(quinolin—2—yl)cyclopropyl)isoquinolin-
1 (2H)-one
[CL] = - 983° (methanol, 1 mg/mL); bright yellow solid.
25
11.11 Preparation of compounds of the formula I in which A is A], X1 is CH and R1 is
Yl-Cyc1
EXAMPLE 223: 8-(Pyridin—4—yl)—2—(2—quinolin—2—yl—ethyl)isoquinolin- l (2H)-one
199
A flask was charged with idin—4-yl)isoquinolin-1(2H)-one (0,113 mmol, 50
mg) in NHg/ethanol (2 mol/L) (15 mL, 30,0 mmol). Then, Raney-Nickel in water (5
drops) was added. At room temperature, the en flow was turned on. The
hydrogenation reaction was stopped after 4 days. Unter nitrogen, the reaction mixture
was filtered over Celite and evaporated to yield 52 mg (80% yield) of the crude title
product as soli, yellow oil. The crude product was purified by Combi-flash
chromatography (gradient elution using methanol/DCM up to a tration of 10%).
LC-MS: 378.2.
10
11.12 Preparation of compounds of the formula I in which A is A4, X1 is CH and R1 is
Yl-Cyc1
EXAMPLE 224: anti (m) 3-(Pyridin—4-yl)—5—(2—(quinolinyl)cyclopropyl)thieno[3,2-
15 c]pyridin-4(5H)-one
N\
mN\ o,/
,\
\
s
224. l 3-(Pyridin—4-yl)thieno [3 yridin—4(5H)—one
3-Bromothieno[3,2-c]pyridin-4(5H)—one (1000 mg, 4.35 mmol) from Example
202.3 was suspended in 2 mL of toluene and 2 mL of ethanol under argon. Then, an
20 aqueous solution of sodiumcarbonate (691 mg, 6.52 mol, 2 M) was added. To the
suspension, pyridin—4-boronic acid (534 mg, 4.35 mmol) and then tetrakis(triphenyl
phosphine)palladium(0) (502 mg, 0.435 mmol) were added. The reaction e was
heated in a Biotage microwave at 130 °C for 30 min. Water and EA were added. The
precipitate formed was collected to give 480 mg of the title nd. The filtrate was
25 acidified with 2 M HCl and extracted with EA (twice). The aqueous phase was basified
and extracted three times with EA. The organic phases were combined, washed with
200
HCl, dried (MgSO4) and evaporated to give further 43 mg of the title compound. Total
yield: 523 mg (52.4%). LC-MS: 229.1 [M+H]+; Rt: 0.427.
224.2 anti (m) 3-(Pyridin—4-yl)(2-(quino1inyl)cyclopropyl)thieno[3,2-c]pyridin-
4(5H)-one
The title compound was prepared in analogy to the method described in Example
222. Yield: 57.7%, LC-MS: 396.1.
11.13 Preparation of compounds of the formula I in which A is A3, X1 is N and R1 is Y1-
10 Cyc1
EXAMPLE 225: Pyridin—4—yl—2—((2—quinolin—2—yl-vinyl)-2H-phthalazinone
/ l
/
N “1‘
N \
The title compound was ed according to the general procedure given above
15 but starting from 8-pyridinyl-2H-phthalazin—1-one. Yield: 5%. LC-MS: 377.1
11.14 Preparation of compounds ofthe formula I in which A is A4, X1 is N and R1 is Y1-
Cyc1
20 EXAMPLE 226: anti (rac) 8-Pyridin—4-y1—2-(2-quinolinyl-cyclopropyl)-2H-
phthalazinone 2,2,2,—trifluoroacetate
N
\
l
/
N 'T‘
N \
Under argon, a flask was charged with (E)(pyridinyl)(2-(quinolin
yl)vinyl)phthalazin—l(2H)—on (85 mg, 0.226 mmol) in dichloroethane, extra dry, (2,823
25 mL) at 0°C. Then, diethylzinc (lmol/L in ) (1,129 mL, 1,129 mmol) was added
within 5min at -3 to 0°C. The on mixture was stirred for 10 min at 0°C.
Diiodomethane (0,182 mL, 2,258 mmol) was added at 0°C within 2 min. The reaction
201
mixture was warmed to room temperature and stirred overnight at room temperature.
Then, a further portion of diethyl zinc (lmol/L in hexane) (1,129 mL, 1,129 mmol) was
added at 0°C followed by a further portion ofdiidomethane (0,182 mL, 2,259 mmol),
and the on e was warmed to room temperature. The reaction mixture was
stirred for fiirther 3 days at room temperature. The reaction mixture was poured onto an
ice-cold aqueous solution ofNaHCO3 (5%). The reaction mixture was extracted with
DCM (3 . The organic phase was washed with brine, water, dried over sodium
e and evaporated. Purification by prep. HPLC yielded 7.] mg (6.23% yield) of the
title compound. LC-MS: 391.1.
10
II. 15 Preparation of compounds of the formula I in which A is Al, X1 is CH, R7 is Y2-
Cyc2 and X3 is 0
EXAMPLE 227: 7-(Pyridin—4-yl)—5—[2—(quinolin—2—yl)ethyl]furo[3,2-c]pyridin-4(5H)-
15 one
/| g
\.
N N |\\
\
o
,f’
\l
N
227.1 7-Bromo(2-(quinolin-2—yl)ethyl)furo[3,2-c]pyridin—4(5H)-one
DIAD (4.91 mmol, 992 mg) was added dropwise to PPh3 (753 mg, 2,80 mmol) in
20 mL of THF. The mixture was stirred for 30 min. Then 7-bromofi1ro[3,2-c]pyridine-
20 4(5H)—one (300 mg, 1.402 mmol) was added followed by the addition of 2-(quinolin
yl)ethanol (243 mg, 1.402 mmol). The reaction e was stirred overnight at room
temperature. The reaction mixture was extracted with water/ ethyl acetate. The organic
phase was extracted with 1N HCl. The acidic aqueous phase was basified with 1N
NaOH and extracted with DCM. The organic phase was extracted with water, dried over
25 MgSO4, filtered, concentrated and d by tography to give the title
compound as white solid (119 mg, 23%).
227.2 7-(Pyridinyl)[2—(quinolin—2—yl)ethyl]furo[3,2-c]pyridin—4(5H)-one
202
The title compound was prepared in analogy to the method described in Example
165.2 but using 7-bromo(2-(quino1iny1)ethy1)furo[3,2-c]pyridin-4(5H)-one (61.7
mg, 0.167 mmol) and pyridin-4—ylboronic acid (22.82 mg, 0.167 mmol mmol). The title
nd was obtained as yellowish solid (yield: 22 mg, 35.89%).
LC-MS: m/e = 368.1 (M+H)+
11.16 Preparation of compounds of the formula I in which A is Al, X1 is CH, R1 is
Yl-Cyc1 and X3 is 0
10 EXAMPLE 228: 3-(Pyridin—4-yl)—5-(2-(quinoliny1)ethyl)fi1ro[3,2-c]pyridin-4(5H)—
one hloride
228.1 (E)(4-Bromofiiranyl)acryloyl chloride
To a solution of (4-bromofi1ran—2—yl)acrylic acid (3.8 g, 17.51 mmol) in 35
15 mL oftrichloromethane was added a solution of 2.6 mL of l chloride in 200 uL of
DMF. The reaction mixture was refluxed for 1 h and after cooling to room temperature
trated to give 4 g (97% yield) ofthe title nd as light brown oil.
228.2 (E)(4-Bromofiiranyl)acryloy1 azide
20 A solution of (E)(4-bromofuran—2—yl)acryloy1 chloride (4.0 g, 16.99 mmol) in
10 mL of 1,4-dioxane was added to a solution of sodium azide (2.21 g, 34.0 mmol) in
10 mL of water and 10 mL of 1,4-dioxane. The reaction mixture was stirred for 2.5 h at
room temperature. The reaction mixture was mixed with ethyl acetate and water. Phases
were separated and the aqueous phase was extracted with ethyl acetate (twice). The
25 combined organic phases were washed with brine, dried, filtrated and concentrated to
give 4 g of the title compound (yield: 97%).
228.3 3-Bromofuro[3,2—c]pyridin-4(5H)—one
203
A on of (E)(4-bromofuran—2-yl)acryloyl azide (4 g, 16.53 mmol) in 20
mL of diphenyl ether was slowly added to 80 mL of diphenyl ether at 230°C. The
mixture was stirred for further 15 min. The reaction mixure was allowed to cool down
to room temperature. 100 mL of cyclohexane were added and the reaction mixture was
stirred overnight. A precipitate was formed, d off and suspended in 50 mL of
cyclohexane. The mixture was stirred for 1 h at room temperature. The precipitate was
filtered off to give 2.76 g (78%) of the title compound as brownish solid.
LC-MS: m/e 215.9 (M+H]+
10 228 .4 3 —(Pyridinyl)furo [3 yridin-4(5H)—one
A reaction tube was charged with 3-bromofi1ro[3,2-c]pyridin-4(5H)-one (1000
mg, 4.67 mmol) and a mixture of 1 mL of ethanol and 1 mL of toluene under argon. To
this mixture, n—4-ylboronic acid (574 mg, 4.67 mmol) and a 2 M on of
N32C03 (743 mg, 7.01 mmol) were added followed by the addition of tetrakis-
15 (triphenylphoshine)palladium (540 mg, 0.467 mmol). The on mixture was heated
in a Cem microwave at about 130 °C for about 30 min. After completion of the reaction,
EA was added followed by the addition of 2 N HCl. The mixture was extracted twice
with EtOAc. The s layer was extracted three times with ethyl acetate. The
combined organic layers were washed with brine, dried over MgSO4, d, and
20 concentrated under reduced pressure. The crude product was purified by
chromatography to give the title compound as dark yellow solid (430 mg, 43.4%).
228.5 3 -(Pyridinyl)-5 -(2-(quino1in-2—y1)ethyl)furo [3 ,2-c]pyridin—4(5H)-one
To a solution of triphenylphosphine (247 mg, 0.942 mmol) in THF (10 mL),
25 DIAD (0.321 mL, 1.65 mmol) was added. The mixture was cooled to 15°C. 3-(Pyridin—
4-y1)furo[3,2-c]pyridin—4(5H)-one (100 mg, 0.471 mmol) and 2-(quinolin—2-yl)ethanol
from example from example a1 were added. After stirring overnight at room
temperature, EA and 2M HCl were added. The phases were separated and extracted
with EA. The organic phase was washed with water. The acidic aqueous phase was
30 basified with 2M NaOH and extracted with ethyl acetate. The combined c layers
were washed with brine, dried over MgSO4, filtered, and concentrated under reduced
204
re. The residue was purified by tography to give 69 mg ofthe title
compound ) as hydrochloride salt as dark yellow solid.
LC-MS: m/e 368.1 (M+H)+
5 The compounds of examples 229 to 231 were prepared in analogy to the method
described in example 228.
EXAMPLE 229: 5-(2-(1H-Benzo[d]imidazolyl)ethyl)(pyridiny1)furo[3,2-
c]pyridin-4(5H)-one hydrochloride
lO
The title compound was obtained as grey solid (Yield: 3.46%).
LC-MS: m/e 357.1 (M+H)+
EXAMPLE 230: 5-(2-(Imidazo[ l ,2-a]pyridin—2—yl)ethyl)(pyridinyl)furo[3 ,2-
15 c]pyridin-4(5H)-one hydrochloride
The title compound was obtained as grey solid (Yield: 30.3%)
LC-MS: m/e 357.1 (M+H)+
20 EXAMPLE 231: 3-(Pyrimidinyl)(2-(quinolinyl)ethyl)furo[3,2-c]pyridin-4(5H)-
0116
The title compound was obtained as bright yellow solid (Yield: 28.13%)
205
LC-MS: m/e 369.1 (M+H)+
11.17 Preparation of compounds ofthe formula I in which A is A4, X1 is CH, R1 is
Yl-Cyc1 and X3 is 0
E 232: anti 3-(Pyridazinyl)—5-(2—(quinolin—2—y1)cyclopropyl)furo[3,2-
c]pyridin-4(5H)-one
232. 1 anti 3-Bromo—5—(2—(quinolin—2—yl)cyclopropyl)furo [3 yridin—4(5H)-one
10 A microwave reaction tube was charged with 3-bromofiiro[3,2-c]pyridin-4(5H)-
one (300 mg, 1.402 mmol) from Example 228.3, syn 2-(2-bromocyclopropyl)quinoline
(348 mg, 1.402 mmol) from example cl), cesium carbonate (913 mg, 2.80 mmol) and 5
mL ofDMF. The reaction mixture was stirred for 1.5 h at 110°C. EA and water were
added. The phases were separated. The aqueous phase was washed with EA (twice).
15 The organic phases were washed with brine, dried over MgSO4, filtered, and
concentrated under reduced pressure. The crude product was purified by
chromatography to give 450 mg (84%) of the title compound as light brown yellow
solid
20 232.2 anti 3-(pyridazinyl)(2-(quinolin—2-yl)cyclopropyl)furo[3,2-c]pyridin—
4(5H)—one
The compound from Example 232.1 was ded in 1 mL oftoluene and 1 mL
of methanol under argon. Then, an aqueous solution of sodium carbonate (41.7 mg, 0.39
mol, 2 M) was added. To the sion, ,5,5-tetramethyl-1,3,2—dioxaborolan—2-
25 yl)pyridazine (54 mg, 0.26 mmol) and then tetrakis(triphenylphosphine)palladium(0)
(30.3 mg, 0.026 mmol) were added. The reaction mixture was heated in a Biotage
microwave at 130 °C for 30 min. Water and EA were added. The aqueous phase was
extracted twice with EA. The organic phases were combined, washed with HCl, dried
(MgSO4) and evaporated. The residue was purified by chromatography to give 15 .5 mg
30 (yield: 15.53%) of the title nd as light brownish solid.
206
LC-MS: m/e 380.8 (M+H)+
EXAMPLE 233: anti 3-(pyridin—4—yl)—5-(2—(quinolinyl)cyclopropyl)furo[3,2-
c]pyridin-4(5H)-one
The title compound was ed according to the method described for example
232.2. The title compound was obtained as yellow solid. LC-MS: m/e 379.9 (M+H)+
11.18 Preparation of compounds of the formula I in which A is A5, X1 is N, R1 is
10 l and x3 is N=C(R8)
EXAMPLE 234: 4-(Pyridin—4-yl)-6—(2—(quino1in—2—yl)allyl)pyrido[2,3-d]pyridazin-
5(6H)-one
15 234.1 (E)—Ethyl 2-((2-acetylhydrazono)methyl)—4-chloronicotinate
To 2.1 g (9.83 mmol) of ethyl 4-chloro-2—formylnicotinate in 60 mL of ethanol
was added 0.874 g (11.80 mmol) of acetohydrazide at room temperature. Then, the
reaction mixture was heated under reflux for 2h. The reaction mixture was extracted
with water/DCM. The c phase was washed with brine, dried, filtrated and
20 trated to give 1.95 g (73.6%) of the title compound as white solid.
234.2 4-Chloropyrido[3,2-d]pyridazin-5(6H)-one
(E)-ethyl 2-((2-acetylhydrazono)methyl)chloronicotinate (2850 mg, 10.57
mmol) in 15 mL of dioxane was mixed with aq. NaOH (42.3 mg, 1.06 mmol, 2 M). The
25 reaction mixture was stirred in a microwave for 60 min at 145°C. After cooling to room
temperature, the solid was filtered off. The solid was dissolved in methanol and the
207
residue was filtered off. The e was concentrated and triturated with EA to give 1.4
g (73.0%) of the title compound as orange brown solid.
234.3 4-(Pyridinyl)pyrido[3,2-d]pyridazin—5(6H)—one
A reaction tube was charged with a solution of4—chloropyrido[3,2-d]pyridazin-
5(6H)-one (0.354 mmol) in 1 mL of ethanol and 1 mL oftoluene under argon. To this
suspension, a 2M solution ofNa2C03 (0.531 mmol) and pyridinylboronic acid (0.354
mmol) were added. Then, tetrakis(triphenylphoshine)palladium (0.035 mmol) was
added. The reaction e was heated in a CEM ave at about 130 °C for about
10 20 min. The reaction was monitored by TLC (DCM/methanol = 9:1). After completion
ofthe reaction, EA was added followed by the addition of water. The organic layer was
basified with NaHCOg. The organic layers were dried over MgSO4, d, and
concentrated under reduced pressure. The crude product was purified by column
chromatography (25.2%).
15
234.4 4-(Pyridinyl)(2-(quinolin-2—yl)allyl)pyrido[2,3-d]pyridazin—5(6H)-one
A reaction tube was charged with 307 mg (1.369 mmol) of 4-(pyridin
yl)pyrido[2,3-d]pyridazin-5(6H)-one, syn(2—bromocyclopropyl)quinoline from
example cl and cesium ate (892 mg, 2.74 mmol). The reaction e was
20 heated for 6h at 110°C under argon. After cooling to room temperature, EA was added
followed by the addition of water. The organic layer was basified with NaHCOg. The
organic layers were dried over MgSO4, filtered, and concentrated under reduced
pressure. The crude product was purified by column chromatography to give 106 mg of
the title compound (yield: ).
25
11.19 Preparation of compounds of the formula I in which A is A4
EXAMPLE 23 5: anti 8-(Oxetan—3-ylamino)(2-(quino lin
yl)cyclopropyl)isoquino lin- 1 (2H)—one
—O
/J
%N\ O HN
N$6
30
208
235.1 anti 8-bromo(2-(quino1in—2—y1)cyclopropyl)isoquinolin- 1 (2H)-one
8-bromoisoquinolin-l(2H)-one (300 mg, 1.339 mmol) and syn(2-
yclopropyl)quinoline (332 mg, 1.339 mmol) from Example cl) were dissolved
in 4 mL ofDMF under argon. Cesium carbonate (873 mg, 2.68 mmol) was added. The
reaction mixture was stirred for 1 h at 115°C. Then, an aqueous solution of sodium
chloride and DCM were added. The phases were separated. The organic phase was
washed with brine, dried (MgSO4) and evaporated. The crude t was taken up in a
small amount of EA. The precipitate formed was sucked off and dried to yield anti 8-
bromo(2-(quinolinyl)cyclopropyl)isoquinolin-1(2H)-one as bright beidge solid
10 (330 mg, 63.0%). LC—MS: 391.0 (M+); Rt: 1.6 min.
Separation of anti 8—bromo—2—(2—(quinolin—2—yl)cyclopropyl)isoquino lin-1(2H)-
one
33g of anti 8-bromo(2-(quinolin—2—yl)cyclopropyl)isoquinolin-1(2H)-one were
15 suspended in pyl acetate/heptane 1:4 (5 mL/g). The racemate was separated by
chiral chromatography to give 16.1 g of anti (+) 8—bromo(2-(quinolin
yl)cyclopropyl)isoquinolin-1(2H)-one (compound 235.1a) R = 4.885 min and 20.25 g
of anti (-) 8-bromo(2-(quinoliny1)cyclopropyl)isoquinolin-1(2H)-one (compound
235.1b), R = 9.253 min.
20
235 .2 anti tanylamino)—2—(2-(quinolinyl)cyclopropyl)isoquinolin- 1 (2H)-
one
A microwave reaction vial was charged with the anti 8-bromo(2-(quinolin
lopropyl)isoquinolin-1(2H)—one from Example 235.1 (70 mg, 0.18 mmol),
25 CS2CO3 (175 mg mg, 0.54 mmol), Pd2(dba)3 (3.28 mg mg, 3.58 umol) and BINAP (6.68
mg, 10.73 umol). The solids were purged with argon for 1 h. A separate flask was
charged with toluene (2 mL) and amine (19.6 mg, 0.18 mmol), degas with
argon for 1 h and then transferred to the microwave reaction vial under inert conditions.
The resulting reaction mixture was heated on microwave at 105 °C for 48 h. The
30 reaction mixture was poured into water and extracted with DCM. The solids were
removed. The organic layer was washed with water, dried over MgSO4, filtered and
209
concentrated in vacuo. The residue was purified on a silica column (eluent:
DCM/methanol) and then triturated with EA to afford the title product (35 mg, 51.0 %).
LC-MS: m/e = 384.2 (M+H)+.
Separation of anti 8-(oxetan—3-y1amino)(2-(quinolin—2-
yl)cyclopropyl)isoquino lin- 1 (2H)—one
484 mg (0.591 mmol) of anti tanylamino)(2—(quino1in—2-
yl)cyclopropyl)isoquinolin-1(2H)-one dissolved in 20 mL of ethanol-DCM (1 :1
mixture) and 1 mL of the solution were tographed on a Whelk-O (R,R) 2 x 25
10 cm (10 mkm particles) column in EtOH (containing 0.1% n-propylamine) at 40 mL/min
and 254 nm detection. Peaks obtained were concentrated to give first-eluting compound
235a (220 mg, chiral purity 98.6%) and second—eluting compound 235b (230 mg, chiral
purity 97.3%), recovery ~93%.
Compound 235a: (+) anti 8-(oxetan—3—ylamino)(2-(quinolin
15 yl)cyclopropyl)isoquino lin- l (2H)-one
Compound 23 5b: (-) anti 8-(oxetan—3-ylamino)(2-(quinolin
yl)cyclopropyl)isoquino lin- l (2H)—one.
20 EXAMPLE 236: anti (-) 8-(pyridazin—4—y1)(2-(quinolin
yl)cyclopropyl)isoquino lin- l (2H)—one
The title compound was prepared according to the method described in example
232.2 starting from anti (-) 8-bromo-2—(2-(quinolinyl)cyclopropyl)isoquinolin-l(2H)-
one und 235.lb). LC-MS: m/e = 391.2 (M+H)+.
25
E 237: anti (-) 8-(6-fluoropyridin—3—yl)—2-(2—(quino1in—2—
yl)cyclopropyl)isoquino lin- 1 (2H)-one
The title compound was prepared ing to the method described in example
30 232 starting from anti (—) 8—bromo—2—(2—(quinolin—2—y1)cyclopropyl)isoquinolin-l(2H)-
one (compound 235.lb) and 2—fluoro(4,4,5,5-tetramethyl—l,3,2-dioxaborolan—2-
yl)pyridine. LC-MS: m/e = 408.2 (M+H)+
210
[ct] = -lO7° (methanol)
EXAMPLE 238: anti (-) 8-(2-fluoropyridiny1)—2-(2-(quinolin
yl)cyclopropyl)isoquino lin- l (2H)—one
The title compound was ed according to the method bed in example
232 starting from anti (-) 8-bromo-2—(2-(quinolin—2-yl)cyclopropyl)isoquinolin-l(2H)-
one und 235.1b) and 2-fluoropyridin—4-ylboronic acid.
LC-MS: m/e = 408.2 (M+H)+
10 EXAMPLE 239: anti 8—(pyridinyl)(2-(quino1inyl)cyclopropyl)isoquinolin-
l(2H)-one hydrochloride
The title compound was prepared ing to the method described in example
232 starting from anti 8-bromo(2-(quinolin—2—yl)cyclopropyl)isoquinolin-l(2H)-one
15 and pyridinylboronic acid. LC-MS: m/e = 390.1 (M+H)+
Separation of anti 8-(pyridin-3—y1)—2-(2-(quinolinyl)cyclopropyl)isoquinolin-
l (2H)-one:
320 mg of anti 8-(pyridin-3—y1)—2—(2-(quinolinyl)cyclopropyl)isoquinolin-
20 l(2H)-one were subjected to a chromatography on a Chiralpak IC column, eluent: 500
parts of n-heptane, 450 parts ofDCM, 50 parts of methanol and 1 part of triethylamine
to give 105 mg of compound 239a (Rt: 4.74 min), 98.8% ee and 120 mg of compound
23% (Rt: 4.68 min), 97.6% ee.
Compound 239a: (+) anti 8-(pyridinyl)(2-(quino1in
25 yl)cyclopropyl)isoquino lin- 1 (2H)-one
[CL] = + 108.5° (methanol)
nd 23%: (—) anti 8-(pyridin—3-yl)—2-(2-(quinolin—2-
yl)cyclopropyl)isoquino lin— l (2H)—one
30 [on] = -94.8° (methanol)
211
EXAMPLE 240: anti 8-(pyrimidin—5—yl)(2-(quinolinyl)cyclopropyl)isoquinolin-
l(2H)—one
The title compound was ed according to the method described in example
232 starting from anti 8-bromo(2-(quinolinyl)cyclopropyl)isoquinolin-1(2H)-one
and pyrimidin-S-ylboronic acid.
LC-MS: m/e = 391.1 (M+H)+
10 tion of anti 8-(pyrimidin—5—y1)—2—(2—(quinolin—2-yl)cyclopropyl)isoquinolin-
l (2H)-one:
330 mg of anti 8-(pyrimidiny1)—2—(2—(quinolinyl)cyclopropyl)isoquinolin-
l(2H)-one were subjected to a chromatography on a Chiralpak IC column, eluent: 500
parts of n-heptane, 450 parts of DCM, 50 parts anol and 1 part of triethylamine
15 to give 112 mg of compound 240a (Rt: 980), 95.6% ee and 98 mg of compound 24%
(R: 5.52), 81.2% ee.
Compound 240a: anti (+) 8-(pyrimidin—5-yl)(2-(quinolin
yl)cyclopropyl)isoquino lin- l (2H)-one
[ct] = + 118.30 (methanol)
20
Compound 240b: anti (-) 8-(pyrimidin—5-yl)—2-(2—(quinolin
yl)cyclopropyl)isoquino lin- l ne
[at] = -l20.4o (methanol)
25 EXAMPLE 241: anti 8-(l-methyl-lH-pyrazolyl)(2-(quinolin
yl)cyclopropyl)isoquino lin- l (2H)-one
CH3
/
—N
/
212
The title compound was prepared according to the method described in example
232 starting from anti 8-bromo-2—(2—(quino1inyl)cyclopropyl)isoquinolin-l(2H)-one
and l-methyl(4,4,5 ramethyl-l ,3 ,2-dioxaborolan—2-yl)- l H-pyrazo le.
LC-MS: m/e = 393.1 (MJrH)+
EXAMPLE 242: anti 8-(3-fluoropyridinyl)—2-(2-(quino1in
yl)cyclopropyl)isoquino lin- l (2H)—one
N\
|
/
\ (IDI F
N/ N
\
The title compound was ed according to the method described in example
10 232 ng from anti 8-bromo—2—(2—(quinolin—2—yl)cyclopropyl)isoquinolin-l(2H)-one
and 3-fluoro(4,4,5 ,5 -tetramethyl—l ,3 ,2—dioxaborolan—2-yl)pyridine.
LC—MS: m/e = 408.1 (M+H)+
EXAMPLE 243: anti 8-(2-fluoropyridin-4—yl)—2—(2-(quinolin
15 yl)cyclopropyl)isoquino lin- l (2H)—one
N F
\
I
/
\ o
/
N N
\
The title nd was prepared according to the method described in example
232 ng from anti 8-bromo—2-(2—(quino1in—2-yl)cyclopropyl)isoquinolin-l(2H)-one
and 2-fluoropyridinylboronic acid. LC—MS: m/e = 408.1 (M+H)+
20
EXAMPLE 244: anti 8-((3S)—3-hydroxypiperidin—l-yl)—2—(2-(quinolin—2-
y1)cyclopropyl)isoquinolin- 1 (2H)-one (2E)-butenedioate
N ,OH
\ O
/
N N
\
The title compound was prepared according to the method described in example
25 173 starting from anti 8-bromo—2—(2—(quinolin—2—yl)cyclopropyl)isoquinolin-l(2H)-one
213
and (S)-piperidinol. The title compound was converted into the fumarate salt. LC-
MS: m/e=4l2.2
Examples 245 to 253 were prepared in analogy to the method described in
5 example 244.
EXAMPLE 245: anti 8-(3-methoxypiperidin—1—yl)—2-(2—(quinolin—2—
yl)cyclopropyl)isoquinolin- 1 (2H)-one (2E)-butenedioate
10 LC-MS: m/e = 426.2
EXAMPLE 246: anti 8-morpholino(2—(quinolin—2-yl)cyclopropyl)isoquinolin-l(2H)-
0116
O
\ Org
15
LC-MS: m/e = 398.2 (M+H)+
tion of anti 8-morpholino—2-(2—(quinolin—2-yl)cyclopropyl)isoquinolin-
l(2H)—one:
20 246 mg of anti 8-morpholino(2-(quinolinyl)cyclopropyl)isoquinolin-1(2H)—
one were subjected to a chromatography on a Chiralpak IC column, eluent: 500 parts of
n-heptane, 450 parts of DCM, 50 parts of methanol and 1 part of triethylamine to give
95 mg of compound 246 a (R: 8.1), 90.2% ee and 74 mg of compound 246b (R: 9.4),
90.2% ee.
25 Compound 246a: anti (+) 8—morpholino—2—(2—(quinolin—2-
yl)cyclopropyl)isoquino lin- l ne
[or] = + l4l.4° (methanol)
214
nd 246b: anti (-) 8—morpholino(2-(quinolin
y1)cyclopropyl)isoquino1in- 1 (2H)—one
[ct] = -142.00 (methanol)
Examples 247: anti 1-(1-oxo(2—(quinolin—2—yl)cyclopropy1)—1 ,2-dihydroisoquino 1in-
8-y1)piperidinecarbonitrile
CN
WE
LC-MS: m/e = 421.2 (M+H)+
10
EXAMPLE 248: anti 8-((3R,4R)—4—fluoro—3—hydroxypiperidin—1-y1)(2-(quinolin
y1)cyclopropy1)isoquinolin- 1 (2H)-one
F
(53m
\ O N
/
N N
\
LC—MS: m/e = 430.2 (M+H)+
15
EXAMPLE 249: anti 8-((3 S)—3-hydroxypyrrolidin— 2-(2-(quino 1in
y1)cyclopropy1)isoquino1in- 1 (2H)—one di[(2E)—butenedioate]
OH
\ Q
0|
N/ N
\
LC-MS: m/e = 398.2 (M+H)+
20
EXAMPLE 250: anti 8—((3R)—3—hydroxypyrrolidin—1—y1)(2-(quinolin—2-
yl)cyclopropy1)isoquino 1in— 1 (2H)—one (2E)—but—2—enedioate
215
OH
\ 0| N
N/ N
\
LC-MS: m/e = 398.2 (M+H)+
EXAMPLE 251: anti 8-(methyl(0xetanyl)amin0)(2-(quin01in
5 y1)cyclopropyl)isoquino lin- 1 (2H)-one
—0
H30\ 4
\ O N
N N
\
LC-MS: m/e = 398.1 (M+H)+
EXAMPLE 252: anti 8-(4-methoxypiperidin—1—y1)—2—(2-(quin01in
1 0 y1)cyclopropyl)isoquinolin- 1 ne (2E)—but—2—enedi0ate
9H3
0
LC—MS: m/e = 426.2 (MJFH)+
EXAMPLE 253: anti 8-(4-hydroxypiperidin—1-y1)(2-(quin01in
1 5 y1)cyc10propyl)isoquinolin- 1 (2H)-0ne (2E)—but—2—enedioate
OH
\ Eli?
0|
N/ N
\
LC-MS: m/e = 412.2 (M+H)+
EXAMPLE 254: anti 8-(1—acetylpiperidin—4—ylamino)—2-(2-quin01in
20 cyclopropy1)isoquino lin- 1 (2H)—one
216
>LCH
Q
\ OHN
/
N N
\
The title compound was prepared in analogy to the method described in example
235.
EXAMPLE 255: anti 8-(piperidinylamino)(2-(quinolin
yl)cyclopropyl)isoquino lin- 1 (2H)-one hloride
/H
Q
\ Ol N
N/ N
\
The title compound was prepared in analogy to the method described in e
213 but g for 3 h under reflux and the solvent used was ethanol.
10 LC-MS: m/e = 411.2 (M+H)+.
EXAMPLE 256: syn 8-(pyridinyl)(2-(quinolinyl)cyclopropyl)isoquinolin-
1(2H)-one hydrochloride
15 25 6. 1 8-(pyridinyl)(2-(quinolin—2—yl)cyclopropyl)isoquino lin- 1 (2H)-one
The title compound was prepared as decribed in example 222.
LC-MS: 390.1 (M+H)+
256.2 Separation of 8-(pyridin—4-y1)—2—(2-(quinolinyl)cyclopropyl)isoquinolin-
20 1 (2H)-one:
2.8 g of 8-(pyridinyl)—2—(2-(quinolin—2—yl)cyclopropyl)isoquinolin—1(2H)-one
were ved in 50 mL ofEA and separated by column chromatography, normal
phase, eluent: DCM/methanol to give compound 222 and compound 256..
Compound 222: anti 8—(pyridin—4—yl)—2—(2—(quinolinyl)cyclopropyl)isoquinolin-
25 l(2H)-one, yield: 80%; LC—MS: 390.1 (M+H)+, Rt: 1.128 min
217
Compound 256: syn 8-(pyridin—4—y1)(2-(quinolinyl)cyclopropyl)isoquinolin-
1(2H)-one, yield: 4.3%; LC-MS: 390.1 (M+H)+, Rt: 1.127 min.
Examples 257 to 275 were prepared in analogy to the methods described above.
EX. Name LC-MS: m/e (M+H)+/ [a]
257 anti 2-(2-(quinolinyl)cyclopropyl)—8- 397.1
(tetrahydro-2H-pyran—4-yl)isoquino lin- 1 (2H)-one
258 anti (-) 2-(2-(quinolinyl)cyclopropyl)(2-oxa- 424.2 / [a] = -194°
6-azaspiro [3 .4]octan—6-yl)isoquino lin- 1 (2H)-one
259 anti (-) 8-(dihydro— 1 [3 ,4—c]pyrrol— 424.2 / [or] = -193°
5 ,6aH)—yl)—2—(2—(quinolin—2—
yl)cyclopropyl)isoquinolin— 1 (2H)—one
260 anti (-) -difluoropiperidin—1—yl)—2—(2— 432.2 /[(x] = -162°
(quinolinyl)cyclopropyl)isoquinolin— 1 (2H)-one
261 anti 8-morpholino(2-(quinolin-2— 398.1
yl)cyclopropyl)isoquino lin- 1 (2H)-one,
dimethanesulfonate
262 anti 8-(3 -(difluoromethyl)pyrrolidin—1-yl)(2- 432.2
(quinolinyl)cyclopropyl)isoquinolin- 1 (2H)-one,
trifluoroacetate
263 anti ,5 S)—3 -oxaazabicyclo[3.2.1]octan—8- 424.2
yl)(2-(quino linyl)cyclopropy1)isoquino lin-
1 (2H)-one
264 anti 8-(4-methylpiperazin— 1 -y1)(2—(quino lin-2— 411.2
yl)cyclopropyl)isoquinolin— 1 (2H)-one,
265 anti 8-(3 -(fluoromethyl)pyrrolidinyl)(2- 414.2
(quinolinyl)cyclopropyl)isoquinolin-1(2H)-one,
trifluoroacetate
266 8-((1R,5 xa—3—azabicyclo[3 .2. 1 ]octan—3-y1)- 424.2
2-(2-(quinolinyl)cyclopropyl)isoquino lin—
1 (2H)-one,
218
Ex. Name LC-MS: m/e (M+H)+/ [a]
267 anti 8-(4-fluorophenyl)(2—(quinolin 407.2
yl)cyclopropyl)isoquinolin— 1 (2H)—one,
268 anti 8-(fi1ran—3-yl)(2-(quinolin-2— 379.1
yl)cyclopropyl)isoquinolin- 1 (2H)—one
269 anti 8-(4,5-dihydrofuran—3—y1)—2—(2-(quinolin—2- 3 81 .2
yl)cyclopropyl)isoquinolin— 1 (2H)—one
270 anti (-) 8-(4-methoxyphenyl)(2-(quinolin 419.2 / [ct] = -68°
yl)cyclopropyl)isoquinolin-1(2H)-one
271 anti 2-(2—(6—fluoroquino lin—2-yl)cyclopropyl)—8- 416.2
morpholinoisoquino lin— l (2H)—one
272 anti 2-((2-(6-fluoroquinolin—2—yl)cyclopropyl)—8- 408.1
in-3 -yl)isoquino lin— 1 (2H)—one
273 anti 2-(2-(6-fluoroquinolin-2—yl)cyclopropyl)—8- 409.1
(pyrimidin-S oquinolin- 1 (2H)—one
274 anti (6-fluoroquinolinyl)cyclopropyl) 408.1
(pyridinyl)isoquino lin- 1 (2H)—one
275 anti 4-fluoro(pyridinyl)—2-(2-(quinolin 408.1
yl)cyclopropyl)isoquino lin- 1 (2H)-one
E 276: anti (-)chloro—8—(pyrimidin—5-yl)(2-(quinolin
yl)cyclopropyl)isoquino lin- 1 (2H)—one
NAN
[
/
\ o
l
/
N N
\
CI
Anti (-)(pyrimidin-5 -yl)(2-(quinolinyl)cyclopropyl)isoquinolin-1(2H)-
one hydrochloride from example 24% was mixed with sodium hydrogencarbonate
solution and DCM. The phases were separated and the organic phase dried. Purification
by column chromatography ethanol) gave the title compound (7.89% yield) as
White solid. LC-MS: m/e = 425.1
Example 276a: anti (-)—4—chloro—8—(pyrimidin—5—yl)(2-(quinolin
yl)cyclopropyl)isoquino lin- 1 (2H)—one hydrochloride
219
[or] = +217.7o (methanol)
EXAMPLE 277: anti 4-(pyridin—4—yl)—6-(2—(quinolinyl)cyclopropyl)pyrido[2,3-
d]pyridazin—5(6H)-one
4-(pyridinyl)pyrido[2,3-d]pyridazin-5(6H)-one (19 mg, 0.085 mmol) was
suspended in 1 mL of DMF under argon. Then, cesium carbonate carbonate (55.2 mg,
0.169 mmol)) and syn 2—(2—bromocyclopropyl)quinoline (22,08 mg from
, 0,089 mmol)
e cl were added. The reaction mixture was heated at 110 °C for 3 h min. Water
10 and EA were added. The aqueous phase was extracted twice with EA. The organic
phases were combined, washed with HCl, dried (MgSO4) and evaporated. The residue
was purified by chromatography to give 12 mg (yield: 36.2%) ofthe title compound as
bright beige solid. LC-MS: m/e 392.1 (M+H)+
15 es 278 to 300 were prepared in y to the methods described above.
Ex. Name LC-MS: m/e (M+H)+/
Rt [min / [0L]
278 anti 2-(2-(6-fluoroquinolin—2—yl)cyclopropyl) 409.1
(pyridinyl)phthalazin- l (2H)—one
279 anti 7-fluoro-3 -(pyridin-4—yl)—5—(2-(quino lin 414. 1
yl)cyclopropyl)thieno[3,2-c]pyridin-4(5H)—one
280 anti 3-(2-fluoropyridinyl)—5-(2—(6-fluoroquinolin—2— 432.1
yl)cyclopropyl)thieno[3,2—c]pyridin—4(5H)—one
281 anti 5-(2-(6-fluoroquinolin—2-yl)cyclopropyl) 414
(pyridinyl)thieno [3 ,2-c]pyridin-4(5H)-one
282 anti imidinyl)(2-(quinolin 397. l
yl)cyclopropyl)thieno [3 ,2—c]pyridin—4(5H)—one
282a anti 3-(pyrimidin—5—yl)—5—(2—(quinolin—2— 397. l
yl)cyclopropyl)thieno[3,2—c]pyridin—4(5H)—one,
220
EX. Name LC-MS: m/e (M+H)+/
Rt [min/ [or]
hydrochloride, enantiorner 1
282b anti 3-(pyrirnidinyl)-5—(2-(quinolin—2— 397.1
yl)cyclopropyl)thieno[3,2-c]pyridin-4(5H)—one,
hydrochloride, omer 2
283 anti 3-(6-fluoropyridiny1)(2-(quinolin—2- 414.1
yl)cyclopropyl)thieno[3,2-c]pyridin-4(5H)-one
hydrochloride
284 anti 3-(2—n1ethylpyrimidin—5-yl)(2-(quinolin 41 1.1
yl)cyclopropyl)thieno[3,2—c]pyridin—4(5H)—one
285 anti idazin—4—yl)—5—(2—(quinolin—2— 397.1
lopropyl)thieno[3,2—c]pyridin—4(5H)—one
286 anti 3-(2-fluoropyridinyl)—5—[(2—(quinolin—2- 414.1
yl)cyclopropyl]thieno[3,2-c]pyridin—4(5H)—one
287 anti 3-(n10rpholinyl)-5[2-(quinolin—2— 404.1
yl)cyclopropyl]thieno[3,2-c]pyridin-4(5H)-one
288 anti 3-(pyridinyl)[2-(thieno[3,2-b]pyridin 401.5
yl)cyclopropyl]thieno[3,2-c]pyridin-4(5H)-one
289 anti 3-(pyridinyl)[2-(quinolin 396.1
yl)cyclopropyl]thieno[3,2—c]pyridin-4(5H)—one
290 anti 3-(pyrirnidinyl)-5—[2-(quinolin—2— 398.1
yl)cyclopropyl]thieno[2,3—d]pyridazin-4(5H)-one,
hydrochloride
291 anti 3-(pyridiny1)[2—(thieno[3,2-b]pyridin
yl)cyclopropyl]thieno[2,3—d]pyridazin-4(5H)-one
292 anti3-(pyridinyl)[2-(thieno[3,2-b]pyridin 402.0
yl)cyclopropyl]thieno[3,2-c]pyridin-4(5H)-one
293 anti 3—(pyridin—4—yl)—5—[2—(quinolin—2— 396.1
yl)cyclopropyl]thieno[3,2—c]pyridin—4(5H)—one
293a anti (+) 3-(pyridin-4—yl)—5—[2—(quinolin—2— 396.1
yl)cyclopropyl]thieno[3,2—c]pyridin—4(5H)—one
221
EX. Name LC-MS:n1/e(M+H)+/
Rt [min/ [0L]
293b anti (-) 3-(pyridinyl)[2-(quinolin 3961/ [0L] = -301.70
yl)cyclopropyl]thieno[3,2-c]pyridin-4(5H)—one (methanol)
294 anti 3-(pyridinyl)[2—(quinolin 397.1/ R = 1.084
yl)cyclopropyl]thieno[2,3—d]pyridazin-4(5H)-one
hydrochloride
m
lopropyl]thieno[2,3-d]pyridazin-4(5H)-one
296 anti 5 —(pyrimidin-5 -y1)—2-[2-(quino lin—2- 3 91.1
yl)cyclopropyl]isoquinolin-1 (2H)—one
297 anti idinyl)—2—[2—(quinolin—2— 390.1
yl)cyclopropyl]isoquinolin— 1 (2H)—one
298 anti 5-(pyridinyl)[2-(quinolin—2— 390.2
yl)cyclopropyl]isoquino lin- 1 (2H)—one
299 anti 5-(morpholinyl)[2-(quinolin—2— 398 .2
yl)cyclopropyl]isoquino lin- 1 ne
300 anti (-) 4-fluoro(pyrimidinyl)(2-(quinolin 396.1
yl)cyclopropyl)isoquino lin- 1 (2H)—one
11.20 Preparation of compounds ofthe formula I in which A is Al, Yl-Cyc1 and X3 is
N=C(R9)
EXAMPLE 301: 8-(pyridinyl)[2—(quinolinyl)ethyl]pyrido[3,4-d]pyridazin—
1 (2H)-one
301 . 1 Ethyl 3—chloro—5—formylisonicotinate
To a solution of l 5—chloropyridine—3,4—dicarboxylate (2.43 g, 9.43 mmol) in
10 100 mL of toluene was added diisobutylaluminiumhydride (2.68 g, 18.86 mL, 1 molar)
in hexane at -70°C. The reaction mixture was stirred for 2 h at this temperature. The
222
reaction mixture was poured into an 5% aqueous acetic acid solution followed by the
addition ofEA. The phases were separated and the organic phase was washed with aq.
NaHC03 on. The organic phase was dried and trated to give 2.02 g (100%)
ofthe title compound as brown oil.
301.2 (E)-ethyl 3-((2-acetylhydrazono)methyl)—5-chloroisonicotinate
To ethyl 3-chloroformylisonicotinate (2 g, 9.36 mmol) in 60 mL of ethanol was
added acetohydrazide (0.832 g, 11.24 mmol) at room temperature. The reaction mixture
was stirred for 2 h. Then, the reaction mixture was mixed with DCM and water. The
10 organic phase was washed with brine, dried and concentrated. The crude title compound
was purified by chromatography (eluent: thanol) to give 220 mg (8.7%) of the
title compound as orange oil.
3 01 .3 8-chloropyrido [4,3-d]pyridazin—1(2H)-one
15 (E)—ethyl 3-((2-acetylhydrazono)methyl)—5—chloroisonicotinate (220 mg, 0.816
mmol) and aq. NaOH solution (3.26 mg, 0.082 mol, 2 molar) in 5 mL of dioxane were
stirred in a ave at 165°C for 60 min. Then the reaction mixture was basified by
addition of aq. NaHC03 and extracted with DCM. The organic phase was washed with
brine, dried and concentrated. The crude title compound was d by
20 chromatography (eluent: thanol) to give 25 mg (16.88%) of the title compound
as beige solid.
3 01 .4 8-chloro(2-(quinolin-2—y1)ethyl)pyrido[4,3-d]pyridazin-1(2H)-one
To 69.3 mg (0.264 mmol) in THF was added diisopropylazodicarboxylate (94 mg,
25 0.463 mmol) in THF under ice-cooling and under nitrogen. Then, the resulting solution
was stirred for 30 min at room temperature to give a suspension. 8-Chloropyrido[4,3-
d]pyridazin-1(2H)-one (24 mg, 0.132 mmol) in THF and then 2-(quinoliny1)ethanol
(22.89 mg, 0.132 mmol) in THF were added and the reaction mixture was stirred
ght at room temperature. The total amount of THF was 60 mL. Then, the reaction
30 mixture was mixed with DCM and water. The organic phase was washed with 1N HCl
and the organic phase was discharged. The aqueous phase was basified by 1N NaOH
223
and extracted with DCM. The organic phase was dried and concentrated to give 34 mg
(76%) of the title compound as bright beige solid. LC-MS: m/e 337.1 (M+H)+.
3 01 .5 8-(pyridinyl) [2-(quino1iny1)ethyl]pyrido [3 ,4-d]pyridazin-1(2H)-one
ro(2-(quinolinyl)ethyl)pyrido[4,3-d]pyridazin—1(2H)-one (34 mg,
0.101 mmol) was suspended in 2 mL of toluene and 2 mL of methanol under argon.
Then, an aqueous solution of sodium carbonate (16.5 mg, 0.15 mol, 2 M) was added.
To the suspension, pyridinboronic acid (13.79 mg, 0.101 mmol) and then
tetrakis(triphenylphosphine)palladium(0) (11.67 mg, 10.10 umol) were added. The
10 on mixture was heated in a CEM microwave at 130 °C for 30 min. Water and EA
were added. The organic phase was ted with water, dried (MgSO4) and
evaporated. The residue was purified by chromatography (eluent: DCM/methanol) and
then recrystallized from sopropyl ether (1 :1) to give 2.6 mg (yield: 6.79%) of the
title compound as off-white solid. LC-MS: m/e 380.1 (M+H)+
15
11.21 Preparation of compounds ofthe formula I in which A is A1
The compounds of example 302 to 409 were ed in analogy to the methods
described above.
Ex. Name LC-MS: m/e (M+H)+
/ Rt[min]
302 5-[2-(imidazo[1,2-a]pyridinyl)ethy1]—7-(1-methyl- 454.0 / 1.69
1H-imidazolyl)(pyridin-4—yl)thieno[2,3-
d]pyridazin—4(5H)-one
303 5 - [2-(imidazo [1 ,2-a]pyridin—2—yl)ethyl]—7—( 1 -methyl-
1H—pyrazolyl)(pyridin—4—yl)thieno[2,3-
d]pyridazin—4(5H)-one
304 5-[2-(imidazo[1,2-a]pyridinyl)ethyl](pyridin 451.2 / 1.74
yl)—3—(pyridin—4—yl)thieno[2,3—d]pyridazin—4(5H)-one
305 5-[2-(6-chloroquinolin—2—yl)ethyl]—3—(pyridin—4- 418. 1
yl)thieno [3 ,2-c]pyridin—4(5H)—one
306 5-[2-(3-methquuinolin—2—yl)ethyl]—3—(pyridin—4- 398.1
224
EX. Name LC-MS: rn/e (M+H)+
/ Rt[rnin]
yl)thieno[3 ,2-c]pyridin—4(5H)—one
307 5-[2-(8-fluoroquinolin-2—yl)ethyl]—3-(pyridin 402. 1
yl)thieno[3 ,2-c]pyridin—4(5H)—one
308 5-[2-(6-fluoroquinolin—2—yl)ethyl]—3—(pyridin 402. 1
yl)thieno[3 ,2-c]pyridin—4(5H)—one hydrochloride
309 5-[2-(6-fluoroquinolinyl)ethyl](pyridin 402. 1
yl)thieno[3 ,2-c]pyridin-4(5H)-one
310 5-[2—(irnidazo[1,2—a]pyridin—2-yl)ethyl](pyridin 373 .3
yl)thieno[3 ,2—c]pyridin—4(5H)—one
3 1 1 3-(pyridin—4-yl)[2—(quinoxalin—Z—yl)ethyl]thieno[2,3- 3 86. 1
d]pyridazin—4(5H)-one hydrochloride
3 12 5-[2-(1,5-naphthyridinyl)ethyl]—3—(pyridin—4- 3 86. 1
yl)thieno[2,3-d]pyridazin-4(5H)-one
3 13 5 - [2-( 1 H-indazol— 1 -yl)ethyl](pyridin—4—yl)thieno [2,3 - 3 74. 1
d]pyridazin—4(5H)-one
3 14 3 -( 1 -methyl— 1 H-pyrazo1yl)[2-(quinolin—2- 3 8 8. 1
yl)ethyl]thieno[2,3-d]pyridazin—4(5H)—one
hydrochloride
315 pyrazol—3-yl)[2—(quinolin—2- 374.1
yl)ethyl]thieno[2,3-d]pyridazin-4(5H)—one
3 16 5 -[2-(1H-benzirnidazol—1-yl)ethyl]—3-(pyridin—4- 3 74. 1
yl)thieno[2,3-d]pyridazin—4(5H)—one
3 17 5-[2-(1H—benzimidazol—2—y1)ethyl](pyridin 374. 1
yl)thieno[2,3-d]pyridazin—4(5H)—one hydrochloride
3 18 6-chloroquino lin—2-yl)ethyl](pyridin 419. 1
yl)thieno[2,3-d]pyridazin-4(5H)-one hydrochloride
3 19 3 -(pyridin—3 yr1yl)—5—[2—(quinolin—2— 409. 1
yl]thieno[2,3—d]pyridazin—4(5H)—one
hydrochloride
320 3-(pyridin—4-ylethynyl)-5—[2—(quinolin—2— 409.1
225
EX. Name LC-MS: m/e (M+H)+
/ Rt[rnin]
yl)ethyl]thieno [2,3 -d]pyridazin—4(5H)—one
hydrochloride
321 5 - [2-(3 ,5 -dirnethy1pyridin-2—y1)ethy1]-3—(pyridin—4— 3 63. 1
y1)thieno[2,3-d]pyridazin—4(5H)—one
322 5 - [2-(7-fluoroquino 1in-2—yl)ethyl]—3—(pyridin 403. 1
y1)thieno[2,3-d]pyridazin-4(5H)-one
323 5 - [2-(pyrazinyl)ethyl](pyridinyl)thieno[2 ,3 - 3 3 6. 1
dazin—4(5H)—one
324 2-[2-(1,6-naphthyridin—2—yl)ethyl]—8—(pyridin—4- 3 79. 1
yl)isoquino lin- 1 (2H)—one
325 2-[2-(8-fluoroquino lin-2—yl)ethy1]—8—(pyridin—4- 3 96. 1
yl)isoquino lin- 1 ne
326 8-(pyridin—4-yl)[ 1 -(quino1in—2—y1)propan—2- 3 92. 1
yl]isoquinolin—1(2H)-one
327 2-[2-(3-rnethy1quino1in—2-yl)ethyl](pyridin—4- 3 92.2
yl)isoquino lin- 1 (2H)-one
2- [2-(irnidazo [1 ,2-a]pyridin—2—yl)ethy1](1H-pyrazol— 3 5 7. 1
328
3 -y1)phthalazin-1(2H)-one
8-(rnorpholin—4-y1) [2-(quinolinyl)ethy1]phthalazin- 3 87. 1
329
1(2H)-one hydrochloride
2-[2-(irnidazo[1,2-a]pyridin—2-yl)ethyl]—8—(1-oxa-4,9- 459.2
3 3 0 diazaspiro [5 .6] dodecyl)phthalazin- 1 (2H)-one
dihydrochloride
2-[2-(imidazo[1,2-a]pyridin—2—yl)ethyl]—8—(2-oxa
33 1 azaspiro[3.5]non—7-yl)phthalazin—1(2H)-one (2E)—but
ate
8- [(3 R)—3—hydroxypiperidin— 1 —yl]—2—[2—(imidazo [1 ,2- 3 90.2
332 a]pyridin—2-y1)ethy1]phthalazin—1(2H)—one ut
enedioate (salt)
3 3 3 8- [(3 S)-3 -hydroxypiperidin—1—y1]—2—[2—(imidazo[1 ,2- 3 90.2
226
EX. Name LC-MS: m/e (M+H)+
/ Rt[rnin]
a]pyridiny1)ethy1]phthalazin- 1 (2H)—one (2E)-but
enedioate (salt)
2- [2-(irnidazo [1 ,2-a]pyridin—2—yl)ethyl]—8-(2-oxa—6— 3 8 8.1
334
azaspiro [3 .3]hepty1)phthalazin— 1 ne
2-[2-(imidazo[1,2-a]pyridin—2-yl)ethyl](1,2- 362.1
3 3 5
oxazolidinyl)phthalazin-1(2H)-one
8-(hexahydrocyclopenta[b][1 ,4]oxazin-4(4aH)-y1)[2- 416.2
3 3 6
(imidazo [1 ,2—a]pyridin—2-yl)ethyl]phthalazin— 1 (2H)-one
2- [2-(imidazo [1 ,2—a]pyridin—2—yl)ethyl]—8— 3 61.2
3 3 7
(tetrahydrofilran-3 —y1)phthalazin— 1 (2H)—one
2- [2-(imidazo [1 ,2-a]pyridin—2—y1)ethy1]—8—(3—oxa 402.2
3 3 8
azabicyclo [3 .2. 1]octy1)phthalazin—1(2H)—one
2- [2-(irnidazo [1 ,2-a]pyridinyl)ethyl]—8—(2—oxa 402.2
3 3 9
azaspiro [3 .4]octy1)phthalazin- 1 (2H)—one
2- [2-(irnidazo [1 ,2-a]pyridinyl)ethy1]—8—(2,2,6,6- 448.1
340
tetrafluorornorpho1iny1)phthalazin— 1 (2H)-one
8-(4-hydroxypiperidiny1)—2—[2-(imidazo[1 ,2- 3 90. 1
341
a]pyridiny1)ethy1]phthalazin— 1 (2H)-one
2- [2-(irnidazo [1 ,2-a]pyridin—2—yl)ethy1](2- 3 83 .2
342
methylpyrimidin-S-y1)phthalazin- 1 (2H)—one
8-(2-cyclopropy1pyrimidin—5-y1)—2—[2-(imidazo [1 ,2- 409. 1
343
a]pyridiny1)ethy1]phthalazin- 1 (2H)—one
2- [2-(imidazo [1 yridin—2—yl)ethyl]—8—(pyridazin 3 69. 1
344
halazin- 1 (2H)-one
8-(5 -fluoropyridin-3 -yl)[2-(imidazo[1,2-a]pyridin 3 86.2
345
yl)ethy1]phtha1azin- one hydrochloride
8-[2-(3—fluorophenyl)morpholin—4—yl]—2—[2— 470.2
346 (imidazo [1 ,2—a]pyridin—2—y1)ethyl]phthalazin— 1 (2H)-one
hloride
347 2- [2-(irnidazo [1 ,2-a]pyridin—2—yl)ethy1]—8—(2— 3 99.1
227
EX. Name LC-MS: rn/e (M+H)+
/ Rt[rnin]
methoxypyrirnidin-S-yl)phthalazin- l (2H)—one
2- [2-(irnidazo [1 ,2-a]pyridin—2-yl)ethy1][2- 436.1
348
orornethyl)pyridinyl]phthalazin- 1 (2H)-one
2- [2-(imidazo [1 ,2-a]pyridin—2-yl)ethyl](8-oxa-3 - 402.2
349
azabicyclo [3 .2. 1]octyl)phthalazin-1(2H)—one
irnidazo[l ,2-a]pyridinyl)ethyl][2- 444.2
3 5 0 (trifluoromethyl)morpholinyl]phthalazin- l (2H)-one
hydrochloride
8-(2,2-dimethylmorpholin—4—yl)—2—[2—(imidazo [1 ,2- 404.2
3 5 1 a]pyridinyl)ethyl]phthalazin— l (2H)—one
hydrochloride
8- [2-(4-chlorophenyl)morpholin—4—yl]—2—[2— 486.2
352 (imidazo [1 ,2-a]pyridin—2-yl)ethyl]phthalazin— 1 (2H)-one
hydrochloride
8- [2-(3 ,4-difluorophenyl)rnorpholin—4-yl]—2-[2- 488 .2
3 5 3
(imidazo [1 ,2-a]pyridin—2-yl)ethyl]phthalazin— 1 (2H)-one
2- nidazo [1 ,2-a]pyridin—2—yl)ethyl](piperidin—4- 3 74.2
354
yl)phthalazin— l (2H)-one hydrochloride
2- [2-(irnidazo [1 ,2-a]pyridin—2—yl)ethyl](tetrahydro- 375 .2
3 5 5
2H-pyran—4-yl)phthalazin—1(2H)—one
8-(2,6-diazabicyclo [3 .2. 1]octy1)—2-[2—(imidazo [1 ,2- 401.2
3 5 6 a]pyridinyl)ethyl]phthalazin—1(2H)—one
dihydrochloride
8-[(l 8,5 S)—3 zabicyclo[3 .2.0]hept-3—yl]—2—[2- 3 87.2
3 5 7 (imidazo [l ,2-a]pyridinyl)ethyl]phthalazin- l (2H)-one
hydrochloride
8-(furan—2—yl)—2— [2—(imidazo[l ,2—a]pyridin—2— 3 5 7.1
3 5 8
yl]phthalazin— l (2H)—one hydrochloride
2- [2-(imidazo [l ,2-a]pyridin—2—yl)ethyl]—8—( 1 —methyl- 3 71 .2
3 5 9
1H-pyrazolyl)phthalazin— 1 (2H)—one hydrochloride
228
EX. Narne LC-MS: rn/e (M+H)+
/ Rt[rnin]
8-(hexahydropyrrolo[3 ,4—c]pyrrol—2(1H)—yl)[2- 401.2
360 azo [1 ,2-a]pyridin—2-yl)ethy1]phthalazin— 1 (2H)-one
dihydrochloride
8-(2,7-diazaspiro[4.4]nony1)—2—[2-(imidazo[1 ,2- 415.2
361 a]pyridinyl)ethyl]phthalazin—1(2H)—one
dihydrochloride
8-[(lS,4S)-2,5-diazabicyclo[2.2.1]heptyl][2- 387.2
362 (imidazo [l ,2—a]pyridin—2-yl)ethyl]phthalazin— 1 ne
roacetate
8-(2,7-diazaspiro [3 .5 ]nor1—7—yl)—2—[2—(imidazo[1 ,2- 415.2
363 a]pyridinyl)ethyl]phthalazin— 1 (2H)—one
hydrochloride
8-(2,6-diazaspiro [3 .5 ]nonyl)—2—[2—(imidazo [1 ,2- 415.2
364 a]pyridinyl)ethyl]phthalazin- 1 (2H)—one
hydrochloride
8-(piperidin—4-yl)[2-(5 ,6,7,8-tetrahydroirnidazo[1 ,2- 378.2
365 a]pyridinyl)ethyl]phthalazin— 1 (2H)-one
hydrochloride
8-[2-(aminomethyl)chloropyrrolidin—1-yl][2- 423.2
366 (irnidazo [1 ,2-a]pyridin—2—yl)ethy1]phthalazin— 1 (2H)-one
trifluoroacetate
2- [2-(irnidazo [1 yridin—2-yl)ethyl]-4,8—di(pyridin— 445.2
367
4-yl)phthalazin— 1 (2H)-one
2-[2-(imidazo[1 ,2-a]pyridin—2—yl)ethyl]—8— 427.2
368 [(3 aR,4S,7R,7aS)-octahydro-1H-4,7-epiminoisoindol—8-
yl]phthalazin-1(2H)-one dihydrochloride
8- [5 —(4—chlorophenyl)—2,5—diazabicyclo[2 .2. 1]hept 497.2
369 yl] [2-(imidazo [1 yridin—2—yl)ethyl]phthalazin-
1 (2H)-one
370 4-brorno[2-(imidazo[1 ,2—a]pyridin—2—yl)ethyl] 448
229
EX. Name LC-MS: rn/e (M+H)+
/ Rt[rnin]
(pyridiny1)phtha1azin— 1 (2H)-one
2- [2-(irnidazo [1 ,2-a]pyridin—2-yl)ethyl][(3aS, 8aS)- 429.2
371 octahydropyrrolo[3,4-c]azepin—2(1H)-yl]phtha1azin—
1(2H)-one dihydrochloride
2-[2-(imidazo[1,2-a]pyridin—2-yl)ethyl][(3aS,8aR)— 429.2
372 octahydropyrrolo[3 ,4-c]azepin—2( 1 H)-yl]phtha1azin-
1(2H)-one dihydrochloride
tert—butyl (3 7R,7aS) {3-[2-(imidazo[1 ,2- 527.3
373 a]pyridin-2—y1)ethy1]—4—oxo—3 ,4—dihydrophthalazin—5 -
y1} octahydro-2H-4,7—epiminoisoindole—2—carboxylate
8-(hexahydro-5H-furo[2,3—c]pyrrol—5—yl)—2—[2— 402.2
374 (imidazo [1 ,2-a]pyridin—2-yl)ethy1]phthalazin— 1 (2H)-one
hydrochloride
irnidazo[1 ,2-a]pyridinyl)ethyl]—8—(1,2,3 ,6- 372.2
375 tetrahydropyridiny1)phthalazin- 1 (2H)—one
hydrochloride
2- [2-(irnidazo [1 ,2-a]pyridin—2—yl)ethy1][(3 S)-
376
tetrahydrofiJran-3 -y1arnino]phthalazin— 1 (2H)-one
2- [2-(irnidazo [1 ,2-a]pyridin—2—yl)ethy1][(3 R)-
377
tetrahydrofilran-3 ino]phthalazin- 1 (2H)-one
8- {[5 -(hydroxyrnethy1)—1,4—dioxan—2-y1]methoxy}[2- 437.1
378
(irnidazo [1 ,2-a]pyridin—2-yl)ethyl]phthalazin-1(2H)—one
2- [2-(imidazo [1 ,2-a]pyridin—2-yl)ethyl](oxetan—3 - 363.1
379
yloxy)phthalazin- 1 (2H)—one
imidazo[1 yridinyl)ethyl](pyridin 398.1
380
ylmethoxy)phthalazin— 1 (2H)-one
2-[2-(imidazo[1 ,2—a]pyridin—2—yl)ethyl]—8—(morpholin-4 390.2
381
ylmethy1)phtha1azin— 1 (2H)—one
2- [2-(imidazo [1 ,2-a]pyridin—2—yl)ethyl]—8—(pyridir1—3 - 384.1
382
yloxy)phtha1azin— 1 (2H)-one
230
EX. Narne LC-MS: rn/e (M+H)+
/ Rt[rnin]
2- [2-(irnidazo [1 ,2-a]pyridin—2—yl)ethy1][(oxetan—3 - 3 76.2
3 83
ylrnethyl)amino]phthalazin— 1 (2H)—one
2- [2-(irnidazo [1 ,2-a]pyridin—2—yl)ethyl](tetrahydro- 3 90.2
3 84
2H—pyran—4-ylamino)phthalazin—1(2H)—one
2-[2-(imidazo[l ,2-a]pyridin—2—yl)ethyl]—8—[( 1 - 375 .2
3 85
methylazetidinyl)amino]phthalazin-1(2H)-one
2-[2-(imidazo[1,2-a]pyridinyl)ethyl](1,3-oxazol 3 72.3
3 86
no)phthalazin— 1 (2H)—one
2-[2-(imidazo[1,2—a]pyridin—2—yl)ethyl]—8— 376.2
3 87
[methyl(oxetan—3-yl)amino]phthalazin— 1 (2H)—one
2- [2-(imidazo [1 ,2-a]pyridin—2—yl)ethyl]—8—(piperidin—4- 3 89.2
3 8 8
no)phthalazin— 1 (2H)-one dihydrochloride
8-[(1-acetylpiperidin—3 -yl)amino]—2—[2—(imidazo[ 1 ,2- 43 1 .2
3 89 a]pyridinyl)ethyl]phthalazin- 1 (2H)—one
hydrochloride
acetylpiperidin—4-yl)arnino][2-(irnidazo[l ,2- 43 1 .2
390
a]pyridinyl)ethyl]phthalazin— 1 (2H)-one
2- [2-(irnidazo [1 ,2-a]pyridin—2—yl)ethyl] 3 76.2
3 91
hydrofuran—3 -ylarnino)phthalazin— 1 (2H)-one
2- [2-(irnidazo [1 ,2-a]pyridin—2—yl)ethy1](tetrahydro- 3 90.2
392 2H-pyran—3-ylarnino)phthalazin— 1 (2H)—one
hydrochloride
2- idazo [l ,2-a]pyridin—2-yl)ethyl](piperidin—3 - 3 89.2
393
ylamino)phthalazin— 1 (2H)—one dihydrochloride
394 2- [2-(imidazo [1 ,2-a]pyridinyl)ethyl] {methyl [(3 - 404.2
methyloxetanyl)methyl]amino}phthalazin-1(2H)-one
395 2- [2-(imidazo [1 ,2—a]pyridin—2—yl)ethyl]—8—(oxetan-3 - 3 62.2
ylamino)phthalazin— 1 (2H)—one
396 8- {[(3 aS,4S,6aS)-octahydrocyclopenta[c]pyrrol 433 .3
ylrnethyl]amino}[2-(5,6,7,8—tetrahydroimidazo[1,2-
231
EX. Name LC-MS: m/e (M+H)+
/ Rt[rnin]
diny1)ethy1]phthalazin- 1 (2H)—one
hydrochloride
397 5 -(rnorpholin—4-y1) [2-(quinolinyl)ethy1]phthalazin- 3 87.2
1(2H)-one hydrochloride
398 2-[2-(1H—benzimidazo1—2—yl)ethyl](pyridin 3 68. 1
y1)phthalazin-1(2H)-one
399 4-(pyridin-3 -y1) [2-(quino [inyl)ethyl]phtha1azin- 3 79. 1
1 (2H)-one
400 5 -(1,4-dihydropyrimidin—5—y1)—2—[2—(5 ,6,7,8— 375 .2
tetrahydroimidazo [1 ,2—a]pyridin—2—yl)ethyl]phthalazin-
1(2H)-one dihydrochloride
401 2- [2-(irnidazo [1 ,2-a]pyridin-2—y1)ethy1]—5—(pyridin—4- 368 . 1
y1)phtha1azin— 1 (2H)-one
402 5 -(pyridin—3 -y1) [2-(quinoliny1)ethy1]phthalazin- 3 79.2
1 (2H)-one
403 2-[2-(irnidazo[1,2-a]pyridin—2-yl)ethy1]{[(3 - 3 90.2
methyloxetan—3-y1)rnethy1]amino}phthalazin— 1 (2H)-one
404 4-(pyridin—4-y1) [2-(quino1in—2—y1)ethyl]pyrido [2,3 - 3 80. 1
d]pyridazin—S(6H)-one
405 4-(rnorpho 1in—4-y1) [2—(quinolin 3 8 8 .2
y1)ethy1]pyrido[2,3-d]pyridazin—5(6H)—one
406 4-(oxetan—3-y1arnino)-6—[2-(quino1in 3 74.1
y1)ethy1]pyrido[2,3-d]pyridazin-5(6H)—one
407 2- methoxypyridin—2-yl)ethyl](pyridin 3 5 8. 1
quino lin- 1 (2H)-one
408 2-[2-(1,3 thiazo lyl)ethyl](pyridin 3 84.1
quino 1111— 1 (2H)—one
409 2- [2-(5-methy1pyridin—2—y1)ethyl]—8—(pyridin—4— 342. 1
y1)isoquino lin- 1 (2H)—one
232
11.22 Preparation of compounds ofthe formula I in which A is A3
The compounds of e 410 to 415 were prepared in analogy to the s
described above.
EX. Name LC-MS: m/e (M+H)+
410 5 - [(E)(6-methoxyquino linyl)ethenyl] 412.8
(pyridinyl)thieno[3 ,2-c]pyridin-4(5H)-one
41 1 8-(pyridinyl) [(E)(quinazo lin 3 77. 1
yl)ethenyl]isoquino lin- 1 (2H)—one
412 5 - [(E)-2—(6—chloroquino1in—2—yl)ethenyl]—3—(pyridin- 416. l
4-yl)thieno [3 ,2—c]pyridin—4(5H)—one
413 5 - [(E)(3 -methquuino1in—2—y1)ethenyl]—3— 3 96. l
(pyridinyl)thieno [3 ,2-c]pyridin—4(5H)—one
414 8-(pyridin—4-yl) [(E)(quino1in—2— 3 76. l
yl)ethenyl]isoquino lin- 1 (2H)-one
415 5 - [(E)(l ,3-benzothiazoly1)etheny1](pyridin— 3 8 8
4-yl)thieno [3 ,2-c]pyridin-4(5H)—one
416 3 -(pyridinyl)-5 - [(E)-2—(quino1in 3 82. l
yl)ethenyl]thieno[3,2-c]pyridin—4(5H)—one
ical Tests
a) Measurement ofPDE activity
The inant PDE proteins are used in in vitro enzymatic reaction for
ement of PDE activity. These recombinant proteins, ing PDElOA (human,
rat and mouse PDElO) and isoforms of PDEs 1, 3, 4, and 5, were purchased from
commercial vendor BPS Bioscience. The enzymatic activity ofPDEs was determined
by cAMP measurement kit from CisBio (IBA) using HTRF technology.
The PDE enzymatic reaction was carried out in assay buffer (20mM Tris-HCl
pH7.5, lOmM MgClz, 0.1% bovine serum albumin) containing enzyme and substrate.
The PDE enzymes concentration ranged from 10pM — 250pM, depending on each
233
enzyme’s specific activity. The substrate cyclic nucleotide (cAMP or cGMP)
concentration used in the assay was 20nM for PDElO, and 100nM for other PDEs. The
inhibitory effect of compound was determined by incubating various concentration of
inhibitor in the enzymatic assay. Typically, compound was serial d in DMSO then
further diluted in assay buffer. Next, the compound at varying tration was mixed
with PDE enzyme. The reaction was ted by addition of cyclic nucleotide substrate,
and incubated for 60 minutes at 29C. The reaction was stopped by addition of lysis
buffer from assay kit. The cAMP-d2 and anti-CAMP cryptate in the lysis buffer detected
the level of CAMP left from the PDE hydrolysis reaction. The PDE activity is reversely
10 correlated with the amount ofCAMP left in the reaction and can be converted to the
percent activity of an uninhibited control (100%). Thus, IC50 value of inhibitor can be
obtained by plotting inhibitor tration t PDE activity at that concentration.
Claims (80)
1. Compound of formula I Q R1 Het A (I) N R2 X1 X2 X3 n Q is O or S; X1 is N or CH; X2 is N or C-R7; X3 is O, S, -X4=C(R8)-, where C(R8) is bound to the carbon atom which carries R2, or -X5=C(R9)-, where X5 is bound to the carbon atom which carries R2; X4 is N or C-R9; X5 is N; Het is selected from i. monocyclic C-bound 6-membered hetaryl having 1 or 2 nitrogen atoms as ring members, which is tituted or may carry 1, 2, 3 or 4 identical or different substituents Rx, ii. fused bicyclic hetaryl having 1 or 2 nitrogen atoms and optionally a further heteroatom selected from O, S and N as ring members, benzothienyl or benzofuryl, where bicyclic hetaryl, benzothienyl and benzofuryl are, independently of each other, unsubstituted or may carry 1, 2, 3 or 4 identical or different substituents Rx, and iii. phenyl, which carries a monocyclic l radical having 1 or 2 nitrogen atoms and ally a further heteroatom selected from O, S and N as ring s, which in addition to monocyclic hetaryl, may carry 1, 2 or 3 identical or different substituents Rx, where (11348828_1):GGG 237 Rx is selected from the group ting of H, halogen, C1-C4-alkyl, C1-C4-alkoxy, C1-C4-fluoroalkyl, C1-C4-fluoroalkoxy, C3-C6- cycloalkyl, C1-C4-alkoxy-C1-C4-alkoxy, C1-C4-alkoxy-C1-C4-alkyl, OH, y-C1-C4-alkyl, O-C3-C6-cycloalkyl, benzyloxy, C(O)O- (C1-C4-alkyl), O-(C1-C4-alkyl)-CO2H, N(Rx1)(Rx2), C(O)N(Rx1)(Rx2), C1-C4-alkyl-N(Rx1)(Rx2), -NRx3-C(O)-N(Rx1)(Rx2), NRx3-C(O)O-(C1-C4-alkyl), -N(Rx3)-SO2-Rx4, phenyl, CN, -SF5, -OSF5, -SO2Rx4, -SRx4 and trimethylsilyl, where Rx1, Rx2, Rx3 and Rx4, independently of each other are ed from the group consisting of hydrogen, C1-C4- alkyl, C1-C4-fluoroalkyl and C3-C6-cycloalkyl or Rx1 and Rx2 form together with the N atom to which they are attached a 3- to 7- membered, nitrogen heterocycle which may have 1, 2 or 3 further ent or identical heteroatoms or heteroatom ning groups selected from the group of O, N, S, SO and SO2 as ring members and which may carry 1, 2, 3, 4, 5 or 6 substituents selected from C1-C4-alkyl; or two radicals Rx which are bound at adjacent carbon atoms may form a fused 5- or 6-membered saturated carbocyclic radical or a fused 5- or 6-membered heterocyclic radical having 1, 2 or 3 heteroatoms as ring s, which are selected from O, S and N; R1 is a moiety Y1-Cyc1; R2 is selected from the group consisting of hydrogen, halogen, OH, C1-C4- alkyl, trimethylsilyl, C1-C4-alkoxy-C1-C4-alkyl, C1-C4-alkoxy, C1-C4- alkoxy-C1-C4-alkoxy, C2-C4-alkenyloxy, C1-C4-fluoroalkyl, C1-C4- fluoroalkoxy, cyclopropyl, optionally tuted by 1, 2 or 3 methyl groups, fluorinated cyclopropyl, CN and NRx1Rx2; A represents one of the following groups A1, A2, A3, A4 or A5: (11348828_1):GGG 238 R3e R3f R6 R5 R4 A' * * * * * * * * * * R4 R3 R5 R5 R4 R4 R5 (A1 ) (A2 ) (A3 ) (A4 ) (A5 ) where * indicates the points of attachment to Het and to the nitrogen atom, respectively, R3, R4, R5, R6 independently of each other are selected from the group consisting of hydrogen, halogen, C1-C4-alkyl, hylsilyl, C1-C4-fluoroalkyl, C1-C4- fluoroalkoxy, C3-C6-cycloalkyl, or the radicals together with the carbon atoms to which they are bound form a saturated 3- to 6-membered carbocycle or a saturated 3- to 6-membered heterocycle having 1 or 2 non-adjacent heteroatoms as ring members, where the carbocycle and the heterocycle are unsubstituted or may carry 1, 2, 3 or 4 substituents selected from ne and methyl or either the radicals R3, R4 or the radicals R5, R6 together with the carbon atom to which they are bound form a saturated 3- to 6-membered carbocycle or a saturated 3- to 6- membered heterocycle having 1 or 2 non-adjacent heteroatoms as ring members, where the carbocycle and the heterocycle are unsubstituted or may carry 1, 2, 3 or 4 substituents selected from fluorine and ; A' is a O, NR3a, CR3bR3c or linear C2-C3-alkandiyl, where one of the CH2- moieties of C2-C3-alkandiyl may be replaced by oxygen or NR3a, and where 1, 2, 3, or 4 of the hydrogen atoms of C2-C3-alkandiyl may be ed by a radical R3d, where R3a is hydrogen or C1-C4-alkyl, R3b, R3c independently of each other are selected from the group consisting of hydrogen, halogen, alkyl or R3b and R3c together form alkandiyl; R3d is selected from the group consisting of halogen and C1-C4- alkyl; (11348828_1):GGG 239 R3e, R3f independently of each other are selected from the group consisting of hydrogen and C1-C4-alkyl; R7 is selected from the group consisting of hydrogen, halogen, OH, C1-C4- alkyl, trimethylsilyl, C1-C4-alkylsulfanyl, C1-C4-alkoxy-C1-C4-alkyl, C1- C4-alkoxy, C1-C4-alkoxy-C1-C4-alkoxy, C1-C4-alkylsulfanyl-C1-C4- alkoxy, C2-C4-alkenyloxy, fluoroalkyl, C1-C4-fluoroalkoxy, cyclopropyl, optionally tuted by 1, 2 or 3 methyl groups, fluorinated cyclopropyl, CN, NRx1Rx2, NRx1Rx2-C1-C4-alkoxy and the moiety Y2-Cyc2; R8 is ed from the group consisting of hydrogen, halogen, OH, C1-C4- alkyl, trimethylsilyl, C1-C4-alkoxy-C1-C4-alkyl, C1-C4-alkoxy, C1-C4- alkoxy-C1-C4-alkoxy, C2-C4-alkenyloxy, C1-C4-fluoroalkyl, C1-C4- fluoroalkoxy, cyclopropyl, optionally substituted by 1, 2 or 3 methyl groups, nated ropyl, CN and NRx1Rx2; R9 is selected from the group consisting of hydrogen, halogen, OH, C1-C4- alkyl, trimethylsilyl, C1-C4-alkylsulfanyl, C1-C4-alkoxy-C1-C4-alkyl, C1- C4-alkoxy, C1-C4-alkoxy-C1-C4-alkoxy, C1-C4-alkylsulfanyl-C1-C4- alkoxy, C2-C4-alkenyloxy, C1-C4-fluoroalkyl, C1-C4-fluoroalkoxy, cyclopropyl, optionally substituted by 1, 2 or 3 methyl groups, fluorinated cyclopropyl, CN, NRx1Rx2, NRx1Rx2-C1-C4-alkoxy and the moiety Y3-Cyc3; Y1, Y2, Y3 independently of each other are selected from a chemical bond, CH2, O, O-CH2, NRy, NRy-CH2, O)2, S, S(O), S(O)2, 1,2-ethandiyl, 1,2- ethendiyl or 1,2-ethyndiyl, where Ry is selected from the group consisting of hydrogen, C1-C4-alkyl, C1-C4-alkylcarbonyl, alkylsulfonyl, C1- C4-fluoroalkylsulfonyl; Cyc1, Cyc2, Cyc3 independently of each other are selected from the group consisting of phenyl, yl, 4- to 8-membered saturated or partially unsaturated heteromonocyclic ls, saturated or partially unsaturated 7- to 10 (11348828_1):GGG 240 membered bicyclic radicals, 5- or 6-membered monocyclic hetaryl, and 8- to 10 membered bicyclic hetaryl, where the saturated or partially unsaturated heteromonocyclic and heterobicyclic radicals have 1, 2, 3 or 4 heteroatoms or heteroatom containing groups as ring members, which are selected from O, S, SO, SO2 and N, and where the 5- or 6-membered monocyclic hetaryl and the 8- to 10-membered bicyclic hetaryl have 1, 2, 3 or 4 heteroatoms as ring members, which are selected from O, S and N, where phenyl, naphthyl, the saturated or partially unsaturated heteromonocyclic and heterobicyclic radicals and the mono- and bicyclic heteroaromatic radicals are unsubstituted or carry 1, 2, 3, 4 or 5 radicals RC1 or one radical Y'-RC2 and 0, 1, 2, 3 or 4 radicals RC1; where RC1 is selected from hydrogen, halogen, OH, CN, NO2, C1-C4-alkyl, C1- C4-alkoxy, alkylsulfanyl, hydroxy-C1-C4-alkyl, C1-C4- -C1-C4-alkyl, C1-C4-alkoxy-C1-C4-alkoxy, cyano-C1-C4- alkyl, C1-C4-fluoroalkyl, C1-C4-fluoroalkoxy, C1-C4-alkylsulfonyl, C(O)Ra, Z-C(O)ORb, Z-C(O)NRcRd, S(O)2NRcRd and f, where Ra is selected from the group consisting of C1-C4-alkyl and C1- C4-fluoroalkyl, Rb is selected from the group consisting of hydrogen, C1-C4- alkyl, C2-C4-alkenyl and fluoroalkyl, Rc, Rd is selected from the group consisting of hydrogen, C1-C4- alkyl, C1-C4-fluoroalkyl, C1-C4-alkoxy and C1-C4- fluoroalkoxy, Re, Rf is selected from the group consisting of en, C1-C4- alkyl, fluoroalkyl, C1-C4-alkoxy and C1-C4- fluoroalkoxy, Z is a covalent bond or alkandiyl, or two radicals RC1 which are bound at adjacent carbon atoms may form a fused 5- or 6-membered carbocyclic radical or a fused 5- or 6-membered heterocyclic radical having 1, 2 or 3 atoms as ring members, which are selected from O, S and N; (11348828_1):GGG 241 or two radicals RC1 which are bound at the same carbon atom may form a spiro 5- or 6-membered carbocyclic radical or a spiro 5- or 6-membered heterocyclic radical having 1 or 2 heteroatoms as ring members, which are selected from O, S and N, or two radicals RC1 which are bound at the same carbon atom may form an oxygen atom, where the fused and the spiro radicals are unsubstituted or carry 1, 2, 3 or 4 radicals RC3; Y' is a chemical bond, CH2, O, O-CH2, S(O)2, NRy', NRy'-CH2 or NRy'-S(O)2, where Ry' is selected from the group consisting of hydrogen, C1-C4-alkyl, C1-C4-alkylcarbonyl, C1-C4-alkylsulfonyl, C1-C4-fluoroalkylsulfonyl; RC2 is a carbocyclic or cyclic l selected from the group ting of phenyl, 3- to 7-membered saturated or partially unsaturated monocarbocyclic radicals, 3- to 7-membered saturated or partially unsaturated heteromonocyclic radicals, having 1, 2 or 3 heteroatoms as ring members, which are selected from O, S and N, and 5- or 6-membered aromatic radicals, having 1, 2 or 3 heteroatoms as ring s, which are selected from O, S and N, where the carbocyclic and the heterocyclic radical is unsubstituted or carries 1, 2, 3, 4 or 5 radicals RC3; RC3 is selected from hydrogen, halogen, OH, CN, C1-C4-alkyl, C1-C4- alkoxy, hydroxy-C1-C4-alkyl, C1-C4-alkoxy-C1-C4-alkyl, cyano-C1- C4-alkyl, C1-C4-fluoroalkyl, C1-C4-fluoroalkoxy, C2-C6-alkenyl, , benzyl, Z-C(O)ORb, Z-C(O)NRcRd, S(O)2NRcRd and ZNReRf , where, Z, Ra, Rb, Rc, Rd, Re and Rf are as d above or two ls RC3 which are bound at the same atom may form an oxygen atom; provided that for X3 being X4=C(R8), one or two of the radicals R1, R7 and R9 are a moiety Y1-Cyc1, Y2-Cyc2 or Y3-Cyc3, respectively; (11348828_1):GGG 242 further provided that for X3 being X5=C(R9), one or two of the radicals R1, R7 and R9 are a moiety 1, Y2-Cyc2 or Y3-Cyc3, respectively; and the N-oxides, the prodrugs, the tautomers and the hydrates f, and the pharmaceutically acceptable salts thereof; wherein prodrugs are derivatives of the compounds of formula I carrying an OH or NH2-group, where one of the hydrogen atoms of the OH or NH2-group is substituted by a C1-C4-alkylcarbonyl group, by benzoyl, or by an acyl group derived from an amino acid, which is linked to the oxygen or nitrogen of the OH or NH2-group via the carbonyl group of the amino acid; or wherein prodrugs are alkylcarbonyloxyalkyl ates or carbamates of compounds I carrying an OH- or oup in which one of the hydrogen atoms of the OH- or NH2-group has been replaced by a group of the formula -C(=O)-O-CHRp-O-C(=O)-Rq in which Rp and Rq are independently of one another C1-C4-alkyl; except for the following compounds: 6-Methylphenyl[2-(2-pyridinyl)ethyl]-thieno[2,3-d]pyrimidin(3H)-one, yl[2-(4-pyridinyl)ethyl]-thieno[2,3-d]pyrimidin(3H)-one, 5-(4-Methylphenyl)[2-(2-pyridinyl)ethyl]-thieno[2,3-d]pyrimidin(3H)-one, 5-(2-Furanyl)[1-methyl(3-pyridinyl)ethyl]-thieno[2,3-d]pyrimidin(3H)-one, 5-(2-Thienyl)[1-methyl(3-pyridinyl)ethyl]-thieno[2,3-d]pyrimidin(3H)-one, 5-(3,4-Dimethylphenyl)[2-(2-pyridinyl)ethyl]-thieno[2,3-d]pyrimidin(3H)-one, 5-(4-Methylphenyl)[2-(4-pyridinyl)ethyl]-thieno[2,3-d]pyrimidin(3H)-one, 5-Phenyl[2-(2-pyridinyl)ethyl]-thieno[2,3-d]pyrimidin(3H)-one, and 5-Phenyl[2-(4-oxophenylthieno[2,3-d]pyrimidin-(3H)yl)ethyl]-thieno[2,3- d]pyrimidin(3H)-one.
2. The compound as claimed in claim 1, wherein X3 is O, S or R8)-, where C(R8) is bound to the carbon atom which carries R2; X4 is N or C-R9; (11348828_1):GGG 243 Het is ed from i. monocyclic d 6-membered hetaryl having 1 or 2 nitrogen atoms as ring members, which is unsubstituted or may carry 1, 2, 3 or 4 identical or different substituents Rx, ii. fused bicyclic hetaryl having 1 or 2 nitrogen atoms and optionally a further heteroatom selected from O, S and N as ring members, benzothienyl or benzofuryl, where bicyclic hetaryl, benzothienyl and benzofuryl are, independently of each other, unsubstituted or may carry 1, 2, 3 or 4 identical or different substituents Rx, and iii. phenyl, which carries a monocyclic hetaryl radical having 1 or 2 nitrogen atoms and optionally a r heteroatom selected from O, S and N as ring members, which in on to clic hetaryl, may carry 1, 2 or 3 identical or different tuents Rx, where Rx is selected from the group consisting of H, halogen, C1-C4-alkyl, C1-C4-alkoxy, C1-C4-fluoroalkyl, C1-C4-fluoroalkoxy, C3-C6- cycloalkyl, C1-C4-alkoxy-C1-C4-alkoxy, C1-C4-alkoxy-C1-C4-alkyl, OH, hydroxy-C1-C4-alkyl, O-C3-C6-cycloalkyl, benzyloxy, C(O)O- (C1-C4-alkyl), O-(C1-C4-alkyl)-CO2H, N(Rx1)(Rx2), C(O)N(Rx1)(Rx2), C1-C4-alkyl-N(Rx1)(Rx2), -NRx3-C(O)-N(Rx1)(Rx2), NRx3-C(O)O-(C1-C4-alkyl), -N(Rx3)-SO2-Rx4, phenyl, CN, -SF5, -OSF5, -SO2Rx4, -SRx4 and trimethylsilyl, where Rx1, Rx2, Rx3 and Rx4, ndently of each other are selected from the group consisting of hydrogen, C1-C4- alkyl, C1-C4-fluoroalkyl and C3-C6-cycloalkyl or Rx1 and Rx2 form together with the N atom to which they are attached a 3- to 7- membered, nitrogen heterocycle which may have 1, 2 or 3 r different or identical heteroatoms or heteroatom ning groups selected from the group of O, N, S, SO and SO2 as ring members and which may carry 1, 2, 3, 4, 5 or 6 substituents selected from C1-C4-alkyl; (11348828_1):GGG 244 A represents one of the following groups A1, A2, A3 or A4: R6 R5 R4 A' * * * * * * * * R4 R3 R5 R5 R4 (A1 ) (A2) (A3) (A4) where * indicates the points of attachment to Het and to the nitrogen atom, respectively, R3, R4, R5, R6 independently of each other are selected from the group consisting of hydrogen, halogen, C1-C4-alkyl, trimethylsilyl, fluoroalkyl, C1-C4- alkoxy, C3-C6-cycloalkyl, or the radicals together with the carbon atoms to which they are bound form a saturated 3- to ered carbocycle or a ted 3- to 6-membered heterocycle having 1 or 2 non-adjacent heteroatoms as ring members, where the carbocycle and the heterocycle are tituted or may carry 1, 2, 3 or 4 substituents selected from fluorine and methyl or either the radicals R3, R4 or the radicals R5, R6 together with the carbon atom to which they are bound form a saturated 3- to 6-membered carbocycle or a saturated 3- to 6- membered cycle having 1 or 2 non-adjacent heteroatoms as ring members, where the carbocycle and the heterocycle are unsubstituted or may carry 1, 2, 3 or 4 substituents selected from fluorine and methyl; A' is a O, NR3a, CR3bR3c or linear C2-C3-alkandiyl, where one of the CH2- moieties of C2-C3-alkandiyl may be replaced by oxygen or NR3a, and where 1, 2, 3, or 4 of the hydrogen atoms of C2-C3-alkandiyl may be replaced by a radical R3d, where R3a is hydrogen or C1-C4-alkyl, R3b, R3c ndently of each other are selected from the group consisting of hydrogen, halogen, C1-C4-alkyl or R3b and R3c together form C2-C3-alkandiyl; (11348828_1):GGG 245 R3d is selected from the group consisting of halogen and C1-C4- alkyl; R8 is selected from the group consisting of hydrogen, halogen, OH, C1-C4- alkyl, trimethylsilyl, alkoxy-C1-C4-alkyl, C1-C4-alkoxy, C1-C4- alkoxy-C1-C4-alkoxy, C2-C4-alkenyloxy, C1-C4-fluoroalkyl, C1-C4- fluoroalkoxy, cyclopropyl, optionally substituted by 1, 2 or 3 methyl groups, fluorinated ropyl, CN and NRx1Rx2; R9 is selected from the group consisting of hydrogen, halogen, OH, C1-C4- alkyl, trimethylsilyl, C1-C4-alkylsulfanyl, C1-C4-alkoxy-C1-C4-alkyl, C1- C4-alkoxy, C1-C4-alkoxy-C1-C4-alkoxy, C1-C4-alkylsulfanyl-C1-C4- alkoxy, C2-C4-alkenyloxy, C1-C4-fluoroalkyl, C1-C4-fluoroalkoxy, cyclopropyl, ally substituted by 1, 2 or 3 methyl groups, fluorinated ropyl, CN, NRx1Rx2, NRx1Rx2-C1-C4-alkoxy and the moiety Y3-Cyc3.
3. The compound as claimed in claim 1 or 2, where X3 is selected from O, S, -X4=C(R8)-, where C(R8) is bound to the carbon atom which carries R2.
4. The compound as claimed in any one of claims 1 to 3, where A is selected from A1, A2, A3 and A4.
5. The compound as claimed in any of claims 1 to 4, where X2 is C-R7.
6. The compound as claimed in claim 5, where R7 is hydrogen or Y2-Cyc2.
7. The compound as d in any of claims 1 to 6, where X1 is N.
8. The compound as d in claim 1 to 6, where X1 is CH.
9. The compound as claimed in any of claims 1 to 8, where X3 is S. (11348828_1):GGG 246
10. The compound as claimed in any of claims 1 to 8, where X3 is O.
11. The compound as claimed in any one of claims 1 to 8, where X3 is C(R9)=C(R8).
12. The compound as claimed in any one of claims 1 to 8, where X3 is N=(CR9).
13. The compound as claimed in any of claims 11 or 12, where R9 is hydrogen or Y3- Cyc3.
14. The compound as claimed in any of claims 1 to 8, where X3 is N=C(R8).
15. The nd as d in any of claims 11 or 14, where R8 is hydrogen.
16. The compound as claimed in any one of the preceding claims, where R2 is ed from the group consisting of hydrogen, fluorine, C1-C4-alkyl, C1-C2-fluoroalkyl, C1- C4-alkoxy, C1-C2-fluoroalkoxy, cyclopropyl, ally substituted by 1, 2 or 3 methyl groups, and fluorinated cyclopropyl.
17. The compound as claimed in claim 16, where R2 is hydrogen.
18. The compound as claimed in any one of the preceding claims, where A is A1.
19. The compound as claimed in claim 18, where R3, R4 are selected from hydrogen and fluorine.
20. The compound as claimed in claim 18 or 19, where R5 and R6 are, independently of each other, selected from the group ting of hydrogen, fluorine and methyl.
21. The compound as claimed in any one of claims 1 to 17, where A is A2.
22. The nd as claimed in any one of claims 1 to 17, where A is A3. (11348828_1):GGG 247
23. The compound as d in claim 22, where R4, R5 are selected from hydrogen and fluorine.
24. The compound as claimed in any one of claims 1 to 17, where A is A4.
25. The compound as claimed in claim 24, where A' is CR3bR3c, where R3b and R3c are independently of each other selected from the group consisting of hydrogen, fluorine and methyl or together form CH2CH2.
26. The compound as d in claim 25, where R3b and R3c are hydrogen.
27. The compound as claimed in any one of claims 1 to 17, where A is A5.
28. The compound as claimed in claim 27, where R3e, R3f, R4 and R5 are each hydrogen.
29. The nd as claimed in any one of the preceding claims, where Het is selected from the group consisting of C-bound 6-membered monocyclic hetaryl, which has 1 or 2 nitrogen atoms as ring members, benzofuryl and C-bound, fused bicyclic hetaryl, which has 1 or 2 nitrogen atoms as ring members and optionally a further heteroatom selected from O, S and N as ring member; where monocyclic hetaryl, uryl and bicyclic hetaryl may be tituted or may carry 1, 2, 3 or 4 substituents Rx.
30. The compound as claimed in claim 29, where Het has at least one imino-nitrogen as ring member, which is located in the position adjacent to the carbon atom which is bound to A.
31. The compound as claimed in claim 30, where Het is selected from the group consisting of 2-pyridyl, 2-pyrimidinyl, midinyl, zinyl, 3-pyridazinyl, 2- quinolinyl, uinolinyl, 2-quinazolinyl, 2-quinoxalinyl, 1,5-naphthyridinyl, 1,8-naphthyridinyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, 1- methylbenzimidazolyl, imidazo[1,2-a]pyridineyl, thieno[3,2-b]pyridineyl, imidazo-[2,1-b]-thiazolyl and 1,2,4-triazolo[1,5-a]pyridineyl, where the aforementioned radicals may carry 1, 2 or 3 radicals ed from fluorine, chlorine, (11348828_1):GGG 248 methyl, fluoromethyl, difluoromethyl, trifluoromethyl, y, fluoromethoxy, difluoromethoxy, trifluoromethoxy, cyclopropyl, optionally substituted by 1, 2 or 3 methyl groups, and fluorinated cyclopropyl.
32. The compound as claimed in any one of the ing , where Y1, Y2 and Y3, ndently of each other, are selected from the group consisting of a chemical bond, O and NH.
33. The compound as claimed in any one of the preceding claims, where Y1, Y2 and Y3 are each a chemical bond.
34. The compound as claimed in any one of the preceding claims, where Q is O.
35. The compound as claimed in any one of the preceding claims, which is of the formulae I-1.A or I-2.A O R1 Het N (I-1.A) R2 R5 R6 N S R7 O R1 Het N (I-2.A) R2 R5 R6 S R7 where Het, R1, R2, R5, R6 and R7 are as defined in any one of the preceding claims.
36. The compound as claimed in any one of claims 1 to 34, which is of the formulae I- 1.B or I-2.B (11348828_1):GGG 249 R3c R3b O R1 Het N (I-1.B) R5 R2 N S R7 R3c R3b O R1 Het N (I-2.B) R5 R2 S R7 where Het, R1, R2, R3b, R3c and R7 are as defined in any one of claims 1 to 35 and R5 is hydrogen.
37. The compound as claimed in any one of claims 1 to 34, which is of the formulae I- 1.C or I-2.C R5 O R1 Het N (I-1.C) R2 N S R7 R5 O R1 Het N ) R2 S R7 where Het, R1, R2, R5, and R7 are as defined in any one of claims 1 to 35.
38. The nd as claimed in any of claim 35, 36 or 37, where R1 is a radical Y1-Cyc1 and R7 is selected from the group consisting of hydrogen, fluorine, C1-C4-alkyl, C1- (11348828_1):GGG 250 C2-fluoroalkyl, C1-C4-alkoxy, C1-C2-fluoroalkoxy, cyclopropyl, ally substituted by 1, 2 or 3 methyl groups, fluorinated cyclopropyl and Y2-Cyc2.
39. The compound as claimed in any one of claims 1 to 34, which is of the formulae I- 3.A or I-4.A O R1 Het R2 N (I-3.A) R5 R6 N R8 R7 R9 O R1 Het R2 N (I-4.A) R5 R6 R8 R7 R9 where Het, R1, R2, R5, R6, R7, R8 and R9 are as defined in any one of claims 1 to 35.
40. The nd as claimed in any one of claims 1 to 34, which is of the formulae I- 3.B or I-4.B R3c R3b O R1 Het R2 N (I-3.B) R5 N R8 R7 R9 (11405124_1):JIN 251 R3c R3b O R1 Het R2 N (I-4.B) R5 R8 R7 R9 where Het, R1, R2, R3b, R3c, R7, R8 and R9 are as defined in any one of claims 1 to 35 and R5 is hydrogen..
41. The compound as claimed in any one of claims 1 to 34, which is of the formulae I- 3.C or I-4.C R5 O R1 Het R2 N (I-3.C) N R8 R7 R9 R5 O R1 Het R2 N (I-4.C) R8 R7 R9 where Het, R1, R2, R5, R7, R8 and R9 are as defined in any one of claims 1 to 35.
42. The compound as claimed in any one of claims 39, 40 or 41, where R1 is a radical Y1-Cyc1 and R7 and R9 are selected, independently of each other, from the group consisting of hydrogen, fluorine, C1-C4-alkyl, fluoroalkyl, alkoxy, C1-C2-fluoroalkoxy, cyclopropyl, optionally tuted by 1, 2 or 3 methyl groups, fluorinated cyclopropyl and Y2-Cyc2 or Y3-Cyc3, respectively.
43. The compound as claimed in any one of claims 1 to 34, which is of the formulae I- 5.A or I-6.A (11405124_1):JIN 252 O R1 Het R2 N (I-5.A) R5 R6 N N R8 R7 O R1 Het R2 N (I-6.A) R5 R6 N R8 R7 where Het, R1, R2, R5, R6, R7 and R8 are as defined in any one of claims 1 to 34.
44. The compound as claimed in any one of claims 1 to 34, which is of the ae I- 5.B or I-6.B R3c R3b O R1 R2 Het N (I-5.B) R5 N N R8 R7 R3c R3b O R1 R2 Het N (I-6.B) R5 N R8 R7 where Het, R1, R2, R3b, R3c, R7 and R8 are as defined in any one of claims 1 to 34 and R5 is hydrogen.
45. The compound as claimed in any one of claims 1 to 34, which is of the formulae I- 5.C or I-6.C (11405124_1):JIN 253 R5 O R1 R2 Het N (I-5.C) N N R8 R7 R5 O R1 R2 Het N (I-6.C) N R8 R7 where Het, R1, R2, R5, R7 and R8 are as defined in any one of claims 1 to 34.
46. The compound as claimed in any one of claims 43, 44 or 45, where R1 is a radical Y1-Cyc1 and R7 is ed from the group consisting of hydrogen, ne, C1-C4-alkyl, C1-C2-fluoroalkyl, alkoxy, C1-C2-fluoroalkoxy, cyclopropyl, optionally substituted by 1, 2 or 3 methyl groups, fluorinated cyclopropyl and Y2-Cyc2.
47. The compound as claimed in any one of claims 1 to 34, which is of the formulae I- 7.A, I-8.A, I-7.B, I-8.B, I-7.C, I-8.C, O R1 O R1 Het Het N N R2 R2 R5 R6 N R5 R6 O O R7 R7 (I-7.A) (I-8.A) R3c R3b O R1 R3c R3b O R1 Het N R5 R2 Het N N O R5 R2 O R7 R7 (I-7.B) (I-8.B) (11405124_1):JIN 254 R5 O R1 R5 O R1 Het N Het N R2 R2 N O O R7 R7 ) (I-8.C) where Het, R1, R2, R3b, R3c, R5, R6, R7 and R8 are as defined in any one of claims 1 to 35.
48. The compound as claimed in claim 47, where R1 is a radical Y1-Cyc1 and R7 is selected from the group consisting of hydrogen, fluorine, C1-C4-alkyl, fluoroalkyl, C1-C4-alkoxy, C1-C2-fluoroalkoxy, ropyl, optionally substituted by 1, 2 or 3 methyl groups, fluorinated cyclopropyl and Y2-Cyc2.
49. The compound as claimed in any one of claims 1 to 34, which is of formulae O R1 O R1 R3c R3b O R1 Het R2 Het R2 N N Het R2 R5 R6 R5 R6 N N N N R5 N N R7 R9 R7 R9 R7 R9 (I-10.A) (I-9.A) (I-9.B) R3c R3b O R1 R5 O R1 R2 R5 O R1 Het N Het R2 R5 N Het R2 N N N N N R7 R9 R7 R9 R7 R9 (I-10.B) (I-9.C) (I-10.C) wher e Het, R1, R2, R3b, R3c, R5, R6, R7, and R9 are as defined in any one of claims 1 to 34.
50. The compound as claimed in claim 49, where R1 is a radical Y1-Cyc1 and R7 and R9 are selected, independently of each other, from the group ting of hydrogen, fluorine, alkyl, C1-C2-fluoroalkyl, C1-C4-alkoxy, C1-C2-fluoroalkoxy, cyclopropyl, optionally substituted by 1, 2 or 3 methyl groups, fluorinated cyclopropyl and Y2-Cyc2 or Y3-Cyc3, (11405124_1):JIN 255 respectively.
51. The compound as claimed in any one of claims 1 to 34, which is of the formulae I- 1.D, I-2.D, I-3.D, I-4.D, I-5.D, I-6.D, I-7.D, I-8.D, I-9.D, I-10.D O O R1 R1 Het Het N N R2 R2 N S S R3e R3f R3e R3f R7 R7 ) (I-1.D) O R1 O R1 Het R2 Het R2 N N N R8 R3e R3f R8 R3e R3f R7 R9 R7 R9 (I-3.D) (I-4.D) O R1 O R1 Het R2 Het R2 N N N R3e R3f N R8 R3e R3f N R8 R7 R7 (I-5.D) (I-6.D) O R1 O R1 Het Het N N R2 R2 N O O R3e R3f R3e R3f R7 R7 (I-7.D) (I-8.D) (11405124_1):JIN 256 O R1 O R1 Het R2 N Het R2 N N N N R3e R3f R3e R3f R7 R9 R7 R9 (I-9.D) (I-10.D) where Het, R1, R2, R3e, R3f, R7, R8 and R9 are as d in any one of claims 1 to 34.
52. The nd as claimed in claim 51, where R1 is a l 1 and R7 is selected from the group consisting of hydrogen, fluorine, C1-C4-alkyl, C1-C2-fluoroalkyl, C1-C4-alkoxy, C1-C2-fluoroalkoxy, cyclopropyl, optionally substituted by 1, 2 or 3 methyl groups, fluorinated cyclopropyl and Y2-Cyc2.
53. The compound as claimed in any one of claims 35 to 52, where R3b, R3c, R5, R6, if present, are hydrogen.
54. The compound as claimed in any one of the preceding claims, where Cyc1 is selected from the group consisting of saturated 4-, 5-, 6-, 7- or 8-membered heteromonocycles and saturated 7-, 8-, 9- or bered heterobicycles, where the heteromonocycles and the heterobicycles have one nitrogen or oxygen atom as ring member and may have one further heteroatom or heteroatom group as ring member, which is selected from the group consisting of O, S, S(=O), S(=O)2 and N, where the saturated heteromonocycle and the saturated heterobicycle are unsubstituted or carry 1, 2, 3, 4 or 5 radicals RC1 or one radical Y'-RC2 and 0, 1, 2, 3 or 4 radicals RC1, where RC1, RC2 and Y' are as defined in claim 1.
55. The compound as claimed in any one of the preceding claims, where Y1-Cyc1, is selected from the group consisting of 1-piperidinyl, 4,4-difluoropiperidinyl, 4- dinyl, 1-methylpiperidinyl, 1-piperazinyl, ylpiperazinyl, morpholinyl, azepaneyl, azepanyl, hexahydrofuro[3,4-c]pyrrolyl, 2,5- diazabicyclo[2.2.1]heptanyl, 3,8-diazabicyclo[3.2.1]octanyl, thiomorpholinyl, 1- oxothiomorpholinyl, N-(oxetanyl)amino, 1,1-dioxothiomorpholinyl and oxetan ylamino. (11405124_1):JIN 257
56. The compound as claimed in any one of claims 1 to 53, where Cyc1 is selected from the group consisting of phenyl, 5- or 6 membered monocyclic hetaryl, and 9- or 10 ed bicyclic hetaryl, where hetaryl has one heteroatom, selected from O, S and N as ring member and optionally one or two r nitrogen atoms as ring members, where phenyl and the hetaryl radical are unsubstituted or either carry, independently of each other, 1, 2, 3, 4 or 5 radicals RC1.
57. The compound as claimed in claim 56, where Y1 is a chemical bond and Cyc1 is selected from the group consisting of phenyl, 5- or 6-membered monocyclic hetaryl selected from the group consisting of pyridyl, dinyl, furyl, thienyl, pyrrolyl, imidazolyl, lyl, oxazolyl and thiazolyl, 9- or 10-membered bicyclic hetaryl selected from the group consisting of indolyl, quinolinyl, isoquinolinyl, olinyl, benzimidazolyl, benzotriazolyl, yrazolyl and benzofuryl, where phenyl and hetaryl are unsubstituted or carry 1, 2 or 3 radicals RC1 which are ed from the group consisting of fluorine, chlorine, CN, methyl, difluoromethyl, trifluoromethyl, methoxy and NH2, or, if Cyc1 is phenyl, two radicals RC1 which are bound to adjacent carbon atoms, together with the phenyl ring to which they are bound, form a bicyclic heterocyclic radical, which is selected from 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzofuranyl, 1,3- dihydroindolonyl, 1,3-dihydroindolonyl, benzo-1,3-dioxolanyl, 1,3- dioxolanyl, benzo-1,4-dioxanyl, benzo-1,4-dioxanyl, benzo-1,5-dioxepanyl and benzo-1,4-dioxepanyl.
58. The compound as claimed in any one of the preceding , where Cyc2 and Cyc3, independently of each other, are selected from the group consisting of saturated 4-, 5-, 6-, 7- or 8-membered heteromonocycles and saturated 7-, 8-, 9- or 10-membered heterobicycles, where the monocycles and the heterobicycles have one nitrogen or oxygen atom as ring member and may have one further atom or atom group as ring member, which is selected from the group consisting of O, S, S(=O), S(=O)2 and N, where the saturated heteromonocycle and the saturated heterobicycle are unsubstituted or carry 1, 2, 3, 4 or 5 radicals RC1 or one radical Y'-RC2 and 0, 1, 2, 3 or 4 radicals RC1, where RC1, RC2 and Y' are as defined in claim 1.
59. The compound as claimed in claim 57, where Y2-Cyc2 and Y3-Cyc3, independently of each other, are is selected from the group consisting of phenyl, 5- or 6-membered (11405124_1):JIN 258 monocyclic hetaryl selected from the group consisting of pyridyl, pyrimidinyl, furyl, thienyl, pyrrolyl, imidazolyl, lyl, oxazolyl and thiazolyl, 9- or 10-membered bicyclic hetaryl selected from the group consisting of indolyl, quinolinyl, isoquinolinyl, quinazolinyl, benzimidazolyl, riazolyl, benzopyrazolyl and benzofuryl, where phenyl and hetaryl are unsubstituted or carry 1, 2 or 3 radicals RC1 which are selected from the group consisting of fluorine, chlorine, CN, methyl, difluoromethyl, trifluoromethyl, methoxy and NH2, or, if Cyc2 or Cyc3 are phenyl, two radicals RC1 which are bound to adjacent carbon atoms, together with the phenyl ring to which they are bound, form a bicyclic heterocyclic l, which is selected from 2,3-dihydrobenzofuranyl, 2,3- obenzofuranyl, 1,3-dihydroindolonyl, 1,3-dihydroindolonyl, benzo- oxolanyl, benzo-1,3-dioxolanyl, benzo-1,4-dioxanyl, benzo-1,4-dioxanyl, benzo-1,5-dioxepanyl and benzo-1,4-dioxepanyl.
60. A compound according to claim 1, which is selected from the group consisting of 3,7-di(pyridinyl)[2-(quinolinyl)ethyl]thieno[2,3-d]pyridazin-4(5H)-one; 3-(pyridinyl)[2-(quinolinyl)ethyl]thieno[2,3-d]pyridazin-4(5H)-one; 3-(pyridinyl)[2-(pyridinyl)ethyl]thieno[2,3-d]pyridazin-4(5H)-one; 3,7-di(pyridinyl)[2-(pyridinyl)ethyl]thieno[2,3-d]pyridazin-4(5H)-one; 5-[2-(quinolinyl)ethyl][4-(trifluoromethyl)phenyl]thieno[2,3-d]pyridazin- one; 3-(4-methylphenyl)[2-(quinolinyl)ethyl]thieno[2,3-d]pyridazin-4(5H)-one; 3-[4-(propanyl)phenyl][2-(quinolinyl)ethyl]thieno[2,3-d]pyridazin-4(5H)- one; 3-(4-ethylphenyl)[2-(quinolinyl)ethyl]thieno[2,3-d]pyridazin-4(5H)-one; 4-{4-oxo[2-(quinolinyl)ethyl]-4,5-dihydrothieno[2,3-d]pyridazin yl}benzonitrile; 3-(4-methoxyphenyl)[2-(quinolinyl)ethyl]thieno[2,3-d]pyridazin-4(5H)-one; 3-(4-fluorophenyl)[2-(quinolinyl)ethyl]thieno[2,3-d]pyridazin-4(5H)-one; 3-(4-ethoxyphenyl)[2-(quinolinyl)ethyl]thieno[2,3-d]pyridazin-4(5H)-one; 3-[4-(dimethylamino)phenyl][2-(quinolinyl)ethyl]thieno[2,3-d]pyridazin- 4(5H)-one; (4-{4-oxo[2-(quinolinyl)ethyl]-4,5-dihydrothieno[2,3-d]pyridazin yl}phenyl)acetonitrile; (11405124_1):JIN 259 3-(4-hydroxyphenyl)[2-(quinolinyl)ethyl]thieno[2,3-d]pyridazin-4(5H)-one; 3-(2-chlorophenyl)[2-(quinolinyl)ethyl]thieno[2,3-d]pyridazin-4(5H)-one; 3-(2-methylphenyl)[2-(quinolinyl)ethyl]thieno[2,3-d]pyridazin-4(5H)-one; 3-(2-ethylphenyl)[2-(quinolinyl)ethyl]thieno[2,3-d]pyridazin-4(5H)-one; 3-(2-fluorophenyl)[2-(quinolinyl)ethyl]thieno[2,3-d]pyridazin-4(5H)-one; 3-(2-methoxyphenyl)[2-(quinolinyl)ethyl]thieno[2,3-d]pyridazin-4(5H)-one; 3-(2-ethoxyphenyl)[2-(quinolinyl)ethyl]thieno[2,3-d]pyridazin-4(5H)-one; 3-(2-hydroxyphenyl)[2-(quinolinyl)ethyl]thieno[2,3-d]pyridazin-4(5H)-one; 5-[2-(quinolinyl)ethyl][2-(trifluoromethyl)phenyl]thieno[2,3-d]pyridazin- 4(5H)-one; 3-[3-(methoxymethyl)phenyl][2-(quinolinyl)ethyl]thieno[2,3-d]pyridazin- 4(5H)-one; 3-(3-methoxyphenyl)[2-(quinolinyl)ethyl]thieno[2,3-d]pyridazin-4(5H)-one; thoxyphenyl)[2-(quinolinyl)ethyl]thieno[2,3-d]pyridazin-4(5H)-one; 3-[3-(dimethylamino)phenyl][2-(quinolinyl)ethyl]thieno[2,3-d]pyridazin- 4(5H)-one; 3-[4-Oxo(2-quinolinyl-ethyl)-4,5-dihydro-thieno[2,3-d]pyridazinyl}- benzonitrile; 3-(3-fluorophenyl)[2-(quinolinyl)ethyl]thieno[2,3-d]pyridazin-4(5H)-one; 3-(3-hydroxyphenyl)[2-(quinolinyl)ethyl]thieno[2,3-d]pyridazin-4(5H)-one; N,N-dimethyl{4-oxo[2-(quinolinyl)ethyl]-4,5-dihydrothieno[2,3- d]pyridazinyl}benzamide; 3-(3-methylphenyl)[2-(quinolinyl)ethyl]thieno[2,3-d]pyridazin-4(5H)-one; quinolinyl)ethyl](thiophenyl)thieno[2,3-d]pyridazin-4(5H)-one; 3-(1-methyl-1H-indolyl)(2-quinolinyl-ethyl)-5H-thieno[2,3-d]pyridazin one; 3-(1H-indolyl)[2-(quinolinyl)ethyl]thieno[2,3-d]pyridazin-4(5H)-one; imidinyl)[2-(quinolinyl)ethyl]thieno[2,3-d]pyridazin-4(5H)-one; 3-(2-methoxypyridinyl)[2-(quinolinyl)ethyl]thieno[2,3-d]pyridazin-4(5H)- one; 3-(pyridinyl)[2-(quinolinyl)ethyl]thieno[2,3-d]pyridazin-4(5H)-one; 3-(4-methoxypyridinyl)[2-(quinolinyl)ethyl]thieno[2,3-d]pyridazin-4(5H)- one; 3-(furanyl)[2-(quinolinyl)ethyl]thieno[2,3-d]pyridazin-4(5H)-one; (11405124_1):JIN 260 3-(quinolinyl)[2-(quinolinyl)ethyl]thieno[2,3-d]pyridazin-4(5H)-one; 3-(isoquinolinyl)[2-(quinolinyl)ethyl]thieno[2,3-d]pyridazin-4(5H)-one; 3-(isoquinolinyl)[2-(quinolinyl)ethyl]thieno[2,3-d]pyridazin-4(5H)-one; 3-(1H-indolyl)(2-quinolinyl-ethyl)-5H-thieno[2,3-d]pyridazinone; 3-(2,3-dihydrobenzofuranyl)(2-quinolinyl-ethyl)-5H-thieno[2,3-d]pyridazin- 4-one; 3-(quinolinyl)[2-(quinolinyl)ethyl]thieno[2,3-d]pyridazin-4(5H)-one; 3-(3,5-dimethyl-1,2-oxazolyl)[2-(quinolinyl)ethyl]thieno[2,3-d]pyridazin- 4(5H)-one; 3-(6-methoxypyridinyl)[2-(quinolinyl)ethyl]thieno[2,3-d]pyridazin-4(5H)- one; 3-(2,3-dihydro-1,4-benzodioxinyl)[2-(quinolinyl)ethyl]thieno[2,3- d]pyridazin-4(5H)-one; ethylpyridinyl)[2-(quinolinyl)ethyl]thieno[2,3-d]pyridazin-4(5H)- one; 3-(5-methoxypyridinyl)[2-(quinolinyl)ethyl]thieno[2,3-d]pyridazin-4(5H)- one; 3-[6-(morpholinyl)pyridinyl][2-(quinolinyl)ethyl]thieno[2,3-d]pyridazin- 4(5H)-one; 3-(1,3-benzodioxolyl)[2-(quinolinyl)ethyl]thieno[2,3-d]pyridazin-4(5H)- one; 3-(quinolinyl)[2-(quinolinyl)ethyl]thieno[2,3-d]pyridazin-4(5H)-one; 3-(1-methyl-1H-pyrazolyl)[2-(quinolinyl)ethyl]thieno[2,3-d]pyridazin- one; 3-[1-(2-methylpropyl)-1H-pyrazolyl][2-(quinolinyl)ethyl]thieno[2,3- d]pyridazin-4(5H)-one; tert-butyl 2-{4-oxo[2-(quinolinyl)ethyl]-4,5-dihydrothieno[2,3-d]pyridazin yl}-1H-pyrrolecarboxylate; 3-(2-methoxypyrimidinyl)[2-(quinolinyl)ethyl]thieno[2,3-d]pyridazin- 4(5H)-one; 5-[2-(quinolinyl)ethyl](2,3,4-trifluorophenyl)thieno[2,3-d]pyridazin-4(5H)- one; 3-(4-fluoromethylphenyl)[2-(quinolinyl)ethyl]thieno[2,3-d]pyridazin-4(5H)- one; (11405124_1):JIN 261 3-(4-fluoromethylphenyl)[2-(quinolinyl)ethyl]thieno[2,3-d]pyridazin-4(5H)- one; 3-(3-chlorofluorophenyl)[2-(quinolinyl)ethyl]thieno[2,3-d]pyridazin-4(5H)- one; 3-(2-chlorofluorophenyl)[2-(quinolinyl)ethyl]thieno[2,3-d]pyridazin-4(5H)- one; 3-(3,4-dimethylphenyl)[2-(quinolinyl)ethyl]thieno[2,3-d]pyridazin-4(5H)-one; -dimethylphenyl)[2-(quinolinyl)ethyl]thieno[2,3-d]pyridazin-4(5H)-one; 3-(2,4-difluorophenyl)[2-(quinolinyl)ethyl]thieno[2,3-d]pyridazin-4(5H)-one; 3-(2,4-dimethoxyphenyl)[2-(quinolinyl)ethyl]thieno[2,3-d]pyridazin-4(5H)- one; 3-(2,5-dimethoxyphenyl)[2-(quinolinyl)ethyl]thieno[2,3-d]pyridazin-4(5H)- one; 3-(2,3-difluorophenyl)[2-(quinolinyl)ethyl]thieno[2,3-d]pyridazin-4(5H)-one; 3-(3,4-dimethoxyphenyl)[2-(quinolinyl)ethyl]thieno[2,3-d]pyridazin-4(5H)- one; 3-(3,4-difluorophenyl)[2-(quinolinyl)ethyl]thieno[2,3-d]pyridazin-4(5H)-one; 3-(5-fluoromethoxyphenyl)[2-(quinolinyl)ethyl]thieno[2,3-d]pyridazin- 4(5H)-one; 3-(4-fluoromethoxyphenyl)[2-(quinolinyl)ethyl]thieno[2,3-d]pyridazin- 4(5H)-one; 3-(3,5-dimethoxyphenyl)[2-(quinolinyl)ethyl]thieno[2,3-d]pyridazin-4(5H)- one; 3-(2,5-difluorophenyl)[2-(quinolinyl)ethyl]thieno[2,3-d]pyridazin-4(5H)-one; 3-(2,3-dimethoxyphenyl)[2-(quinolinyl)ethyl]thieno[2,3-d]pyridazin-4(5H)- one; 3-(3-fluoromethoxyphenyl)[2-(quinolinyl)ethyl]thieno[2,3-d]pyridazin- 4(5H)-one; 3-(2-fluoromethoxyphenyl)[2-(quinolinyl)ethyl]thieno[2,3-d]pyridazin- 4(5H)-one; 3-(3,5-difluorophenyl)[2-(quinolinyl)ethyl]thieno[2,3-d]pyridazin-4(5H)-one; 3-(3-fluoromethoxyphenyl)[2-(quinolinyl)ethyl]thieno[2,3-d]pyridazin- 4(5H)-one; (11405124_1):JIN 262 ethoxymethylphenyl)[2-(quinolinyl)ethyl]thieno[2,3-d]pyridazin- 4(5H)-one; 3-(2,5-dichlorophenyl)[2-(quinolinyl)ethyl]thieno[2,3-d]pyridazin-4(5H)-one; 3-(naphthalenyl)[2-(quinolinyl)ethyl]thieno[2,3-d]pyridazin-4(5H)-one; 3-phenyl[2-(quinolinyl)ethyl]thieno[2,3-d]pyridazin-4(5H)-one; 3-(1-benzofuranyl)[2-(quinolinyl)ethyl]thieno[2,3-d]pyridazin-4(5H)-one; 3-(1H-indazolyl)[2-(quinolinyl)ethyl]thieno[2,3-d]pyridazin-4(5H)-one; 3-(1-methyl-1H-pyrazolyl)[2-(quinolinyl)ethyl]thieno[2,3-d]pyridazin- 4(5H)-one; 3-(4,5-difluoromethoxyphenyl)[2-(quinolinyl)ethyl]thieno[2,3-d]pyridazin- 4(5H)-one; 3-(2-fluoromethylphenyl)[2-(quinolinyl)ethyl]thieno[2,3-d]pyridazin-4(5H)- one; 3-(2-fluoromethoxyphenyl)[2-(quinolinyl)ethyl]thieno[2,3-d]pyridazin- 4(5H)-one; 3-methyl{4-oxo[2-(quinolinyl)ethyl]-4,5-dihydrothieno[2,3-d]pyridazin yl}benzonitrile; 5-[2-(6-fluoroquinolinyl)ethyl](pyridinyl)thieno[2,3-d]pyridazin-4(5H)-one; 5-[2,2-difluoro(quinolinyl)ethyl](pyridinyl)thieno[2,3-d]pyridazin-4(5H)- one; 3-(pyridinyl)[2-(thieno[3,2-b]pyridinyl)ethyl]thieno[2,3-d]pyridazin-4(5H)- one; 5-[2-(imidazo[1,2-a]pyridinyl)ethyl](pyridinyl)thieno[2,3-d]pyridazin- one; 7-fluoroimidazo[1,2-a]pyridinyl)ethyl](pyridinyl)thieno[2,3- d]pyridazin-4(5H)-one; 8-(pyridinyl)[2-(quinolinyl)ethyl]phthalazin-1(2H)-one; 2-[2-(quinolinyl)ethyl][4-(trifluoromethyl)phenyl]phthalazin-1(2H)-one; 8-(4-methylphenyl)[2-(quinolinyl)ethyl]phthalazin-1(2H)-one; 8-[4-(propanyl)phenyl][2-(quinolinyl)ethyl]phthalazin-1(2H)-one; 8-(4-ethylphenyl)[2-(quinolinyl)ethyl]phthalazin-1(2H)-one; 4-{4-oxo[2-(quinolinyl)ethyl]-3,4-dihydrophthalazinyl}benzonitrile; 8-(4-methoxyphenyl)[2-(quinolinyl)ethyl]phthalazin-1(2H)-one; 8-(4-fluorophenyl)[2-(quinolinyl)ethyl]phthalazin-1(2H)-one; (11405124_1):JIN 263 (4-{4-oxo[2-(quinolinyl)ethyl]-3,4-dihydrophthalazinyl}phenyl)acetonitrile; 8-(4-hydroxyphenyl)[2-(quinolinyl)ethyl]phthalazin-1(2H)-one; 8-(2-chlorophenyl)[2-(quinolinyl)ethyl]phthalazin-1(2H)-one; ethylphenyl)[2-(quinolinyl)ethyl]phthalazin-1(2H)-one; 8-(2-ethylphenyl)[2-(quinolinyl)ethyl]phthalazin-1(2H)-one; 8-(2-fluorophenyl)[2-(quinolinyl)ethyl]phthalazin-1(2H)-one; 8-(2-methoxyphenyl)[2-(quinolinyl)ethyl]phthalazin-1(2H)-one; ethoxyphenyl)[2-(quinolinyl)ethyl]phthalazin-1(2H)-one; 3-{4-oxo[2-(quinolinyl)ethyl]-3,4-dihydrophthalazinyl}benzonitrile; 8-(3-fluorophenyl)[2-(quinolinyl)ethyl]phthalazin-1(2H)-one; 8-(3-hydroxyphenyl)[2-(quinolinyl)ethyl]phthalazin-1(2H)-one; N,N-dimethyl{4-oxo[2-(quinolinyl)ethyl]-3,4-dihydrophthalazin yl}benzamide; 8-(3-methylphenyl)[2-(quinolinyl)ethyl]phthalazin-1(2H)-one; 2-[2-(quinolinyl)ethyl](thiophenyl)phthalazin-1(2H)-one; 8-(1-methyl-1H-indolyl)[2-(quinolinyl)ethyl]phthalazin-1(2H)-one; 8-(3,5-dimethyl-1H-pyrazolyl)[2-(quinolinyl)ethyl]phthalazin-1(2H)-one; 8-(1H-indolyl)[2-(quinolinyl)ethyl]phthalazin-1(2H)-one; 8-(1H-indolyl)[2-(quinolinyl)ethyl]phthalazin-1(2H)-one; 8-(pyrimidinyl)[2-(quinolinyl)ethyl]phthalazin-1(2H)-one; 8-(2-methoxypyridinyl)[2-(quinolinyl)ethyl]phthalazin-1(2H)-one; 8-(pyridinyl)[2-(quinolinyl)ethyl]phthalazin-1(2H)-one; 8-(furanyl)[2-(quinolinyl)ethyl]phthalazin-1(2H)-one; 8-(quinolinyl)[2-(quinolinyl)ethyl]phthalazin-1(2H)-one; 8-(1H-indolyl)[2-(quinolinyl)ethyl]phthalazin-1(2H)-one; 8-(2,3-dihydrobenzofuranyl)[2-(quinolinyl)ethyl]phthalazin-1(2H)-one; 8-(3,4-dihydro-2H-1,5-benzodioxepinyl)[2-(quinolinyl)ethyl]phthalazin- one; 8-(1-benzofuranyl)[2-(quinolinyl)ethyl]phthalazin-1(2H)-one; 8-(6-methoxypyridinyl)[2-(quinolinyl)ethyl]phthalazin-1(2H)-one; 8-(2,3-dihydro-1,4-benzodioxinyl)[2-(quinolinyl)ethyl]phthalazin-1(2H)- one; 8-(2-methylpyridinyl)[2-(quinolinyl)ethyl]phthalazin-1(2H)-one; 8-(5-methoxypyridinyl)[2-(quinolinyl)ethyl]phthalazin-1(2H)-one; (11405124_1):JIN 264 8-(5-fluoropyridinyl)[2-(quinolinyl)ethyl]phthalazin-1(2H)-one; 8-(1,3-benzodioxolyl)[2-(quinolinyl)ethyl]phthalazin-1(2H)-one; 8-(1-methyl-1H-pyrazolyl)[2-(quinolinyl)ethyl]phthalazin-1(2H)-one; 8-[1-(2-methylpropyl)-1H-pyrazolyl][2-(quinolinyl)ethyl]phthalazin-1(2H)- one; utyl 2-{4-oxo[2-(quinolinyl)ethyl]-3,4-dihydrophthalazinyl}-1H- pyrrolecarboxylate; 8-(3-chlorofluorophenyl)[2-(quinolinyl)ethyl]phthalazin-1(2H)-one; 8-(2-chlorofluorophenyl)[2-(quinolinyl)ethyl]phthalazin-1(2H)-one; 8-(3,4-dimethylphenyl)[2-(quinolinyl)ethyl]phthalazin-1(2H)-one; 8-(2,4-dimethoxyphenyl)[2-(quinolinyl)ethyl]phthalazin-1(2H)-one; 8-(2,5-dimethoxyphenyl)[2-(quinolinyl)ethyl]phthalazin-1(2H)-one; 8-(2,3-difluorophenyl)[2-(quinolinyl)ethyl]phthalazin-1(2H)-one; 8-(3,4-dimethoxyphenyl)[2-(quinolinyl)ethyl]phthalazin-1(2H)-one; 8-(3,4-difluorophenyl)[2-(quinolinyl)ethyl]phthalazin-1(2H)-one; luoromethoxyphenyl)[2-(quinolinyl)ethyl]phthalazin-1(2H)-one; 8-(4-fluoromethoxyphenyl)[2-(quinolinyl)ethyl]phthalazin-1(2H)-one; 8-(3,5-dimethoxyphenyl)[2-(quinolinyl)ethyl]phthalazin-1(2H)-one; 8-(2,5-difluorophenyl)[2-(quinolinyl)ethyl]phthalazin-1(2H)-one; 8-(3-fluoromethoxyphenyl)[2-(quinolinyl)ethyl]phthalazin-1(2H)-one; 8-(2-fluoromethoxyphenyl)[2-(quinolinyl)ethyl]phthalazin-1(2H)-one; 8-(3,5-difluorophenyl)[2-(quinolinyl)ethyl]phthalazin-1(2H)-one; 8-(3-fluoromethoxyphenyl)[2-(quinolinyl)ethyl]phthalazin-1(2H)-one; 8-(naphthalenyl)[2-(quinolinyl)ethyl]phthalazin-1(2H)-one; 8-phenyl[2-(quinolinyl)ethyl]phthalazin-1(2H)-one; 8-(1-benzofuranyl)[2-(quinolinyl)ethyl]phthalazin-1(2H)-one; ethyl-1H-pyrazolyl)[2-(quinolinyl)ethyl]phthalazin-1(2H)-one; 8-(4,5-difluoromethoxyphenyl)[2-(quinolinyl)ethyl]phthalazin-1(2H)-one; 8-(2-fluoromethylphenyl)[2-(quinolinyl)ethyl]phthalazin-1(2H)-one; 8-(2-fluoromethoxyphenyl)[2-(quinolinyl)ethyl]phthalazin-1(2H)-one; 2-[2-(imidazo[1,2-a]pyridinyl)ethyl](pyridinyl)phthalazin-1(2H)-one; 2-[2-(imidazo[1,2-a]pyridinyl)ethyl](pyridinyl)phthalazin-1(2H)-one; 2-[2-(imidazo[1,2-a]pyridinyl)ethyl](3-methoxypyridinyl)phthalazin-1(2H)- one; (11405124_1):JIN 265 2-[2-(imidazo[1,2-a]pyridinyl)ethyl](pyrimidinyl)phthalazin-1(2H)-one; 2-[2-(imidazo[1,2-a]pyridinyl)ethyl](1-methyl-1H-pyrazolyl)phthalazin- one; 8-(furanyl)[2-(imidazo[1,2-a]pyridinyl)ethyl]phthalazin-1(2H)-one; 2-[2-(imidazo[1,2-a]pyridinyl)ethyl](2-oxo-2,3-dihydro-1H-indol yl)phthalazin-1(2H)-one; 8-(3,4-dihydro-2H-chromenyl)[2-(imidazo[1,2-a]pyridinyl)ethyl]phthalazin- 1(2H)-one; 8-(1,1-dioxidothiomorpholinyl)[2-(quinolinyl)ethyl]phthalazin-1(2H)-one; imidazo[1,2-a]pyridinyl)ethyl](morpholinyl)phthalazin-1(2H)-one; 8-(1,1-dioxidothiomorpholinyl)[2-(imidazo[1,2-a]pyridin yl)ethyl]phthalazin-1(2H)-one; 2-[2-(imidazo[1,2-a]pyridinyl)ethyl](tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)- yl)phthalazin-1(2H)-one; 8-(5,5-difluorohexahydrocyclopenta[c]pyrrol-2(1H)-yl)[2-(imidazo[1,2-a]pyridin- 2-yl)ethyl]phthalazin-1(2H)-one; 2-[2-(imidazo[1,2-a]pyridinyl)ethyl](piperazinyl)phthalazin-1(2H)-one; 8-(4,4-difluoropiperidinyl)[2-(imidazo[1,2-a]pyridinyl)ethyl]phthalazin- 1(2H)-one; 8-[4-(chloromethyl)(hydroxymethyl)piperidinyl][2-(imidazo[1,2-a]pyridin- 2-yl)ethyl]phthalazin-1(2H)-one; 2-[2-(imidazo[1,2-a]pyridinyl)ethyl](piperidinyl)phthalazin-1(2H)-one; 8-(2,3-dihydro-4H-1,4-benzoxazinyl)[2-(imidazo[1,2-a]pyridin yl)ethyl]phthalazin-1(2H)-one; 2-[2-(imidazo[1,2-a]pyridinyl)ethyl][4-(trifluoromethyl)piperidin yl]phthalazin-1(2H)-one; 2-[2-(imidazo[1,2-a]pyridinyl)ethyl](4-methylpiperazinyl)phthalazin-1(2H)- one; 8-(1,3-dihydro-2H-isoindolyl)[2-(imidazo[1,2-a]pyridinyl)ethyl]phthalazin- 1(2H)-one; 8-(7-benzyl-2,7-diazaspiro[4.4]nonyl)[2-(imidazo[1,2-a]pyridin yl]phthalazin-1(2H)-one; 8-({[(3aR,4S,6aS)benzyloctahydrocyclopenta[c]pyrrolyl]methyl}amino)[2- (imidazo[1,2-a]pyridinyl)ethyl]phthalazin-1(2H)-one; (11405124_1):JIN 266 tert-butyl (3R)({3-[2-(imidazo[1,2-a]pyridinyl)ethyl]oxo-3,4- dihydrophthalazinyl}amino)pyrrolidinecarboxylate; 8-(2,6-dimethylmorpholinyl)[2-(imidazo[1,2-a]pyridinyl)ethyl]phthalazin- 1(2H)-one; 2-[2-(imidazo[1,2-a]pyridinyl)ethyl](1,4-oxazepanyl)phthalazin-1(2H)-one; tert-butyl 2-(imidazo[1,2-a]pyridinyl)ethyl]oxo-3,4-dihydrophthalazin yl}-3,6-dihydropyridine-1(2H)-carboxylate; 3-(3-methoxypyridinyl)[2-(quinolinyl)ethyl]thieno[3,2-c]pyridin-4(5H)-one; 3-(3-hydroxypyridinyl)[2-(quinolinyl)ethyl]thieno[3,2-c]pyridin-4(5H)-one; 3-(1-methyl-1H-pyrazolyl)[2-(quinolinyl)ethyl]thieno[3,2-c]pyridin-4(5)H- one; 3-(pyridinyl)[2-(quinolinyl)ethyl]thieno[3,2-c]pyridin-4(5H)-one; 3-(pyrimidinyl)(2-quinolinyl)ethyl)thieno[3,2-c]pyridin-4(5H)-one; 3-(2-oxoindolinyl)[2-(quinolinyl)ethyl]thieno[3,2-c]pyridin-4(5H)-one; 3-(3-hydroxyphenyl)[2-(quinolinyl)ethyl]thieno[3,2-c]pyridin-4(5H)-one; 5-[2-(5-ethylpyridinyl)ethyl](pyridinyl)thieno[3,2-c]pyridin-4(5H)-one; 5-[2-(imidazo[1,2-a]pyridinyl)ethyl](pyridinyl)thieno[3,2-c]pyridin-4(5H)- one; 3-(morpholinyl)[2-(quinolinyl)ethyl]thieno[3,2-c]pyridin-4(5H)-one; tert-butyl(4-oxo(2-quinolinyl)ethyl)-4,5-dihydrothieno[3,2-c]pyridinyl)- 5,6-dihydropyridine-1(2H) carboxylate; 5-(2-(quinolinyl)ethyl)(1,2,3,6-tetrahydropyridinyl)thieno[3,2-c]pyridin- 4(5H)-one; tert-butyl(4-oxo(2-quinolinyl)ethyl)-4,5-dihydrothieno[3,2-c]pyridinyl)- piperidine-1 carboxylate; 3-(piperidinyl)[2-(quinolinyl)ethyl]thieno[3,2-c]pyridin-4(5H)-one; 3-(pyridinyl)[2-(5,6,7,8-tetrahydroquinolinyl)ethyl]thieno[2,3-d]pyridazin- 4(5H)-one; (R)-tert-butyl 3-(3-(2-(imidazo[1,2-a]pyridinyl)ethyl)oxo-3,4- dihydrophthalazinylamino)pyrrolidinecarboxylate; 2-[2-(imidazo[1,2-a]pyridinyl)ethyl][(3R)-pyrrolidinylamino]phthalazin- 1(2H)-one; ydroxyphenyl)[2-(quinolinyl)ethyl]phthalazin-1(2H)-one; (E)(pyridinyl)(2-(quinolinyl)vinyl)isoquinolin-1(2H)-one; (11405124_1):JIN 267 anti (rac) 8-(pyridinyl)(2-(quinolinyl)cyclopropyl)isoquinolin-1(2H)-one; anti (+)(pyridinyl)(2-(quinolinyl)cyclopropyl)isoquinolin-1(2H)-one; anti (-)(pyridinyl)(2-(quinolinyl)cyclopropyl)isoquinolin-1(2H)-one; 8-(pyridinyl)(2-quinolinyl-ethyl)isoquinolin-1(2H)-one; anti (rac) 3-(pyridinyl)(2-(quinolinyl)cyclopropyl)thieno[3,2-c]pyridin- 4(5H)-one; anti (+) 3-(pyridinyl)(2-(quinolinyl)cyclopropyl)thieno[3,2-c]pyridin-4(5H)- one; anti (-) 3-(pyridinyl)(2-(quinolinyl)cyclopropyl)thieno[3,2-c]pyridin-4(5H)- one; (E)pyridinyl(2-quinolinyl-vinyl)-2H-phthalazinone; anti (rac) 8-pyridinyl(2-quinolinyl-cyclopropyl)-2H-phthalazinone; anti (+) 8-pyridinyl(2-quinolinyl-cyclopropyl)-2H-phthalazinone; anti (-) 8-pyridinyl(2-quinolinyl-cyclopropyl)-2H-phthalazinone; and the N-oxides thereof, the prodrugs thereof as defined in claim 1, the ers thereof and the hydrates f, and the pharmaceutically acceptable salts thereof.
61. A compound according to claim 1, which is selected from the group consisting of 3-(pyridinyl)(2-(quinolinyl)ethyl)furo[3,2-c]pyridin-4(5H)-one; 5-(2-(1H-benzo[d]imidazolyl)ethyl)(pyridinyl)furo[3,2-c]pyridin-4(5H)-one; imidazo[1,2-a]pyridinyl)ethyl)(pyridinyl)furo[3,2-c]pyridin-4(5H)-one; 3-(pyrimidinyl)(2-(quinolinyl)ethyl)furo[3,2-c]pyridin-4(5H)-one; 4-(pyridinyl)(2-(quinolinyl)allyl)pyrido[2,3-d]pyridazin-5(6H)-one; syn 8-(pyridinyl)(2-(quinolinyl)cyclopropyl)isoquinolin-1(2H)-one; syn 3-(pyridinyl)(2-(quinolinyl)cyclopropyl)thieno[3,2-c]pyridin-4(5H)-one; anti 3-(pyridazinyl)(2-(quinolinyl)cyclopropyl)furo[3,2-c]pyridin-4(5H)-one; syn idazinyl)(2-(quinolinyl)cyclopropyl)furo[3,2-c]pyridin-4(5H)-one; anti 3-(pyridinyl)(2-(quinolinyl)cyclopropyl)furo[3,2-c]pyridin-4(5H)-one; syn 3-(pyridinyl)(2-(quinolinyl)cyclopropyl)furo[3,2-c]pyridin-4(5H)-one; anti 8-(oxetanylamino)(2-(quinolinyl)cyclopropyl)isoquinolin-1(2H)-one; syn 8-(oxetanylamino)(2-(quinolinyl)cyclopropyl)isoquinolin-1(2H)-one; anti 8-(pyridazinyl)(2-(quinolinyl)cyclopropyl)isoquinolin-1(2H)-one; syn 8-(pyridazinyl)(2-(quinolinyl)cyclopropyl)isoquinolin-1(2H)-one; anti 8-(6-fluoropyridinyl)(2-(quinolinyl)cyclopropyl)isoquinolin-1(2H)-one; (11405124_1):JIN 268 syn 8-(6-fluoropyridinyl)(2-(quinolinyl)cyclopropyl)isoquinolin-1(2H)-one; anti 8-(2-fluoropyridinyl)(2-(quinolinyl)cyclopropyl)isoquinolin-1(2H)-one; syn 8-(2-fluoropyridinyl)(2-(quinolinyl)cyclopropyl)isoquinolin-1(2H)-one; anti 8-(pyridinyl)(2-(quinolinyl)cyclopropyl)isoquinolin-1(2H)-one; syn 8-(pyridinyl)(2-(quinolinyl)cyclopropyl)isoquinolin-1(2H)-one; anti 8-(pyrimidinyl)(2-(quinolinyl)cyclopropyl)isoquinolin-1(2H)-one; syn 8-(pyrimidinyl)(2-(quinolinyl)cyclopropyl)isoquinolin-1(2H)-one; anti 8-(1-methyl-1H-pyrazolyl)(2-(quinolinyl)cyclopropyl)isoquinolin-1(2H)-one; syn 8-(1-methyl-1H-pyrazolyl)(2-(quinolinyl)cyclopropyl)isoquinolin-1(2H)-one; anti 8-(3-fluoropyridinyl)(2-(quinolinyl)cyclopropyl)isoquinolin-1(2H)-one; syn 8-(3-fluoropyridinyl)(2-(quinolinyl)cyclopropyl)isoquinolin-1(2H)-one; anti 8-(2-fluoropyridinyl)(2-(quinolinyl)cyclopropyl)isoquinolin-1(2H)-one; syn luoropyridinyl)(2-(quinolinyl)cyclopropyl)isoquinolin-1(2H)-one; anti 8-((3S)hydroxypiperidinyl)(2-(quinolinyl)cyclopropyl)isoquinolin-1(2H)- one; syn 8-((3S)hydroxypiperidinyl)(2-(quinolinyl)cyclopropyl)isoquinolin-1(2H)- one; anti 8-(3-methoxypiperidinyl)(2-(quinolinyl)cyclopropyl)isoquinolin-1(2H)-one; syn 8-(3-methoxypiperidinyl)(2-(quinolinyl)cyclopropyl)isoquinolin-1(2H)-one; anti 8-morpholino(2-(quinolinyl)cyclopropyl)isoquinolin-1(2H)-one; syn 8-morpholino(2-(quinolinyl)cyclopropyl)isoquinolin-1(2H)-one; anti 1-(1-oxo(2-(quinolinyl)cyclopropyl)-1,2-dihydroisoquinolinyl)piperidine carbonitrile; syn 1-(1-oxo(2-(quinolinyl)cyclopropyl)-1,2-dihydroisoquinolinyl)piperidine itrile; anti 8-((3R,4R)fluorohydroxypiperidinyl)(2-(quinolin lopropyl)isoquinolin-1(2H)-one; syn 8-((3R,4R)fluorohydroxypiperidinyl)(2-(quinolin yl)cyclopropyl)isoquinolin-1(2H)-one; anti 8-((3S)hydroxypyrrolidinyl)(2-(quinolinyl)cyclopropyl)isoquinolin-1(2H)- one; syn 8-((3S)hydroxypyrrolidinyl)(2-(quinolinyl)cyclopropyl)isoquinolin-1(2H)- one; anti 8-((3R)hydroxypyrrolidinyl)(2-(quinolinyl)cyclopropyl)isoquinolin-1(2H)- (11405124_1):JIN 269 one; syn 8-((3R)hydroxypyrrolidinyl)(2-(quinolinyl)cyclopropyl)isoquinolin-1(2H)- one; anti 8-(methyl(oxetanyl)amino)(2-(quinolinyl)cyclopropyl)isoquinolin-1(2H)-one; syn hyl(oxetanyl)amino)(2-(quinolinyl)cyclopropyl)isoquinolin-1(2H)-one; anti 8-(4-methoxypiperidinyl)(2-(quinolinyl)cyclopropyl)isoquinolin-1(2H)-one; syn 8-(4-methoxypiperidinyl)(2-(quinolinyl)cyclopropyl)isoquinolin-1(2H)-one; anti 8-(4-hydroxypiperidinyl)(2-(quinolinyl)cyclopropyl)isoquinolin-1(2H)-one; syn 8-(4-hydroxypiperidinyl)(2-(quinolinyl)cyclopropyl)isoquinolin-1(2H)-one; anti 8-(1-acetylpiperidinylamino)(2-quinolincyclopropyl)isoquinolin-1(2H)-one; syn 8-(1-acetylpiperidinylamino)(2-quinolincyclopropyl)isoquinolin-1(2H)-one; anti 8-(piperidinylamino)(2-(quinolinyl)cyclopropyl)isoquinolin-1(2H)-one; syn 8-(piperidinylamino)(2-(quinolinyl)cyclopropyl)isoquinolin-1(2H)-one; anti 2-(2-(quinolinyl)cyclopropyl)(tetrahydro-2H-pyranyl)isoquinolin-1(2H)-one; syn 2-(2-(quinolinyl)cyclopropyl)(tetrahydro-2H-pyranyl)isoquinolin-1(2H)-one; anti 2-(2-(quinolinyl)cyclopropyl)(2-oxaazaspiro[3.4]octanyl)isoquinolin- 1(2H)-one; syn 2-(2-(quinolinyl)cyclopropyl)(2-oxaazaspiro[3.4]octanyl)isoquinolin- 1(2H)-one; anti 8-(dihydro-1H-furo[3,4-c]pyrrol-5(3H,6H,6aH)-yl)(2-(quinolin yl)cyclopropyl)isoquinolin-1(2H)-one; syn 8-(dihydro-1H-furo[3,4-c]pyrrol-5(3H,6H,6aH)-yl)(2-(quinolin yl)cyclopropyl)isoquinolin-1(2H)-one; anti -difluoropiperidinyl)(2-(quinolinyl)cyclopropyl)isoquinolin-1(2H)-one; syn 8-(4,4-difluoropiperidinyl)(2-(quinolinyl)cyclopropyl)isoquinolin-1(2H)-one; anti 8-morpholino(2-(quinolinyl)cyclopropyl)isoquinolin-1(2H)-one; syn 8-morpholino(2-(quinolinyl)cyclopropyl)isoquinolin-1(2H)-one; anti 8-(3-(difluoromethyl)pyrrolidinyl)(2-(quinolinyl)cyclopropyl)isoquinolin- 1(2H)-one; syn 8-(3-(difluoromethyl)pyrrolidinyl)(2-(quinolinyl)cyclopropyl)isoquinolin- 1(2H)-one; anti 8-((1R,5S)oxaazabicyclo[3.2.1]octanyl)(2-(quinolinyl)cyclopropyl )isoquinolin-1(2H)-one; syn 8-((1R,5S)oxaazabicyclo[3.2.1]octanyl)(2-(quinolinyl)cyclo- (11405124_1):JIN 270 )isoquinolin-1(2H)-one; anti 8-(4-methylpiperazinyl)(2-(quinolinyl)cyclopropyl)isoquinolin-1(2H)-one; syn 8-(4-methylpiperazinyl)(2-(quinolinyl)cyclopropyl)isoquinolin-1(2H)-one; anti 8-(3-(fluoromethyl)pyrrolidinyl)(2-(quinolinyl)cyclopropyl)isoquinolin- 1(2H)-one; syn 8-(3-(fluoromethyl)pyrrolidinyl)(2-(quinolinyl)cyclopropyl)isoquinolin- 1(2H)-one; anti 8-((1R,5S)oxaazabicyclo[3.2.1]octanyl)(2-(quinolin yl)cyclopropyl)isoquinolin-1(2H)-one; syn 8-((1R,5S)oxaazabicyclo[3.2.1]octanyl)(2-(quinolin yl)cyclopropyl)isoquinolin-1(2H)-one; anti 8-(4-fluorophenyl)(2-(quinolinyl)cyclopropyl)isoquinolin-1(2H)-one; syn 8-(4-fluorophenyl)(2-(quinolinyl)cyclopropyl)isoquinolin-1(2H)-one; anti 8-(furanyl)(2-(quinolinyl)cyclopropyl)isoquinolin-1(2H)-one; syn 8-(furanyl)(2-(quinolinyl)cyclopropyl)isoquinolin-1(2H)-one; anti 8-(4,5-dihydrofuranyl)(2-(quinolinyl)cyclopropyl)isoquinolin-1(2H)-one; syn 8-(4,5-dihydrofuranyl)(2-(quinolinyl)cyclopropyl)isoquinolin-1(2H)-one; anti 8-(4-methoxyphenyl)(2-(quinolinyl)cyclopropyl)isoquinolin-1(2H)-one; syn 8-(4-methoxyphenyl)(2-(quinolinyl)cyclopropyl)isoquinolin-1(2H)-one; anti 2-(2-(6-fluoroquinolinyl)cyclopropyl)morpholinoisoquinolin-1(2H)-one; syn 2-(2-(6-fluoroquinolinyl)cyclopropyl)morpholinoisoquinolin-1(2H)-one; anti 6-fluoroquinolinyl)cyclopropyl)(pyridinyl)isoquinolin-1(2H)-one; syn 2-(2-(6-fluoroquinolinyl)cyclopropyl)(pyridinyl)isoquinolin-1(2H)-one; anti 2-(2-(6-fluoroquinolinyl)cyclopropyl)(pyrimidinyl)isoquinolin-1(2H)-one; syn 2-(2-(6-fluoroquinolinyl)cyclopropyl)(pyrimidinyl)isoquinolin-1(2H)-one; anti 2-(2-(6-fluoroquinolinyl)cyclopropyl)(pyridinyl)isoquinolin-1(2H)-one; syn 2-(2-(6-fluoroquinolinyl)cyclopropyl)(pyridinyl)isoquinolin-1(2H)-one; anti 4-fluoro(pyridinyl)(2-(quinolinyl)cyclopropyl)isoquinolin-1(2H)-one; syn 4-fluoro(pyridinyl)(2-(quinolinyl)cyclopropyl)isoquinolin-1(2H)-one; anti 4-chloro(pyrimidinyl)(2-(quinolinyl)cyclopropyl)isoquinolin-1(2H)-one; syn 4-chloro(pyrimidinyl)(2-(quinolinyl)cyclopropyl)isoquinolin-1(2H)-one; anti 4-(pyridinyl)(2-(quinolinyl)cyclopropyl)pyrido[2,3-d]pyridazin-5(6H)-one; syn4-(pyridinyl)(2-(quinolinyl)cyclopropyl)pyrido[2,3-d]pyridazin-5(6H)-one; anti 6-fluoroquinolinyl)cyclopropyl)(pyridinyl)phthalazin-1(2H)-one; (11405124_1):JIN 271 syn 2-(2-(6-fluoroquinolinyl)cyclopropyl)(pyridinyl)phthalazin-1(2H)-one; anti 7-fluoro(pyridinyl)(2-(quinolinyl)cyclopropyl)thieno[3,2-c]pyridin-4(5H)- one; syn 7-fluoro(pyridinyl)(2-(quinolinyl)cyclopropyl)thieno[3,2-c]pyridin-4(5H)- one; anti 3-(2-fluoropyridinyl)(2-(6-fluoroquinolinyl)cyclopropyl)thieno[3,2-c]pyridin- 4(5H)-one; syn luoropyridinyl)(2-(6-fluoroquinolinyl)cyclopropyl)thieno[3,2-c]pyridin- 4(5H)-one; anti 5-(2-(6-fluoroquinolinyl)cyclopropyl)(pyridinyl)thieno[3,2-c]pyridin-4(5H)- one; syn 6-fluoroquinolinyl)cyclopropyl)(pyridinyl)thieno[3,2-c]pyridin-4(5H)- one; anti 3-(pyrimidinyl)(2-(quinolinyl)cyclopropyl)thieno[3,2-c]pyridin-4(5H)-one; syn 3-(pyrimidinyl)(2-(quinolinyl)cyclopropyl)thieno[3,2-c]pyridin-4(5H)-one; anti 3-(pyrimidinyl)(2-(quinolinyl)cyclopropyl)thieno[3,2-c]pyridin-4(5H)-one; syn 3-(pyrimidinyl)(2-(quinolinyl)cyclopropyl)thieno[3,2-c]pyridin-4(5H)-one; anti 3-(pyrimidinyl)(2-(quinolinyl)cyclopropyl)thieno[3,2-c]pyridin-4(5H)-one; syn 3-(pyrimidinyl)(2-(quinolinyl)cyclopropyl)thieno[3,2-c]pyridin-4(5H)-one; anti 3-(6-fluoropyridinyl)(2-(quinolinyl)cyclopropyl)thieno[3,2-c]pyridin-4(5H)- one; syn 3-(6-fluoropyridinyl)(2-(quinolinyl)cyclopropyl)thieno[3,2-c]pyridin-4(5H)- one; anti 3-(2-methylpyrimidinyl)(2-(quinolinyl)cyclopropyl)thieno[3,2-c]pyridin- 4(5H)-one; syn 3-(2-methylpyrimidinyl)(2-(quinolinyl)cyclopropyl)thieno[3,2-c]pyridin- 4(5H)-one; anti 3-(pyridazinyl)(2-(quinolinyl)cyclopropyl)thieno[3,2-c]pyridin-4(5H)-one; syn 3-(pyridazinyl)(2-(quinolinyl)cyclopropyl)thieno[3,2-c]pyridin-4(5H)-one; anti 3-(2-fluoropyridinyl)(2-(quinolinyl)cyclopropyl]thieno[3,2-c]pyridin-4(5H)- one; syn 3-(2-fluoropyridinyl)(2-(quinolinyl)cyclopropyl]thieno[3,2-c]pyridin-4(5H)- one; anti 3-(morpholinyl)-5[2-(quinolinyl)cyclopropyl]thieno[3,2-c]pyridin-4(5H)-one; (11405124_1):JIN 272 syn 3-(morpholinyl)-5[2-(quinolinyl)cyclopropyl]thieno[3,2-c]pyridin-4(5H)-one; anti 3-(pyridinyl)[2-(thieno[3,2-b]pyridinyl)cyclopropyl]thieno[3,2-c]pyridin- 4(5H)-one; syn 3-(pyridinyl)[2-(thieno[3,2-b]pyridinyl)cyclopropyl]thieno[3,2-c]pyridin- 4(5H)-one; anti 3-(pyridinyl)[2-(quinolinyl)cyclopropyl]thieno[3,2-c]pyridin-4(5H)-one; syn 3-(pyridinyl)[2-(quinolinyl)cyclopropyl]thieno[3,2-c]pyridin-4(5H)-one; anti imidinyl)[2-(quinolinyl)cyclopropyl]thieno[2,3-d]pyridazin-4(5H)-one; syn 3-(pyrimidinyl)[2-(quinolinyl)cyclopropyl]thieno[2,3-d]pyridazin-4(5H)-one; anti idinyl)[2-(thieno[3,2-b]pyridinyl)cyclopropyl]thieno[2,3-d]pyridazin- 4(5H)-one; syn -(pyridinyl)[2-(thieno[3,2-b]pyridinyl)cyclopropyl]thieno[2,3-d]pyridazin- 4(5H)-one; anti 3-(pyridinyl)[2-(thieno[3,2-b]pyridinyl)cyclopropyl]thieno[3,2-c]pyridin- 4(5H)-one; syn 3-(pyridinyl)[2-(thieno[3,2-b]pyridinyl)cyclopropyl]thieno[3,2-c]pyridin- 4(5H)-one; anti 3-(pyridinyl)[2-(quinolinyl)cyclopropyl]thieno[3,2-c]pyridin-4(5H)-one; syn 3-(pyridinyl)[2-(quinolinyl)cyclopropyl]thieno[3,2-c]pyridin-4(5H)-one; anti 3-(pyridinyl)[2-(quinolinyl)cyclopropyl]thieno[2,3-d]pyridazin-4(5H)-one; syn 3-(pyridinyl)[2-(quinolinyl)cyclopropyl]thieno[2,3-d]pyridazin-4(5H)-one; anti 4-fluoro(pyrimidinyl)(2-(quinolinyl)cyclopropyl)isoquinolin-1(2H)-one; syn 4-fluoro(pyrimidinyl)(2-(quinolinyl)cyclopropyl)isoquinolin-1(2H)-one; 8-(pyridinyl)[2-(quinolinyl)ethyl]pyrido[3,4-d]pyridazin-1(2H)-one; 5-[2-(imidazo[1,2-a]pyridinyl)ethyl](1-methyl-1H-imidazolyl)(pyridin yl)thieno[2,3-d]pyridazin-4(5H)-one; 5-[2-(imidazo[1,2-a]pyridinyl)ethyl](1-methyl-1H-pyrazolyl)(pyridin yl)thieno[2,3-d]pyridazin-4(5H)-one; 5-[2-(imidazo[1,2-a]pyridinyl)ethyl](pyridinyl)(pyridinyl)thieno[2,3- d]pyridazin-4(5H)-one; 5-[2-(6-chloroquinolinyl)ethyl](pyridinyl)thieno[3,2-c]pyridin-4(5H)-one; 5-[2-(3-methylquinolinyl)ethyl](pyridinyl)thieno[3,2-c]pyridin-4(5H)-one; 8-fluoroquinolinyl)ethyl](pyridinyl)thieno[3,2-c]pyridin-4(5H)-one; 5-[2-(6-fluoroquinolinyl)ethyl](pyridinyl)thieno[3,2-c]pyridin-4(5H)-one; (11405124_1):JIN 273 6-fluoroquinolinyl)ethyl](pyridinyl)thieno[3,2-c]pyridin-4(5H)-one; 5-[2-(imidazo[1,2-a]pyridinyl)ethyl](pyridinyl)thieno[3,2-c]pyridin-4(5H)-one; 3-(pyridinyl)[2-(quinoxalinyl)ethyl]thieno[2,3-d]pyridazin-4(5H)-one; 1,5-naphthyridinyl)ethyl](pyridinyl)thieno[2,3-d]pyridazin-4(5H)-one; 5-[2-(1H-indazolyl)ethyl](pyridinyl)thieno[2,3-d]pyridazin-4(5H)-one; 3-(1-methyl-1H-pyrazolyl)[2-(quinolinyl)ethyl]thieno[2,3-d]pyridazin-4(5H)-one; 3-(1H-pyrazolyl)[2-(quinolinyl)ethyl]thieno[2,3-d]pyridazin-4(5H)-one; 5-[2-(1H-benzimidazolyl)ethyl](pyridinyl)thieno[2,3-d]pyridazin-4(5H)-one; 5-[2-(1H-benzimidazolyl)ethyl](pyridinyl)thieno[2,3-d]pyridazin-4(5H)-one; 5-[2-(6-chloroquinolinyl)ethyl](pyridinyl)thieno[2,3-d]pyridazin-4(5H)-one; 3-(pyridinylethynyl)[2-(quinolinyl)ethyl]thieno[2,3-d]pyridazin-4(5H)-one; 3-(pyridinylethynyl)[2-(quinolinyl)ethyl]thieno[2,3-d]pyridazin-4(5H)-one; 5-[2-(3,5-dimethylpyridinyl)ethyl](pyridinyl)thieno[2,3-d]pyridazin-4(5H)-one; 5-[2-(7-fluoroquinolinyl)ethyl](pyridinyl)thieno[2,3-d]pyridazin-4(5H)-one; 5-[2-(pyrazinyl)ethyl](pyridinyl)thieno[2,3-d]pyridazin-4(5H)-one; 2-[2-(1,6-naphthyridinyl)ethyl](pyridinyl)isoquinolin-1(2H)-one; 2-[2-(8-fluoroquinolinyl)ethyl](pyridinyl)isoquinolin-1(2H)-one; 8-(pyridinyl)[1-(quinolinyl)propanyl]isoquinolin-1(2H)-one; 2-[2-(3-methylquinolinyl)ethyl](pyridinyl)isoquinolin-1(2H)-one; 2-[2-(imidazo[1,2-a]pyridinyl)ethyl](1H-pyrazolyl)phthalazin-1(2H)-one; 8-(morpholinyl)[2-(quinolinyl)ethyl]phthalazin-1(2H)-one; 2-[2-(imidazo[1,2-a]pyridinyl)ethyl](1-oxa-4,9-diazaspiro[5.6]dodec yl)phthalazin-1(2H)-one; 2-[2-(imidazo[1,2-a]pyridinyl)ethyl](2-oxaazaspiro[3.5]nonyl)phthalazin- 1(2H)-one; 8-[(3R)hydroxypiperidinyl][2-(imidazo[1,2-a]pyridinyl)ethyl]phthalazin- 1(2H)-one; 8-[(3S)hydroxypiperidinyl][2-(imidazo[1,2-a]pyridinyl)ethyl]phthalazin-1(2H)- one; imidazo[1,2-a]pyridinyl)ethyl](2-oxaazaspiro[3.3]heptyl)phthalazin- 1(2H)-one; 2-[2-(imidazo[1,2-a]pyridinyl)ethyl](1,2-oxazolidinyl)phthalazin-1(2H)-one; 8-(hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl)[2-(imidazo[1,2-a]pyridin yl)ethyl]phthalazin-1(2H)-one; (11405124_1):JIN 274 2-[2-(imidazo[1,2-a]pyridinyl)ethyl](tetrahydrofuranyl)phthalazin-1(2H)-one; 2-[2-(imidazo[1,2-a]pyridinyl)ethyl](3-oxaazabicyclo[3.2.1]octyl)phthalazin- 1(2H)-one; 2-[2-(imidazo[1,2-a]pyridinyl)ethyl](2-oxaazaspiro[3.4]octyl)phthalazin- 1(2H)-one; 2-[2-(imidazo[1,2-a]pyridinyl)ethyl](2,2,6,6-tetrafluoromorpholinyl)phthalazin- 1(2H)-one; 8-(4-hydroxypiperidinyl)[2-(imidazo[1,2-a]pyridinyl)ethyl]phthalazin-1(2H)-one; 2-[2-(imidazo[1,2-a]pyridinyl)ethyl](2-methylpyrimidinyl)phthalazin-1(2H)-one; 8-(2-cyclopropylpyrimidinyl)[2-(imidazo[1,2-a]pyridinyl)ethyl]phthalazin-1(2H)- one; 2-[2-(imidazo[1,2-a]pyridinyl)ethyl](pyridazinyl)phthalazin-1(2H)-one; 8-(5-fluoropyridinyl)[2-(imidazo[1,2-a]pyridinyl)ethyl]phthalazin-1(2H)-one; 8-[2-(3-fluorophenyl)morpholinyl][2-(imidazo[1,2-a]pyridinyl)ethyl]phthalazin- 1(2H)-one; 2-[2-(imidazo[1,2-a]pyridinyl)ethyl](2-methoxypyrimidinyl)phthalazin-1(2H)- one; 2-[2-(imidazo[1,2-a]pyridinyl)ethyl][2-(trifluoromethyl)pyridinyl]phthalazin- 1(2H)-one; 2-[2-(imidazo[1,2-a]pyridinyl)ethyl](8-oxaazabicyclo[3.2.1]octyl)phthalazin- 1(2H)-one; 2-[2-(imidazo[1,2-a]pyridinyl)ethyl][2-(trifluoromethyl)morpholinyl]phthalazin- 1(2H)-one; -dimethylmorpholinyl)[2-(imidazo[1,2-a]pyridinyl)ethyl]phthalazin-1(2H)- one; 8-[2-(4-chlorophenyl)morpholinyl][2-(imidazo[1,2-a]pyridinyl)ethyl]phthalazin- 1(2H)-one; 3,4-difluorophenyl)morpholinyl][2-(imidazo[1,2-a]pyridin yl)ethyl]phthalazin-1(2H)-one; 2-[2-(imidazo[1,2-a]pyridinyl)ethyl](piperidinyl)phthalazin-1(2H)-one; 2-[2-(imidazo[1,2-a]pyridinyl)ethyl](tetrahydro-2H-pyranyl)phthalazin-1(2H)- one; 8-(2,6-diazabicyclo[3.2.1]octyl)[2-(imidazo[1,2-a]pyridinyl)ethyl]phthalazin- 1(2H)-one; (11405124_1):JIN 275 8-[(1S,5S)-3,6-diazabicyclo[3.2.0]heptyl][2-(imidazo[1,2-a]pyridin yl)ethyl]phthalazin-1(2H)-one; 8-(furanyl)[2-(imidazo[1,2-a]pyridinyl)ethyl]phthalazin-1(2H)-one; 2-[2-(imidazo[1,2-a]pyridinyl)ethyl](1-methyl-1H-pyrazolyl)phthalazin-1(2H)- one; 8-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)[2-(imidazo[1,2-a]pyridin yl)ethyl]phthalazin-1(2H)-one; -diazaspiro[4.4]nonyl)[2-(imidazo[1,2-a]pyridinyl)ethyl]phthalazin-1(2H)- one; 8-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptyl][2-(imidazo[1,2-a]pyridin yl)ethyl]phthalazin-1(2H)-one; 8-(2,7-diazaspiro[3.5]nonyl)[2-(imidazo[1,2-a]pyridinyl)ethyl]phthalazin-1(2H)- one; 8-(2,6-diazaspiro[3.5]nonyl)[2-(imidazo[1,2-a]pyridinyl)ethyl]phthalazin-1(2H)- one; 8-(piperidinyl)[2-(5,6,7,8-tetrahydroimidazo[1,2-a]pyridinyl)ethyl]phthalazin- 1(2H)-one; 8-[2-(aminomethyl)chloropyrrolidinyl][2-(imidazo[1,2-a]pyridin yl)ethyl]phthalazin-1(2H)-one; 2-[2-(imidazo[1,2-a]pyridinyl)ethyl]-4,8-di(pyridinyl)phthalazin-1(2H)-one; 2-[2-(imidazo[1,2-a]pyridinyl)ethyl][(3aR,4S,7R,7aS)-octahydro-1H-4,7- epiminoisoindolyl]phthalazin-1(2H)-one; 8-[5-(4-chlorophenyl)-2,5-diazabicyclo[2.2.1]heptyl][2-(imidazo[1,2-a]pyridin yl)ethyl]phthalazin-1(2H)-one; 4-bromo[2-(imidazo[1,2-a]pyridinyl)ethyl](pyridinyl)phthalazin-1(2H)-one; 2-[2-(imidazo[1,2-a]pyridinyl)ethyl][(3aS,8aS)-octahydropyrrolo[3,4-c]azepin- 2(1H)-yl]phthalazin-1(2H)-one; 2-[2-(imidazo[1,2-a]pyridinyl)ethyl][(3aS,8aR)-octahydropyrrolo[3,4-c]azepin- 2(1H)-yl]phthalazin-1(2H)-one; tert-butyl (3aR,4S,7R,7aS){3-[2-(imidazo[1,2-a]pyridinyl)ethyl]oxo-3,4- ophthalazinyl}octahydro-2H-4,7-epiminoisoindolecarboxylate; ahydro-5H-furo[2,3-c]pyrrolyl)[2-(imidazo[1,2-a]pyridin yl)ethyl]phthalazin-1(2H)-one; 2-[2-(imidazo[1,2-a]pyridinyl)ethyl](1,2,3,6-tetrahydropyridinyl)phthalazin- (11405124_1):JIN 276 1(2H)-one; 2-[2-(imidazo[1,2-a]pyridinyl)ethyl][(3S)-tetrahydrofuranylamino]phthalazin- 1(2H)-one; 2-[2-(imidazo[1,2-a]pyridinyl)ethyl][(3R)-tetrahydrofuranylamino]phthalazin- 1(2H)-one; 8-{[5-(hydroxymethyl)-1,4-dioxanyl]methoxy}[2-(imidazo[1,2-a]pyridin yl)ethyl]phthalazin-1(2H)-one; 2-[2-(imidazo[1,2-a]pyridinyl)ethyl](oxetanyloxy)phthalazin-1(2H)-one; 2-[2-(imidazo[1,2-a]pyridinyl)ethyl](pyridinylmethoxy)phthalazin-1(2H)-one; 2-[2-(imidazo[1,2-a]pyridinyl)ethyl](morpholinylmethyl)phthalazin-1(2H)-one; imidazo[1,2-a]pyridinyl)ethyl](pyridinyloxy)phthalazin-1(2H)-one; 2-[2-(imidazo[1,2-a]pyridinyl)ethyl][(oxetanylmethyl)amino]phthalazin-1(2H)- one; 2-[2-(imidazo[1,2-a]pyridinyl)ethyl](tetrahydro-2H-pyranylamino)phthalazin- 1(2H)-one; imidazo[1,2-a]pyridinyl)ethyl][(1-methylazetidinyl)amino]phthalazin- 1(2H)-one; 2-[2-(imidazo[1,2-a]pyridinyl)ethyl](1,3-oxazolylamino)phthalazin-1(2H)-one; 2-[2-(imidazo[1,2-a]pyridinyl)ethyl][methyl(oxetanyl)amino]phthalazin-1(2H)- one; 2-[2-(imidazo[1,2-a]pyridinyl)ethyl](piperidinylamino)phthalazin-1(2H)-one; 8-[(1-acetylpiperidinyl)amino][2-(imidazo[1,2-a]pyridinyl)ethyl]phthalazin- 1(2H)-one; 8-[(1-acetylpiperidinyl)amino][2-(imidazo[1,2-a]pyridinyl)ethyl]phthalazin- 1(2H)-one; 2-[2-(imidazo[1,2-a]pyridinyl)ethyl](tetrahydrofuranylamino)phthalazin-1(2H)- one; imidazo[1,2-a]pyridinyl)ethyl](tetrahydro-2H-pyranylamino)phthalazin- 1(2H)-one; 2-[2-(imidazo[1,2-a]pyridinyl)ethyl](piperidinylamino)phthalazin-1(2H)-one; 2-[2-(imidazo[1,2-a]pyridinyl)ethyl]{methyl[(3-methyloxetanyl)methyl]amino}- phthalazin-1(2H)-one; 2-[2-(imidazo[1,2-a]pyridinyl)ethyl](oxetanylamino)phthalazin-1(2H)-one; 8-{[(3aS,4S,6aS)-octahydrocyclopenta[c]pyrrolylmethyl]amino}[2-(5,6,7,8- (11405124_1):JIN 277 tetrahydroimidazo[1,2-a]pyridinyl)ethyl]phthalazin-1(2H)-one; 5-(morpholinyl)[2-(quinolinyl)ethyl]phthalazin-1(2H)-one; 2-[2-(imidazo[1,2-a]pyridinyl)ethyl]{[(3-methyloxetanyl)methyl]amino}- phthalazin-1(2H)-one; 4-(pyridinyl)[2-(quinolinyl)ethyl]pyrido[2,3-d]pyridazin-5(6H)-one; 4-(morpholinyl)[2-(quinolinyl)ethyl]pyrido[2,3-d]pyridazin-5(6H)-one; 4-(oxetanylamino)[2-(quinolinyl)ethyl]pyrido[2,3-d]pyridazin-5(6H)-one; 6-methoxypyridinyl)ethyl](pyridinyl)isoquinolin-1(2H)-one; 2-[2-(1,3-benzothiazolyl)ethyl](pyridinyl)isoquinolin-1(2H)-one; 5-methylpyridinyl)ethyl](pyridinyl)isoquinolin-1(2H)-one; 5-[(E)(6-methoxyquinolinyl)ethenyl](pyridinyl)thieno[3,2-c]pyridin-4(5H)- one; 8-(pyridinyl)[(E)(quinazolinyl)ethenyl]isoquinolin-1(2H)-one; 5-[(E)(6-chloroquinolinyl)ethenyl](pyridinyl)thieno[3,2-c]pyridin-4(5H)-one; 5-[(E)(3-methylquinolinyl)ethenyl](pyridinyl)thieno[3,2-c]pyridin-4(5H)-one; 8-(pyridinyl)[(E)(quinolinyl)ethenyl]isoquinolin-1(2H)-one; 5-[(E)(1,3-benzothiazolyl)ethenyl](pyridinyl)thieno[3,2-c]pyridin-4(5H)-one; 3-(pyridinyl)[(E)(quinolinyl)ethenyl]thieno[3,2-c]pyridin-4(5H)-one; and the enantiomers thereof , the N-oxides f, the prodrugs thereof as defined in claim 1, the tautomers thereof and the hydrates thereof, and the pharmaceutically acceptable salts thereof.
62. The compound which is selected from the group consisting of 7-(pyridinyl)[2-(quinolinyl)ethyl]thieno[2,3-d]pyridazin-4(5H)-one; 5-(pyridinyl)[2-(quinolinyl)ethyl]phthalazin-1(2H)-one; 5-(pyrimidinyl)[2-(quinolinyl)ethyl]phthalazin-1(2H)-one; 5-(1-methyl-1H-pyrazolyl)[2-(quinolinyl)ethyl]phthalazin-1(2H)-one; 5-(1,1-dioxidothiomorpholinyl)[2-(quinolinyl)ethyl]phthalazin-1(2H)-one; 2-[2-(imidazo[1,2-a]pyridinyl)ethyl](pyridinyl)phthalazin-1(2H)-one; imidazo[1,2-a]pyridinyl)ethyl](pyrimidinyl)phthalazin1(2H)-one; 2-[2-(imidazo[1,2-a]pyridinyl)ethyl](morpholinyl)phthalazin-1(2H)-one; 2-[2-(imidazo[1,2-a]pyridinyl)ethyl](tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)- yl)phthalazin-1(2H)-one; (11405124_1):JIN 278 2-[2-(imidazo[1,2-a]pyridinyl)ethyl](pyrimidinyl)phthalazin-1(2H)-one; 2-[2-(imidazo[1,2-a]pyridinyl)ethyl](morpholinyl)phthalazin-1(2H)-one; 3-methyl(pyridinyl)(2-(quinolinyl)ethyl)thieno[3,2-c]pyridin-4(5H)-one; 5-(3-hydroxyphenyl)[2-(quinolinyl)ethyl]phthalazin-1(2H)-one; 7-(pyridinyl)[2-(quinolinyl)ethyl]furo[3,2-c]pyridin-4(5H)-one; anti 5-(pyrimidinyl)[2-(quinolinyl)cyclopropyl]isoquinolin-1(2H)-one; syn imidinyl)[2-(quinolinyl)cyclopropyl]isoquinolin-1(2H)-one; anti 5-(pyridinyl)[2-(quinolinyl)cyclopropyl]isoquinolin-1(2H)-one; syn 5-(pyridinyl)[2-(quinolinyl)cyclopropyl]isoquinolin-1(2H)-one; anti 5-(pyridinyl)[2-(quinolinyl)cyclopropyl]isoquinolin-1(2H)-one; syn 5-(pyridinyl)[2-(quinolinyl)cyclopropyl]isoquinolin-1(2H)-one; anti pholinyl)(2-(quinolinyl)cyclopropyl]isoquinolin-1(2H)-one; syn 5-(morpholinyl)(2-(quinolinyl)cyclopropyl]isoquinolin-1(2H)-one; pholinyl)[2-(quinolinyl)ethyl]phthalazin-1(2H)-one; 2-[2-(1H-benzimidazolyl)ethyl](pyridinyl)phthalazin-1(2H)-one; 4-(pyridinyl)[2-(quinolinyl)ethyl]phthalazin-1(2H)-one; 5-(1,4-dihydropyrimidinyl)[2-(5,6,7,8-tetrahydroimidazo[1,2-a]pyridin yl)ethyl]phthalazin-1(2H)-one; imidazo[1,2-a]pyridinyl)ethyl](pyridinyl)phthalazin-1(2H)-one; 5-(pyridinyl)[2-(quinolinyl)ethyl]phthalazin-1(2H)-one; and the enantiomers thereof, the N-oxides thereof, the prodrugs thereof, the tautomers thereof and the hydrates thereof, and the pharmaceutically able salts thereof, wherein gs are derivatives of the compounds of formula I carrying an OH or NH2-group, where one of the hydrogen atoms of the OH or NH2-group is substituted by a C1-C4- alkylcarbonyl group, by benzoyl, or by an acyl group derived from an amino acid, which is linked to the oxygen or nitrogen of the OH or NH2-group via the carbonyl group of the amino acid; or wherein prodrugs are alkylcarbonyloxyalkyl carbonates or carbamates of compounds I carrying an OH- or oup in which one of the hydrogen atoms of the OH- or NH2-group has been replaced by a group of the formula -C(=O)-O-CHRp-OC (=O)-Rq in which Rp and Rq are independently of one another C1-C4-alkyl.
63. The compound as claimed in claim 1 being anti (rac) 8-(pyridinyl)(2-(quinolin- 2-yl)cyclopropyl)isoquinolin-1(2H)-one, or an enantiomer thereof, or a N-oxide thereof, or (11405124_1):JIN 279 a prodrug thereof as defined in claim 1, or a tautomer thereof or a hydrate thereof, or a pharmaceutically acceptable salt thereof.
64. The compound as claimed in claim 1 being anti 3-(pyridazinyl)(2-(quinolin yl)cyclopropyl)furo[3,2-c]pyridin-4(5H)-one, or an enantiomer thereof, or a N-oxide thereof, or a g thereof as defined in claim 1, or a tautomer thereof or a hydrate thereof, or a pharmaceutically acceptable salt thereof.
65. The compound as claimed in claim 1 being anti 3-(pyridinyl)(2-(quinolin yl)cyclopropyl)furo[3,2-c]pyridin-4(5H)-one, or an enantiomer f, or a e thereof, or a N-oxide thereof, or a prodrug thereof as defined in claim 1, or a tautomer f or a hydrate f, or a pharmaceutically acceptable salt thereof.
66. The compound as claimed in any one of the preceding claims for use in therapy.
67. Pharmaceutical composition which comprises at least one compound as claimed in any one of claims 1 to 65 and at least one excipient.
68. The compounds according to any of claims 1 to 65 for treating a medical disorder, which can be treated by inhibition of phosphodiesterase type 10A.
69. The compounds according to claim 68 where the l disorder is ed from neurological and psychiatric disorders.
70. The compounds according to any of claims 1 to 65 for treating CNS disorders in a mammalian.
71. The compounds according to any of claims 1 to 65 for treating schizophrenia in a mammalian.
72. The compounds according to any of claims 1 to 65 for treating ive dysfunction associated with schizophrenia in a mammalian. (11405124_1):JIN 280
73. The compounds according to any of claims 1 to 65 for ng r disorders in a mammalian.
74. The compounds according to any of claims 1 to 65 for treating depression in a mammalian.
75. The compounds according to any of claims 1 to 65 for treating cognitive dysfunction associated with Alzheimer's disease in a mammalian.
76. The compounds according to any of claims 1 to 65 for treating diet-induced obesity in a mammalian.
77. The compounds according to any of claims 1 to 65 for treating Huntington's disease in a mammalian.
78. The compounds according to any of claims 1 to 65 for treating anxiety in a mammalian.
79. The compounds ing to any of claims 1 to 65 for ng substance-related disorders in a mammalian.
80. Use of at least one compound as d in any of claims 1 to 65 for the manufacture of a medicament for treating a medical disorder, selected from neurological and atric disorders which can be treated by inhibition of phosphodiesterase type 10A. AbbVie Deutschland GmbH & Co. KG AbbVie Inc. By the Attorneys for the Applicant SPRUSON & FERGUSON Per: (11405124_1):JIN
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
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US201161557874P | 2011-11-09 | 2011-11-09 | |
US61/557,874 | 2011-11-09 | ||
PCT/EP2012/072150 WO2013068470A1 (en) | 2011-11-09 | 2012-11-08 | Inhibitors of phosphodiesterase type 10a |
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NZ623727A NZ623727A (en) | 2016-06-24 |
NZ623727B2 true NZ623727B2 (en) | 2016-09-27 |
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